Gender and sex differences in occupation-specific infectious diseases: a systematic review.

Occupational infectious disease risks between men and women have often been attributed to the gendered distribution of the labour force, with limited comparative research on occupation-specific infectious disease risks. The objective of this study was to compare infectious disease risks within the same occupations by gender. A systematic review of peer-reviewed studies published between 2016 and 2021 was undertaken. To be included, studies were required to report infectious disease risks for men, women or non-binary people within the same occupation. The included studies were appraised for methodological quality. A post hoc power calculation was also conducted. 63 studies were included in the systematic review. Among high-quality studies with statistical power (9/63), there was evidence of a higher hepatitis risk for men than for women among patient-facing healthcare workers (HCWs) and a higher parasitic infection risk for men than for women among farmers (one study each). The rest of the high-quality studies (7/63) reported no difference between men and women, including for COVID-19 risk among patient-facing HCWs and physicians, hepatitis risk among swine workers, influenza risk among poultry workers, tuberculosis risk among livestock workers and toxoplasmosis risk among abattoir workers. The findings suggest that occupational infectious disease risks are similarly experienced for men and women within the same occupation with a few exceptions showing a higher risk for men. Future studies examining gender/sex differences in occupational infectious diseases need to ensure adequate sampling by gender.

Gender in healthcare: a practical approach.

Transgender law is complex and developing. Increasing general practitioner referrals for gender dysphoria without sufficient resources for specialist units have left gaps in transgender healthcare. Surveys repeatedly find transgender patients have lower satisfaction with healthcare experiences, stating doctors have a poor understanding of their needs. Meanwhile, waiting times for referrals remain high.This review article outlines UK laws and guidelines relevant to trans healthcare, including practical advice for clinicians. Current issues are explored, including the referral process for gender dysphoria.Transgender law is continually evolving; currently, individuals require a diagnosis of gender dysphoria to legally change gender. However, the gender on NHS records can be changed without legally changing gender.Clinicians may find support from the General Medical Council for this area. Specifically, guidance exists for including trans patients in screening programmes relevant to their assigned sex at birth. Similarly, advice exists for ensuring the privacy of patients' gender history.

Systematic Review: Puberty suppression with GnRH analogues in adolescents with gender incongruity.

CONTEXT: Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE: Systematically review the treatment of gender incongruity with GnRHa analogues. DATA SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS: Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. LIMITATION: There are few consistent studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study.

BACKGROUND: Marijuana use is increasingly prevalent in the United States. Effects of marijuana use on sexual function are unclear, with contradictory reports of enhancement and detriment existing. AIM: To elucidate whether a relation between marijuana use and sexual frequency exists using a nationally representative sample of reproductive-age men and women. METHODS: We analyzed data from cycle 6 (2002), cycle 7 (2006-2010), and continuous survey (2011-2015) administrations of the National Survey of Family Growth, a nationally representative cross-sectional survey. We used a multivariable model, controlling for demographic, socioeconomic, and anthropographic characteristics, to evaluate whether a relationship between marijuana use and sexual frequency exists. OUTCOMES: Sexual frequency within the 4 weeks preceding survey administration related to marijuana use and frequency in the year preceding survey administration. RESULTS: The results of 28,176 women (average age = 29.9 years) and 22,943 men (average age = 29.5) were analyzed. More than 60% of men and women were Caucasian, and 76.1% of men and 80.4% of women reported at least a high school education. After adjustment, female monthly (incidence rate ratio [IRR] = 1.34, 95% CI = 1.07-1.68, P = .012), weekly (IRR = 1.36, 95% CI = 1.15-1.60, P < .001), and daily (IRR = 1.16, 95% CI = 1.01-1.32, P = .035) marijuana users had significantly higher sexual frequency compared with never users. Male weekly (IRR = 1.22, 95% CI = 1.06-1.41, P = .006) and daily (IRR = 1.36, 95% CI = 1.21-1.53, P < .001) users had significantly higher sexual frequency compared with never users. An overall trend for men (IRR = 1.08, 95% CI = 1.05-1.11, P < .001) and women (IRR = 1.07, 95% CI = 1.04-1.10, P < .001) was identified showing that higher marijuana use was associated with increased coital frequency. CLINICAL IMPLICATIONS: Marijuana use is independently associated with increased sexual frequency and does not appear to impair sexual function. STRENGTHS AND LIMITATIONS: Our study used a large well-controlled cohort and clearly defined end points to describe a novel association between marijuana use and sexual frequency. However, survey responses were self-reported and represent participants only at a specific point in time. Participants who did not answer questions related to marijuana use and sexual frequency were excluded. CONCLUSION: A positive association between marijuana use and sexual frequency is seen in men and women across all demographic groups. Although reassuring, the effects of marijuana use on sexual function warrant further study. Sun AJ, Eisenberg ML. Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study. J Sex Med 2017;14:1342-1347.

