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Background: Operative mortality for high-grade liver injury (HGLI) remains 42% to 66%, with near-universal mortality after retrohepatic caval injury. The objective of this study was to evaluate mortality and complications of operative and nonoperative management (OM and NOM) of HGLI at our institution, characterized by a trauma surgery-liver surgery collaborative approach to trauma care., Methods: This was an observational cohort study of adult patients (age ≥16) with HGLI (The American Association for Surgery of Trauma (AAST) grades IV and V) admitted to an urban level I trauma center from January 2010 to November 2021. Data were obtained from the electronic medical record and state trauma registry. Patients were categorized by management strategy: immediate OM or planned NOM. The primary outcome was 30-day mortality., Results: Our institution treated 179 patients with HGLI (78% blunt, 22% penetrating); 122 grade IV (68%) and 57 grade V (32%) injuries. All abdominal gunshot wounds and 49% of blunt injuries underwent initial OM; 51% of blunt injuries were managed initially by NOM. Procedures at the initial operation included hepatorrhaphy±packing (66.4%), nonanatomic resection (5.6%), segmentectomy (9.3%), and hepatic lobectomy (7.5%). Thirty-day mortality in the OM group was substantially lower than prior reports (23.4%). Operative mortality attributable to the liver injury was 15.7%. 19.4% of patients failed NOM with one death (1.4%)., Conclusion: We report an operative mortality of 23.4% for HGLI in a trauma care system characterized by a collaborative approach by trauma surgeons and liver surgeons., Level of Evidence: III., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Despite sparse systematic evidence, current exercise heat safety recommendations suggest that antihistamines blunt sweating and increase the risk for heat-related injury during exertional heat stress. The primary purpose of the present study was to examine whether diphenhydramine hydrochloride (DPH), a first-generation antihistamine, affects the sweating, core temperature, and heart rate (HR) response during exertional heat stress using a double-blind randomized crossover design., Methods: On two occasions separated by >48 h, 20 healthy adults (10 females, 23 ± 3 yr, body surface area: 1.9 ± 0.2 m 2 , body mass index: 23.7 ± 2.2 kg·m -2 ) orally consumed either 50 mg of DPH or placebo (PLA), and then rested for 2 h in a climate-controlled room maintained at 30°C and 35% relative humidity (heat index of ~29°C), followed by a 60-min fixed-heat production treadmill walk (6.3 ± 1.0 W·kg -1 ). Whole-body sweat loss, local sweat rate, rectal temperature ( Trec ), and HR were measured., Results: Whole-body sweat loss was not different between conditions (PLA: 406 ± 78 g, DPH: 396 ± 75 g; P = 0.26, treatment effect: -10 g; 95% confidence interval, -28 to 8). No differences were observed for the onset of sweating (PLA: 13.5 ± 2.4 min, DPH: 13.3 ± 2.7 min; P = 0.79) and steady-state local sweat rate (PLA: 0.83 ± 0.26 mg·cm -2 ·min -1 , DPH: 0.82 ± 0.27 mg·cm -2 ·min -1 ; P = 0.99). No difference in baseline Trec was observed (PLA: 37.09°C ± 0.35°C, DPH: 37.13°C ± 0.33°C; P = 0.68), and the 60-min Δ Trec was not different ( P = 0.99) between PLA (0.83°C ± 0.29°C) and DPH (0.81°C ± 0.30°C). HR was similar at baseline (PLA: 86 ± 13 bpm, DPH: 84 ± 11 bpm; P = 0.30) and end-exercise (PLA: 134 ± 28 bpm, DPH: 132 ± 26 bpm; P = 0.90)., Conclusions: Fifty milligrams of DPH does not modify the sweating, core temperature, and HR response during exertional heat stress in young healthy adults., (Copyright © 2024 by the American College of Sports Medicine.)

