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Background: Daptomycin is a high-use intravenous antimicrobial agent affording the convenience of once-daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight-based dosing but this approach has not been studied prospectively., Methods: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non-obese adults. At least, three daptomycin concentrations were measured at steady-state for each patient. A population pharmacokinetic model was constructed to evaluate concentration-time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24-h area under the curve (AUC 0-24 ) ≥ 666 mg∙h/L) and toxicity (minimum concentration (C min ) ≥24.3 mg/L) targets for fixed (500-1000 mg) and weight-based (6-12 mg/kg) daptomycin doses., Results: Thirty-one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC 0-24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight-based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight-based regimens., Conclusions: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy-to-toxicity ratio, transitions of care, and costs compared to weight-based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient-specific basis., (© 2024 Pharmacotherapy Publications, Inc.)

Purpose: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes., Methods: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression., Findings: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization., Conclusions: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Platelets contribute to COVID-19 clinical manifestations, of which microclotting in the pulmonary vasculature has been a prominent symptom. To investigate the potential diagnostic contributions of overall platelet morphology and their α-granules and mitochondria to the understanding of platelet hyperactivation and micro-clotting, we undertook a 3D ultrastructural approach. Because differences might be small, we used the high-contrast, high-resolution technique of focused ion beam scanning EM (FIB-SEM) and employed deep learning computational methods to evaluate nearly 600 individual platelets and 30 000 included organelles within three healthy controls and three severely ill COVID-19 patients. Statistical analysis reveals that the α-granule/mitochondrion-to-plateletvolume ratio is significantly greater in COVID-19 patient platelets indicating a denser packing of organelles, and a more compact platelet. The COVID-19 patient platelets were significantly smaller -by 35% in volume - with most of the difference in organelle packing density being due to decreased platelet size. There was little to no 3D ultrastructural evidence for differential activation of the platelets from COVID-19 patients. Though limited by sample size, our studies suggest that factors outside of the platelets themselves are likely responsible for COVID-19 complications. Our studies show how deep learning 3D methodology can become the gold standard for 3D ultrastructural studies of platelets.

Objective: Polydioxanone (PDS) plates are utilized in septorhinoplasty to reconstruct the nasal septum. Our goal was to analyze factors affecting short- and long-term complications in patients undergoing septorhinoplasty using PDS plates with a particular focus on smoking and diabetes., Methods: This is a retrospective review of patients undergoing septorhinoplasty with PDS plates analyzing risk factors and outcomes. Early complications included infection, hematoma, extrusion, and septal thickening. Late complications included septal perforation, obstruction, revision, and infection. Complication rate was assessed as a function of demographics, diabetes, smoking, autoimmune disease, cancer, and trauma. Multivariate analyses assessed the contributions of these variables, and Chi-square analyses specifically addressed smoking and diabetes., Results: A total of 119 patients were included. In multivariate analysis, current smoking had a large negative effect on late outcomes (OR 2.00, 95% CI 0.59-6.55), while diabetes did not show any significant difference. Targeted Chi-squared analysis showed a statistically significant effect of current smoking on increased early complications (OR 3.65, 95% CI 1.67-7.63) and a large but not statistically significant increase in long-term complications (OR 4.20, 95% CI 0.72-22.74). In