Evaluation of the Glasgow Coma Scale-Pupils score for predicting inpatient mortality among patients with traumatic subdural hematoma at United States trauma centers.

OBJECTIVE: The Glasgow Coma Scale-Pupils (GCS-P) score has been suggested to better predict patient outcomes compared with GCS alone, while avoiding the need for more complex clinical models. This study aimed to compare the prognostic ability of GCS-P versus GCS in a national cohort of traumatic subdural hematoma (SDH) patients. METHODS: Patient data were obtained from the National Trauma Data Bank (2017-2019). Inclusion criteria were traumatic SDH diagnosis with available data on presenting GCS score, pupillary reactivity, and discharge disposition. Patients with severe polytrauma or nonsurvivable head injury at presentation were excluded. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of GCS-P versus GCS scores for inpatient mortality prediction were evaluated across the entire cohort, as well as in subgroups based on age and traumatic brain injury (TBI) type (blunt vs penetrating). Calibration curves were plotted based on predicted probabilities and actual outcomes. RESULTS: A total of 196,747 traumatic SDH patients met the study inclusion criteria. Sensitivity (0.707 vs 0.702), specificity (0.821 vs 0.823), and AUC (0.825 vs 0.814, p < 0.001) of GCS-P versus GCS scores for prediction of inpatient mortality were similar. Calibration curve analysis revealed that GCS scores slightly underestimated inpatient mortality risk, whereas GCS-P scores did not. In patients > 65 years of age with blunt TBI (51.9%, n = 102,148), both GCS-P and GCS scores underestimated inpatient mortality risk. In patients with penetrating TBI (2.4%, n = 4,710), the AUC of the GCS-P score was significantly higher (0.902 vs 0.851, p < 0.001). In this subgroup, both GCS-P and GCS scores underestimated inpatient mortality risk among patients with lower rates of observed mortality and overestimated risk among patients with higher rates of observed mortality. This effect was more pronounced in the GCS-P calibration curve. CONCLUSIONS: The GCS-P score provides better short-term prognostication compared with the GCS score alone among traumatic SDH patients with penetrating TBI. The GCS-P score overestimates inpatient mortality risk among penetrating TBI patients with higher rates of observed mortality. For penetrating TBI patients, which comprised 2.4% of our SDH cohort, a low GCS-P score should not justify clinical nihilism or forgoing aggressive treatment.

Functional Localization of the Human Auditory and Visual Thalamus Using a Thalamic Localizer Functional Magnetic Resonance Imaging Task.

Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due in part to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmark their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.

Monocyte Production of C1q Potentiates CD8+ T Cell Function Following Respiratory Viral Infection.

Respiratory viral infections remain a leading cause of morbidity and mortality. Using a murine model of human metapneumovirus (HMPV), we identified recruitment of a C1q-expressing inflammatory monocyte population concomitant with viral clearance by adaptive immune cells. Genetic ablation of C1q led to reduced CD8+ T cell function. Production of C1q by a myeloid lineage was necessary to enhance CD8+ T cell function. Activated and dividing CD8+ T cells expressed a C1q receptor, gC1qR. Perturbation of gC1qR signaling led to altered CD8+ T cell IFN-γ production, metabolic capacity, and cell proliferation. Autopsy specimens from fatal respiratory viral infections in children demonstrated diffuse production of C1q by an interstitial population. Humans with severe COVID-19 infection also demonstrated upregulation of gC1qR on activated and rapidly dividing CD8+ T cells. Collectively, these studies implicate C1q production from monocytes as a critical regulator of CD8+ T cell function following respiratory viral infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Exploring the utility of bedside tests for predicting cardiorespiratory fitness in older adults.