Cancer screening attendance rates in transgender and gender-diverse patients: a systematic review and meta-analysis.

OBJECTIVES: To examine disparities in attendance rates at cancer screening services between transgender and gender-diverse (TGD) people in comparison with their cisgender (CG) counterparts, and to determine whether these differences were based on the anatomical organ screened. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, EMBASE (via Ovid), CINAHL Complete (via EBSCO) and Cochrane Library from inception to 30 September 2023. METHODS: Studies for inclusion were case-control or cross-sectional studies with quantitative data that investigated TGD adults attending any cancer screening service. Exclusion criteria were studies with participants who were ineligible for cancer screening or without samples from TGD individuals, qualitative data and a cancer diagnosis from symptomatic presentation or incidental findings. A modified Newcastle-Ottawa Scale was used to assess risk of bias, during which seven reports were found incompatible with the inclusion criteria and excluded. Results were synthesised through random-effects meta-analysis and narrative synthesis. RESULTS: We identified 25 eligible records, of which 18 were included in the analysis. These were cross-sectional studies, including retrospective chart reviews and survey analyses, and encompassed over 14.8 million participants. The main outcomes measured were up-to-date (UTD) and lifetime (LT) attendance. Meta-analysis found differences for UTD cervical (OR 0.37, 95% CI 0.23 to 0.60, p<0.0001) and mammography (OR 0.41, 95% CI 0.20 to 0.87, p=0.02) but not for prostate or colorectal screening. There were no meaningful differences seen in LT attendance based on quantitative synthesis. Narrative synthesis of the seven remaining articles mostly supported the meta-analysis. Reduced rates of screening engagement in TGD participants were found for UTD cervical and mammography screening, alongside LT mammography screening. CONCLUSIONS: Compared with their CG counterparts, TGD individuals had lower rates of using cervical and mammography screening at the recommended frequencies but displayed similar prevalences of LT attendance. The greatest disparity was seen in UTD cervical screening. Limitations of this review included high risk of bias within studies, high heterogeneity and a lack of resources for further statistical testing. Bridging gaps in healthcare to improve cancer screening experiences and outcomes will require consolidated efforts including working with the TGD community. PROSPERO REGISTRATION NUMBER: CRD42022368911.

Hypersexuality in neurological disorders: A systematic review.

BACKGROUND: Hypersexuality (HS) accompanying neurological conditions remains poorly characterized despite profound psychosocial impacts. Objective We aimed to systematically review the literature on HS in patients with neurological disorders. Study selection and analysis We conducted a systematic review to identify studies that reported HS in neurological disorders. HS was defined as a condition characterized by excessive and persistent preoccupation with sexual thoughts, urges, and behaviors that cause significant distress or impairment in personal, social, or occupational functioning. Data on demographics, assessment techniques, associated elements, phenotypic manifestations, and management strategies were also extracted. Findings The final analysis included 79 studies on HS, encompassing 32 662 patients across 81 cohorts with neurological disorders. Parkinson's disease was the most frequently studied condition (55.6%), followed by various types of dementia (12.7%). Questionnaires were the most common assessment approach for evaluating HS, although the techniques varied substantially. Alterations in the dopaminergic pathways have emerged as contributing mechanisms based on the effects of medication cessation. However, standardized treatment protocols still need to be improved, with significant heterogeneity in documented approaches. Critical deficiencies include risks of selection bias in participant sampling, uncontrolled residual confounding factors, and lack of blinded evaluations of reported outcomes. Conclusions and clinical implications Despite growth in the last decade, research on HS remains limited across neurological conditions, with lingering quality and methodological standardization deficits. Key priorities include advancing assessment tools, elucidating the underlying neurobiology, and formulating management guidelines. PROSPERO REGISTRATION NUMBER: CRD42017036478.

