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A Mouse Model of the Protease-Activated Receptor 4 Pro310Leu Variant has Reduced Platelet Reactivity
Get PDFBackground: Protease-activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated that a single nucleotide polymorphism in extracellular loop 3 and PAR4-P310L (rs2227376) leads to a hyporeactive receptor. Objectives: The goal of this study was to determine how the hyporeactive PAR4 variant in extracellular loop 3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L). Methods: A point mutation was introduced into the PAR4 gene F2rl3 via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride–induced carotid artery injury model. Results: PAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis. Conclusion: PAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts
Risk for Diagnosis or Treatment of Mood or Anxiety Disorders in Adults After SARS-CoV-2 Infection, 2020–2022
Get PDFCOVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06–1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01–1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13–1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30–1.40])
Sexual Function After Gender Affirming Surgery
Get PDFPurpose of Review: Sexual function and satisfaction in the transgender community is a nascent field with a paucity of data due to the fast paced nature of improving upon surgical technique and variety of patient experiences. The authors aim to review the current literature for areas of success as well as areas of improvement in order to better the sexual health of the transgender community. Recent Findings: Gender dysphoria is a feeling of distress experienced by those whose gender assigned at birth is not in line with their gender identity. While social transition to the desired gender can suffice for some, medical and surgical interventions are often sought out to achieve gender euphoria, the decrease or absence of gender dysphoria. Often, issues with sexual function and satisfaction can trigger gender dysphoria, especially prior to social, medical, or surgical transition. Summary: Surgical genital gender affirmation has been the most studied in terms of sexual function and improvement of gender dysphoria. Surgical complications, hormonal changes, and other organic causes of sexual dysfunction can still interfere with one’s overall sexual satisfaction. A validated measure of sexual function for trans men and trans women is needed to better assess outcomes
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