Objectives: Cardiorespiratory fitness (CRF) declines with advancing and has also, independent of age, been shown to be predictive of all-cause mortality, morbidity, and poor clinical outcomes. In relation to the older patient, there is a particular wealth of evidence highlighting the relationship between low CRF and poor surgical outcomes. Cardiopulmonary exercise testing (CPET) is accepted as the gold-standard measure of CRF. However, this form of assessment has significant personnel and equipment demands and is not feasible for those with certain age-associated physical limitations, including joint and cardiovascular comorbidities. As such, alternative ways to assess the CRF of older patients are very much needed. Methods: Sixty-four participants (45% female) with a median age of 74 (65-90) years were recruited to this study via community-based advertisements. All participants completed three tests of physical function: (1) a step-box test; (2) handgrip strength dynamometry; and (3) a CPET on a cycle ergometer; and also had their muscle architecture (vastus lateralis) assessed by B-mode ultrasonography to provide measures of muscle thickness, pennation angle, and fascicle length. Multivariate linear regression was then used to ascertain bedside predictors of CPET parameters from the alternative measures of physical function and demographic (age, gender, body mass index (BMI)) data. Results: There was no significant association between ultrasound-assessed parameters of muscle architecture and measures of CRF. VO2peak was predicted to some extent from fast step time during the step-box test, gender, and BMI, leading to a model that achieved an R 2 of 0.40 (p < 0.001). Further, in aiming to develop a model with minimal assessment demands (i.e., using handgrip dynamometry rather than the step-box test), replacing fast step time with non-dominant HGS led to a model which achieved an R 2 of 0.36 (p < 0.001). Non-dominant handgrip strength combined with the step-box test parameter of fast step time and BMI delivered the most predictive model for VO2peak with an R 2 of 0.45 (p < 0.001). Conclusions: Our findings show that simple-to-ascertain patient characteristics and bedside assessments of physical function are able to predict CPET-derived CRF. Combined with gender and BMI, both handgrip strength and fast step time during a step-box test were predictive for VO2peak. Future work should apply this model to a clinical population to determine its utility in this setting and to explore if simple bedside tests are predictive of important clinical outcomes in older adults (i.e., post-surgical complications).

Ghanaian women's experience of intimate partner violence (IPV) during group antenatal care: a brief report from a cluster randomised controlled trial.

Intimate partner violence (IPV) impacts women of reproductive age globally and can lead to significant negative consequences during pregnancy. This study describes an exploratory aim of a cluster randomised controlled trial designed to assess the outcomes of Group Antenatal Care (ANC) in Ghana. The purpose was to understand the effect of a healthy relationship Group ANC module on experiences of IPV and safety planning as well as to explore the relationship between self-efficacy on the experiences of IPV and safety planning. Data were collected at baseline and at 11-14 months postpartum (post). Survey measures captured reported experiences of violence, self-efficacy, and safety. The chi-square test was used to compare baseline and post scores, and a logistic regression was performed to ascertain the effects of self-efficacy on the experiences of IPV in both groups. The sample included 1,751 participants, of whom 27.9% reported IPV at baseline. Between baseline and postpartum, there was a small increase in reported emotional (6.2% vs. 4.6%) and sexual (5.4% vs. 3.2%) violence in the intervention group compared to the control group. Logistic regression demonstrated that an increasing self-efficacy score was associated with an increased likelihood of experiencing IPV. There were no changes in safety knowledge. This study found higher rates of reported sexual and emotional violence post-intervention among the intervention group. Group ANC may be just one part of a portfolio of interventions needed to address IPV at all socio-ecological levels.Paper ContextMain findings: There was no reduction in experiences of intimate partner violence or increases in safety planning among Ghanaian pregnant women participating in a Group Antenatal Care session focused on healthy relationships and safety planning.Added knowledge: Group Antenatal Care has been identified as an effective modality for providing antenatal care and facilitating conversations about sensitive topics such as intimate partner violence and safety. However, this study highlights the importance of developing multifaceted approaches to decrease the risk of intimate partner violence among women, especially during the critical times of pregnancy and postpartum.Global health impact for policy and action: Effective global health action and policy must extend beyond educational efforts, incorporating multifaceted strategies that include healthcare provider training, robust community engagement, and legislation aimed at preventing intimate partner violence, with a special focus on safeguarding the well-being of women during pregnancy and the postpartum period.

Legacies of millennial-scale climate oscillations in contemporary biodiversity in eastern North America.