both models, diabetes was not shown to have an effect on early or late complications., Conclusion: Current smokers undergoing septorhinoplasty with a PDS plate showed a statistically significant association with early complications and large but not statistically significant association with late complications. Diabetic patients were not found to have an increased complication risk., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Objectives: The American Joint Committee on Cancer's 8th edition (AJCC-8) separates oropharyngeal squamous cell carcinomas (OPSCCs) into human papillomavirus-positive (HPV+) tumors and HPV-negative tumors. Although AJCC-8 improves prognostic prediction for survival for the majority of HPV+ OPSCC, outliers are still encountered. The goal of this manuscript is to validate the AJCC-8 as a better metric of survivability than the AJCC-7 in an historically under-served rural population with confounding variables, such as tobacco use, alcohol consumption, and poor health care access and to analyze the role of extranodal extension (ENE) in this population., Design: Retrospective cohort study., Results: Compared to AJCC-7, AJCC-8 had a higher odds ratio (OR) for predicting mortality of stage IV HPV+ OPSCCs versus stages I-III. On multivariate analysis, HPV+ OPSCCs with ENE had a higher OR of mortality compared to ENE- OPSCCs. In addition, HPV+ OPSCC patients with a Charlson Comorbidity Index (CCI) > 3 had a higher OR of mortality compared to those with a CCI ≤ 3. Patients with Medicaid/self-pay status had a higher OR of mortality compared to those with private insurance/Medicare. Finally, patients from rural populations had a higher OR of presenting with stage IV disease, a CCI > 3, and Medicaid/self-pay status., Conclusions: Despite not being a discrete part of the AJCC-8 staging rubric, ENE was found to have a significant impact on mortality among this population, whereas tobacco use had no effect. Rural patients were more likely to present with stage IV disease, CCI > 3, and Medicaid/self-pay status. Stage IV disease was also associated with a higher OR of mortality., Level of Evidence: 4 Laryngoscope, 133:2621-2626, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Malawi, as a low-income country in southeastern Africa, severely lacks early identification, diagnosis and intervention measures for hearing loss. Due to its constrained resources, an educational awareness campaign targeted at professionals can be a cost-effective instrument in promoting good health care through awareness, prevention, and early identification of hearing loss. The aim of this study is to assess school teachers' knowledge of hearing health, audiology services, identification, and management of hearing issues before and after an educational intervention., Methods: A Pre-Survey, followed by an educational intervention, and a Post-Survey were completed by teacher participants. A similar World Health Organization-derived survey was also administered to compare to our locally adapted survey. Trends related to efficacy, performance, and survey improvement were evaluated., Results: A total of 387 teachers participated. The average score on the Post-Survey was significantly improved compared to the Pre-Survey (71% to 97% correct responses) with the educational intervention. The only predictive variable related to performance was the location of the school within the capital of Lilongwe compared to rural sites outside of the capital. Our locally adapted survey compared favorably to the WHO survey., Conclusions: The results suggest that there is a statistically significant improvement in the implementation of an educational program to increase the knowledge and awareness of hearing health care among teachers. Some topics were more poorly understood than others, suggesting the need for targeted awareness interventions. Location within the capital city had some effect on performance but a high rate of correct responses was achievable across the participants independent of age, teaching experience, or gender. Our data support the idea that hearing health awareness interventions can be an effective and low-cost option to equip teachers to effectively serve as an advocate for improved identification, early diagnosis and appropriate referral of students with hearing loss.

