Hypobaria During Aeromedical Evacuation and Systemic Inflammation after Porcine Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is utilized by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation following TBI that could contribute to more severe TBI-related secondary injury. STUDY DESIGN: Thirty-six female pigs were used to test TBI vs. TBI sham, hypoxia vs. normoxia, and hypobaria vs. ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 feet were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, UCH-L1 and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein (GFAP) and phosphorylated tau (p-tau). RESULTS: Serum IL-1b, IL-6, and TNFα were significantly elevated following TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared to ground level/normoxia. No difference in TBI biomarkers following TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue GFAP or p-tau when comparing the most different conditions of sham TBI+ground/normoxia to the TBI+hypobaria/hypoxia group was noted. CONCLUSION: The hypobaric environment of AE induces systemic inflammation following TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE following TBI.

Re-Evaluating the Use of High Sensitivity Troponin to Diagnose Blunt Cardiac Injury.

INTRODUCTION: Blunt cardiac injury (BCI) can be challenging diagnostically, and if misdiagnosed, can lead to life-threatening complications. Our institution previously evaluated BCI screening with troponin and electrocardiogram (EKG) during a transition from troponin I to high sensitivity troponin (hsTnI), a more sensitive troponin I assay. The previous study found an hsTnI of 76 ng/L had the highest capability of accurately diagnosing a clinically significant BCI. The aim of this study was to determine the efficacy of the newly implemented protocol. METHODS: Patients diagnosed with a sternal fracture from March 2022 to April 2023 at our urban level-1 trauma center were retrospectively reviewed for EKG findings, hsTnI trend, echocardiogram changes, and clinical outcomes. The BCI cohort and non-BCI cohort ordinal measures were compared using Wilcoxon's two-tailed rank sum test and categorical measures were compared with Fisher's exact test. Youden indices were used to evaluate hsTnI sensitivity and specificity. RESULTS: Sternal fractures were identified in 206 patients, of which 183 underwent BCI screening. Of those screened, 103 underwent echocardiogram, 28 were diagnosed with clinically significant BCIs, and 15 received intervention. The peak hsTnI threshold of 76 ng/L was found to have a Youden index of 0.31. Rather, the Youden index was highest at 0.50 at 40 ng/L (sensitivity 0.79 and specificity 0.71) for clinically significant BCI. CONCLUSIONS: Screening patients with sternal fractures for BCI using hsTnI and EKG remains effective. To optimize the hsTnI threshold, this study determined the hsTnI threshold should be lowered to 40 ng/L. Further improvements to the institutional protocol may be derived from multicenter analysis.

Just Say NO: Inhaled Nitric Oxide Effect on Respiratory Parameters Following Traumatic Brain Injury in Humans and a Porcine Model.

INTRODUCTION: The mechanism of post-traumatic brain injury (TBI) hypoxemia involves ventilation/perfusion mismatch and loss of pulmonary hypoxic vasoconstriction. Inhaled nitric oxide (iNO) has been studied as an adjunct treatment to avoid the use of high positive end-expiratory pressure and inspired oxygen in treatment-refractory hypoxia. We hypothesized that iNO treatment following TBI would improve systemic and cerebral oxygenation via improved matching of pulmonary perfusion and ventilation. METHODS: Thirteen human patients with isolated TBI were enrolled and randomized to receive either placebo or iNO with measured outcomes including pulmonary parameters, blood gas data, and intracranial pressure (ICP) /perfusion. To complement this study, a porcine model of TBI (including 10 swine) was utilized with measured outcomes of brain tissue blood flow and oxygenation, ventilator parameters, and blood gas data both after administration and following drug removal and clearance. RESULTS: There were no clinically significant changes in pulmonary parameters in either the human or porcine arm following administration of iNO when compared to either the placebo group (human arm) or the internal control (porcine arm). Analysis of pooled human data demonstrated the preservation of alveolar recruitment in TBI patients. There were no clinically significant changes in human ICP or cerebral perfusion pressure following iNO administration compared to controls. CONCLUSIONS: iNO had no significant effect on clinically relevant pulmonary parameters or ICPs following TBI in both human patients and a porcine model. The pressure-based recruitment of the human lungs following TBI was preserved. Further investigation will be needed to determine the degree of utility of iNO in the setting of hypoxia after polytrauma.