The Atlantic meridional overturning circulation (AMOC) has caused significant climate changes over the past 90 000 years. Prior work has hypothesized that these millennial-scale climate variations effected past and contemporary biodiversity, but the effects are understudied. Moreover, few biogeographic models have accounted for uncertainties in palaeoclimatic simulations of millennial-scale variability. We examine whether refuges from millennial-scale climate oscillations have left detectable legacies in the patterns of contemporary species richness in eastern North America. We analyse 13 palaeoclimate estimates from climate simulations and proxy-based reconstructions as predictors for the contemporary richness of amphibians, passerine birds, mammals, reptiles and trees. Results suggest that past climate changes owing to AMOC variations have left weak but detectable imprints on the contemporary richness of mammals and trees. High temperature stability, precipitation increase, and an apparent climate fulcrum in the southeastern United States across millennial-scale climate oscillations aligns with high biodiversity in the region. These findings support the hypothesis that the southeastern United States may have acted as a biodiversity refuge. However, for some taxa, the strength and direction of palaeoclimate-richness relationships varies among different palaeoclimate estimates, pointing to the importance of palaeoclimatic ensembles and the need for caution when basing biogeographic interpretations on individual palaeoclimate simulations. This article is part of the theme issue 'Ecological novelty and planetary stewardship: biodiversity dynamics in a transforming biosphere'.

Induction of islet autoimmunity to defective ribosomal product of the insulin gene as neoantigen after anti-cancer immunotherapy leading to autoimmune diabetes.

Introduction: The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INS-DRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity. Method: T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry. Results: Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INS-DRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP. Discussion: These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity.

Brain Injury Associated Shock: An Under-Recognized and Challenging Prehospital Phenomenon.

OBJECTIVE: Hemodynamic collapse in multi-trauma patients with severe traumatic brain injury (TBI) poses both a diagnostic and therapeutic challenge for prehospital clinicians. Brain injury associated shock (BIAS), likely resulting from catecholamine storm, can cause both ventricular dysfunction and vasoplegia but may present clinically in a manner similar to hemorrhagic shock. Despite different treatment strategies, few studies exist describing this phenomenon in the early post-injury phase. This retrospective observational study aimed to describe the frequency of shock in isolated TBI in prehospital trauma patients and to compare their clinical characteristics to those patients with hemorrhagic shock and TBI without shock. METHODS: All prehospital trauma patients intubated by prehospital medical teams from New South Wales Ambulance Aeromedical Operations (NSWA-AO) with an initial Glasgow Coma Scale (GCS) of 12 or less were investigated. Shock was defined as a pre-intubation systolic blood pressure under 90mmHg and the administration of blood products or vasopressors. Injuries were classified from in-hospital computed tomography (CT) reports. From this, three study groups were derived: BIAS, hemorrhagic shock, and isolated TBI without shock. Descriptive statistics were then produced for clinical and treatment variables. RESULTS: Of 1,292 intubated patients, 423 had an initial GCS of 12 or less, 24 patients (5.7% of the original cohort) had shock with an isolated TBI, and 39 patients had hemorrhagic shock. The hemodynamic parameters were similar amongst these groups, including values of tachycardia, hypotension, and elevated shock index. Prehospital clinical interventions including blood transfusion and total fluids administered were also similar, suggesting they were indistinguishable to prehospital clinicians. CONCLUSIONS: Hemodynamic compromise in the setting of isolated severe TBI is a rare clinical entity. Current prehospital physiological data available to clinicians do not allow for easy delineation between these patients from those with hemorrhagic shock.

Accuracy of Influenza ICD-10 Diagnosis Codes in Identifying Influenza Illness in Children.

