Thomas J. Baranski

Introduction: Adolescence is a period of drastic biopsychosocial change that affects the trajectory of health into adulthood. Cross-sectional studies have reported that older youth typically exhibit lower experimental pain sensitivity than younger youth, but only one study thus far has directly examined this longitudinally. The factors contributing to changes in pain sensitivity remain unclear, but sex hormones, which dramatically fluctuate during adolescence, could play a key role. Objectives: This longitudinal study aimed to examine changes in experimental pain sensitivity/modulation and their relationship to changes in sex hormone levels. Methods: Healthy girls (n = 35, 9–16 years old) completed quantitative sensory testing (QST) at baseline and 1-year follow-up including thermal/pressure pain threshold; heat/cold pain intensity; cold pain tolerance; mechanical temporal summation; offset analgesia; and heat/pressure conditioned pain modulation. Serum blood samples were analyzed for total testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione (A4). Pain measures that significantly differed from baseline to follow-up were dependent variables in bootstrapped linear regression models with sex hormones as individual predictors in separate models. Additional regressions included baseline age and changes in pubertal stage and menstrual phase as covariates. Results: Cold pain threshold (CPT) increased over 1 year (baseline = 11.93°C, follow-up = 15.72°C, P = 0.012). Increased ΔDHT predicted increased ΔCPT after controlling baseline age, Δpubertal stage, and Δmenstrual phase ( ΔR ² = 0.294, ΔF _1,18 = 9.49, P = 0.006, β = 0.583), but no other relationships between ΔQST measures and Δsex hormones were significant. Conclusion: These findings suggest that during puberty, changes in sex hormone levels may have minor contributions to changes in experimental pain sensitivity in healthy girls.

Introduction: Puberty is a critical developmental period during which changes in pain sensitivity are observed. Previous studies found that older and more mature adolescents have lower experimental pain sensitivity. However, it is unclear whether the differences in pain sensitivity are due to age or the pubertal maturation effect. Objectives: This observational study examined the relationships between the pubertal maturation stage, age, and experimental pain sensitivity in healthy girls. Methods: Healthy adolescent girls (n = 52, mean age 12.0 ± 1.4 years) completed the Pubertal Developmental Scale (PDS) to assess their pubertal stage. In addition, they completed a comprehensive quantitative sensory testing session, including pain thresholds, pain ratings to noxious stimuli, and pain modulation tests. Separate regression models were performed to assess the effect of pubertal maturation and age on experimental pain sensitivity as well as differences in experimental pain sensitivity between girls in different subjective self-perceived pubertal timing relative to peers. Results: No relationships were found between the PDS score and experimental pain sensitivity; however, age was significantly related to cold pain tolerance (P = 0.030). In addition, to differentiate between puberty and age, experimental pain sensitivity was compared in a subsample of girls of the same age but at different pubertal stages, and no differences in experimental pain sensitivity were observed. No differences were also found when comparing girls who mature early, same, or late relative to their peers. Conclusion: Puberty and age may have no effect on experimental pain sensitivity in healthy girls.

Disorders of lipid metabolism such as obesity have become some of the most significant diseases of the twenty-first century. Despite these metabolic diseases affecting more than a third of the population in highly industrialized nations, the mechanisms underlying disease development remain poorly understood. Insect models, such as Drosophila melanogaster, offer a means of systematically examining conserved lipid metabolism and its pathology. Over the past several decades, Drosophila melanogaster has been used to greatly expand on our knowledge of metabolic disease, often taking advantage of the extensive genetic tools available to researchers. Additionally, Drosophila melanogaster has served and will continue to serve as a powerful tool for validating the results of genome-wide approaches to the study of diseases. This chapter explores the advancements of insect models in the study of lipid metabolism disorders as well as highlight opportunities for future areas of research.

Disorders of lipid metabolism such as obesity have become some of the most significant diseases of the twenty-first century. Despite these metabolic diseases affecting more than a third of the population in highly industrialized nations, the mechanisms underlying disease development remain poorly understood. Insect models, such as Drosophila melanogaster, offer a means of systematically examining conserved lipid metabolism and its pathology. Over the past several decades, Drosophila melanogaster has been used to greatly expand on our knowledge of metabolic disease, often taking advantage of the extensive genetic tools available to researchers. Additionally, Drosophila melanogaster has served and will continue to serve as a powerful tool for validating the results of genome-wide approaches to the study of diseases. This chapter explores the advancements of insect models in the study of lipid metabolism disorders as well as highlight opportunities for future areas of research.

Background: Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. Objective: This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. Methods: This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. Results: This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. Conclusions: The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. Trial Registration: ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707 International Registered Report Identifier (IRRID): DERR1-10.2196/53092

BACKGROUND Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. OBJECTIVE This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. METHODS This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. RESULTS This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. CONCLUSIONS The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. CLINICALTRIAL ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/53092

Insulin resistance is associated with obesity, cardiovascular disease, non-alcoholic fatty liver disease, and type 2 diabetes. These complications are exacerbated by a high-calorie diet, which we used to model type 2 diabetes in Drosophila melanogaster. Our studies focused on the fat body, an adipose- and liver-like tissue that stores fat and maintains circulating glucose. A gene regulatory network was constructed to predict potential regulators of insulin signaling in this tissue. Genomic characterization of fat bodies suggested a central role for the transcription factor Seven-up (Svp). Here, we describe a new role for Svp as a positive regulator of insulin signaling. Tissue-specific loss-of-function showed that Svp is required in the fat body to promote glucose clearance, lipid turnover, and insulin signaling. Svp appears to promote insulin signaling, at least in part, by inhibiting ecdysone signaling. Svp also impairs the immune response possibly via inhibition of antimicrobial peptide expression in the fat body. Taken together, these studies show that gene regulatory networks can help identify positive regulators of insulin signaling and metabolic homeostasis using the Drosophila fat body.

This interesting case demonstrates the clinical consequences of the balance between blocking and stimulating autoantibodies to the TSH receptor. This case illustrates the need for clinicians to understand that autoimmune responses can be something of a moving target. Why some people switch types of antibodies is not clear, but this will likely become more common rather than less given the wave of new rheumatologic and cancer therapies that employ immune modulators. In …

Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.