Background: Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods., Methods and Results: Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance., Conclusions: Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

The present study assessed agreement between a wireless sweat rate monitor (KuduSmart® device) and the ventilated capsule (VC) technique for measuring: (i) minute-averaged local sweat rate (LSR), (ii) sweating onset, (iii) sudomotor thermosensitivity, and (iv) steady-state LSR, during passive heat stress and exercise. It was hypothesized that acceptable agreement with no bias would be observed between techniques for all assessed sweating characteristics. On two separate occasions for each intervention, participants were either passively heated by recirculating hot water (49 °C) through a tube-lined garment until rectal temperature increased 1 °C over baseline ( n  = 8), or a 60 min treadmill march at a fixed rate of heat production (∼500 W, n  = 9). LSR of the forearm was concurrently measured with a VC and the KuduSmart® device secured within ∼2 cm. Using a ratio scale Bland-Altman analysis with the VC as the reference, the KuduSmart® device demonstrated systematic bias and not acceptable agreement for minute-averaged LSR (1.17 [1.09, 1.27], CV = 44.5%), systematic bias and acceptable agreement for steady-state LSR (1.16 [1.09,1.23], CV = 19.5%), no bias and acceptable agreement for thermosensitivity (1.07 [0.99, 1.16], CV = 23.2%), and no bias and good agreement for sweating onset (1.00 [1.00, 1.00], CV = 11.1%). In total, ≥73% of all minute-averaged LSR observations with the KuduSmart ® device ( n  = 2743) were within an absolute error of <0.2 mg/cm 2 /min to the VC, the reference minimum detectable change in measurement error of a VC on the forearm. Collectively, the KuduSmart ® device may be a satisfactory solution for assessing the sweating response to heat stress where a VC is impractical., Competing Interests: The KuduSmart® device was provided at no cost to Dr. Nicholas Ravanelli from Crossbridge Scientific Ltd. Crossbridge Scientific Ltd was not involved in study design, data collection, analysis, interpretation of results, or manuscript preparation.

Objectives: This study aims to estimate the levels of COVID-19 vaccine hesitancy in 53 low-income and middle-income countries, differences across population groups in hesitancy, and self-reported reasons for being hesitant to take the COVID-19 vaccine., Methods: This paper presents new evidence on levels and trends of vaccine hesitancy in low-income and middle-income countries based on harmonised high-frequency phone surveys from more than 120 000 respondents in 53 low-income and middle-income countries collected between October 2020 and August 2021. These countries represent a combined 53% of the population of low-income and middle-income countries excluding India and China., Results: On average across countries, one in five adults reported being hesitant to take the COVID-19 vaccine, with the most cited reasons for hesitancy being concerns about the safety of the vaccine, followed by concerns about its efficacy. Between late 2020 and the first half of 2021, there tended to be little change in hesitancy rates in 11 of the 14 countries with available data, while hesitancy increased in Iraq, Malawi and Uzbekistan. COVID-19 vaccine hesitancy was higher among female, younger adults and less educated respondents, after controlling for selected observable characteristics., Conclusions: Country estimates of vaccine hesitancy from the high-frequency phone surveys are correlated with but lower than those from earlier studies, which often relied on less representative survey samples. The results suggest that vaccine hesitancy in low-income and middle-income countries, while less prevalent than previously thought, will be an important and enduring obstacle to recovery from the pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

