Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

High mortality rates among individuals misdiagnosed with tuberculosis: a matched retrospective cohort study of individuals diagnosed with tuberculosis in Brazil.

We conducted a matched retrospective cohort study comparing mortality among individuals receiving a false-positive tuberculosis diagnosis (n=3701) to individuals correctly diagnosed with TB (n=8595) in Brazil from 2007-2016. Over an average 5.4-year follow-up period, we estimated a mortality rate ratio of 1.95 (95% confidence interval: 1.80, 2.11) for individuals incorrectly diagnosed with TB compared to controls. The leading causes of death among the misdiagnosed were malignant neoplasms (40.9%) and respiratory system disorders (15.9%), conditions with symptoms similar to tuberculosis. Our findings highlight the need for improved follow-up care after identification of false-positive cases to increase survival for this high-risk population.

Cost-effectiveness of Low-complexity Screening Tests in Community-based Case-finding for Tuberculosis.

INTRODUCTION: In high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood. METHODS: We developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs. RESULTS: Universal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted. CONCLUSIONS: Screening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

Multicomponent Strategy with Decentralized Molecular Testing for Tuberculosis.

BACKGROUND: Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease. METHODS: We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions. RESULTS: A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40). CONCLUSIONS: A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.).

FOXA1/2 depletion drives global reprogramming of differentiation state and metabolism in a human liver cell line and inhibits differentiation of human stem cell-derived hepatic progenitor cells.

FOXA factors are critical members of the developmental gene regulatory network (GRN) composed of master transcription factors (TF) which regulate murine cell fate and metabolism in the gut and liver. How FOXA factors dictate human liver cell fate, differentiation, and simultaneously regulate metabolic pathways is poorly understood. Here, we aimed to determine the role of FOXA2 (and FOXA1 which is believed to compensate for FOXA2) in controlling hepatic differentiation and cell metabolism in a human hepatic cell line (HepG2). siRNA mediated knockdown of FOXA1/2 in HepG2 cells significantly downregulated albumin (p < .05) and GRN TF gene expression (HNF4α, HEX, HNF1ß, TBX3) (p < .05) and significantly upregulated endoderm/gut/hepatic endoderm markers (goosecoid [GSC], FOXA3, and GATA4), gut TF (CDX2), pluripotent TF (NANOG), and neuroectodermal TF (PAX6) (p < .05), all consistent with partial/transient reprograming. shFOXA1/2 targeting resulted in similar findings and demonstrated evidence of reversibility of phenotype. RNA-seq followed by bioinformatic analysis of shFOXA1/2 knockdown HepG2 cells demonstrated 235 significant downregulated genes and 448 upregulated genes, including upregulation of markers for alternate germ layers lineages (cardiac, endothelial, muscle) and neurectoderm (eye, neural). We found widespread downregulation of glycolysis, citric acid cycle, mitochondrial genes, and alterations in lipid metabolism, pentose phosphate pathway, and ketogenesis. Functional metabolic analysis agreed with these findings, demonstrating significantly diminished glycolysis and mitochondrial respiration, with concomitant accumulation of lipid droplets. We hypothesized that FOXA1/2 inhibit the initiation of human liver differentiation in vitro. During human pluripotent stem cells (hPSC)-hepatic differentiation, siRNA knockdown demonstrated de-differentiation and unexpectedly, activation of pluripotency factors and neuroectoderm. shRNA knockdown demonstrated similar results and activation of SOX9 (hepatobiliary). These results demonstrate that FOXA1/2 controls hepatic and developmental GRN, and their knockdown leads to reprogramming of both differentiation and metabolism, with applications in studies of cancer, differentiation, and organogenesis.

Back from the sideline, but back to baseline? A pediatric case study examining neuropsychological functioning after sustaining multiple sport-related concussions.

Most individuals recover quickly from a concussion; however, youth who sustain multiple concussions may be at risk for long-term cognitive impairments. This case study examines the neuropsychological performance of a 13-year-old malewith five head injuries. After his first concussion during study participation (fourth injury overall), several improvements were observed, likely due to practice effects, yet after sustaining another concussion <2 years later,declines were observed in visuoconstruction, verbal memory, and intellectual functioning. Across serial re-evaluation, his vocabulary knowledge declined, and fewer improvements were observed than anticipated when accounting for serial practice effects, highlighting the possible cumulative impact of multiple concussions.

Interventions to reengage people living with HIV who are lost to follow-up from HIV treatment programs: A systematic review and meta-analysis.

