Dry January has evolved into a year-round movement as growing evidence shows that reducing—or eliminating—alcohol can lead to lasting improvements in physical and mental health. by Mary B Grosvenor, MS, RD  and Lori A Smolin, PhD   Dry January – pledging to abstain from drinking alcohol for the month of January – is a popular New Year's resolution. This challenge, which began in the United Kingdom in 2012, encourages participants to refrain from alcohol for the 31 days of January in order to reset their drinking habits.[1] It began as a public health initiative but is now a popular personal challenge taken up by millions of Americans.[2] However, in light of the World Health Organization’s Statement that no amount of alcohol is safe, many people are extending the goal of reducing alcohol consumption to beyond January and turning to non-alcoholic versions of traditional beers, wines, and spirits.[3] Alcoholic Beverages Alcoholic beverages include beer, wine, and distilled spirits, as well as beverages made with these. Chemically any molecule that contains an –OH group attached to a carbon atom is an alcohol, but ethanol is the type of alcohol we consume in alcoholic beverages. It is produced by fermentation, a process whereby microorganisms convert the sugars in fruits, vegetables, and grains to ethanol. Alcohol has been used for thousands of years as a beverage as well as in medicine and religious ceremonies; there is evidence that beer was brewed by civilizations in Mesopotamia starting around 4000 BCE.[4] Today we still consume alcoholic beverages at social gatherings, celebrations, and ceremonies.  How Alcohol Consumption Impacts Health When consumed, alcohol is rapidly absorbed into the blood stream and distributed to all parts of the body. How alcohol affects health depends on the amount and pattern of drinking. Alcohol is a depressant so in the short term, low to moderate alcohol consumption has a relaxing effect and reduces inhibitions. But as the level of intake increases, alcohol can impair coordination, increasing the risk of injury from falls and drowning. It also affects judgment, leading to high-risk behaviors such as violence, driving while intoxicated, and having unprotected sex. Excessive intake over a short period of time can cause alcohol poisoning, which can disrupt breathing and heart function and lead to coma and death.[5] In the long term, alcohol consumption contributes to high blood pressure, heart disease, liver cirrhosis, pancreatitis, and mental health disorders such as depression and anxiety. Even relatively low levels of intake are now linked to increased risk for cancers, including those of the breast, liver, colon, mouth, throat, and esophagus.[5] Long-term use also increases the risk of developing Alcohol Use Disorder, which is characterized by an inability to stop or control alcohol use despite adverse social, occupational, or health consequences. Alcohol Use Disorder affects the psychiatric and physical health of millions of Americans. In light of all these potential health impacts, recent research suggests that less alcohol is better than more, and no level of alcohol intake is risk-free. [6,7,8]   Benefits of Reducing Alcohol Consumption Growing concern about the health consequences of alcohol, even at moderate levels, is fueling a reduction in alcohol intake. Currently about 54% of American adults say they drink alcohol, the lowest rate since tracking alcohol intake began in 1939.[9] A majority of U.S. adults now believe that moderate drinking is harmful to health. Younger adults are drinking less and are more likely to abstain. [10] While avoiding alcohol is best, even just participating in Dry January provides health benefits that last way beyond January. Eliminating alcohol for just 31 days can result in improved sleep, mood, diet, and energy levels, and contribute to weight loss, and reductions in liver fat and blood sugar levels.  Research indicates that those who participate in Dry January often continue to drink less alcohol even after the month ends. This sustained moderation can lead to lasting changes in drinking habits and overall health, including improved weight control and mental health and a reduced risk of heart disease, liver disease, and several cancers.[11] Even moderate reduction in alcohol intake, called Damp January, has been shown to have health benefits.  Keys to Reducing Alcohol Intake Experts suggest that the success rate of reducing alcohol intake can be improved by setting clear goals such as completely eliminating alcohol or limiting intake to a specific number of drinks per week. Chances of success are also improved by enlisting support from friends and support groups, either online or in person. Having alcohol alternatives available can also improve success rates. Currently, non-alcoholic beer, wine, and distilled spirits, such as gin and whiskey, are readily available and recipes for mocktails made from these abound on the internet. The consumption of these products in the U.S. grew by 20 percent in 2023 and this high growth rate is expected to continue through 2028.[12] So, ring in a healthier New Year with a traditional non-alcoholic beverage or choose a mocktail made with specialty alcohol alternative. You might be interested in checking out this mocktail recipe by Mary B Grosvenor, MS, RD and  Lori A Smolin, PhD  Mary Recommends Looking to extend Dry January—or go alcohol-free all year? Check out these mocktail recipe books. As an Amazon Associate FibonacciMD earns from qualifying purchases. The Art of Mixology Mocktails recipe book delivers creative, alcohol-free drinks—from sparkling mocktails to fruit-forward blends—perfect for Dry January and beyond. [ https://amzn.to/4qiyaim ] Mocktail Party : Plant-Based, Non-Alcoholic Mocktail Recipes for Every Occasion by Diana Licalzi, Kerry Benson, et al. [ https://amzn.to/455j7jF ] Mocktail Hour : 70 Sips for Anytime Delights and Hangover-Free Nights by Callie Gullickson [ https://amzn.to/4pEWrhw ] References [1] Sober serious: alcohol-free drinks go mainstream Alcohol-free Drinks - Sober Serious - I by IMD - America. IMD business school for management and leadership courses. Published February 3, 2025. https://www.imd.org/ibyimd/2025-trends/sober-serious-alcohol-free-drinks-go-mainstream/ [2] Dry January: Giving up alcohol can mean better sleep, weight loss and more energy. news.  Published January 4, 2023. https://health.ucdavis.edu/news/headlines/dry-january-giving-up-alcohol-can-mean-better-sleep-weight-loss-and-more-energy/2023/01 [3] World Health Organization. No level of alcohol consumption is safe for our health. World Health Organization. Published January 4, 2023. ` ‌ [4] Hardy J. The Birth of Booze: Who Invented Alcohol and How It Shaped History? | History Cooperative. History Cooperative. Published December 25, 2023. https://historycooperative.org/who-invented-alcohol/ ‌ [5] CDC. Alcohol Use and Your Health. Alcohol Use. Published June 11, 2024. https://www.cdc.gov/alcohol/about-alcohol-use/index.html ‌ [6] The Health Risks of Drinking Alcohol | Johns Hopkins Bloomberg School of Public Health. Johns Hopkins Bloomberg School of Public Health. Published November 18, 2025. https://publichealth.jhu.edu/2025/the-health-risks-of-drinking-alcohol ‌ [7] World Health Organization. No level of alcohol consumption is safe for our health. World Health Organization. Published January 4, 2023. https://www.who.int/europe/news/item/04-01-2023-no-level-of-alcohol-consumption-is-safe-for-our-health ‌ [8] Anderson BO, Berdzuli N, Ilbawi A, et al. Health and cancer risks associated with low levels of alcohol consumption. The Lancet Public Health. 2023;8(1):e6-e7. doi: https://doi.org/10.1016/s2468-2667(22)00317-6 ‌ [9] Saad L. U.S. Drinking Rate at New Low as Alcohol Concerns Surge. Gallup.com . Published August 13, 2025. https://news.gallup.com/poll/693362/drinking-rate-new-low-alcohol-concerns-surge.aspx ‌ [10] Sanders L. Record number of Americans see moderate drinking as harmful: poll. AP News. Published August 13, 2025. https://apnews.com/article/drinking-alcohol-beer-wine-liquor-poll-health-091aa28c3375d30d728d48c628a9023a ‌ [11] O’Connor R. Dry January: What Happens to Your Body After One Month Without Alcohol. Newsweek. Published December 6, 2025. Accessed December 29, 2025. https://www.newsweek.com/dry-january-what-happens-to-your-body-after-one-month-without-alcohol-11160907 ‌ [12] Escoffier. 2025 Alcohol and Beverage Trends: Key Statistics on What’s Pouring in Bars and Homes. Escoffier. Published January 24, 2025. https://www.escoffier.edu/blog/world-food-drink/alcohol-and-beverage-trends/

What Recent Testing Reveals About Lead in Protein Powders and Consumer Safety Culinary Medicine The global market for protein powder supplements is currently estimated at $30 billion a year.  A balanced diet generally provides enough protein, but protein supplements have become very popular, promoted for muscle health.   Consumer Reports , in October 2025, analyzed 23 powders and ready-to-drink shakes and found that two-thirds of them contained elevated levels of lead. One contained 16 times what Consumer Reports  considered the safe daily limit for lead ingestion, while others were considered safe for daily consumption.  The lead levels in plant-based products averaged nine times higher than those made with dairy proteins like whey, and twice as high as those made with beef proteins. All the plant-based products tested were made from pea protein, which is used because of its flavor and low allergenic potential.  Consumer Reports  did not investigate where the contamination occurred, whether it was in the peas or during the manufacturing process.  Lead occurs naturally in water and soil, but it can also be introduced through industrial contamination.   As an Amazon Associate FibonacciMD earns from qualifying purchases. The Brondell Coral UC300 under sink water filtration system reduces over 99% of lead, PFAS, mercury, and other contaminants. [ https://amzn.to/49y7yUD ] The Ninja Fit Compact Personal Blender quickly blends protein powder, fruit, and frozen ingredients directly into portable 16-oz. cups. [ https://amzn.to/3N28Tdx ] Brita Water Pitcher removes 99% of Lead, Chlorine (taste and odor), Cadmium, Mercury, Benzene, Asbestos, and more. [ https://amzn.to/3KVncAd ] Consumer Reports  stated that many of the protein powders were safe to consume occasionally, and even those with the highest lead levels were far below the concentration needed to cause immediate harm.  However, chronic use of some of them may lead to an unhealthy increase in lead levels. Estimates from the FDA, along with other data, suggest that dietary lead intake for the average American adult ranges from 1.7 to 5.3 micrograms per day.  The protein powder tested by Consumer Reports  with the highest lead content contained 7.7 micrograms of lead per serving, adding to the baseline lead intake.  Three products also exceeded Consumer Reports ’ level of concern for cadmium and inorganic arsenic, both of which have been classified as possible carcinogens. Chronic lead toxicity can cause a myriad of symptoms, including: Nausea and abdominal pain Anemia Numbness and tingling in the extremities, memory loss, slurred speech, headache Mood disorders and insomnia  Decreased sperm count and increased risk of miscarriage    High blood pressure  Kidney impairment  In children: permanent intellectual disabilities and behavioral disorders While no amount of lead ingestion is truly considered safe, a potential criticism of the report is that the maximum safe level of lead exposure used by Consumer Reports  was based on the California standard of a maximum lead ingestion of 0.5 micrograms per day to prevent reproductive toxicity.  This is much lower than current federal guidelines, and the FDA has issued “interim reference levels” for a maximum lead ingestion of 2.2 micrograms for infants and 8.8 micrograms per day for pregnant women.  The California standard for maximum daily lead ingestion, which poses no significant risk of developing cancer, is 15 micrograms per day.  If you use protein supplements, it is recommended that you read the Consumer Reports article  to determine whether the product you are using is considered safe.  There are also third-party testers that award certification seals, allowing consumers to check which food and supplement products were tested and which problematic substances were tested for.  Some of those include:  The Clean Label Project   USP (U.S. Pharmacopeia)    NSF Certified for Sport Protein powders can be convenient, but informed choices matter. Reviewing test results and choosing third-party–certified products can help reduce exposure to lead in protein powders. You may find these other articles interesting about toxins in the food and environment: The Effects of Plastics on Human Health How Much Artificial Dye Is in Food? Eating Brown Rice Found to Potentially Exceed Safe Levels of Arsenic for Infants Potentially Toxic Trace Metals Found in Tampons Herbicide Found in Blood and Semen in Infertility Clinic Study References Protein Supplements Market Size, Share & Industry Analysis. Fortune Business Insights. Last Updated: December 01, 2025. Retrieved from:  https://www.fortunebusinessinsights.com/protein-supplements-market-106511 Martineau P. Protein Powders and Shakes Contain High Levels of Lead. Consumers Reports. October 14, 2025·Updated October 22, 2025. Retrieved from:  https://www.consumerreports.org/lead/protein-powders-and-shakes-contain-high-levels-of-lead-a4206364640/ Gavelek A et al. Lead exposures in older children (males and females 7-17 years), women of childbearing age (females 16-49 years) and adults (males and females 18+ years): FDA total diet study 2014-16. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2020;37(1):104-109. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/31647750/ Lead Poisoning. WHO. 27 September 2024. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/lead-poisoning-and-health Adult Lead Poisoning. Florida Health. Last Reviewed Apr 8, 2025. Retrieved from: https://www.floridahealth.gov/environmental-health/lead-poisoning/adults.html Proposition 65 No Significant Risk Levels (NSRLs) and Maximum Allowable Dose Levels (MADLs). State of California Office of Environmental Health Hazard Assessment. October 27, 2023. Retrieved from: https://oehha.ca.gov/proposition-65/general-info/proposition-65-no-significant-risk-levels-nsrls-and-maximum-allowable-dose-levels-madls

