Effect of Feminizing Hormone Therapy on QTc Interval: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial investigates the effect of spironolactone and cyproterone acetate hormone therapy on the QT interval corrected for heart rate among transgender women and nonbinary or transfeminine individuals.

Conductive gradient hydrogels allow spatial control of adult stem cell fate.

Electrical gradients are fundamental to physiological processes including cell migration, tissue formation, organ development, and response to injury and regeneration. Current electrical modulation of cells is primarily studied under a uniform electrical field. Here we demonstrate the fabrication of conductive gradient hydrogels (CGGs) that display mechanical properties and varying local electrical gradients mimicking physiological conditions. The electrically-stimulated CGGs enhanced human mesenchymal stem cell (hMSC) viability and attachment. Cells on CGGs under electrical stimulation showed a high expression of neural progenitor markers such as Nestin, GFAP, and Sox2. More importantly, CGGs showed cell differentiation toward oligodendrocyte lineage (Oligo2) in the center of the scaffold where the electric field was uniform with a greater intensity, while cells preferred neuronal lineage (NeuN) on the edge of the scaffold on a varying electric field at lower magnitude. Our data suggest that CGGs can serve as a useful platform to study the effects of electrical gradients on stem cells and potentially provide insights on developing new neural engineering applications.

Enhancing Therapeutic Insulin Transport from Macroencapsulated Islets Using Sub-Minute Pressure at Physiological Levels.

Cadaveric islet and stem cell-derived transplantations hold promise as treatments for type 1 diabetes. To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques have been developed that utilize diffusion to transport insulin across an immunoisolating barrier. However, despite several devices progressing to human clinical trials, none have successfully managed to attain physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with homeostatic, on-demand insulin delivery and physiologic glucose regulation, when reliant solely on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical proof and experimental validation that applying pressure at levels comparable to physiological diastolic blood pressure significantly enhances insulin flux across immunoisolation membranes-increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pump-based extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, effectively replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation. One Sentence Summary: Towards improved glucose control, applying sub-minute pressure at physiological levels enhances therapeutic insulin transport from macroencapsulated islets.

The Impact of Gender-Affirming Hormone Therapy on Physical Performance.

CONTEXT: The inclusion of transgender people in elite sport has been a topic of debate. This narrative review examines the impact of gender-affirming hormone therapy (GAHT) on physical performance, muscle strength, and markers of endurance. EVIDENCE ACQUISITION: MEDLINE and Embase were searched using terms to define the population (transgender), intervention (GAHT), and physical performance outcomes. EVIDENCE SYNTHESIS: Existing literature comprises cross-sectional or small uncontrolled longitudinal studies of short duration. In nonathletic trans men starting testosterone therapy, within 1 year, muscle mass and strength increased and, by 3 years, physical performance (push-ups, sit-ups, run time) improved to the level of cisgender men. In nonathletic trans women, feminizing hormone therapy increased fat mass by approximately 30% and decreased muscle mass by approximately 5% after 12 months, and steadily declined beyond 3 years. While absolute lean mass remains higher in trans women, relative percentage lean mass and fat mass (and muscle strength corrected for lean mass), hemoglobin, and VO2 peak corrected for weight was no different to cisgender women. After 2 years of GAHT, no advantage was observed for physical performance measured by running time or in trans women. By 4 years, there was no advantage in sit-ups. While push-up performance declined in trans women, a statistical advantage remained relative to cisgender women. CONCLUSION: Limited evidence suggests that physical performance of nonathletic trans people who have undergone GAHT for at least 2 years approaches that of cisgender controls. Further controlled longitudinal research is needed in trans athletes and nonathletes.

Disruption of gender-affirming health care, and COVID-19 illness, testing, and vaccination among trans Australians during the pandemic: a cross-sectional survey.

