This Banana Smoothie is a Creamy, Nutrient-Packed Breakfast or Guilt-Free Dessert Rich in protein, fiber, and potassium, this smoothie completely redefines how we look at whole-fat dairy. Creative Cooking for the Health-Conscious Gourmet FibonacciRECIPES | Culinary Medicine by Mary B Grosvenor, MS, RD and Lori A. Smolin, PhD Need a quick nutritious breakfast or a healthy dessert? This smoothie offers the creamy texture and flavor of a milkshake with the health benefits of whole milk and fruit. It provides plenty of protein, fiber, and potassium. And, it will use up those overripe bananas that you tossed in the freezer. Dress it up with some berries, fresh or frozen, or add some chia or flaxseeds. Ingredients 1 cup whole milk 1 large, ripe frozen banana 1 tsp honey Sprinkle of cinnamon Instructions Pour milk into a blender. Cut banana into quarters. Add banana and honey to the blender, along with any extra fruit or seeds. Blend on high speed for 30 seconds. If not yet smooth, pulse at 15 second intervals until it reaches the desired consistency. Pour into a glass, sprinkle with cinnamon, and serve immediately. Makes 1 Serving Nutrition Information per Smoothie (without extra berries or seeds) Calories 255, Total Fat 8g, Saturated Fat 4.7g, Cholesterol 24 mg, Total Carbohydrate 39g, Dietary fiber 3g, Protein 9g, Potassium 746mg, Sodium 106mg Editor’s Note: This recipe officially qualifies as a low calorie, low carb, low saturated fat, lacto-vegetarian meal and a “good” source of fiber. Our article on the health benefits of whole-fat dairy also provides a more positive perspective than previous traditional conventional wisdom. See Is Whole-Fat Dairy Healthy? Mary Recommends As an Amazon Associate FibonacciMD earns from qualifying purchases. Small Magic Bullet Blender [https://amzn.to/49XdLt4]

By Stuart M. Caplen, MD Medicinal Use of Mercury Mercury has been used medicinally for centuries, dating back to ancient Egypt and China. In the third century BC, Chinese emperor Qin Shi Huang ingested large amounts of mercury in an attempt to achieve immortality. He reportedly became mentally unstable and died at age 49. Following his death, he was buried in a tomb believed to contain pools of mercury that, even today, could pose safety concerns if opened. Mercury sulfide (also known as cinnabar), the ore from which mercury is extracted, was used by ancient Greek physicians and during medieval times to treat a number of maladies, including depression (melancholy), syphilis, parasitic infections, and constipation. Ingested mercury can turn stools black and historically was thought to remove “black bile”, one of the four body “humors” (along with blood, phlegm, and yellow bile), the balance of which was necessary for good health. A major proponent of using mercury to treat syphilis was Philippus von Hohenheim (1493-1541), better known as Paracelsus. It was known that mercury was a potent diuretic (increases urination) and can cause excess salivation at toxic doses. It was thought that these processes would help rid the body of disease. Topical, oral, and even inhalational forms of mercury were considered the primary treatments for syphilis from the Middle Ages until the early 20th century. “A night with Venus, and a lifetime with Mercury." was a common saying. Although mercury can kill the syphilis spirochete (Treponema pallidum), the amount needed to effectively treat the disease is toxic to humans. The rash caused by syphilis typically resolves spontaneously, sometimes years before severe systemic symptoms occur, which contributed to the mistaken belief in the healing power of mercury. “Calomel”, a mercury chloride medication, was used from the 16th to the 20th centuries to treat a variety of conditions including constipation, typhoid fever, yellow fever, mumps, depression, and even teething pain. Its name is derived from the Greek kalos meaning good and melas meaning black. “Blue Mass” pills, named for their blue color, contained elemental mercury along with other ingredients such as sugar, licorice, or honey were commonly prescribed as a cure-all. One of the most famous users of blue mass pills was Abraham Lincoln, who reportedly took them for melancholy. He stopped taking the pills, possibly due to mercury-induced side effects, before becoming President. During the Civil War, William A. Hammond, the Union Army Surgeon General, attempted to limit the administration of calomel to the troops. He felt that dehydration from mercury-induced diarrhea, combined with the risk of toxicity, was harmful rather than beneficial to soldiers. His anti-mercury views were not popular with most army physicians, who staged a “calomel rebellion”, and ultimately, he was fired. Louisa May Alcott, who served as a Civil War nurse, contracted typhoid fever and was treated with calomel. She attributed her lifelong health problems to that treatment. During World War I, a kit containing calomel ointment was marketed as the “Doughboy Prophylactic” for the prevention of venereal disease. Arsenic- and bismuth-based therapies replaced mercury as a treatment for syphilis in the early 20th century, but it was not until the 1940s, when penicillin became available, that the disease became reliably curable. Toxicity Mercury is toxic and in high doses, whether ingested, absorbed through the skin, or inhaled, can cause tremors, incoordination, peripheral neuropathy, impaired vision, cognitive decline, and mood disorders such as depression. It can also lead to hypertension, decreased fertility, birth defects, and kidney damage. It is thought that the “Mad Hatter” character in Alice in Wonderland may have been inspired by symptomatic hat makers who chronically inhaled vapor from liquid mercury used to convert fur to felt. The term “Mad as a Hatter” was coined in the mid-18th century in England. The “Danbury Shakes” was a term used to describe the tremors (as well as incoherent speech, difficulty in walking, and eventual cognitive decline) of hat makers in Danbury, Connecticut, which was a center of hat making in the 1800s. As an Amazon Associate FibonacciMD earns from qualifying purchases. Alice In Wonderland: Rebirth Collector's Edition | The Original Illustrations by John Tenniel - buy on Amazon [https://amzn.to/3RfLR5i] Mercury Use and Exposure Today Today, mercury is still found in thimerosal (a mercury-containing preservative used in some multi-dose vaccine vials) and dental amalgams. Numerous large-scale studies conducted over several decades have found no evidence linking thimerosal in vaccines to autism or other neurodevelopmental disorders, but it has been removed from nearly all routine childhood vaccines in the United States as a precautionary measure. Dental amalgams contain mercury and can release small amounts of mercury vapor that can be absorbed by the body. Available evidence has not demonstrated adverse health outcomes in the general population from use of amalgams. However, the U.S. Food and Drug Administration (FDA) recommends caution with some groups and consideration of using other types of dental fillings for them. These groups include pregnant women and their developing fetuses, individuals planning pregnancy, nursing women and infants, young children (particularly those under six years of age), individuals with pre-existing neurological conditions, those with impaired kidney function, and individuals with known hypersensitivity to mercury or other components of dental amalgam. However, the use of mercury for both these above applications still remains a topic of public debate. The most common exposure in the U.S. to mercury is by eating seafood, as nearly all fish and shellfish contain trace amounts of methylmercury. Mercury can enter waterways through geological weathering, volcanic activity, manufacturing, and mining. Once in the water, it is converted to methylmercury by bacteria which are subsequently ingested by marine organisms. For adults, typical consumption of fish and shellfish does not lead to observable adverse health effects. The FDA does recommend that pregnant women and children can obtain health benefits by eating seafood but need to limit their mercury exposure. If you liked this article, you may also enjoy reading The History of Insulin and Type 1 Diabetes. You may also find these other FibonacciMedicine articles interesting: The History of “Snake Oil” and “Snake Oil Salesmen” The History of Nitroglycerin, an Explosive with Medical Benefits The History of Heroin, the “Non-addictive” Substitute for Morphine The Story of the Most “Kissed” Face in the World “Gentlemen this is no humbug” - The First Use of General Anesthesia in Surgery and the Battle for Recognition that Ensued The History of the Coney Island Incubator Babies The Dancing Plague of 1518 Benjamin Franklin, Mesmerism, and the First Use of Placebos in Science Penicillin, the Accidental Antibiotic The History of Leeches in Medicine and the Era of the “Leech Mania” The History of the “Whale Cure” for Rheumatism The History of Antiseptic Surgery The History of the Electrocardiogram (EKG/ECG) References Mendelson WB. Heavy Metal Blues: The History of Medicinal Mercury. Psychology Today. Updated January 31, 2024. Retrieved from: https://www.psychologytoday.com/us/blog/psychiatry-a-history/202304/heavy-metal-blues-the-history-of-medicinal-mercury O’Shea JG. Two minutes with Venus, two years with mercury'-mercury as an antisyphilitic chemotherapeutic agent. Journal of the Royal Society of Medicine. Volume 83 June 1990. Pp. 392-395. Retrieved from: https://journals.sagepub.com/doi/pdf/10.1177/014107689008300619 ToxFAQsTM for Mercury, Agency for Toxic Substances and Disease Registry. November 05, 2024. Retrieved from: https://wwwn.cdc.gov/TSp/ToxFAQs/ToxFAQsDetails.aspx?faqid=113&toxid=24 Schwarcz J. A Little Mercurial History. McGill University Office for Science and Society. 10 Apr 2019. Retrieved from: https://www.mcgill.ca/oss/article/history/little-mercurial-history Blosser F. NIOSH Backgrounder: Alice’s Mad Hatter & Work-Related Illness. National Institute for Occupational Safety and Health. Last Reviewed: August 6, 2012. Retrieved from: https://archive.cdc.gov/www_cdc_gov/niosh/updates/upd-03-04-10.html Schwarcz J. The “Danbury Shakes”. McGill University. 10 Apr 2017. Retrieved from: https://www.mcgill.ca/oss/article/did-you-know/danbury-shakes Thimerosal and Vaccines. FDA. 01/15/2025. Retrieved from: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/thimerosal-and-vaccines Dental Amalgam Fillings. FDA. 02/18/2021. Retrieved from: https://www.fda.gov/medical-devices/dental-devices/dental-amalgam-fillings Mercury in Food. FDA. 03/05/2024. Retrieved from: https://www.fda.gov/food/environmental-contaminants-food/mercury-food Advice about eating Fish. FDA, Advice revised October 2021. Retrieved from: https://www.fda.gov/media/102331/download?attachment Photo - Vandiver M. Poison as Medicine in Lynchburg. Lynchburg Museum System. Retrieved from: https://laura-lembas.squarespace.com/digital-exhibit-poison-as-medicine Photo- Murray CM. Pills. Professor Hedgehog's Journal. 17/10/2019. Retrieved from: https://professorhedgehogsjournal.uk/2019/10/17/pills/ Photo – Jhansonxi. Eli Lilly & Company - Ointment No. 8 - Ammoniated Mercury 10%, 1 ounce (28 grams). Wikimedia Commons. 5 September 2011. Retrieved from: https://commons.wikimedia.org/wiki/File:Eli_Lilly_%26_Company_-_Ointment_No._8_-_Ammoniated_Mercury.jpg#filelinks

While nutrition guidelines once shunned whole-fat dairy, modern science suggests that the unique "food matrix" of full-fat dairy may actually support heart health. Culinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD Which type of dairy should you choose? For over 40 years nutrition guidelines have recommended that we choose low- or fat-free rather than whole-fat dairy products. However, the most recent guidelines advise us to include whole-fat, also known as “full-fat” dairy in our diets. Why the change? It turns out that the hypothesis that low-fat dairy products are superior to full fat in terms of heart disease risk is not fully supported by scientific studies. [1] Experts now believe that whole-fat dairy products can be part of a healthy diet.[2] Why Was Whole-Fat Dairy Considered Unhealthy? Whole-fat dairy products are high in saturated fat and saturated fat intake is correlated with elevated blood cholesterol and an increased risk of cardiovascular disease (CVD).[3] These facts led to the assumption that full-fat dairy increases the risk of CVD and to the recommendation to consume low-fat dairy to reduce saturated fat intake and CVD risk. [4] However, many of the studies that supported the relationship between saturated fat and CVD looked at total saturated fat intake and not specifically at intake from dairy products. When dairy alone is examined, results suggest that despite its high saturated fat content, full-fat dairy foods, particularly milk, yogurt, and cheese, are not associated with an increased risk of CVD. [2, 5] An Updated Understanding of Dairy and Health For years, scientists focused on individual nutrients to assess the healthfulness of foods. However, we now recognize that nutrients don’t function in insolation. The combination of nutrients, other bioactive compounds, and structures in a food and how they interact, known as the food matrix, can be more important than the amount of any individual nutrient. [6,7] The food matrix influences the digestion, absorption, and physiological effects of nutrients and ultimately the health impact of a food.[2] The dairy matrix contains lipids, proteins, and carbohydrates, as well as vitamins and minerals. It also contains bioactive compounds such as immunoglobulins, antibacterial peptides, and oligosaccharides and microstructures such as milk-fat globules. [6] Milk-fat globules are small droplets of lipids surrounded by a membrane of proteins and phospholipids; their structure stabilizes the lipids in aqueous milk. Milk-fat globules act as a delivery system for transferring nutrients and bioactive compounds from one organism to another and are not found in other foods with similar nutrients. [6] In the digestive tract milk-fat globules modulate the rate of lipid digestion, and when broken down, release bioactive compounds that have effects in the gastrointestinal tract and throughout the body at all stages of life. [6,8] In infants, components of the milk fat globule membranes help promote brain development, immune function, and gastrointestinal health.[9,10] In adults, these membrane components improve the gut microbiota composition, decrease inflammation, and protect against dyslipidemia.[8] The dairy matrix, and in particular milk fat globules, may have a greater influence on heart health than saturated fat intake. This is supported by epidemiological and clinical studies that do not show an association between the fat content of dairy foods and CVD risk. [2] Dairy is One Part of the Healthy Diet While scientists now understand that full-fat dairy is not a significant contributor to CVD risk this does not mean that it is the key to health. Health is affected both by the type of dairy consumed and the overall diet. There are good reasons to include dairy products in your diet but different product provide different health benefits. 11] Milk, yogurt, and cheese are good sources of many essential nutrients including protein, calcium, potassium, magnesium, and vitamins A, D, and B12. Full-fat milk, as well yogurt and cheese made from full-fat milk, all contain milk-fat globules, which provide cardioprotective properties. Cream and butter are made primarily from milk fat, so are much higher in saturated fat and calories than whole milk. Cream is the high-fat-layer that rises to the top of unhomogenized whole milk. It contains a high concentration of milk-fat globules but is much lower in protein, calcium, and many water-soluble nutrients than milk. Butter is made by churning cream, which breaks down the milk-fat globules, allowing the fat to clump together. Most of the milk-fat globule membranes as well as the protein, calcium, and other water-soluble nutrients are lost. [7,12] Low-fat and non-fat dairy products are produced by removing the fat from whole milk. This reduces the number of health-promoting milk-fat globules, but protein and water-soluble micronutrients are retained and vitamins A and D are restored through fortification. Yogurt, kefir, buttermilk, and cheese are fermented dairy products; this processing adds probiotic bacteria and their digestive benefits to the matrix. Despite these benefits, dairy products are only one component of a balanced diet. A healthy diet includes a variety of vegetables, fruits, whole grains, dairy, seafood, legumes, and nuts. It limits, saturated fats from meats and butter and added sugars from sweetened foods and beverages. Following this dietary pattern promotes a nutrient-rich diet that can lower the risk of CVD and promote overall health. [2] Bottom Line Current scientific evidence supports moderate consumption of full-fat dairy products within a healthy dietary pattern. This is based on the theory that consuming saturated fat as part of the dairy matrix does not increase the risk of CVD. Include your favorite diary foods but make them part of a healthy dietary pattern. Editor’s Note: Traditional thought would suggest that a significant drawback of whole-fat dairy is the extra calories leading to weight gain. Because of its increased fat content, whole-fat dairy would be more caloric and would be counter-productive to any attempt at weight loss. However, more recent studies have shown that whole-fat dairy is not associated with weight gain and may actually promote satiety (due to its fat and protein content) which would actually help control overeating and reduce overall calorie intake. [13] This should be studied more. References [1] Hirahatake KM, Astrup A, Hill JO, Slavin JL, Allison DB, Maki KC. Potential Cardiometabolic Health Benefits of Full-Fat Dairy: The Evidence Base. Advances in Nutrition. 2020;11(3). doi:https://doi.org/10.1093/advances/nmz132 [2] Lamarche B, Astrup A, Eckel RH, et al. Regular-fat and low-fat dairy foods and cardiovascular diseases: Perspectives for future dietary recommendations. American Journal of Clinical Nutrition. Published online March 1, 2025. doi:https://doi.org/10.1016/j.ajcnut.2025.03.009 [3] Maki KC, Dicklin MR, Kirkpatrick CF. Saturated fats and cardiovascular health: Current evidence and controversies. Journal of Clinical Lipidology. 2021;15(6):765-772. doi:https://doi.org/10.1016/j.jacl.2021.09.049 [4] Sendra E. Dairy Fat and Cardiovascular Health. Foods. 2020;9(6):838. doi:https://doi.org/10.3390/foods9060838 [5] Astrup A, Geiker NRW, Magkos F. Effects of Full-Fat and Fermented Dairy Products on Cardiometabolic Disease: Food Is More Than the Sum of Its Parts. Advances in Nutrition. 2019;10(5):924S930S. doi:https://doi.org/10.1093/advances/nmz069 [6] Comerford KB, Unger AL, Cifelli CJ, et al. Decrypting the messages in the matrix: The proceedings of a symposium on dairy food matrix science and public health opportunities. Critical Reviews in Food Science and Nutrition. 2025;65(30):7105-7118. doi:https://doi.org/10.1080/10408398.2025.2460606 [7] Dunne S, Gibney ER, McGillicuddy FC, Feeney EL. The effects of saturated fat intake from dairy on CVD markers: the role of food matrices. Proceedings of the Nutrition Society. Published online February 6, 2024:1-9. doi:https://` [8] Bruno RS, Pokala A, Torres-Gonzalez M, Blesso CN. Cardiometabolic health benefits of dairy-milk polar lipids. Nutrition Reviews. 2021;79(Supplement_2):16-35. doi:https://doi.org/10.1093/nutrit/nuab085 [9] Ozturk G, Paviani B, Rai R, et al. Investigating Milk Fat Globule Structure, Size, and Functionality after Thermal Processing and Homogenization of Human Milk. Foods. 2024;13(8):1242. doi:https://doi.org/10.3390/foods13081242 [10] Wilmot L, Miller C, Patil I, Kelly AL, Jimenez-Flores R. The relevance of a potential bioactive ingredient: The milk fat globule membrane. Journal of Dairy Science. Published online October 15, 2024. doi:https://doi.org/10.3168/jds.2024-25412 [11] Mulet-Cabero AI, Torres-Gonzalez M, Geurts J, et al. The Dairy Matrix: Its Importance, Definition, and Current Application in the Context of Nutrition and Health. Nutrients. 2024;16(17):2908. Published 2024 Aug 31. doi:10.3390/nu16172908 [12] de Goede, J, Geleijnse, JM, Ding, EL et al. (2015) Effect of cheese consumption on blood lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 73, 259–275. [13] Anderson GH, Chen CZ, Zhou CZ, Vien S, Soo M, Salamat S, Akbarifakhrabadi M, Chomka L, Kathirvel P, Siddiqi F, Fabek H, Luhovyy B. The Effect of Three Daily Servings of Full-Fat Dairy for 12 Weeks on Body Weight, Body Composition, Energy Metabolism, Blood Lipids, and Dietary Intake of Adults with Overweight and Obesity. Nutrition and Disease. Volume 156, Issue 4 101373 April 2026

Indulge in roasted tomatoes and peppers paired with creamy burrata. An elegant, 100-calorie appetizer by nutrition experts that's quick, easy, and impressive. Creative Cooking for the Health-Conscious Gourmet FibonacciRECIPES | Culinary Medicine by Mary B Grosvenor, MS, RD and Lori A Smolin, PhD This appetizer combines luscious burrata cheese with roasted vegetables. Burrata is a cheese made from mozzarella and cream. It has a firm outer shell that releases a creamy interior when sliced open. Drizzle with balsamic glaze to add a sweet tang. This recipe is quick and easy yet looks extravagant. Ingredients 6 oz Burrata cheese ½ c Balsamic vinegar 2 Tbsp sugar 2 cups cherry tomatoes 8-10 mini sweet peppers 3 Tbsp olive oil ½ tsp coarse salt ¼ tsp black pepper Mary Recommends As an Amazon Associate FibonacciMD earns from qualifying purchases. Buy Burrata on Amazon: Bel Gioioso Burrata [https://amzn.to/4tCx5Ui] A great Balsamic vinegar is [https://amzn.to/49iNhSo] Instructions Bring burrata to room temperature by removing it from the refrigerator about 30 minutes before serving. Preheat the oven to 425°F Make balsamic glaze by mixing vinegar and sugar in a small saucepan. Heat to a boil, then reduce heat and simmer for 10-15 minutes stirring frequently until it thickens to a consistency that coats the back of a spoon. Set aside to cool. While glaze is cooking, spread the tomatoes and peppers on a parchment-lined sheet pan, toss in olive oil and sprinkle with salt and black pepper. Bake for 15-20 minutes until tomatoes skins are beginning to wrinkle. Place burrata on a serving platter and drizzle with balsamic glaze. Surround cheese with the roasted tomatoes and peppers and serve warm or at room temperature. Notes Bringing the burrata to room temperature ensures that rich velvety interior will flow, adding to the presentation of this appetizer. If you are not interested in making your own balsamic glaze, there are many commercial products available. Makes 8 Appetizer-Size Servings Nutrition Information per serving Calories 100, Total Fat 7.5 g, Saturated Fat 3.5g, Cholesterol 20 mg, Total Carbohydrate 25g, Dietary fiber 2.2g, Protein 3.5g, Potassium 250mg, Sodium 180mg Editor’s Note: This recipe is appropriate for a low cholesterol, low saturated fat, and low carb, lacto-vegetarian dietary regimen.

