seX & whY

Show Notes for Episode Twenty of seX & whY: Interview With Dr Shirin Heidari Part 1: Sex and Gender Variables in Science Research

Host: Jeannette Wolfe Guest: Shirin Heidari PhD, virologist and experimental oncologist, founding President of Gendro.

Part 1 of this podcast spotlights the opportunity to do better science by paying more attention to the variables of sex and gender.

Many times, we simply assume that when we study a medical question in a clinical trial that who is in the trial, adequately represents the population of folks who are affected by the condition being studied. When it comes to the consideration of gender, often this is not true. Dr Heidari and her team did a systemic review that evaluated study participant's gender in HIV research trials, although more than 50% of people who have HIV are women, only 19% of participants in anti-retroviral trials were women.

In 1993 the NIH passed the Revitalization Act in which NIH funded studies would be required to study both men and women. A parallel mandate for basic science research passed over 20 years later in 2015. In some ways this is incredibly nonsensical because most of medical research starts out in the basic science lab. If you don't include animals of both sexes, in adequate numbers, from the beginning, you could be later blindsided in an expensive clinical trial by a physiological sex-based differences that could have been picked up earlier.

Even though there has been progress over the past 30 years, Dr Heidari repeatedly makes the case that just because there are guidelines to include males and females in trials, this does not mean that these guidelines are adhered to or adequately enforced. In addition, there is often a large divide between including men and women in a study and doing an appropriate analysis to see what happens to those men and women. Essentially including both men and women isn't all that helpful unless you breakdown your results also by gender. Importantly, the very best studies go even a step further - they include a calculation in the original study design to determine how many men and how many women would need to be included in a study so that if a difference is found that the researchers can be more confident that the difference represents a real finding and not a statistical blip.

Another important point discussed, is the chance for skewing of study results if researchers don't consider the gender breakdown of who drops out of a trial. Although it is not uncommon for studies to have a small number of participants drop out (and this can happen for a bunch of different reasons ranging from side effects to an inconvenient study location) it is uncommon for them to report the gender breakdown of the dropouts. If significantly more women, or men, drop out of a trial this could be a red flag that something else might be going on and hint to potential problems with the study's conclusions.

Our conversation then veered to discussing pharmacokinetics and pharmacodynamics. Pharmacokinetics tells us about how the body influences a drug - specifically how a drug gets absorbed, distributed, and metabolized. Pharmacodynamics, on the other hand, tells us how the drug influences the body. An example I like to use is to compare giving someone a medication to hiring a secret agent. In both cases, there is a break in, a job and an exit. Traditionally it was believed that, outside of extreme differences in body weight, that drugs worked similarly- break in/job/exit - in male and female bodies if the drug did not target a reproductive organ. We now know this default "no sex difference" assumption is not scientifically valid as there are many drugs which work differently in male and female bodies and that these differences have clinical relevancy.

An example of this is a study we discussed on marijuana pharmacokinetics with women requiring far less amount of marijuana to experience the same cognitive effects. In the discussion section of this paper it suggests that previous studies may have under-appreciated this sex-based difference because they often had higher dropout rates in women which likely skewed their final study results. And here is the link to some of the material we discussed surrounding the knowledge gap on pregnancy and pot-smoking and how this gap has caused some pregnant women to reach out to non-traditional resources to get information.

Other studies we mentioned

Here is a study that suggests that the gender of the researcher or lab tech may subtly influence research results.

Here is a study that suggests that male and female animals both have similar amounts of hormonal variation.

Show Notes for Episode Nineteen of seX & whY: About Vaccine Research

Host: Jeannette Wolfe Guests:

• Christine Dahlke, Biologist and vaccine researcher at University Medical Center Hamburg-Eppendor and The German Center for Infection Research
• Marylyn M Addo, Physician, Professor, Infectious disease specialist and vaccine researcher from University Medical Center Hamburg-Eppendor and The German Center for Infection Research