This paper examines how the COVID-19 pandemic affected the employment of different groups of workers across 40 mostly low and middle-income countries. Employment outcomes during the crisis are tracked through high-frequency phone surveys conducted by the World Bank and national statistics offices. Our results show that larger shares of female, young, less educated, and urban workers stopped working at the beginning of the pandemic. Gender gaps in work stoppage stemmed mainly from gender differences within sectors rather than differential employment patterns of men and women across sectors. Differences in work stoppage between urban and rural workers were markedly smaller than those across gender, age, and education groups. Preliminary results from 10 countries suggest that following the initial shock at the start of the pandemic, employment rates partially recovered between April and August 2020, with greater gains for those groups that had borne the brunt of the early jobs losses. Although the high-frequency phone surveys over-represent household heads and therefore overestimate employment rates, a validation exercise for five countries suggests that they provide a reasonably accurate measure of disparities in employment levels by gender, education, and urban/rural location following the onset of the crisis, although they perform less well in capturing disparities between age groups. These results shed new light on the distributional labor market consequences of the COVID-19 crisis in developing countries, and suggest that real-time phone surveys, despite their lack of representativeness, are a valuable source of information to measure differential employment impacts across groups during an unfolding crisis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has been implicated in numerous oncogenic processes. GSK-3 inhibitor elraglusib (9-ING-41) has shown promising preclinical and clinical antitumor activity across multiple tumor types. Despite promising early-phase clinical trial results, there have been limited efforts to characterize the potential immunomodulatory properties of elraglusib. We report that elraglusib promotes immune cell-mediated tumor cell killing of microsatellite stable colorectal cancer (CRC) cells. Mechanistically, elraglusib sensitized CRC cells to immune-mediated cytotoxicity and enhanced immune cell effector function. Using western blots, we found that elraglusib decreased CRC cell expression of NF-κB p65 and several survival proteins. Using microarrays, we discovered that elraglusib upregulated the expression of proapoptotic and antiproliferative genes and downregulated the expression of cell proliferation, cell cycle progression, metastasis, TGFβ signaling, and anti-apoptotic genes in CRC cells. Elraglusib reduced CRC cell production of immunosuppressive molecules such as VEGF, GDF-15, and sPD-L1. Elraglusib increased immune cell IFN-γ secretion, which upregulated CRC cell gasdermin B expression to potentially enhance pyroptosis. Elraglusib enhanced immune effector function resulting in augmented granzyme B, IFN-γ, TNF-α, and TRAIL production. Using a syngeneic, immunocompetent murine model of microsatellite stable CRC, we evaluated elraglusib as a single agent or combined with immune checkpoint blockade (anti-PD-1/L1) and observed improved survival in the elraglusib and anti-PD-L1 group. Murine responders had increased tumor-infiltrating T cells, augmented granzyme B expression, and fewer regulatory T cells. Murine responders had reduced immunosuppressive (VEGF, VEGFR2) and elevated immunostimulatory (GM-CSF, IL-12p70) cytokine plasma concentrations. To determine the clinical significance, we then utilized elraglusib-treated patient plasma samples and found that reduced VEGF and BAFF and elevated IL-1 beta, CCL22, and CCL4 concentrations correlated with improved survival. Using paired tumor biopsies, we found that tumor-infiltrating immune cells had a reduced expression of inhibitory immune checkpoints (VISTA, PD-1, PD-L2) and an elevated expression of T-cell activation markers (CTLA-4, OX40L) after elraglusib treatment. These results address a significant gap in knowledge concerning the immunomodulatory mechanisms of GSK-3 inhibitor elraglusib, provide a rationale for the clinical evaluation of elraglusib in combination with immune checkpoint blockade, and are expected to have an impact on additional tumor types, besides CRC., Competing Interests: Elraglusib (9-ING-41) has been licensed to Actuate Therapeutics. K.E.H., P.S., and W.S.E-D. receive research funding for preclinical studies from Actuate Therapeutics, Inc (March 2022- Feb. 2024). B.A.C. received institutional funding for a clinical trial related to 9-ING-41 from Actuate Therapeutics, Inc. F.J.G. has served as a consultant to Actuate Therapeutics, Inc. Daniel Newhouse is an employee and shareholder of NanoString Technologies Inc. All remaining authors report no disclosures.