Background: The COVID-19 pandemic has demonstrated the need for efficient and comprehensive, simultaneous assessment of multiple combined novel therapies for viral infection across the range of illness severity. Randomized Controlled Trials (RCT) are the gold standard by which efficacy of therapeutic agents is demonstrated. However, they rarely are designed to assess treatment combinations across all relevant subgroups. A big data approach to analyzing real-world impacts of therapies may confirm or supplement RCT evidence to further assess effectiveness of therapeutic options for rapidly evolving diseases such as COVID-19., Methods: Gradient Boosted Decision Tree, Deep and Convolutional Neural Network classifiers were implemented and trained on the National COVID Cohort Collaborative (N3C) data repository to predict the patients' outcome of death or discharge. Models leveraged the patients' characteristics, the severity of COVID-19 at diagnosis, and the calculated proportion of days on different treatment combinations after diagnosis as features to predict the outcome. Then, the most accurate model is utilized by eXplainable Artificial Intelligence (XAI) algorithms to provide insights about the learned treatment combination impacts on the model's final outcome prediction., Results: Gradient Boosted Decision Tree classifiers present the highest prediction accuracy in identifying patient outcomes with area under the receiver operator characteristic curve of 0.90 and accuracy of 0.81 for the outcomes of death or sufficient improvement to be discharged. The resulting model predicts the treatment combinations of anticoagulants and steroids are associated with the highest probability of improvement, followed by combined anticoagulants and targeted antivirals. In contrast, monotherapies of single drugs, including use of anticoagulants without steroid or antivirals are associated with poorer outcomes., Conclusions: This machine learning model by accurately predicting the mortality provides insights about the treatment combinations associated with clinical improvement in COVID-19 patients. Analysis of the model's components suggests benefit to treatment with combination of steroids, antivirals, and anticoagulant medication. The approach also provides a framework for simultaneously evaluating multiple real-world therapeutic combinations in future research studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Moradi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: While COVID-19 vaccines reduce adverse outcomes, post-vaccination SARS-CoV-2 infection remains problematic. We sought to identify community factors impacting risk for breakthrough infections (BTI) among fully vaccinated persons by rurality., Methods: We conducted a retrospective cohort study of US adults sampled between January 1 and December 20, 2021, from the National COVID Cohort Collaborative (N3C). Using Kaplan-Meier and Cox-Proportional Hazards models adjusted for demographic differences and comorbid conditions, we assessed impact of rurality, county vaccine hesitancy, and county vaccination rates on risk of BTI over 180 days following two mRNA COVID-19 vaccinations between January 1 and September 21, 2021. Additionally, Cox Proportional Hazards models assessed the risk of infection among adults without documented vaccinations. We secondarily assessed the odds of hospitalization and adverse COVID-19 events based on vaccination status using multivariable logistic regression during the study period., Results: Our study population included 566,128 vaccinated and 1,724,546 adults without documented vaccination. Among vaccinated persons, rurality was associated with an increased risk of BTI (adjusted hazard ratio [aHR] 1.53, 95% confidence interval [CI] 1.42-1.64, for urban-adjacent rural and 1.65, 1.42-1.91, for nonurban-adjacent rural) compared to urban dwellers. Compared to low vaccine-hesitant counties, higher risks of BTI were associated with medium (1.07, 1.02-1.12) and high (1.33, 1.23-1.43) vaccine-hesitant counties. Compared to counties with high vaccination rates, a higher risk of BTI was associated with dwelling in counties with low vaccination rates (1.34, 1.27-1.43) but not medium vaccination rates (1.00, 0.95-1.07). Community factors were also associated with higher odds of SARS-CoV-2 infection among persons without a documented vaccination. Vaccinated persons with SARS-CoV-2 infection during the study period had significantly lower odds of hospitalization and adverse events across all geographic areas and community exposures., Conclusions: Our findings suggest that community factors are associated with an increased risk of BTI, particularly in rural areas and counties with high vaccine hesitancy. Communities, such as those in rural and disproportionately vaccine hesitant areas, and certain groups at high risk for adverse breakthrough events, including immunosuppressed/compromised persons, should continue to receive public health focus, targeted interventions, and consistent guidance to help manage community spread as vaccination protection wanes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Anzalone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The objective of this study was to determine antibiotic appropriateness based on Loeb minimum criteria (LMC) in patients with and without altered mental status (AMS)., Design: Retrospective, quasi-experimental study assessing pooled data from 3 periods pertaining to the implementation of a UTI management guideline., Setting: Academic medical center in Lexington, Kentucky., Patients: Adult patients aged ≥18 years with a collected urinalysis receiving antimicrobial therapy for a UTI indication., Methods: Appropriateness of UTI management was assessed in patients prior to an institutional UTI guideline, after guideline introduction and education, and after implementation of a prospective audit-and-feedback stewardship intervention from September to November 2017-2019. Patient data were pooled and compared between patients noted to have AMS versus those with classic UTI symptoms. Loeb minimum criteria were used to determine whether UTI diagnosis and treatment was warranted., Results: In total, 600 patients were included in the study. AMS was one of the most common indications for testing across the 3 periods (19%-30.5%). Among those with AMS, 25 patients (16.7%) met LMC, significantly less than the 151 points (33.6%) without AMS ( P < .001)., Conclusions: Patients with AMS are prescribed antibiotic therapy without symptoms indicative of UTI at a higher rate than those without AMS, according to LMC. Further antimicrobial stewardship efforts should focus on prescriber education and development of clearly defined criteria for patients with and without AMS., (© The Author(s) 2022.)

Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (T RM ) CD8 + T-cells is of great interest, but limited data exist on T RM -like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8 + T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally T RM -like profile distinct from blood CD8 + T-cells. In PLWH, CD8 + T RM -like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8 + T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8 + T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8 + T RM -like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs., Competing Interests: AKS reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Clarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, Empress Therapeutics, and Dahlia Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fardoos, Nyquist, Asowata, Kazer, Singh, Ngoepe, Giandhari, Mthabela, Ramjit, Singh, Karim, Buus, Anderson, Porterfield, Sibiya, Bipath, Moodley, Kuhn, Berger, Nguyen, de Oliveira, Ndung’u, Goulder, Shalek, Leslie and Kløverpris.)

Objectives: Although the World Health Organization (WHO) Clinical Progression Scale for COVID-19 is useful in prospective clinical trials, it cannot be effectively used with retrospective Electronic Health Record (EHR) datasets. Modifying the existing WHO Clinical Progression Scale, we developed an ordinal severity scale (OS) and assessed its usefulness in the analyses of COVID-19 patient outcomes using retrospective EHR data., Materials and Methods: An OS was developed to assign COVID-19 disease severity using the Observational Medical Outcomes Partnership common data model within the National COVID Cohort Collaborative (N3C) data enclave. We then evaluated usefulness of the developed OS using heterogenous EHR data from January 2020 to October 2021 submitted to N3C by 63 healthcare organizations across the United States. Principal component analysis (PCA) was employed to characterize changes in disease severity among patients during the 28-day period following COVID-19 diagnosis., Results: The data set used in this analysis consists of 2 880 456 patients. PCA of the day-to-day variation in OS levels over the totality of the 28-day period revealed contrasting patterns of variation in disease severity within the first and second 14 days and illustrated the importance of evaluation over the full 28-day period., Discussion: An OS with well-defined, robust features, based on discrete EHR data elements, is useful for assessments of COVID-19 patient outcomes, providing insights on the progression of COVID-19 disease severity over time., Conclusions: The OS provides a framework that can facilitate better understanding of the course of acute COVID-19, informing clinical decision-making and resource allocation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objective: The previously described TALK score (T-stage, Albumin, Liquor, Karnofsky Performance Status) has been proposed as a method to predict laryngectomy-free survival (LFS) in patients undergoing definitive chemoradiation (CRT). This study assesses its use as well as a modification to include continued tobacco use., Study Design: Retrospective chart review., Setting: Academic institution from 2004 to 2020., Methods: Patients diagnosed with larynx or hypopharynx cancer undergoing CRT were reviewed. Clinically relevant variables were collected (TALK), which were dichotomized per previously set cutoffs. Concurrent tobacco use was evaluated and also dichotomized as 0 or 1. Multivariate analysis was conducted to determine which factors were most predictive of the key outcomes of survival and LFS., Results: A total of 2514 patient charts were evaluated. Patients treated for larynx cancer with primary CRT with complete data were included, ultimately totaling 300. Of these, 78 patients required salvage total laryngectomy (TL). Multivariate analysis demonstrated that LFS was best predicted by tobacco use during treatment (odds ratio [OR] 0.3465, 95% confidence interval [CI] 0.1862-0.6300) and Karnofsky Performance Status (OR 0.1646, 95% CI 0.0673-0.3662). Tobacco use during treatment was also strongly predictive of survival. Excluding T4 tumors, the utilization of tobacco in place of T-stage improved the accuracy of the predictive model in this cohort., Conclusion: Given that a T-stage of 4 is typically treated with total laryngectomy, modification of the TALK score to include tobacco use during treatment (tALK) for patients with T < 4 can be used to improve prediction of 3-year LFS and overall survival.

HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4+ T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4+ T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4+ T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown.

Background: Cryptococcosis is classically associated with the immunocompromised patients but there is a rising appreciation for its impact on the immunocompetent hosts. We sought to analyse the trends, diagnosis, treatment of different hosts and the effect of immunodeficiency and chronic liver disease on relapse and in-house mortality., Methods: This is a retrospective study of 12 years of patients with cryptococcosis, divided into three different groups: HIV-infected, transplant and non-HIV non-transplant (NHNT). Data were analysed with Chi-square, unpaired parametric t test, simple and multivariate logistic regression analysis., Results: Of 114 identified patients, 23 (20.2%) had HIV infection, 11 (9.6%) had transplant, 80 (70.2%) were NHNT patients. Overall, mortality was 28.1% (32/114) and relapse occurred in 10.5% (12/114) of patients. The mortality trend was higher (OR = 2.346, p = .287) in the transplant group (45.5%, 5/11) than in HIV (26.1%, 6/23) and NHNT groups (26.3%, 21/80). HIV was associated with relapse; 30.4% (7/23) for HIV-positive patients and 5.5% (5/91) for HIV-negative patients (OR = 7.525, p = .002). Chronic liver disease had a large and statistically significant association with mortality on multivariate analysis (OR = 3.583, p = .013) which was more pronounced than the HIV or transplant groups. It was independently associated with mortality by chi-square analysis (OR 3.137, p = .012)., Conclusion: Chronic liver disease represented 30.7% (35/114) of all studied patients. It was a risk factor for in-hospital mortality. HIV infection and transplant were not statistically significant for mortality. Relapse was highest in the HIV-infected patients at 30.4% (7/23). These data highlight the effect of type and degree of immunocompromise on cryptococcosis., (© 2021 Wiley-VCH GmbH.)