How Do PBMs Control the Prescription Drug Market? Go to our CME Site, Read Article,  Take Test ,  and Get FREE 🎓 CME Certificate with Valid Email We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Take CME for Credit By Stuart M. Caplen, MD  Pharmacy benefit managers (PBMs) are the intermediaries in the U.S. medication distribution system and are positioned to hold down drug costs for insurers and consumers.  Industry representatives have stated that their services reduce drug prices.[2]   However, PBM business practices have actually been associated with increased drug prices.  This article examines the history of PBMs, how they operate within the pharmaceutical industry, and current efforts to limit the extent of their control over drug pricing.    History  Insurance coverage for medical prescriptions began expanding in the 1960s, when only 4% of prescriptions were covered.  This increased to 32% by the 1980s.  The first PBMs were started by pharmacists in 1965.  These pharmacist-led PBMs were controversial with major pharmacy trade organizations complaining about recordkeeping obligations, variability in coverage, and reimbursement rates.[3] In 1974, the Employee Retirement Income Security Act ( ERISA ) was passed, creating federal standards for employment-based retirement and health plans.  ERISA allowed large employers to adopt cost-containment strategies for their employees, including hiring PBMs to manage their prescription drug benefits.[3] Vertical integration of PBMs began in 1972 when healthcare companies began acquiring them.  In the 1990s, pharmaceutical companies first, followed by pharmacy chains and then insurance companies, started purchasing PBMs.  Antitrust inquiries by the U.S. Department of Justice blocked some PBM-involved mergers, but other mergers were permitted.[3] Vertical Integration in the Pharmaceutical Industry with Percentages of U.S. Market Share in 2023. [4] (Drug private labeler - a company that markets and sells drugs under its own brand name but does not manufacture them.  “PBM GPO” Rebate Aggregator – see Negotiations  section)  Formulary Design One of the most important functions of a PBM is the development of a drug formulary that specifies which drugs the PBM will cover and what costs patients will incur.  Formularies are described as open, where almost all marketed drugs are available, or as closed which limits drug availability.  A PBM may have numerous formularies with differing drug lists, tiers, and costs depending on client preferences.  PBM clients can be employers, insurance companies, or public entities such as state Medicaid programs.  PBMs also determine the incentives used to encourage use of preferred drugs.  If a drug is not on the formulary, a patient may be required to pay the full retail price or attempt to appeal the PBM’s decision.[3] Prescription Management    PBMs can influence prescribing through various utilization management strategies such as prior authorization, instituting step therapy requirements, limiting dosage or number of days of medication per prescription, or using financial incentives such as levels of deductibles, co-payments, or coinsurance.  Prior authorization  typically requires the prescribing physician to provide documentation justifying the need for a certain medication before the PBM will approve payment.  Step therapy  (also known as “fail first”)  is the process of requiring a patient to try and fail an approved, typically less expensive medication before a more expensive one is authorized.   With vertical integration, insurance companies may own PBMs and pharmacy chains and strongly incentivize patients to use pharmacies that they own if they want the insurance company to pay for their medications.[3]  PBMs can restrict the number of days of medication a patient can receive from a retail pharmacy, aiming to have the patient use an affiliated mail-order pharmacy service.  This allows patients to obtain larger quantities of medication at one time from the affiliated pharmacy than from an unaffiliated retail pharmacy, sometimes with reduced copayments.[3]   PBM Negotiations  A PBM negotiates with pharmacies, wholesalers, and drug manufacturers on behalf of its clients.  As a result, the price a PBM pays for medications may be lower than manufacturers’ list prices.  The actual net prices paid by PBMs are generally not publicly disclosed.[3] Several issues are problematic in the PBM negotiation process.  First, drug manufacturers often pay rebates to the PBMs to have their drugs included on formularies or placed on preferred tiers.  These rebates can represent a significant revenue stream for PBMs, and they may or may not end up reducing costs for the consumer.  Rebates may incentivize higher list prices and larger price concessions and may lead to higher-cost or brand-name medications being preferred over less expensive, generic or biosimilar alternatives which may generate fewer profits for the PBMs.    If a drug manufacturer declines paying requested rebates, or price concessions, its drugs may not be included within the formulary and therefore, will not be covered by patients’ insurance at pharmacies.[3] Many PBMs and their vertically integrated companies have set up corporate entities called rebate aggregators  (or group purchasing organization aggregators).  In theory their role is to negotiate better rebate terms with manufacturers by leveraging the prescription volumes of multiple PBMs.  In actual practice they provide a method for PBMs to capture and retain rebates in ways that make it difficult for plan sponsors or regulators to determine the true flow of funds.  Instead of passing the manufacturers’ rebates directly to the plan sponsor (client), the rebates are paid to the rebate aggregator, where fees, service charges, or other administrative costs may be deducted before the remainder of the rebate is shared with the PBM.  The PBM then acts as if it has no knowledge of the rebate aggregator’s actions and can then report drug prices to the plan sponsor without revealing any profits or rebates taken by the rebate aggregator.  This lack of transparency allows PBMs to conceal their true cost for drugs from the plan sponsors as well as the true profit margins.  This is not an issue for vertically integrated companies as they own each step of the process.  However, for smaller insurance companies or companies that self-insure and use PBMs they do not own, it may be problematic.  Some rebate aggregators have been incorporated offshore potentially limiting governmental oversight.[5]  PBMs may also retrospectively recoup (claw back) funds from pharmacies if a patient’s copayment exceeds the PBM’s negotiated payment or if contractual performance metrics are not met.[1] Pharmacy Network PBMs have the responsibility of creating and maintaining a network of pharmacies for their clients’ employees to obtain their medications.  Large PBMs can increase competition between pharmacies by restricting access to the PBM’s pharmacy network, which can result in the pharmacies having to accept lower prices for dispensing medications to achieve network inclusion.[3]  Owning mail-order pharmacies is another way PBMs and insurance companies have vertically integrated.  In North America, approximately $37.8 billion in medications were delivered by mail in 2024.[6]  Incentives to use PBM-owned mail order pharmacies might be three months of prescription medications instead of one month if filled by a local pharmacy, resulting in a lower copayment for the consumer using mail order.[3]   How Do PBMs Make Money? PBMs generate revenue through several mechanisms, including:   The ability to retain all or part of the rebates and other price concessions paid to PBMs by drug manufacturers.  In the past, the industry average has been for PBMs to retain 0.4% of Medicare Part D and up to 22% of the rebates in the commercial insurance market.  Spread pricing, in which the plan sponsor pays a set price for a drug while the PBM reimburses the pharmacy a lower amount, with the PBM retaining the difference. Charging administrative fees for its services.[3]  These practices may incentivize maximizing rebates and minimizing pharmacy reimbursement.  Larger PBMs with more clients get the most benefit from these strategies, which has led to horizontal integration, where PBMs are merged together or purchased.[3]    Thus, PBMs have placed themselves at the center of the U.S. prescription drug pricing and distribution market and have the ability to control the flow and cost of drugs in all aspects of distribution, directly affecting manufacturers, pharmacies, insurance companies, and consumers.[3] Issues with PBMs Concentration of Market Share There has been a concentration of market share resulting in limited competition.  In 2022, three PBM companies (CVS Health - Caremark, Cigna - Express Scripts, and UnitedHealth Group - OptumRx) controlled 79% of the U.S. prescription business.  That same year five of the six largest PBMs were owned by health insurers.[7] Pricing Issues The PBMs’ use of rebates and fees has incentivized high-cost, high-rebate medications receiving preferred positions on formularies, as these medications are more profitable than lower-priced alternatives.  Some PBMs are contractually required to pass 100% of the rebate back to their clients.  In response, some drug manufacturers have established a two-price system to secure placement of their medications on PBM formularies: a high-priced, high-rebate option for PBMs permitted to retain rebates, and a lower-priced, no-rebate option for those required to pass rebates through.  In 2018, the state auditor of Ohio conducted a one-year review of Medicaid prescriptions.  It was reported that PBMs were retaining 31% of Medicaid generic drug prescription prices, 0.8% of brand-name drug prices and 1.1% of specialty drug prices.  86% of the Medicaid prescriptions filled that year in Ohio were for generic medications.  Overall, PBMs were earning 8.9% of the total amount spent by Ohio on drugs for Medicaid patients, or $224 million out of a total of $2.526 billion spent.[8]  Another issue with the use of rebates is that the patient’s share of cost for medications is typically based on the list price, not the price minus the rebate.  Because patient cost-sharing is typically based on list price rather than post-rebate net price, rebates may lower PBM net costs without proportionately reducing patient out-of-pocket expenses. Increases in drug prices, copayments, or coinsurance can lead patients to forgo filling or picking up their prescriptions.  One 2019 review reported that prescription abandonment rates are less than 5% when prescriptions have no out-of-pocket cost, 45% when the cost is over $125 and 60% when the cost is over $500.[9]  The U.S. Department of Health and Human Services’ 2020 Drug Formulary Rebate Rule for Medicare Part D coverage clarified that a patient’s out-of-pocket spending was intended to correlate to the post-rebate price rather than the list price in an effort to address this issue.[3]  Price Transparency  Another criticism of PBMs has been their lack of transparency in reporting pricing, costs and other financial activities.  For example, PBMs have the ability to move a drug to a more preferred tier of a formulary, possibly due to a larger rebate, without having to provide any clinical or financial justification.  There is also a lack of transparency on how PBMs set pharmacy reimbursement as well as the amount of retroactive pharmacy clawbacks.[3] Federal Trade Commission (FTC) Interim Report In 2024, the FTC issued an interim report titled Pharmacy Benefit Managers: The Powerful Middlemen Inflating Drug Costs and Squeezing Main Street Pharmacies .  There were several conclusions highlighted in that report: The market for PBM services has become highly concentrated, and the largest PBMs are now also vertically integrated with the nation’s largest health insurers and specialty and retail pharmacies. As a result of this high degree of consolidation and vertical integration, the leading PBMs can now exercise significant power over Americans’ access to drugs and the prices they pay. Vertically integrated PBMs may have the ability and incentive to prefer their own affiliated businesses, entering into complex and opaque contractual relationships, which can, in turn, disadvantage unaffiliated pharmacies and increase prescription drug costs. PBMs and brand drug manufacturers sometimes negotiate prescription drug rebates that are expressly conditioned on limiting access to potentially lower cost generic alternatives.[4] An audit of two cancer drugs in the report found that pharmacies owned by commercial health plans were paid by their affiliated PBMs 80% to 90% more than unaffiliated pharmacies for dispensing those drugs.  Medicare Part D plans paid 30% more to insurance company affiliated pharmacies than unaffiliated ones for those two medications.[4]  The report concluded that higher payments to pharmacies in vertically integrated companies allow them to game regulations.  Medical loss ratios  (MLRs) are regulated under the Affordable Care Act and represent the percentage of collected premium revenue that health plans are required to spend on clinical care and quality improvement initiatives (typically 80 to 85 percent).  If an insurer pays an inflated price for medication to its own affiliated pharmacy, the higher payment is credited as spending for clinical care and helps the insurer satisfy its MLR obligations.  The higher payments may increase the pharmacy’s profits which eventually flow back to the insurer owner.  In addition, the higher cost of the medications allows the PBM to bill unaffiliated insurers or self-insured employers for higher drug costs, even though they have recaptured that money in their pharmacies.  Inflated drug costs for Medicare Part D plans move recipients into the phase where the government covers drug expenses faster and can increase Medicare expenses, which may lead Medicare Advantage plans to request increased reimbursement from Medicare the following year.[4]   Copay Coupons and Alternative-funding Plans Many drug manufacturers provide copay coupons for their higher-cost medications (most often dispensed from specialty pharmacies) to help defray out-of-pocket costs for consumers who use their medications.  This has led to several strategies by PBMs to increase profits that are not necessarily in a patient’s best interests.  With a copay accumulator program,   the value of a manufacturer’s copay coupon is paid to the PBM each time a prescription is filled but that amount does not decrease an enrollee’s deductible or out-of-pocket maximum.  This results in the PBM essentially getting paid twice, once by the coupon and then later by the patient for a future prescription as the coupon has not been applied to reduce the patient’s deductible.  When the patient’s eligibility for these coupons has reached the maximal yearly amount permitted, the enrollee may then be subject to deductibles and co-payments, which may be very expensive.[10] For a copay maximizer program, the value of the copay coupons   is spread out evenly over the year and is not used to reduce the copay or insurance deductible for the patient, resulting in double payments to the PBM.[10]   For both of these programs, the PBM or insurance company is paid part or all the patient copays but does not use those funds to decrease patients’ yearly deductibles. This has the effect of raising profits and increasing patients’ out-of-pocket costs.[11]  In alternative funding plans,  to decrease costs, the employer and the PBM remove some high-cost drugs from the formulary in a cost-shifting strategy.  An enrollee who needs the medication is referred to third-party vendors called alternative funding vendors  who attempt to find manufacturer programs or charities to defray the costs.  This practice can lead to delays, increased paperwork and there is no guarantee that the enrollee will actually be able to receive coverage for the medication.[12] Legislation and Administrative Actions In response to the perception that PBMs have too much control over the pharmaceutical distribution system, are making excessive profits, and lack price transparency, some states have passed legislation or changed administrative policies to limit their power.  In 2017, West Virginia stopped using PBMs to administer pharmacy benefits for state workers and Medicaid beneficiaries.  The State’s Bureau for Medical Services’ Office of Pharmacy Services (OPS) started acting as its own PBM.  West Virginia estimated that its Medicaid managed care program would save $38 million in the first year,[13] but it actually saved $54.4 million.[14] In 2021, West Virginia passed legislation, House Bill 2263, which mandated that any rebates PBMs received from drug manufacturers be passed on to patients.  For example, if a drug’s list price was $100 and the PBM got a $40 rebate from the manufacturer the drug would actually cost the PBM $60.  However, typically before this law was passed patients who had not met their deductible would still pay the list price of $100, leaving the PBM with an additional $40 profit on top of its normal fees.  After the passage of House Bill 2263, the PBM can only charge the patient $60, passing the rebate directly to them.[15] In 2025, the West Virginia insurance commissioner released a report on the effect the PBM rebate legislation had on insurance premiums.  As can be seen in the chart below, the rebate pass-through for almost every insurer listed reduced the amount of rate increase the insurers requested for the following year.[16] 2024 Filings (2025 Plan Year) West Virginia Insurance Rate Increase Requests for 2025 [16] In Arkansas, in 2025, House Bill 1150 (now Act 624) was passed.  This was an attempt to protect the interests and viability of independent pharmacies in the state and aimed to reduce conflicts of interest and promote more competition.  The bill prohibited PBMs from owning or operating pharmacies.  However, legal battles and a court injunction have thus far prevented its implementation.[17]  In Massachusetts, a law was enacted in 2025 called the PBM Licensing and Transparency Law (Senate bill 3012), which required PBMs to be registered, and included requirements of detailed reporting and oversight mechanisms for PBMs operating within the state.[17] California and Colorado passed delinking laws (Senate Bill 41 and House Bill 1094), which alters how PBMs are compensated.  These prohibit PBM remuneration being tied to the price of drugs, and transitions PBM compensation to a flat administrative fee model.  This aims to remove incentives for PBMs to favor higher-priced medications for their formularies due to the higher rebates.[17]  The California law also attempts to  increase transparency as it requires PBMs to report payments and rebates received from manufacturers to pharmacies and health plans.  It ensures manufacturers’ rebates are passed on to payers and patients and prohibits PBMs from steering patients to their own affiliated pharmacies.[18]  Similar legislation regulating PBMs has been introduced in other states.   Recent Federal Reactions to PBM Practices There has been recent activity with regard to PBM practices from the federal government.  In April 2025, as a presidential executive order regarding lowering drug prices, several governmental agencies were asked to research how best to promote a more competitive, efficient, transparent, and resilient pharmaceutical value chain to deliver lower drug prices for Americans.[19] In response to that presidential order, on January 30, 2026, the Department of Labor’s Employee Benefits Security Administration published proposed regulations intended to increase PBM transparency for private companies, unions, and employee organizations offering insurance plans to employees regulated under ERISA (Employee Retirement Income Security Act).  