Asian lineage Zika virus (ZIKV) strains emerged globally, causing outbreaks linked with critical clinical disease outcomes unless the virus is effectively restricted by host immunity. We have previously shown that retinoic acid-inducible gene-I (RIG-I) senses ZIKV to trigger innate immunity to direct interferon (IFN) production and antiviral responses that can control ZIKV infection. However, ZIKV proteins have been demonstrated to antagonize IFN. Here, we conducted in vitro analyses to assess how divergent prototypic ZIKV variants differ in virologic properties, innate immune regulation, and infection outcome. We comparatively assessed African lineage ZIKV/Dakar/1984/ArD41519 (ZIKV/Dakar) and Asian lineage ZIKV/Malaysia/1966/P6740 (ZIKV/Malaysia) in a human epithelial cell infection model. De novo viral sequence determination identified amino acid changes within the ZIKV/Dakar genome compared to ZIKV/Malaysia. Viral growth analyses revealed that ZIKV/Malaysia accumulated viral proteins and genome copies earlier and to higher levels than ZIKV/Dakar. Both ZIKV strains activated RIG-I/IFN regulatory factor (IRF3) and NF-κB pathways to induce inflammatory cytokine expression and types I and III IFNs. However, ZIKV/Malaysia, but not ZIKV/Dakar, potently blocked downstream IFN signaling. Remarkably, ZIKV/Dakar protein accumulation and genome replication were rescued in RIG-I knockout (KO) cells late in acute infection, resulting in ZIKV/Dakar-mediated blockade of IFN signaling. We found that RIG-I signaling specifically restricts viral protein accumulation late in acute infection where early accumulation of viral proteins in infected cells confers enhanced ability to limit IFN signaling, promoting viral replication and spread. Our results demonstrate that RIG-I-mediated innate immune signaling imparts restriction of ZIKV protein accumulation, which permits IFN signaling and antiviral actions controlling ZIKV infection. IMPORTANCE ZIKV isolates are classified under African or Asian lineages. Infection with emerging Asian lineage-derived ZIKV strains is associated with increased incidence of neurological symptoms that were not previously reported during infection with African or preemergent Asian lineage viruses. In this study, we utilized in vitro models to compare the virologic properties of and innate immune responses to two prototypic ZIKV strains from distinct lineages: African lineage ZIKV/Dakar and Asian lineage ZIKV/Malaysia. Compared to ZIKV/Dakar, ZIKV/Malaysia accumulates viral proteins earlier, replicates to higher levels, and robustly blocks IFN signaling during acute infection. Early accumulation of ZIKV/Malaysia NS5 protein confers enhanced ability to antagonize IFN signaling, dampening innate immune responses to promote viral spread. Our data identify the kinetics of viral protein accumulation as a major regulator of host innate immunity, influencing host-mediated control of ZIKV replication and spread. Importantly, these findings provide a novel framework for evaluating the virulence of emerging variants., Competing Interests: The authors declare no conflict of interest.

Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson's disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.