Cervical cancer in a transgender man: lessons learnt to improve care.

We describe a case of rapid progression of cervical dysplasia to stage IVB cervical cancer in a previously healthy transgender young adult man on testosterone therapy. The cancer diagnosis came 7 months after routine pap smear showed low-grade dysplasia with high-risk human papillomavirus in preparation for gender-affirming hysterectomy/bilateral-salpingo-oophorectomy. After diagnosis, our patient faced unique challenges as a transgender man receiving gynecologic oncology care. This case highlights the challenges of and barriers to cervical cancer screening and treatment that transgender men confront. This case also considers whether gender-affirming testosterone therapy is associated with cervical cancer risk. We offer suggestions on how to improve cervical cancer screening and treatment for the transgender population.

Increased sexual function after intake of clomethiazole.

An octogenarian woman showed increased sexual function after replacing alprazolam with clomethiazole, a sedative-hypnotic drug commonly prescribed in French-speaking Switzerland for the treatment of anxiety and insomnia in elderly patients. The patient's sexual symptoms did not improve after resuming alprazolam, but disappeared after interrupting clomethiazole, and did not reappear when alprazolam was discontinued. Considering the chronology of the events, increased sexual function was likely a manifestation of the introduction of clomethiazole. However, because alprazolam was interrupted when clomethiazole was introduced, we cannot exclude an association between increased sexual function and alprazolam interruption.

Validity and reliability of the Thai version of the Utrecht Gender Dysphoria Scale-Gender Spectrum (UGDS-GS) in Thai youths and young adults with gender dysphoria.

Background: Many people who are gender variant have undiagnosed gender dysphoria, resulting in delayed receipt of gender-affirming support and prolonged distress in living with their gender-non-conforming sex. The Utrecht Gender Dysphoria Scale-Gender Spectrum (UGDS-GS) is a newly developed tool that measures dissatisfaction with gender identity and expression. However, there is no translated version of this tool in Thai. Moreover, the sensitivity, specificity and cut-off point of the UGDS-GS to detect gender dysphoria in people who are transgender remain unknown. Aims: This study translated the UGDS-GS into Thai and then examined the validity and reliability of the Thai UGDS-GS. Methods: 185 participants with and without gender dysphoria were selected from the Gender Variation Clinic in Ramathibodi Hospital and from social media platforms. The UGDS-GS was translated into Thai according to the World Health Organization (WHO) guidelines on translation. The medical records of patients with gender dysphoria and semi-structured interviews were used to confirm the diagnosis of gender dysphoria. Subsequently, the validity and reliability of the instrument were analysed. Results: The mean age of participants was 30.43 (7.98) years among the 51 assigned males (27.6%) and 134 assigned females (72.4%) at birth. The Thai UGDS-GS average score was 77.82 (9.71) for those with gender dysphoria (n=95) and 46.03 (10.71) for those without gender dysphoria (n=90). Cronbach's alpha coefficient was 0.962, showing excellent internal consistency. In addition, exploratory factor analysis showed compatibility with the original version's metrics. The value of the area under the curve was 0.976 (95% confidence interval: 0.954 to 0.998), indicating outstanding concordance. At the cut-off point of '60', sensitivity and specificity were good (96.84% and 91.11%, respectively). Conclusions: The Thai UGDS-GS is an excellent, psychometrically reliable and valid tool for screening gender dysphoria in clinical and community settings in Thailand. The cut-off point of '60' scores suggests a positive indicator or a high chance of gender dysphoria.

