Proarrhythmic major adverse cardiac events with donepezil: A systematic review with meta-analysis.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are regularly used in Alzheimer's disease. Of the three ChEIs approved for dementia, donepezil is among the most prescribed drugs in the United States with nearly 6 million prescriptions in 2020; however, it is classified as a "known risk" QT interval-prolonging medication (QTPmed). Given this claim is derived from observational data including single case reports, we aimed to evaluate high-quality literature on the frequency and nature of proarrhythmic major adverse cardiac events (MACE) associated with donepezil. METHODS: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onwards for randomized controlled trials (RCTs) involving patients age ≥18 years comparing donepezil to placebo. The MACE composite included mortality, sudden cardiac death, non-fatal cardiac arrest, Torsades de pointes, ventricular tachyarrhythmia, seizure or syncope. Random-effects meta-analyses were performed with a treatment-arm continuity correction for single and double zero event studies. RESULTS: Sixty RCTs (n = 12,463) were included. Twenty-five of 60 trials (n = 5886) investigated participants with Alzheimer's disease and 33 trials monitored electrocardiogram data. The mean follow-up duration was 31 weeks (SD = 36). Mortality was the most commonly reported MACE (252/331, 75.8% events), the remainder were syncope or seizures, with no arrhythmia events. There was no increased risk of MACE with exposure to donepezil compared to placebo (risk ratio [RR] 1.08, 95% CI 0.88-1.33, I2 = 0%) and this was consistent in the subgroup analysis of trials including participants with cardiovascular morbidities (RR 1.14, 95% CI 0.88-1.47). Subgroup analysis suggested a trend toward more events with donepezil with follow-up ≥52 weeks (RR: 1.32, 0.98-1.79). CONCLUSIONS: This systematic review with meta-analysis found donepezil may not be arrhythmogenic. Donepezil was not associated with mortality, ventricular arrhythmias, seizure or syncope, although longer durations of therapy need more study. Further research to clarify actual clinical outcomes related to QTPmed is important to inform prescribing practices.

Variation in Sedative and Analgesic Use During the COVID-19 Pandemic and Associated Outcomes.

BACKGROUND: Providing analgesia and sedation is an essential component of caring for many mechanically ventilated patients. The selection of analgesic and sedative medications during the COVID-19 pandemic, and the impact of these sedation practices on patient outcomes, remain incompletely characterized. RESEARCH QUESTION: What were the hospital patterns of analgesic and sedative use for patients with COVID-19 who received mechanical ventilation (MV), and what differences in clinical patient outcomes were observed across prevailing sedation practices? STUDY DESIGN AND METHODS: We conducted an observational cohort study of hospitalized adults who received MV for COVID-19 from February 2020 through April 2021 within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 Registry. To describe common sedation practices, we used hierarchical clustering to group hospitals based on the percentage of patients who received various analgesic and sedative medications. We then used multivariable regression models to evaluate the association between hospital analgesia and sedation cluster and duration of MV (with a placement of death [POD] approach to account for competing risks). RESULTS: We identified 1,313 adults across 35 hospitals admitted with COVID-19 who received MV. Two clusters of analgesia and sedation practices were identified. Cluster 1 hospitals generally administered opioids and propofol with occasional use of additional sedatives (eg, benzodiazepines, alpha-agonists, and ketamine); cluster 2 hospitals predominantly used opioids and benzodiazepines without other sedatives. As compared with patients in cluster 2, patients admitted to cluster 1 hospitals underwent a shorter adjusted median duration of MV with POD (ß-estimate, -5.9; 95% CI, -11.2 to -0.6; P = .03). INTERPRETATION: Patients who received MV for COVID-19 in hospitals that prioritized opioids and propofol for analgesia and sedation experienced shorter adjusted median duration of MV with POD as compared with patients who received MV in hospitals that primarily used opioids and benzodiazepines.

The Association of Anticoagulation Intensity with Outcomes in Hospitalized COVID-19 Patients.