The Ether Dome and the Dawn of Anesthesia A quick dive into the history of anesthesia with a look at the Ether Dome and the first public demonstration of surgical anesthesia. Learn about the key players, the debates surrounding the discovery, and the lasting legacy of this medical milestone. Medical Trivia by Stuart M. Caplen, MD   updated 11/29/2025 Photo of the first surgical use of ether in the Ether Dome - 1846 On October 16, 1846, in Massachusetts General Hospital’s (MGH) surgical amphitheater, now known as the Ether Dome, the first recognized surgery using general anesthesia was performed.  In 1844, Hartford, Connecticut, dentist Horace Wells became aware of the painkilling effects of nitrous oxide.  He attended an event where volunteers inhaled the gas and noticed that one of them injured his leg without realizing it.  He started using nitrous oxide in his practice with some success, and in 1845, he attempted to demonstrate it in a dental extraction at MGH. However, the demonstration went badly, and he was ridiculed.  After that, he continued to use nitrous oxide successfully in his dental practice.  His partner, William T.G. Morton, who later practiced in Boston, learned about ether from Charles T. Jackson, a professor of chemistry at Harvard.  Morton and Jackson used ether successfully for a dental extraction, and then Morton persuaded MGH co-founder and surgeon John Collins Warren to allow him to try his technique on a surgical patient.  On October 16, 1846, a patient who had a vascular neck tumor was operated on with ether anesthesia.  Morton used a newly developed apparatus he later called the “Morton Etherizer” to administer the ether while Warren did the surgery.  The procedure was successful, and the patient announced that he had felt a scratching sensation but no pain.  Warren then turned to the observers in the amphitheater and proclaimed, “Gentlemen, this is no humbug.” Wells, Jackson, and Morton all claimed to have been the first to discover anesthesia.   There was a battle in the court of public opinion about who was the discoverer of ether as well as a race to try to capitalize on the discovery.  Jackson and Morton together obtained a patent for ether as Letheon, a mixture of ether and oil of orange.  As it was soon realized, the active ingredient in Letheon was ether, an already discovered compound; therefore, the patent was worthless.   Morton later submitted a request to Congress for $100,000 for the army’s battlefield use of ether, but it was unsuccessful. There were also bills in Congress to appropriate $200,000 to the discoverers of ether anesthesia, but none were passed.  Morton ended up a bitter man.  Despite his many efforts and litigation   to try to capitalize on ether, he received fame and some medals but did not make much money for being the “discoverer” of ether.   Jackson, who had previously claimed that Samuel Morse stole the idea of the telegraph from him, ended up in an asylum in his later years.     In 1848, at the age of 32, Wells moved his dental practice to New York City, wanting to establish himself there before sending for his wife and son.  Feeling lonely and depressed, he started abusing chloroform.  His mental state deteriorated, and he was arrested after throwing acid on a group of women.  He was incarcerated in the Tombs prison, and while there, committed suicide.  Wells eventually did get some credit for his use of nitrous oxide, as in 1864 he was recognized as the discoverer of anesthesia by the American Dental Association, and in 1870 by the American Medical Association.  Ironically, it turned out that none of the participants in the Ether Dome procedure had actually been the first to use ether anesthesia in surgery.  A small-town Georgia doctor named Dr. Crawford Williamson Long had started performing operations using ether in 1842, but he didn’t publish his results until 1849 and, therefore, received little credit for the innovation. ________________________________________________________________________________________________________ You may also enjoy reading these other FibonacciMedicine history of medicine articles: The History of Insulin and Type 1 Diabetes.   Penicillin, the Accidental Antibiotic The History of the Electrocardiogram (EKG/ECG) The History of Nitroglycerin, an Explosive with Medical Benefits The History of Heroin, the “Non-addictive” Substitute for Morphine The History of the Iron Lung The History of the Coney Island Incubator Babies The Story of the Most “Kissed” Face in the World Dr. Robert Liston and the 300% Mortality Surgery _______________________________________________________________________________________________________ Resources About The Ether Dome. Paul Russell Museum of Medical History and Innovation, Massachusetts General Hospital.  Retrieved from: https://www.russellmuseum.org/ether-dome/ Story J. The Interesting History of… The Ether Dome. Show me Your Stethoscope. October 25, 2021. Retrieved from: https://smysofficial.org/the-interesting-history-of-the-ether-dome/ Ether Dome. Wikipedia. last edited on 22 March 2024. Retrieved from: https://en.wikipedia.org/wiki/Ether_Dome Gifford EE. Horace Wells Discovers Pain-free Dentistry. Connecticuthistory.org . December 10, 2021. Retrieved from: https://connecticuthistory.org/horace-wells-discovers-pain-free-dentistry/ Baker PM. The Ether War: In Sickness & In Health: Medicine in the Old Colony. Pilgrim Hall Museum. 2021. Retrieved from: https://www.pilgrimhall.org/the_ether_war.htm Chaturvedi R, Gogna RL Retd. Ether day: an intriguing history. Med J Armed Forces India. 2011;67(4):306-308. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920664/ Pinsker S and Harding RS. Guide to the Morton Family Collection. Archives Center, National Museum of American History. 1986.Retrieved from: https://sirismm.si.edu/EADpdfs/NMAH.AC.0118.pdf Jackson CT and Morton WTG. Improvement of Surgical Operations. US patent Office. November 12, 1846. Retrieved from: https://patentimages.storage.googleapis.com/59/14/82/14508c21024c52/US4848.pdf

and the Contributions of Louis Pasteur and Joseph Lister Explore the groundbreaking work of Louis Pasteur and Joseph Lister, whose pioneering contributions to germ theory and antiseptic surgery transformed medicine and saved countless lives. Up until the mid-1800s, it was believed that living things, such as microbes, could arise from inanimate matter in a process known as spontaneous generation. There was also the miasma theory that stagnant, foul-smelling air carried disease. Louis Pasteur Louis Pasteur , a leading French scientist, believed in germ theory and wanted to disprove spontaneous generation and miasma as causes of disease.  He did so with a now-famous experiment. In his first experiment, he boiled bacteria-filled broth in a normal-shaped flask and saw, when viewed under a microscope, that the boiling had killed off the bacteria.  When the flask was stoppered, no bacteria ever grew in the flask.  However, when the plug was removed, bacteria returned to the broth.  He believed he had proven germ theory, but people who believed in miasma theory gave a counter-explanation, which was that the stopper had not allowed air in, and that could explain the lack of organisms in the stoppered flask. Swan-neck flask used by Louis Pasteur It was then that Pasteur invented the swan-neck flask.  The curvature of the neck allowed air in, but the swan-neck prevented any outside materials from entering.  In that flask nothing grew after initially boiling the broth.  In a second flask, the swan neck was broken off which allowed both air and material from the air to enter, and bacteria grew in that flask.  Thus, with this elegant experiment, Pasteur proved germ theory and refuted miasma and spontaneous generation theories.  Disease prevention transformed from trying to suppress odors in the air to identifying bacteria that could cause disease and working on improving public sanitation.    Joseph Lister Joseph Lister was a prominent British surgeon who lived from 1827 to 1912.  In the 1800s, wound sepsis was a leading cause of death, with mortality rates after surgical procedures being as high as 40-50%.  Surgeons frequently did not wash their hands between cases and wore blood-soaked clothes into surgeries.  Lister was interested in decreasing infectious operative complications and was influenced and intrigued by Pasteur’s findings and proof of germ theory.  He hypothesized that wound infections were caused by bacteria in the air. In 1865, Lister used carbolic acid, also known as creosote, to disinfect compound fractures (fractures open to the skin that have a high likelihood of becoming infected). He first treated an 11-year-old boy by inserting a carbolic acid pad in the wound.  Over the next two years, he treated 11 more compound fractures with carbolic acid.  The results were published in The Lancet medical journal.  Only one of the patients got an infection and needed an amputation.  In 1867, he started using carbolic acid lotion in wounds during surgery and applied carbolic acid paste to the outside of the sutured wound.  In 1867, he reported that he had had no sepsis cases for nine months. Based on his experience he advised surgeons to wear clean gloves and to wash their hands and surgical instruments using a 5% carbolic acid solution.  He also advised not using porous materials in the handles of surgical instruments as they could carry bacteria.  In 1871, Lister started spraying the operating room with a 1:100 carbolic acid solution in an attempt to kill germs there.  As carbolic acid was later found to damage living tissue, Lister started reducing the strength of carbolic acid he was using. Between 1864 and 1866, 46% of Lister’s surgical patients died.  From 1867 to 1870, only 15% died.  By 1910, using Lister’s techniques, operative mortality rates at King’s College London, where Lister had previously been the Chair of Clinical Surgery, were reduced to 3%.  Joseph Lister has been called both “the father of modern surgery” and the “father of antiseptic surgery”. Pasteur and Lister revolutionized the understanding of disease processes and the delivery of healthcare.  Their contributions have saved countless lives. Click here to read about another major historical surgical advance, “Gentlemen this is no humbug” - The First Use of General Anesthesia in Surgery and the Battle for Recognition that Ensued. If you liked this article, you may also enjoy reading these other FibonacciMedicine articles : The History of Insulin and Type 1 Diabetes.   Penicillin, the Accidental Antibiotic The History of the Electrocardiogram (EKG/ECG) The History of Nitroglycerin, an Explosive with Medical Benefits The History of Heroin, the “Non-addictive” Substitute for Morphine The History of the Iron Lung The History of the Coney Island Incubator Babies The Story of the Most “Kissed” Face in the World References Smythe T. Savior with a Swan’s Neck; or How a Simple Glass Flask Saved Millions of Lives. Corning Museum of Glass Blog. July 20, 2016. Retrieved from: https://blog.cmog.org/2016/savior-swans-neck-or-how-simple-glass-flask-saved-millions-lives Michaleas SN et al. Joseph Lister (1827-1912): A Pioneer of Antiseptic Surgery. Cureus . 2022;14(12):e32777. Published 2022 Dec 21. Retrieved from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9854334/ Isaac S. Lord Joseph Lister of Lyme Regis (1827-1912): the father of modern surgery. 06 The Royal College of Surgeons of England. Oct 2017. Chandak P. Lord Lister, 'Father of antiseptic surgery'. King’s College London. 16 March 2017. Retrieved from: https://www.kcl.ac.uk/lord-lister-father-of-antiseptic-surgery-2 Photo: Swan-necked flask used by Pasteur. Wellcome Trust Corporate Archive. Retrieved from: https://wellcomecollection.org/works/fw5ejz5m Photo: Joseph Lister/. Wellcome Collection Retrieved from:  https://wellcomecollection.org/search/images?query=joseph+lister#z3xaqv23

References for the Article " Private Equity in Healthcare - What Are the Facts? " References [1] Cai C, Song Z. A Policy Framework for the Growing Influence of Private Equity in Health Care Delivery. JAMA. 2023;329(18):1545-1546. Retrieved from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10699936/ [2] PESP Private Equity Hospital Tracker. The Private Equity Stakeholder Project. Retrieved from: https://pestakeholder.org/private-equity-hospital-tracker/ [3] Morgenson G and Rosner J. These Are the Plunderers. Simon & Schuster. 2023.  [4] Gao J, Kim Y, Merih Sevilir M. Private equity in the hospital industry. Journal of Financial Economics. Volume 171. 2025. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0304405X25001151 [5] Blumenthal D.  Private Equity’s Role in Health Care. The Commonwealth Fund. November 17, 2023. Retrieved from: https://www.commonwealthfund.org/publications/explainer/2023/nov/private-equity-role-health-care [6] Shrank WH, Rogstad TL, Parekh N. 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Retrieved from: https://www.cms.gov/newsroom/fact-sheets/no-surprises-understand-your-rights-against-surprise-medical-bills [15] Appelbaum E & Rosemary Batt R. Private Equity and Surprise Medical Billing.  Institute for New Economic Thinking.  Sep 4, 2019. Retrieved from: https://www.ineteconomics.org/perspectives/blog/private-equity-and-surprise-medical-billing [16] Olsen E.  Staffing firm American Physician Partners files for bankruptcy. Healthcare Dive. Sept. 21, 2023. Retrieved from: https://www.healthcaredive.com/news/american-physician-partners-files-chapter-11-bankruptcy/694360/ [17] Muoio D. Hospital, ED staffer American Physician Partners files for Chapter 11 bankruptcy. Fierce Healthcare. Sep 20, 2023. Retrieved from: https://www.fiercehealthcare.com/providers/hospital-ed-staffer-american-physician-partners-files-chapter-11-bankruptcy [18] Halleman S. Envision Healthcare files for Chapter 11 bankruptcy. May 15, 2023. Retrieved from: https://www.healthcaredive.com/news/envision-chapter-11-bankruptcy/650277/ [19] Bruch JD, Gondi S, Song Z. Changes in Hospital Income, Use, and Quality Associated With Private Equity Acquisition. JAMA Intern Med. 2020 Nov 1;180(11):1428-1435. Retrieved from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7445629/ [20] Kannan S, Bruch JD, Song Z. Changes in Hospital Adverse Events and Patient Outcomes Associated With Private Equity Acquisition. JAMA. 2023;330(24):2365–2375. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/2813379 [21] Gupta A, Howell S, Yannelis C, Gupta A. Does Private Equity Investment in Healthcare Benefit Patients? Evidence from Nursing Homes. Published online February 2021. Retrieved from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790212 [22] Kannan S et al. Hospital Staffing and Patient Outcomes After Private Equity Acquisition. Ann Intern Med. [Epub 23 September 2025]. Retrieved from:   https://www.acpjournals.org/doi/10.7326/ANNALS-24-03471 [23] Chalfin DB et al. DELAY-ED study group. Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit. Crit Care Med. 2007 Jun;35(6):1477-83. Retrieved from: https://journals.lww.com/ccmjournal/abstract/2007/06000/impact_of_delayed_transfer_of_critically_ill.4.aspx [24] Bugbee M. Steward Health Care’s bankruptcy: one year later. The Private Equity Stakeholder Project May 6, 2025. Retrieved from: https://pestakeholder.org/news/steward-health-cares-bankruptcy-one-year-later/ [25] Vogel, S. Prospect Medical Holdings files for bankruptcy. Healthcare Dive. Jan. 13, 2025 https:// www.healthcaredive.com/news/prospect-medical-holdings-files-bankruptcy/737138/ [26]Klein L. Judge OKs Yale New Haven Health's $45M payout to Prospect over failed hospital deal. 'We would like ...to ...move on'. New Have Register. Oct 10, 2025. Retrieved from: https://www.nhregister.com/business/article/ct-yale-health-prospect-hospitals-waterbury-21094583.php [27] Rinehart KE et al. Yale New Haven Health Services vs. Prospect Medical Holdings, Inc., Superior Court filing, Judicial District of Hartford. May 28, 2024. Retrieved from: https://viceroyresearch.org/wp-content/uploads/2024/05/Yale-New-Haven-Health-v-Prospect-Medical-Holdings.pdf [28] Klein L. Judge OKs Yale New Haven Health's $45M payout to Prospect over failed hospital deal. 'We would like ...to ...move on'. The New Haven Register. Oct 10, 2025. https://www.nhregister.com/business/article/ct-yale-health-prospect-hospitals-waterbury-21094583.php [29] Private Equity in Health Care Shown to Harm Patients, Degrade Care and Drive Hospital Closures. Senate Budget Committee. 01.07.25. Retrieved from: https://www.budget.senate.gov/ranking-member/newsroom/press/private-equity-in-health-care-shown-to-harm-patients-degrade-care-and-drive-hospital-closures article: " Private Equity in Healthcare - What Are the Facts?"