Importance: Studies of influenza in children commonly rely on coded diagnoses, yet the ability of International Classification of Diseases, Ninth Revision codes to identify influenza in the emergency department (ED) and hospital is highly variable. The accuracy of newer International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to identify influenza in children is unknown. Objective: To determine the accuracy of ICD-10 influenza discharge diagnosis codes in the pediatric ED and inpatient settings. Design, Setting, and Participants: Children younger than 18 years presenting to the ED or inpatient settings with fever and/or respiratory symptoms at 7 US pediatric medical centers affiliated with the Centers for Disease Control and Prevention-sponsored New Vaccine Surveillance Network from December 1, 2016, to March 31, 2020, were included in this cohort study. Nasal and/or throat swabs were collected for research molecular testing for influenza, regardless of clinical testing. Data, including ICD-10 discharge diagnoses and clinical testing for influenza, were obtained through medical record review. Data analysis was performed in August 2023. Main Outcomes and Measures: The accuracy of ICD-10-coded discharge diagnoses was characterized using molecular clinical or research laboratory test results as reference. Measures included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Estimates were stratified by setting (ED vs inpatient) and age (0-1, 2-4, and 5-17 years). Results: A total of 16 867 children in the ED (median [IQR] age, 2.0 [0.0-4.0] years; 9304 boys [55.2%]) and 17 060 inpatients (median [IQR] age, 1.0 [0.0-4.0] years; 9798 boys [57.4%]) were included. In the ED, ICD-10 influenza diagnoses were highly specific (98.0%; 95% CI, 97.8%-98.3%), with high PPV (88.6%; 95% CI, 88.0%-89.2%) and high NPV (85.9%; 95% CI, 85.3%-86.6%), but sensitivity was lower (48.6%; 95% CI, 47.6%-49.5%). Among inpatients, specificity was 98.2% (95% CI, 98.0%-98.5%), PPV was 82.8% (95% CI, 82.1%-83.5%), sensitivity was 70.7% (95% CI, 69.8%-71.5%), and NPV was 96.5% (95% CI, 96.2%-96.9%). Accuracy of ICD-10 diagnoses varied by patient age, influenza season definition, time between disease onset and testing, and clinical setting. Conclusions and Relevance: In this large cohort study, influenza ICD-10 discharge diagnoses were highly specific but moderately sensitive in identifying laboratory-confirmed influenza; the accuracy of influenza diagnoses varied by clinical and epidemiological factors. In the ED and inpatient settings, an ICD-10 diagnosis likely represents a true-positive influenza case.

Utility of protein-protein binding surfaces composed of anti-parallel alpha-helices and beta-sheets selected by phage display.

Over the past 3 decades, a diverse collection of small protein domains have been used as scaffolds to generate general purpose protein-binding reagents using a variety of protein display and enrichment technologies. To expand the repertoire of scaffolds and protein surfaces that might serve this purpose, we have explored the utility of (i) a pair of anti-parallel alpha-helices in a small highly disulfide-bonded 4-helix bundle, the CC4 domain from reversion-inducing Cysteine-rich Protein with Kazal Motifs and (ii) a concave beta-sheet surface and two adjacent loops in the human FN3 domain, the scaffold for the widely used monobody platform. Using M13 phage display and next generation sequencing, we observe that, in both systems, libraries of ∼30 million variants contain binding proteins with affinities in the low µM range for baits corresponding to the extracellular domains of multiple mammalian proteins. CC4- and FN3-based binding proteins were fused to the N- and/or C-termini of Fc domains and used for immunostaining of transfected cells. Additionally, FN3-based binding proteins were inserted into VP1 of AAV to direct AAV infection to cells expressing a defined surface receptor. Finally, FN3-based binding proteins were inserted into the Pvc13 tail fiber protein of an extracellular contractile injection system particle to direct protein cargo delivery to cells expressing a defined surface receptor. These experiments support the utility of CC4 helices B and C and of FN3 beta-strands C, D, and F together with adjacent loops CD and FG as surfaces for engineering general purpose protein-binding reagents.

Appendectomy versus antibiotic treatment for acute appendicitis.