The proposed regulations included increasing PBM transparency for drug pricing and profit margins, disclosing formulary placement incentives and arrangements with manufacturers, and having the PBM act as an ERISA fiduciary and disclose any conflicts of interest.[20,21]   On February 3, 2026, the Consolidated Appropriations Act was signed into law.  Part of that budgetary agreement included regulations for PBMs requiring the following:  Transparency and improved reporting of Medicare Part D drug prices. Requiring Part D insurance plans to allow any pharmacy that meets specified criteria to participate in a PBM’s network. The law also establishes a method for pharmacies to report contract-related violations without fear of retaliation and authorizes enforcement actions and penalties against insurance plans or PBMs that fail to comply with the rules.  Increased price transparency for prescription drugs purchased by employer health plans which requires PBMs to provide detailed data on prescription drug spending, drug rebates, spread pricing arrangements, drug formulary placement rationale, and information about financial relationships with their affiliated pharmacies.[22] On February 4, 2026, the Federal Trade Commission (FTC) secured a settlement with Express Scripts, one of the largest PBMs, that at this writing is awaiting comments from the public before acceptance.  The FTC sued Express Scripts for inflating the price of insulin by using anticompetitive and unfair rebating practices, impairing patients’ access to lower list price products, and ultimately shifting the cost of high insulin list prices to patients.  The FTC expects to drive down patients’ out-of-pocket costs for drugs like insulin by up to $7 billion over 10 years and bring millions of dollars in new revenue to community pharmacies.  As part of the settlement, Express Scripts has agreed to improve transparency on drug pricing, use lower-cost alternatives rather than high-cost versions, stop using inflated list prices to calculate patients’ out-of-pocket costs, move its rebate aggregator (GPO) from Switzerland to the U.S., treat community pharmacies more fairly, lower out-of-pocket costs for insulin and allow sponsor access to TrumpRx.[23]  TrumpRx is a website that was recently instituted where patients with commercial insurance may receive coupons for these lower-priced drugs to present to local pharmacies.[24]   If fully implemented, these measures could materially alter the economics of the medication distribution system in the U.S.  Effect of Direct-to-Consumer Pharmacies and Price Limits on Certain Drugs  There have been some recent changes in the pharmaceutical industry that are affecting the power of PBMs.  One has been the rise of direct-to-consumer mail-order pharmacies.  Some sell only generic medications at a minimal markup, while others sell a wider selection of drugs.[3]  The Centers for Medicare & Medicaid Services (CMS) also began negotiating prices with drug manufacturers for Medicare Part D.  Ten drugs for 2026 and fifteen for 2027 have been selected that have no biosimilar or generic versions and CMS estimates that Medicare savings could approach 44% or $12 billion a year on those drugs.[25,26]   Summary PBMs were originally created to manage prescription drug benefits and control costs. However, vertical and horizontal integration, rebate-driven revenue models, and limited pricing transparency appear to have contributed to higher drug prices and increased costs for patients, governmental entities, and insurance plan sponsors that are not affiliated with PBMs. State and federal reforms are increasingly targeting PBM rebate structures, pricing models, transparency, relationships with community pharmacies, vertical integration, and fiduciary responsibilities.   Ongoing regulatory and legislative efforts may significantly reshape PBM operations and the U.S. pharmaceutical distribution system in the coming years. Author’s Note:  Thank you to Dr. Theodor Feigelman for editing this learning activity.   ✅ Earn Free CME Credit for Reading this Article on Our CME Site Eligible for 0.75 PRA Category 1 Credit Click the button below to complete the course and take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Take CME for Credit References [1] Understanding Pharmacy Benefit Managers.  Courtesy of the Colorado Health Institute, www.ColoradoHealthInstitute.org , 1999 Broadway, Suite 600, Denver, CO 80202. Last updated: March 10, 2023. Retrieved from: https://www.coloradohealthinstitute.org/research/understanding-pharmacy-benefit-managers [2] Medicare Part D: Use of Pharmacy Benefit Managers and Efforts to Manage Drug Expenditures and Utilization (GAO-19-498). U.S. Government Accountability Office. July 2019. Retrieved from: https://www.gao.gov/assets/gao-19-498.pdf?utm_source=chatgpt.com [3] Mattingly TJ, Hyman DA, Bai G. Pharmacy Benefit Managers: History, Business Practices, Economics, and Policy. JAMA Health Forum. 2023;4(11). Retrieved from: https://jamanetwork.com/journals/jama-health-forum/fullarticle/2811344 [4] Pharmacy Benefit Managers: The Powerful Middlemen Inflating Drug Costs and Squeezing Main Street Pharmacies. U.S. Federal Trade Commission Office of Policy Planning. July 2024.   https://www.ftc.gov/system/files/ftc_gov/pdf/pharmacy-benefit-managers-staff-report.pdf [5] A Turning Point for Fiduciary Accountability: PBM-Owned Rebate Aggregators in the Spotlight. Buchanan Ingersoll & Rooney PC. Sept. 10 2025. Retrieved from: https://www.bipc.com/a-turning-point-for-fiduciary-accountability-pbm-owned-rebate-aggregators-in-the-spotlight [6] Mail Order Pharmacy Market Trends, Opportunities and Strategies, 2019-2024 & 2025-2034: CVS Health Leads the $550 Billion Fragmented Market, Followed by Walmart Pharmacy and Kroger Health. Globe Newswire. Feb. 21, 2025.  Retrieved from: https://finance.yahoo.com/news/mail-order-pharmacy-market-trends-104800922.html [7] Fein AJ. The Top Pharmacy Benefit Managers of 2022: Market Share and Trends for the Biggest Companies. Drug Channels. May 23, 2023. Retrieved from:  https://www.drugchannels.net/2023/05/the-top-pharmacy-benefit-managers-of.html [8] Auditor’s Report: Pharmacy Benefit Managers Take Fees of 31% on Generic Drugs Worth $208M in One-Year Period. Press Release • Ohio Auditor of State. August 16, 2018. Retrieved from: https://ohioauditor.gov/news/pressreleases/details/5042 [9] Medicine Spending and Affordability in the U.S. IQVIA. Aug 04, 2020. Retrieved from: https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/medicine-spending-and-affordability-in-the-us [10]Long M et al. Copay Adjustment Programs: What Are They and What Do They Mean for Consumers? KFF. Oct 24, 2024. Retrieved from: https://www.kff.org/health-costs/copay-adjustment-programs-what-are-they-and-what-do-they-mean-for-consumers/ [11] Copay Maximizers. MMIT. Retrieved from: https://www.mmitnetwork.com/glossary/copay-maximizers/ [12] Gliadkovskaya A. A new wave of middlemen offers 'alternative funding' for specialty drugs. Patients bear the risks. Fierce Healthcare. Last updated on October 24, 2025. Retrieved from: https://www.fiercehealthcare.com/payers/new-wave-middlemen-promise-savings-specialty-drugs-patients-bear-risks [13] States Take Administrative Actions to Curb Medicaid Drug Costs. The National Academy for State Health Policy. 10/16/18. Retrieved from: https://nashp.org/states-take-administrative-actions-to-curb-medicaid-drug-costs/ [14] West Virginia Medicaid saves $54.4 million with prescription drug carve-out. National Community Pharmacists Association. March 13, 2019. Retrieved from: https://ncpa.org/newsroom/news-releases/2019/03/13/west-virginia-medicaid-saves-%2454.4-million-with-prescription-drug-carve-out#:~:text=In%20July%202017%2C%20the%20West%20Virginia%20Medicaid,West%20Virginia%20*%20Fair%20reimbursement%20for%20pharmacies [15] Laganga S. West Virginia becomes the first state to lower patient costs by sharing the savings. PhRMA. April 20, 2021. Retrieved from: https://phrma.org/blog/west-virginia-becomes-the-first-state-to-lower-patient-costs-by-sharing-the-savings [16] McVey AL,  Insurance Commissioner. Prescription Drug Rebate Impact to Commercial Health Insurance. West Virginia Insurance Bulletin No. 25-01. February 13, 2025. Retrieved from: https://www.wvinsurance.gov/Portals/0/pdf/pol_leg/IB_25-01_Prescription_Drug_Rebate_Impact_to_Commercial_Health_Insurance.pdf [17] Kimbrough L. State Pharmacy Benefit Management Reform in 2025. Multistate. October 23, 2025. Retrieved from: https://www.multistate.us/insider/2025/10/23/state-pharmacy-benefit-management-reform-in-2025 [18] Senate Bill No. 41. California Legislative Information. 10/13/2025 Retrieved from: https://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=202520260SB41 [19]A Presidential Document by the Executive Office of the President. Lowering Drug Prices by Once Again Putting Americans First.  Federal Register. 04/18/2025. Retrieved from: https://www.federalregister.gov/documents/2025/04/18/2025-06837/lowering-drug-prices-by-once-again-putting-americans-first [20] Welle NJ et al. DOL Proposes Sweeping New Disclosure Rules for Pharmacy Benefit Managers. The National Law Review. February 2, 2026. Retrieved from: https://natlawreview.com/article/dol-proposes-sweeping-new-disclosure-rules-pharmacy-benefit-managers [21] Improving Transparency into Pharmacy Benefit Manager Fee Disclosure. Department of Labor. 01/30/2026. Retrieved from: https://public-inspection.federalregister.gov/2026-01907.pdf [22] A New Era for Patients: Carter celebrates President Trump signing PBM reforms into law. Buddy Carter Press release. February 3, 2026. Retrieved from: https://buddycarter.house.gov/news/documentsingle.aspx?DocumentID=16308 [23] FTC Secures Landmark Settlement with Express Scripts to Lower Drug Costs for American Patients. FTC. February 4, 2026. Retrieved from: https://www.ftc.gov/news-events/news/press-releases/2026/02/ftc-secures-landmark-settlement-express-scripts-lower-drug-costs-american-patients [24] TrumpRX. Retrieved from: https://trumprx.gov/ [25] Medicare Drug Price Negotiation Program: Negotiated Prices for Initial Price Applicability Year 2026. CMS. August 2023. Retrieved from: https://www.cms.gov/files/document/fact-sheet-medicare-selected-drug-negotiation-list-ipay-2026.pdf [26] Medicare Drug Price Negotiation Program: Negotiated Prices for Initial Price Applicability Year 2027. November 2025. CMS. Retrieved from: https://www.cms.gov/files/document/fact-sheet-negotiated-prices-ipay-2027.pdf

By Stuart M Caplen MD Commentary by Arno Housman, MD , a urologist’s perspective updated May 19, 2025 The goal of screening for prostate cancer is to identify localized disease that can be successfully treated before it becomes advanced and metastatic. Testing men for prostate cancer has become a controversial topic due to a significant percentage of false positive blood prostate-specific antigen (PSA) results leading to invasive testing that may potentially have negative effects on health. In addition, in most men prostate cancer is a disease that may slowly become symptomatic, potentially longer than the person’s life expectancy. This is balanced against the improvement in mortality and symptoms that can be obtained from early diagnosis and treatment of aggressive forms of prostate cancer. This article will look at the latest guidelines and consensus opinions regarding screening asymptomatic patients for prostate cancer and the benefits and risks of testing and follow-up procedures. Prostate Cancer Statistics In the United States, the lifetime risk of contracting prostate cancer is estimated to be 12.6% and the risk of dying from it is 2.5%. There were an estimated 268,490 new cases and 34,500 deaths from prostate cancer in 2022, the fifth leading cause of death in men.[1] The median age of death from prostate cancer is estimated to be 80 years of age and two-thirds are over 75 years of age. Black men have a higher risk of death from prostate cancer of 4.2% compared to white men where the risk is 2.3%.[2] Many men with prostate cancer never are diagnosed. In autopsy studies of men aged 70 to 79, who died of other causes, 21.2 % of Asians, 36% of whites and 51% of Blacks were found to have undiagnosed prostate cancer.[3] Undetected prostate cancer was also found on autopsy in younger men; 22% of men 50-59 years old and 29% of men 60-69 years old.[3] Mortality depends on whether the cancer is low grade, localized and slow growing or an aggressive form of prostate cancer. The much higher autopsy percentages of undiagnosed prostate cancer compared to clinically diagnosed cases suggests that there is a large pool of silent, slow growing tumors that may not cause symptoms in a man’s lifetime, but if tested for and treated may possibly result in morbidity from invasive procedures.[4] Rectal exams Palpating the prostate gland to feel for signs of malignancy by a digital rectal exam has been a time-honored part of the annual physical examination. A systematic review of the literature found that when performed by general practitioners the sensitivity of the rectal exam for prostate cancer was 28.6% and if the exam was normal there was still a 15.8% chance that the patient had prostate cancer. The authors recommended that any patient with symptoms suggestive of prostate cancer be investigated further regardless of the rectal exam results.[5] Another study found that the rectal exam was not a sensitive tool when compared to blood testing in discovering prostate cancer in men under 50 years of age.[6] Both the US Preventive Services Task Force (USPSTF) and the American Association of Family Practitioners (AAFP) guidelines recommend not performing a digital rectal exam for asymptomatic prostate cancer screening due a lack of evidence of the benefit.[2,7] Prostate-specific Antigen Testing Testing for prostate cancer is done by measuring prostate-specific antigen (PSA) in the blood. There can be false positives from benign prostatic hyperplasia, prostatitis, urologic procedures, taking testosterone and recent ejaculation may also increase the PSA level for a short time. As men age, PSA levels normally increase even without cancer.[2] The standard screening PSA test used is a total blood PSA level. There is no specific cutoff point of PSA that can accurately diagnose prostate cancer. Many clinicians use a PSA level of 4 nanograms per milliliter (ng/mL) or higher when deciding if a patient might need further testing, while others might recommend further testing at a lower level, such as 2.5 or 3 ng/mL.[8] Most men without prostate cancer have PSA levels under 4 ng/mL. A level below 4 ng/ml is not a guarantee that a man doesn’t have cancer and about 12%-23% of men with a PSA below 4 will be found to have prostate cancer by biopsy. Men with a PSA level between 4 and 10 ng/mL have about a 25% chance of having prostate cancer. Men with a PSA level above 10 ng/mL have over a 50% chance of having prostate cancer.[8,9] PSA occurs in two major forms in the blood. One type is attached to blood proteins, while the other circulates as a free form. Another test used is the percent-free PSA which is the ratio of free PSA to the total PSA level. While not absolute, generally the percentage of free PSA is lower in men who have prostate cancer than in men who do not. Some authors have suggested the free-to-total PSA ratio may be used as an additional screen to help prevent some men with false positive total PSA results needing a prostate biopsy.[8,10,11] Evidence from a longitudinal PSA trial in men aged 55 to 69 indicate PSA screening may prevent approximately 1.3 deaths per 1000 men from prostate cancer over approximately 13 years.[2,12] PSA screening programs may also prevent approximately 3.1 cases of metastatic prostate cancer per 1000 men screened.[13] In the 16-year European Randomized Study of Screening for Prostate Cancer trial, no benefit from screening was found for men 70 to 74 years old.[14] Many clinical guidelines do not recommend PSA screening for prostate cancer in men 70 years and older. False positive PSA tests are not uncommon. In one large study of over 60,000 subjects, 17.8% had one or more false positive PSA results, and 50% of those had a second false positive later on. However, men with false positives were more likely to be later diagnosed with prostate cancer than those with negative results (10% vs 2.6-2.7%). Most of the cancers found in subjects with earlier false positives were localized cancers but 6.3% were aggressive types. The authors were not sure if the higher rate of cancer found in men with false positive PSA tests was due to an actual increase in incidence in that group or just the result of more intense follow-up.[15] Negative Effects of PSA Testing A positive PSA test frequently leads to prostate biopsy to confirm whether or not there is cancer which may have some adverse effects. In the 16-year European Randomized Study of Screening for Prostate Cancer trial, only 25% or about 5,000 of over 20,000 biopsies performed were positive for cancer after an elevated PSA.[14] The USPSTF guidelines cite literature estimates that 20% to 50% of prostate cancers are overdiagnosed.[2] In one trial the following symptoms were reported 35 days after having a prostate biopsy. 44% of men reported pain and 7.3% rated it as a moderate or serious problem. 20% still had fever with 5.5% of the men reporting the fever as a moderate or serious problem. 66% had blood in the urine; 6% found this a moderate or serious problem. 37% had blood in the stool and 2% found this a moderate or serious problem. 90% had blood in the semen and 25% found this a moderate or serious problem.[16] One large study found hospital admission rates after prostate biopsy increased from 1% in 1996 to 4.1% in 2005, mostly from infection complications. The 30-day mortality rate for prostate biopsy was .09%. Complications occurred mostly in older more unhealthy patients.[17] Another study found a mortality rate of 1.3% in the biopsy group vs 0.3 % in a control no biopsy group after 120 days. The mortality rate was 0.2% for men under 60 years of age and 2.5 % in men 76-80 years of age in that study.[18] Temporary urinary retention may be another complication of prostate biopsy. If radical prostatectomy or radiation therapy are performed as a result of a positive prostate biopsy, potential adverse effects may increase. About 20% of men who undergo radical prostatectomy develop long-term urinary incontinence, and about two- thirds will experience long-term erectile dysfunction. More than half of men who receive radiation therapy will experience long-term sexual erectile dysfunction and up 16% experience long-term bothersome bowel symptoms including bowel urgency and incontinence.[2] How Accurate is a Standard Transrectal Biopsy? In the standard transrectal systematic biopsy typically 12 or more core samples are taken from different areas of the prostate for analysis. Some authors recommend a higher number of core samples to try to improve sensitivity. The false negative rate of transrectal biopsy can be as high as 30%.[19] Even 20 core sample biopsies were found to have close to a 10% false negative rate in one study.[19] In another study standard transrectal ultrasonic biopsy was only 48% sensitive for finding clinically significant prostate cancer.[20] As a result of the false negative rate, many men will require multiple biopsies to confirm a diagnosis of prostate cancer. Another biopsy method that has gained some popularity is the transperineal template biopsy. The samples are taken directly through the perineal skin into the prostate gland. A targeted template biopsy is used if the intention is to focus on one part of the prostate because previous assessments have identified the location of the significant disease. A saturation template biopsy is used if the intention is to assess the whole of the prostate, taking many tissue samples.