Venous thromboembolism (VTE) risk is increased in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A key question was whether increased intensity of anticoagulation would help prevent VTE and improve patient outcomes, including transfer to the intensive care unit (ICU) and mortality. At the start of the coronavirus disease-19 (COVID-19) pandemic, our institution, Boston Medical Center, instituted a VTE risk stratification protocol based on patients' initial D-dimer levels, medical history, and presence of thrombosis to determine whether they should receive standard-dose prophylaxis, high-dose prophylaxis, or therapeutic anticoagulation. We performed a retrospective observational cohort study examining the association of degree of anticoagulation with outcomes in 915 hospitalized COVID-19 patients hospitalized initially on the general inpatient wards between March 1,, 2020, and June 1, 2020. Patients directly hospitalized in the ICU were excluded. Most, 813 patients (89%), in our cohort were on standard-dose prophylaxis; 32 patients (3.5%) received high-dose prophylaxis; 70 patients (7.7%), were treated with therapeutic anticoagulation. VTE occurred in 45 patients (4.9%), and the overall in-hospital mortality rate was 5.4% (49 deaths). On multivariable analysis of clinical outcomes in relation to type of anticoagulation, in the high-dose prophylaxis group, there was a trend towards increased in-hospital mortality (odds ratio 2.4 (0.8-7.5, 95% CI)) and increased ICU transfer (odds ratio 2.2 (0.9-5.7, 95% CI)). Our results suggest that patients receiving high-dose prophylaxis had more severe disease that was not mitigated by intermediate-dose anticoagulation.

Measures of retention in HIV care: A protocol for a mixed methods study.

INTRODUCTION: Retention in HIV care is necessary to achieve adherence to antiretroviral therapy, viral load suppression, and optimal health outcomes. There is no standard definition for retention in HIV care, which compromises consistent and reliable reporting and comparison of retention across facilities, jurisdictions, and studies. OBJECTIVE: The objective of this study is to explore how stakeholders involved in HIV care define retention in HIV care and their preferences on measuring retention. METHODS: We will use an exploratory sequential mixed methods design involving HIV stakeholder groups such as people living with HIV, people involved in providing care for PLHIV, and people involved in decision-making about PLHIV. In the qualitative phase of the study, we will conduct 20-25 in-depth interviews to collect the perspectives of HIV stakeholders on using their preferred retention measures. The findings from the qualitative phase will inform the development of survey items for the quantitative phase. Survey participants (n = 385) will be invited to rate the importance of each approach to measuring retention on a seven-point Likert scale. We will merge the qualitative and quantitative findings phase findings to inform a consensus-building framework for a standard definition of retention in care. ETHICAL ISSUES AND DISSEMINATION: This study has received ethics approval from the Hamilton Integrated Research Ethics Board. The findings will be disseminated through peer-reviewed publications, conference presentations, and among stakeholder groups. LIMITATIONS: This study has limitations; we won't be able to arrive at a standard definition; a Delphi technique amongst the stakeholders will be utilized using the framework to reach a consensus globally accepted definition.

The role of GammaTile in the treatment of brain tumors: a technical and clinical overview.

Malignant and benign brain tumors with a propensity to recur continue to be a clinical challenge despite decades-long efforts to develop systemic and more advanced local therapies. GammaTile (GT Medical Technologies Inc., Tempe AZ) has emerged as a novel brain brachytherapy device placed during surgery, which starts adjuvant radiotherapy immediately after resection. GammaTile received FDA clearance in 2018 for any recurrent brain tumor and expanded clearance in 2020 to include upfront use in any malignant brain tumor. More than 1,000 patients have been treated with GammaTile to date, and several publications have described technical aspects of the device, workflow, and clinical outcome data. Herein, we review the technical aspects of this brachytherapy treatment, including practical physics principles, discuss the available literature with an emphasis on clinical outcome data in the setting of brain metastases, glioblastoma, and meningioma, and provide an overview of the open and pending clinical trials that are further defining the efficacy and safety of GammaTile.

Functional Near-Infrared Spectrometry as a Useful Diagnostic Tool for Understanding the Visual System: A Review.