Potential Bias and Incorrect Results In the Medical Literature and Why You Shouldn’t Believe Everything You Read Continuing Medical Education Overview: This article will discuss potential causes of bias in the medical literature and why some clinical decisions based on the medical literature may have incorrect conclusions. ✅ Earn Free CME Credit for Reading This Article Eligible for 0.25 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 Biases and Incorrect Results Reported in the Medical Literature There are a number of potential biases that may affect results in the medical literature. There can be bias on the part of the researcher doing the experiment, bias in the experimental design, bias in the way the study is written for publication or bias by journals when deciding which articles to publish. Career advancement in academia is to a significant degree based on publication of articles which in some cases may lead to some data manipulation by authors to achieve that goal.[1] One type of bias that can affect medical literature is publication bias . It has been found that a trial with positive results is much more likely to be published. Positive result publication bias is common as journals benefit by being noticed and cited more when they publish positive papers.[1,2] The predominance of positive trials can create citation bias which is that the more a research paper is discussed and disseminated, the more its effect may be amplified in future publications and clinical practice.[2] Authors are much more likely to be published if their experimental results were positive. In one review of 105 antidepressant trials, 98% of the positive trials and only 48% of the negative trials reviewed ended up getting published.[2,3] A Cochrane Review found that trials that were statistically significant, had findings perceived to be important or striking, or showed a positive treatment effect, had nearly four times the odds of being published compared to trials that did not meet those criteria.[4] In a study of Indian medical journals 72% of published articles had positive outcomes compared to a publishing rate of 28% for negative articles.[5] This positive publication bias in the literature can distort the results of meta-analyses. A meta-analysis is an article that combines the results of many trials, to try to determine with a higher certainty than smaller trials can, if there are statistically significant results. There are a number of possible errors in meta-analysis results. One source of potential error is incorrect weighting of the studies. Trials are given different levels of importance or weighted by precision, validity or risk of bias. It is common for one or just a couple of studies to carry much or most of the weight of the meta-analysis, which may affect the conclusions. Author judgment is involved in the evaluation of study quality and weight.[6,7] A study on the effect of positive paper publication bias on meta-analyses using simulation models found that if statistically significant positive results on a topic were published four times more often than negative results (80% positive, 20% negative) depending on study size, there was an 11% to 100% chance of the meta-analysis author(s) making a type I statistical error (false positive) and finding a significant result when there actually was none. If statistically significant positive results were published four times more often than negative results and there was large amount of heterogeneity in the studies used in the meta-analysis, there was a more than a 90% chance of finding a statistically significant result when there actually was none (type I error).[8] Heterogeneity is a measure of the variation in trial outcomes. There may be differences between trials in the treatment or population studied, the study design, or the data analysis method that may lead to different results. If the trials are very dissimilar with a large amount of heterogeneity, combining them into one group for a meta-analysis may lead to erroneous conclusions.[7,9] Outcome reporting bias occurs when authors write up only the positive results in a trial and fail to report those that appear negative. In that previously discussed review of 105 antidepressant trials, ten antidepressant studies which were considered negative by the FDA were reported as positive by the researchers. This was accomplished by switching a secondary outcome with a primary one and reporting it as if it were the original intent of the researchers, or simply by not reporting negative results. The scientific method requires that primary outcomes be used as endpoints, and you cannot switch them once the experiment has started.[2,3] In a study of 102 trials in the medical literature looking at outcome reporting bias , about half of the outcomes on whether tested drugs were effective, and about two-thirds of the outcomes on whether the treatment caused harm were incompletely reported. Positive outcomes were more likely to be reported. That same study examined experimental protocols and found that 62% of the trials reviewed had at least one primary outcome that was changed, introduced later on, or omitted. The authors of this study concluded that the reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with the authors’ own protocols. “Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention.”[10] There is also evidence that drug company-funded trials which are negative may never be released. In the case of the drug oseltamivir for influenza, it was discovered that adverse events and negative trials sponsored by a drug company had been presented at meetings but never published. Only when this was discovered, and the company was pressured to release the data could the true efficacy and adverse reactions to the drug be accurately determined.[11] Data dredging is where researchers start comparing multiple secondary outcomes or data elements that were not part of the original experimental design to try to find some positive correlations that are statistically significant. This is not considered proper scientific method because if authors compare enough data elements they will find some statistical significance just by chance due to a false positive type 1 statistical error. Authors may spin experimental results, which refers to using language, often in the abstract or summary sections of the study, to make negative results appear positive. In the previously discussed antidepressant study, in 15 of the negative articles, 11 authors used spin to improve their experimental results. Some used non-statistically significant results(trends) as if they were positive, by referring only to the numerical outcomes. Only four of the 15 articles reported negative results without embellishing the results.[2,3] Observer bias and confirmation bias [12] can occur when either consciously or subconsciously experimenters’ observations or conclusions are slanted towards what they want or expect the results of the trial to be. Blinded studies where the researchers do not know which treatment the patient is getting is the best form of experimentation to avoid observer and confirmation bias.[13] Trials be may also be inadvertently biased just from the way they were designed or even the way questions are phrased on a questionnaire.[12] Trial conclusions may be incorrect if there is an unequal loss to follow-up of participants with different outcomes called loss-to follow-up bias . If three people in a trial with adverse events are lost to follow-up, those adverse events may never be reported or be reported as less significant than they truly are.[14] Volunteer or self-selection bias can occur when individuals who volunteer for a trial differ in clinical characteristics from those who do not.[14] The completeness of the methods section in the medical literature varies widely from minimal to very complete. The methods section should be as complete as possible to allow reviewers or readers to understand exactly how the experiment was performed. Inadequate methods sections may sometimes be due to authors hiding problematic parts of the trial. A complete methods sections is important to have for reference if someone else wishes to replicate the same trial to confirm the findings. Approximately 30% of rejections by journals are related to issues with the methods section.[15] Meticulous peer review before publication may help uncover and correct some of the biases or omissions by authors that may not be discovered in a non-peer reviewed journal publication. It has been found that double-blind peer review, where reviewers do not know the names or institutions of the authors, is a less biased way of doing peer review. It appears to lessen the bias of reviewers more favorably reviewing articles for publication from well-known authors or institutions.[16] Conclusion As discussed in this article there are a number of issues that may make it challenging to decide if a finding in a published clinical trial is correct. Data dredging, redesign of experimental endpoints after the experiment has started, omitting data, using data trends which are not statistically significant as a positive result, a tendency to publish positive results more than negative ones, and other forms of potential bias all contribute to make some of the medical literature suspect. To improve the quality of the medical literature, publications should increase the number of negative articles they present and ensure that authors do not change outcomes, omit data, or spin their negative results to appear positive. Authors also need to ensure that the methods sections of trials are complete so reviewers and readers can determine if scientific procedures were followed correctly. Important studies, especially smaller ones, should be repeated to ensure other investigators can achieve the same results and that the first author’s study result was not a type I error or a false positive just due to chance. Accurate methods sections are needed to allow that to happen. Double-blinded peer review can help reduce errors of commission and omission in medical articles and reduce reviewer bias. Medical decisions for patients are made on the basis of published trials in the medical literature. The medical community as a whole needs to both understand and hopefully strive to continue to reduce the biases that can distort the medical literature. Author’s note: If you wish to learn more about medical statistics it will be discussed further in an upcoming FibonacciMD blog article, Medical Statistics for the Non-Mathematician, for which AMA PRA Category 1 Credit(s)™ will be available. 🎓  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] Fanelli D. Do Pressures to Publish Increase Scientists' Bias? An Empirical Support from US States Data. PLOS ONE. April 21, 2010. Retrieved from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010271 [2] Carroll AE, Congratulations. Your Study Went Nowhere. The New York Times. Sept. 24, 2018. Retrieved from: https://www.nytimes.com/2018/09/24/upshot/publication-bias-threat-to-science.html [3] De Vries, Y., Roest, A., De Jonge, P., Cuijpers, P., Munafò, M., & Bastiaansen, J. (2018). The cumulative effect of reporting and citation biases on the apparent efficacy of treatments: The case of depression. Psychological Medicine, 48 (15), 2453-2455. Retrieved from: https://www.cambridge.org/core/journals/psychological-medicine/article/cumulative-effect-of-reporting-and-citation-biases-on-the-apparent-efficacy-of-treatments-the-case-of-depression/71D73CADE32C0D3D996DABEA3FCDBF57 [4] Hopewell S, Loudon K, Clarke MJ, Oxman AD, Dickersin K. Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: MR000006. Retrieved from: https://www.cochrane.org/MR000006/METHOD_publication-bias-in-clinical-trials-due-to-statistical-significance-or-direction-of-trial-results [5] Charan J, Chaudhari M, Jackson R, et al. Comparison of methodological quality of positive versus negative comparative studies published in Indian medical journals: a systematic review. BMJ Open 2015;5:e007853. Retrieved from: https://bmjopen.bmj.com/content/5/6/e007853 [6] Direct weighting. Cochrane. Retrieved from: https://handbook-5-1.cochrane.org/chapter_8/8_8_4_1_direct_weighting.htm [7] Bastian H. 5 Tips for Understanding Data in Meta-Analyses. PLOS Blogs. July 3, 2017. Retrieved from: https://absolutelymaybe.plos.org/2017/07/03/5-tips-for-understanding-data-in-meta-analyses/ [8] Kicinski M. How does under-reporting of negative and inconclusive results affect the false-positive rate in meta-analysis? A simulation study. BMJ Open 2014;4:e004831. Retrieved from: https://bmjopen.bmj.com/content/bmjopen/4/8/e004831.full.pdf [9] von Hippel, P.T. The heterogeneity statistic I2 can be biased in small meta-analyses. BMC Med Res Methodol 15, 35 (2015). Retrieved from: https://doi.org/10.1186/s12874-015-0024-z [10] Chan A, Hróbjartsson A, Haahr MT, Gøtzsche PC, Altman DG. Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials: Comparison of Protocols to Published Articles. JAMA. 2004;291(20):2457–2465. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/198809 [11] Yogendra Kumar Gupta YK et al. The Tamiflu fiasco and lessons learnt. Indian J Pharmacol. 2015 Jan-Feb; 47(1): 11–16. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375804/# [12] Teo C C. Types of cognitive biases you need to be aware of as a researcher. UX Collective. Sept 27, 2016. Retrieved from: https://uxdesign.cc/cognitive-biases-you-need-to-be-familiar-with-as-a-researcher-c482c9ee1d49 [13] Forbes D. Blinding: an essential component in decreasing risk of bias. Evid Based Nurs July 2013 | volume 16 | number 3. Retrieved from: https://ebn.bmj.com/content/ebnurs/16/3/70.full.pdf [14] Tripepi G et al. Selection Bias and Information Bias in Clinical Research. Nephron Clin Pract 2010. Retrieved from: https://www.karger.com/Article/Fulltext/312871# [15] Ghasemi A, Bahadoran Z, Zadeh-Vakili A, Montazeri SA, Hosseinpanah F. The Principles of Biomedical Scientific Writing: Materials and Methods. Int J Endocrinol Metab . 2019;17(1):e88155. Published 2019 Jan 28. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413392/ [16] Tomkins A. Reviewer bias in single- versus double-blind peer review. PNAS. November 14, 2017. Retrieved from: https://www.pnas.org/doi/10.1073/pnas.1707323114