Background: To meet the rising interest in surgical global health, some surgical residency programs offer global health experiences. The level of interest in these programs, however, and their role in residency recruitment and career planning has not been systematically evaluated., Objective: (1) Define interest in global health among Otolaryngology residents in the USA. (2) Assess engagement of Otolaryngology residencies in global health training. (3) Determine barriers to global health training in residency., Methods: A survey questionnaire was developed and sent to all Otolaryngology Residency Program Directors for distribution to all current Otolaryngology residents in the US., Results: A total of 91 complete surveys were collected. A majority of respondents felt that global health was either "very important" or "extremely important" (67%). Two-thirds of respondents had prior global health experience (68%). While 56% of respondents would definitely participate in a global health elective and 78% would likely or definitely participate, only 37% of residency programs offered a global health experience. The availability of a global health elective significantly correlated with residency match choice in respondents with previous global health experience. The three most common barriers to participation were insufficient time, insufficient funding, and lack of program., Conclusion: Participation in bilateral and equitable international electives is a unique experience of personal and professional growth. There is an interest in these opportunities during residency training among Otolaryngology residents that is not reflected in availability within training programs. This suggests the need for development of humanitarian outreach exposure through global health experiences during surgical residency training., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Purpose: Appalachian residents have higher cancer prevalence and invasive cancer incidence in almost all cancer types relative to non-Appalachian residents. Public health interventions have been carried out to increase preventive cancer screening participation. However, no studies have evaluated the effectiveness of existing interventions targeting cancer screening uptake in this high-risk population. The main objective of this study is to assess the effectiveness of interventions aimed at increasing uptake and/or continuing participation in screened cancers (breast, cervical, colorectal, lung, and prostate) in Appalachia., Methods: We conducted a systematic review of electronic databases and gray literature using a combination of MeSH and free-text search terms related to breast, cervical, colorectal, lung, and prostate cancer; mass screening; health promotion; and Appalachia. We identified 3,014 articles of which 15 articles were included. We assessed methodological quality using validated tools and analyzed findings using narrative synthesis., Findings: Fifteen studies reported uptake and/or continued participation in screening interventions; these focused on cervical (n = 7), colorectal (n = 5), breast (n = 2), and lung (n = 1) cancers in Appalachia. Interventions included diverse components: mass media campaigns, community outreach events, community health workers, interpersonal counseling, and educational materials. We found that multi-strategy interventions had higher screening uptake relative to interventions employing 1 intervention strategy. Studies that targeted noncompliant populations and leveraged existing community-based organization partnerships had a substantial increase in screening participation versus others., Conclusions: There is an urgent need for further research and implementation of effective cancer prevention and screening interventions to reduce disparities in cancer morbidity and mortality in Appalachian populations., (© 2020 National Rural Health Association.)

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.

Objectives: To undertake a large-scale review of otogenic intracranial sepsis in an area of highly prevalent HIV and tuberculosis (TB) to re-examine and inform early diagnosis and treatment efforts., Methods: Seventy-seven consecutive cases of otogenic intracranial sepsis in KwaZulu-Natal, South Africa were reviewed for demographics, presentation, imaging, HIV status, culture results, and outcomes., Results: The most common intracranial complications were intracranial abscess (46.8%), hydrocephalus (31.2%), subdural empyema (28.6%), and epidural empyema (26.0%). Ear discharge (87.0%), postauricular abscess (29.9%), and hearing loss (29.9%) were notable presenting symptoms. Overall mortality was 15.6%. Of the 45.5% of patients with HIV testing, 54.2% were HIV+, Mortality among HIV+ patients was 15.8% but only 6.3% in HIV- patients (p = 0.61, OR = 2.8). Eight patients (10.4%) had culture or histological evidence of TB infection., Conclusions: Otogenic intracranial complications continue to present late and are associated with significant mortality and morbidity, despite advances in diagnostic and treatment modalities. This study represents one of the largest case-series in the literature, and the first to specifically evaluate the effects of HIV and TB infection.Patient presentation and severity of illness varied; however, a majority of patients presented with ear discharge and no focal neurological signs. An effect size for higher mortality among HIV+ patients compared with HIV- patients was noted but was not significant. Tuberculosis infection was prevalent compared with previous studies.This study reinforces the need for enhanced screening and early treatment of ear disease to minimize associated mortality and morbidity, particularly in immunocompromised patients.