This comprehensive review explores the role of Functional Near-Infrared Spectroscopy (fNIRS) in advancing our understanding of the visual system. Beginning with an introduction to fNIRS, we delve into its historical development, highlighting how this technology has evolved over time. The core of the review critically examines the advantages and disadvantages of fNIRS, offering a balanced view of its capabilities and limitations in research and clinical settings. We extend our discussion to the diverse applications of fNIRS beyond its traditional use, emphasizing its versatility across various fields. In the context of the visual system, this review provides an in-depth analysis of how fNIRS contributes to our understanding of eye function, including eye diseases. We discuss the intricacies of the visual cortex, how it responds to visual stimuli and the implications of these findings in both health and disease. A unique aspect of this review is the exploration of the intersection between fNIRS, virtual reality (VR), augmented reality (AR) and artificial intelligence (AI). We discuss how these cutting-edge technologies are synergizing with fNIRS to open new frontiers in visual system research. The review concludes with a forward-looking perspective, envisioning the future of fNIRS in a rapidly evolving technological landscape and its potential to revolutionize our approach to studying and understanding the visual system.

Disminución de la debilidad muscular adquirida en una unidad de cuidados intensivos con la implementación de un protocolo multicomponente: ensayo clínico cuasiexperimental

Introducción. La debilidad adquirida en las unidades de cuidados intensivos es una complicación frecuente de los pacientes con enfermedades críticas, que puede tener un impacto negativo en su pronóstico a corto y a largo plazo. Objetivos. Evaluar si la utilización de un protocolo multicomponente, que incluye movilidad activa temprana, manejo efectivo del dolor, reducción de la sedación, medidas no farmacológicas para prevenir el delirium, estimulación cognitiva y apoyo familiar, puede disminuir la incidencia de debilidad adquirida en las unidades de cuidados intensivos al momento del egreso del paciente. Materiales y métodos. Se trata de un ensayo clínico, no aleatorizado, en dos unidades de cuidados intensivos mixtas de un hospital de tercer nivel. Los participantes fueron pacientes mayores de 14 años con ventilación mecánica invasiva por más de 48 horas. Se aplicó como intervención un protocolo multicomponente y como control se utilizó el cuidado usual o estándar. Resultados. Ingresaron 188 pacientes al estudio, 82 al grupo de intervención y 106 al grupo control. La tasa de debilidad adquirida en las unidades de cuidados intensivos al egreso de la unidad fue significativamente menor en el grupo de intervención (41,3 % versus 78,9 %, p<0,00001). La mediana del puntaje de movilidad al momento del alta de la unidad de cuidados intensivos fue mayor en el grupo de intervención (3,5 versus 2, p<0,0138). No se encontraron diferencias estadísticamente significativas en las medianas de días libres de respiración mecánica asistida, ni de unidad de cuidados intensivos al día 28, tampoco en la tasa de mortalidad general al egreso del hospital (18 versus 15 días, p<0,49; 18,2 % versus 27,3 %, p<0,167). Conclusiones. Un protocolo multicomponente que incluía movilidad activa temprana tuvo un impacto significativo en la reducción de la debilidad adquirida en las unidades de cuidados intensivos al egreso en comparación con el cuidado estándar.

Introduction. Intensive care unit-acquired weakness is a frequent complication that affects the prognosis of critical illness during hospital stay and after hospital discharge. Objectives. To determine if a multicomponent protocol of early active mobility involving adequate pain control, non-sedation, non-pharmacologic delirium prevention, cognitive stimulation, and family support, reduces intensive care unit-acquired weakness at the moment of discharge. Materials and methods. We carried out a non-randomized clinical trial in two mixed intensive care units in a high-complexity hospital, including patients over 14 years old with invasive mechanical ventilation for more than 48 hours. We compared the intervention -the multicomponent protocol- during intensive care hospitalization versus the standard care. Results. We analyzed 82 patients in the intervention group and 106 in the control group. Muscle weakness acquired in the intensive care unit at the moment of discharge was less frequent in the intervention group (41.3% versus 78.9%, p<0.00001). The mobility score at intensive unit care discharge was better in the intervention group (median = 3.5 versus 2, p < 0.0138). There were no statistically significant differences in the invasive mechanical ventilation-free days at day 28 (18 versus 15 days, p<0.49), and neither in the mortality (18.2 versus 27.3%, p<0.167). Conclusion. A multi-component protocol of early active mobility significantly reduces intensive care unit-acquired muscle weakness at the moment of discharge.