OBJECTIVES: To assess rates of disruption of gender-affirming health care, of coronavirus disease 2019 (COVID-19) illness, testing, and vaccination, and of discrimination in health care among Australian trans people during the COVID-19 pandemic. DESIGN, SETTING: Online cross-sectional survey (1-31 May 2022); respondents were participants recruited by snowball sampling for TRANSform, an Australian longitudinal survey-based trans health study, 1 May - 30 June 2020. PARTICIPANTS: People aged 16 years or older, currently living in Australia, and with a gender different to their sex recorded at birth. MAIN OUTCOME MEASURES: Proportions of respondents who reported disruptions to gender-affirming health care, COVID-19 illness, testing, and vaccination, and positive and negative experiences during health care. RESULTS: Of 875 people invited, 516 provided valid survey responses (59%). Their median age was 33 years (interquartile range, 26-45 years); 193 identified as women or trans women (37%), 185 as men or trans men (36%), and 138 as non-binary (27%). Of 448 respondents receiving gender-affirming hormone therapy, 230 (49%) reported disruptions to treatment during the pandemic; booked gender-affirming surgery had been cancelled or postponed for 37 of 85 respondents (44%). Trans-related discrimination during health care was reported by a larger proportion of participants than in a pre-pandemic survey (56% v 26%). COVID-19 was reported by 132 respondents (26%), of whom 49 reported health consequences three months or more after the acute illness (37%; estimated Australian rate: 5-10%). Three or more COVID-19 vaccine doses were reported by 448 participants (87%; Australian adult rate: 70%). CONCLUSIONS: High rates of COVID-19 vaccination among the trans people we surveyed may reflect the effectiveness of LGBTIQA+ community-controlled organisation vaccination programs and targeted health promotion. Training health care professionals in inclusive services for trans people could improve access to appropriate health care and reduce discrimination.

Wirelessly Powered-Electrically Conductive Polymer System for Stem Cell Enhanced Stroke Recovery.

Effective stroke recovery therapeutics remain limited. Stem cell therapies have yielded promising results, but the harsh ischemic environment of the post-stroke brain reduces their therapeutic potential. Previously, we developed a conductive polymer scaffold system that enabled stem cell delivery with simultaneous electrical modulation of the cells and surrounding neural environment. This wired polymer scaffold proved efficacious in optimizing ideal conditions for stem cell mediated motor improvements in a rodent model of stroke. To further enable preclinical studies and enhance translational potential, we identified a method to improve this system by eliminating its dependence upon a tethered power source. We have herein developed a wirelessly powered, electrically conductive polymer system that eases therapeutic application and enables full mobility. As a proof of concept, we demonstrate that the wirelessly powered scaffold is able to stimulate neural stem cells in vitro, as well as in vivo in a rodent model of stroke. This system modulates the stroke microenvironment and increases the production of endogenous stem cells. In summation, this novel, wirelessly powered conductive scaffold can serve as a mobile platform for a wide variety of therapeutics involving electrical stimulation.

Epidemiology of Intensive Care Patients Classified as a Third Sex in Australia and New Zealand.

BACKGROUND: Patient sex affects treatment and outcomes in critical illness. Previous studies of sex differences in critical illness compared female and male patients. In this study, we describe the group of patients classified as a third sex admitted to ICUs in Australia and New Zealand. RESEARCH QUESTION: What are the admission characteristics and outcomes of ICU patients classified as belonging to a third sex group compared with patients classified as female or male? STUDY DESIGN AND METHODS: Retrospective observational study of admissions to 200 ICUs, recorded in the Australian and New Zealand Intensive Care Society's Adult Patient Database from 2018 to 2022. We undertook mixed effect logistic regression to compare hospital mortality across the sex groups, adjusted for illness severity, diagnosis, treatment limitation, year, and hospital. RESULTS: We examined 892,161 admissions, of whom 525 (0.06%) were classified as third sex. Patients classified as third sex were represented across all diagnostic categories, jurisdictions, and hospital types. On average, they were younger than the groups classified as female (59.2 ± 20.0 vs 61.3 ± 18.4 years; P = .02) or male (63.2 ± 16.7 years; P < .001), respectively. Patients classified as third sex were more likely to be admitted after orthopedic surgery (10.1% third sex admissions [95% CI, 7.7%-13.0%]; 6.2% female [95% CI, 6.1%-6.3%]; 4.8% male [95% CI, 4.7%-4.9%]) and drug overdose (8.8% third sex admissions [95% CI, 6.5%-11.5%]; 4.2% female [95% CI, 4.1%-4.2%]; 3.1% male [95% CI, 3.0%-3.1%]). There was no difference in the adjusted hospital mortality of patients classified as third sex compared with the other groups. INTERPRETATION: Patients classified as third sex composed a small minority group of adult ICU patients. This group had a different diagnostic case mix but similar outcomes to the groups classified as female or male. Further characterizing a third sex group will require improved processes for recording sex and gender in health records.