Children may be the optimal target for HIV vaccine development as they generate substantially more frequent and more potent broadly HIV neutralizing antibodies (bnAbs) than adults. Development of a biomarker that correlates with neutralization breadth in this group could function as a powerful tool to facilitate the development of an HIV vaccine. Previously, we observed that this preferential ability in HIV-infected children over adults to generate bnAbs is associated with an enrichment of circulating follicular helper T-cells (T FH ) with an effector phenotype, and the presence of IL-21 secreting HIV-specific T FH within lymphoid tissue germinal centers (GC). In adults, bnAbs development has been linked with high plasma levels of CXCL13, a chemoattractant for CXCR5-expressing T FH cells to the lymph node GC. We sought to test this relationship in HIV-infected children, but found no association between neutralization breadth and plasma levels of CXCL13, or with the Th2 cytokines IL-4 and IL-13, or the T FH associated factor Activin A. However, we did find an unexpected association between plasma IL-5 levels and bnAb development in these children. Importantly, although CXCL13 correlated with total circulating T FH cells, it was not associated with effector T FH . Additionally, raised CXCL13 expression was associated with a lower CD4 percentage, higher viral load and a loss of immune function, implying it is associated with progressive disease rather than HIV-specific GC activity in these subjects. Taken together, our data suggests that IL-5 should be evaluated further as a candidate plasma biomarker for HIV neutralization breadth and for monitoring vaccine responses in the pediatric age group.

Despite widespread BCG vaccination and effective anti-TB drugs, Tuberculosis (TB) remains the leading cause of death from an infectious agent worldwide. Several recent publications give reasons to be optimistic about the possibility of a more effective vaccine, but the only full-scale clinical trial conducted failed to show protection above BCG. The immunogenicity of vaccines in humans is primarily evaluated by the systemic immune responses they generate, despite the fact that a correlation between these responses and protection from TB disease has not been demonstrated. A novel approach to tackling this problem is to study the local immune responses that occur at the site of TB infection in the human lung, rather than those detectable in blood. There is a growing understanding that pathogen specific T-cell immunity can be highly localized at the site of infection, due to the existence of tissue resident memory T-cells (Trm). Notably, these cells do not recirculate in the blood and thus may not be represented in studies of the systemic immune response. Here, we review the potential role of Trms as a component of the TB immune response and discuss how a better understanding of this response could be harnessed to improve TB vaccine efficacy.

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5 . R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5 , despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2 / ccr5 down-regulation, suggesting that the phenotype is heritable., Competing Interests: EG, PR, UI, RL, SM, AC, JP, TL, VM, DR, BW, SD, RS No competing interests declared

The lungs represent a complex immune setting, balancing external environmental signals with a poised immune response that must protect from infection, mediate tissue repair, and maintain lung function. Innate lymphoid cells (ILCs) play a central role in tissue repair and homeostasis, and mediate protective immunity in a variety of mucosal tissues, including the lung. All three ILC subsets are present in the airways of both mice and humans; and ILC2s shown to have pivotal roles in asthma, airway hyper-responsiveness, and parasitic worm infection. The involvement of ILC3s in respiratory diseases is less well-defined, but they are known to be critical in homeostasis, infection and inflammation at other mucosal barriers, such as the gut. Moreover, they are important players in the IL17/IL22 axis, which is key to lung health. In this review, we discuss the emerging role of ILC3s in the context of infectious and inflammatory lung diseases, with a focus on data from human subjects.

Chronic Suppurative Otitis Media (CSOM) is a widely prevalent disease, which is a leading cause of acquired deafness worldwide, and is associated with complications with significant mortality and morbidity. It often responds poorly to standard of care therapy and places a disproportionate burden on at-risk populations. The microbiology and antibiotic resistance of CSOM varies based on local factors, including health care access, comorbidities, and antibiotic prescribing practices. We evaluated the role and feasibility of using routine culture for the treatment of CSOM in rural areas as a means of improving treatment of CSOM. More than 400 patients were screened in a rural clinic in South Africa over six weeks, and 14 met study criteria and consented for participation. Gram-negative organisms predominated overall, although Staphylococcus aureus was the most commonly isolated single species. A majority of the pathogens were relatively sensitive to commonly prescribed antibiotics, but two cases of methicillin resistant Staphylococcus aureus were cultured, and one patient grew a Scedosporium species. Treatment on follow-up was able to be directed by culture results, suggesting routine culture at the initial point of contact with the health care system may play a pivotal role in addressing this widely prevalent and devastating disease.