Despite modern trends vilifying bread as a health risk, it remains a nutrient-rich foundation of a healthy diet. Culinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD The mouth-watering aroma of freshly baked bread arouses feelings of home, happiness, and security. Bread has been called the staff of life; throughout human history it has contributed a substantial portion of our calorie and nutrient intake. [1,2] Recently however, low-carb and gluten-free diet trends have vilified bread as a cause of weight gain, diabetes, and other health problems. Is bread good for us or not? Should bread maintain its place as a staple of our diet? History and Cultural Significance Bread has nourished man for 30,000 years.[2] The earliest breads were made by grinding grain, mixing it with water, and then spreading it on a rock by the fire to cook. These flat breads fit well with a nomadic lifestyle because they are quick to prepare from simple ingredients. Traditional unleavened flat breads are still common in the Middle East and Africa. Leavened bread appeared in ancient Egypt when cooks noticed that dough left sitting out overnight produced a lighter bread.   [3] This occurred because wild yeast contaminated the dough.  Yeast causes fermentation, which releases gas bubbles that expand the dough producing an airy texture when baked.  Please help us continue publishing.  Consider purchasing one of these Amazon products As an Amazon Associate FibonacciMD earns from qualifying purchases. Take your home baking to the next level with this Banneton Bread Proofing Basket Set and Sourdough Bread Baking Supplies , includes all the essential tools you need to create bakery-quality loaves. [ https://amzn.to/4pPqe7X ] Bake bakery-quality loaves at home with the Cuisinart Bread Maker , featuring 12 programmable menu options and customizable settings for the perfect crust and size every time. [ https://amzn.to/4sgJYTS ] Keep your bread fresh with this Sunhoo Wooden Bread Box , featuring a charming vintage farmhouse design and a two-layer storage layout with clear acrylic windows. [ https://amzn.to/3YIIaFs ] Bread is a ubiquitous part of our diet, but the type is specific to each culture – naan in India, baguettes in France, focaccia in Italy, tortillas in Mexico, pita in the Middle East, and challah in Jewish communities. The type of bread that arose in a culture was determined in part by the available grains; wheat is the most common, but rye, corn, rice, and cassava have all been used to make bread. [4]  In addition to the type of grain, how bread is processed affects its taste and texture. Early breads were made from roughly ground grain and had a coarse consistency, but as technology advanced so did our ability to grind and separate parts of the grain kernel, allowing for the development of refined grains, which produce a whiter, softer, airier bread. Within societies, economics and social status often determined the type of bread consumed: coarse, whole-grained bread was available to the lower classes, while finer, refined-grain varieties were reserved for upper classes.  Nutritional Contribution of Bread  Bread makes significant contributions to our nutrient intake, in part because we eat so much of it. In Medieval times bread provided three-quarters of the calories in the human diet.[5] This percentage has decreased over time as our diet has become more varied. By the 1950s, about half of the calories in the American diet came from bread and other grain products. [6] And today grains only provide about 15% of our calories with less than half of this coming from bread, defined as bread, rolls and tortillas. [7,8] Nonetheless bread still provides an important source of nutrients.   Bread is typically high in carbohydrates, provides a few grams of protein and a small amount of fat. The amounts of fiber and micronutrients are affected by whether the grain is whole or refined. Whole grains include all parts of the grain kernel: the bran, which is high in fiber, the endosperm, which contains most of the starch and protein, and the germ, which contains most of the fat. Refined grains are made up primarily of the starchy endosperm. Whole grains, because they include the bran and germ, are higher in fiber, selenium, magnesium, zinc, copper, vitamin E, and phytochemicals than refined grains. Refined grains, because they are enriched with added nutrients, are higher in iron, thiamin, riboflavin, niacin, and folate than whole grains.  Bread, Obesity, and Diabetes We often hear that too much bread will make us fat. While it does contain about 80 Calories per slice, bread itself is not fattening. Like any food, bread can contribute to weight gain if consumed in excess, but epidemiological research has not demonstrated a direct association between bread intake and body weight. [8] Studies have shown that limiting refined grains in favor of whole grains may even support efforts to maintain a healthy weight.[9] The high carbohydrate content of bread - about 13 g in an average slice - has raised alarms about its role in diabetes. Diets high in carbohydrates, particularly those with more than 70% of calories from carbohydrate, have been associated with a greater risk of type 2 diabetes.[10] However, the type of carbohydrate is also important. The carbohydrate in bread is primarily starch and fiber. When we eat starch, it is broken down into sugars, which are quickly absorbed into the bloodstream causing blood glucose to rise rapidly. When fiber, which is not digested by human enzymes, is consumed along with starch, digestion and absorption are slowed, blunting the rise in blood glucose. So, choosing a whole-grain bread will have less impact on blood sugar than a refined white bread. [11] Consumption of whole grains, including whole grain breads, is associated with a lower risk of diabetes, heart disease, and cancer.[12] Choosing a Healthy Loaf Bread is part of a healthy diet, particularly when you choose carefully. Nutrition recommendations tell us to eat 6 servings of bread (or other grains) each day, with half of this coming from whole grains.   But choosing from breads labeled whole-grain, multi-grain, keto, sprouted, gluten-free, and more can be overwhelming unless you know what to look for.  Only bread labeled as 100% whole grain is made with only whole grains.  Breads labeled 7-grain or multigrain may be a mixture of whole and refined grains. To see if your bread is made primarily from whole grains look at the Ingredient List on the label. If a whole grain is first in the list, whole grain is the most abundant ingredient by weight. Whole grains include whole wheat, whole corn, whole rye, and whole spelt; cracked or sprouted grains; oats and rolled oats; quinoa; and brown rice.  Wheat flour, enriched wheat flour, degerminated corn meal, and rice flour are refined grains.[13] Whole grain breads are a healthy choice, but specialty breads such as sour dough, gluten-free, and keto may also have health benefits for some consumers. Sourdough is made using a fermentation process that makes it easier to digest, less impactful on blood glucose, and enhances the absorption of iron, zinc, and magnesium. [14] Gluten-free bread was developed for individuals who could not tolerate the protein gluten, one of the major proteins in wheat, rye, and barley. Bread made without gluten can be heavy and dense because gluten traps the gas released during leavening giving bread its light chewy texture. As gluten-free breads have become more popular, they better mimic the texture of gluten-containing breads but offer no specific health benefits to those without an intolerance to gluten or other wheat components [13]. Keto bread was developed for consumers who severely restrict their carbohydrate intake, often for weight loss.  Keto breads can be higher in fiber, protein, and/or fat than traditional breads but frequently contain many added components like gums, artificial sweeteners, and stabilizers to mimic the texture of traditional breads. Bottom line  Bread can be a nutrient-rich staple in a healthy diet. Whole-grain breads provide fiber, B vitamins, vitamin E, and minerals while refined breads are enriched to provide additional iron and certain B vitamins. Bread does not cause obesity, diabetes, or other chronic diseases, but it can contribute to them if you eat too much and choose only refined breads. This does not mean you can never enjoy a fresh baguette. So, aim for whole-grain breads, do not eat too much, and enjoy the cornucopia of bread from cultures around the globe. References [1] Stanley M. Food Staple | National Geographic Society. education.nationalgeographic.org . Published October 19, 2023. https://education.nationalgeographic.org/resource/food-staple/ [2] History of Bread - Significance of Bread. Historyofbread.com . Published 2025. Accessed December 13, 2025. https://www.historyofbread.com [3] Bread: The Staff of Life - Feasts of History. Feasts of History. Published March 2, 2023. Accessed December 13, 2025. https://feastsofhistory.com/bread-the-staff-of-life/ [4] Mesta-Corral M, Gómez-García R, Balagurusamy N, Torres-León C, Hernández-Almanza AY. Technological and Nutritional Aspects of Bread Production: An Overview of Current Status and Future Challenges. Foods. 2024;13(13):2062. doi: https://doi.org/10.3390/foods13132062 [5] Schofield PR. Medieval Diet and Demography. Published online July 6, 2006:239-253. doi: https://doi.org/10.1093/oso/9780199273492.003.0017 [6] Benson A. The Rise and Fall of Bread in America. ScholarsArchive@JWU. Published 2025. Accessed December 13, 2025. https://scholarsarchive.jwu.edu/ac_symposium/21 [7] Drewnowski A, Rozenn Gazan, Matthieu Maillot. Healthy Grains in Healthy Diets: The Contribution of Grain Foods to Diet Quality and Health in the National Health and Nutrition Examination Survey 2017–2023. Nutrients. 2025;17(16):2674-2674. doi: https://doi.org/10.3390/nu17162674 ‌  [8] Ribet L, Kassis A, Jacquier E, Monnet C, Mickaël Durand-Dubief, Bosco N. The nutritional contribution and relationship with health of bread consumption: a narrative review. Critical Reviews in Food Science and Nutrition. Published online November 18, 2024:1-28. doi: https://doi.org/10.1080/10408398.2024.2428593 [9] Wan Y, Tobias DK, Dennis KK, et al. Association between changes in carbohydrate intake and long-term weight changes: prospective cohort study. BMJ. 2023;382:e073939. doi: https://doi.org/10.1136/bmj-2022-073939 [10] Hosseini, F., Jayedi, A., Khan, T.A. et al. Dietary carbohydrate and the risk of type 2 diabetes: an updated systematic review and dose–response meta-analysis of prospective cohort studies. Sci Rep 12, 2491 (2022). https://doi.org/10.1038/s41598-022-06212-9 [11] Nazari J, Yadegari N, Khodam S, Almasi-Hashian A, Amini S. Effect of Consumption of Whole-Wheat Breads on FBS, HbA1c, and Blood Lipids in Patients with Type 2 Diabetes. Prev Nutr Food Sci. 2021 Sep 30;26(3):269-274. doi: 10.3746/pnf.2021.26.3.269.  [12] Aune D, Keum N, Giovannucci E, et al. Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies. BMJ. 2016;353(2716):i2716. doi: https://doi.org/10.1136/bmj.i2716 [13] Center for Science in the Public Interest. Moyer L, Koch M. Healthy bread: How to decode labels and buy a better loaf. Center for Science in the Public Interest. Published March 19, 2025. https://www.cspi.org/article/healthy-bread-how-decode-labels-and-buy-better-loaf [14] Ribet L, Dessalles R, Lesens C, Brusselaers N, Durand-Dubief M. Nutritional benefits of sourdoughs: A systematic review. Advances in Nutrition. 2023;14(1):22-29. doi: https://doi.org/10.1016/j.advnut.2022.10.003 [15] United States Department of Agriculture. Dietary Guidelines for Americans 2020-2025 . USDA; 2020. https://www.dietaryguidelines.gov/sites/default/files/2020-12/Dietary_Guidelines_for_Americans_2020-2025.pdf ‌

Depression Treatments: Ketamine, Propofol, Nitrous Oxide, Psychedelics, and Transcranial Magnetic Stimulation. What Is the Evidence? Integrative Medicine By Stuart M Caplen, MD In 2020, an estimated 8.4% of the US adult population (21 million adults) and 12% of the U.S. population aged 12 to 17 (2.9 million adolescents) had at least one major depressive episode. Depression with severe impairment is defined by a two week or more period of depressed mood or loss of interest or pleasure in daily activities, with many associated symptoms such as problems with sleeping, eating, energy, concentration, or self-worth.[1] Depression is typically treated with a combination of antidepressants and psychotherapy. However, only 40 to 70% of depressed patients respond to these treatments, and about 10% to 30% of patients with a major depressive disorder develop severe treatment resistant depression (TRD).[2] In the past, electroconvulsive therapy (ECT) was used as the main treatment when other methods had failed. Recently, other modalities such as ketamine, propofol, nitrous oxide, psychedelics, and transcranial magnetic stimulation have been evaluated as alternative treatments for severe TRD to avoid the potentially severe side effects of ECT. This article will look at how successful those modalities are in treating TRD, and the level of scientific evidence for their usefulness. Ketamine Ketamine is an anesthetic agent with analgesic properties that has been utilized for procedural sedation in emergency departments and operating rooms. It was first synthesized in the 1960s as a derivative of phencyclidine. Ketamine rapidly produces a hypnotic state with profound analgesia and anesthesia without reducing respirations. It may produce amnesia, with the eyes typically remaining open, and the patient feeling disconnected from their body in a condition called dissociative anesthesia. Ketamine has potential central nervous system (CNS) side effects including hallucinations, intense dreams, delusions, and as the patient awakens, emergence delirium.[3] Laryngospasm, another potential adverse effect may require expert airway management skills during intravenous therapy. Ketamine is a potent NMDA antagonist.[4] Research points to the N-methyl-D- aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors as factors in the pathophysiology of major depression, and locations where antidepressant treatments work to improve depressive symptoms. Inhibition of NMDA receptors and activation of GABA receptors are thought to be factors in the improvement of depressive symptoms.[5] Ketamine for injection consists of two enantiomers ( molecules that are mirror images of each other), the S and R forms of ketamine. S-ketamine (esketamine) has four-times the affinity of R-ketamine (arketamine) for the NMDA receptor, and arketamine appears to have fewer psychotropic side effects. The two compounds have been found to have differing effects on some areas of the brain in animal studies. In some pre-clinical studies arketamine has been found to possibly be a better and longer acting agent for depression than esketamine, which is the form currently being used.[6,7] One study using a mixture of ar- and esketamine found the mixture caused less side effects than esketamine used alone, with similar results in treating depression. The authors of that study suggest more clinical studies are needed, but an ar- and esketamine mixture may be a better combination to use rather than esketamine alone.[6]. In a pilot study published in 2000, nine subjects with major depression were given either ketamine or a placebo. Intravenous ketamine treatment produced significantly greater reductions on a depression rating scale than saline treatment.[4] In 2016, a placebo-controlled study of 30 patients found that intravenous esketamine reduced depression symptoms in 64%-67% of the subjects (results varied by dosage of ketamine used) compared to 0% of the controls.[8] Based partially on that study, intranasal esketamine was approved by the FDA for the treatment of TRD.[3] However, only two of the five studies submitted to the FDA by the manufacturer in the approval process actually demonstrated a benefit from intranasal esketamine.[6] A 66-subject proof-of-concept trial of intranasal esketamine versus placebo, given in addition to standard-of-care treatment, found that it may produce both rapid improvement in depressive symptoms and suicidal ideation.[9] Patients receiving intranasal esketamine must be observed in a monitored environment for at least two hours due to some potential side effects including sedation, reduced attention, dissociation (judgment and thinking alteration, depersonalization and derealization), misuse, abuse, or suicidal thoughts.[3] One systematic review of the literature concluded that ketamine appears to be effective in reducing depressive symptoms in TRD patients, and has a reasonable safety profile based on the results of the clinical trials. However, the authors noted that the clinical relevance of the treatment effect, and the safety demonstrated by many clinical trials, cannot be guaranteed in the real-world setting.[10] Another systematic review of the long-term effects of esketamine found mixed results for long-term effectiveness after termination of therapy. The authors’ conclusion was that the level of proof of esketamine’s efficacy in long-term TRD treatment remains low, and more randomized controlled trials with larger sample sizes and active comparators were needed. It is possible that continued therapy might be needed to prevent relapses.[11] A Cochrane Review of the literature on ketamine for depression concluded that ketamine and esketamine may be more efficacious than placebo for treatment of TRD at 24 hours, but how those findings translated into clinical practice was not entirely clear.[12] A review of a total of 83 trials, and both systemic reviews and meta-analyses in the literature on ketamine treatment concluded there was a large amount of evidence for a rapid and transient antidepressant effect from ketamine in unipolar and bipolar depression, and TRD. Repeated doses appeared to increase the duration of effectiveness. The authors also concluded that in numerous studies ketamine was found to have short-lived anti- suicidal properties. The authors did warn that the conclusions should be interpreted with caution because of the high risk of bias in the experimental design of many of the included studies.[13] Propofol Propofol is an intravenous general anesthetic that potentiates the function of GABA receptors, and inhibits the function of NMDA receptors. In one pilot study of 10 patients who received 10 treatments, 60% of the patients responded positively with no serious side effects. One of the 6 responders relapsed a few months after the final propofol treatment while the other 5 remained well for at least 3 months of follow- up.