Sexual Health Care for Transgender and Gender Diverse People.

The proportion of people who identify as transgender and gender diverse (TGD) is increasing. Health care for TGD people, including sexual health care, must affirm and respect patients' gender identities and expressions. Here, the authors outline strategies to make health care settings more welcoming to and inclusive of TGD people and describe concrete steps to improve sexual health care for TGD populations.

Patterns of psychotropic medication prescribing and potential drug-hormone interactions among transgender and gender-diverse adults within 2 years of hormone therapy.

BACKGROUND: Transgender and gender-diverse (TGD) people have a high prevalence of psychotropic medication use, yet knowledge about the patient-level psychotropic medication burden is limited. TGD patients may take hormone therapy to meet their gender expression goals. Potential drug-hormone interactions exist between psychotropic medications and hormone therapy, requiring increased knowledge about psychotropic medication use for TGD adults undergoing hormone therapy. OBJECTIVES: The objective of this study was to examine the extent of psychotropic medication polypharmacy in a cohort of TGD adults within 2 years of starting hormone therapy. We also characterized potential drug-hormone interactions and the association with psychotropic polypharmacy. METHODS: Retrospective cross-sectional analysis of patients with ≥1 transgender health-related visit (2007-2017) in the University of Washington Medical System (Seattle, WA). Eligible patients had ≥1 psychotropic medication including antidepressants, antipsychotics, mood stabilizers, and sedative-hypnotics ordered within 2 years of starting hormone therapy (testosterone or estradiol with or without spironolactone, progesterone, finasteride, or dutasteride). We defined psychotropic polypharmacy as ≥2 psychotropic medication orders with overlapping treatment durations for at least 90 days and characterized potential drug-hormone interactions (Lexicomp, Hudson, OH). We descriptively summarized patients with and without polypharmacy (frequencies and percentages) and compared drug-hormone interactions using chi-square or Fishers exact tests (P < 0.05 considered significant). RESULTS: A total of 184 patients had ≥1 psychotropic medication order within 2 years of hormone therapy; 68 patients (37.0%) had psychotropic polypharmacy. The most frequent type of psychotropic polypharmacy was antidepressant+sedative-hypnotic (18 of 68, 26.5%). More patients had a potential drug-hormone interaction among those with psychotropic polypharmacy (23 of 68, 33.8%) versus those without (8 of 116, 6.9%, P < 0.001). CONCLUSION: Among TGD patients on psychotropic medications within 2 years of hormone therapy, one-third had psychotropic polypharmacy. Most polypharmacy types appeared to align with mental health treatment guidelines. The number of patients with a potential drug-hormone interaction was significantly higher among those with polypharmacy. Prospective studies are needed to characterize drug-hormone interactions.

Incremental value of volumetric multiparametric MRI over Fudan score for prognosis of unresectable intrahepatic cholangiocarcinoma treated with systemic chemotherapy.

BACKGROUND: Individualized patient care requires prognostic models customized to a tumor and an individual's disease profile for reliable survival prediction. MRI has prognostic value for intrahepatic cholangiocarcinoma (ICCA). Existing prognostic models for ICCA exclude imaging-based information about an individual's tumor that may reflect important aspects of tumor's biology. Fudan score, a prognostic model applicable to unresectable ICCA, is limited by subjective morphologic imaging parameters. OBJECTIVES: To assess the prognostic value of baseline volumetric multiparametric MRI in unresectable intrahepatic cholangiocarcinoma (ICCA) treated with systemic chemotherapy and the incremental value of MRI over the Fudan score. METHODS: This retrospective study included 114 ICCA patients treated with systemic chemotherapy between 2007 and 2021 after a baseline MRI. The single largest tumor was volumetrically assessed for anatomic (total tumor volume and diameter) and functional parameters (viable tumor volume, percentage-viable tumor volume, viable tumor burden, and ADC). A derivation cohort of 30 patients was utilized to identify MRI parameters associated with overall survival (OS) using Cox regression analysis. The incremental value of MRI over Fudan score was assessed on an independent sub-cohort of 84 patients using Kaplan-Meier analysis and C-index. RESULTS: 114 patients (64 years +/- 11; 61 women) were evaluated. Pre-treatment high (>1350x10-6 mm2/sec) ADC was the only independent predictor of OS (HR, 8.07; P < 0.001). Replacing subjective tumor boundary with objective ADC value, and using modified biochemical thresholds increased the prognostic stratification for the risk groups in the modified ADC-Fudan model compared to the original Fudan model (median survival 12 and 4.5 months; P = 0.055; vs. 11 and 3 months; P < 0.001). The modified ADC-Fudan model demonstrated an 11 % improvement over the original Fudan model (c-index: 0.80 vs. 0.69; P = 0.044) for survival prediction. CONCLUSIONS: High pre-treatment volumetric ADC was associated with unfavorable prognosis in patients with unresectable intrahepatic cholangiocarcinoma treated with systemic chemotherapy. Supplementing the original Fudan model with ADC and modified serum marker thresholds improved the survival prediction performance by 11% in the resulting modified ADC-Fudan model. CLINICAL IMPACT: Volumetric MRI could improve the survival prediction among ICCA patients prior to receiving potentially toxic and expensive palliative chemotherapies. This could potentially guide individualized therapy for this patient cohort.