The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites.

Glycine Transporter 2 (GlyT2) inhibitors have shown considerable potential as analgesics for the treatment of neuropathic pain but also display considerable side effects. One potential source of side effects is irreversible inhibition. In this study, we have characterized the mechanism of ORG25543 inhibition of GlyT2 by first considering three potential ligand binding sites on GlyT2-the substrate site, the vestibule allosteric site and the lipid allosteric site. The three sites were tested using a combination of molecular dynamics simulations and analysis of the inhibition of glycine transport of a series point mutated GlyT2 using electrophysiological methods. We demonstrate that the lipid allosteric site on GlyT2 is the most likely binding site for ORG25543. We also demonstrate that cholesterol derived from the cell membrane can form specific interactions with inhibitor-bound transporters to form an allosteric network of regulatory sites. These observations will guide the future design of GlyT2 inhibitors with the objective of minimising on-target side effects and improving the therapeutic window for the treatment of patients suffering from neuropathic pain.

Early Access to Testosterone Therapy in Transgender and Gender-Diverse Adults Seeking Masculinization: A Randomized Clinical Trial.

Importance: Testosterone treatment is a necessary component of care for some transgender and gender-diverse individuals. Observational studies have reported associations between commencement of gender-affirming hormone therapy and improvements in gender dysphoria and depression, but there is a lack of data from randomized clinical trials. Objective: To assess the effect of testosterone therapy compared with no treatment on gender dysphoria, depression, and suicidality in transgender and gender-diverse adults seeking masculinization. Design, Setting, and Participants: A 3-month open-label randomized clinical trial was conducted at endocrinology outpatient clinics and primary care clinics specializing in transgender and gender-diverse health in Melbourne, Australia, from November 1, 2021, to July 22, 2022. Participants included transgender and gender-diverse adults aged 18 to 70 years seeking initiation of testosterone therapy. Interventions: Immediate initiation of testosterone commencement (intervention group) or no treatment (standard care waiting list of 3 months before commencement). This design ensured no individuals would be waiting longer than the time to standard care. Main Outcomes and Measures: The primary outcome was gender dysphoria, as measured by the Gender Preoccupation and Stability Questionnaire. Secondary outcomes included the Patient Health Questionnaire-9 (PHQ-9) to assess depression and the Suicidal Ideation Attributes Scale (SIDAS) to assess suicidality. Questionnaires were undertaken at 0 and 3 months. The evaluable cohort was analyzed. Results: Sixty-four transgender and gender-diverse adults (median [IQR] age, 22.5 [20-27] years) were randomized. Compared with standard care, the intervention group had a decrease in gender dysphoria (mean difference, -7.2 points; 95% CI, -8.3 to -6.1 points; P < .001), a clinically significant decrease in depression (ie, change in score of 5 points on PHQ-9; mean difference, -5.6 points; 95% CI, -6.8 to -4.4 points; P < .001), and a significant decrease in suicidality (mean difference in SIDAS score, -6.5 points; 95% CI, -8.2 to -4.8 points; P < .001). Resolution of suicidality assessed by PHQ-9 item 9 occurred in 11 individuals (52%) with immediate testosterone commencement compared with 1 (5%) receiving standard care (P = .002). Seven individuals reported injection site pain/discomfort and 1 individual reported a transient headache 24 hours following intramuscular administration of testosterone undecanoate. No individual developed polycythemia. Conclusions and Relevance: In this open-label randomized clinical trial of testosterone therapy in transgender and gender-diverse adults, immediate testosterone compared with no treatment significantly reduced gender dysphoria, depression, and suicidality in transgender and gender-diverse individuals desiring testosterone therapy. Trial Registration: ANZCTR Identifier: ACTRN1262100016864.