[21] The main advantage of the transperineal route is a significant decrease in the post-biopsy infection rate compared to the transrectal route as the trocar is going through skin rather than through the rectal wall. The disadvantages are that as it is more painful, it is typically done under general anesthesia and it is a longer procedure than a transrectal biopsy. A meta-analysis and systematic review found transrectal and transperineal biopsies were similar in their ability to diagnose prostate cancer. It was found that transperineal biopsy significantly decreased the risk of rectal bleeding and fever, while transrectal biopsy resulted in less pain. There was no significant difference in acute urinary retention and hematuria.[22] Another meta-analysis found a sepsis rate of 0.09 % to 0.13% after transperineal biopsy.[23] In one study of 245 transperineal biopsies there were zero cases of sepsis. The authors stated that in the literature, rates of sepsis after transperineal biopsy were 40 to 70 times lower than transrectal.[24] MRI MRI has improved the diagnosis of prostate cancer. Although not perfect, MRI may potentially be used after an abnormal PSA to determine the need for biopsy. It can also be used during a prostate biopsy to help localize the areas that need testing. The most common test performed for cancer localization is the multiparametric MRI (MPMRI) where a standard MRI of the prostate is done followed by an additional MRI scan to examine other prostate tissue parameters, such as diffusion weighted imaging or dynamic contrast enhanced MRI. [25] In the traditional transrectal ultrasound biopsy, the physician takes a number of core samples of the prostate. In an MRI/ultrasound fusion-guided transrectal prostate biopsy, during the biopsy procedure transrectal ultrasound is used to view to prostate, and a computer program fuses the previously done MRI and ultrasound images together for the clinician to view. This allows the clinician to more accurately get biopsy samples from any suspicious areas seen on the MRI images.[25] How Accurate is MRI for Prostate Cancer? Below are the findings of one systemic review of MPMRI for diagnosing clinically significant prostate cancer in men without a previous biopsy who had an elevated PSA. Men without a previous biopsy and elevated PSA Diagnostic Accuracy of MPMRI for clinically significant prostate cancer Sensitivity 87.8%-96% Specificity 29.2% - 43.3% Positive Predictive Value 45.9% to 60.2% Negative Predictive Value 79.7% to 92% [26] What these statistics indicate is that most men who have clinically significant prostate cancer will often be picked up by MPMRI. (87.8%-96%) However, due to the low specificity (29.2%-43.3%) there are many false positives, resulting in a low positive predictive value of 45.9%- 60.2% (Positive predictive value is the probability that a patient who gets an abnormal result truly has the disease.) Due to the high sensitivity, with fewer false negative results, a negative result has a 79.7-92% probability that it is a true negative and the person does not have the disease. (Negative predictive value)[26] In another meta-analysis, the sensitivity of MPMRI for detecting any type of prostate cancer (not just clinically significant cancer) was 74%, or a false negative rate of 26%.[27] Based on their data, the authors of one trial postulated that use of MPMRI as triage would decrease unnecessary biopsies by 27%, and result in a 5% decrease in clinically insignificant cancers being found and potentially treated.[20] Use of fusion MPMRI in transrectal biopsy procedures instead of standard transrectal ultrasonic biopsies would result in 18% more clinically significant cancers being found.[20] An additional MRI targeting method is an in-bore prostate biopsy. The procedure is carried out within the MRI scanner, and areas of interest are selected and biopsied using guidance from serial scans during the procedure.[28] One study comparing fusion MPMRI versus in-bore MRI prostate biopsies found in-bore to be superior to fusion MRI in detection of cancer in targeted lesions but no difference was found in cancer detection in systematic untargeted sampling between the two methods.[29] A Cochrane review of the literature compared MRI screening versus systematic transrectal prostate biopsy for evaluation of an elevated PSA test or an abnormal rectal exam. The authors concluded that both the MRI pathway and systematic prostate biopsy missed considerable numbers of grade 2 or higher prostate cancers, but that the MRI pathway performed better than systematic transrectal biopsy did. They further found that the MRI pathway missed more grade 1 prostate cancer than systematic biopsy did in men and the MRI pathway could potentially reduce the amount of overdiagnosis, and harms related to overtreatment. They concluded that MRI before any prostate biopsy and use of MRI as the replacement for systematic biopsy in certain specified circumstances, might provide the most favorable diagnostic strategy.[30] Conclusion : MRI can be used as a tool to improve biopsy accuracy, but MRI is nowhere near 100% accurate for detecting or ruling out clinically significant prostate cancer by itself. The risks and benefits of following up and monitoring men with positive PSA results with only MPMRIs instead of performing a biopsy should be discussed with the patient. Active Surveillance Active monitoring or surveillance in selected cases of biopsy positive prostate cancer rather than going on to radiation therapy or radical prostatectomy has become a more popular option. In the US from 2005-2009 about 10% of men with low-risk prostate cancer received it. That had risen to 40.4% in 2010-2013.[2,32] One study found that 6.0% of men in the active surveillance group developed metastatic cancer, compared with 2.7% in the radiation therapy group and 2.3% in the radical prostatectomy groups. During the 10-year study follow-up period, 54.8% of men in the active surveillance group required active treatment, while 44% did not.[2,32] A large study of over 1,600 subjects over 15 years found no significant difference in the death rates between active monitoring, prostatectomy or radiation therapy. There was a higher rate of metastases in the active monitoring group than the other two treatments. ( 9.4% versus 4.7% and 5.0%) [32A] The data from these trials suggests that active monitoring/surveillance requires frequent monitoring of patients choosing this option. Recommendations Men Over 70 Years of Age The US Preventive Services Task Force (USPSTF) recommendation is to not screen any asymptomatic male over the age of 70. In one study the 10-year survival rate for localized prostate cancer was 99% regardless of whether the subjects received active monitoring, surgery or radiation therapy.[33] In men over 70 years of age, there is a lack of trial evidence of benefit, a low likelihood of benefit given the time frame to realize benefit, and increased risk of harm from false-positive results, biopsies, overdiagnosis and overtreatment of prostate cancer.[2]. However, the USPSTF did recognize that some clinicians and men over 70 may still want PSA testing, but recommended that the risks and benefits should be discussed. Men Between 55 and 69 Years of Age For men aged 55 to 69 years, the USPSTF recommendation is that the decision to have periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death and metastatic spread from prostate cancer in some men. However, many men will experience potential harm from screening, including false-positive results that require additional testing and possible prostate biopsy and treatment complications such as incontinence and erectile dysfunction.[2] Special Considerations Black men are more likely than white men to develop prostate cancer, have higher rates of aggressive cancer and are more than twice as likely to die from prostate cancer (44.1 vs 19.1 deaths per 100,000 men). Black men are also seven times more likely to have infectious complications after prostate biopsy than non-Black men.[2] There are a number of studies that have demonstrated genetic links to prostate cancer in some families. Men who have one or more first-degree relative/s who have had a severe case of prostate cancer were 30% more likely to be diagnosed with prostate cancer than men without a family history.[2] The USPSTF guidelines were unable to make specific recommendations about whether black men or men with first degree family members who had prostate cancer should be screened more liberally than the general population, and suggested more research is needed. However other guidelines do address that issue.[2] The American Cancer Society’s guidelines recommend Black men and first-degree relatives of prostate cancer patients have a discussion about screening at 45 years of age.[33] The American College of Physicians’ (ACP) guidelines suggest those who are at high risk such as Black men or have a strong family history may benefit from earlier screening beginning at age 45, while higher risk men (those with two or more first-degree relatives with prostate cancer before age 65) may benefit from being screened at age 40. The ACP guidelines also suggest that screening is not recommended in men who have a life expectancy of less than 10 to 15 years.[34] Similar 10 to 15-year life expectancy guidelines are also in the American Urological Association’s guidelines.[35] The Canadian Task Force on Preventive Health Care has somewhat different guidelines, stating that PSA screening for asymptomatic patients of all ages is not recommended due to concerns of harms outweighing benefits. However, for high-risk patients or men that want screening there should be a discussion of the risks and benefits to facilitate informed decision making.[36] Conclusion The decision to screen asymptomatic individuals for prostate cancer is a complex issue. Due to false positive PSA tests, too much testing may result in iatrogenic harm in patients that have clinically insignificant prostate cancer or no cancer, and doing too little testing might cause some men with aggressive forms of prostate cancer to not be diagnosed in time for adequate treatment. Also problematic is that no one test or combination of tests has 100% sensitivity and specificity. Due to these issues, the most common recommendation is to use shared decision making between the patient and the clinician to determine an individual’s risk/benefit tolerance in choosing prostate cancer screening testing. Due to the slow growing nature of most prostate cancers and autopsy evidence of incidental prostate cancer found in 36% to 51% of men in their 70s, the recommendation is not to do PSA screening in asymptomatic men over the age of 70. In asymptomatic men 55 to 69 years of age, shared decision making is recommended before drawing a PSA to allow men to make an informed decision on how they want to proceed. Asymptomatic Black men and men with close relatives who have had prostate cancer may benefit from screening at younger ages, and some clinical guidelines support this. These men should be informed of their higher risk for prostate cancer when discussing PSA testing. However, further research is needed regarding the best course of action in these high-risk groups. Digital rectal exam may be helpful as a screen for prostate cancer if positive for a mass, but some guidelines recommend not performing it on asymptomatic patients due to a lack of evidence of benefits. There are however, other reasons to do a rectal exam in an annual physical, such as finding rectal carcinoma or occult bleeding from a cancer, diseases where the benefits of early discovery and treatment are clearer than with prostate cancer. MRI fusion guided transrectal biopsies seem to improve accuracy over standard transrectal ultrasonic biopsy. MPMRI screening after a positive PSA has the potential to decrease unnecessary biopsies but this is countered but the fact that MPMRI will both under and over diagnose prostate cancer, and both clinicians and patients should be aware of this. Transperineal biopsies have been found to have much lower infection rates than transrectal biopsies, but the transperineal route typically requires general anesthesia. Screening for prostate cancer with PSA testing is far from a perfect process given the high false positive rate. Follow-up testing and treatment may save lives, but also may cause iatrogenic harms if treating a cancer that may never have become symptomatic in that patient’s lifetime. MPMRI and fusion guided biopsies represent incremental advances over past methods but hopefully, in the future, further improvements in screening and testing modalities will allow better methods to diagnose and treat prostate cancer. Update: Recently, former President Biden was diagnosed with metastatic prostate cancer, and as this is written all the facts of his case are not public at this time.  It brings into focus the issue of testing for PSA in men over 70 years of age and potentially having false positive tests or slow growing cancers which can result in unnecessary testing and invasive treatments, or not testing at all and having a patient die from metastatic disease.  Guidelines, such as not testing for PSA in men over the age of 70, are designed to produce maximal benefits for the most patients, but may not be the best course for everyone.  In addition, it is based on a 10-year life expectancy which may be too short for some men over 70.  Unfortunately, it is not knowable beforehand who will benefit from PSA testing and who ultimately be harmed by PSA testing leading to unnecessary treatments.  One urologist I am acquainted with bases PSA testing of patients over 70 on their baseline medical condition and predicted life expectancy, rather than setting a fixed age limit of 70 years, which seems to be another reasonable approach with some literature support.[37]   INDICATIONS FOR PROSTATE CANCER SCREENING A urologist’s perspective By Arno Housman, MD The controversy regarding whether or not to pursue prostate cancer screening is the direct consequence not of the prevalence, or lethal nature of the disease, but rather our current inability to accurately identify the natural history and aggressiveness of the tumor on an individualized basis. The optimal strategy for management of prostate cancer remains a subject of ongoing debate. This is due to the heterogeneity of the disease, causing it to present and behave differently with each patient. Concern regarding overdiagnosis, and over treatment of men with low-risk tumors must be weighed against the consequences of underdiagnosis and under treatment of high-risk tumors. The controversy does not stop there. Once diagnosed, the urologist must decide whether it is appropriate to “actively observe” a patient or pursue active treatment, and even then, the optimal sequence of treatment remains a subject of continuing debate. This is no less true when contemplating a management strategy for patients found to have metastatic disease at the time of discovery. So, returning to the controversy “to screen or not to screen”: the purpose of screening is to detect disease early enough to not only prevent avoidable mortality from metastatic disease but also morbidity. With the management of prostate cancer this goal includes finding the disease at a stage that allows either cure or at least conversion of the disease from a highly morbid process to a manageable “disease of chronic illness”. Screening with a combination of PSA blood testing and rectal examination has its benefits and drawbacks but appears to be exquisitely sensitive in detecting prostatic abnormalities but not very specific regarding prostate cancer. In some studies, rectal exam is reported to be nearly 30% sensitive overall for detecting prostate cancer and nearly 84% specific for ruling it out if the examination is normal.[5] The prostate exam is essentially free and without any appreciable morbidity. Once the screener has detected a prostatic abnormality it is the responsibility of the urologist to determine whether observation, further blood testing, imaging or biopsy is indicated. Hopefully as new diagnostic techniques and therapeutic nomograms evolve this decision-making process will be less controversial. References [1] National Cancer Institute. Cancer stat facts: prostate cancer. Retrieved from: https://seer.cancer.gov/statfacts [2] Screening for Prostate Cancer. US Preventive Services Task Force Recommendation Statement. May 08, 2018. Retrieved from: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate- cancer-screening [3] Jahn JL, Giovannucci EL, Stampfer MJ. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the prostate-specific antigen-era. Int J Cancer. 2015;137(12):2795-2802. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485977/ [4] Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst. 2009;101(6):374-383. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720697/ [5] Jones, D., Friend, C., Dreher, A. et al. The diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic patients: a systematic review. BMC Fam Pract 19 , 79 (2018). Retrieved from: https://bmcprimcare.biomedcentral.com/articles/10.1186/s12875-018-0765-y#citeas [6] Arsov, C, Albers, P, Herkommer, K, et al. A randomized trial of risk-adapted screening for prostate cancer in young men—Results of the first screening round of the PROBASE trial. Int. J. Cancer. 2022; 150( 11): 1861- 1869. Retrieved from: https://onlinelibrary.wiley.com/doi/10.1002/ijc.33940 [7] Clinical Preventive Service Recommendation Prostate Cancer. AAFP. Copyright 2023. Retrieved from: https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical- recommendations/prostate-cancer.html [8] Screening Tests for Prostate Cancer. American Cancer Society. Last Revised: January 4, 2021. Retrieved from: https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis- staging/tests.html#:~:text=Many%20doctors%20recommend%20a%20prostate,some%20men%20avoid% 20unnecessary%20biopsies [9] Barry MJ. Prostate-Specific–Antigen Testing for Early Diagnosis of Prostate Cancer. NEJM. 344:1373- 1377. May 3, 2001. Retrieved from: https://www.nejm.org/doi/10.1056/NEJM200105033441806?url_ver=Z39.88- 2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed [10] Walz, J., Haese, A., Scattoni, V., Steuber, T., Chun, F.K.H., Briganti, A., Montorsi, F., Graefen, M., Huland, H. and Karakiewicz, P.I. (2008), Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer, 113: 2695-2703. Retrieved from: https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.23885 www.FibonacciMD.app 12 www.FibonacciMD.com [11] Catalona WJ et al. Use of the Percentage of Free Prostate-Specific Antigen to Enhance Differentiation of Prostate Cancer From Benign Prostatic Disease. JAMA, May 20, 1998—Vol 279, No. 19. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/187545 [12] Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow J. Prostate-Specific Antigen–Based Screening for Prostate Cancer: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018;319(18):1914–1931. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/2680554 [13] Schröder FH, Hugosson J, Carlsson S, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2012;62(5):745-752. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22704366/ [14] Hugosson J, Roobol MJ, Månsson M, et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol. 2019;76(1):43-51. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513694/#SD1 [15] Kilpeläinen TP et al. False-positive screening results in the European randomized study of screening for prostate cancer. European Journal of Cancer. Volume 47, Issue 18, 2011, Pages 2698-2705. Retrieved from: https://www.ejcancer.com/article/S0959-8049(11)00493-X/fulltext [16] Rosario D J et al. Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study BMJ 2012; 344 :d7894. https://www.bmj.com/content/344/bmj.d7894 [17] Nam RK, Saskin R, Lee Y, Liu Y, Law C, Klotz LH, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol2010;183:963-8. https://www.auajournals.org/doi/abs/10.1016/j.juro.2009.11.043 [18] Gallina A, Suardi N, Montorsi F, Capitanio U, Jeldres C, Saad F, et al. Mortality at 120 days after prostatic biopsy: a population-based study of 22,175 men. Int J Cancer2008;123:647-52. https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.23559 [19] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668408/ [20] H.U. Ahmed, A. El-Shater Bosaily, L.C. Brown, R. Gabe, R. Kaplan, M.K. Parmar, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study Lancet, 389 (2017), pp. 815-822. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32401-1/fulltext [21] Template Biopsy. Birmingham Prostate Clinic. 2023. Retrieved from: https://www.birminghamprostateclinic.co.uk/prostate/assessments/template-biopsy/ [22] Xiang, J., Yan, H., Li, J. et al. Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: a systematic review and meta-analysis. World J Surg Onc 17, 31 (2019). Retrieved from: https://wjso.biomedcentral.com/articles/10.1186/s12957-019-1573-0#citeas www.FibonacciMD.app 13 www.FibonacciMD.com Serefoglu EC et al. How reliable is 12-core prostate biopsy procedure in the detection of prostate cancer?. Can Urol Assoc J. 2013;7(5-6):E293-E298. Retrieved from: [23] Castellani D et al. Infection Rate after Transperineal Prostate Biopsy with and without Prophylactic Antibiotics: Results from a Systematic Review and Meta-Analysis of Comparative Studies. Journal of Urology. Volume 207. Issue 1, January 2022. Retrieved from: https://www.auajournals.org/eprint/AYIGAYWQKNEHV4J5CGDN/full [24] Grummet JP, Weerakoon M, Huang S, et al. Sepsis and 'superbugs': should we favour the transperineal over the transrectal approach for prostate biopsy?. BJU Int. 2014;114(3):384-388. Retrieved from: https://bjui-journals.onlinelibrary.wiley.com/doi/abs/10.1111/bju.12536 [25] Tests to Diagnose and Stage Prostate Cancer. American Cancer Society. Last Revised: February 21, 2023. Retrieved from: https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/how- diagnosed.html [26] Haider MA et al. Multiparametric Magnetic Resonance Imaging in the Diagnosis of Clinically Significant Prostate Cancer: an Updated Systematic Review. Clinical Oncology. Volume 33, Issue 12, 2021, Pages e599-e612. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0936655521002831 [27] de Rooij M et al. American Journal of Roentgenology 2014 202:2, 343-351. Retrieved from: https://www.ajronline.org/doi/abs/10.2214/AJR.13.11046 [28] Giganti F, Moore C. A critical comparison of techniques for MRI-targeted biopsy of the prostate. Translational Andrology and Urology; Vol 6, No 3 (June 23, 2017). Retrieved from: https://tau.amegroups.com/article/view/14530/html [29] Prince M et al. In-Bore Versus Fusion MRI–Targeted Biopsy of PI-RADS Category 4 and 5 Lesions: A Retrospective Comparative Analysis Using Propensity Score Weighting. American Journal of Roentgenology 2021 217:5, 1123-1130. Retrieved from: https://www.ajronline.org/action/showCitFormats?doi=10.2214%2FAJR.20.25207 [30] Drost FH, Osses DF, Nieboer D, et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019;4(4):CD012663. Published 2019 Apr 25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483565/#CD012663-sec- 0073title [31] Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990- 2013. JAMA. 2015;314(1):80-82. Retrieved from: https://escholarship.org/uc/item/1bh2b3dh [32] Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375(15):1415-1424. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1606220?url_ver=Z39.88- 2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov [32A] Hamdy FC et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. NEJM 388:1547-1558. April 27, 2023. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2214122 www.FibonacciMD.app 14 www.FibonacciMD.com [33] Wolf AMD et al. American Cancer Society Guideline for the Early Detection of Prostate Cancer: Update 2010. CA: A Cancer Journal for Clinicians. Retrieved from: https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.20066 [34] Amir Qaseem, Michael J. Barry, Thomas D. Denberg, et al; for the Clinical Guidelines Committee of the American College of Physicians . Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med.2013;158:761-769. 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Lower Your Exposure to Microplastics Practical steps to reduce plastic particles and chemical leaching from common household sources. How to Reduce Exposure to Microplastics and Chemicals Leaching from Plastics by Stuart M. Caplen, MD   Plastics, made from petrochemicals, are ubiquitous in our society, and there is increasing evidence that exposure to both the chemicals leaching out of plastic products and ingesting plastic microparticles can have adverse health impacts. This article discusses how to reduce exposure to potentially harmful plastics. The generic term “microplastics” is used in this article, but readers should know that that term also includes smaller nanoplastic particles.  Recommended Interventions 1) Reduce drinking fluids from plastic bottles.  Researchers have reported approximately 240,000 micro and nano-particles are found per liter of bottled water.[1]  Another study found microplastics in 93% of 11 brands of globally sourced bottled water.[2]  Consumer Reports found heavy metals and per- and polyfluoroalkyl substances, known as PFAS, had leached into some brands of bottled water.[3]   Use of glass or stainless-steel bottles can decrease microplastic and chemical ingestion from bottled liquids.[4]  2) Filter tap water.  A study of globally sourced tap waters found human-made fiber particles consistent with microplastics in 81% of the samples.[5]  Microplastic particles have been found both in groundwater and in the oceans.  Filtering drinking water has been shown to reduce microplastic levels, but performance can vary greatly between models.  One study reported that water filters which incorporated microfiltration or membrane filtration removed more plastic than those that did not use that technology.[6]  Reverse osmosis water filters may also effectively filter microplastics, but comparison data on home systems are limited.  The performance data sheet from the manufacturer can tell you if a filter has been tested for filtration of microplastics and how well it functions. As an Amazon Associate FibonacciMD earns from qualifying purchases. Enjoy cleaner, safer water with the elegant LifeStraw Home 7-Cup Glass Pitcher , featuring advanced filtration that removes bacteria, parasites, lead, PFAS, and microplastics while looking stunning in any kitchen with its sleek stormy blue silicone base.[ https://amzn.to/3NO1UG2 ] 3) Store food in glass or silicone containers. Store food in glass or silicone containers rather than plastic containers to avoid chemicals leaching into the food, as well as microplastic contamination.[4]  4) Do not microwave food in plastic containers.  There are over 13,000 chemicals used in the manufacture of various plastic products.  Some of these chemicals may leach into food or liquids that are in contact with plastic.[7,8]  Heat can further increase the leaching of chemicals from plastics.  Microwaving foods packed in plastic may increase that process.[8]  Keep in mind that products such as bottled water may be transported in un-air-conditioned trucks or via shipping crates, which can get very hot in the summer or in warm climates, and potentially increase chemical contamination.  As an Amazon Associate FibonacciMD earns from qualifying purchases. The OXO Good Grips 12-Piece Smart Seal Glass Container Set  features a removable silicone seal  that is easy to clean and dry, effectively preventing the moisture and mold buildup  often found in other storage lids. [ https://amzn.to/4matxpp ] 5) Reduce infant exposure to plastics.  A source of ingested microplastics in infants is polyethylene infant milk bottles, which have been found to give off numerous microparticles which may then be ingested.[9]  Warming the milk up in those bottles can also increase the amount of microparticles in the milk.[9]  This source of plastic contamination can be eliminated by using glass bottles and silicone nipples.  Microplastics have been found both in cow’s milk and 75% of samples in one study of human breast milk, so total elimination of microplastic ingestion from milk may not be possible.[10,11] A recent study reported higher amounts of microplastics per gram of stool in infants than adults, indicating that infant exposure may be greater than that for adults.[12]  Teething rings have been found to leach chemicals and microplastics[13,14], suggesting that plastic ones should be avoided.  Plastic toys which infants may put in their mouths can also be a source of ingested microplastics and chemicals.[14] Dust on the floor may contain both plastic fragments, as well as chemicals from polyester carpets and other items made of plastic in the house.  Infants frequently crawl on the floor and can ingest or inhale this dust or carpet fibers.  Consider covering polyester carpets with a natural fabric, such as cotton, when letting an infant crawl on it.  Measuring the number of particulates in the air, and if elevated, using a HEPA filter (high-efficiency particulate air filter) may reduce plastic and other substances in the air that later become dust.  Vacuuming floors frequently with a vacuum cleaner that has a HEPA filter may also help.[15]  6) Plastic cutting trays Plastic cutting trays have been found to add plastic particles to food, as well as to wastewater when washed off.  Consider using wood or silicone cutting boards.[4,16] As an Amazon Associate FibonacciMD earns from qualifying purchases. The KeeCHEE Bamboo Cutting Board is dishwasher safe, hygienic, non-porous surface  that is both easy to sanitize and safe for all food prep. [ https://amzn.to/47tn1nM ] 7) Eat freshly prepared food.  Almost all foods have been found to have microplastics in them.[17,18,19,20,21]  Microplastics in soil can be taken up by plant roots and then incorporated into fruits and vegetables.[17]  Fish and animals may ingest and retain microplastics, which are then eaten by humans.[19]  Plastic tubing used in food processing may increase microplastics found in the food.[19]  While nearly impossible to avoid entirely, freshly prepared food has been found to have fewer chemicals and plastic microparticles from plastic than highly processed or fast foods.[4]   8) When composting, do not add plastic to the waste.  As the plastic breaks down   into  micro- and nanoparticles in the soil, these can enter a plant’s roots and become incorporated into fruits and vegetables.  It has also been suggested that the practice of covering crops with a plastic film to protect them may increase the amount of microplastics in the soil.[8] Comments:  It is nearly impossible in modern societies to avoid ingesting either the chemicals that leach from plastics or microplastics.  They are both currently in the food chain, and evidence has shown that both the chemicals and microplastics which are absorbed into the body can potentially adversely affect human health.  The best one can do is to try to decrease the amount ingested of these substances. For more information on the adverse effects of plastics on human health, click here. For more information on issues with respect to plastic recycling, click here. References  [1] Qian N et al. Rapid single-particle chemical imaging of nanoplastics by SRS microscopy. Proceedings of the National Academy of Sciences. January 8, 2024. Retrieved from: https://www.pnas.org/doi/10.1073/pnas.2300582121 [2] Mason SA, Welch VG, Neratko J. Synthetic Polymer Contamination in Bottled Water. Front Chem. 2018;6:407. Published 2018 Sep 11. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141690/ [3] Felton R. Consumer Reports. September 24, 2020. Retrieved from: https://www.consumerreports.org/water-quality/whats-really-in-your-bottled-water-a5361150329/ [4] Friedman LF. How to Reduce Your Exposure to Plastic in Food (and Everywhere Else) Consumer Reports. January 4, 2024. Retrieved from:  https://www.consumerreports.org/health/food-contaminants/how-to-reduce-exposure-to-plastic-in-food-everywhere-else-a9640874767/ [5] Mary Kosuth, Sherri A. Mason & Elizabeth V. Wattenberg, Anthropogenic contamination of tap water, beer, and sea salt, 13(4) PLoS ONE e0194970 (2018). Retrieved from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194970 [6] Cherian AG et al. Microplastic Removal from Drinking Water Using Point-of-Use Devices. Polymers (Basel). 2023;15(6):1331. Published 2023 Mar 7. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054062/ [7] Chemicals in Plastics - A Technical Report. UN Environment Programme. 03 May 2023. Retrieved from:  https://www.unep.org/resources/report/chemicals-plastics-technical-report [8] Azoulay D et al. Plastic & Health The hidden Costs of a Plastic Planet. Ciel. February 2019. Retrieved from: https://www.ciel.org/wp-content/uploads/2019/02/Plastic-and-Health-The-Hidden-Costs-of-a-Plastic-Planet-February-2019.pdf [9] Li D, Shi Y, Yang L, et al. Microplastic release from the degradation of polypropylene feeding bottles during infant formula preparation. Nat Food. 2020;1(11):746-754. Retrieved from: https://www.tara.tcd.ie/bitstream/handle/2262/94127/NATFOOD-just%20accepted%20edition_110920.pdf;jsessionid=0CE1E8FECBA28FBB0842AABDD1143634?sequence=4 [10] Irédon Adjama I et al. Microplastics in dairy products and human breast milk: Contamination status and greenness analysis of available analytical methods. Journal of Hazardous Materials Letters. Volume 5, 2024. Retrieved from: https://www.sciencedirect.com/science/article/pii/S2666911024000194\ [11] Ragusa A, Notarstefano V, Svelato A, et al. Raman Microspectroscopy Detection and Characterisation of Microplastics in Human Breastmilk. Polymers (Basel). 2022;14(13):2700. Published 2022 Jun 30. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269371/ [12] Zang J al. Occurrence of Polyethylene Terephthalate and Polycarbonate Microplastics in Infant and Adult Feces. Environ. Sci. Technol. Lett. 2021, 8, 11, 989–994. Retrieved from: https://pubs.acs.org/doi/abs/10.1021/acs.estlett.1c00559 [13] Asimakopoulos A et al. Migration of Parabens, Bisphenols, Benzophenone-Type UV Filters, Triclosan, and Triclocarban from Teethers and Its Implications for Infant Exposure. Environmental Science & Technology. Vol 50, Issue 24. 12/20/2016. Retrieved from: https://pubs.acs.org/doi/abs/10.1021/acs.est.6b04128 [14] Mišľanová C et al. An Overview of the Possible Exposure of Infants to Microplastics. Life (Basel). 2024;14(3):371. Published 2024 Mar 12. Retrieved from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10971803/ [15] Loria K and Wroclawski D. The Danger in Your Dust. Consumer Reports. July 3, 2024. Retrieved from: https://www.consumerreports.org/appliances/indoor-air-quality/the-danger-in-your-dust-a2604125005/ [16] Habib RZ, Kindi RA, Salem FA, et al. Microplastic Contamination of Chicken Meat and Fish through Plastic Cutting Boards. Int J Environ Res Public Health. 2022;19(20):13442. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602623/ [17] Azeem I et al. Uptake and Accumulation of Nano/Microplastics in Plants: A Critical Review. Nanomaterials (Basel). 2021;11(11):2935. Published 2021 Nov 2. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618759/ [18] Conti GO et al. Micro- and nano-plastics in edible fruit and vegetables. The first diet risks assessment for the general population. Environmental Research. Volume 187, 2020. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0013935120305703 [19] Milne MH et al. Exposure of U.S. adults to microplastics from commonly consumed proteins. Environmental Pollution. Volume 343, 2024. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0269749123022352?via%3Dihub#fig2 [20] Dessì C et al. Plastics contamination of store-bought rice. Journal of Hazardous Materials. Volume 416, 2021. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0304389421007421 [21] Liebezeit, G., & Liebezeit, E. (2013). Non-pollen particulates in honey and sugar. Food Additives & Contaminants: Part A, 30(12), 2136–2140.Retrieved from: https://www.tandfonline.com/doi/full/10.1080/19440049.2013.843025 initially published 12/23/2024

How the Transfusion Affair Led to the 1668 Châtelet Conspiracy and Controversy Over Early Blood Transfusion Experiments Lamb to Human Blood Transfusion by  Stuart M. Caplen, MD  The 1668 Châtelet conspiracy. More than meets the eye! In 1667, the “ Transfusion Affair ” sparked intense controversy in Paris, France.  The issue involved the transfusion of animal blood into humans as therapy.  One parliamentary lawyer wrote, “There was never anything that divided opinion as much as we presently witness with the transfusions.”   Jean Denis and Paul Emmerez were Parisian physicians, who between June 1667 and July 1668 transfused five seriously ill patients with small amounts of calf, lamb, or goat blood.  Two of the patients died but three survived.  Typically, they inserted a silver or brass tube into the animal’s artery and connected it to a goose quill to infuse the blood into a patient’s vein.  This caused a rift in the French medical establishment, with the majority opposing animal transfusion, and led to a larger societal debate about whether the procedure should be performed at all.   The “Transfusion Affair” began after Antoine Mauroy de Saint-Amant, an ex-valet, was treated for dementia by Denis and Emmerez.  The first two transfusions of lamb’s blood went smoothly.  However, a month or so later, his condition worsened.  His wife, Périne, insisted that Denis perform additional transfusions which led to Monsieur de Saint-Amant’s death.  His wife immediately buried him and no autopsy was performed.   She subsequently filed a lawsuit against Denis, and a trial was held in the Châtelet court.  (The Châtelet was a medieval fortress that later served as a judicial center until the French Revolution.)  In April 1668, the Châtelet court ruled that Denis was not liable for the death, as Monsieur de Saint-Amant’s widow was found guilty of poisoning her husband with arsenic, and three unnamed doctors at the Paris Medical School were accused of  bribing her to bring charges against Denis.  Reportedly, Madame de Saint-Amant had been giving her husband arsenic in his broth, which can cause delirium, tremors, and seizures.  The case was appealed to the Parliament of Paris, where part of the ruling banned doctors and surgeons from “exercising the transfusion of blood under penalty of corporeal (sic)  punishment.”  This restriction lasted over 130 years until the French Revolution.  If you liked this article, you may also enjoy reading The History of Insulin and Type 1 Diabetes.   You may also find these other FibonacciMedicine articles interesting: The History of Nitroglycerin, an Explosive with Medical Benefits The History of Heroin, the “Non-addictive” Substitute for Morphine The History of the Coney Island Incubator Babies The Story of the Most “Kissed” Face in the World “Gentlemen this is no humbug” - The First Use of General Anesthesia in Surgery and the Battle for Recognition that Ensued Benjamin Franklin, Mesmerism, and the First Use of Placebos in Science Penicillin, the Accidental Antibiotic The History of Leeches in Medicine and the Era of the “Leech Mania” The History of Antiseptic Surgery The History of the Electrocardiogram (EKG/ECG) As an Amazon Associate FibonacciMD earns from qualifying purchases. If you want to dive deeper into the "Transfusion Affair" and the shadowy figures behind the Châtelet conspiracy, Blood Work: A Tale of Medicine and Murder in the Scientific Revolution by Holly Tucker provides the definitive, full-length account of the trial and the cutthroat medical rivalries of 17th-century France. [ https://amzn.to/41CY5Xe ] References   Sahlins P. Beast in the Blood Jean Denis and the “Transfusion Affair”.  The Public Domain Review. March 22, 2023. Retrieved from:  https://publicdomainreview.org/essay/beast-in-the-blood-jean-denis-and-the-transfusion-affair/ Tucker H.   Blood Work: A Tale of Medicine and Murder in the Scientific Revolution. W. W. Norton & Company 2012.  Retrieved from: https://www.scribd.com/document/210540650/Blood-Work-Holly-Tucker the book is available on Amazon [ https://amzn.to/41CY5Xe ] Châtelet. Encyclopaedia Britannica. Retrieved from: https://www.britannica.com/topic/Chatelet-building-Paris-France Image- Purmann MG. Grosser und gantz neugewundener Lorbeer-Krantz, oder Wund Artzney ... Zum andern Mahl vermehrt heraus gegeben. 1705. A early blood transfusion from lamb to man. Wikimedia commons attributed to the Wellcome Collection. Retrieved from: https://commons.wikimedia.org/wiki/File:A_early_blood_transfusion_from_lamb_to_man_Wellcome_L0000096.jpg  and https://wellcomecollection.org/works/e6ds4hp5/items