[14] Further published studies on the effectiveness of propofol for depression were not found on internet searches. Nitrous Oxide It has been postulated that inhaled nitrous oxide is a NMDA antagonist that may be useful in treating TRD. A proof-of-concept trial with 20 patients comparing inhaled nitrous oxide versus placebo for severe TRD found that nitrous oxide had rapid antidepressant effects in some patients. In two one-hour intervals one week apart each patient received an inhalation treatment of either 50% nitrous oxide or a 50% nitrogen-50% oxygen placebo. All patients received both the nitrous oxide and placebo in random order. Nitrous oxide treatment resulted in a treatment response in 20% of patients with TRD and remission in an additional 15%. The antidepressant effects were sustained for at least 24 hours, and in some patients for one week. Some patients experienced adverse events such as nausea, anxiety, or vomiting requiring a short interruption or discontinuation of treatment.[15] A phase-two trial was performed which with 24 patients who each received 50% nitrous oxide, 25% nitrous oxide or a placebo in a randomly chosen sequence, with a one-hour treatment once a month for three months. At the end of three months, 85% of patients had improved with a decreased Hamilton depression rating scale (HDRS- the most commonly used depression scale), 55% had a treatment response, saying their depression was less intense, and 40% were in remission, with a HDRS<7. There was no significant difference in the efficacy of depression treatment between the 25% or 50% nitrous oxide, both being significantly better than placebo, but 25% nitrous oxide had a markedly lower rate of adverse side effects compared to 50% nitrous oxide. It was suggested by the authors that the antidepressant effects of nitrous oxide may last between 2 and 4 weeks in responders.[16] Psychedelics Lysergic acid diethylamide (LSD) and psilocybin are psychedelic drugs that produce perceptual distortions and mind-altering effects, mainly by being agonists of the serotonin 5-HT2A brain receptor.[17] Long term pessimism also known as “trait” pessimism seen in severe depression, has been linked to deficient 5-HT2A receptor stimulation.[17] For depression therapy, microdoses of psychedelics are administered at approximately one tenth of the dose that causes hallucinogenic effects.[18] In most trials of psychedelics, an assessment is necessary to determine if the patient is suitable for psychedelic therapy. Currently, people with a personal or family history of psychosis and bipolar disorder are excluded, as are those with significant health issues such as significant hypertension, because psychedelics transiently increase blood pressure. Certain medications should be stopped or reduced before the treatment, because they can block or attenuate the effect of the psychedelic. Medications that block 5-HT2A receptors including amitriptyline, olanzapine, quetiapine, risperidone, and trazodone should be withdrawn. Serotonin reuptake inhibitors ideally should be stopped or, if that is not feasible, tapered down, because they can also decrease the sensitivity of the 5- HT2A receptor.[19] An MRI study found psilocybin caused a significant decrease in the connectivity between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), and decreased activity in the anterior cingulate cortex and mPFC. These results suggested that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition (mind- altering effects). Activity in and connectivity with the mPFC is known to be elevated in depression, which becomes normalized after effective treatment. The results of this study suggested that psilocybin works by decreasing mPFC activity via 5-HT2A receptor stimulation and increasing GABA transmission.[17] One meta-analysis of eight studies of psychedelic use for depression found a significant decrease in depression on day one as well as at six months. No serious adverse effects were reported in any included studies. A transient increase of the heart rate, blood systolic, and diastolic pressure were found after psychedelic administration compared with placebo.[20] Another trial found that 71% of psilocybin treated patients still had significant antidepressant effects at 4-weeks post therapy. [21] However, a 59-patient trial of psilocybin versus escitalopram found that psilocybin was no better at improving TRD symptoms than the antidepressant.[22] Transcranial Magnetic Stimulation People with depression do not produce enough of some neurotransmitters, such as serotonin and dopamine, and electrical impulses to the brain can stimulate production of those neurotransmitters. Repetitive transcranial magnetic stimulation (rTMS) uses highly focused repetitive magnetic pulses to induce an electrical current two to three centimeters deep, typically in the left prefrontal section of the cerebral cortex. That region of the brain acts as an emotion modulator, and appears to underproduce neurotransmitters in depression. Typically, rTMS protocols consist of treatments over four to six weeks in daily high frequency stimulation sessions to the left dorsolateral prefrontal cortex.[23] rTMS is FDA-approved for major depressive disorder in patients who have not responded to an adequate antidepressant trial.[24] Standard rTMS is seldom useful in acutely suicidal patients because of a delayed time-to-response.[23] The most common side effects of rTMS include transient headache, scalp discomfort and a tapping sensation of the head in time with the magnetic pulses during sessions. The most concerning adverse side effect is the potential of grand mal seizures.[25] The risk of grand mal seizure varies, but is thought to be 0.003% for standard rTMS, .02% for Theta burst TMS, and 1.4% to 2.9% in patients with an underlying seizure disorder.[26] Attempts are being made to try to increase the efficacy of TMS by varying the administration of the treatment. It can be administered in a number of different ways; high or low frequency, unilateral or bilateral, with priming doses, accelerated, with theta- burst impulses, or synchronized with alpha waves.[27] In accelerated TMS (aTMS), the time intervals between treatments are shortened, so that it takes days rather than weeks to complete. Another method is combining rTMS and theta burst stimulation (TBS) where the TMS mimics endogenous hippocampal theta patterns.[23] In synchronized rTMS, three magnets provide low energy stimulation, the frequency of which is based on and synchronized to an individual patient’s own alpha wave frequency.[28] The literature on rTMS has produced mixed results, with some trials showing a statistically significant benefit over sham treatment, and others no benefit. Part of the issue might be that there are a number of manufacturers of TMS machines,[29] as well as many different ways to administer the therapy. Almost all the meta-analyses suggested larger trials were needed to resolve how effective TMS actually is. In 2007, the first trial of TMS versus sham treatment found a significant improvement of depression with TMS over placebo, and the FDA approved the first device for administering TMS based on that study.[29,30] A National Institute of Mental Health trial found that 14% of patients with drug-resistant major depressive disorder experienced a remission of symptoms after repetitive transcranial magnetic stimulation (rTMS) while a control group reported only a 5% rate of remission. However, some authorities felt those results were similar to the success rate of antidepressants alone.[25,31] In a Cochrane review of the literature, 14 trials were analyzed and most comparisons did not show differences between repetitive (rTMS) and other interventions. The authors concluded that there was no strong evidence for the efficacy of transcranial magnetic stimulation for the treatment of depression, although the results did not exclude the possibility of benefit.[32] A number of other meta-analyses found no evidence of a difference between rTMS and sham therapy,[33,34] while other trials and meta-analyses found it was significantly better than sham therapy.[23,35,36,37] One of those meta-analyses looked at high-frequency rTMS (HF- rTMS) and found 29.3% of the subjects responded to the therapy, and 18.6% went into remission, compared with 10.4% responders and 5% remission rates in the sham group.[36] TMS has also been compared to ECT. One study of ECT versus rTMS found no statistically significant difference between the two procedures.[38] In a systemic review and meta-analysis ECT was found to be superior to HF-rTMS in terms of response (64.4% vs. 48.7%) and remission (52.9% vs. 33.6%) of depressive symptoms. The superiority of ECT was more apparent in those with psychotic depression, while HF-rTMS was as effective as ECT when used for non-psychotic depression. This review noted the lack of good quality trials comparing the long-term outcome and cognitive effects of rTMS compared to ECT.[39] Conclusion There is currently an interest in psychiatry to find treatments for severe TRD that are less invasive than ECT using TMS or medications that inhibit NMDA receptors or activate GABA or 5-HT2A receptors. Ketamine seems promising and does have some literature support. An intranasal form of esketamine has been approved for TRD treatment. Propofol also seems promising, but more trials are needed to assess its value for TRD treatment. Nitrous oxide had positive effects in two small studies, and would be easier to administer than some of the other treatments discussed, but larger trials are needed to confirm its effectiveness. Microdosed psychedelics have some literature support for treating TRD, but a recent trial found no improvement over using an oral antidepressant alone. TMS is currently an FDA approved procedure to treat TRD. Trials have had very mixed results, some positive, and others negative, with some authorities questioning its value. Differences in TMS machines or how the TMS is administered may be responsible for some of the differences. ECT was found superior to TMS in some comparative trials, but TMS also had some positive effects on depression in those trials. Different protocols for TMS treatments, such as adding theta waves, changing the frequency used, accelerating the doses to complete the therapy faster, trying bilateral treatments instead of unilateral, and deeper brain stimulation are being tested to see if outcomes can be improved. Larger randomized controlled trials are needed to confirm the effectiveness of the procedure. The medical practice of treating TRD using methods other than ECT is in its infancy, and while these treatments offer these patients some hope, more randomized controlled trials with larger numbers of subjects are needed to determine how effective they truly are. References [1] Major Depression. National Institute of Mental Health. Last Updated: January 2022. Retrieved from: https://www.nimh.nih.gov/health/statistics/major-depression [2] Jaffe, D.H., Rive, B. & Denee, T.R. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry 19, 247 (2019). Retrieved from: https://doi.org/10.1186/s12888-019-2222-4 [3] Carboni Ezio C et al. Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success? Frontiers in Neuroscience. 30 April 2021. Retrieved from: https://www.frontiersin.org/articles/10.3389/fnins.2021.657714/full#B28 [4] Berman R et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry. 47, 351–354. 2000. Retrieved from: https://doi.org/10.1016/s0006-3223(99)00230-9 [5] Mickey BJ, White AT, Arp AM, et al. Propofol for Treatment-Resistant Depression: A Pilot Study. Int J Neuropsychopharmacology. 2018;21(12):1079-1089. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ [6] Passie T et al. Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers. European Neuropsychopharmacology, Volume 44, Pages 92-104. 2021. Retrieved from: https://doi.org/10.1016/j.euroneuro.2021.01.005 [7] Wei, Y., Chang, L., and Hashimoto, K. A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacol. Biochem. Behav. 190:172870. 2020. Retrieved from: https://doi.org/10.1016/j.pbb.2020.172870 [8] Singh JB et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424–431. 2016. Retrieved from: https://www.biologicalpsychiatryjournal.com/article/S0006-3223(15)00914-2/fulltext [9] Canuso CM. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am. J. Psychiatry 175, 620–630. 2018. Retrieved from: https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060720 [10] Sapkota A, Khurshid H, Qureshi IA, et al. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus. 2021;13(8):e17352. 2021 Aug 21. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381465/ [11] Capuzzi E, Caldiroli A, Capellazzi M, et al. 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Therapeutic Advances in Psychopharmacology. January 2020. Retrieved from: https://journals.sagepub.com/doi/full/10.1177/2045125320950567 [19] Nutt D, Carhart-Harris R. The Current Status of Psychedelics in Psychiatry. JAMA Psychiatry. 2021;78(2):121–122. Retrieved from: https://www.deepdyve.com/lp/american-medical-association/the-current-status-of-psychedelics-in-psychiatry-0B901rvlVy [20] Romeo B, Karila L, Martelli C, Benyamina A. Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. Journal of Psychopharmacology. 2020;34(10):1079-1085. Retrieved from: https://journals.sagepub.com/doi/abs/10.1177/0269881120919957 [21] Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial [published correction appears in JAMA Psychiatry. 2021 Feb 10. Retrieved from: JAMA Psychiatry. 2021;78(5):481-489. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643046/ [22] Carhart-Harris R et al. Trial of Psilocybin versus Escitalopram for Depression. NEJM, 384:1402-1411. April 15, 2021. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa2032994?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed [23] Sonmez AI, Camsari DD, Nandakumar AL, et al. Accelerated TMS for Depression: A systematic review and meta-analysis. Psychiatry Res. 2019;273:770-781. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582998/#R11 [24] Connolly KR et al. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012 Apr;73(4):e567-73. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22579164/ [25] Nash J. Attractive Therapy: Magnetic Brain Stimulation Gaining Favor as Treatment for Depression. Scientific American. August 30, 2010. Retrieved from: https://www.scientificamerican.com/article/transcranial-magnetic-stimulation-rtms/ [26] Stultz DJ et al. Transcranial Magnetic Stimulation (TMS) Safety with Respect to Seizures: A Literature Review. Neuropsychiatric Disease and Treatment Volume 16:2989-3000. December 2020. Retrieved from: https://www.researchgate.net/publication/347392741_Transcranial_Magnetic_Stimulation_TMS_Safety_with_Respect_to_Seizures_A_Literature_Review [27] Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. JAMA Psychiatry. 2017;74(2):143–152. Retrieved from: https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2594387 [28] Watts V. New TMS Device Reduces Depression Symptoms. Psychiatric News, American Psychiatric Association, 4 Sep 2015. Retrieved from: https://psychnews.psychiatryonline.org/doi/full/10.1176/appi.pn.2015.PP9a2 [29] Novey W. Are all rTMS machines equal? New research suggests there may be clinically significant differences. Ment Illn. 2019;11(1):8125. Published 2019 Jun 11. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589540/ [30] John P. O’Reardon JP et al. Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial. Biological Psychiatry, Volume 62, Issue 11, 2007, Pages 1208-1216. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0006322307001461 [31] George MS, Lisanby SH, Avery D, et al. Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial. Arch Gen Psychiatry. 2010;67(5):507–516. Retrieved from: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210744 [32] Rodriguez‐Martin JL et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2002. 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Explore cutting-edge Parkinson's treatments! Review advanced DBS, gene, and stem cell therapies, and new drug delivery methods in this FREE online CME. Read Article, Take Test , Get FREE 🎓 CME Certificate with Valid Email We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 By Stuart M. Caplen, MD  Parkinson’s disease (PD) is an incurable neurodegenerative disorder that may present with bradykinesia, resting tremor, rigidity, postural instability, subtle motor features, and/or many non-motor symptoms.  