Decrease in the intensive care unit-acquired weakness with a multicomponent protocol implementation: A quasi-experimental clinical trial / Disminución de la debilidad muscular adquirida en una unidad de cuidados intensivos con la implementación de un protocolo multicomponente: ensayo clínico cuasiexperimental

Introduction: Intensive care unit-acquired weakness is a frequent complication that affects the prognosis of critical illness during hospital stay and after hospital discharge. Objectives: To determine if a multicomponent protocol of early active mobility involving adequate pain control, non-sedation, non-pharmacologic delirium prevention, cognitive stimulation, and family support, reduces intensive care unit-acquired weakness at the moment of discharge. Materials and methods: We carried out a non-randomized clinical trial in two mixed intensive care units in a high-complexity hospital, including patients over 14 years old with invasive mechanical ventilation for more than 48 hours. We compared the intervention ­the multicomponent protocol­ during intensive care hospitalization versus the standard care. Results: We analyzed 82 patients in the intervention group and 106 in the control group. Muscle weakness acquired in the intensive care unit at the moment of discharge was less frequent in the intervention group (41.3% versus 78.9%, p<0.00001). The mobility score at intensive unit care discharge was better in the intervention group (median = 3.5 versus 2, p < 0.0138). There were no statistically significant differences in the invasive mechanical ventilation-free days at day 28 (18 versus 15 days, p<0.49), and neither in the mortality (18.2 versus 27.3%, p<0.167). Conclusion: A multi-component protocol of early active mobility significantly reduces intensive care unit-acquired muscle weakness at the moment of discharge.

Introducción: La debilidad adquirida en las unidades de cuidados intensivos es una complicación frecuente de los pacientes con enfermedades críticas, que puede tener un impacto negativo en su pronóstico a corto y a largo plazo. OBJETIVOS: Evaluar si la utilización de un protocolo multicomponente, que incluye movilidad activa temprana, manejo efectivo del dolor, reducción de la sedación, medidas no farmacológicas para prevenir el delirium, estimulación cognitiva y apoyo familiar, puede disminuir la incidencia de debilidad adquirida en las unidades de cuidados intensivos al momento del egreso del paciente. Materiales y métodos: Se trata de un ensayo clínico, no aleatorizado, en dos unidades de cuidados intensivos mixtas de un hospital de tercer nivel. Los participantes fueron pacientes mayores de 14 años con ventilación mecánica invasiva por más de 48 horas. Se aplicó como intervención un protocolo multicomponente y como control se utilizó el cuidado usual o estándar. RESULTADOS: Ingresaron 188 pacientes al estudio, 82 al grupo de intervención y 106 al grupo control. La tasa de debilidad adquirida en las unidades de cuidados intensivos al egreso de la unidad fue significativamente menor en el grupo de intervención (41,3 % versus 78,9 %, p<0,00001). La mediana del puntaje de movilidad al momento del alta de la unidad de cuidados intensivos fue mayor en el grupo de intervención (3,5 versus 2, p<0,0138). No se encontraron diferencias estadísticamente significativas en las medianas de días libres de respiración mecánica asistida, ni de unidad de cuidados intensivos al día 28, tampoco en la tasa de mortalidad general al egreso del hospital (18 versus 15 días, p<0,49; 18,2 % versus 27,3 %, p<0,167). CONCLUSIONES: Un protocolo multicomponente que incluía movilidad activa temprana tuvo un impacto significativo en la reducción de la debilidad adquirida en las unidades de cuidados intensivos al egreso en comparación con el cuidado estándar.

Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review.

OBJECTIVES: We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). DATA SOURCES: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. DATA SYNTHESIS: By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I2 = 0%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. CONCLUSIONS: Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Retrospective and Prospective Outcomes of Distal Radioulnar Joint Prosthesis Arthroplasty at a Single Center.