Errors in the delivery of medical care are clearly a significant issue. This article examines key causes of medical errors, shares real-life examples, and explores potential solutions. While healthcare may never be entirely error-free, every healthcare professional has a responsibility to minimize preventable mistakes. General Medicine ✅ Earn Free CME Credit for Reading This Article Eligible for 0.75 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 by Stuart M. Caplen, MD The Institute of Medicine’s landmark report in 1999, "To Err is Human," estimated that there were 44,000 to 98,000 iatrogenic deaths a year in the U.S., making it the sixth leading cause of death.[1,2] A later study in 2016, estimated that there were actually 251,254 deaths per year from medical errors using studies published after the Institute of Medicine’s report, which made medical errors the third largest cause of death in the U.S.[2] A study of errors in a busy emergency department involving 1,935 patients found there were 346 errors in one week. Twenty-two percent of the errors involved diagnostic studies, 16% administrative procedures, 16% pharmacotherapy, 13% documentation, 12% communication, 11% environmental, and 9% other issues. Reported errors occurred in almost every aspect of emergency care and were made by all staff categories of the care team. Seven of the 346 errors, or 2%, caused adverse events for patients. Using the numbers from that study, a 50,000 per year visit emergency department would be expected to have about 8,941 errors and 181 adverse patient events a year.[3] A review of 30,195 records of hospitalized patients in New York State found that approximately 1% of the patients had negligent care with 2.6% of that group receiving permanently disabling injuries and 13.6% dying from the errors in their care. The authors, extrapolating that data to the whole population of New York State, estimated a statewide total of 27,179 injuries, including 877 cases of permanent disability and 6,895 deaths from errors per year. The most common areas of negligence in this study were diagnostic mishaps, noninvasive therapeutic mishaps, errors in management and care that occurred in the emergency department.[4,5] Errors in the delivery of medical care are clearly a significant issue. This article will delve into some of the important causes of medical errors, with some real-life examples of medical errors and possible ways to correct them. Why Are Near Misses Important? There is the Swiss cheese theory of error where serious errors are prevented from causing injury by a series of barriers. Each barrier has unintended weaknesses, or holes like Swiss cheese. When by chance all the holes are perfectly aligned, meaning there were multiple errors or omissions, the error reaches the patient and can cause harm. In a near miss for example, two people can make mistakes while taking care of a patient, but a third person might be the stopgap that prevents patient harm from occurring. All near misses are opportunities for process improvement and should all be investigated to close the holes, perfect the process, and prevent future harm.[6] Swiss Cheese Theory of Error The Example of Wrong Site Surgery In 2004, due to a number of reports of wrong site surgeries, the Joint Commission mandated a universal protocol to be used in all surgical suites.[7] It included a complete pre-procedure verification process, clearly marking the procedure site, and performing a time-out before the procedure where all the team members agree that it is the correct patient, the correct operative site, and the correct procedure is going to be performed.[8] Despite this, between 2007 and 2009, a hospital in Rhode Island performed five wrong-site surgeries, for which it was fined, mandated to install cameras in each operating room, and a state health inspector was assigned to the operating room suite for a least a year.[9] Wrong-site surgery, although significantly reduced by the Joint Commission protocol, still continues. In the year 2021, there were 85 wrong-site surgery events and an additional 28 wrong-patient, wrong-procedure or wrong-implant events in the United States reported to the Joint Commission. Problems found included documents being missing or incomplete, inconsistent use of operative site marking, inadequate patient verification by the team because of rushing or other distractions, ineffective handoff communication, site marks being removed during prep, the time-out being performed without full staff participation, and possibly most important, organizational focus on patient safety was inconsistent, staff was passive or not empowered to speak up, and policy changes were not followed by adequate and consistent staff education.[10] The issue of wrong site surgery represents how hard it is to achieve perfection in medical practice. There is a Joint Commission mandated well-designed protocol in place that potentially could be close to 100% effective in reducing errors but due to organizational deficiencies and individuals not precisely following the protocol, wrong site surgery is still occurring. Had just one person in the affected cases spoken up, the error might not have occurred. Is 99% Error-Free Good Enough? Is 99% error-free good enough? That depends on the process involved, the number of people affected and the state of knowledge. In the U.S., if 99% of airplanes arrived safely, 450 planes would crash every day. At 99.99% airline safety, 4 to 5 airplanes would crash every day and many people would refuse to fly.[11] If midwives and obstetricians in the U.S. safely caught 99% of newborns during delivery, approximately 36,000 babies would be dropped on the floor each year.[12] It is clear that for some procedures 99% error-free is far from acceptable and may in fact represent failure. One of the real challenges and goals of medical care should be to try to be as error-free as possible. There are several models from industry that have been tried with varying levels of success in healthcare. One is six sigma which uses statistical analysis and a management system to try to reduce errors so that 99.99966% of all opportunities are free of defects (which equals 3.4 errors per one million opportunities), or an error rate that is six standard deviations from the mean. Just because an error correcting procedure is working correctly when it is first launched does not mean it will still be the standard practice a few months later. In six sigma one of the major principles is not assuming an error correction process is working after introduction and to recheck it on a regular basis to ensure compliance. In the lean manufacturing process developed at Toyota, everyone who works in the factory is also expected to incorporate quality control as part of their assignments. The workers literally have the ability, called an andon, to stop the assembly line if they find an error that cannot easily be fixed. It is felt it is better and less expensive to fix a problem before manufacturing is completed rather than trying to retroactively fix it after manufacturing has been completed. One hospital that uses lean concepts is Virginia – Mason Hospital in Washington State. One of the processes they instituted was a type of andon which allowed any employee to send an alert whenever there’s an object, person or process that could potentially cause harm to a patient. These alerts could be transmitted in person, by phone or via a website form. A problem they had to overcome was changing the hospital’s culture to one that could examine issues that caused errors without necessarily assigning blame for the error or near miss. They also needed to create a system that the employees could trust would respond in a timely fashion when an alert was activated.[13] Examples of System Failures A nurse was recently convicted of gross neglect and negligent homicide after trying to get Versed (midazolam) from a computerized medication cabinet but instead took out and administered the paralytic agent vecuronium, which caused the patient’s death. The nurse initially tried to withdraw Versed from a cabinet by typing in “VE” without realizing she should have been using its generic name, midazolam. When the cabinet did not dispense Versed, the nurse triggered an override function that unlocked a larger group of medications, then searched for “VE” again. This time, the cabinet offered to dispense vecuronium. Using overrides was common at the hospital, as an upgrade to the hospital’s electronic health records system was causing significant delays using the medication cabinets. The nurse did not recognize the error even though she overlooked or bypassed at least five warnings or pop-ups saying she was withdrawing a paralyzing medication.[14] Additionally, midazolam is a liquid and vecuronium is a powder that needs to be mixed for administration.[15,16] Another case involved a famous actor’s children in which his newborn twins were twice given 1,000 times the intended dosage of heparin, as did one other child. Nurses mistakenly administered heparin with a concentration of 10,000 units per milliliter instead of 10 units per milliliter. A pharmacy technician took the heparin from the pharmacy’s supply without having a second technician verify the drug’s concentration, as was required by hospital policy. When the heparin was delivered to a satellite pharmacy in the pediatrics unit, a different technician there did not verify the concentration, as was required. Finally, the nurses who administered the heparin to the patients violated policy by neglecting to verify that it was the correct medication and dose beforehand. None of the infants were fortunately injured by the mishap, but needed protamine sulfate to reverse the heparin.[17] In a case the author is aware of, a patient came to an emergency department complaining of headache and had a CT scan of the head. The overnight radiologist’s reading of the CT scan noted an abnormality, but he couldn’t actually define it. The emergency department physician did not call the overnight radiologist to get more information and the patient was diagnosed with sinusitis and sent home on oral antibiotics. The next day the hospital radiologist officially read the CT scan abnormality as a brain abscess but did not apparently call anyone about that finding. No one in the ED reviewed this obviously positive report. A few days later the patient returned doing much worse, needed emergency surgery and ended up with permanent severe neurological deficits. The above three cases all reflect total system breakdowns and in two of the cases multiple people did not follow established procedure. There was also ineffective communication in some of the above cases, and no review of a positive finding in one. System breakdowns like these consist of both individual failures as well as institutional ones. Prevention of System Failures An organization should create patient care systems that are as foolproof as possible, ensure adequate staff education and then a critical step is intermittently reviewing the procedure to see that it is in fact in compliance and actually does ensure error reduction or elimination. One of the main keys to successful process improvement is data collection to objectively determine what is occurring with frequent re-evaluation of the process to ensure compliance. Mindfulness is paying attention to what is happening in the moment. A common factor in many of the discussed clinical vignettes is that the practitioner was running on autopilot and not fully paying attention and truly being in the moment. Most people have probably experienced the phenomenon called highway hypnosis of driving while thinking about something else and then suddenly realizing there was no recollection of driving for a few minutes. The same thing can happen while performing repetitive tasks and it is critical while involved in patient care that the practitioner not allow that to happen. As some of these cases demonstrate, just a moment of inattention may be potentially disastrous for the patient and career-ending for the practitioner. One pilot study trained nurses to perform a rapid awareness scan of their body from head to feet and then focus on the sensation of one breath just before preparing medication and again before administering it to help them be fully present for the tasks.[18,19] This is one technique that can be used to improve focus and awareness while at work. Another study gave mindfulness training to nurses and found there was a self-reported decrease in medication errors after the training.[20] Medication errors are common. One study identified 6.5 adverse events related to medication use per 100 inpatient admissions with more than a quarter of these events due to preventable errors.[21,22] In another study of serious medication errors 39% occurred during the ordering stage, 38% during medication administration, and the remaining 23% occurred in about equal numbers during the transcription and dispensing stages.[23] To try to decrease medication errors some organizations have mandated barcode scanning of both the medication and the patient’s wrist band before administration to ensure the correct medication and dose is given to the correct patient. In one study the rate of potential adverse drug events (other than those associated with timing errors) fell from 3.1% without the use of the bar-code to 1.6% with bar-coding. Transcription errors occurred at a rate of 6.1% on units that did not use the bar-code but were completely eliminated on units that did use it. The rate of timing errors in medication administration fell by 27.3% with the use of bar-coding.[21] After the Versed-vecuronium error described previously, some automated medication system manufacturers have switched to requiring inputting five letters for a requested drug rather than just two letters to try to prevent similar errors.[14] With respect to the issue of radiology and laboratory report follow-up , one recommendation that allows each practitioner to do quality control is to keep a list of patients who had labs and radiologic tests and then check to see if they have come back and need action. By doing this, the effectiveness of the system at an institution or office can quickly be ascertained as to how much trust a practitioner should put in the process, or if it needs to be changed. During my career I occasionally found some laboratory and radiologic test reports that never returned, as well as radiologists and laboratory technicians that had not called about a critical result as they were mandated to by protocol. Sometimes a test was not performed and cancelled by the lab for something as simple as the blood in the tube had clotted, or had an insufficient quantity of blood and it was only when I tracked down the test that I found this out, as no result or report ever came back. There were also some occasions when others who were responsible for following up my patients’ results on days I was not working did not do so. Checklists have been used in the aviation industry to ensure safety and are now used extensively in healthcare. Checklists allow complex tasks to be correctly done in the correct order. It basically lays out a procedure in steps so that even inexperienced or temporary staff can perform it, and it may also be helpful in seldomly done or critical tasks. Checklists can also include instructions on what to do if there is a problem. They have been shown to improve compliance with procedures. Checklists additionally provide a record that can be reviewed later on to ensure that the correct procedure was performed.[24] Are Errors Possible With Computerized Systems? While helpful, a computerized system is not a total panacea for preventing errors. The author is aware of an electronic medical record (EMR) that had computerized radiological and laboratory test ordering and reporting where results were supposed to go back to the inbox of the ordering doctor or the site where it was ordered. Unfortunately, some of the laboratories had incorrect data codes for a number of the providers and some lab reports were not ending up in anyone’s inbox. On top of that, when radiology requests had missing information, the EMR was sending the reports to a dead letter type file and they were not necessarily being returned to the practitioners. It was not until these shortcomings were realized as issues that these problems were corrected. In 2016, a computerized EMR cardiovascular risk calculator used by about a third of general practitioners in England, incorrectly calculated the risk to patients. There was concern that thousands of patients may have been incorrectly prescribed or taken off statins as a result of that computer error.[25] A large health care institution reduced wrong-patient orders by 41% by requiring the clinicians to type in the patient’s initials, gender and age when placing an order. A more passive system of the EMR giving an ID-verifying alert needing a single-click confirmation of the patient’s identity only reduced wrong-patient electronic orders by 16%. They were not able to reduce the error rate more than 41% due to providers entering incorrect patients' initials, gender and age when they were on the wrong patient’s data screen without carefully verifying it was the correct patient; essentially an autopilot issue.[26] EMRs can do many things well such as allow for instant access to a patient’s medical history or give notice of a potential adverse drug interaction but as can be seen, using a computer system does not necessarily prevent all errors. To avoid making errors practitioners cannot go on autopilot and cede complete control to the EMR when making clinical decisions. Errors in Diagnostic Interpretation. One potential source of error is in diagnostic testing interpretation. If a test has a 90% sensitivity and comes back negative is the patient truly negative for the condition or is the patient one of the 10% false negative group? Trying to apply population statistics to an individual patient without further information may not be accurate. In the 90% sensitivity example if the clinician decides a negative test alone means the patient does not have the condition, 10% of the time that conclusion will be wrong. This is where the art of medicine comes in, knowing when to get further diagnostic procedures when a test is negative or knowing when to stop testing to avoid unneeded testing and possibly creating more errors with false positive results. Knowing the limitations of each test that is ordered is critical. For example, if a CT scan is ordered to diagnose pulmonary embolism the clinician needs to understand that for a patient with low probability of an embolism, a CT angiogram only has a total positive predictive value of 58%. Positive predictive value (PPV) is the probability that a patient with a positive (abnormal) test result actually has the disease. This varies widely depending on what location of the lung the clot is seen. A main or lobar pulmonary artery location has a 97% PPV, while a subsegmental pulmonary artery location only has a 25% PPV. Conversely, in a patient with a high probability of an embolism, a negative CT angiogram only has a negative predictive value (NPV) for pulmonary embolism of 60%. Simply thinking a positive CT angiogram represents a pulmonary embolism and a negative one rules it out may lead to a number of diagnostic errors.