Search

Nasal high flow therapy has been previously studied for the management of acute hypoxic respiratory failure in patients with chronic obstructive pulmonary disease but the data regarding its use outside of the intensive care unit are sparse. We aimed to evaluate safety and efficacy of nasal high flow therapy outside of the intensive care unit in patients with acute hypoxic respiratory failure and known chronic obstructive pulmonary disease. We conducted a retrospective matched historic cohort study of adult patients with diagnosed chronic obstructive pulmonary disease presenting with acute hypoxic respiratory failure between December 2017 to June 2019, after the initiation of a new protocol, which allowed patients to be managed with nasal high flow therapy on the medical/surgical wards instead of transferring them to the ICU per prior standard of care. Nasal high flow therapy was initiated either in the emergency department or on the medical/surgical wards. Patients were matched with historical cohorts who were managed with prior standard of care based on age, body mass index, comorbidities, and home oxygen use. Primary outcome of interest was difference in rates of mechanical ventilation. Secondary outcomes included hospital length of stay, total number of days spent in the intensive care unit, and in-hospital mortality. A total of 90 patients met study inclusion criteria and were matched to 90 historical control patients. Among the study group, 8% required mechanical ventilation versus 9% in the control group (p = 0.79). Hospital length of stay was 7 days in study group versus 6 days in control group (p = 0.02), and in-hospital mortality was the same in both study and control groups at 12% (p = 0.99). Nineteen percent of study group patients required ICU level of care at any time during the admission compared with 49% of control group (p

Robert Shapiro,1,2 Alec Sunyecz,3 Stanley Zaslau,1,2 Manuel C Vallejo,1,4 Tyler Trump,2 Omar Dueñas-Garcia1 1Department of Obstetrics and Gynecology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA; 2Department of Urology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA; 3West Virginia University School of Medicine, Morgantown, WV, 26506, USA; 4Department of Anesthesiology, West Virginia University School of Medicine, Morgantown, WV, 26506, USACorrespondence: Robert ShapiroHealth Science Center North, West Virginia University, PO Box 9001A, Morgantown, WV, 26506, USATel +1 304-293-5631Fax +1 304-293-5160Email rshapiro@hsc.wvu.eduBackground: In this study, we aim to compare outcomes after cystotomy repair between standard sutures (910 polyglactin, poliglecaprone) versus barbed (V-LocTM 90) suture. As a secondary outcome, we analyzed factors for suture preference between the two groups.Methods: A retrospective chart review was undertaken for surgeries complicated by cystotomy, identified by ICD-9/10 codes from 2016 to 2019 at West Virginia University (WVU) Hospital. Comparisons were made between cystotomy repair using barbed suture versus standard braided suture. Injuries were categorized by procedure, surgical route, type of suture used in repair, and subsequent complications related to repair. Primary endpoints were examined by Pearson’s Chi-square test and interval data by t-test. A p < 0.05 was significant.Results: Sixty-eight patients were identified with iatrogenic cystotomy at WVU. Barbed suture was used for cystotomy repair in 11/68 (16.2%) patients. No significant difference was seen in postoperative outcomes between patients repaired with barbed suture versus standard braided suture. Barbed suture was significantly more likely to be used for cystotomy repair in minimally invasive surgery (p = 0.001). It was most often utilized in a robotic approach 7/11 (63.6%) followed by laparoscopic 3/11 (27.3%). Body mass index (BMI) was significantly higher in patients receiving a barbed suture repair (p = 0.005).Conclusion: Barbed suture may be comparable to standard braided suture for cystotomy repair. Barbed suture may offer a practical alternative to facilitate cystotomy repair in minimally invasive surgery, especially in patients with a high BMI.Keywords: barbed suture, cystotomy, minimally invasive surgery, obesity

Background Awake prone positioning (APP) is widely used in the management of patients with coronavirus disease (COVID-19). The primary objective of this study was to compare the outcome of COVID-19 patients who received early versus late APP. Methods Post hoc analysis of data collected for a randomized controlled trial (ClinicalTrials.gov NCT04325906). Adult patients with acute hypoxemic respiratory failure secondary to COVID-19 who received APP for at least one hour were included. Early prone positioning was defined as APP initiated within 24 h of high-flow nasal cannula (HFNC) start. Primary outcomes were 28-day mortality and intubation rate. Results We included 125 patients (79 male) with a mean age of 62 years. Of them, 92 (73.6%) received early APP and 33 (26.4%) received late APP. Median time from HFNC initiation to APP was 2.25 (0.8–12.82) vs 36.35 (30.2–75.23) hours in the early and late APP group (p p p = 0.039), but no difference was found in intubation rate. Advanced age (OR 1.12 [95% CI 1.0–1.95], p = 0.001), intubation (OR 10.65 [95% CI 2.77–40.91], p = 0.001), longer time to initiate APP (OR 1.02 [95% CI 1.0–1.04], p = 0.047) and hydrocortisone use (OR 6.2 [95% CI 1.23–31.1], p = 0.027) were associated with increased mortality. Conclusions Early initiation ( Trial registration ClinicalTrials.gov NCT04325906.