A deeper understanding of complex biological processes, including tumor development and immune response, requires ultra high-plex, spatial interrogation of multiple "omes". Here we present the development and implementation of a novel spatial proteogenomic (SPG) assay on the GeoMx Digital Spatial Profiler platform with next-generation sequencing readout that enables ultra high-plex digital quantitation of proteins (>100-plex) and RNA (whole transcriptome, >18,000-plex) from a single formalin-fixed paraffin-embedded (FFPE) sample. This study highlighted the high concordance, R > 0.85 and <15% change in sensitivity between the SPG assay and the single-analyte assays on various cell lines and tissues from human and mouse. Furthermore, we demonstrate that the SPG assay was reproducible across multiple users. When used in conjunction with advanced cellular neighborhood segmentation, distinct immune or tumor RNA and protein targets were spatially resolved within individual cell subpopulations in human colorectal cancer and non-small cell lung cancer. We used the SPG assay to interrogate 23 different glioblastoma multiforme (GBM) samples across four pathologies. The study revealed distinct clustering of both RNA and protein based on pathology and anatomic location. The in-depth investigation of giant cell glioblastoma multiforme (gcGBM) revealed distinct protein and RNA expression profiles compared with that of the more common GBM. More importantly, the use of spatial proteogenomics allowed simultaneous interrogation of critical protein posttranslational modifications alongside whole transcriptomic profiles within the same distinct cellular neighborhoods., Significance: We describe ultra high-plex spatial proteogenomics; profiling whole transcriptome and high-plex proteomics on a single FFPE tissue section with spatial resolution. Investigation of gcGBM versus GBM revealed distinct protein and RNA expression profiles., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: We aimed to describe our procedure for vascular reconstruction and back table bench preparation for the right lobe live donor allograft. Live donor liver transplantation (LDLT) remains an important option for the expansion of the donor pool. The procedure has been widely used, and its success is dependent on a technically perfect operation with appropriate inflow and outflow of the allograft. Adequate preparation of the right lobe (RL) allograft prior to implantation remains a vital part of the procedure., Methods: Our technique of back table vascular reconstruction of the RL allograft has been performed using a hepatic vein patch venoplasty, inferior hepatic vein inclusion, portal vein reconstruction, and segment V and VIII reconstruction for all of our LDLTs., Results: Between March 2009 and January 2020, 321 consecutive adult LDLTs were performed and underwent back table reconstruction with the techniques described. During that time period, no patients had hepatic insufficiency. There was a single thrombosis of a superior mesenteric vein (SMV) to PV jump conduit., Conclusions: Our technique of back table reconstruction of the LDLT right lobe graft remains a crucial part of the operative procedure. Our experience with RL grafts without middle hepatic vein (MHV) and our systematic approach for inflow and outflow reconstruction has yielded excellent results with no technical outflow issues and minimal inflow complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine., Competing Interests: Declaration of interests OHSU and Drs. Malouli, Früh, Picker, Hansen, and Sacha have a significant financial interest in Vir Biotechnology, Inc., a company that may have a financial interest in the results of this research and technology. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Contemporary guideline-directed medical therapy (GDMT) confers a significant mortality benefit for patients with heart failure with reduced ejection fraction (HFrEF), as compared to GDMT prevalent at the time of landmark primary prevention implantable cardioverter-defibrillator (ICD) trials. The impact of modern era GDMT on survival in this population is unknown., Objectives: This study sought to investigate the impact of number of GDMT medications prescribed for HFrEF on all-cause mortality in recipients of primary prevention ICD., Methods: A cohort of 4,972 recipients with primary prevention ICD (n = 3,210) or cardiac resynchronization therapy-defibrillator (CRT-D) (n = 1,762) was studied. The association of number of GDMT medications prescribed at the time of device implantation and all-cause mortality at 2 years post implantation was examined., Results: In our primary prevention cohort, 5%, 20%, 52%, and 23% of patients were prescribed 0, 1, 2, or 3-4 GDMT medications, respectively. After risk adjustment for age, sex, ejection fraction, body mass index, the Elixhauser comorbidity score, the type of cardiomyopathy, and the year of device implantation, each additional GDMT conferred a reduction in the risk of death of 36% in recipients of ICD (HR: 0.64; P < 0.001) and 30% in recipients of CRT-D (HR: 0.70; P < 0.001)., Conclusions: A higher number of prescribed GDMT medications is associated with an incremental 1-year survival in recipients of primary prevention ICD with or without CRT. Initiation of maximum number of tolerated GDMT medications should therefore be the goal for all patients with HFrEF. In the setting of robust GDMT, the risk versus benefit of a primary prevention ICD warrants re-examination in future studies., Competing Interests: Funding Support and Author Disclosures Dr Saba has received research support from Boston Scientific and Abbott; and has performed advisory board work with Medtronic and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Innate immunity and type 1 interferon (IFN) defenses are critical for early control of HIV infection within CD4 + T cells. Despite these defenses, some acutely infected cells silence viral transcription to become latently infected and form the HIV reservoir in vivo. Latently infected cells persist through antiretroviral therapy (ART) and are a major barrier to HIV cure. Here, we evaluated innate immunity and IFN responses in multiple T cell models of HIV latency, including established latent cell lines, Jurkat cells latently infected with a reporter virus, and a primary CD4 + T cell model of virologic suppression., Results: We found that while latently infected T cell lines have functional RNA sensing and IFN signaling pathways, they fail to induce specific interferon-stimulated genes (ISGs) in response to innate immune activation or type 1 IFN treatment. Jurkat cells latently infected with a fluorescent reporter HIV similarly demonstrate attenuated responses to type 1 IFN. Using bulk and single-cell RNA sequencing we applied a functional genomics approach and define ISG expression dynamics in latent HIV infection, including HIV-infected ART-suppressed primary CD4 + T cells., Conclusions: Our observations indicate that HIV latency and viral suppression each link with cell-intrinsic defects in specific ISG induction. We identify a set of ISGs for consideration as latency restriction factors whose expression and function could possibly mitigate establishing latent HIV infection., (© 2022. The Author(s).)