Link to their paper: Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens

Take-home points

• Vaccine development has evolved over the years from having each vaccine be independently developed "one drug for one bug" to "plug and play" platform technology in which a vector that predictably and effectively triggers the immune system is attached to a new pathogen's antigen (or mRNA or DNA that codes for that antigen), allowing for a much more accelerated development of new vaccines because researchers are not starting from scratch every time.
• Researchers often test antibody levels to determine vaccine efficacy but, immunization changes other aspects of the immune system such as t cell response and some innate immunity too. These changes may be more difficult to test but may also be important for long term protection even if antibody levels fall.
• Traditionally, drug companies have not been all that excited about developing vaccines due to the lack of a profit margin compared to a drug someone needs to take every day. The Coalition for Epidemic Preparedness Innovation (CEPI) helped jump start vaccine development in 2017 (apparently this was sparked by the realization that Ebola could have become a global pandemic and that we needed more tools to develop rapid turn- around vaccines.)
• Sex differences - due to sex hormones and chromosomes - influence how a body's innate and adaptative immune system works. Women generally having an advantage in fighting off infection by having a more robust innate and adaptative immune system. This may come at a cost of increased risk for autoimmune disease and in Covid, women are also much more likely to have long haul Covid symptoms. Age can act as an additional confounder with males having more impaired antibody response and increased innate inflammatory responses with age
• Most immune cells have sex steroid receptors on them
• Many genes that influence the immune system are housed on the X chromosome and some of them like Toll-like receptor 7 - aka the Paul Revere of the early immune response, may not undergo X-inactivation leading to it's over expression in females and possibly giving them an advantage in decreasing their viral load compared to males after similar exposures.

Other references:

Paper referred in podcast about Dr Klein: Bishof E, Wolfe J, Klein S - Clinical trials for COVID-19 should include sex as a variable.

Podcast from last summer with my interview with Evelyn Bishof and Sabra Klein about Sex Differences in Immunology and Drug Therapy

Herpes vaccine trial showing efficacy in females and not in males.

Here are some videos on the immune system:

• Dr Iwasaki
• Made Easy
• New York Times article nicely explaining how different vaccines work

Show Notes for Episode Eighteen of seX & whY: Mike Gisondi Announces Stanford's New, Open Access Course, "Teaching LGBTQ+ Health"

Host: Jeannette Wolfe Guest: Dr Mike Gisondi, Vice Chair of Education at the Department of Emergency Medicine at Stanford University

How prepared are you to teach the next generation of medical learners about issues surrounding care issues of LGBTQ patients?

What if you could have a free (yes, free) and totally cool resource to increase your knowledge and confidence about this material.

Drumroll……

Introducing- with perfect timing to align with LGBTQ health awareness week- an online CME course called:

Teaching LGTBQ+ Health: a faculty development course for health professions educators.

Access through Stanford Educational Technology

Not a health care provider? No problem! You can access this information too! Did we say that it is free, free, free!

Trailer: http://bit.ly/TeachLGBTQHealth

Course Site: https://mededucation.stanford.edu/courses/teaching-lgbtq-health

Stanford's Teaching LGBTQ+ Health course: Learners across the health professions demand improved LGBTQ+ health content and additional training opportunities in their schools' curricula. However, most clinician educators received little, if any, training in LGBTQ+ health when they were students. This free, online, CME course addresses the gap between expected faculty teaching competency and a lack of previous faculty training.

The course is open access to educators across the health professions, as well as other providers, staff, trainees, and patients. It includes both LGBTQ+ health content and recommendations for teaching this material to trainees in any discipline or clinical department. Educators may freely download portions of the course for use in their daily clinical teaching or their school's curriculum.

Authors: Michael A. Gisondi, MD Shana Zucker, MD/MPH/MS (cand.) Timothy Keyes, MD/PhD (cand.) Deila Bumgardner, MA

Show Notes for Episode Seventeen of seX & whY: Impact of Gendered Masculinity in Health Engagement and Decision-making

Host: Jeannette Wolfe

Guests: Dr Fahad Saeed, Nephrologist and Palliative Care Specialist from the University of Rochester

Dr Lauren J. Parker, PhD, Dual PhD in Gerontology and Health Promotion, scientist at the Johns Hopkins Bloomberg School of Public Health

The topic today discussed how masculinity and race can impact access to health and health related decisions.

Take home points

• Overall, men have a shorter life expectancy than women and this is likely influenced by both biologically and sociocultural based factors associated with an individual's gender identity
• Race based stressors amplify these sociocultural mortality differences
• Men are less likely to access preventative health care services and some of this is likely related to biological sex differences and behavioral patterns that begin in early adulthood as females are more likely to interact with health systems due to pregnancy and child related issues.
• Sociocultural "masculinity norms" may discourage health engagement due to an individual's desire to be perceived as tough and independent.
• Ways to better engage men with their health (with an emphasis on men of color)

Increase public messaging to normalize the need for men's preventative health

Increase diversity amongst medical providers

Reach men where they are like sporting events, barber shops and churches

Acknowledge and appreciate the unique roles and challenges that many men face

Target and adjust messaging to engage men at different life points

• Men can get caught in a warrior-like mentality which may impact their end-of-life choices. In cancer patients this may make them less receptive to palliative care due to a concern that it may suggest that they are "giving up".