BACKGROUND: Optimizing services to facilitate engagement and retention in care of people living with HIV (PLWH) on antiretroviral therapies (ARTs) is critical to decrease HIV-related morbidity and mortality and HIV transmission. We systematically reviewed the literature for the effectiveness of implementation strategies to reestablish and subsequently retain clinical contact, improve viral load suppression, and reduce mortality among patients who had been lost to follow-up (LTFU) from HIV services. METHODS AND FINDINGS: We searched 7 databases (PubMed, Cochrane, ERIC, PsycINFO, EMBASE, Web of Science, and the WHO regional databases) and 3 conference abstract archives (CROI, IAC, and IAS) to find randomized trials and observational studies published through 13 April 2020. Eligible studies included those involving children and adults who were diagnosed with HIV, had initiated ART, and were subsequently lost to care and that reported at least one review outcome (return to care, retention, viral suppression, or mortality). Data were extracted by 2 reviewers, with discrepancies resolved by a third. We characterized reengagement strategies according to how, where, and by whom tracing was conducted. We explored effects, first, among all categorized as LTFU from the HIV program (reengagement program effect) and second among those found to be alive and out of care (reengagement contact outcome). We used random-effect models for meta-analysis and conducted subgroup analyses to explore heterogeneity. Searches yielded 4,244 titles, resulting in 37 included studies (6 randomized trials and 31 observational studies). In low- and middle-income countries (LMICs) (N = 16), tracing most frequently involved identification of LTFU from the electronic medical record (EMR) and paper records followed by a combination of telephone calls and field tracing (including home visits), by a team of outreach workers within 3 months of becoming LTFU (N = 7), with few incorporating additional strategies to support reengagement beyond contact (N = 2). In high-income countries (HICs) (N = 21 studies), LTFU were similarly identified through EMR systems, at times matched with other public health records (N = 4), followed by telephone calls and letters sent by mail or email and conducted by outreach specialist teams. Home visits were less common (N = 7) than in LMICs, and additional reengagement support was similarly infrequent (N = 5). Overall, reengagement programs were able to return 39% (95% CI: 31% to 47%) of all patients who were characterized as LTFU (n = 29). Reengagement contact resulted in 58% (95% CI: 51% to 65%) return among those found to be alive and out of care (N = 17). In 9 studies that had a control condition, the return was higher among those in the reengagement intervention group than the standard of care group (RR: 1.20 (95% CI: 1.08 to 1.32, P < 0.001). There were insufficient data to generate pooled estimates of retention, viral suppression, or mortality after the return. CONCLUSIONS: While the types of interventions are markedly heterogeneity, reengagement interventions increase return to care. HIV programs should consider investing in systems to better characterize LTFU to identify those who are alive and out of care, and further research on the optimum time to initiate reengagement efforts after missed visits and how to best support sustained reengagement could improve efficiency and effectiveness.

Evaluation of HIV treatment outcomes with reduced frequency of clinical encounters and antiretroviral treatment refills: A systematic review and meta-analysis.

BACKGROUND: Global HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART. METHODS AND FINDINGS: We searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97-1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75-1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98-1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63-3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa. CONCLUSIONS: Based on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Cost and Cost-Effectiveness of a Digital Adherence Technology for Tuberculosis Treatment Support in Uganda.

OBJECTIVES: Digital adherence technologies like 99DOTS are increasingly considered as an alternative to directly observed therapy for tuberculosis (TB) treatment supervision. We evaluated the cost and cost-effectiveness of 99DOTS in a high-TB-burden setting. METHODS: We assessed the costs of implementing 99DOTS in Uganda through a pragmatic, stepped-wedge randomized trial. We measured costs from the health system perspective at 5 of 18 study facilities. Self-reported service activity time data were used to assess activity-based service costs; other costs were captured from budgets and key informant discussions using standardized forms. We estimated costs and effectiveness considering the 8-month study period ("trial specific") and using a 5-year time horizon ("extended activities"), the latter including a "marginal clinic" expansion scenario that ignored above-site implementation costs. Cost-effectiveness was assessed as cost per patient successfully completing treatment, using Monte Carlo simulation, cost-effectiveness acceptability curves, and sensitivity analyses to evaluate uncertainty and robustness of results. RESULTS: The total cost of implementing 99DOTS in the "trial-specific" scenario was $99 554 across 18 clinics (range $3771-$6238 per clinic). The cost per treatment success in the "trial-specific" scenario was $355 (range $229-$394), falling to $59 (range $50-$70) assuming "extended activities," and $49 (range $42-$57) in the "marginal clinic" scenario. The incremental cost-effectiveness of 99DOTS in the "extended-activity" scenario was $355 per incremental treatment success. CONCLUSIONS: Costs and cost-effectiveness of 99DOTS were influenced by the degree to which infrastructure is scaled over time. If sustained and scaled up, 99DOTS can be a cost-effective option for TB treatment adherence support in high-TB-burden settings like Uganda.