'In fact, that's when I stopped using contraception': a qualitative study exploring women's experiences of using contraceptive methods in KwaZulu-Natal, South Africa.

OBJECTIVES: This study explored women's experiences of using contraceptive methods in KwaZulu-Natal, South Africa. SETTING: In October 2021, we conducted a qualitative study at Umlazi Township in KwaZulu-Natal province, South Africa, through face-to-face in-depth interviews. PARTICIPANTS: Women from four primary healthcare facilities were recruited through a criterion-based sampling strategy. Using NVivo V.11, two skilled researchers independently conducted thematic data analysis, as a mechanism for quality assurance, before the results were collated and reconciled. RESULTS: The study included 15 female participants, aged between 18 and 35 years, of whom two-thirds were aged 18-24 years. We found that women were concerned about unpleasant contraceptive methods side effects such as prolonged or irregular menstrual periods, bleeding, weight gain and/or severe pains, resulting in discontinuation of their use. In addition to contraceptive stockouts, women indicated that healthcare providers did not appropriately counsel or inform them about the available contraceptive methods, including how to use them. Key themes included the following: negative effects of contraceptive methods; stockouts of preferred contraceptive methods; inconsistent or incorrect use of contraceptive methods; lack of counselling regarding contracepive methods; and misconceptions about contraception. CONCLUSIONS: Interventions aimed at reducing contraceptive stockouts are required to ensure that women are empowered to choose contraception based on their own preference, convenience and/or experience. It is imperative that counselling on contraceptive methods' side effects be improved, to ensure that women have freedom to make informed decisions about their preferred method, proper management of side effects and to assist them with method switching as needed, instead of discontinuation.

Sexual dysfunction and associated factors in Thai patients with psychiatric disorders.

Background: Sexual dysfunction is common among patients with psychiatric disorders but might be under-reported due to Asian sociocultural factors. Recognition of sexual dysfunction and associated factors in this vulnerable population would help clinicians properly assess and manage related conditions. Aims: We aimed to examine the prevalence of sexual dysfunction and its associated factors among patients with psychiatric disorders in Thailand. Methods: This was a cross-sectional study. We enrolled participants aged 18 and older who visited the psychiatry clinic at King Chulalongkorn Memorial Hospital in Bangkok, Thailand between August 2020 and December 2021. Demographic and clinical data were assessed, and all psychiatric disorders and sexual dysfunctions were diagnosed by clinical interview using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Statistical analysis was done to explore the association between sexual dysfunction and related factors. Results: Sexual dysfunction was diagnosed in 101 (50.0%) of the total 202 participants. The mean (standard deviation, SD) age was 30.2 (9.0) years, and the majority of patients were men (54.5%), single (81.2%), employed (47.5%) and had a coexisting depressive disorder (48.0%). Multivariable logistic regression analysis showed a significant association between sexual dysfunction and quality of life, unemployment, and the dosage of antidepressants and benzodiazepines. Conclusions: The prevalence of sexual dysfunction among this population was relatively high. However, the findings may represent only a portion of affected psychiatric patients for others with sexual dysfunction symptoms but without functional impairment did not meet the diagnostic criteria for sexual dysfunction. Improvement of quality of life and optimising antidepressant/benzodiazepine dosage should be further investigated for promoting sexual function in patients with mental disorders.

Quality of life of transgender people under the lens of social determinants of health: a scoping review protocol.