A PD presentation can be classified as tremor-dominant, rigid-akinetic (often associated with postural instability and gait disorders), or intermediate with components of both.  Non-motor symptoms of PD include constipation, depression, pain, sleep disorders, loss of smell, as well as cognitive decline, and autonomic dysfunction.[1]  Many motor symptoms in Parkinson’s disease are a result of the loss of the dopaminergic neurons in the substantia nigra pars compacta, which send axons to the striatum (consisting of the caudate, putamen, and the nucleus accumbens). Most of the current pharmacologic therapy for PD is aimed at restoring dopaminergic tone in the striatum. The most commonly prescribed medication is levodopa, which is converted to dopamine in the brain.  It is typically combined with carbidopa (a decarboxylase inhibitor), which prevents the levodopa from breaking down before it reaches the brain.  Many symptoms of PD, such as cognitive impairment and autonomic dysfunction, mainly have a non-dopaminergic basis due to neurodegeneration at other sites in the central, enteric and autonomic nervous systems.[2]  It is estimated that there are approximately one million patients with PD in the U.S. and 90,000 new cases per year.[3] While medications such as levodopa can improve motor functioning, there are a number of issues associated with its use. There may be variability in medication absorption and its ability to cross the blood-brain barrier. There may be side effects from delivering dopamine to extra-striatal regions of the brain, such as the non-physiological release of dopamine in the basal ganglia.  Patients with PD who are treated with levodopa can develop cognitive problems, levodopa-induced dyskinesias, and on-off fluctuations, which consist of good symptom control periods, with improved mobility and possibly an increase in levodopa-induced dyskinesias, varying with poor symptom control periods.[2]  Levodopa has a short plasma half-life of 36-96 minutes, which requires multiple doses during the day and leads to an “off” period, particularly overnight while sleeping.[4]  Because of the lack of full control of PD by medications such as levodopa, other modalities are being researched.[2] Other Medications and Delivery Methods for PD Treatment There are a number of medications besides levodopa that can be used to help reduce PD symptoms. Amantadine is an antiviral medication that may be prescribed to reduce levodopa-induced dyskinesias.  The exact mechanism by which amantadine achieves this effect is unknown.  One theory is that it causes inhibition of  N-methyl-D-aspartate (NMDA)-glutamate receptors that may correct dysregulation of glutamatergic transmission in the basal ganglia, which may be a cause of the dyskinesias.  Amantadine also appears to increase dopamine release and blocks dopamine reuptake.[4,5] Enzyme inhibitors reduce the activity of enzymes that break down dopamine to enhance the activity of dopamine.  Monoamine oxidase B (MAO-B) inhibitors include safinamide, selegiline, and rasagiline. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and opicapone may also be prescribed.[2,5] Anticholinergic medications, such as benztropine mesylate and trihexyphenidyl, block acetylcholine’s action.  Imbalances in the dopaminergic and cholinergic neurological pathways can lead to overactivity of cholinergic pathways, which can cause dyskinesia and tremors.  Anticholinergics may help reduce these symptoms.[4,5] Dopamine agonists, such as pramipexole, ropinirole, rotigotine, bromocriptine, and cabergoline are typically used in younger patients or in early stages of PD.  They activate dopamine receptors and may lengthen the time levodopa is effective decreasing symptoms in the levodopa “off” phase.[4,5]  Apomorphine, which was in the past used as an emetic, is also a dopamine agonist and can be administered intravenously or subcutaneously to prevent off-time symptoms in patients with more advanced PD, or in those undergoing surgical procedures.[6]    Cholinesterase inhibitors block the enzyme cholinesterase, which breaks down acetylcholine. Rivastigmine and donepezil are two cholinesterase inhibitors that have been in preliminary studies testing their ability to improve gait and reduce falls in PD patients.[2] Noradrenaline reuptake inhibitors such as methylphenidate and atomoxetine are being investigated for their effects on balance and gait in PD in an ongoing trial. Adenosine A2A antagonists, such as istradefylline, can help improve motor symptom control especially during levodopa “off” periods.  Adenosine is thought to block dopamine release in the basal ganglia and thus blocking adenosine may increase dopamine levels.[5] Levodopa gel can be administered via a percutaneous endoscopic gastrostomy tube to prevent off-time symptoms as it had been found that continuous dopaminergic stimulation may reduce dyskinesias.[6] A specially designed gastric-retentive oral drug delivery system containing carbidopa and levodopa in both immediate and extended-release forms was tested to try to prevent the on-off cycles of dyskinesias at high blood levels of levodopa and worsening of PD symptoms with low levodopa blood levels.  Unfortunately, a phase 3 trial showed no advantage over standard carbidopa/levodopa oral medication. [7,8] Alpha-synuclein Inhibition Alpha-synuclein (α-synuclein) is a protein of unknown function, found mostly in brain tissue, that is thought to be involved in normal neurotransmission.  In PD, misfolded alpha-synuclein is thought to form clumps (or aggregates) that can cause inflammation and interfere with neuron function.  These clumps of protein, primarily composed of alpha-synuclein, are known as Lewy bodies.  Lewy bodies are also found in Lewy body dementia, but in PD the Lewy bodies primarily affect dopamine-producing neurons. There are case reports of families with mutations or duplications in the gene that produces alpha-synuclein, where members have a high predisposition for PD as the mutation is passed on as an autosomal dominant gene.[2,9,10,11] Experimentally, researchers have tried to treat PD with monoclonal antibodies to reduce serum alpha-synuclein, in the hope of reducing brain alpha-synuclein.  Prasinezumab reduced serum levels of alpha-synuclein by about 97% in phase 1 trials and further phase 2 trials are ongoing.  Another antibody trial, testing the monoclonal antibody cinpanemab, was terminated due to lack of meeting predetermined outcome measures.[2] PD01A is an experimental vaccine which is designed to induce an active immune response against alpha-synuclein.  PD01A passed phase 1 trials and is now in phase 2 testing.  ACI-7104 is another antibody-inducing vaccine that is now in phase 2 testing.[2]  There are a number of other phase 1 trials or in recruitment for phase 2 trials for other vaccines in attempts to produce alpha-synuclein antibodies.[12] Other approaches, such as creating anti-sense oligonucleotide or using ribonucleic acid (RNAi) interference medications to reduce alpha-synuclein are also under early investigation.[2] There are some issues with attempting to reduce alpha-synuclein levels with vaccines. It is not established that symptoms of PD are actually caused by alpha-synuclein. It is not known how much of the antibodies produced will cross the blood-brain barrier and actually get into the brain. Since the normal function of alpha-synuclein is not fully understood, it is not clear whether suppressing production could lead to other problems.[2] As an example, one study found that injecting small-interfering RNA targeted to alpha-synuclein into rat brains caused some problematic neurodegeneration.[13] Medications already in use that have been found to reduce alpha-synuclein levels include terazosin, β-agonists, drugs that impair mitochondrial function such as ursodeoxycholic acid and N-acetylcysteine, anti-neuroinflammation drugs such as azathioprine and sargramostim, and exenatide, a GLP-1-receptor activator. Many of these and more compounds are currently in clinical trials.[2] Neurotrophic factors Putamen brain injections of neurotrophic factors, which are necessary for the growth, survival and maintenance of neurons, have been trialed.  Certain proteins such as glial cell line-derived neurotrophic factors, and cerebral dopamine neurotrophic factor, which have been shown in animal studies to protect dopaminergic neurons, have been tried in humans with mixed results.[2] Gene Therapies Gene therapies are being evaluated in an attempt to increase dopamine levels in the striatum through the introduction of genes that mediate dopamine synthesis.  A number of these are being tested using adeno-associated virus (AAV) or lentivirus (LV) as carriers, which are infused directly into the putamen. One advantage of gene therapy is that only one administration is needed as compared to neurotrophic factors, which require multiple injections.[2,12] Stem Cell Therapy In the 1980s and 1990s, fetal mesencephalic dopaminergic tissue was implanted into human putamens and some open-label studies demonstrated improvement in PD symptoms.  However, in 2001 a double-blind study that included a sham surgery arm reported that at one year there was no significant difference between groups receiving the implant and those receiving sham surgery.  15% of the patients developed dyskinesias or dystonia when not on PD medications.  The grafts were associated with improved motor function in the off-medication state in younger patients but not in patients older than 60 years, the typical age range for PD.[14] In recent years with more advances in stem cell research, implanting dopaminergic stem cells has again become an area of interest.  In 2025, there were two published reports on phase 1/2 or phase 1 trials.  In one, seven subjects received bilateral transplants of dopaminergic stem cells derived from induced pluripotent stem cells* at varying doses.  The subjects were given the immunosuppressive drug tacrolimus for 15 months.  At one year there were no off-time graft-induced dyskinesias during “off” periods, although dyskinesias from medications during “on” periods did worsen in six of the patients.  No serious side effects were reported.  Four of the subjects showed improvement in motor function during the medication-off periods.  Subjects who received higher doses of stem cells produced more dopamine at the transplant site than those who received lower doses.  No new tumors at the transplant sites were found.[15] The other study was a phase 1 trial with 12 participants receiving either low-dose or high-dose human embryonic stem cells* injected into the putamen.  The patients were put on immunosuppressive steroids and tacrolimus for a year to prevent rejection.  The only significant adverse side effect was a single seizure in one patient soon after the surgery.  There were no tumors or graft-induced dyskinesias.  There was also improvement in DS-UPDRS Part III scores** for levodopa off-times, with more improvement seen in the higher dose group.[16] (*The difference between embryonic and pluripotent stem cells is that the embryonic stem cells are derived from blastocyst cells, and induced pluripotent stem cells are created from reprogramming somatic cells, such as skin cells.  Both are actually pluripotent and have the ability to differentiate into almost any type of body cell.) (** The motor examination section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale, a standardized assessment tool.) Deep Brain Electrical Stimulation (DBS) Before the use of levodopa in the late 1960s, PD was often treated surgically with ablation of neural pathways that seemed to improve PD symptoms.  In the 1990s, it was discovered that providing electrical impulses to those neural pathways duplicated the effects of ablation.  DBS has some advantages over ablation as no tissue is destroyed, it can be turned on and off, and the amount and type of energy used can be adjusted.  One theory that partially explains why DBS works is that the high-frequency stimulation disrupts the pathological neuronal firing pattern in the targeted brain cells.[1] The procedure involves surgically inserting electrodes into the brain through a burr hole and then tunneling the wires to the anterior chest to a subcutaneously placed battery and controller in the upper anterior chest.  Once DBS is started, it is considered a lifelong treatment.  If the battery depletes or another technical issue acutely terminates DBS, a severe rebound of PD symptoms may occur, which may necessitate emergency medical care until the problem can be solved.  Regular battery and device monitoring is required to try to avoid these issues.[1] Three areas of the brain that are typically targeted in DBS are the ventral intermediate nucleus of the thalamus (VIM), the globus pallidus internus (GPi), and the subthalamic nucleus (STN).  All three have various advantages and disadvantages, which will be discussed later.  DBS can be unilateral or bilateral, and is usually performed bilaterally in patients with more severe disease.  Bilateral DBS of the GPi is typically better tolerated than bilateral VIM or STN, because it carries less risk of stimulation-induced dysarthria.[1] Genetic screening might be recommended for younger patients and those with atypical presentations of PD.  Certain familial genetic mutations that predispose to PD have been found to respond to DBS better than others.  Patients with mutation in the Parkin gene or the leucine-rich repeat kinase 2 (LRRK2) gene generally have a good long-lasting outcome from DBS, while patients with glucocerebrosidase mutations do not.[1] There are ongoing preliminary studies of using DBS in other parts of the brain, such as the pedunculopontine nucleus, substantia nigra reticularis, and the dentato–rubro–thalamic tract to try to determine if efficacy can be improved and side effects decreased.[1,2] Effectiveness on Symptoms by DBS Type Ventral Intermediate Nucleus of the Thalamus DBS Of the three approaches, VIM DBS is the most effective for tremors, however it has less of an effect than the other two commonly used brain DBS targets for rigidity, akinesia gait, and dyskinesias.  Thus, it is mainly used for patients whose main clinical issue is tremors.  Besides the risk of dysarthria, balance disturbances may also be an adverse effect due to spread of the current to the adjacent motor internal capsule.[1] Globus Pallidus Internus DBS GPi DBS is most commonly used to correct dopamine induced dyskinesias, which include painful dystonia, rigidity, akinesia and tremors.  It has a lesser effect on gait disturbances, such as freezing of gait. There is no age limit for use of GPi DBS and the risk of negative effects on balance and dysarthria are less than with VIM DBS.  Given its positive effect on dyskinesias, GPi DBS allows the patient to continue dopaminergic medications or even increase them if needed, without the risk of dopamine-induced dyskinesias.[1] Subthalamic Nucleus DBS STN DBS has a similar effect on tremors and rigidity as GPi with an added advantage of being the best of the three approaches for akinesia, gait and axial disturbances, (axial disturbances are balance, posture, speech, swallowing, locomotion, freezing of gait, and axial rigidity).  It is not as effective as GPi DBS for dyskinesias but is better than VIM DBS.  Potential issues with STN DBS include dysarthria, as well as mood swings and behavioral changes due to its proximity to the limbic cortical structures.  There is also a potential risk for eyelid opening apraxia (difficulty opening the eyelids that can be treated with botulinum injections).  Doses of dopaminergic medications, especially dopamine agonists, need to be decreased after surgery, as STN DBS will potentiate their effect, which can lead to increased impulsivity and mania.  However, if dopaminergic medications are decreased too much because of improved motor function, patients may suffer from apathy and depression.  The required adjustment of medication doses makes STN DBS somewhat more challenging to manage than GPi DBS.[1] In preparation for implantation of an STN DBS, several tests need to be performed.  One is the levodopa challenge, where motor symptoms are quantified before and after the administration of levodopa.  