Background Awake prone positioning (APP) has been advocated to improve oxygenation and prevent intubations of patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). This paper aims to synthesize the available evidence on the efficacy of APP.Methods: We performed a systematic review of proportional outcomes from observational studies to compare intubation rate in patients treated with APP or with standard care.Results: A total of 46 published and 4 unpublished observational studies that included 2994 patients were included, of which 921 patients were managed with APP, and 870 patients were managed with usual care. APP was associated with significant improvement of oxygenation parameters in 381 cases of 19 studies that reported this outcome. Among the 41 studies assessing intubation rates (870 patients treated with APP, and 852 patients treated with usual care), the intubation rate was 27%(95%CI, 19 to 37%), as compared to 30%(95%CI, 20 to 42%)(p=0.71), even when duration of application, use of adjunctive respiratory assist device (high flow nasal cannula or non-invasive ventilation) and severity of oxygenation deficit were taken into account. There appeared to be a trend toward improved mortality when treated with APP was compared with usual care (11% v.s. 22%), which was not statistically significant.Conclusions: APP was associated with improvement of oxygenation but did not reduce the intubation rate in patients with acute respiratory failure due to COVID-19. This finding is limited by the high heterogeneity and the observational nature of included studies. Randomized controlled clinical studies are needed to definitively assess whether APP could improve key outcome such as intubation and mortality rate in these patients.

Jeffrey C Cegan,1 Benjamin D Trump,1 Susan M Cibulsky,2 Zachary A Collier,3 Christopher L Cummings,4 Scott L Greer,5 Holly Jarman,5 Kasia Klasa,1,5 Gary Kleinman,2 Melissa A Surette,6 Emily Wells,1 Igor Linkov1 1US Army Engineer Research and Development Center, US Army Corps of Engineers, Vicksburg, MS, USA; 2US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Boston, MA, USA; 3Radford University, Davis College of Business and Economics, Department of Management, Radford, VA, USA; 4North Carolina State University, Genetic Engineering and Society Center, Raleigh, NC, USA; 5University of Michigan, School of Public Health, Department of Health Management and Policy, Ann Arbor, MI, USA; 6Federal Emergency Management Agency, Region I, Boston, MA, USACorrespondence: Jeffrey C Cegan; Igor LinkovUS Army Engineer Research and Development Center, US Army Corps of Engineers, 696 Virginia Road, Concord, MA, 01742, USATel +1-978-318-8881; +1-617-233-9869Email Jeffrey.C.Cegan@usace.army.mil; Igor.Linkov@usace.army.milAbstract: Many efforts to predict the impact of COVID-19 on hospitalization, intensive care unit (ICU) utilization, and mortality rely on age and comorbidities. These predictions are foundational to learning, policymaking, and planning for the pandemic, and therefore understanding the relationship between age, comorbidities, and health outcomes is critical to assessing and managing public health risks. From a US government database of 1.4 million patient records collected in May 2020, we extracted the relationships between age and number of comorbidities at the individual level to predict the likelihood of hospitalization, admission to intensive care, and death. We then applied the relationships to each US state and a selection of different countries in order to see whether they predicted observed outcome rates. We found that age and comorbidity data within these geographical regions do not explain much of the international or within-country variation in hospitalization, ICU admission, or death. Identifying alternative explanations for the limited predictive power of comorbidities and age at the population level should be considered for future research.Keywords: comorbidity, health outcomes, COVID-19, mortality rates

The SARS-CoV-2 virus is responsible for the novel coronavirus disease 2019 (COVID-19), which continues to spread to populations throughout the continental United States. Most state and local governments have adopted some level of “social distancing” policy, but infections have continued to spread despite these efforts. Absent a vaccine, authorities have few other tools by which to mitigate further spread of the virus. This begs the question of how effective social policy really is at reducing new infections that, left alone, would likely overwhelm the existing hospitalization capacity of many states. We developed a mathematical model that captures correlations between state-level “social distancing” policies and infection kinetics for all U.S. states, and use it to illustrate the link between social policy decisions, disease dynamics, and an effective reproduction number that changes over time, for case studies of Massachusetts, New Jersey, and Washington states. In general, our findings indicate that the potential for second waves of infection, which result after reopening states without an increase to immunity, can be mitigated by a return of social distancing policies as soon as possible after the waves are detected.

American Indian/Alaska Native (AI/AN) populations have proven particularly susceptible to the opioid crisis in the USA, but the White House’s 2019 national opioid policy roadmap is not structured to address AI/AN vulnerabilities. The concept of resilience, usually considered a positive system attribute, can be applied to complex systems to understand the larger compensatory interactions that restore systems to previous structures despite disruptions or interventions. The opioid crisis is a case of detrimental resilience because even effective interventions have not succeeded in eradicating opioid abuses. Resilience-based systemic interventions are needed to disrupt various aspects of systems while enhancing the social and cognitive abilities of affected populations to withstand the threat. This paper examines community characteristics, healthcare, and law enforcement within the context of AI/AN populations to emphasize the mechanisms that promote undesirable resilience for the opioid crisis. A research agenda bringing together systems science and management is needed to coordinate sectoral interventions and establish strategies to disrupt the resilient cycle of opioid addiction.

Introduction The phosphodiesterase inhibitors theophylline and pentoxifylline have anti‐inflammatory properties that may make them useful in COVID‐19 pneumonia. We conducted a retrospective review of hospitalized COVID‐19 patients requiring oxygen who received these drugs. Objectives To examine the potential efficacy and safety of theophylline and pentoxifylline in COVID‐19 pneumonia patients. Methods Adults with a positive test for SARS‐COV2 and were hospitalized due to pneumonia requiring either high flow nasal cannula or mechanical ventilation were included. Patients with a history of asthma or chronic obstructive pulmonary disease were preferentially given theophylline. All other patients received pentoxifylline 400 mg orally TID. A group of hospitalized COVID‐19 patients receiving standard of care acted as a comparison group. The coprimary outcomes were a change in C‐reactive protein (CRP) and ROX score between groups from day 1 to day 4 of therapy. Results Two hundred and nine inpatients were reviewed. Fifty‐eight patients received pentoxifylline/theophylline, with 151 patients serving as the comparison group. Active therapy was associated with an increase in the ROX score (mean: 2.9 (95% CI: 0.6, 5.1)) and decrease in CRP (mean: −0.7 (95% CI: −4.7, 3.2). Mortality rates were theophylline/pentoxifylline 24% and comparison group had a 26%, respectively. Conclusion In this retrospective study, theophylline and pentoxifylline were associated with an increase in ROX score and nominal decreases in CRP and mortality. Treatment was safe with few adverse reactions documented. We believe that this study could the basis for randomized‐controlled trials to further explore these drugs’ role in COVID‐19.

