Deconvoluting kinase inhibitor induced cardiotoxicity

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways

HIV-related stigma within communities of gay men: A literature review

While stigma associated with HIV infection is well recognised, there is limited information on the impact of HIV-related stigma between men who have sex with men and within communities of gay men. The consequences of HIV-related stigma can be personal and community-wide, including impacts on mood and emotional well-being, prevention, testing behaviour, and mental and general health. This review of the literature reports a growing division between HIV-positive and HIV-negative gay men, and a fragmentation of gay communities based along lines of perceived or actual HIV status. The literature includes multiple references to HIV stigma and discrimination between gay men, men who have sex with men, and among and between many gay communities. This HIV stigma takes diverse forms and can incorporate aspects of social exclusion, ageism, discrimination based on physical appearance and health status, rejection and violence. By compiling the available information on this understudied form of HIV-related discrimination, we hope to better understand and target research and countermeasures aimed at reducing its impact at multiple levels

Measurement of the mass difference m(D-s(+))-m(D+) at CDF II

We present a measurement of the mass difference m(D-s(+))-m(D+), where both the D-s(+) and D+ are reconstructed in the phipi(+) decay channel. This measurement uses 11.6 pb(-1) of data collected by CDF II using the new displaced-track trigger. The mass difference is found to be m(D-s(+))-m(D+)=99.41+/-0.38(stat)+/-0.21(syst) MeV/c(2)

Inadequate prophylaxis in patients with trauma: anti-Xa-guided enoxaparin dosing management in critically ill patients with trauma

Methods This prospective observational study included patients with trauma admitted to the trauma intensive care unit (ICU) from January 2021 to September 2022. Enoxaparin dosing was adjusted based on anti-Xa levels as standard of care via a performance improvement initiative. The primary outcome was the proportion of subtarget anti-Xa levels (<0.2 IU/mL) on 30 mg two times per day dosing of enoxaparin. Secondary outcomes included the dosing modifications to attain goal anti-Xa levels, VTE and bleeding events, and hospital and ICU lengths of stay.Results A total of 282 consecutive patients were included. Baseline demographics revealed a median age of 36 (26–55) years, and 44.7% with penetrating injuries. Of these, 119 (42.7%) achieved a target anti-Xa level on a starting dose of 30 mg two times per day. Dose modifications for subtarget anti-Xa levels were required in 163 patients (57.8%). Of those, 120 underwent at least one dose modification, which resulted in 78 patients (47.8%) who achieved a target level prior to hospital discharge on a higher dose of enoxaparin. Overall, only 69.1% of patients achieved goal anti-Xa level prior to hospital discharge. VTE occurred in 25 patients (8.8%) and major bleeding in 3 (1.1%) patients.Conclusion A majority of critically injured patients do not meet target anti-Xa levels with 30 mg two times per day enoxaparin dosing. This study highlights the need for anti-Xa-based dose modification and efficacy of a pharmacy-driven protocol. Further optimization is warranted to mitigate VTE events.Level of evidence Therapeutic/care management, level II