Palliative care is a specialty that helps patients, and their families cope with a life shortening illness and to optimize their quality of life. Patients in palliative care can still receive aggressive disease modifying therapy like chemotherapy with the except of patients receiving "hospice care". Hospice care, although still under the palliative care umbrella, has slightly different rules. Under hospice, it is recognized that a patient is likely in their last 6 months of life and that they would no longer benefit from aggressive treatments, all care is redirected to optimize comfort.

Dr Saeed's tips surrounding palliative care engagement in men with advanced cancer

• Normalize messaging such that palliative care is considered a natural part of cancer treatment
• Appreciate impact of non-verbal language- be authentic in conversation
• Recognize that most conversations have a logical and emotional component and appreciate that both need to be addressed
• Take time to know the patient's story, this humanizes the interaction and increases empathy
• Remember goal is to figure out their preferences and then honor them
• Sometimes shifting focus from fighting terminal cancer to fighting for comfort and to ease families suffering can make patients more amenable to palliative care services

Links

- Dr Lauren Parker's paper that examines ways to more effectively engage men in their health. - List of her other publications- TEDX Rochester talk by Dr Saeed - Links to Dr Saeed's publications - His specific research that we discussed - 2012 paper that Dr Saeed referenced by Susan Wong

Show Notes for Episode Sixteen of seX & whY: Interview with Dr Saralyn Mark

Host: Jeannette Wolfe

Dr Mark has had an incredibly interesting and eclectic career. She is trained in Endocrine, Geriatrics and Women's Health and has worked for and/or consulted with:

The Office of Women's Health in Department of Health and Human Services, NASA and 4 different Whitehouse Administrations

She has also written the book Stellar Medicine: A Journey through the Universe of Women's Health

In addition, she has founded two different companies

• Solamed Solutions a boutique consulting firm that advances scientific and strategic direction for public and non-public sectors
• The non-profit iGIANT (Impact of Gender and Sex on Innovations and Novel Technologies)

Our discussion features some of the highlights of Dr Mark's career as well as surveys a bunch of uncommonly recognized, yet important sex and gender based differences in medicine, technology and industry. We talk about sex and gender based differences in military equipment, PPE, laparoscopic tools, automobile safety and Covid-19.

Show Notes for Episode Fifteen of seX & whY: Sex Differences in Immunology and Drug Therapy

Host: Jeannette Wolfe

Guests:

Evelyne Bischof MD, Associate Professor of Medicine at Shanghai University of Medicine and Health Sciences and internist at University Hospital of Basel Switzerland

Sabra Klein, PhD, Professor of Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health

This podcast focused on sex differences in immunology and pharmacology and its relevance to the Covid-19 pandemic.

Key points

• Males are more likely to be admitted to the ICU and die from COVID-19 compared to females
• Males and females have differences in both innate and adaptive immunity (which likely are a combo of chromosomal, hormonal and epigentic differences)
• One difference in Innate immunity (the initial non-specific reaction to a foreign pathogen) is Toll-like receptor 7 (TLR7) This is a major player in the initial physiological response to a foreign pathogen and the gene for it is on the X chromosome. X-lined genes (like Ace-2 which is the receptor which SARS-Cov-2 initially binds to in the body) are interesting because they immediately bring up two considerations. First, if someone has a specific variant of that gene, it could change their susceptibility to certain pathogens. Males, as they have an XY pair of sex chromosomes, only have one X chromosome and thus could be more adversely impacted than females (XX) who have a second copy of the gene (which may or may not express the same variant) from their other X chromosome. The second consideration is that in the cells of most females, one of the X chromosomes is automatically turned off (X inactivation). It appears however, that some X-linked immune cells- like TLR7- don't do this, leading to the possibility of increased expression of the gene like getting an "extra dose".
• In adaptive immunity (which involved B and T cells), females generally have a greater immunological response to most pathogens.
• As such, females generally exhibit a more robust immune response to natural infections and vaccinations. The flip side, however, is compared to men, women are also at greater risk for autoimmune diseases and are more likely to get local and systemic reactions after a vaccination.
  • When testing the effectiveness and side effects of SARS-CoV-2 vaccines it would be ideal to consider the variables of biological sex and age.
  • In an influenza study, when women were given a ½ dose of the flu vaccine, they mounted a similar immune response to males who got full dose. If the same held true for developing SARS-Cov2 vaccinations, it could potentially increase the amount of vaccine available (though it is unclear if this is even being considered in early vaccine trials).
  • Aging can also impair the immune response and older adults may require higher doses of booster doses of some vaccines to optimize their immune response
• The use of Artificial Intelligence in drug development may revolutionize the pharmaceutical research industry by allowing more predictive drug modeling leading to more successful drug development.
• This could also be used to better identify potentially important biological sex- based pharmacodynamic and pharmacokinetic differences earlier in drug development.