Summary Background Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov , NCT04325906 , NCT04347941 , NCT04358939 , NCT04395144 , NCT04391140 , and NCT04477655 . Findings Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75−0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62−0·91), and the HR for mortality was 0·87 (0·68−1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. Interpretation Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. Funding Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interregional, Appel d'Offre 2020, Groupement Interregional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion a Tours de la Reanimation Medicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd.

Robert Shapiro,1,2 Omar Felipe Dueñas-Garcia,1 Manuel Vallejo,1 Tyler Trump,2 Makenzy Sufficool,3 Stanley Zaslau1,2 1Department of Obstetrics & Gynecology, West Virginia University School of Medicine, Morgantown, WV 26506, USA; 2Department of Urology, West Virginia University School of Medicine, Morgantown, WV 26506, USA; 3West Virginia University School of Medicine, Morgantown, WV 26506, USACorrespondence: Robert ShapiroDepartment of Obstetrics & Gynecology, West Virginia University School of Medicine, Morgantown, WV 26506, USAEmail rshapiro@hsc.wvu.eduIntroduction: Patients may develop recurrent urinary tract infections, pain syndromes, dyspareunia, and voiding difficulty after mid-urethral sling placement that can be treated by partial sling excision.Objective: The primary objective of this study was to evaluate the incidence of de novo incontinence and voiding difficulty after partial sling excision. A secondary objective was to assess risk factors associated with future incontinence surgery in this subset of patients.Methods: From 2009 to 2017, 95 female patients with subjective complaints of pelvic pain, dyspareunia, or voiding difficulty following synthetic mid-urethral sling placement for stress urinary incontinence underwent partial sling excision at a single institution. The incidence of urinary incontinence was assessed 6 months after partial sling excision. Patients were also assessed for resolution of voiding difficulty and future incontinence surgery. Primary endpoints were examined by Pearson’s Chi-square test and interval data by t-test. A p < 0.05 was significant.Results: About 72% of patients were more likely to be continent after partial sling excision irrespective of initial symptoms prior to surgery. No difference was seen in voiding difficulty between the continent and incontinent patients after partial sling excision (p=0.09). Patients with a retropubic mid-urethral sling were more likely to be continent after partial sling excision (p=0.03). Preoperative maximum flow rate > 16 mL/sec was associated as an independent variable to develop incontinence surgery after partial sling excision (p=0.009).Conclusion: In conclusion, partial sling excision poses a low risk for de novo urinary incontinence regardless of preoperative symptoms. Stress urinary incontinence may be less likely to reoccur in those patients having a retropubic approach. A preoperative maximum flow rate of > 16 mL/sec is a risk factor for future incontinence surgery after partial sling excision and should be taken into consideration when formulating a treatment plan.Keywords: sling excision, mesh, incontinence, mid-urethral sing

Brain metastases are rarely observed in urothelial cancers but confer a uniformly poor prognosis. We sought to evaluate the clinical characteristics and course of brain metastases in four patients with primary urothelial cancer with secondary molecular brain tumor characterization available in 3 patients. Mean age was 68 years. Three of the patients were men. Two patients had both primary upper tract and bladder urothelial cancers, and two had bladder cancer alone. Three patients had initial nephroureterectomy and/or radical cystectomy, with subsequent development of initial distant metastasis at a median of 7.9 months. All four patients received platinum-based systemic therapy following initial metastasis. Median onset of brain metastasis from initial distant metastasis was 11.5 months. Median overall survival (OS) from the diagnosis of brain metastasis was 6 months (range: 3.1 – 12.8 months). Three patients who had comprehensive somatic tumor profiling of the brain metastasis using the Oncomine® panel showed mutations in the APC, TP53, and FGFR3 genes, loss of function in TP53 and BRCA-2, and deletion of MHS2. Our findings suggest brain metastases is a uniformly fatal diagnosis and a need for future exploration of primary tumor and metastatic sequencing in order to better define the role of current therapies for metastatic brain urothelial cancers which remains an area of increased unmet need.

An innovative form of Fisher ratio (F-ratio) analysis (FRA) is developed for use with comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC × GC-TOFMS) data and applied to the investigation of the changes in the metabolome in human plasma for patients with injury to their anterior cruciate ligament (ACL). Specifically, FRA provides a supervised discovery of metabolites that express a statistically significant variance in a two-sample class comparison: patients and healthy controls. The standard F-ratio utilizes the between-class variance relative to the pooled within-class variance. Because standard FRA is adversely impacted by metabolites expressed with a large within-class variance in the patient class, "control-normalized FRA" has been developed to provide complementary information, by normalizing the between-class variance to the variance of the control class only. Thirty plasma samples from patients who recently suffered from an ACL injury, along with matched controls, were subjected to GC × GC-TOFMS analysis. Following both standard and control-normalized FRA, the concentration ratio for the top 30 "hits" in each comparison was obtained and then t-tested for statistical significance. Twenty four out of 30 metabolites plus the therapeutic agent, naproxen (24/30), passed the t-test for the control-normalized FRA, which included 8/24 unique to control-normalized FRA and 16/24 in common with the standard FRA. Likewise, standard FRA provided 21/30 metabolites passing the t-test, with 5/21 undiscovered by control-normalized FRA. The complementary information obtained by both F-ratio analyses demonstrates the general utility of the new approach for a variety of applications.