The impact of the first three months of the COVID-19 pandemic on the Australian trans community.

Background: Trans and gender diverse individuals (people who identify with a gender different to what was presumed for them at birth) are one of the most medically and socially marginalized groups in our community. The COVID-19 pandemic may compound preexisting depression and thoughts of self-harm or suicide. Aim: We aimed to explore the impact of the COVID-19 pandemic on the Australian trans community. Methods: An online cross-sectional survey was conducted between 1st May 2020 and 30th June 2020, amidst strict Australia-wide social restrictions. Australian trans people aged ≥16 years were eligible to participate. Survey questions explored the impact of the COVID-19 pandemic on living situation, employment, financial situation, and healthcare. Logistic regression to assess negative impacts due to COVID-19 on depression and thoughts of self-harm or suicide (measured by Patient Health Questionnaire-9 (PHQ-9) are presented as odds ratios (95% confidence interval)). Results: Of 1019 participants, 49.6% reported experiencing financial strain, 22% had reduced working hours, and 22.4% were unemployed (three times the national rate). Concerningly, 61.1% experienced clinically significant symptoms of depression (Patient Health Questionnaire-9 score ≥10), considerably higher than pre-COVID rates for the trans community and over twice the national rate. Moreover, 49% reported thoughts of self-harm or suicide (over three times the national rate) which was more likely if a person experienced cancelation or postponement of gender-affirming surgery (OR 1.56 (1.04, 2.35)), financial strain (OR 1.80 (1.36, 2.38)), or felt unsafe or afraid in their household (OR 1.96 (1.23, 3.08)). Discussion: Given rates of clinically significant depression and thoughts of self-harm or suicide are far higher in trans people than the general population, specific strategies to improve mental health in the trans community during the COVID-19 pandemic must be made a priority for policymakers, researchers, and health service providers to prevent suicide.Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1890659.

Implications of gender-affirming endocrine care for sports participation.

Many transgender (trans) individuals utilize gender-affirming hormone therapy (GAHT) to promote changes in secondary sex characteristics to affirm their gender. Participation rates of trans people in sport are exceedingly low, yet given high rates of depression and increased cardiovascular risk, the potential benefits of sports participation are great. In this review, we provide an overview of the evidence surrounding the effects of GAHT on multiple performance-related phenotypes, as well as current limitations. Whilst data is clear that there are differences between males and females, there is a lack of quality evidence assessing the impact of GAHT on athletic performance. Twelve months of GAHT leads to testosterone concentrations that align with reference ranges of the affirmed gender. Feminizing GAHT in trans women increases fat mass and decreases lean mass, with opposite effects observed in trans men with masculinizing GAHT. In trans men, an increase in muscle strength and athletic performance is observed. In trans women, muscle strength is shown to decrease or not change following 12 months of GAHT. Haemoglobin, a measure of oxygen transport, changes to that of the affirmed gender within 6 months of GAHT, with very limited data to suggest possible reductions in maximal oxygen uptake as a result of feminizing GAHT. Current limitations of this field include a lack of long-term studies, adequate group comparisons and adjustment for confounding factors (e.g. height and lean body mass), and small sample sizes. There also remains limited data on endurance, cardiac or respiratory function, with further longitudinal studies on GAHT needed to address current limitations and provide more robust data to inform inclusive and fair sporting programmes, policies and guidelines.

Effect of gender-affirming hormone therapy on hair growth: a systematic review of the literature.