Purpose: Distal radioulnar joint (DRUJ) arthritis can cause painful and limited motion of the forearm leading to decreased function. When conservative treatment options are exhausted, surgical treatments are the next step. The purpose of this study was to retrospectively and prospectively evaluate outcomes of Scheker DRUJ total arthroplasty at a single center and add to the limited data on this procedure. Methods: In a retrospective and prospective cohort of 12 patients, 13 DRUJ prosthetics implanted from 2014 to 2021 were evaluated from a single center. The primary outcome was patient satisfaction with the procedure, including comparisons of preoperative and postoperative visual analog scale, Disabilities of the Arm, Shoulder, and Hand, and willingness to repeat the procedure. Secondary outcomes included range of motion, subjective grip strength, need for hardware revision, subsequent procedures, and postoperative complaints. Results: Out of 12 patients that were at least 1-year after surgery from DRUJ arthroplasty, 1 was deceased at the time of final survey and 1 underwent bilateral DRUJ arthroplasty. Seven of 12 available patients were surveyed over the phone. On average, patient range of motion after surgery was 76° in each direction for pronation and supination. There was a clinically significant improvement in the Disabilities of the Arm, Shoulder, and Hand score and a statistically significant improvement in visual analog scale pain rating. Seventy-five percent of patients surveyed were satisfied with their outcomes and would undergo the surgery again. Only one patient required additional surgery, and there were no instances of hardware failure at an average follow-up of 40 months. Conclusions: Our study has shown positive outcomes with decrease in pain, improvement in function via Disabilities of the Arm, Shoulder, and Hand evaluation, and subjective patient satisfaction, with a 100% prosthesis survival rate. The DRUJ arthroplasty prosthesis is a viable alternative to other DRUJ salvage procedures. Type of study/level of evidence: Therapeutic Level III.

Concentrated Grape Powder Consumption Modulates Cholesterol Metabolism and Homeostasis in Healthy Subjects.

SCOPE: Four weeks' of concentrated grape powder (GP) consumption reduces circulating cholesterol in healthy free-living subjects consuming a low-fiber/low-polyphenol diet. Here, the study aims to investigate the underlying mechanisms for cholesterol reduction by evaluating biomarkers of cholesterol de novo biosynthesis, intestinal absorption, miRNA involved in transcriptional regulation of cholesterol metabolism, as well as cholesterol oxidation. METHODS AND RESULTS: Fasting plasma samples collected from 19 healthy free-living subjects at baseline and week 4 of GP consumption are used in this study. Gas chromatography-mass (GC-MS) analysis of plasma samples shows that lathosterol, a precursor of cholesterol synthesis, is significantly decreased after GP consumption indicating reduced cholesterol de novo biosynthesis. Markers of intestinal absorption, campesterol, and ß-sitosterol are not changed. Realtime PCR shows that plasma exosomal miRNA-1 is increased after GP consumption. GC-MS also shows that GP consumption reduces the plasma cholesterol oxidation product 27-hydroxycholesterol (27-HC). CONCLUSIONS: This study enhances the understanding of the mechanisms of the cholesterol lowering effects of GP, and provides new insights into the potential health benefits of grape consumption.

Micronutrient deficiencies in patients with gastrointestinal cancer: To treat or not to treat.

Nutrition supplements are widely used among patients with cancer. The general public perceives supplements as more natural anticancer and antitoxicity agents, and often supplements are used without the knowledge of the treating physician. In the clinical setting, there are concerns that supplements may decrease effectiveness of chemotherapy and/or radiotherapy and, as a result, supplementation is avoided. There is a body of literature evaluating micronutrient deficiencies, supplementation, and cancer risk; however, little is known about the risks of treatment of micronutrient deficiencies in specific cancers. Of the types of cancers, patients with gastrointestinal cancers are at high risk of developing malnutrition and, subsequently, possible micronutrient deficiencies. This review aims to evaluate the effects of supplementation of specific micronutrients in patients with cancer of the digestive tract.

Empirical progression criteria thresholds for feasibility outcomes in HIV clinical trials: a methodological study.

INTRODUCTION: Pilot and feasibility trials use predetermined thresholds for feasibility outcomes to decide if a larger trial is feasible. These thresholds may be derived from the literature, observational data, or clinical experience. The aim of this study was to determine empirical estimates for feasibility outcomes to inform future HIV pilot randomized trials. METHODS: We conducted a methodological study of HIV clinical trials indexed in the past 5 years (2017-2021) in the PubMed database. We included trials of people living with HIV individually randomized to any type of intervention and excluded pilot trials and cluster randomized trials. Screening and data extraction were conducted in duplicate. We computed estimates for recruitment, randomization, non-compliance, lost to follow-up, discontinuation, and the proportion analyzed using a random effects meta-analysis of proportions and reported these estimates according to the following subgroups: use of medication, intervention type, trial design, income level, WHO region, participant type, comorbidities, and source of funding. We report estimates with 95% confidence intervals. RESULTS: We identified 2122 studies in our search, of which 701 full texts were deemed relevant, but only 394 met our inclusion criteria. We found the following estimates: recruitment (64.1%; 95% CI 57.7 to 70.3; 156 trials); randomization (97.1%; 95% CI 95.8 to 98.3; 187 trials); non-compliance (3.8%; 95% CI 2.8 to 4.9; 216 trials); lost to follow-up (5.8%; 95% CI 4.9 to 6.8; 251 trials); discontinuation (6.5%; 95% CI 5.5 to 7.5; 215 trials); analyzed (94.2%; 95% CI 92.9 to 95.3; 367 trials). There were differences in estimates across most subgroups. CONCLUSION: These estimates may be used to inform the design of HIV pilot randomized trials with careful consideration of variations due to some of the subgroups investigated.