People prefer to experience pleasant (vs. unpleasant) emotions and thus will take actions to repair unpleasant emotions. In addition, consumers perceive brands as possessing personality characteristics. This research demonstrates that consumers experiencing unpleasant emotions are attracted to brands with opposing, pleasant personalities as a means to repair their emotions. Studies 1a and 1b find that consumers respond more favorably to an exciting brand when they are motivated to repair the unpleasant emotional state of boredom (1a) and that a reduction in boredom in response to the exciting brand drives this effect (1b). Study 2 extends this finding by showing that anxious consumers are motivated to respond more favorably to a calm brand to repair their anxiety. In both cases, the effects only hold when participants are not first given the opportunity to alleviate their unpleasant emotion, thus providing evidence that motivation is the process driving consumers to respond more favorably to brands with pleasant personalities.

BACKGROUND: High-flow nasal cannula (HFNC) is an option for respiratory support in patients with acute hypoxic respiratory failure. To improve patient outcomes, reduce ICU-associated costs, and ease ICU bed availability, a multi-phased, comprehensive strategy was implemented to make HFNC available outside the ICU under the supervision of pulmonology or trauma providers in cooperation with a dedicated respiratory therapy team. The purpose of this study was to describe the education and implementation process for initiating HFNC therapy outside the ICU and to convey key patient demographics and outcomes from the implementation period. METHODS: HFNC therapy was implemented at a tertiary hospital in the Midwest, with systematic roll-out to all in-patient floors over a 9-month period. Utilization of the therapy and patient outcomes were tracked to ensure safety and efficacy of the effort. RESULTS: During the implementation period, 346 unique subjects met study inclusion criteria. Median (interquartile range) hospital length of stay was 8 d (4–12), and median duration of HFNC therapy was 44 h (18–90). Two thirds of subjects (n = 238) received the entire course of HFNC therapy outside the ICU, and more than half of subjects (n = 184) avoided the ICU for their entire hospitalization. Moreover, 6% of subjects in the study group escalated from HFNC to noninvasive ventilation, and 5% of subjects escalated from HFNC to mechanical ventilation. CONCLUSIONS: A comprehensive implementation process and a robust therapy protocol were integral to initiating and managing HFNC in all hospital locations. Study findings indicate that patients with acute hypoxic respiratory failure can safely receive HFNC therapy outside the ICU with appropriate patient selection and staff education.

Ru-HKUST-1 (Ru3(btc)2X1.5; btc3– = 1,3,5-benzenetricarboxylate; X– = chloride, acetate, trimesate, hydroxide) has received considerable attention as a result of its structure type, tunability, and ...

Prior research in the behavioral sciences has demonstrated that reminders can be an effective tool for encouraging health-related behavior changes. This article extends that literature by reporting the outcome of a randomized controlled trial of mailed vaccination reminders. In addition to making a substantive contribution regarding the efficacy of mailed reminders, this article also makes a methodological contribution: it illustrates how researchers can study the causal impact of an intervention even when a pure parallel trial is not possible. In this study, the Louisiana Department of Health sent postcard reminders regarding four recommended vaccinations (influenza, tetanus, shingles and pneumonia) to 208,867 senior residents of Louisiana. We used block randomization and a stepped wedge design to assess the efficacy of the intervention. Individuals were blocked by their prior vaccine record and randomized to receive the postcard in one of four consecutive months (October–January). The reminder postcard had an overall positive effect on vaccination rates. The statistically significant and substantively small increase in overall vaccination rates was driven by participants who received the postcard reminder early in the intervention period.

Context Military service members commonly sustain lower extremity stress fractures (SFx). How SFx risk factors influence bone metabolism is unknown. Understanding how SFx risk factors influence bone metabolism may help to optimize risk-mitigation strategies. Objective To determine how SFx risk factors influence bone metabolism. Design Cross-sectional study. Setting Military service academy. Patients or Other Participants Forty-five men (agepre = 18.56 ± 1.39 years, heightpre = 176.95 ± 7.29 cm, masspre = 77.20 ± 9.40 kg; body mass indexpre = 24.68 ± 2.87) who completed Cadet Basic Training (CBT). Individuals with neurologic or metabolic disorders were excluded. Intervention(s) We assessed SFx risk factors (independent variables) with (1) the Landing Error Scoring System (LESS), (2) self-reported injury and physical activity questionnaires, and (3) physical fitness tests. We assessed bone biomarkers (dependent variables; procollagen type I amino-terminal propeptide [PINP] and cross-linked collagen telopeptide [CTx-1]) via serum. Main Outcome Measure(s) A markerless motion-capture system was used to analyze trunk and lower extremity biomechanics via the LESS. Serum samples were collected post-CBT; enzyme-linked immunosorbent assays determined PINP and CTx-1 concentrations, and PINP : CTx-1 ratios were calculated. Linear regression models demonstrated associations between SFx risk factors and PINP and CTx-1 concentrations and PINP : CTx-1 ratio. Biomarker concentration mean differences with 95% confidence intervals were calculated. Significance was set a priori using α ≤ .10 for simple and α ≤ .05 for multiple regression analyses. Results The multiple regression models incorporating LESS and SFx risk factor data predicted the PINP concentration (R2 = 0.47, P = .02) and PINP : CTx-1 ratio (R2 = 0.66, P = .01). The PINP concentration was increased by foot internal rotation, trunk flexion, CBT injury, sit-up score, and pre- to post-CBT mass changes. The CTx-1 concentration was increased by heel-to-toe landing and post-CBT mass. The PINP : CTx-1 ratio was increased by foot internal rotation, lower extremity sagittal-plane displacement (inversely), CBT injury, sit-up score, and pre- to post-CBT mass changes. Conclusions Stress fracture risk factors accounted for 66% of the PINP : CTx-1 ratio variability, a potential surrogate for bone health. Our findings provide insight into how SFx risk factors influence bone health. This information can help guide SFx risk-mitigation strategies.