In addition to the direct health effects of the Coronavirus disease (COVID-19) pandemic, the pandemic has increased the risks of foregone non-COVID-19 healthcare. Likely, these risks are greatest in low- and middle-income countries (LMICs), where health systems are less resilient and economies more fragile. However, there are no published studies on the prevalence of foregone healthcare in LMICs during the pandemic. We used pooled data from phone surveys conducted between April and August 2020, covering 73 638 households in 39 LMICs. We estimated the prevalence of foregone care and the relative importance of various reported reasons for foregoing care, disaggregated by country income group and region. In the sample, 18.8% (95% CI 17.8-19.8%) of households reported not being able to access healthcare when needed. Financial barriers were the most-commonly self-reported reason for foregoing care, cited by 31.4% (28.6-34.3%) of households. More households in wealthier countries reported foregoing care for reasons related to COVID-19 [27.2% (22.5-31.8%) in upper-middle-income countries compared to 8.0% (4.7-11.3%) in low-income countries]; more households in poorer countries reported foregoing care due to financial reasons [65.6% (59.9-71.2%)] compared to 17.4% (13.1-21.6%) in upper-middle-income countries. A substantial proportion of households in LMICs had to forgo healthcare in the early months of the pandemic. While in richer countries this was largely due to fear of contracting COVID-19 or lockdowns, in poorer countries foregone care was due to financial constraints., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Zika virus infection can result in devastating pregnancy outcomes when it crosses the placental barrier. For human pregnancies, the mechanisms of vertical transmission remain enigmatic. Utilizing a human placenta-cotyledon perfusion model, we examined Zika virus exposure in the absence of maternal factors. To distinguish responses related to viral infection vs. recognition, we evaluated cotyledons perfused with either active or inactivated Zika virus. Active Zika virus exposure resulted in infection, cell death and syncytium injury. Pathology corresponded with transcriptional changes related to inflammation and innate immunity. Inactive Zika virus exposure also led to syncytium injury and related changes in gene expression but not cell death. Our observations reveal pathologies and innate immune responses that are dependent on infection or virus placenta interactions independent of productive infection. Importantly, our findings indicate that Zika virus can infect and compromise placentas in the absence of maternal humoral factors that may be protective., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Louis J. Picker and Scott G. Hansen declare their role as consultants for, and their substantial financial interest in Vir Biotechnology, Inc. as a Conflict of Interest that is managed by OHSU. No other authors have any conflicts to disclose.

Country-level census data are typically collected once every 10 years. However, conflicts, migration, urbanization, and natural disasters can rapidly shift local population patterns. This study demonstrates the feasibility of a "bottom-up"-method to estimate local population density in the between-census years by combining household surveys with contemporaneous geo-spatial data, including village-area and satellite imagery-based indicators. We apply this technique to the case of Sri Lanka using Poisson regression models based on variables selected using the Least Absolute Shrinkage and Selection Operator (LASSO). The model is estimated in villages sampled in the 2012/13 Household Income and Expenditure Survey, and is employed to obtain out-of-sample density estimates in the non-surveyed villages. These estimates approximate the census density accurately and are more precise than other bottom-up studies using similar geo-spatial data. While most open-source population products redistribute census population "top-down" from higher to lower spatial units using areal interpolation and dasymetric mapping techniques, these products become less accurate as the census itself ages. Our method circumvents the problem of the aging census by relying instead on more up-to-date household surveys. The collective evidence suggests that our method is cost effective in tracking local population density with greater frequency in the between-census years., Competing Interests: NO authors have competing interests.

Importance: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention., Objective: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin., Design, Setting, and Participants: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018., Exposures: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure., Main Outcomes and Measures: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort., Results: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding., Conclusions and Relevance: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