Exposure to Family Member Deaths Across the Life Course for Hispanic Individuals.

The present study documents differences in exposure to family member deaths among foreign-born and U.S.-born Hispanic individuals compared with non-Hispanic Black and non-Hispanic White individuals. We use data from the Health and Retirement Study (HRS; 1992-2016, ages 51+; N = 23,228) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; Waves I-V, ages 12-43; N = 11,088) to estimate the risk of exposure to the death of a mother, father, spouse, sibling, and child across the life course. HRS results show more inequities in exposure to family deaths compared with Add Health results, suggesting differences by age or birth cohort. Compared with non-Hispanic Whites, U.S.-born Hispanic individuals in the HRS have a higher risk of experiencing a child's death throughout adulthood and a sibling's death in later life; the latter is explained by larger sibship size, indicating a greater lifetime risk of bereavement experiences. The higher risk of parental death during childhood for U.S.-born and foreign-born Hispanic individuals is explained by covariates (e.g., lower levels of educational attainment). Hispanic individuals generally have a lower risk of family deaths than non-Hispanic Black individuals, but at times a higher risk of exposure relative to non-Hispanic White individuals.

Provider- and Facility-Level Variation in Precancerous Cervical Biopsy Diagnoses.

OBJECTIVES: Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities. METHODS: We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation. RESULTS: A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36). CONCLUSIONS: Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.

Variation in Troponin I Measurement and the Cardiovascular Management Approach Following Elevated Troponin I Among Critically Ill Patients With Sepsis.

Troponin I is frequently elevated in sepsis, but optimal clinical approaches to diagnosis and management of troponin I during sepsis are unclear. OBJECTIVES: We aimed to describe the variation in troponin I measurement and the cardiovascular diagnostic and therapeutic approach to elevated troponin I among critically ill adults with sepsis. DESIGN SETTING AND PARTICIPANTS: Observational cohort study of the hospital-level variation in serial troponin I measurement, trending troponin I to peak, echocardiography, cardiac stress test, cardiac catheterization, antiplatelet agents, therapeutic anticoagulation, beta-blockers, and statins quantified using hospital median odds ratios-the median odds of receiving an intervention at randomly selected higher versus lower rate hospitals-derived from multivariable-adjusted random-effects logistic regression models with hospital site as the random effect. The Premier Healthcare Database was used. Patients were adults aged greater than 18 years admitted to the ICU with sepsis from 2016 to 2020. MAIN OUTCOMES AND MEASURES: The hospital-level median odds ratios of troponin I measurement as well as cardiovascular diagnostics and therapeutics. RESULTS: Among 85,830 adults with sepsis, 53,058 (61.8%) had a troponin I measured, with a median odds ratio of troponin measurement across hospitals of 5.30 (95% CI, 4.98-5.67). Among 27,665 adults (32.2%) with sepsis and an elevated troponin I level, 84.8% had serial troponin I measurements, 66.0% had troponin trended to peak level, 66.7% had an echocardiogram, 4.1% had a cardiac stress test, 6.6% underwent cardiac catheterization, 48.3% received antiplatelet agents, 8.3% received therapeutic anticoagulation, 50.5% received beta-blockers, and 38.1% received statins. The median odds ratios between hospitals for cardiovascular diagnostics and therapeutics ranged from 1.28 (95% CI, 1.24-1.32) for use of beta-blockers to 7.58 (95% CI, 6.43-8.77) for use of therapeutic anticoagulation. CONCLUSIONS AND RELEVANCE: Both troponin I measurement and the approach to an elevated troponin I among critically ill adults with sepsis varied widely across hospitals consistent with disparate practice and care efficiency. Prospective studies are needed to guide an informed approach to troponin I measurement and cardiovascular evaluation in sepsis.