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state. Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.

The fast‐paced field of synthetic biology is fundamentally changing the global biosecurity framework. Current biosecurity regulations and strategies are based on previous governance paradigms for pathogen‐oriented security, recombinant DNA research, and broader concerns related to genetically modified organisms (GMOs). Many scholarly discussions and biosecurity practitioners are therefore concerned that synthetic biology outpaces established biosafety and biosecurity measures to prevent deliberate and malicious or inadvertent and accidental misuse of synthetic biology's processes or products. This commentary proposes three strategies to improve biosecurity: Security must be treated as an investment in the future applicability of the technology; social scientists and policy makers should be engaged early in technology development and forecasting; and coordination among global stakeholders is necessary to ensure acceptable levels of risk., Biosecurity policies and practices must be updated to accommodate the novel challenges associated with synthetic biology and to maximize technological benefits while minimizing its dual‐use potential. This Commentary proposes three strategies to improve biosecurity.

Our previous studies demonstrated that resolvin D1 (RvD1) and its aspirin-trigged (AT) form AT-RvD1, are effective in decreasing inflammation while restoring saliva flow rates in a Sjogren's syndrome (SS) like mouse model before and after disease onset. Resolvins are specialized pro-resolving mediators (SPM) that actively regulate inflammation. However, we only have extensive data within the salivary glands for RvD1 and AT-RvD1, both of which bind to the receptor ALX/FPR2. As such, the presence of other SPM receptors is unknown within salivary glands. Therefore, the goal of this study was to determine the expression of SPM receptors in non-SS and SS patients. For this purpose, six human minor salivary glands from female subjects were analyzed by H&E using the Chisholm and Mason classification to determine the degree of lymphocytic infiltration. Next, confocal immunofluorescence analysis was performed to determine the presence and distribution of different SPM receptors in mucous acini and striated ducts. We observed diffuse presence of lymphocytic infiltration and clinical data were consistent with SS diagnosis in three patients. Moreover, confocal immunofluorescence analysis indicated the presence of the receptors ALX/FPR2, BLT1 and CMKLR1 in the mucous acini and striated ducts of both non-SS and SS patients. GPR32 was absent in SS and non-SS minor salivary glands. In summary, our results showed that various SPM receptors are expressed in non-SS and SS minor salivary glands, all of which may pose as potential targets for promoting pro-epithelial and anti-inflammatory/pro-resolution signaling on SS patients.

Background Because of their direct patient contact, healthcare workers (HCW) face an unprecedented risk of exposure to COVID-19. The aim of this study was to examine incidence of COVID-19 disease among asymptomatic HCW and community participants in Northern Virginia during 6 months of follow-up. Methods This is a prospective cohort study that enrolled healthy HCW and residents who never had a symptomatic COVID-19 infection prior to enrolment from the community in Northern Virginia from April to November 2020. All participants were invited to enrol in study, and they were followed at 2-, and 6-months intervals. Participants were evaluated by commercial chemiluminescence SARS-CoV-2 serology assays as part of regional health system and public health surveillance program to monitor the spread of COVID-19 disease. Findings Of a total of 1,819 asymptomatic HCW enrolled, 1,473 (96%) had data at two-months interval, and 1,323 (73%) participants had data at 6-months interval. At baseline, 21 (1.15%) were found to have prior COVID-19 exposure. At two-months interval, COVID-19 rate was 2.8% and at six months follow-up, the overall incidence rate increased to 4.8%, but was as high as 7.9% among those who belong to the youngest age group (20–29 years). Seroconversion rates in HCW were comparable to the seropositive rates in the Northern Virginia community. The overall incidence of COVID-19 in the community was 4.5%, but the estimate was higher among Hispanic ethnicity (incidence rate = 15.3%) potentially reflecting different socio-economic factors among the community participants and the HCW group. Using cross-sectional logistic regression and spatio-temporal mixed effects models, significant factors that influence the transmission rate among HCW include age, race/ethnicity, resident ZIP-code, and household exposure, but not direct patient contact. Interpretation In Northern Virginia, the seropositive rate of COVID-19 disease among HCW was comparable to that in the community.

Background We sought to determine if participating in a surgical training session using perfused fresh human cadavers (PFHC) had a positive effect on urology residents’ confidence in performing open and endoscopic procedures. Methods Urology residents at our institution participated in a surgical training session in the West Virginia University Fresh Tissue Training Program, which utilized fresh cadavers with vascular perfusion. The session consisted of performing different urologic procedures (open and endoscopic) on the perfused fresh human cadavers (PFHC). Residents were given a survey to rate their confidence in different urologic procedures before, after, and 6 months after the session. Each procedure on the survey had 3–6 questions associated with it, with scores ranging from 0 (no confidence) to 4 (great confidence). Scores for each procedure before and after the session were compared. Results Six residents participated in the session. There was an increase in the score for every procedure performed after the session. Scores at 6 month follow up remained higher than the pre-session scores. Conclusion PFHCs offer an excellent opportunity to teach a wide variety of urologic procedures to residents. Incorporation of PFHCs may be very useful in urologic training, and further studies on its use are warranted.