Iris Atrophy After Administration of Intracameral Dexycu in Routine Cataract Surgery: A Case Series.

ABSTRACT: Dexycu (Icon Bioscience INC, Newark, CA) is an FDA-approved single-dose, sustained release intracameral steroid designed to mitigate postoperative inflammation after cataract surgery as an alternative to topical steroid therapy. The purpose of this study was to look at long-term and adverse events associated with Dexycu use. Eighteen eyes from nine patients who underwent cataract surgery were included. Patients were followed for an average of 97 days (range 28-319 days) after surgery on the first eye. Thirteen eyes were treated with Dexycu, and the other five eyes were treated with standard postoperative anti-inflammatory drops. Four of the thirteen eyes receiving Dexycu developed clinically evident iris atrophy (30.7%). None of the five eyes treated with traditional anti-inflammatory drops developed iris atrophy. The Dexycu intraocular dexamethasone implant was designed to mitigate postoperative inflammation and reduce need for topical therapy but may be associated with other potential adverse effects that warrant consideration.

Early Prediction of Intensive Care Admission in Emergency Department Patients With Asthma.

BACKGROUND: Emergency physicians must choose whether patients with asthma are admitted to a hospital ward or a higher level of care, such as an intermediate care unit (IMC) or intensive care unit (ICU). OBJECTIVE: This study aimed to determine which variables, available early during emergency department (ED) visits, are associated with IMC/ICU admission. METHODS: In this retrospective chart review (records from 2015-2018), two trained abstractors, blinded to study hypothesis, abstracted data on predictor variables and disposition (ward vs. IMC/ICU). Predictor variables were defined explicitly and abstracted from the periods of ED arrival and after treatment with 7.5 mg nebulized albuterol. Distress was defined as tripod positioning or speaking in broken sentences. "Arrival" and "after treatment" scoring systems were derived based on adjusted odds ratios (aOR) for predictor variables. We performed analyses using SASⓇ, version 9.4 (SAS Institute). RESULTS: Among 273 patients, 105 required admission to an IMC/ICU. At presentation, distress (aOR 2.1, 95% confidence interval [CI] 1.1-3.9), room air SpO2 ≥95% (aOR 0.29, 95% CI 0.14-0.62), respiratory rate > 20 breaths/min (aOR 1.9, 95% CI 1.0-3.3), and retractions (aOR 1.9, 95% CI 1.1-3.3) were associated with IMC/ICU admission. After initial bronchodilator therapy, heart rate > 120 beats/min (aOR 7.1, 95% CI 2.0-25), room air SpO2 ≥ 95% (aOR 0.15, 95% CI 0.07-0.34), and noninvasive ventilation (aOR 6.5, 95% CI 2.5-17) were associated with IMC/ICU admission. Both scoring systems stratified risk of IMC/ICU admission into low-risk (9-10%) and high-risk (70-100%) groups. CONCLUSIONS: Combinations of predictor variables, available early in a patient's stay, stratify risk of admission to an IMC/ICU bed.

Herpes Zoster and Postherpetic Neuralgia: Changing Incidence Rates From 1994 to 2018 in the United States.

BACKGROUND: The incidence of herpes zoster (HZ) has been increasing in recent decades. Although 2 vaccines for HZ are available, there have been few studies on the incidence rates of HZ and postherpetic neuralgia (PHN) since their introduction. This study examined the incidence rates of HZ and PHN from 1994 to 2018 in the United States to determine if they have continued to increase since introduction of the HZ vaccines. METHODS: A de-identified longitudinal administrative claims database, the OptumLabs Data Warehouse, was used to assess incidence rates among individuals continuously enrolled in the database for ≥365 days with no prior history of HZ or PHN. Unstandardized and standardized incidence rates were calculated by year, 10-year age groups, sex, and race/ethnicity. RESULTS: There were 610 766 individuals with HZ (median age, 56.3; interquartile range, 43.0-68.7 years; 59.8% women; 70.6% white). From 1994 to 2018, the incidence of HZ increased from 286.0 (95% confidence interval [CI], 259.1-312.8) to 579.6 (95% CI, 554.2-605.0) cases per 100 000 person-years, an annual increase of 3.1% (95% CI, 2.5-3.6%). Since 2007, annual HZ incidence rates have decreased in individuals ≤20 and >60 years old. The overall incidence rate of PHN was 57.5 (95% CI, 56.0-59.0) cases per 100 000 person-years. The proportion of individuals with HZ who developed PHN was higher from 2007 to 2018 than from 1994 to 2006. CONCLUSIONS: HZ incidence rates have continued to increase in age groups for which HZ vaccines are not currently recommended, warranting a review of current vaccine recommendations.