Gender-affirming hormone therapy (GAHT) leads to changes in body composition, secondary sex characteristics and in the distribution and pattern of hair growth. Transgender individuals undergoing GAHT may experience altered hair growth patterns that may be affirming and desirable, or undesirable with a subsequent impact on their quality of life. Given increasing numbers of transgender individuals commencing GAHT worldwide and the clinical relevance of the impact of GAHT on hair growth, we systematically reviewed the existing literature on the impact of GAHT on hair changes and androgenic alopecia (AGA). The majority of studies used grading schemes or subjective measures of hair changes based on patient or investigator's examination. Very few studies used objective quantitative measures of hair parameters but demonstrated statistically significant changes in hair growth length, diameter and density. Feminizing GAHT with estradiol and/or antiandrogens in transgender women may reduce facial and body hair growth and also can improve AGA. Masculinizing GAHT with testosterone in transgender men may increase facial and body hair growth as well as induce or accelerate AGA. The impact of GAHT on hair growth may not align with a transgender person's hair growth goals and specific treatment for AGA and/or hirsutism may be sought. Further research on how GAHT affects hair growth is required.

Gender-Affirming Hormone Therapy for the Trans, Gender Diverse, and Nonbinary Community: Coordinating World Professional Association for Transgender Health and Informed Consent Models of Care.

Purpose: Before commencing gender-affirming hormone therapy, people undergo assessments through the World Professional Association for Transgender Health (WPATH) model (typically with a mental health clinician), or an informed consent (IC) model (without a formal mental health assessment). Despite growing demand, these remain poorly coordinated in Australia. We aimed to compare clients attending WPATH and IC services; compare binary and nonbinary clients; and characterize clients with psychiatric diagnoses or longer assessments. Methods: Cross-sectional audit of clients approved for gender-affirming treatment (March 2017-2019) at a specialist clinic (WPATH model, n=212) or a primary care clinic (IC model, n=265). Sociodemographic, mental health, and clinical data were collected from electronic records, and analyzed with pairwise comparisons and multivariable regression. Results: WPATH model clients had more psychiatric diagnoses (mean 1.4 vs. 1.1, p<0.001) and longer assessments for hormones (median 5 vs. 2 sessions, p<0.001) than IC model clients. More IC model clients than WPATH model clients were nonbinary (27% vs. 15%, p=0.016). Nonbinary clients had more psychiatric diagnoses (mean 1.7 vs. 1.1, p<0.001) and longer IC assessments (median 3 vs. 2 sessions, p<0.001) than binary clients. Total psychiatric diagnoses were associated with nonbinary identities (ß 0.7, p=0.001) and health care cards (ß 0.4, p=0.017); depression diagnoses were associated with regional/remote residence (adjusted odds ratio [aOR] 2.2, p=0.011); and anxiety disorders were associated with nonbinary identities (aOR 2.8, p=0.012) and inversely associated with employment (aOR 0.5, p=0.016). Conclusion: WPATH model clients are more likely to have binary identities, mental health diagnoses, and longer assessments than IC model clients. Better coordination is needed to ensure timely gender-affirming care.

The Effect of Gender-Affirming Hormones on Gender Dysphoria, Quality of Life, and Psychological Functioning in Transgender Individuals: A Systematic Review.

Gender-affirming hormone therapy (GAHT) is an essential part of gender affirmation for many transgender (including people with binary and nonbinary identities) individuals and although controlled studies are unethical, there remains limited evidence on the impact of GAHT on gender dysphoria, quality of life (QoL), and psychological functioning. Some clinicians and policy makers use the lack of evidence to argue against providing gender-affirming care. The aim of this review is to systematically and critically assess the available literature on the influence of GAHT on improving gender- and body-related dysphoria, psychological well-being, and QoL. Using Preferred Reporting Items for Systematic Review and Meta-analysis guidelines, we searched Ovid MEDLINE®, Embase®, and Ovid PsycINFO® from inception to March 6, 2019 to assess the influence of GAHT on (1) gender dysphoria, (2) body uneasiness, (3) body satisfaction, (4) psychological well-being, (5) QoL, (6) interpersonal and global functioning, and (7) self-esteem. Our search strategy found no randomized controlled trials. Ten longitudinal cohort studies, 25 cross-sectional studies, and 3 articles reporting both cross-sectional and longitudinal data were identified. While results are mixed, the majority of studies demonstrate that GAHT reduces gender dysphoria, body dissatisfaction, and uneasiness, subsequently improving psychological well-being and QoL in transgender individuals. However, all current researches are of low to moderate quality comprising longitudinal cohort studies and cross-sectional studies, making it difficult to draw clear conclusions and do not reflect external social factors unaffected by GAHT, which significantly impact on dysphoria, well-being, and QoL.