The human parainfluenza virus (hPIV) hemagglutinin-neuraminidase (HN) protein binds (H) oligosaccharide receptors that contain N-acetylneuraminic acid (Neu5Ac) and cleaves (N) Neu5Ac from these oligosaccharides. In order to determine if one of HN's two functions is predominant, we measured the affinity of H for its ligands by a solid-phase binding assay with two glycoprotein substrates and by surface plasmon resonance with three monovalent glycans. We compared the dissociation constant (Kd) values from these experiments with previously determined Michaelis-Menten constants (Kms) for the enzyme activity. We found that glycoprotein substrates and monovalent glycans containing Neu5Acα2-3Galβ1-4GlcNAc bind HN with Kd values in the 10 to 100 μM range. Km values for HN were previously determined to be on the order of 1 mM (M. M. Tappert, D. F. Smith, and G. M. Air, J. Virol. 85:12146-12159, 2011). A Km value greater than the Kd value indicates that cleavage occurs faster than the dissociation of binding and will dominate under N-permissive conditions. We propose, therefore, that HN is a neuraminidase that can hold its substrate long enough to act as a binding protein. The N activity can therefore regulate binding by reducing virus-receptor interactions when the concentration of receptor is high.

Many viruses package their genomes concomitant with assembly. Here, we show that this reaction can be described by three coefficients: association of capsid protein (CP) to nucleic acid (NA), KNA; CP-CP interaction, ω; and α, proportional to the work required to package NA. The value of α can vary as NA is packaged. A phase diagram of average lnα versus lnω identifies conditions where assembly is likely to fail or succeed. NA morphology can favor (lnα > 0) or impede (lnα < 0) assembly. As lnω becomes larger, capsids become more stable and assembly becomes more cooperative. Where (lnα + lnω) < 0, the CP is unable to contain the NA, so that assembly results in aberrant particles. This phase diagram is consistent with quantitative studies of cowpea chlorotic mottle virus, hepatitis B virus, and simian virus 40 assembling on ssRNA and dsDNA substrates. Thus, the formalism we develop is suitable for describing and predicting behavior of experimental studies of CP assembly on NA., (Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

UV spectra of viruses are complicated by overlapping protein and RNA absorbance and light scattering. We describe and validate methodology for estimating RNA and protein concentration from such spectra. Importantly, we found that encapsidation did not substantially affect RNA absorbance. Combining absorbance data with a known T number, we confirmed that brome mosaic virus packages about 3100 nucleotides/capsid, consistent with its genome. E. coli-expressed hepatitis B virus (HBV) packages host RNA based on capsid charge and volume. We examined HBV capsid protein (Cp183, +15 charge) and a less basic mutant (Cp183-EEE, +12 charge) that mimics a phosphorylated state. Cp183-EEE packaged ~3450 nucleotides per T=4 capsid and Cp183 packaged ~4800 nucleotides, correlating to the size of HBV's RNA pre-genome and mature DNA genome, respectively. The RNA:protein charge ratio (about 1.4 phosphates per positive charge) was consistent with that of other ssRNA viruses. This spectroscopic method is generalizable to any virus-like particle., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A critical feature of a viral life cycle is the ability to selectively package the viral genome. In vivo, phosphorylated hepatitis B virus (HBV) core protein specifically encapsidates a complex of pregenomic RNA (pgRNA) and viral polymerase; it has been suggested that packaging is specific for the complex. Here, we test the hypothesis that core protein has intrinsic specificity for pgRNA, independent of the polymerase. For these studies, we also evaluated the effect of core protein phosphorylation on assembly and RNA binding, using phosphorylated core protein and a phosphorylation mimic in which S155, S162, and S170 were mutated to glutamic acid. We have developed an in vitro system where capsids are disassembled and assembly-active core protein dimer is purified. With this protein, we have reassembled empty capsids and RNA-filled capsids. We found that core protein dimer bound and encapsidated both the HBV pregenomic RNA and heterologous RNA with high levels of cooperativity, irrespective of phosphorylation. In direct competition assays, no specificity for pregenomic RNA was observed. This suggests that another factor, such as the viral polymerase, is required for specific packaging. These results also beg the question of what prevents HBV core protein from assembling on nonviral RNA, preserving the protein for virus production.