Presymptomatic Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Among Residents and Staff at a Skilled Nursing Facility: Results of Real-time Polymerase Chain Reaction and Serologic Testing.

High rates of asymptomatic coronavirus disease 2019 infection suggest benefits to routine testing in congregate care settings. Screening was undertaken in a single nursing facility without a known case of coronavirus disease 2019, demonstrating an 85% prevalence among residents and 37% among staff. Serology was not helpful in identifying infections.

Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing.

Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti-donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.

Burdensome Transitions of Care for Patients with End-Stage Liver Disease and Their Caregivers.

BACKGROUND: Patients with end-stage liver disease (ESLD) experience frequent readmissions; however, studies focused on patients' and caregivers' perceptions of their transitional care experiences to identify root causes of burdensome transitions of care are lacking. AIM: To explore the transitional care experiences of patients with ESLD and their caregivers in order to identify their supportive care needs. METHODS: We conducted interviews with 15 patients with ESLD and 14 informal caregivers. We used semi-structured interview guides to explore their experiences since the diagnosis of ESLD including their care transitions. Two raters coded interviews independently (κ = 0.95) using template analysis. RESULTS: Participants reported feeling unprepared to manage their informational, psychosocial, and practical care needs as they transitioned from hospital to home after the diagnosis of ESLD. Delay in the timely receipt of supportive care services addressing these care needs resulted in hospital readmissions, emotional distress, caregiver burnout, reduced work capacity, and financial hardship. Participants shared the following resources that they perceived would improve their quality of care: (1) discharge checklist, (2) online resources, (3) mental health support, (4) caregiver support and training, and (5) financial navigation. CONCLUSION: Transitional care models that attend to the informational, psychosocial, and practical domains of care are needed to better support patients with ESLD and their caregivers at the time of diagnosis and beyond. Without attending to the multidimensional care needs of newly diagnosed patients with ESLD and their caregivers, they are at risk of burdensome transitions of care, high healthcare utilization, and poor health-related quality of life.

Emergency Department Asthma "Spacing Trials": Institutional Variability and Time Cost.

BACKGROUND: Some admitting physicians request a medication-free interval ("spacing trial") in the emergency department (ED) to determine whether a patient with an acute exacerbation of asthma can be safely admitted to a hospital ward bed, where bronchodilators are only available every 4 h. OBJECTIVE: Our objectives were to estimate the frequency of ED spacing trials in different hospitals and their associated time cost. METHODS: This multicenter retrospective cohort study examined patients admitted for asthma from 2015 to 2018. We included all university records and a random sample of records from two community hospitals in the same urban area. Two team members abstracted data from each record using recommended methods, with group consensus to resolve differences. Proportion confidence intervals were calculated using normal binomial approximation. We calculated mean differences in ED stay associated with spacing trials, using multivariable linear regression to adjust for age, hospital type, history of intubation, initial pulse, initial respiratory rate, initial signs of distress. RESULTS: We collected data from 274 patients in the university hospital, and 71 and 70 cases from the community hospitals. An explicit spacing trial was noted in 52 of 274 (19%) university hospital records vs. 3 of 141 (2%) community hospital records, with a difference of 17% (95% confidence interval [CI] 11-23%). Delayed patient decompensation occurred in 3%, with no difference between hospitals. Spacing trials were associated with an adjusted mean of 159 min (95% CI 102-217 min) increase in ED stay. CONCLUSIONS: The practice of spacing varies widely between hospitals and is associated with substantial delay without an apparent benefit.

Differential Brain Mechanisms of Selection and Maintenance of Information during Working Memory.

Working memory is our ability to select and temporarily hold information as needed for complex cognitive operations. The temporal dynamics of sustained and transient neural activity supporting the selection and holding of memory content is not known. To address this problem, we recorded magnetoencephalography in healthy participants performing a retro-cue working memory task in which the selection rule and the memory content varied independently. Multivariate decoding and source analyses showed that selecting the memory content relies on prefrontal and parieto-occipital persistent oscillatory neural activity. By contrast, the memory content was reactivated in a distributed occipitotemporal posterior network, preceding the working memory decision and in a different format than during the visual encoding. These results identify a neural signature of content selection and characterize differentiated spatiotemporal constraints for subprocesses of working memory.SIGNIFICANCE STATEMENT Our brain selects and maintains information during short time windows in a way that is essential to reasoning and learning. Recent advances in multivariate analysis of brain activity allowed the characterization of brain regions that stores the memory. We applied multivariate analysis to time-resolved brain signals to characterize the spatiotemporal signature underlying these subprocesses. The selection of information relies on sustained oscillatory activity in a network that includes the ventrolateral prefrontal cortex while memory content is transiently replayed in an occipitotemporal network that differs from encoding. Our results characterized differentiated spatiotemporal activity underlying encoding, selection, and maintenance of information during working memory.