Two unexpected findings associated with COVID-19

• Males appear to be more vulnerable to cytokine storm (mechanism still not entirely clear may be differences in ACE-2 receptors, or chromosomal/hormonal differences in innate/adaptive immune system)
• Elderly sick males who survived COVID-19 appear to have significant protective antibody production against SARS-Cov2

References:

Bischof E, Wolfe J, Klein S: Clinical trials for Covid-19 should include Sex as a Variable. JCI 2020

Engler R, Nelson M, Klote M, et al. Half- vs Full-Dose Trivalent Inactivated Influenza Vaccine (2004-2005) Age, Dose, and Sex Effects on Immune Responses, JAMA Internal Medicine 2008

Gender and COVID-19 Working Group website

Global Health 50/50 global deaths disaggregated by sex

Klein S, Pekosz A, Park H. et al. Sex, age and hospitalization drive antibody responses in a Covid-19 convalescent plasma donor population. JCI 2020

Roberts M, Genway S How Artificial Intelligence is transforming drug design. DDW

Souyris M, Cenac C, Azar P, et al. TLR7 Escapes X Chromosome Inactivation in Immune Cells. Autoimmune Disease 2018

Takehiro T, Ellingson M, Wong P et al. Sex Differences in Immune Responses that underlie COVID-19 disease outcomes. Nature 2020

Zucker I, Prendergast B. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences 2020

Special thanks to Doug Deems for help with editing

Show Notes for Episode Fourteen of seX & whY: COVID-19 through a Gender Based Lens Part 2

Host: Jeannette WolfeGuests: Dr Gary Barker CEO of Promundo- an organization that promotes healthy masculinity and gender equality

Dr Stephen Burrell Assistant Professor in the Dept of Sociology at Durham University - whose area of focus in on engaging men and boys in the prevention of violence against women.

Here are some of the take-home points of our discussion.

• The need to clearly label preliminary studies as "preliminary" to avoid early adoption of inadequately proven therapies
• The importance of both including both males and females in research drug trials and in analyzing results by biological sex. (For example, from toxicology research it is known that females are at greater risk for drug-induced QTc prolongation - which can trigger a dangerous arrhythmia- than men, yet this consideration was not taken into the design and analysis of almost all the hydroxychloroquine studies even though we know that QTc prolongation is one of this drug's most well-known side effects.
• The need to go beyond biological sex to look at social and environmental determinants that help identify "which men" or "which women" (or "which nonbinary person") is at greatest risks so that we can better direct interventions. This approach often quickly spotlights longstanding heath inequity issues.
• If the goal is to improve health outcomes to consider subtly shifting the approach away from how can men better engage with health care systems towards how can health care systems better engage with men is quite important. Dr Barker shared an excellent example of a project he was involved with in Brazil in which men were approached during their partners prenatal clinic visits to make their own health related appointments.
• This pandemic has been associated with some significant collateral health related damage including: people being afraid to seek out medical care for true emergencies; huge shortages of reproductive health services; increasing prevalence of domestic violence; and mental health related issues triggered by loneliness and isolation.

Here is the link to the Pew Study that Dr Barker mentioned.

Here is the link for the Harvard GenderSci

Here are some links for the challenges India is having with obstetrical care including this NY Times article

Amanda Nguyen's Rise UP 19 program that allows domestic violence victims to be helped by restaurant owners.

Special thanks to Doug Deems who helped me edit this podcast.

Show Notes for Episode Fourteen of seX & whY: COVID-19 through a Gender Based Lens Part 1

This is a discussion on how gender-associated norms impact disease process.

Host: Jeannette Wolfe Guests: Dr Gary Barker CEO of Promundo- an organization that promotes healthy masculinity and gender equality

Dr Stephen Burrell Assistant Professor in the Dept of Sociology at Durham University- who's area of focus in on engaging men and boys in the prevention of violence against women.

Today's podcast features the first part of our discussion which focuses on how "gender" roles and norms impact general health and the COVID-19 pandemic. Both of our guests are experts on how societal perceptions and stereotypes surrounding "masculinity" influence the health and well-being of both men and women. Through Promundo, Dr Barker has done significant amounts of work in Brazil where toxic masculinity has been associated with the early deaths of millions of young men and Dr Burrell recently wrote the article: Coronavirus reveals just how deep macho stereotypes run through society.