This paper describes a poverty reduction approach to addressing an important determinant of health and well-being among Canada's First Nations. The Poverty Action Research Project (PARP) has its origins in the Make Poverty History Committee established by the Assembly of First Nations (AFN) in 2008. Academic members of the Committee in cooperation with the AFN subsequently applied for an action research grant to the Canadian Institutes of Health Research (CIHR). The project selected five volunteer First Nations from different parts of Canada, hiring a coordinator in each, undertaking background research, developing a profile and working with First Nation representatives in the development of a strategy to address upstream determinants of health and well-being. Subsequently, project team members within each region assisted where needed with plan implementation, supporting some initiatives with small grants. This paper provides insights from the project in several key areas, including First Nation rejection of the concept of poverty as usually defined, the importance of taking action to strengthen collectivities as well as individuals, the feasibility of assisting First Nations who are at different points in their development journey, the strengths of the leadership within the First Nations, and finding the appropriate balance between the elected and business leadership. These insights emerged from dialogue and reflection among project team members and community participants over the life of the project. We also describe what we have learned about how to engage effectively and with mutual respect with First Nations in this kind of project. The paper concludes with a review of our experiences with the policies and practices of the national research granting councils and the universities, which have not fully adjusted to the requirements of action research involving First Nations.

The Parenteral Drug Association (PDA) has identified 11 current questions related to data management and control that have been frequently cited in U.S. Food and Drug Administration (FDA) inspections or have led to FDA regulatory actions. The purpose of this document is to help to clarify some of these issues for industry and to help facilitate better compliance by sharing PDA members' expertise in and understanding of current best practices.Data integrity inspectional observations by health authorities can have a severe impact on a firm from a regulatory and public perception perspective and should not result from a lack of clarity by industry about what is required. In addition, firms are concerned that the inability to produce a requested record or document during an inspection, even if not a standard report or existing quality system document, could be construed as delaying, denying, limiting, or refusing inspection, which also has significant consequences.The PDA acknowledges it may not be possible for a single firm or site to have a meaningful discussion of these issues in the context of an inspection or inspection response and is offering these best practices so that industry can proactively comply and properly prioritize its efforts to improve document management and control and good manufacturing practices in the most efficient and effective means possible. The PDA acknowledges there are many more questions to be addressed and hopes that there can be an ongoing dialogue between industry and regulators to facilitate answers., (© PDA, Inc. 2018.)

The changing demographics in the country require new strategies for providing culturally competent care. The Northern California Region Member Patient Survey provides detailed information for the clinician when the data is segmented into subsets by age, gender, and race/ethnicity. Any gaps identified allow for the clinician to focus on key areas for improvement in an efficient manner respecting the time constraints of a busy practice.

This paper examines the relationship between health aid and infant mortality, using data from 118 countries between 1973 and 2004. Health aid has a beneficial and statistically significant effect on infant mortality: doubling per capita health aid is associated with a 2 percent reduction in the infant mortality rate. For the average country, this implies that increasing per capita health aid by US$1.60 per year is associated with 1.5 fewer infant deaths per thousand births. The estimated effect is small, relative to the 2015 target envisioned by the Millennium Development Goals. It implies that achieving the MDG target through additional health aid alone would require a roughly 15-fold increase in current levels of aid.

To combat childhood overweight in the US, which has risen dramatically in the past three decades, many medical and public health organizations have called for students to spend more time in physical education (PE) classes. This paper is the first to examine the impact of state PE requirements on student PE exercise time. It also exploits variation in state laws as quasi-natural experiments in order to estimate the causal impact of PE on overall student physical activity and weight. We study nationwide data from the Youth Risk Behavior Surveillance System for 1999, 2001, and 2003 merged with data on state minimum PE requirements from the 2001 Shape of the Nation Report. We find that high school students with a binding PE requirement report an average of 31 additional minutes per week spent physically active in PE class. Our results also indicate that additional PE time raises the number of days per week that girls report having exercised vigorously or having engaged in strength-building activity. We find no evidence that PE lowers BMI or the probability that a student is overweight. We conclude that raising PE credit requirements may make girls more physically active overall but there is not yet the scientific base to declare raising PE requirements an anti-obesity initiative for either boys or girls., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Just three years ago, Loyola University Medical Center, with a 92 percent occupancy rate, instituted a computerized approach to housekeeping under the auspices of its building service contractor , Admiral Maintenance Service Company. To date, the Maywood , Illinois-based medical center has operated with a dramatically reduced budget and reduced its staff by 10 percent, and "is still the cleanest place in town," some patients say. I spoke with Loyola 's Director of Housekeeping, Minnie Samp 'l, and to computer designer and systems analyst Donald Campbell, of the Chicago-based contractor , to learn details.