BACKGROUND: Acute appendicitis is one of the most common emergency general surgical conditions worldwide. Uncomplicated/simple appendicitis can be treated with appendectomy or antibiotics. Some studies have suggested possible benefits with antibiotics with reduced complications, length of hospital stay, and the number of days off work. However, surgery may improve success of treatment as antibiotic treatment is associated with recurrence and future need for surgery. OBJECTIVES: To assess the effects of antibiotic treatment for uncomplicated/simple acute appendicitis compared with appendectomy for resolution of symptoms and complications. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registers (World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov) on 19 July 2022. We also searched for unpublished studies in conference proceedings together with reference checking and citation search. There were no restrictions on date, publication status, or language of publication. SELECTION CRITERIA: We included parallel-group randomised controlled trials (RCTs) only. We included studies where most participants were adults with uncomplicated/simple appendicitis. Interventions included antibiotics (by any route) compared with appendectomy (open or laparoscopic). DATA COLLECTION AND ANALYSIS: We used standard methodology expected by Cochrane. We used GRADE to assess the certainty of evidence for each outcome. Primary outcomes included mortality and success of treatment, and secondary outcomes included number of participants requiring appendectomy in the antibiotic group, complications, pain, length of hospital stay, sick leave, malignancy in the antibiotic group, negative appendectomy rate, and quality of life. Success of treatment definitions were heterogeneous although mainly based on resolution of symptoms rather than incorporation of long-term recurrence or need for surgery in the antibiotic group. MAIN RESULTS: We included 13 studies in the review covering 1675 participants randomised to antibiotics and 1683 participants randomised to appendectomy. One study was unpublished. All were conducted in secondary care and two studies received pharmaceutical funding. All studies used broad-spectrum antibiotic regimens expected to cover gastrointestinal bacteria. Most studies used predominantly laparoscopic surgery, but some included mainly open procedures. Six studies included adults and children. Almost all studies aimed to exclude participants with complicated appendicitis prior to randomisation, although one study included 12% with perforation. The diagnostic technique was clinical assessment and imaging in most studies. Only one study limited inclusion by sex (male only). Follow-up ranged from hospital admission only to seven years. Certainty of evidence was mainly affected by risk of bias (due to lack of blinding and loss to follow-up) and imprecision. Primary outcomes It is uncertain whether there was any difference in mortality due to the very low-certainty evidence (Peto odds ratio (OR) 0.51, 95% confidence interval (CI) 0.05 to 4.95; 1 study, 492 participants). There may be 76 more people per 1000 having unsuccessful treatment in the antibiotic group compared with surgery, which did not reach our predefined level for clinical significance (risk ratio (RR) 0.91, 95% CI 0.87 to 0.96; I2 = 69%; 7 studies, 2471 participants; low-certainty evidence). Secondary outcomes At one year, 30.7% (95% CI 24.0 to 37.8; I2 = 80%; 9 studies, 1396 participants) of participants in the antibiotic group required appendectomy or, alternatively, more than two-thirds of antibiotic-treated participants avoided surgery in the first year, but the evidence is very uncertain. Regarding complications, it is uncertain whether there is any difference in episodes of Clostridium difficile diarrhoea due to very low-certainty evidence (Peto OR 0.97, 95% CI 0.24 to 3.89; 1 study, 1332 participants). There may be a clinically significant reduction in wound infections with antibiotics (RR 0.25, 95% CI 0.09 to 0.68; I2 = 16%; 9 studies, 2606 participants; low-certainty evidence). It is uncertain whether antibiotics affect the incidence of intra-abdominal abscess or collection (RR 1.58, 95% CI 0.61 to 4.07; I2 = 19%; 6 studies, 1831 participants), or reoperation (Peto OR 0.13, 95% CI 0.01 to 2.16; 1 study, 492 participants) due to very low-certainty evidence, mainly due to rare events causing imprecision and risk of bias. It is uncertain if antibiotics prolonged length of hospital stay by half a day due to the very low-certainty evidence (MD 0.54, 95% CI 0.06 to 1.01; I2 = 97%; 11 studies, 3192 participants). The incidence of malignancy was 0.3% (95% CI 0 to 1.5; 5 studies, 403 participants) in the antibiotic group although follow-up was variable. Antibiotics probably increased the number of negative appendectomies at surgery (RR 3.16, 95% CI 1.54 to 6.49; I2 = 17%; 5 studies, 707 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Antibiotics may be associated with higher rates of unsuccessful treatment for 76 per 1000 people, although differences may not be clinically significant. It is uncertain if antibiotics increase length of hospital stay by half a day. Antibiotics may reduce wound infections. A third of the participants initially treated with antibiotics required subsequent appendectomy or two-thirds avoided surgery within one year, but the evidence is very uncertain. There were too few data from the included studies to comment on major complications.

Informing Equitable Prevention Practices: A Statewide Disaggregated Analysis of Suicide for Ethnoracially Minoritized Adolescents.

The increase in adolescent suicide rates in the United States is a pervasive public health issue, and ethnoracial youth with diverse identities are disproportionately impacted, yet less studied. National planning efforts reinforce state-level approaches to suicide prevention through an equitable lens to prevent adolescent suicide. This study examined disaggregated state-level data over time to determine changes to suicide outcomes based on race/ethnicity, sex, sexual orientation, and the intersection of these identities and determined which sub-groups had higher odds of suicide outcomes. Data from the 1991-2019 Centers for Disease Control and Prevention Youth Risk Behavioral Surveillance System were analyzed for 17,419 ethnoracially minoritized high school adolescents in North Carolina. Descriptive analyses and multinominal logistic regression models were employed. Findings indicated that subgroups within categories of ethnoracial populations, specifically Black female adolescents unsure of their sexual orientation, reported higher rates of suicide attempts. Additionally, Multiracial adolescents reported higher means for suicide consideration and attempts over time. Recommendations for investigating state-level suicide data by focusing on diverse intersecting identities to illuminate areas for potential prevention efforts and support health equity are provided.