The greater the improvement of symptoms after a levodopa challenge, the more likely that the patient will benefit from STN DBS.  A psychiatric evaluation of the patient should be performed to avoid using STN DBS in patients with severe or untreated depression.  In some patients, there may be cognitive decline after STN DBS, so neuropsychologic testing is also generally performed to evaluate cognitive skills, including memory and executive function.  Studies have also revealed that while older patients may attain some improvement, they do not respond to STN DBS as effectively as younger patients.[1] To be approved for STN DBS, patients should have no or only mild cognitive impairment;  absence of, or well controlled psychiatric disease; younger age (in some centers, a cutoff age of  69-70 years has been instituted); and good response to the levodopa challenge. There has been some research into whether administering STN DBS to younger patients with PD earlier in the course of their illness might be helpful.  The EARLYSTIM study looked at this.  Subjects with troubling on/off symptoms who underwent STN DBS a median of seven years after diagnosis had better quality-of-life and motor outcome measurements compared to those treated 11 or more years after disease diagnosis.[1,17] In patients with dopaminergic medication-induced impulse control disorders, STN DBS may be considered instead of GPi DBS, because only STN DBS allows decreasing the dose of dopaminergic medication.[1] DBS Side Effect Control    Some adverse side effects of DBS may be controlled by an alteration of electrical stimulus strength, amplitude, pulse width, frequency, or polarity.[1] Adaptive Deep Brain Stimulation ( aDBS) In March 2025, the FDA approved a device that can deliver adaptive deep brain stimulation (aDBS).  Unlike standard DBS, aDBS adjusts stimulation parameters in real time, based on brain activity, whereas standard DBS only uses fixed parameters.  aDBS is based on measuring local field potential (LFP) in the GPi or STN. (aDBS measures LFP beta-band activity, a specific frequency range.)  LFP is thought to be a measure of synaptic input to neurons.  It has been found that the level of LFP activity decreases with PD medications and is present at higher levels in approximately 95% of patients in the off-medication state.  By delivering electrical impulses based on the patient’s LFP levels, aDBS can automatically adjust stimulation during “on” and “off” states. By measuring and responding to brain activity, aDBS potentially may reduce medication needs, improve off-time motor symptoms, and reduce periods of dyskinesia from excessive levodopa therapy.  aDBS may be most useful in STN DBS, where DBS in combination with levodopa can lead to adverse effects.[18,19] This technology was approved on the basis of the ADAPT-PD trial.  In that trial, 84% of the subjects had an LFP signal strong enough to use for aDBS programming.  There were two aDBS modes used in the study.  One was the single-threshold mode, with the device being set at a higher or lower level of stimulation based on the LFP signal setpoint used.  Dual threshold programming adds a middle zone, which allows for a more gradual increase and decrease of the electrical impulses.  Depending on the clinical setting, one mode may prove superior to the other.[18,19] Some patients have already received aDBS implants in 2025.  As more of these devices are implanted, additional research and refinements to the technique are likely to follow. Magnetic Resonance Imaging-guided Focused Ultrasound (MRgFUS) There has also been interest in MRgFUS as an alternative to DBS.  In MRgFUS, an externally directed ultrasound beam heats and ablates brain tissue.  No anesthesia is required.  A meta-analysis and systematic review of 20 studies and 258 subjects with drug-resistant PD, reported that the motor examination section of the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) improved for tremor and bradykinesia in MRgFUS treated patients, but over time the therapeutic effect decreased.  This decrease could represent an issue with the long-term effectiveness of MRgFUS or may be due to the progressive nature of PD.  MRgFUS had a positive impact on the treatment of motor symptoms in drug-resistant PD patients, especially in terms of tremor and bradykinesia.  There were adverse events in about 25% of subjects including: headache, ataxia, speech disorders, and dizziness.  Most adverse effects resolved within three months.  The authors concluded that more rigorous study designs, larger sample sizes, and longer follow-up times were needed to fully evaluate this modality.[20] Spinal Cord Stimulation Therapy for Gait Dysfunction Epidural spinal cord stimulation has been used to relieve chronic neuropathic back pain in patients.  There has been some research looking at this modality to alleviate motor and gait disorders in PD.  Authors of a comprehensive review looked at 27 case reports and studies.  The mechanism of action of epidural spinal cord stimulation for PD is not known, but one theory is that it disrupts aberrant low-frequency synchronous oscillations typically seen in neural pathways in PD.  In the reviewed studies, the electrodes were most commonly placed in the thoracic T7–T12 region or in the cervical C2–C3 region.  The authors concluded that while there may be some benefit to spinal cord stimulation in helping gait disorders in PD patients with neuropathic pain, the results have been mixed in patients without pain.  It is unclear whether relief from pain is what improves gait or if the electrical stimulation has a direct effect on PD. Much of the literature on this modality consists of case reports.  There have been no double-blinded studies, so it is not known how much improvement was from a placebo effect and at the present time it is unclear if this modality is effective for treating PD.[21] Summary PD is a progressive, incurable disease with multiple symptoms.  The only two proven modalities that are generally available to patients to reduce PD symptoms are medications and deep brain electrical stimulation.  The approval of adaptive DBS adds a new dimension to PD treatment that hopefully will improve symptom control.  There is a significant amount of research currently being performed using modalities such as alpha-synuclein reducers, gene therapies, stem cells, neurotrophic factors, MRgFUS, and spinal cord stimulation for PD, but much of this work is preliminary and it may take years to further validate safety and efficacy before they become available outside of a research setting. Author’s note: Thank you to Theodor Feigelman, MD for editing this article. References ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 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.  😇

Stay up to date on common sexually transmitted infections (STIs)—including gonorrhea, syphilis, chlamydia, HIV, and more—with key updates on screening, clinical management, and emerging threats. What’s New in Adult Sexually Transmitted Infections Management and Prevention By Stuart M. Caplen, MD   Reviewed and edited by Harish Moorjani MD This article highlights the latest advancements in the management and prevention of adult sexually transmitted infections (STIs).  We’ll explore updated treatment recommendations, promising new therapies and vaccine developments for some common STIs. Gonorrhea According to the Centers for Disease Control (CDC), there were 601,319 reported cases of gonorrhea, caused by Neisseria gonorrhoeae,  (a gram-negative diplococcus bacterium) in the U.S. in 2023, a decrease of 7% from 2022.[1,2]  Globally, in 2022, the World Health Organization (WHO) estimated that there were 82 million gonorrhea infections.[3] Gonorrhea typically presents with a white, yellow or greenish vaginal or urethral discharge.  More serious disease such as pelvic inflammatory disease, conjunctivitis (also seen in newborns if the mother is infected), pharyngitis, and disseminated infection with the possibility of arthritis, skin lesions, meningitis or endocarditis. There are three major updates in the treatment of gonorrhea.  The first is the concerning emergence of drug-resistant Neisseria gonorrhoeae , unresponsive to ceftriaxone therapy.  Ceftriaxone-resistant isolates increased in China from 2.9% in 2017 to 8.1% in 2022.[4]  In 2020 the CDC increased the standard dosage of ceftriaxone for uncomplicated gonorrhea from 250mg to 500mg due to increasing resistance.[5] Gram-negative intracellular diplococci of Neisseria gonorrhoeae Zoliflodacin, a new oral antibiotic to treat gonorrhea is in phase 3 clinical testing and in vitro has shown effectiveness in strains resistant to ceftriaxone and azithromycin.  Zoliflodacin inhibits the bacterial enzyme type II topoisomerase, which is needed for bacterial function and reproduction.[6,7] Two types of vaccines are currently being tested to prevent gonorrhea.  One is the meningococcal B vaccine (already in use to prevent Neisseria meningitidis  meningitis), to see if there is cross reactivity with Neisseria gonorrhoeae , as both organisms are Neisseria  species.[8] The second potential vaccine is in pre-clinical testing and creates an immunogenic response against small polysaccharide–protein outer membrane vesicles (OMVs).  OMVs are naturally created by many gram-negative bacteria using their bacterial cell membrane as the outer sphere of the OMV which is then extruded from the bacteria.  OMVs, after being released from the bacteria, then carry proteins to host cells which can result in biochemical changes in the host that allow the bacteria to better survive and multiply.  OMVs have antigens on their surfaces from the bacterial cell membrane that can be used in a vaccine to induce immunity.[9] OMV formation in gram-negative bacteria [10] Click here for current recommended gonorrhea therapy and for information on complicated infections. Syphilis Syphilis is a systemic bacterial infection caused by the spirochete Treponema pallidum . In 2023, the CDC reported there were 209,253 cases of syphilis in the U.S., an increase of 84% from 2018, and the highest number of cases reported since 1950.[1,2]  The WHO estimated that in 2022 there were eight million infections world-wide.[12] Two Treponema pallidum spirochetal bacteria magnified 950 times under darkfield illumination microscopy A syphilis vaccine has so far eluded scientists.[13] The treatment for uncomplicated primary and secondary syphilis in non-pregnant adults remains a single dose of benzathine penicillin G.  For penicillin-allergic non-pregnant patients, doxycycline is recommended.  Although azithromycin has in the past been effective in treating syphilis, due increasing resistance, it is no longer recommended.[14] Pregnant women who are allergic to penicillin should undergo desensitization for penicillin G prior to treatment.[14,15,16]  The treatment of pregnant women with syphilis differs from non-pregnant women and clinicians are advised to use the link below to get more information. There was a benzathine penicillin G shortage in early 2024 at which time the CDC recommended treating only pregnant women and neonates with congenital syphilis with benzathine penicillin.  The recommendation was to treat everyone else with doxycycline, but as of September 2024 the shortage had ended and benzathine penicillin G is again the recommended antibiotic for all.[14,17]     Click here for further information on syphilis, syphilis and pregnancy, tertiary and neurosyphilis and HIV patients with syphilis . Chlamydia Chlamydial infection, caused by Chlamydia trachomatis  is the most frequently reported bacterial infectious disease in the U.S.  In 2023 there were 1,648,568 reported cases of chlamydia, a decrease of 6% from 2018.[1,2]  In 2020, the WHO estimated there were 129 million chlamydial infections worldwide.[18] Doxycycline is first line treatment in adults, with azithromycin and levofloxacin as alternatives, although levofloxacin should not be used routinely due to potential adverse quinolone side effects.[19]  In pregnant women, azithromycin is first line therapy with amoxicillin as an alternative. Expedited partner therapy for chlamydial infections is permissible in 47 states and potentially allowable in three, although not specifically legislated for in those three states.  This allows patients to be given prescriptions for their partners, to try to reduce disease transmission and complications.[20] There is an experimental chlamydia vaccine currently called CTH522 which has completed a phase 1 trial.  In that trial, there were 3 intramuscular injections at 0, 1 and 4 months followed by intranasal administration at 4.5 and 5 months.  The vaccine induced anti-CTH522 IgG seroconversion in 100% of the fifteen subjects.[21] Click here for further information on chlamydial infections and treatment during pregnancy. Trichomoniasis An estimated 2.6 million people in the U.S. are infected with trichomonas, caused by the flagellated protozoan parasite Trichomonas vaginalis. [22]  According to the WHO, in 2020 there were approximately 156 million new cases worldwide of T. vaginalis  infections among people aged 15–49 years old.[23] Trichomoniasis is typically asymptomatic in men but may occasionally cause urethritis or prostatitis symptoms.  Women may be asymptomatic or present with a yellow-green vaginal discharge. Flagellated Trichomonas vaginalis The medication of choice is oral metronidazole, with tinidazole as an alternate drug.  Men can be treated with a single dose of metronidazole while women are generally treated for 7 days.[22]  Treatment recommendations are different when breast feeding or during pregnancy and providers are advised to review current recommendations. There is no current human vaccine for trichomoniasis but there is basic science research underway to try to develop one.[24] Click here for further information on Trichomonas  infections including during pregnancy and while breast feeding . HIV There are two new developments with respect to HIV (human immunodeficiency virus) treatment and prevention.  A phase1/2 trial was completed with five patients using the drug EBT-101, a CRISPR derived gene editing therapy designed to cure HIV.  It was well tolerated by the subjects.  However, three of the patients developed a rebound serum HIV viral load, indicative of a return of their HIV disease.  While EBT-101 at this dose did not succeed, further research into this type of therapy will continue, possibly at higher doses of EBT-101.[25] In 2022, the antiviral lenacapavir was approved by the FDA for treatment for patients with multiple drug-resistant HIV.  One of the advantages of lenacapavir is that it only needs be administered subcutaneously once every 6 months.[26] In July 2024, a phase 3 study for pre-exposure prophylaxis (PrEP) of HIV compared every 6-month subcutaneous lenacapavir versus daily oral HIV PrEP.  It was reported that no cases of HIV developed in 2,134 women who received subcutaneous lenacapavir.  Lenacapavir’s zero HIV conversion rate compared to 1.5%-1.8% new cases of HIV in the oral PrEP groups.  Lenacapavir’s 100% effectiveness in the phase 3 study is felt to be a major step forward in drug compliance and effective prevention of HIV.[27]  However, the cost of lenacapavir may be an issue as it currently costs tens of thousands of dollars more per year than oral HIV PrEP medications.  FDA approval is now being sought to allow use of subcutaneous lenacapavir for HIV PrEP.[26] Genital Herpes Simplex An estimated 491 million people worldwide ages 15-49 (13% of the total population) have had a herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.[28]  In 2018, among people aged 14-49 the CDC estimated that there were 572,000 new genital herpes infections in the U.S.[29]  Although much less common, herpes simplex virus type 1 (HSV-1), typically seen in the mouth or on the lips, can also cause genital herpes. The medications recommended in the treatment of genital herpes simplex are acyclovir, famciclovir, or valacyclovir. Recommended therapies for an initial infection are below. Recommended therapy for recurrent infections: EBT-104 is an investigational CRISPR-editing therapy for herpes simplex, still in pre-clinical investigation.  It has been reported that a single dose reduced herpes virus DNA by over 99.99% in laboratory cells[25] and significantly decreased viral shedding in a rabbit keratitis (corneal infection) model.