INTRODUCTION: There is an urgent need for knowledge about the transgender population to inform the development of clinical protocols and training of health professionals on the unique issues affecting this population. Discussing transgender quality of life (QoL) through the lens of social determinants of health (SDOHs) would enable gender-specific health interventions. Here, we aimed to review the evidence on the QoL of transgender people from an SDOH perspective. METHODS AND ANALYSIS: A scoping review (ScR) protocol following the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews statement and guided by the Joanna Briggs Institute was used. MEDLINE/PubMed, Cochrane Library, Embase, PsycINFO, Web of Science, Scopus and registry sites such as ClinicalTrials.gov and WHO ICTRP will be searched. Additional sources to be searched include ProQuest Dissertations/Theses Global, British Library, Google Scholar and Preprints for Health Sciences-medRXiv. Two independent researchers will carry out the selection, data charting and data synthesis. No date restriction will be applied in this ScR. The search will be restricted to articles published in English, Spanish and Portuguese. The results will be presented in tables, narrative summaries and graphs and will be graded on the type of data presented and the results. The search strategy will be updated in April 2023. The expected completion date of this ScR is July 2023. ETHICS AND DISSEMINATION: This ScR protocol does not require ethical approval. Dissemination plans include peer-reviewed publications, conference presentations to be shared with experts in the field, and advisory groups to inform discussions on future research. It is hoped that our findings will be of interest to practitioners, researchers, stakeholders, public and private managers, and the general population concerned with this emerging public health issue. TRIAL REGISTRATION NUMBER: osf.io/9ukz6.

Gender-affirming care in undergraduate nursing education: a scoping review protocol.

INTRODUCTION: Transgender and gender-diverse (TGD) people face a multitude of barriers to safe, accessible healthcare. One way to overcome access inequities is through the provision of gender-affirming care. Gender-affirming care is culturally safe and engaged care that values TGD identities and is focused on depathologising TGD people. Additionally, gender-affirming care encompasses awareness and support of TGD individuals as unique beings, including supporting gender-affirming medical goals for those who are interested. The discipline of nursing is well situated to advocate for gender-affirming care, however, receives little undergraduate education in the subject. Undergraduate schools of nursing (including faculty and curriculum) are in a crucial position to implement gender-affirming care, though how they have done this is not widely known. Our scoping review aims to understand how Canadian and US undergraduate schools of nursing teach and integrate gender-affirming education. METHODS AND ANALYSIS: Our scoping review will follow the six stages by Arksey and O'Malley and the advancements by Levac et al, reported on as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. The review will be completed in 2023, with the database searches carried out in spring 2023, followed by screening and analysis. ETHICS AND DISSEMINATION: Ethics approval is not required for this protocol. To aid in knowledge translation, a visual representation of the findings will be created. Results from the final scoping review will be published in a peer-reviewed journal, promoted on social media to schools of nursing, and presented at conferences and seminars. PROTOCOL REGISTRATION NUMBER: Open Science Framework (https://doi.org/10.17605/OSF.IO/Q68BD).

Sex and gender differences in healthcare utilisation trajectories: a cohort study among Quebec workers living with chronic pain.

OBJECTIVES: Chronic pain (CP) is a poorly recognised and frequently inadequately treated condition affecting one in five adults. Reflecting on sociodemographic disparities as barriers to CP care in Canada was recently established as a federal priority. The objective of this study was to assess sex and gender differences in healthcare utilisation trajectories among workers living with CP. DESIGN: Retrospective cohort study. PARTICIPANTS: This study was conducted using the TorSaDE Cohort which links the 2007-2016 Canadian Community Health Surveys and Quebec administrative databases (longitudinal claims). Among 2955 workers living with CP, the annual number of healthcare contacts was computed during the 3 years after survey completion. OUTCOME: Group-based trajectory modelling was used to identify subgroups of individuals with similar patterns of healthcare utilisation over time (healthcare utilisation trajectories). RESULTS: Across the study population, three distinct 3-year healthcare utilisation trajectories were found: (1) low healthcare users (59.9%), (2) moderate healthcare users (33.6%) and (3) heavy healthcare users (6.4%). Sex and gender differences were found in the number of distinct trajectories and the stability of the number of healthcare contacts over time. Multivariable analysis revealed that independent of other sociodemographic characteristics and severity of health condition, sex-but not gender-was associated with the heavy healthcare utilisation longitudinal trajectory (with females showing a greater likelihood; OR 2.6, 95% CI 1.6 to 4.1). CONCLUSIONS: Our results underline the importance of assessing sex-based disparities in help-seeking behaviours, access to healthcare and resource utilisation among persons living with CP.