Effectiveness of adenosine triphosphate to monitor manual cleaning and disinfection efficacy of flexible endoscopes in Hong Kong.

Background and Aim: Adenosine triphosphate (ATP) bioluminescence assay is widely adopted in the West to allow rapid evaluation of endoscopes for bacteriologic/biologic residue, but this practice is rarely adopted in Asia. In this continuous quality improvement program, we evaluated the utility of ATP in bacteriologic surveillance on endoscope reprocessing. Methods: A total of 456 samples (304 ATP samples and 152 culture samples) of 38 flexible endoscopes were assessed after routine clinical use in a private hospital in Hong Kong. Endoscopes were assessed with an ATP system and bacterial cultures at different time points during the reprocessing. Results: After pre-cleaning, the ATP values ranged from 228 to 65 163 relative light units (RLU) through all endoscope types. After manual cleaning, ATP values were decreased to 7-81 RLU (median, 19 RLU) for endoscope surface and 3-671 RLU (median, 12 RLU) for channel rinsate. There was a significant reduction in ATP levels between pre-cleaning and after manual cleaning. One of the 38 (2.6%) endoscopes (a duodenoscope) had an ATP value of 671 RLU from channel rinsate, which exceeded the benchmark for cleanliness of >200 RLU, and was sent back for re-cleaning. All endoscopes cultured no bacteria after high-level disinfection (HLD) by automated endoscope reprocessor (AER) and storage up to 24 h. ATP values were <200 RLU for all endoscopes after HLD and storage. Conclusions: Adenosine triphosphate bioluminescence assay offers a rapid, practical, and cost-effective alternative for detection of endoscope microbial residue as well as a routine monitoring tool for endoscope cleanliness in the clinical setting.

Pelvic Pain in Transgender People Using Testosterone Therapy.

Purpose: This descriptive study aimed to assess the characteristics of pelvic pain and explore predictive factors for pelvic pain in transgender (trans) individuals using testosterone therapy. Methods: An online cross-sectional survey was open between August 28, 2020, and December 31, 2020, to trans people presumed female at birth, using testosterone for gender affirmation, living in Australia, and >16 years of age. The survey explored characteristics of pelvic pain following initiation of testosterone therapy, type and length of testosterone therapy, menstruation history, and relevant sexual, gynecological, and mental health experiences. Logistic regression was applied to estimate the effect size of possible factors contributing to pain after starting testosterone. Results: Among 486 participants (median age = 27 years), 351 (72.2%)* reported experiencing pelvic pain following initiation of testosterone therapy, described most commonly as in the suprapubic region and as "cramping." Median duration of testosterone therapy was 32 months. Persistent menstruation, current or previous history of post-traumatic stress disorder, and experiences of pain with orgasm were associated with higher odds of pelvic pain after testosterone therapy. No association was observed with genital dryness, intrauterine device use, previous pregnancy, penetrative sexual activities, touching external genitalia, or known diagnoses of endometriosis, vulvodynia, vaginismus, depression, anxiety, or obesity. Conclusions: Pelvic pain is frequently reported in trans people following initiation of testosterone therapy. Given the association with persistent menstruation and orgasm, as well as the known androgen sensitivity of the pelvic floor musculature, further research into pelvic floor muscle dysfunction as a contributor is warranted.