Previous studies demonstrated that salivary gland morphogenesis and differentiation are enhanced by modification of fibrin hydrogels chemically conjugated to Laminin-1 peptides. Specifically, Laminin-1 peptides (A99: CGGALRGDN-amide and YIGSR: CGGADPGYIGSRGAA-amide) chemically conjugated to fibrin promoted formation of newly organized salivary epithelium bothin vitro(e.g.,using organoids) andin vivo(e.g.,in a wounded mouse model). While these studies were successful, the model’s usefulness for inducing regenerative patterns after radiation therapy remains unknown. Therefore, the goal of the current study was to determine whether transdermal injection with the Laminin-1 peptides A99 and YIGSR chemically conjugated to fibrin hydrogels promotes tissue regeneration in irradiated salivary glands. Results indicate that A99 and YIGSR chemically conjugated to fibrin hydrogels promote formation of functional salivary tissue when transdermally injected to irradiated salivary glands. In contrast, when left untreated, irradiated salivary glands display a loss in structure and functionality. Together, these studies indicate that fibrin hydrogel-based implantable scaffolds containing Laminin-1 peptides promote secretory function of irradiated salivary glands.

INTRODUCTION AND OBJECTIVE:Prostate cancer (PC) provides an opportunity for secondary chemoprevention in men diagnosed with National Comprehensive Cancer Network very low, low, or favorable interme...

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Intrinsic and/or acquired resistance to cisplatin is a significant obstacle in the treatment of muscle-invasive bladder cancer. p73, a p53 homolog and determinant of chemosensitivity, is rarely mutated in bladder cancer (BC). However p73 expression and therefore function can be repressed through epigenetic changes. In this study, we sought to identify DNA methylation status of p73, expression of TAp73 isoform, and their role in cisplatin sensitivity in BC. Primary tumor samples from 338 bladder cancer patients showed decreased TAp73 expression in MIBC compared to superficial BC. Low TAp73 protein expression was associated with shorter overall survival. To investigate if the loss of expression was methylation dependent, we utilized Illumina 450K methylation arrays to interrogate over 150 BC patient samples. We found 12 distinct CpGs in the p73 gene locus that were hypermethylated in tumors compared to adjacent normal tissues. Patients with high p73 promoter methylation specifically at CpG site cg07382920 had worse survival. In vitro, treatment with a DNA demethylating agent, decitabine (DAC), decreased TAp73 methylation and upregulated expression in both CR-T24 (cisplatin resistant T24 cells) and wild type T24 cells. Furthermore, treatment with DAC increased cisplatin response in wild type T24 and CR-T24. Our studies indicate that TAp73 expression and P1 promoter methylation, specifically at the cg073892920 site, may have prognostic and diagnostic value in MIBC. In the setting of P1 promoter hypermethylation, DAC could be used as a potentiating agent of cisplatin-based chemotherapy.

Background Vitamin D3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin-based chemotherapy, however 30%-50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown. Methods To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D3 (1,25D3 ). Lastly, using BCa cell lines, T24 and RT-112, the mechanism of action of 1,25D3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT-PCR. Results In this study, we determined that low serum 25 hydroxyvitamin D3 (25D3 ) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3 , reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro-apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 and cisplatin in a TAp73 dependent manner. Conclusions Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.

Purpose We describe the use of liposomal amphotericin B and amphotericin B deoxycholate in a critically ill patient with pulmonary blastomycosis receiving both venovenous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Summary A 50-year-old African American man presented for dyspnea and cough and was noted to have blastomycosis on bronchoscopy. He developed respiratory failure and acute kidney injury, requiring mechanical ventilation, ECMO, and CRRT. After 4 days of liposomal amphotericin, the transmembrane pressure gradient on the membrane oxygenator increased dramatically without visualization of a clot, requiring a circuit exchange. A trough amphotericin B level taken the day before the exchange was undetectable for amphotericin B. After the circuit exchange, the patient was switched to amphotericin B deoxycholate. A subsequent trough level was 3.8 μg/mL. The patient improved and was able to be decannulated. However, he did require tracheostomy and long-term hemodialysis. Conclusion In our case we believe that liposomal amphotericin B was significantly removed by ECMO and was responsible for the failure of the ECMO circuit. We would suggest amphotericin B deoxycholate be used in such patients preferentially and that serum levels of the drug be assessed when possible.

Bacterial and fungal infections are a major cause of morbidity and mortality in neutropenic patients. Donor-derived neutrophil transfusions have been used for prophylaxis or treatment for infection in neutropenic patients. However, the short half-life and the limited availability of large numbers of donor-derived neutrophils for transfusion remain a significant hurdle in the implementation of neutrophil transfusion therapy. Here, we investigate the in vitro and in vivo activity of neutrophils generated from human induced pluripotent stem cells (iPSC), a potentially unlimited resource to produce neutrophils for transfusion. Phenotypic analysis of iPSC-derived neutrophils reveal reactive oxygen species production at similar or slightly higher than normal peripheral blood neutrophils, but have an ∼50%–70% reduced Escherichia coli phagocytosis and phorbol 12-myristate 13-acetate induced formation of neutrophil extracellular traps (NET). Signaling of granulocytic precursors identified impaired AKT activation, but not ERK or STAT3, in agonist-stimulated iPSC-derived neutrophils. Expression of a constitutively activated AKT in iPSC-derived neutrophils restores most phagocytic activity and NET formation. In a model of bacterial induced peritonitis in immunodeficient mice, iPSC-derived neutrophils, with or without corrected AKT activation, migrate similarly to the peritoneal fluid as peripheral blood neutrophils, whereas the expression of activated AKT significantly improves their phagocytic activity in vivo. Stem Cells Translational Medicine 2019;8:557–567