Our discussion focuses on:

• The intentionality required to engage diverse groups of people to actually talk about how gender and masculinity associated issues significantly impact health outcomes.
• Research from Promundo which suggests that of the about overall 5 year mortality difference between men and women, that about 20% of that gap is due to genetics and about 50% is associated with the following three factors:
  • diet
  • smoking
  • substance abuse
• The recognition that more men than women are dying of Covid-19 and that we need to go beyond binomial data to look at "which" men and "which" women are at highest risk for death which leads us to the intersection of biological sex and other sociocultural influences.
• How the words different countries use to describe the pandemic often appear to reflect that country's approach in how they are addressing it.
• The importance of intentionally creating neuro and cultural diversity amongst teams tasked to solve complicated problems.

Show Notes for Episode Thirteen of seX & whY: LGTBQI Health-related Issues Part 3

How best to support students and colleagues in the LGBTQ community

This is a very special podcast and I want to deeply thank Shana Zucker, Ellie Ragone and Mike Gisondi for sharing their very personal experiences.

Host: Jeannette Wolfe Guests:

Shana Zucker, MS

• Shana is a rising 4th year medical student at Tulane in the MD/PhD program
• When she was a first-year medical student at Tulane she helped to create The Queericulum, an educational program geared at helping medical students become more culturally competent surrounding LGTBQ health related issues and patient interactions
• Since its creation, it has now become a mandatory course for all first-year Tulane medical students and she is currently working to expand the program to other medical schools
• In addition, she and Mike are creating (with another MD/PhD student at Stanford) an online educational program to help medical educators teach medical students about LGTBQ health
• Here is Shana's talk at Feminem's Fix conference in NYC

Ellie Ragone DO

• Is a first-year emergency medical resident at UMMS-Baystate
• Ellie is a transwoman and has graciously shared her personal experiences about transitioning as a medical student
• One of her largest concerns about transitioning was being able to successfully identify a primary care provider who was both competent and comfortable with LGTBQ patients and their health-related needs

Michael Gisondi

• Vice chair of education at the Dept of EM at Stanford
• Mike shares how his identity formation was actually quite different at different points of his own life
• He reflects on the generational differences of LGBTQ physicians

Tips offered by the group

• If you have a trans colleague and you misgender them, besides apologizing in real-time, consider sending them an email or text later on to let them know you have reflected upon the mistake and appreciate the challenges they are routinely facing and that you want to support them.
• When you are looking at a program or job, be authentic and find the program who accepts you for who you are versus trying to be the image of the person you think the program wants.
• Let medical students and residents lead. They often are much more on point about what does and doesn't work than most senior educators

Accountability buddy article

https://www.aliem.com/peer-accountability-strategy-maintaining-commitment/

Special thanks to Doug Deems who helped me edit this podcast

Show Notes for Episode Thirteen of seX & whY: LGTBQI Health-related Issues Part 2

How to take better care of transgender patients when they seek medical care

Host: Jeannette Wolfe Guests:

• Dr Elizabeth Samuels Assistant Professor of Emergency Medicine Warren Alpert School of Medicine at Brown University
• Dr Michelle Forcier Professor of Pediatrics at Warren Alpert School of Medicine at Brown University and Director of Gender and Sexual Health Services

Quotes used are from Dr Samuel and her team's paper: "Sometimes You Feel Like the Freak Show": A Qualitative Assessment of Emergency Care Experiences Among Transgender and Gender-Nonconforming Patients Ann Emerg Med 2018

Here are 10 take-home points

1. Delivering Intentional habits to care for our transgender patients actually helps us deliver better care to our cisgender patients too.
2. Appreciate that many trans and gender non-conforming patients are incredibly reluctant to seek out medical care due to previous discriminatory treatment,
3. Don't assume a trans patient is out to the other people in the room and offer to speak with them privately
4. Ask their name, if different than expected ask them if they have a different legal name, then confirm how they would like to be addressed and what pronouns they use.
5. Respectfully update other team members about this information so that the patient doesn't need to unnecessarily repeat themselves. Importantly how we model this message to our staff can set the tone for how these patients will be treated, so take this responsibility seriously.
6. When asking about past medical history, surgical histories and current medication make sure that you are clear as to why you are asking and how it relates to their current medical problem.
7. In trans patients that present with abdominal pain, don't assume because they physically look like their asserted sex that they lack organs from their biological one such as ovaries or a prostate. Remember to ask.
8. When admitting a trans patient, if a private room is unavailable they should be roomed with patients of their asserted gender.
9. If not already doing so, encourage your hospital to use software that allows an individual's sexual orientation and gender identity to be included in a separate field of their medical record
10. If you are a medical educator, look for ways to include an issue