[30] Click here for further information on genital herpes simplex infections including chronic suppressive therapy, treatment during pregnancy, severe infections and patient counseling . Human Papilloma Virus (HPV) There are about 200 viruses that can cause an HPV infection.  Some cause genital or oropharyngeal warts and some high-risk types can cause cancer, typically of the cancers of the vulva, vagina, mouth/throat, penis and rectum.[31]  About 90% of HPV infections are effectively eliminated by the immune system within two years, but some continue on to become cancerous.  It is estimated by the CDC that about 13 million Americans become infected each year and about 36,500 people per year are diagnosed with a cancer caused by HPV infection.[32,33]  In 2019, it was estimated by the WHO that HPV caused approximately 620,000 cancer cases in women and 70,000 cancer cases in men worldwide.[31] The CDC recommends two doses of HPV vaccine for all adolescents at age 11 or 12 years, that has been found to be over 90% effective at preventing HPV warts and induced cancers.[34] Click here for more information about the HPV vaccine . Click here for further information on the treatment of anogenital warts . Mycoplasma genitalium [35] Mycoplasma genitalium  has been found to be the cause in 15% to 40% of cases of urethritis in men.  In women with cervicitis, M. genitalium  has been found in 10% to 30% of cases and found in 4% to 22% of women who have pelvic inflammatory disease. M. genitalium  is an extremely slow-growing organism and culture can take up to six months.  The nucleic acid amplification test (NAAT) is considered the test of choice. There is increasing macrolide resistance to M. genitalium  and azithromycin is only recommended as first line therapy if macrolide sensitivity testing is available. Otherwise, the recommended treatment is doxycycline followed by moxifloxacin, each for 7 days. There appears to be a lack of consensus regarding the dosing schedule of azithromycin in pregnancy or when breast feeding.  Moxifloxacin and doxycycline are contraindicated during pregnancy.  In some areas of the world, pristinamycin is a second line drug for pregnant patients, but it is not available in the U.S. and data is limited as to safety.  Clinicians are advised to review the latest information before treating pregnant women.[36,37] Click here for more information on Mycoplasma genitalium  diagnosis and treatment . Summary Sexually transmitted infections affect millions of people each year.  Increasing antibiotic resistance, especially for gonorrhea, may present therapeutic challenges.  A new antibiotic to treat gonorrhea, zoliflodacin, is currently in clinical trials.  The incidence of syphilis is rising, but benzathine penicillin G is still the drug of choice. For HIV pre-exposure prophylaxis, an every 6-month injection of lenacapavir has been found to be very effective.  It is still waiting FDA approval in the U.S. for that indication and is more expensive than oral prophylaxis, which may be an issue limiting use. Vaccines, such as the HPV vaccine and ones being developed and tested for gonorrhea and chlamydia may be crucial in the future to help control global STI incidence. References

The Unconventional History of Coney Island's Incubator Babies Incubator exhibit at the Buffalo Pan-American Exposition in 1901 By Stuart M. Caplen, MD It's hard to believe that there was a time when the safest place for premature babies was in an amusement park exhibit rather than a hospital, but that was precisely the situation in from the late 1800s through to the 1940s. In the 1870s, Dr. Stéphane Tarnier, a French obstetrician, witnessed an incubator warming baby chickens at a Parisian zoo and thought if he could make a similar device, it could save premature babies from dying of hypothermia.  At the time, most premature infants died, and many doctors felt caring for them was pointless.  Tarnier’s initial designs weren't much better than blankets or hot water bottles used in many maternity wards.  However, Pierre Budin was a French physician who improved on the design, adding thermostats and improved ventilation. He reportedly asked his German medical student Dr. Martin Couney, to show off his device at the 1896 Berlin World’s Fair.  They “borrowed” six babies from a Berlin hospital, all of whom survived.  Couney later decided to exhibit the incubators at various exhibitions: London in 1897, Omaha in 1898, and Buffalo in 1901.  In 1903, he opened an incubator baby exhibit at the Luna Park section of the Coney Island Amusement Park and charged visitors to view the infants.  It soon became one of the most popular exhibits at Coney Island and was situated next to rides and freak shows.  There were barkers outside the exhibit to help attract customers.  In 1922, one of them was Archibald Leach, a British actor who would later change his name to Cary Grant. The cost of admission was 25 cents (about $9 in today’s dollars), but it was costing around $15 per day to take care of each infant (about $545 in today’s dollars).  Couney never charged the parents for his services and took care of infants of all races and classes.  He eventually opened a second unit in the Coney Island Dreamland section (which burned down in 1911 with no injuries to the babies) and later opened an Atlantic City exhibit, as well as showing the incubator babies at other exhibitions, including the 1933 Chicago World’s Fair and the 1939 New York World’s Fair. Coney Island Baby Incubator exhibit on the right side behind the luna ride. Premature infants were sent to him from local maternity wards, which were not able to properly take care of them, but occasionally parents would bring them in.  Doctors, nurses, and wet nurses were hired to take care of the infants and offered a standard of care that no hospital in the country could match.  He had exacting standards, and it was reported he would fire any wet nurse found eating hot dogs or having an orange sugared drink.  He even treated one of his daughters in the exhibit who was born prematurely, and who as an adult later worked as a nurse with the infants. Martin and Hildegarde Couney with boy looking at baby in incubator at NY World’s Fair His therapy was not accepted by the medical establishment for many years.  He was viewed by some as a tasteless showman.  The New York Society for the Prevention of Cruelty to Children accused Couney of exploiting the babies and endangering their lives by putting them in an exhibit.  However, one of Couney’s supporters was Dr. Julius Hess, considered today to be the father of American neonatology, who, at the 1933-1934 Chicago World’s Fair, partnered with Couney to open an incubator baby exhibit. Couney claimed to have an 85% survival rate, and over the course of his career saved 6,500 infants.  Even as late as the 1930s, a U.S. hospital might have no incubators or only one.  Care of these infants could prove to be prohibitively expensive, needing round-the-clock care, so Couney still received premature infants needing care from hospitals. Martin Couney holding two babies at the NY World’s Fair Beth Allen, born in 1941 and one of the babies treated by Couney, spoke of hospital medical care for premature infants at the time: “The doctors didn’t want it. They felt that the babies were weaklings. Either they lived or they died, and nobody made any great effort to save them.” The 1939-1940 New York World’s Fair was a financial disaster for Couney.  The structure was very expensive to build, requiring living quarters for over 20 staff members, and incubator babies were by this time no longer new and exciting to the general public.  In 1940, he tried to donate his incubators to the City of New York, but the offer was refused. In 1943, feeling his work was done, Couney closed his Coney Island exhibit when Cornell Hospital in New York City became the first hospital in the country to have a dedicated premature infant unit with incubators.  He died in 1950, reportedly penniless. The idea of a premature infant incubator exhibit, located next to amusement park rides and freak shows, and financed by the admission fees of visitors, sounds amazingly implausible today.  However, Couney’s treatment of premature infants was years ahead of the U.S. medical establishment, which took over 40 years to officially adopt his methods. ….….But that is not the end of the story.  Further investigation years later discovered that Couney was actually born Martin Cohen (or Cohn) in Prussia.  Although he said he studied medicine in Leipzig and Berlin, there was no evidence he actually was enrolled there.  One author claimed Couney was too young when he emigrated to the U.S. to have studied with Pierre Budin.  There is a question whether he actually was at the Berlin World’s Fair at all.  In the 1910 census, Couney reportedly listed his occupation as “surgical instruments”, but in 1930 his occupation on the census was “physician”  Thus, Couney’s entire background history may have been fraudulent, and if so, he could have potentially faced arrest.  There is a possibility that Couney imitated Alexandre Lion, a European inventor who improved Tarnier’s initial incubator designs and started running infant incubator exhibits at international exhibitions.  However, despite all that possibly being true, Couney’s contributions to premature infant care and the thousands of infants whose lives he saved cannot be denied. Baby incubator exhibit 1939 NY World’s Fair Click here to read the interesting story of how insulin was discovered and its first use in humans in  The History of Insulin and Type 1 Diabetes. You may also find these other history of medicine articles interesting: 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 Phrenology; Just Another Bump in the Road? References Erin Blakemore. Baby Incubators: From Boardwalk Sideshow to Medical Marvel. History. Last Updated: January 27, 2025. Retrieved from: https://www.history.com/articles/baby-incubators-boardwalk-sideshows-medical-marvels Rego Barry R. Coney Island’s Incubator Babies. JSTOR. August 15, 2018. Retrieved from: https://daily.jstor.org/coney-islands-incubator-babies/ Brangham W. How a Coney Island sideshow advanced medicine for premature babies. PBS News. Jul 21, 2015. Retrieved from: https://www.pbs.org/newshour/health/coney-island-sideshow-advanced-medicine-premature-babies Pollack M. The Incubated Babies of the Coney Island Boardwalk. The New York Times. July 31, 2015. Retrieved from: https://www.nytimes.com/2015/08/02/nyregion/the-incubated-babies-of-the-coney-island-boardwalk.html New York World’s Fair, 1939-1940. Neonatology on the Web . Last Updated on 11/19/24. Retrieved from: https://neonatology.net/gallery/exhibitions/new-york-worlds-fair-1939-1940/ Thorton  K. The Infantorium . 99% Invisible. Retrieved from: https://99percentinvisible.org/episode/the-infantorium/ Prentice C. The Man Who Ran a Carnival Attraction That Saved Thousands of Premature Babies Wasn’t a Doctor at All. Smithsonian magazine. August 19, 2016. Retrieved from: https://www.smithsonianmag.com/history/man-who-pretended-be-doctor-ran-worlds-fair-attraction-saved-lives-thousands-premature-babies-180960200/ Getlen L. Fake doctor saved thousands of infants and changed medical history. NY POST. Published July 23, 2018.Updated July 24, 2018. Retrieved from: https://nypost.com/2018/07/23/how-fake-docs-carnival-sideshow-brought-baby-incubators-to-main-stage/ Madrigal I. How Martin Couney’s Coney Island Incubator Showcase Saved Thousands of Premature Babies. Untapped New York. August 23, 2022. Retrieved from: https://www.untappedcities.com/martin-couney-coney-island-incubator-showcase/ Gras T. Alexandre Lion: The Forgotten Inventor of Incubator Shows. Pediatrics. Volume 150, Issue 3. September 2022. Retrieved from: https://publications.aap.org/pediatrics/article/150/3/e2021054576/188774/Alexandre-Lion-The-Forgotten-Inventor-of-Incubator?autologincheck=redirected Photos: Incubators on display at an exhibition in 1901. Library of Congress. Nesensohn C, Luna Park: Facing Luna Ride and Baby Incubators, Rare Book & Manuscript Library, Columbia University, Retrieved from: https://blogs.library.columbia.edu/longview/2018/10/under-the-lens-coney-islands-baby-incubators/ Martin and Hildegarde Couney with boy looking at baby in incubator. NY Public library. Retrieved from: https://digitalcollections.nypl.org/items/5e66b3e8-bd2d-d471-e040-e00a180654d7 Martin Couney holding two babies. NY Public Library. Retrieved from: https://digitalcollections.nypl.org/items/5e66b3e9-0a07-d471-e040-e00a180654d7 Wurts brothers. Baby Incubators exhibit building at the New York World's Fair. Museum of the City of New York. 1939. https://collections.mcny.org/CS.aspx?VP3=DamView&VBID=24UP1GZ0ENGCV&SMLS=1&RW=1869&RH=919

Medical Trivia During the American Civil War many soldiers were treated with morphine which led to a wave of morphine addiction in the second half of the 19th century, and a search to try to find safer alternatives. by Stuart M. Caplen, MD   In 1874, Charles Romley Alder Wright, a chemist looking for a non-addictive painkiller, boiled anhydrous morphine alkaloid with acetic anhydride and produced an acetylated form of morphine, called diamorphine (or diacetylmorphine).  There was not much interest in this compound until 1897.  In that year, Heinrich Dreser, the head of the  pharmaceutical division at Bayer Company, asked chemist Felix Hoffman to come up with a way to synthesize the compound as a result of some favorable reports from investigators and a growing interest in the drug by the medical profession. (Hoffman had just synthesized aspirin two weeks before this.) Hoffman came up with a way to synthesize the compound commercially.  After trying the drug, a chemist at Bayer supposedly said it made him feel heroic ( heroisch in German) and because of that statement, it was decided to call the drug heroin. It was advertised by Bayer as a non-addictive substitute for morphine and could be used for a variety of disorders, especially cough, even in children.  Heroin was also used to combat codeine and morphine addiction.  Bayer heroin and aspirin were often advertised together.  Unfortunately, heroin is rapidly metabolized into morphine and other active morphine metabolites inside the body.  In the early 1900s, the problematic nature of heroin came to be noticed, and soon heroin addiction replaced morphine addiction as a major social problem.  In 1910, Bellevue Hospital in New York City admitted its first heroin addict, but five years later, it admitted 425 heroin addicts. The Public Health Service Hospitals in the United States discontinued dispensing heroin in 1916.  In 1920, the House of Delegates of the American Medical Association recommended “that heroin be eliminated from all medicinal preparations and that it should not be administered, prescribed, nor dispensed; and that the importation, manufacture, and sale of heroin should be prohibited in the United States.” In 1913, Bayer stopped manufacturing heroin, and in 1924, heroin was banned in the U.S.  An interesting bit of trivia is how the word "junkie" came into being to describe heroin addicts.  It was purportedly coined due to addicts going through junkyards looking for scrap metal to sell to obtain money.  ________________________________________________________________________________________________________ Links to other history of medicine articles you may find interesting: The History of Cocaine The Creation of the Gin and Tonic; a Medical Odyssey The History of the Iron Lung The History of the Coney Island Incubator Babies Benjamin Franklin, Mesmerism, and the First Use of Placebos in Science The Story of the Most “Kissed” Face in the World ________________________________________________________________________________________________________ Resources History of Heroin. United Nations. 1/1/1953. https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page004.html Schwarcz J. Why are people addicted to heroin called “junkies?” Office for Science and Society, McGill University. 11 Sep 2021 https://www.mcgill.ca/oss/article/history-you-asked/why-are-people-addicted-heroin-called-junkies The history of heroin and its predecessors. UK Addiction Treatment Centres. Last Updated: December 5th, 2023. https://www.ukat.co.uk/blog/substance-abuse/the-history-of-heroin-and-its-predecessors/ The history of heroin: From King Tut to cough remedy. The Palm Beach Post. 2018. https://heroin.palmbeachpost.com/history-of-heroin/