Did the COVID-19 pandemic affect levels of burnout, anxiety and depression among doctors and nurses in Bangladesh? A cross-sectional survey study.

INTRODUCTION: COVID-19 has caused severe disruption to clinical services in Bangladesh but the extent of this, and the impact on healthcare professionals is unclear. We aimed to assess the perceived levels of anxiety, depression and burnout among doctors and nurses during COVID-19 pandemic. METHODS: We undertook an online survey using RedCap, directed at doctors and nurses across four institutions in Bangladesh (The Sheikh Russel Gastro Liver Institute & Hospital (SRNGIH), Dhaka Medical College Hospital (DMCH), Mugda Medical College Hospital (MMCH) and M Abdur Rahim Medical College (MARMC) Hospital). We collected information on demographics, awareness of well-being services, COVID-19-related workload, as well as anxiety, depression and burnout using two validated questionnaires: the Hospital Anxiety and Depression Scale (HADS) and the Maslach Burnout Inventory (MBI). RESULTS: Of the 3000 participants approached, we received responses from 2705 (90.2%). There was a statistically significant difference in anxiety, depression and burnout scores across institutions (p<0.01). Anxiety, depression and burnout scores were statistically worse in COVID-19 active staff compared with those not working on COVID-19 activities (p<0.01 for HADS anxiety and depression and MBI emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA)). Over half of the participants exhibited some level of anxiety (SRNGIH: 52.2%; DMCH: 53.9%; MMCH: 61.3%; MARMC: 68%) with a high proportion experiencing depression (SRNGIH: 39.5%; DMCH: 38.7%; MMCH: 53.7%; MARMC: 41.1%). Although mean burnout scores were within the normal range for each institution, a high proportion of staff (almost 20% in some instances) were shown to be classified as experiencing burnout by their EE, DP and PA scores. CONCLUSION: We identified a high prevalence of perceived anxiety, depression and burnout among doctors and nurses during the COVID-19 pandemic. This was worse in staff engaged in COVID-19-related activities. These findings could help healthcare organisations to plan for future similar events.

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression.

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

IFN-λ drives distinct lung immune landscape changes and antiviral responses in human metapneumovirus infection.

Human metapneumovirus (HMPV) is a primary cause of acute respiratory infection, yet there are no approved vaccines or antiviral therapies for HMPV. Early host responses to HMPV are poorly characterized, and further understanding could identify important antiviral pathways. Type III interferon (IFN-λ) displays potent antiviral activity against respiratory viruses and is being investigated for therapeutic use. However, its role in HMPV infection remains largely unknown. Here, we show that IFN-λ is highly upregulated during HMPV infection in vitro in human and mouse airway epithelial cells and in vivo in mice. We found through several immunological and molecular assays that type II alveolar cells are the primary producers of IFN-λ. Using mouse models, we show that IFN-λ limits lung HMPV replication and restricts virus spread from upper to lower airways but does not contribute to clinical disease. Moreover, we show that IFN-λ signaling is predominantly mediated by CD45- non-immune cells. Mice lacking IFN-λ signaling showed diminished loss of ciliated epithelial cells and decreased recruitment of lung macrophages in early HMPV infection along with higher inflammatory cytokine and interferon-stimulated gene expression, suggesting that IFN-λ may maintain immunomodulatory responses. Administration of IFN-λ for prophylaxis or post-infection treatment in mice reduced viral load without inflammation-driven weight loss or clinical disease. These data offer clinical promise for IFN-λ in HMPV treatment. IMPORTANCE: Human metapneumovirus (HMPV) is a common respiratory pathogen and often contributes to severe disease, particularly in children, immunocompromised people, and the elderly. There are currently no licensed HMPV antiviral treatments or vaccines. Here, we report novel roles of host factor IFN-λ in HMPV disease that highlight therapeutic potential. We show that IFN-λ promotes lung antiviral responses by restricting lung HMPV replication and spread from upper to lower airways but does so without inducing lung immunopathology. Our data uncover recruitment of lung macrophages, regulation of ciliated epithelial cells, and modulation of inflammatory cytokines and interferon-stimulated genes as likely contributors. Moreover, we found these roles to be distinct and non-redundant, as they are not observed with knockout of, or treatment with, type I IFN. These data elucidate unique antiviral functions of IFN-λ and suggest IFN-λ augmentation as a promising therapeutic for treating HMPV disease and promoting effective vaccine responses.