The Toxoplasma subpellicular network is highly interconnected and defines parasite shape for efficient motility and replication.

Apicomplexan parasites possess several specialized structures to invade their host cells and replicate successfully. One of these is the inner membrane complex (IMC), a peripheral membrane-cytoskeletal system underneath the plasma membrane. It is composed of a series of flattened, membrane-bound vesicles and a cytoskeletal subpellicular network (SPN) comprised of intermediate filament-like proteins called alveolins. While the alveolin proteins are conserved throughout the Apicomplexa and the broader Alveolata, their precise functions and interactions remain poorly understood. Here, we describe the function of one of these alveolin proteins, TgIMC6. Disruption of IMC6 resulted in striking morphological defects that led to aberrant motility, invasion, and replication. Deletion analyses revealed that the alveolin domain alone is largely sufficient to restore localization and partially sufficient for function. As this highlights the importance of the IMC6 alveolin domain, we implemented unnatural amino acid photoreactive crosslinking to the alveolin domain and identified multiple binding interfaces between IMC6 and two other cytoskeletal proteins - IMC3 and ILP1. To our knowledge, this provides the first direct evidence of protein-protein interactions in the alveolin domain and supports the long-held hypothesis that the alveolin domain is responsible for filament formation. Collectively, our study features the conserved alveolin proteins as critical components that maintain the parasite's structural integrity and highlights the alveolin domain as a key mediator of SPN architecture.

Effects of convalescent plasma infusion on the ADAMTS13-von Willebrand factor axis and endothelial integrity in patients with severe and critical COVID-19.

Background: Convalescent plasma infusion (CPI) was given to patients with COVID-19 during the early pandemic with mixed therapeutic efficacy. However, the impacts of CPI on the ADAMTS13-von Willebrand factor (VWF) axis and vascular endothelial functions are not known. Objectives: To determine the impacts of CPI on the ADAMTS13-VWF axis and vascular endothelial functions. Methods: Sixty hospitalized patients with COVID-19 were enrolled in the study; 46 received CPI and 14 received no CPI. Plasma ADAMTS13 activity, VWF antigen, endothelial syndecan-1, and soluble thrombomodulin (sTM) were assessed before and 24 hours after treatment. Results: Patients with severe and critical COVID-19 exhibited significantly lower plasma ADAMTS13 activity than the healthy controls. Conversely, these patients showed a significantly increased VWF antigen. This resulted in markedly reduced ratios of ADAMTS13 to VWF in these patients. The levels of plasma ADAMTS13 activity in each patient remained relatively constant throughout hospitalization. Twenty-four hours following CPI, plasma ADAMTS13 activity increased by ∼12% from the baseline in all patients and ∼21% in those who survived. In contrast, plasma levels of VWF antigen varied significantly over time. Patients who died exhibited a significant reduction of plasma VWF antigen from the baseline 24 hours following CPI, whereas those who survived did not. Furthermore, patients with severe and critical COVID-19 showed significantly elevated plasma levels of syndecan-1 and sTM, similar to those found in patients with immune thrombotic thrombocytopenic purpura. Both syndecan-1 and sTM levels were significantly reduced 24 hours following CPI. Conclusion: Our results demonstrate the relative deficiency of plasma ADAMTS13 activity and endothelial damage in patients with severe and critical COVID-19, which could be modestly improved following CPI therapy.

Refined pancreatobiliary UroVysion criteria and an approach for further optimization.

Pancreatobiliary strictures are a common source of false negatives for malignancy detection. UroVysion is more sensitive than any other method but remains underutilized because of conflicting sensitivities and specificities due to a lack of standardized cutoff criteria and confusion in interpreting results in the context of primary sclerosing cholangitis. We set out to determine the sensitivities and specificities of UroVysion, brushing cytology, forceps biopsies, and fine needle aspiration (FNAs) for pancreatobiliary stricture malignancy detection. A retrospective review was performed of all biopsied pancreatobiliary strictures at our institution over 5 years. UroVysion was unquestionably the most sensitive method and all methods were highly specific. Sensitivity was highest while maintaining specificity when a malignant interpretation was limited to cases with 5+ cells with the same polysomic signal pattern and/or loss of one or both 9p21 signals. Only UroVysion detected the metastases and a neuroendocrine tumor. In reviewing and analyzing the signal patterns, we noticed trends according to location and diagnosis. Herein we describe our method for analyzing signal patterns and propose cutoff criteria based upon observations gleaned from such analysis.

Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility.

As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond rule of 5" molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D7.4dec/w - mlipocLogP + bscaffold, where log D7.4dec/w is the experimental decadiene-water distribution coefficient (pH 7.4), cLogP is the calculated octanol-water partition coefficient, and mlipo and bscaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.

A new opiine (Hymenoptera, Braconidae) from Australia with discussion of Diachasma Foerster.

A new species of Opiinae, Diachasma dentatum Shirley, Restuccia & Ly, is described from Australia. This species is similar to several other Australian opiines previously described or included in the genus Diachasma, but the mandibles are unusually broad, nearly exodont. Notable differences between Australian and Palaearctic Diachasma are discussed. Diachasma tasmaniae Fischer, 1995, originally described from Tasmania and New South Wales, is newly recorded from Victoria. Diachasma rufipes Szépligeti, 1905 is transferred to Notiopambolus, new combination.