Real-Time and Wireless Assessment of Adherence to Antiretroviral Therapy With Co-Encapsulated Ingestion Sensor in HIV-Infected Patients: A Pilot Study.

Adherence with antiretroviral therapy is important for preventing disease progression and HIV transmission. The co-encapsulated pill sensor system sends a signal through a cutaneous patch and allows real-time monitoring of pill ingestion. A 16-week pilot study used a sensor system in 15 HIV-infected individuals with real-time monitoring of pill-taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow-up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co-encapsulated pills were "unable to take" or "poorly tolerated." At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10-15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures

Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients

Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OH-efavirenz) have not been robustly evaluated in older HIV-infected persons

Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug–drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART

Background HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy. Objectives To investigate clinically applicable dose-adjustment strategies to overcome the known drug–drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz. Results No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively). Conclusions These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz–levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009

Regimen Simplification to Atazanavir‐Ritonavir Alone as Maintenance Antiretroviral Therapy: Final 48‐Week Clinical and Virologic Outcomes

Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)–sparing benefits, low pill burden, once-daily dosage, and safety

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Etravirine pharmacokinetics in HIV-infected pregnant women

__Background__ The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. __Methods__ IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). __Results__ Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred. __Conclusion__ Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. __Clinical Trial registration:__ The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929

Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Phase 2 safety and antiviral activity of SAB-185, a novel polyclonal antibody therapy for non-hospitalized adults with COVID-19

SAB-185, a novel fully-human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for non-hospitalized adults with mild-moderate COVID-19.Participants received intravenous SAB-185 3,840 units/kg (low-dose) or placebo, or 10,240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal SARS-CoV-2 RNA &lt;lower limit of quantification (LLoQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.Two-hundred thirteen participants received low-dose SAB-185/placebo (n=107/106) and 215 high-dose SAB-185/placebo (n=110/105). The proportions with SARS-CoV-2 RNA &lt;LLoQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB versus placebo only, relative risk (95% CI) 1.23 (1.01, 1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo, differences in medians of -0.78 log10copies/mL (p=0.08) and -0.71 log10copies/mL (p=0.10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (p=0.24) for low-dose SAB-185/placebo and 8/10 days (p=0.50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk non-hospitalized adults with COVID-19

Does administration of non-steroidal anti-inflammatory drug determine morphological changes in adrenal cortex: ultrastructural studies

Rofecoxib (Vioxx© made by Merck Sharp & Dohme, the USA) is a non-steroidal anti-inflammatory drug which belongs to the group of selective inhibitors of cyclooxygenasis-2, i.e., coxibs. Rofecoxib was first registered in the USA, in May 1999. Since then the drug was received by millions of patients. Drugs of this group were expected to exhibit increased therapeutic action. Additionally, there were expectations concerning possibilities of their application, at least as auxiliary drugs, in neoplastic therpy due to intensifying of apoptosis. In connection with the withdrawal of Vioxx© (rofecoxib) from pharmaceutical market, attempts were made to conduct electron-microscopic evaluation of cortical part of the adrenal gland in preparations obtained from animals under influence of the drug. Every morning animals from the experimental group (15 rats) received rofecoxib (suspension in physiological saline)—non-steroidal anti-inflammatory drug (Vioxx©, Merck Sharp and Dohme, the USA), through an intragastric tube in the dose of 1.25 mg during 8 weeks. In the evaluated material, there was found a greater number of secretory vacuoles and large, containing cholesterol and other lipids as well as generated glucocorticoids, lipid drops in cytoplasm containing prominent endoplasmic reticulum. There were also found cells with cytoplasm of smaller density—especially in apical and basal parts of cells. Mitochondria occasionally demonstrated features of delicate swelling. The observed changes, which occurred on cellular level with application of large doses of the drug, result from mobilization of adaptation mechanisms of the organism