Biochemical Changes During the First Year of Feminizing Hormone Therapy in Transfeminine Individuals.

BACKGROUND: Persons with assigned male sex at birth (AMAB) might wish to obtain feminization and/or demasculinization according to the person's gender identity and are therefore treated with estradiol and/or antiandrogens. AIM: The aim was to evaluate biochemical changes and side effects in AMAB individuals treated with guideline-based feminizing hormone treatment (FHT). METHODS: Medical charts of 99 AMAB individuals ≥ 18 years referred to the Center for Gender Identity; Aalborg University hospital, Denmark, between January 2017 and July 2019 were reviewed to identify adverse side effects. Furthermore, data from the laboratory information system (Labka II) were retrieved to obtain biochemical parameters. Biochemical plasma concentrations after initiation of FHT were compared to concentrations prior to FHT and to existing guidelines. OUTCOMES: After 11-19 months, 29% of the trans feminine individuals had plasma estradiol concentrations within the treatment target. RESULTS: The plasma concentration of estradiol varies greatly during FHT. Plasma levels of estrogen were within the treatment target after 11-19 months of treatment, whereas 100% had concentrations within the reference range for premenopausal cis-women. Furthermore, plasma concentrations of lipids and hematological parameters approached female reference ranges after 11 months of FHT. CLINICAL IMPLICATIONS: The target levels of plasma estradiol concentrations during FHT could be expanded, making the wanted physiological changes easier to obtain. STRENGTHS & LIMITATION: This cohort study included 99 AMAB individuals and biochemical evaluation was possible in 67 individuals. Only one individual was lost during follow-up. However, the follow-up period was limited making evaluation of long-term side effects impossible. CONCLUSION: Plasma concentration of estradiol varies greatly during guideline based FHT, making plasma estradiol levels within the target level difficult to attain. JA Hojbjerg, AD Højgaard, A-M Hvas. Biochemical Changes During the First Year of Feminizing Hormone Therapy in Transfeminine Individuals. Sex Med 2021;10:100472.

A randomised controlled trial of fluoxetine versus naltrexone in compulsive sexual behaviour disorder: presentation of the study protocol.

BACKGROUND: Compulsive sexual behaviour disorder is a new disorder in the International Classification of Diseases (ICD-11), and is associated with negative consequences in different areas of life. Evidence for pharmacological treatment of compulsive sexual behaviour disorder is weak and treatment options are limited. This proposed study will be the largest and the first randomised controlled trial comparing the efficacy and tolerability of two active drugs in compulsive sexual behaviour disorder. METHODS AND ANALYSIS: Eighty adult participants with compulsive sexual behaviour disorder according to ICD-11 will be randomised to receive either naltrexone 25-50 mg or fluoxetine 20-40 mg for 8 weeks, followed by 6 weeks without treatment. The study will be conducted in a subspecialised outpatient sexual medicine unit at Karolinska University Hospital, Stockholm, Sweden. The study is financed by grants and entirely independent of the manufacturers.Exclusion criteria include severe psychiatric or psychical illness, changes to concurrent medication and non-compatible factors contraindicating the use of either drug. The primary outcome measure is the Hypersexual Disorder: Current Assessment Scale (HD: CAS), and tolerability will be assessed by the Udvalg for Kliniske Undersogelser side effect rating scale (UKU), drug accountability, adherence to treatment and drop-out rate. Participants will complete questionnaires at regular intervals, with the main endpoint for efficacy after 8 weeks (end of treatment) and after 14 weeks (follow-up). Blood chemistry will be repeatedly collected as a safety precaution and for research purposes. The results will be analysed using an appropriate analysis of variance model or a mixed model, depending on the distribution of HD: CAS and the extent of missing data. ETHICS AND DISSEMINATION: The Swedish Ethical Review Authority and the Swedish Medical Products Agency have approved the study on 27 May 2020 and 4 June 2020, respectively (ref. no. 2020-02069 and ref. no. 5.1-2020-48282). Findings will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: 2019-004255-36.