Incidence Rate of Herpes Zoster Ophthalmicus: A Retrospective Cohort Study from 1994 through 2018.

PURPOSE: To analyze the incidence rate (IR) of herpes zoster ophthalmicus (HZO) and differences by age, gender, race, and region from 1994 through 2018. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: Patients with a new International Classification of Diseases, Ninth or Tenth Edition, codes for herpes zoster (HZ) and HZO from January 1, 1994, through December 31, 2018, in the OptumLabs Data Warehouse (OptumLabs, Cambridge, MA). METHODS: OptumLabs Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data, was used to identify enrollees with continuous enrollment in the database for 365 days or more. Patients with no history of HZ or HZO and a new code for HZ and HZO were counted as incident cases. The IR of HZO was calculated by year, 10-year age groups, gender, race, and region. MAIN OUTCOME MEASURES: Differences in IR from 1994 through 2018 by 10-year age groups and gender. RESULTS: From 1994 through 2018, 633 474 cases of HZ were reported, with 49 745 (7.9%) having HZO. The incidence of HZO increased from 1994 through 2018 by an estimated 1.1 cases per 100 000 person-years annually (95% confidence interval [CI], 1.0-1.3; P < 0.001). The estimated relative increase was 3.6% annually (95% CI, 3.0%-4.1%). HZO IR increased in all ages over 10 years until 2007, then began declining in individuals younger than 21 and older than 60, stabilizing in individuals 21 to 30 years old, and increasing more slowly among individuals 31 to 60 years old. Men showed an HZO incidence rate ratio (IRR) of 0.74 compared with women. Compared with white patients, the IRRs were 0.70, 0.75, and 0.64 for Asians, black patients, and Hispanics, respectively. CONCLUSIONS: The incidence of HZO has increased 3.6% per year from 1994 to 2018 in the United States. Since 2008, HZO incidence declined in individuals younger than 21 years and older than 60 years while increasing at a lower rate in middle-aged adults. Given the continued increase, greater efforts should be made to vaccinate eligible adults 50 years of age and older. More research on earlier vaccination is warranted.

18F-Sodium fluoride PET/CT predicts overall survival in patients with advanced genitourinary malignancies treated with cabozantinib and nivolumab with or without ipilimumab.

PURPOSE: We evaluated the prognostic value of 18F-sodium fluoride (NaF) PET/CT in patients with urological malignancies treated with cabozantinib and nivolumab with or without ipilimumab. METHODS: We prospectively recruited patients with advanced urological malignancies into a phase I trial of cabozantinib plus nivolumab with or without ipilimumab. NaF PET/CT scans were performed pre- and 8 weeks post-treatment. We measured the total volume of fluoride avid bone (FTV) using a standardized uptake value (SUV) threshold of 10. We used Kaplan-Meier analysis to predict the overall survival (OS) of patients in terms of SUVmax, FTV, total lesion fluoride (TLF) uptake at baseline and 8 weeks post-treatment, and percent change in FTV and TLF. RESULT: Of 111 patients who underwent NaF PET/CT, 30 had bone metastases at baseline. Four of the 30 patients survived for the duration of the study period. OS ranged from 0.23 to 34 months (m) (median 6.0 m). The baseline FTV of all 30 patients ranged from 9.6 to 1570 ml (median 439 ml). The FTV 8 weeks post-treatment was 56-6296 ml (median 448 ml) from 19 available patients. Patients with higher TLF at baseline had shorter OS than patients with lower TLF (3.4 vs 14 m; p = 0.022). Patients with higher SUVmax at follow-up had shorter OS than patients with lower SUVmax (5.6 vs 24 m; p = 0.010). However, FTV and TLF 8 weeks post-treatment did not show a significant difference between groups (5.6 vs 17 m; p = 0.49), and the percent changes in FTV (12 vs 14 m; p = 0.49) and TLF (5.6 vs 17 m; p = 0.54) also were not significant. CONCLUSION: Higher TLF at baseline and higher SUVmax at follow-up NaF PET/CT corresponded with shorter survival in patients with bone metastases from urological malignancies who underwent treatment. NaF PET/CT may be a useful predictor of OS in this population.