Tyler Trump,1 Amr A Elbakry,1 Ahmad Haffar,2 Daniel McClelland,1 Chad Morley,1 Osama Al-Omar1 1West Virginia University Department of Urology, Morgantown, WV, USA; 2West Virginia University School of Medicine, Morgantown, WV, USACorrespondence: Tyler Trump Tel +1 304-575-6976Email ttrump@hsc.wvu.eduBackground: The American Urological Association published guidelines in 2014 regarding management of undescended testicles (UDT). Despite these guidelines, prior studies have indicated discordance between guidelines and actual practice, especially in rural states. This study aims to identify if educating referring providers improves management of UDT.Methods: Patients with UDT referred to our institution were divided into two groups: those referred prior to (Group 1) and after (Group 2) targeted education. A retrospective review was performed to compare the groups in terms of age at time of referral and surgery, laterality, specialty, and practice setting of referring provider, and whether or not ultrasound (US) was performed prior to referral.Results: A total of 100 patients were identified in Group 1 and 168 in Group 2. No significant differences were noted between groups regarding age, variability of referring provider, or those receiving US prior to referral. Median age at referral was 20.7 months (range=0– 194) and 33 months (range=0– 205.1) in Groups 1 and 2, respectively (p=0.26). Sixty-two (37%) patients underwent surgical evaluation within 18 months of age or younger in Group 1 compared to 39 (39%) in Group 2 (p=0.73). Private practice pediatricians comprised the majority of referring providers in both cohorts. US was performed prior to referral in 41% of patients in Group 1 compared to 35.8% in Group 2 (p=0.51). The number of US ordered prior to referral significantly decreased from 10 (50%) to six (19%) following education among academic providers (p=0.02). No significant difference was found following education for private practice physicians (p=0.27).Conclusion: Targeted education did not improve age at referral in the short-term, which may reflect suboptimal healthcare access. Additionally, more research is needed to evaluate whether more diverse targeted education provided on a regular basis to both physician and mid-level providers would have a meaningful impact.Keywords: undescended testicle, guideline adherence, orchidopexy

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults. Single-cell sequencing reveals pre-activated immunity as important for milder COVID-19 symptoms in children.

Background Parabens, widely used as preservatives in cosmetics, foods, and other consumer products, are suspected of contributing to allergy susceptibility. The detection of parabens in the placenta or amniotic fluid raised concerns about potential health consequences for the child. Recently, an increased asthma risk following prenatal exposure has been reported. Here, we investigated whether prenatal paraben exposure can influence the risk for atopic dermatitis (AD). Methods 261 mother-child pairs of the German mother-child study LINA were included in this analysis. Eight paraben species were quantified in maternal urine obtained at gestational week 34. According to the parental report of physician-diagnosed AD from age 1 to 8 years, disease onset, and persistence, childhood AD was classified into four different phenotypes. Results 4.6% (n = 12) and 12.3% (n = 32) of the children were classified as having very early-onset AD (until age two) either with or without remission, 11.9% (n = 31) as early-onset (after age two), and 3.1% (n = 8) as childhood-onset AD (after age six). Exposure to ethylparaben and n-butylparaben was associated with an increased risk to develop very early-onset AD without remission (EtP: adj.OR/95% CI:1.44/1.04-2.00,nBuP:adj.OR/95% CI:1.95/1.22-3.12). The effects of both parabens were predominant in children without a history of maternal AD and independent of children's sex. Conclusion Prenatal EtP or nBuP exposure may increase children's susceptibility for persistent AD with disease onset at very early age. This association was particularly pronounced in children without a history of maternal AD, indicating that children without a genetic predisposition are more susceptible to paraben exposure.

Background: Awake prone positioning (APP) has been advocated to improve oxygenation and prevent intubations of patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). This paper aims to synthesize the available evidence on the efficacy of APP. Methods: We performed a prospective systematic review and meta-analysis of observational studies to compare in-hospital intubation and mortality rates in patients treated with APP or with standard care.Results: A total of 46 published and 4 unpublished observational studies that included 2994 patients were included. The intubation rate was 27% (95%CI, 19 to 37%) in the 870 patients treated with APP, as compared to 30% (95%CI, 20 to 42%) in the 852 patients treated with usual care (p=0.71). The mortality rate was 11% (95CI%, 6 to 20%) in the 767 patients treated with APP, as compared to 22% (95%CI, 13 to 36%) in those treated with usual care. This difference was not statistically significant (p=0.10). APP was associated with significant improvement of various oxygenation parameters in 19 studies (n=381) that reported this outcome.Conclusions: In this prospective meta-analysis of observational studies of patients with acute hypoxemic respiratory failure due to COVID-19, APP did not result in lower intubation or mortality rates, despite reported improvements in oxygenation parameters. Data from randomized controlled trials are needed. Routine implementation of APP outside of a clinical trial is not supported by current evidence. Registered on PROSPERO on August 3d, 2020, CRD42020201947.

The novel coronavirus (COVID-19) has had sweeping consequences upon global societies, public health, and economies. It stubbornly persisted and spread throughout 2020, despite a range of policy and social response strategies from frontline global public health institutions and countries alike. Consequences of such policy responses will persist for years and even decades, reshaping both government practices and social behaviors. The responses and impacts from COVID will shape and influence the global order for collective responses to everything from public health issues to climate change. However, questions abound regarding how the public and private sectors might best anticipate similarly situated systemic risks and position society to better recover from and adapt to the “new normal” associated with rapid global change.