Gaps in the screening process for women diagnosed with cervical cancer in four diverse US health care settings.

BACKGROUND: Potential care gaps in the cervical cancer screening process among women diagnosed with cervical cancer in an era with increased human papillomavirus (HPV) testing have not been extensively evaluated. METHODS: Women diagnosed with cervical cancer between ages 21 and 65 at four study sites between 2010 and 2014 were included. Screening histories were ascertained from 0.5 to 4 years prior to cervical cancer diagnosis. We identified potential care gaps in the screening history for each woman and classified them into one of three mutually exclusive types: lack of a screening test, screening test failure, and diagnostic/treatment care gap. Distributions of care gaps were tabulated by stage, histology, and study site. Multivariable nominal logistic regression was used to examine the associations between demographic and cancer characteristics and type of care gap. RESULTS: Of 499 women evaluated, 46% lacked a screening test in the time window examined, 31% experienced a screening test failure, and 22% experienced a diagnostic/treatment care gap. More than half of the women with advanced cancer and squamous cell carcinoma lacked a screening test compared to 31% and 24% of women with localized cancer and adenocarcinoma, respectively. Women aged 21-29 at diagnosis were more likely to experience screening test failure and diagnostic/treatment care gap, while those aged 50-65 were more likely to lack a screening test, compared to women aged 30-39. CONCLUSIONS: Our findings demonstrate a continuing need to develop interventions targeting unscreened and under-screened women and improve detection and diagnosis of adenocarcinoma in women undergoing cervical cancer screening and diagnostic follow-up.

Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review.

BACKGROUND: Due to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. Nonetheless, none has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumor. A complete systematic review and discussions for overcoming design issues might be important to better understand why oncology trials have shown low success rates in early phase trials. METHODS: We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. Searches were conducted using the electronic database of PubMed, Google Scholar and ClinicalTrials.gov for potentially eligible publications from inception by two independent researchers up to May 26, 2022. The followings were key words for the literature search as index terms or free-text words: "phase II trials", "glioblastoma", and "two-stage design". We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status. RESULTS: Among examined 29 trials, 12 trials (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. Most trials (90%) used Simon's two-stage designs. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. CONCLUSIONS: Right implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials.

Spinal cord injury is associated with changes in synaptic properties of the mouse major pelvic ganglion.

Spinal cord injury (SCI) has substantial impacts on autonomic function. In part, SCI results in loss of normal autonomic activity that contributes to injury-associated pathology such as neurogenic bladder, bowel, and sexual dysfunction. Yet little is known of the impacts of SCI on peripheral autonomic neurons that directly innervate these target organs. In this study, we measured changes in synaptic properties of neurons of the mouse major pelvic ganglion (MPG) associated with acute and chronic SCI. Our data show that functional and physiological properties of synapses onto MPG neurons are altered after SCI and differ between acute and chronic injury. After acute injury excitatory postsynaptic potentials (EPSPs) show increased rise and decay time constants leading to overall broader and longer EPSPs, whereas in chronic-injured animals EPSPs are reduced in amplitude and show faster rise and decay leading to shorter EPSPs. Synaptic depression and low-pass filtering are also altered in injured animals. Finally, cholinergic currents are smaller in acute-injured animals but larger in chronic-injured animals relative to control animals. These changes in synaptic properties are associated with differences in nicotinic receptor subunit expression as well. MPG CHRNA3 mRNA levels decreased after injury, whereas CHRNA4 mRNAs increased. Furthermore, changes in the correlations of α- and ß-subunit mRNAs suggest that nicotinic receptor subtype composition is altered after injury. Taken together, our data demonstrate that peripheral autonomic neurons are fundamentally altered after SCI, suggesting that longer-term therapeutic approaches could target these neurons directly to potentially help ameliorate neurogenic target organ dysfunction.NEW & NOTEWORTHY Spinal cord injury (SCI) has substantial impacts on autonomic function, yet little is known of the impacts of SCI on autonomic neurons that directly innervate effectors impacted by injury. Here we investigated changes at the cellular level associated with SCI in neurons that are "downstream" of the central injury. An understanding of these off-target impacts of SCI ultimately will be critical in the context of effective restoration of function through neuromodulation of pharmacological therapeutic approaches.