Nasopharyngeal metatranscriptomics reveals host-pathogen signatures of pediatric sinusitis.

Acute sinusitis (AS) is the fifth leading cause of antibiotic prescriptions in children. Distinguishing bacterial AS from common viral upper respiratory infections in children is crucial to prevent unnecessary antibiotic use but is challenging with current diagnostic methods. Despite its speed and cost, untargeted RNA sequencing of clinical samples from children with suspected AS has the potential to overcome several limitations of other methods. However, the utility of sequencing-based approaches in analysis of AS has not been fully explored. Here, we performed RNA-seq of nasopharyngeal samples from 221 children with clinically diagnosed AS to characterize their pathogen and host-response profiles. Results from RNA-seq were compared with those obtained using culture for three common bacterial pathogens and qRT-PCR for 12 respiratory viruses. Metatranscriptomic pathogen detection showed high concordance with culture or qRT-PCR, showing 87%/81% sensitivity (sens) / specificity (spec) for detecting bacteria, and 86%/92% (sens/spec) for viruses, respectively. We also detected an additional 22 pathogens not tested for in the clinical panel, and identified plausible pathogens in 11/19 (58%) of cases where no organism was detected by culture or qRT-PCR. We assembled genomes of 205 viruses across the samples including novel strains of coronaviruses, respiratory syncytial virus (RSV), and enterovirus D68. By analyzing host gene expression, we identified host-response signatures that distinguished bacterial and viral infections and correlated with pathogen abundance. Ultimately, our study demonstrates the potential of untargeted metatranscriptomics for in depth analysis of the etiology of AS, comprehensive host-response profiling, and using these together to work towards optimized patient care.

Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season - New Vaccine Surveillance Network, October 2023-February 2024.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.

Low-velocity penetrating brain injury: a review of the literature and illustrative case.

INTRODUCTION: Low-velocity penetrating brain injury (LVPBI) is a class of brain injury where a foreign object violates the skull and damages the brain. Such injuries are rare and consequently understudied. CASE: As such, we report an illustrative case of a 29-year-old female with a dense, plastic spike penetrating her right orbit and into her midbrain. After assessment with a CT scan and angiography, the object was removed with careful attention to possible vascular injury. The patient had an uncomplicated post-operative course and received antibiotic and antiepileptic prophylaxis. She was discharged on post-operative day 5, experiencing only mild left-sided weakness. DISCUSSION: Common concerns regarding LVPBI include infection, post-traumatic epilepsy, and vascular injury. A review of published LVPBI cases over the past 20 years demonstrated that most cases (55.2%) are due to accidents. Of patients undergoing surgery, 43.4% underwent a craniotomy, and 22.8% underwent a craniectomy. Despite the grave nature of LVPBI, only 13.5% of the patients died. Additionally, 6.5% of patients developed an infection over their clinical course. CONCLUSION: In all, more reported cases further paint a picture of the current state of management and outcomes regarding LVPBI, paving the way for more cohesive guidelines to ensure the best possible patient outcomes.

Prioritizing Mental Health within HIV and Tuberculosis Services in PEPFAR.

Underprioritization of mental health is a global problem and threatens the decades-long progress of the US President's Emergency Plan for AIDS Relief (PEPFAR) program. In recent years, mental health has become globally recognized as a part of universal healthcare, making this an opportune moment for the global community to integrate mental health services into routine programming. PEPFAR is well positioned to lead by example. We conceptualized 5 key strategies that might help serve as a framework to support mental health programming as part of PEPFAR's current 5-year strategic plan. PEPFAR and the global community have an opportunity to identify mental health service gaps and interweave global mental health priorities with actions to end the HIV and TB epidemics by 2030.

High-throughput mRNA sequencing of human placenta shows sex differences across gestation.

INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.