State governments in the U.S. have been facing difficult decisions involving tradeoffs between economic and health-related outcomes during the COVID-19 pandemic. Despite evidence of the effectiveness of government-mandated restrictions mitigating the spread of contagion, these orders are stigmatized due to undesirable economic consequences. This tradeoff resulted in state governments employing mandates in widely different ways. We compare the different policies states implemented during periods of restriction (lockdown) and reopening with indicators of COVID-19 spread and consumer card spending at each state during the first wave of the pandemic in the U.S. between March and August 2020. We find that while some states enacted reopening decisions when the incidence rate of COVID-19 was minimal or sustained in its relative decline, other states relaxed socioeconomic restrictions near their highest incidence and prevalence rates experienced so far. Nevertheless, all states experienced similar trends in consumer card spending recovery, which was strongly correlated with reopening policies following the lockdowns and relatively independent from COVID-19 incidence rates at the time. Our findings suggest that consumer card spending patterns can be attributed to government mandates rather than COVID-19 incidence in the states. We estimate the recovery in states that reopened in late April was more than the recovery in states that did not reopen in the same period - 15% for consumer card spending and 18% for spending by high income households. This result highlights the important role of state policies in minimizing health impacts while promoting economic recovery and helps planning effective interventions in subsequent waves and immunization efforts., Comment: Revised on October 4, 2021

The SARS-CoV-2 pandemic was an enormous challenge for risk communicators. From the basic life sciences questions regarding the viruses and its effects to the efficacy of associated interventions, communicators around the world had to compete with an endless array of hostile and inaccurate messaging – often within an environment of equally considerable uncertainty and urgency. There were many successes with such public engagement, but considerable opportunities to improve upon. This chapter discusses some of the causes of communication breakdowns, and describes how the corresponding social dilemmas and complexities of socioecological systems can be more effectively characterized and addressed for future crises.

Ureteroiliac artery fistulas are a rare, life-threatening condition that requires a high index of suspicion for prompt diagnosis. Presurgical diagnosis is challenging as this condition can lie hidden despite advanced imaging modalities. We present two cases of patients presenting with gross hematuria and exsanguination in the setting of a ureteroiliac artery fistula. These cases highlight the difficulties in timely diagnosis and treatment in a multidisciplinary team.

Summary Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling., Graphical Abstract, Highlights • G3BPs act non-redundantly in the TSC-mTORC1 signaling axis • G3BPs reside at the lysosomal surface and inhibit mTORC1 • The TSC complex requires G3BPs as its lysosomal tether • G3BP1 deficiency phenocopies TSC complex loss in cancer cells and neurons, Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.

The SARS-CoV-2 novel coronavirus 13 (COVID-19) pandemic has revealed the technical requirements needed to enhance scientific analysis and epidemic modelling, but also the social and institutional challenges of operating in a global crisis. The large-scale and turbulent nature of the pandemic has exemplified that healthcare and public health safety organizations resilience is critical for maintaining function and community support in times of crises with unclear outcomes and implications. Conceptualizations of organizational resilience need support swift organizational decision-making that simultaneously prepares for and responds to adverse events and system strains under uncertainty. This chapter presents a modelling approach towards bolstering organizational resilience for healthcare organizations facing COVID-19 called “real-time anticipatory response,” which considers how organizations concurrently prepare for and respond to the pandemic under conditions of high pressure and high uncertainty. The framework supports strategic planning based on limited information and immediate need for organizational response which can be applied to a vast array of natural disaster and other crises that require stakeholders to enact quick decisions that facilitate organizational preparation and response simultaneously

Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.

In COVID-19, hypertension and cardiovascular diseases have emerged as major risk factors for critical disease progression. Concurrently, the impact of the main anti-hypertensive therapies, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), on COVID-19 severity is controversially discussed. By combining clinical data, single-cell sequencing data of airway samples andin vitroexperiments, we assessed the cellular and pathophysiological changes in COVID-19 driven by cardiovascular disease and its treatment options. Anti-hypertensive ACEi or ARB therapy, was not associated with an altered expression of SARS-CoV-2 entry receptorACE2in nasopharyngeal epithelial cells and thus presumably does not change susceptibility for SARS-CoV-2 infection. However, we observed a more critical progress in COVID-19 patients with hypertension associated with a distinct inflammatory predisposition of immune cells. While ACEi treatment was associated with dampened COVID-19-related hyperinflammation and intrinsic anti-viral responses, under ARB treatment enhanced epithelial-immune cell interactions were observed. Macrophages and neutrophils of COVID-19 patients with hypertension and cardiovascular comorbidities, in particular under ARB treatment, exhibited higher expression ofCCL3, CCL4, and its receptorCCR1, which associated with critical COVID-19 progression. Overall, these results provide a potential explanation for the adverse COVID-19 course in patients with cardiovascular disease, i.e. an augmented immune response in critical cells for the disease course, and might suggest a beneficial effect of clinical ACEi treatment in hypertensive COVID-19 patients.

Vulnerable populations such as the uninsured, unemployed, and unhoused face significant morbidity and mortality from influenza but are less likely to receive the annual vaccine and have limited access to medical care. We describe an interprofessional, student-run vaccine outreach program (VOP) in Davidson County, Tennessee that lowers barriers to vaccination through free vaccination events in nontraditional community locations. We provide this framework as a model to expand novel, seasonal, or outbreak-oriented vaccine outreach to resource-poor populations. Demographic data were collected from the patients who received an influenza vaccine between 2015 and 2019 through an optional survey to determine whether these events were reaching unhoused, uninsured, and/or unemployed individuals. Of 1,803 patients, 1,733 (96.1%) completed at least one field of the demographic form. Overall, 481 (27.8%) were individuals without homes or living in temporary housing and 673 (38.8%) were unemployed. Most patients, 1,109 (64.0%), did not have health insurance at any point during the prior two years. With the addition of a nurse practitioner student to VOP leadership, the 2018-2019 VOP reached the most unhoused or temporarily-housed (228, 32.3%), unemployed (313, 18.5%), and disabled (60, 8.5%) patients. The VOP can be adapted to meet community needs, funding, and volunteer interest. The VOP model may be applicable to a SARS-CoV-2 vaccine, especially since the economic impact of COVID-19 has increased unemployment rates and housing instability. Healthcare students serve as an eager, underutilized resource who can be leveraged to disseminate vaccines to individuals with limited access to care.

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand–receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.