[27] Use of D-dimer testing in low probability patients may be helpful in decision making, with negative testing making the diagnosis highly unlikely. In a high probability patient ordering a CT venogram of the lower extremities in addition to a CT angiogram increases the NPV of testing from 60% to 82%.[27] Provider Cognitive Bias There are over 30 types of cognitive bias that can affect decision making. A review of cognitive bias studies found that 50% to 100% of tested physicians were affected by a least one cognitive bias. The presence of cognitive biases was associated with diagnostic inaccuracies in 36.5% to 77% of presented case-scenarios in those studies. Cognitive biases and personality traits may affect clinical reasoning processes which may lead to errors in the diagnosis, management, or treatment of medical conditions. Evidence from some studies suggest that physicians who exhibit anchoring, information bias, overconfidence, premature closure, representativeness and confirmation bias are more likely to make diagnostic errors.[28] Use of heuristics is common in medicine as it improves efficiency. A heuristic is a mental shortcut that helps the user make decisions and judgments quickly,[20] but may ignore part of available information.[29] Heuristics are used in rule-out protocols, as a guide to diagnosing and treating patients, but can be potentially misleading if the initial diagnostic impression is incorrect. An example might be looking for ST-segment elevation on an EKG as a sign of myocardial infarction which then triggers aspirin administration, activation of the catheterization lab, etc. However, if the ST segment elevation is actually more consistent with pericarditis and not recognized or thought of, a series of unnecessary interventions may take place. Confirmation bias occurs when clinicians selectively accentuate the importance of evidence that supports their beliefs or what they want to believe to be true, while ignoring evidence that serves to not confirm those ideas.[30] A true life example of confirmation bias the author is aware of was a patient who had a seizure and complained of the worst headache of her life. She was admitted to a hospital and despite telling the doctors multiple times she did not drink alcohol was given a discharge diagnosis of alcohol withdrawal seizure and sent home. She returned to a different hospital a few days later with a new severe headache and was diagnosed with a subarachnoid hemorrhage due to an aneurysm. Anchoring bias is closely related to confirmation bias and comes into play when interpreting evidence. It refers to physicians’ practices of prioritizing information and data that support their initial impressions, even when those first impressions are wrong.[31] A true life example of anchoring bias as well as confirmation bias the author is aware of was an intoxicated patient in an emergency department whom the doctors were trying to discharge after he sobered up, but he refused to leave. The patient was complaining of back pain and leg weakness which the doctors shrugged off. They continued to attempt to get him to leave, refusing to admit him to the hospital, but the patient continued to refuse to leave. A fever of 104 degrees F was documented on the chart late at night but was discounted by the physicians because the next day the patient was afebrile. After being in the emergency department almost a day, a new physician re-examined the patient and found the patient had leg weakness, a history of fever and back pain. Within a few hours the patient was in the operating room for his epidural abscess. Framing , also known as the framing effect, occurs when decisions are influenced by the way information is presented. Physicians in one study recommended timelier follow-up for cancer screening when presented with the frequency events such as 2 in 100 patients, rather than as a 2% percent probability of developing cancer. It was also found that data presented as an increase in mortality rate with non-intervention was more likely to influence physicians to make a recommendation for a cancer procedure than the same data presented as a decrease in survival rate .[32] Premature closure is the acceptance of a diagnosis before it has been objectively established and alternative diagnoses have been fully investigated.[33] Representativeness heuristic is where people make judgments about how likely a specific event is based on comparison with an existing mental prototype. While it speeds the diagnostic process it may be based on incomplete information. In one study nurses and student nurses who received historical information not directly related to the patient’s symptoms such as the presence of a job loss or alcohol use, were more likely to dismiss a patient’s heart attack or stroke symptoms in favor of a less serious diagnosis due to the representativeness heuristic.[34] Overconfidence bias is a frequent cause of delayed and missed diagnoses. Confidence is valued over uncertainty in the medical field, and it may be viewed as a weakness and a sign of vulnerability for clinicians to appear unsure. Overconfidence bias seems to be especially dependent on the manner in which the individual gathers evidence to support a belief. Overconfidence bias and confirmation bias are frequently seen together.[35] A trial of rural healthcare workers that investigated the issue of overconfidence bias found that overconfident healthcare workers were 26% less likely to manage patients correctly. Overconfident providers performed 18% fewer history questions and physical examinations than providers who did not overestimate the quality of their medical judgment. The authors of the study concluded that overconfidence led to two undesirable behaviors. The first was that information was gathered less thoroughly, due to overestimation that their intuition was correct. The second was that overconfident providers were less likely to feel the need for assistance in the form of clinical guidelines or advice from peers.[36] Errors from Interruptions, Psychological Issues and Work Safety In a self-reporting study, physicians with symptoms of burnout, fatigue and recent suicidal ideation were more likely to report making an error. In addition, those physicians who worked in facilities with worse work unit safety grades (a reflection of the patient safety practices in a work unit) also reported more errors. The authors suggested that a combination of physician-targeted burnout interventions and unit-targeted patient safety improvement measures were needed in order to provide the most effective error prevention.[37] A study of emergency physicians found they were interrupted from their work flow an average of 11.12 times per hour and found many of the interruptions occurred at the staff station by colleagues which may increase one's cognitive burden and potentially cause mishaps, delays, and unintentional errors. More than half of the interruptions in the patient rooms were considered low priority, which if eliminated, could allow physicians to concentrate solely on immediate patient care.[38] Another study found emergency physicians were interrupted an average of 9.7 times per hour compared with 3.9 times per hour for primary care physicians (PCPs). However, the PCPs spent an average of 11.4 minutes per hour performing simultaneous tasks compared with 6.4 minutes per hour for emergency physicians. Interruptions have been found to be one of the major factors contributing to drug-dispensing errors, and may contribute to physician job stress, fatigue, and sleep deprivation.[39] Conclusions A number of studies have indicated that errors in medicine are unfortunately frequent and have the potential to cause patient harm. This article has looked at only a sampling of possible errors. Individual practitioners can try to be aware of their own biases and not let them influence the care they deliver. They also can ensure protocols designed to reduce error are followed precisely. They can be mindful when practicing and avoid going on autopilot, which is a frequent source or error. This is especially important given the number of interruptions and multitasking clinicians experience daily at work. As practiced in lean manufacturing, each person can become a quality assurance inspector for their organization, and report any near-misses or quality issues that arise. A simple process improvement assessment that can be done by any practitioner is checking to see if radiology and laboratory test reporting is being handled correctly by their facility. While computers can be helpful in some ways to reduce errors, they are not foolproof and orders still need to reviewed carefully to ensure they are correct. Clinicians also need to understand the limitations of their testing, and what the results actually mean. For every medication ordered, drug interactions should be checked, and of course, the patient should be specifically asked about allergies before a medication is given as they may have forgotten to tell someone about a serious allergy during triage or on a previous visit. Organizations should have a culture of excellence and use protocols and technology to assist in error reduction goals. Near misses should all be investigated to help avoid a future error that causes damage. Checklists may be helpful for complex, critically important or infrequently performed tasks where errors are likely, and also may be helpful when less experienced or temporary people are working. A common institutional error is to assume just because a process is in place it is functioning well. Critical error reduction processes should be reviewed on a regularly scheduled basis to see if they are being performed properly or if there has been a falloff in compliance. Employees should be encouraged to inform leadership when potential errors are observed, without fear of retribution and there needs to be a robust education process to ensure quality is maintained. Finally, workplace wellness programs and improving safety in the workplace may help decrease some of the psychological and environmental issues that can lead to errors. “To Err is Human”[40] reflects the reality of the human condition and the practice of health care will never be completely error-free, but each person involved in healthcare should strive each day to reduce the number of avoidable errors to the best of their ability. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References [1] Carver N, Gupta V, Hipskind JE. Medical Error. [Updated 2021 Nov 20]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK430763/ [2] Makary MA, Daniel M. Medical error—the third leading cause of death in the US. The BMJ. BMJ 2016;353:i2139. Retrieved from: https://www.bmj.com/content/353/bmj.i2139 [3] Fordyce J et al. Errors in a busy emergency department. Annals of Emergency Medicine Volume 42, ISSUE 3, P324-333, September 01, 2003. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/12944883/ [4] Brennan TA et al. Incidence of Adverse Events and Negligence in Hospitalized Patients — Results of the Harvard Medical Practice Study I. N Engl J Med 1991; 324:370-376. February 7, 1991. Retrieved from: https://www.nejm.org/doi/10.1056/NEJM199102073240604?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov [5] Leape LL et al. The Nature of Adverse Events in Hospitalized Patients — Results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324:377-384. February 7, 1991. Retrieved from: https://www.nejm.org/doi/10.1056/NEJM199102073240605?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov [6] Perneger TV. The Swiss cheese model of safety incidents: are there holes in the metaphor?. BMC Health Serv Res. 2005;5:71. Published 2005 Nov 9. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1298298/ [7] Universal Protocol for Preventing Wrong Site, Wrong Procedure, Wrong Person Surgery. Patient Safety Network, Agency for Healthcare Research and Quality. April 26, 2006. Retrieved from: https://psnet.ahrq.gov/issue/universal-protocol-preventing-wrong-site-wrong-procedure-wrong-person-surgery [8] The Universal Protocol for Preventing Wrong Site, Wrong Procedure, and Wrong Person Surgery. The Joint Commission. 2022. Retrieved from: https://www.jointcommission.org/-/media/tjc/documents/standards/universal-protocol/up_poster1pdf.pdf [9] Fiore K. Hospital Fined for Wrong-Site Surgery. Medpage Today. November 3, 2009 Retrieved from: https://www.medpagetoday.com/hospitalbasedmedicine/hospitalists/16788 [10] Sentinel Event Data, General Information & 2021 Update. The Joint Commission. Retrieved from: https://www.jointcommission.org/-/media/tjc/documents/resources/patient-safety-topics/sentinel-event/sentinel-event-general-information-and-2021-update.pdf [11] Federal Aviation Authority. Air Traffic By The Numbers. March 18, 2022 Retrieved from: https://www.faa.gov/air_traffic/by_the_numbers/ [12] Births and Natality. CDC. last reviewed: February 16, 2022. Retrieved from: https://www.cdc.gov/nchs/fastats/births.htm [13] McIntyre M. How Can Andons Improve Patient Safety? Virginia Mason Institute. February 17, 2016. Retrieved from: https://www.virginiamasoninstitute.org/how-can-andons-improve-patient-safety/ [14] Kelman B. As a nurse faces prison for a deadly error, her colleagues worry: Could I be next? NPR. March 22, 2022. Retrieved from: https://www.npr.org/sections/health-shots/2022/03/22/1087903348/as-a-nurse-faces-prison-for-a-deadly-error-her-colleagues-worry-could-i-be-next [15] Kelman B. Nurse Convicted of Neglect and Negligent Homicide for Fatal Drug Error. Kaiser Family Foundation. March 25, 2022. Retrieved from: https://khn.org/news/article/radonda-vaught-nurse-drug-error-vanderbilt-guilty-verdict/ [16] Kelman B. In Nurse’s Trial, Investigator Says Hospital Bears ‘Heavy’ Responsibility for Patient Death. Kaiser Family Foundation. March 24, 2022. Retrieved from: https://khn.org/news/article/radonda-vaught-fatal-drug-error-vanderbilt-hospital-responsibility/ [17] Ornstein C. Dennis Quaid files suit over drug mishap. Los Angeles Times. Sept. 16, 2014. Retrieved from: https://www.latimes.com/entertainment/gossip/la-me-quaid5dec05-story.html [18] Durham ML. DNP et al. Reducing Medication Administration Errors in Acute and Critical Care: Multifaceted Pilot Program Targeting RN Awareness and Behaviors. The Journal of Nursing Administration: February 2016 - Volume 46 - Issue 2 - p 75-81. Retrieved from: https://journals.lww.com/jonajournal/Abstract/2016/02000/Reducing_Medication_Administration_Errors_in_Acute.6.aspx [19] Durham ML, Mindfulness for medication safety, Break the cycle of rushing and multitasking. American Nurse Journal. Volume 15, Number 7 pp. 24-26. July 2020. Retrieved from: https://www.myamericannurse.com/wp-content/uploads/2020/06/an7-Mindfulness-622.pdf [20] Daigle S, Talbot F, French DJ. Mindfulness-based stress reduction training yields improvements in well-being and rates of perceived nursing errors among hospital nurses. J Adv Nurs. 2018 Oct;74(10):2427-2430. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/29869350/ [18]Poon EG. Effect of Bar-Code Technology on the Safety of Medication Administration. N Engl J Med 2010; 362:1698-1707. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejmsa0907115 [21] Poon EG. Effect of Bar-Code Technology on the Safety of Medication Administration. N Engl J Med 2010; 362:1698-1707. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejmsa0907115 [22] Bates DW, Cullen DJ, Laird N, et al. Incidence of Adverse Drug Events and Potential Adverse Drug Events: Implications for Prevention. JAMA. 1995;274(1):29–34. [23] Leape LL, Bates DW, Cullen DJ, et al. Systems Analysis of Adverse Drug Events. JAMA. 1995;274(1):35–43. Retrieved from: https://jamanetwork.com/journals/jama/article-abstract/389137 [24] A Gawande. The Checklist Manifesto, How To Get Things Right. Metropolitan Books, Henry Holt and Company LLC. 2009. [25] Iacobucci G. Computer error may have led to incorrect prescribing of statins to thousands of patients BMJ 2016; 353 :i2742. Retrieved from: https://www.bmj.com/content/353/bmj.i2742 [26] Adelman JS et al. Understanding and preventing wrong-patient electronic orders: a randomized controlled trial, Journal of the American Medical Informatics Association, Volume 20, Issue 2, March 2013, Pages 305–310, Retrieved from: https://doi.org/10.1136/amiajnl-2012-001055 [27] Stein et al., Diagnostic Pathways in Acute Pulmonary Embolism: Recommendations of the PIOPED II Investigators, Radiology 2007. Retrieved from: https://pubs.rsna.org/doi/10.1148/radiol.2421060971 [28] Saposnik, G et al. Cognitive biases associated with medical decisions: a systematic review. BMC Med Inform Decis Mak 16, 138 (2016). https://doi.org/10.1186/s12911-016-0377-1 [29] Pines JM. Profiles in Patient Safety: Confirmation Bias in Emergency Medicine. Volume 13, Issue 1, Pages: 1-116. January 2006. Retrieved from: https://onlinelibrary.wiley.com/doi/epdf/10.1197/j.aem.2005.07.028 [30] Marewski JN, Gigerenzer G. Heuristic decision making in medicine. Dialogues Clin Neurosci. 2012;14(1):77-89. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341653/ [31] Doherty TS, Carroll AE. Believing in Overcoming Cognitive Biases. AMA Journal of Ethics. Sept. 2020. Retrieved from: https://journalofethics.ama-assn.org/article/believing-overcoming-cognitive-biases/2020-09 [32] Bui TC, Krieger HA, Blumenthal-Barby JS. Framing Effects on Physicians' Judgment and Decision-Making. Psychol Rep. 2015;117(2):508-522. doi:10.2466/13.PR0.117c20z0. [33] Maurier D, Barnes DK. Premature Closure: Was It Just Syncope? PSNet. November 25, 2020. Retrieved from: https://psnet.ahrq.gov/web-mm/premature-closure-was-it-just-syncope#4 [34] Brannon LA, Carson KL. The representativeness heuristic: influence on nurses’ decision making. Applied Nursing Research, Volume 16, Issue 3, Pages 201-204. 2003. Retrieved from: https://doi.org/10.1016/S0897-1897(03)00043-0. [35] Croskerry P, Norman G., PhD Overconfidence in Clinical Decision Making. The American Journal of Medicine (2008) Vol 121 (5A), S24 –S29. Retrieved from: https://www.amjmed.com/article/S0002-9343(08)00152-6/fulltext [36] Roxanne J et al. Overconfident health workers provide lower quality healthcare, Journal of Economic Psychology, Volume 76. 2020. Retrieved from: https://doi.org/10.1016/j.joep.2019.102213 [37] Tawfik DS, Profit J, Morgenthaler TI, et al. Physician Burnout, Well-being, and Work Unit Safety Grades in Relationship to Reported Medical Errors. Mayo Clin Proc . 2018;93(11):1571-1580. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258067/ [38] Blocker RC et al. Physician, Interrupted: Workflow Interruptions and Patient Care in the Emergency Department, The Journal of Emergency Medicine, Volume 53, Issue 6, 2017,Pages 798-804. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/29079489/ [39] Chisholm CD, Dornfeld AM, Nelson DR, Cordell WH. Work interrupted: a comparison of workplace interruptions in emergency departments and primary care offices. Ann Emerg Med. 2001 Aug;38(2):146-51. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/11468609/ [40] Alexander Pope quote. BrainyQuote.com. Retrieved from: https://www.brainyquote.com/authors/alexander-pope-quotes IMIT takes pride in its work, and the information published on the IMIT Platform is believed to be accurate and reliable. The IMIT Platform is provided strictly for informational purposes, and IMIT recommends that any medical, diagnostic, or other advice be obtained from a medical professional. Read full disclaimer.

A Taste of Spring: The Perfect Blend of Strawberries and Toasted Almonds Celebrate the arrival of spring with this nutritionist-crafted Strawberry Almond Cake. By utilizing Greek yogurt for a protein boost and natural sweetness from fruit, this dessert offers a lighter way to indulge. Dietary Profile:  This recipe is specifically designed to be appropriate for a low-calorie, low carb, lacto-ovo vegetarian dietary regimen , providing a satisfying treat that aligns with your wellness goals without sacrificing flavor. Creative Cooking for the Health-Conscious Gourmet FibonacciRECIPES  | Culinary Medicine    by Mary B Grosvenor, MS, RD and Lori A. Smolin, PhD What better way to welcome the freshness of spring than with strawberries.  This delicious strawberry cake can be made with fresh strawberries, but if they are not yet available in your area, frozen berries work well too. With every bite the crisp, crackly almond top gives way to a soft, custardy center. Ingredients 16 oz fresh or frozen strawberries 2 large eggs 1 1/3 cup flour 1 ¼ tsp baking powder 1 cup + 1 Tbsp sugar  1 stick unsalted butter, softened ½ cup plain, nonfat Greek yogurt  ½ tsp vanilla extract  ¼ tsp almond extract  ¼ cup sliced almonds ¼ tsp salt Mary Recommends As an Amazon Associate FibonacciMD earns from qualifying purchases. Amazon's Happy Belly Sliced Almonds [ https://amzn.to/4rhCVsb ] Caraway Non-Stick Ceramic 9” Circle Pan [ https://amzn.to/47aDPzN ] Instructions  Preheat oven to 350 degrees. Spray a 9-inch round pan with cooking spray and cut parchment paper to cover the bottom of the pan. Slice strawberries. If using frozen, defrost them first and drain off excess liquid before and after slicing. In a medium bowl, mix the flour, baking powder, and salt. Set aside. Combine butter and 1 cup sugar in a large bowl and mix until fluffy, about 5 minutes. Add eggs, one at a time, beating after each egg. Add vanilla and almond extract and mix well. Add reserved flour mixture and yogurt. Blend well, making sure to scrape the sides of bowl. Gently fold in strawberries. Spoon batter into prepared pan and smooth. Top with sliced almonds and the remaining Tbsp of sugar. Bake for 35 minutes, until toothpick inserted 1 inch from edge comes out clean. Cool before removing from pan. Makes 12 small slices Nutrition Information per slice Calories 190, Fat 9g, Saturated fat 5g, Cholesterol 52 mg, Carbohydrate 23g, Fiber 1g, Protein 3g, Sodium 106mg, Potassium 86 mg Editor’s Note: Appropriate for a low-calorie, low carb, lact-ovo vegetarian dietary regimen. If you enjoyed this recipe, you might like to dive deeper into the science behind its star ingredient - strawberries in our " Sweet Science: Unpacking the Health Benefits of Strawberries " more health conscious recipes here

by Stuart M. Caplen, MD Last Updated 12/25/2025 Examining a U.S. hospital bill often reveals a huge difference between what a hospital charges and what insurance companies actually pay the hospital. Hospital charges can be up to 10 times higher than what Medicare will pay,[1] or 10 times more than what the hospital will accept from cash-paying patients for the same service. This is indicative of a significant disconnect between hospital charges and the actual costs of the billed services. This article will examine some of the reasons why these discrepancies in charges versus payments occur. Actual bill for hospital services that was reduced 88% due to insurance company agreement. Reducing Tax Burdens About half of all hospitals in the U.S. are nonprofit, tax-exempt corporations, thereby saving billions of dollars in expenses annually. In 2011, nonprofit status was estimated to be worth approximately $24.6 billion in aggregate to these hospitals.[2] To obtain these tax exemptions, the IRS requires hospitals to provide programs or services, collectively called community benefits, that advance medical or health knowledge, reduce or relieve the burden of government or other community efforts, or improve community health and increase access to healthcare.[3] However, there has been some criticism that many nonprofit hospitals do not contribute enough back to the community to justify their tax-exempt status. One study using Medicare cost reports from nonprofit hospitals found that, on aggregate, they provided less charity care than for-profit hospitals, equaling about 2.3% versus 3.8% of expenses respectively.[4] A review of 1,773 nonprofit hospitals’ IRS filings found that 77% of them spent less for community benefits than they received in tax benefits as nonprofit institutions. The total “fair share” deficit (defined as the amount spent on community benefits minus the value of the tax deduction) for all these hospitals amounted to $14.2 billion in 2020 according to the report.[5] However, the report did not include accounting for Medicaid payment shortfalls, spending on research, or training medical professionals as part of hospitals’ fair share. [6] In 2020, the Government Accountability Office (GAO) reported that in 2016, 30 nonprofit hospitals reported to the IRS that they had offered no community benefits.[7] Loss of nonprofit status can be very expensive for a hospital. For example, in 2015 a medical center in New Jersey lost a lawsuit that determined it was not meeting nonprofit criteria. The judge ruled that in a number of ways the medical center acted like a for-profit institution and subsequently lost its property tax exemption. The medical center agreed to pay the city in which it was located $15.5 million in back taxes and penalties, as well as paying taxes on 24% of its property for the next 10 years.[8] In the past, hospitals could increase their reported community benefits simply by raising prices, which in turn led to greater reported losses for patients receiving financial assistance. The 2010 Patient Protection and Affordable Care Act closed that accounting loophole by requiring tax-exempt hospitals to not charge individuals eligible for financial assistance more for medical services than the negotiated rates they accept from insured patients.[7,10] However, hospitals in many states consider the difference between billed services and Medicaid reimbursement, known as the Medicaid shortfall, to be part of their community benefits equation.[6,11,12] Higher hospital charges increase the calculated community benefit from the Medicaid shortfall, with the most expensive hospitals tending to show the greatest paper losses from treating Medicaid patients.[12] It has been reported that close to 45% of community benefits claimed by nonprofit hospitals are from the Medicaid shortfall.[11,12] For-profit hospitals can also claim tax deductions for losses from uncompensated care. Again, the higher the charges the larger the tax deduction.[2] These reasons alone could explain why hospital charges are so much higher than their costs, but some hospitals have pursued a different strategy that can also lead to increased charges. Out-of-Network Hospitals In 2011, a New Jersey hospital was reported to be the most expensive hospital in the country.[13] The hospital went out-of-network with every private insurance company. It then billed those insurance companies at extremely high rates for any patients who were brought to their emergency department or admitted as an emergency. They were able to do this because New Jersey regulations mandated that insurance companies pay whatever an out-of-network hospital billed them for emergency patient visits. The result was that, instead of operating at a loss, the hospital made a profit of $17 million within two years of instituting the policy.[14] Eventually the largest insurer in the state and the hospital came to an agreement on pricing,[15] although some years later the entire situation recurred until another agreement was reached.[16] Another large for-profit healthcare chain also has been reported to use this type of model to increase revenues.[17] Price Transparency National regulations now require hospitals to make their prices public in an attempt to increase hospital pricing transparency and allow the public to compare costs between different hospitals. In a limited survey of three hospital websites, price schedules were examined by this author. In one New York City hospital the billed price and the cash price were exactly the same. However, different insurance companies’ payments to the hospital for the same procedure or service varied significantly. In contrast, a suburban New Jersey community hospital’s billed prices for similar services were higher than the first hospital, but the cash payment prices were only 10% of the billed prices, thereby making it less expensive for a cash-paying patient. A large tertiary New York City medical center’s pricing portal was not functioning correctly, but there was a large Microsoft Excel file that could be downloaded. In that file, cash payer prices for services at this medical center were about 19% of billed prices. The medical center’s payments from each insurance company for specific services again varied widely between insurance companies. This very limited survey revealed that for uninsured or cash paying patients, hospitals vary from charging full price to offering variable discounts off the billed price. Despite these national requirements an August 2022 investigative report revealed that only 16% of hospitals were in compliance with the price transparency regulation. A repeat report in July of 2023 found a compliance rate of 36%.[18] A different survey found that 64% of Americans have never checked prices for a healthcare service.[19] Summary Hospital charges appear to have little or no relation to actual costs or insurance payments. The high charges appear to be at least partially due to how community benefits and/or tax deductions are calculated for nonprofits and for-profit hospitals respectively. As compared to commercial insurance companies, Medicaid and Medicare reimbursements for services are fixed and not negotiable by the hospital. The negotiations between hospitals and insurance companies result in wide variations in payments for services to each hospital. It also results in differing insurance payment amounts to different hospitals for the same services depending on each hospital’s, or medical center’s negotiating strength and geographic location. Some hospitals and hospital chains have gone out-of-network with all private insurance companies and then raised their charges to extremely high levels to take advantage of state regulations requiring full reimbursement for emergency visits and admissions for insured out-of-network patients. There appears to be a significant amount of gaming of the current system by hospitals and insurance companies. There may also be some cost-shifting by hospitals from insured and cash paying patients to cover shortfalls in Medicaid and Medicare reimbursement rates which may be lower than actual costs.[20] (Though not discussed, drug company and pharmacy benefit managers’ policies and pricing also play a role in hospital charges.) The result of the current health care environment is that each stakeholder is trying to maximize revenue and/or decrease expenditures. This results in artificially elevated hospital charges that have no relationship to actual costs to improve a hospital’s negotiating position with insurance companies, aid in tax reduction strategies, and possibly increase revenues from cash payers. Price transparency seems like a good idea, but the pricing system used by different institutions found in my limited survey does not appear to be standardized in any way. Hospitals appear to independently calculate charges, cash payer prices and what is accepted as payment from commercial insurance companies. Not all hospital services were listed on some of the user-friendly hospital price transparency web sites I visited, and using a large Microsoft Excel file to try to find a specific procedure may be difficult for many patients. In addition, it appears that many hospitals are not in compliance with price transparency regulations.[18] As long as the current system remains in place it seems that clarity of actual hospital pricing and a reasonable correlation of billed hospital charges to actual costs will likely not occur. ________________________________________________________________________________________________________ You may also find these other FibonacciMedicine articles interesting: Communication Issues in Healthcare Solving the Difficult Problem of Medical Errors Private Equity in Healthcare Potential Bias in the Medical Literature ________________________________________________________________________________________________________ References [1] Washburn L. Archive: Hospitals' new bottom line. NorthJersey.com. March 20, 2019. Originally ran in The Record on Aug. 24, 2014. Retrieved from: https://www.northjersey.com/story/archive/2019/03/20/archive-hospitals-new-bottom-line/3228347002/ [2] Zaretsky R. Tax-Exempt Hospitals and Charity Care: Should Those Hospitals Do More? Tax Policy Center. July 7, 2021. Retrieved from: https://www.taxpolicycenter.org/taxvox/tax-exempt-hospitals-and-charity-care-should-those-hospitals-do-more [3] About Community Benefit. The Catholic Health Association of the United States. Retrieved from: https://www.chausa.org/communitybenefit/resources/defining-community-benefit [4] Bai G et al. Analysis Suggests Government And Nonprofit Hospitals’ Charity Care Is Not Aligned With Their Favorable Tax Treatment. Health Affairs Vol. 40, No. 4. April 2021. Retrieved from: https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2020.01627?journalCode=hlthaff [5] Lown Institute Hospitals Index. April 11, 2023. Retrieved from: https://lownhospitalsindex.org/2023-fair-share-spending/ [6] Miller A, Hawryluk M. States Consider Redefining Charity as Tax-Exempt Hospitals Thrive. Governing. July 17, 2023. Retrieved from: https://www.governing.com/finance/states-consider-redefining-charity-as-tax-exempt-hospitals-thrive [7] IRS Oversight of Hospitals’ Tax-Exempt Status. U.S. Government Accountability Office. Apr 26, 2023. Retrieved from: https://www.gao.gov/products/gao-23-106777 [8] Tax Court Rules Against Hospital in Morristown Property Tax Case; Legislative Action. NJ Center for Nonprofits. Updated September 9, 2021. Retrieved from: https://njnonprofits.org/propertytax_morristownmedical/ [9] Darragh T. Morristown hospital loses property tax court case; judge says facility does not meet nonprofit status. NJ.com. Jun. 26, 2015. Retrieved from: https://www.nj.com/morris/2015/06/morristown_medical_center_loses_tax_case_raising_f.html [10] Levinson Z, Hulver S, Neuman T. Hospital Charity Care: How It Works and Why It Matters. Health costs. Nov 03, 2022. Retrieved from: https://www.kff.org/health-costs/issue-brief/hospital-charity-care-how-it-works-and-why-it-matters/ [11] Garber J. Are nonprofit hospitals serving their fair share of Medicaid patients? Lown Institute. March 5, 2022. Retrieved from: https://lowninstitute .org/are-nonprofit-hospitals-serving-their-fair-share-of-medicaid-patients/ [12] Wen G, Zare H, Eisenberg MD, Anderson G. Association between non-profit hospital community benefit spending and health outcomes. Health Serv Res. 2023;58(1):107-115. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9836951/ [131] Creswell C, Meier B, Craven McGinty, J. New Jersey Hospital Has Highest Billing Rates in the Nation. The New York Times. May 16, 2013. Retrieved from: https://www.nytimes.com/2013/05/17/business/bayonne-medical-center-has-highest-us-billing-rates.html [14] Washburn L. Archive: Hospitals' new bottom line. NorthJersey.com. March 20,2019. Retrieved from: https://www.northjersey.com/story/archive/2019/03/20/archive-hospitals-new-bottom-line/3228347002/ [15] Bayonne Medical Center Announces Agreement with Horizon Blue Cross Blue Shield. Fierce healthcare. September 16, 2011. Retrieved from: https://www.fiercehealthcare.com/payer/bayonne-medical-center-announces-agreement-horizon-blue-cross-blue-shield [16] McDonald CW. CarePoint, Horizon settle $76 million legal fight with in-network deal. NJ.com. Aug. 30, 2017. Retrieved from: https://www.nj.com/hudson/2017/08/carepoint_inks_in-network_agreement_with_states_la.html [17] Hiltzik M. Feds say Prime Healthcare has figured out how to make money from hospitals — through fraud. Los Angels Times. July 15, 2016. Retrieved from: https://www.latimes.com/business/hiltzik/la-fi-hiltzik-prime-feds-20160717-snap-story.html [18] Fifth Semi-Annual Hospital Price Transparency Compliance Report’. Patient Right Advocate.Org. July 2023 Retrieved from: https://static1.squarespace.com/static/60065b8fc8cd610112ab89a7/t/64beb5900a0c5603529e96a8/1690219961931/July+20+2023+PRA+Hospital+Price+Transparency+Compliance+Report+2.pdf [19] Gordon D. 64% Of Consumers Have Never Tried To Find Healthcare Prices, New Survey Shows. Forbes. Oct 11, 2022. Retrieved from: https://www.forbes.com/sites/debgordon/2022/10/11/64-of-consumers-have-never-tried-to-find-healthcare-prices-new-survey-shows/?sh=6b355e0467d5 [20] AMERICAN HOSPITAL ASSOCIATION UNDERPAYMENT BY MEDICARE AND MEDICAID FACT SHEET. American Hospital Association. February 2022. Retrieved from: https://www.aha.org/system/files/media/file/2020/01/2020-Medicare-Medicaid-Underpayment-Fact-Sheet.pdf

The Cabbage Soup Diet: A 7-Day Rapid Weight Loss Plan The Cabbage Soup Diet , sometimes referred to as the Mayo Clinic Diet  (although there is no association with the Mayo Clinic), is a short-term 7-day diet plan designed for rapid weight loss . Culinary Medicine by Stefanie Schwartz, MS, RD, CDN This 7-day cabbage soup diet is an approach designed for short-term results, often used to jumpstart a shift in eating habits. What Is the Cabbage Soup Diet? The plan centers around consuming large quantities of cabbage soup , which contains approximately 45 calories per cup . Dieters are encouraged to eat as much soup as desired throughout the day , while also following a specific food schedule for each of the seven days (see plan below). Cabbage Soup Diet Recipe There are several variations of the cabbage soup recipe, but a common version includes the following ingredients: Ingredients 1–2 garlic cloves, minced 2 onions 2 green peppers 1–2 cans tomatoes 3 carrots 1 container mushrooms 1 bunch celery ½ head cabbage cut into bite size pieces 48 oz low-sodium V8 (optional) Water to fill pot Instructions Clean and chop all vegetables into bite-size pieces. Add vegetables to an 8-quart pot . Pour in the low-sodium V8 (optional)  and add water to fill the pot. Cover and bring to a boil. Reduce heat and simmer for about 2 hours , or until vegetables are tender. Mary Recommends As an Amazon Associate FibonacciMD earns from qualifying purchases. Perfect for preparing cabbage soup, the 23-in-1 Versatile Vegetable Chopper  quickly slices, dices, and shreds vegetables with ultra-sharp stainless steel blades. [ https://amzn.to/4sFgJcu ] The 7-Day Cabbage Soup Diet Plan Persons following this diet must be sure to ingest as much soup as possible each day , since it affords just 45 calories/cup. Along with eating the soup, patients should follow this diet strictly: Day 1: Eat only fruit (no bananas). Day 2: Eat only green leafy vegetables. Day 3: Eat fruits (no bananas) and non-starchy vegetables. Day 4: Eat bananas, milk, and yogurt. Day 5: Eat tomatoes and beef, chicken, turkey, or fish. Day 6: Eat beef and green leafy vegetables. Day 7: Eat brown rice, fruit juices, and green leafy vegetables. Important Considerations While on the 7-Day Diet Hydration:  Drink plenty of water throughout the week. Short-Term Only:  This plan is not intended for use beyond 7 days due to its restrictive nature. Listen to Your Body:  Side effects like fatigue or lightheadedness can occur. It is recommended to avoid strenuous exercise during this week. Consultation:  If you have any underlying health conditions, it is best to speak with a healthcare provider before beginning a calorie-restricted plan like this. Potential Side Effects and Nutritional Concerns While the 7-day cabbage soup diet  may lead to quick weight loss, it is not nutritionally balanced. Common adverse reactions may include: Weakness Fatigue Difficulty concentrating Because the plan limits carbohydrates, protein, and total calories , it lacks the nutritional balance needed for long-term health. Patients are also advised not to exercise during the seven-day period , as calorie intake may be too low to safely support physical activity. Additionally, some individuals may be sensitive to cruciferous vegetables like cabbage , which can cause significant flatulence or digestive discomfort . Integrative Medicine Perspective From an integrative medicine perspective , the diet drastically reduces calories and is low in fat, complex carbohydrates, and essential nutrients. Most of the weight loss that occurs during this program is due to water loss , along with some fat and possibly muscle mass. Because of these limitations, it is intended only as a short-term weight loss strategy , not a sustainable lifestyle plan. The Cabbage Soup Diet does not promote a sustainable, long-term healthy lifestyle . Individuals with existing medical conditions or comorbidities  should consult their physician before beginning any rapid weight loss program to ensure safety. Read this article:  The Year of the Cabbage  from FibonacciMD explores the vegetable’s rich history, gut-health benefits, and why cabbage has become one of 2026’s biggest culinary medicine trends. Fun Fact:  Brussels sprouts are actually miniature members of the cabbage family! Learn more in our: "Brussels Sprouts: From Dreaded to Delectable " . Cabbage is one of the low-potassium food to add to your diet if you have chronic Hyperkalemia - read more in "Elevated Potassium - Hyperkalemia"