Validation of Preload Assessment Technologies at Altitude in a Porcine Model of Hemorrhage.

INTRODUCTION: Dynamic preload assessment measures including pulse pressure variation (PPV), stroke volume variation (SVV), pleth variability index (PVI), and hypotension prediction index (HPI) have been utilized clinically to guide fluid management decisions in critically ill patients. These values aid in the balance of correcting hypotension while avoiding over-resuscitation leading to respiratory failure and increased mortality. However, these measures have not been previously validated at altitude or in those with temporary abdominal closure (TAC). METHODS: Forty-eight female swine (39 ± 2 kg) were separated into eight groups (n = 6) including all combinations of flight versus ground, hemorrhage versus no hemorrhage, and TAC versus no TAC. Flight animals underwent simulated aeromedical evacuation via an altitude chamber at 8000 ft. Hemorrhagic shock was induced via stepwise hemorrhage removing 10% blood volume in 15-min increments to a total blood loss of 40% or a mean arterial pressure of 35 mmHg. Animals were then stepwise transfused with citrated shed blood with 10% volume every 15 min back to full blood volume. PPV, SVV, PVI, and HPI were monitored every 15 min throughout the simulated aeromedical evacuation or ground control. Blood samples were collected and analyzed for serum levels of serum IL-1ß, IL-6, IL-8, and TNF-α. RESULTS: Hemorrhage groups demonstrated significant increases in PPV, SVV, PVI, and HPI at each step compared to nonhemorrhage groups. Flight increased PPV (P = 0.004) and SVV (P = 0.003) in hemorrhaged animals. TAC at ground level increased PPV (P < 0.0001), SVV (P = 0.0003), and PVI (P < 0.0001). When TAC was present during flight, PPV (P = 0.004), SVV (P = 0.003), and PVI (P < 0.0001) values were decreased suggesting a dependent effect between altitude and TAC. There were no significant differences in serum IL-1ß, IL-6, IL-8, or TNF-α concentration between injury groups. CONCLUSIONS: Based on our study, PPV and SVV are increased during flight and in the presence of TAC. Pleth variability index is slightly increased with TAC at ground level. Hypotension prediction index demonstrated no significant changes regardless of altitude or TAC status, however this measure was less reliable once the resuscitation phase was initiated. Pleth variability index may be the most useful predictor of preload during aeromedical evacuation as it is a noninvasive modality.

Co-producing Human and Animal Experimental Subjects: Exploring the Views of UK COVID-19 Vaccine Trial Participants on Animal Testing.

Preclinical (animal) testing and human testing of drugs and vaccines are rarely considered by social scientists side by side. Where this is done, it is typically for theoretically exploring the ethics of the two situations to compare relative treatment. In contrast, we empirically explore how human clinical trial participants understand the role of animal test subjects in vaccine development. Furthermore, social science research has only concentrated on broad public opinion and the views of patients about animal research, whereas we explore the views of a public group particularly implicated in pharmaceutical development: experimental subjects. We surveyed and interviewed COVID-19 vaccine trial participants in Oxford, UK, on their views about taking part in a vaccine trial and the role of animals in trials. We found that trial participants mirrored assumptions about legitimate reasons for animal testing embedded in regulation and provided insight into (i) the nuances of public opinion on animal research; (ii) the co-production of human and animal experimental subjects; (iii) how vaccine and medicine testing, and the motivations and demographics of clinical trial participants, change in an outbreak; and (iv) what public involvement can offer to science.

Predictive Value of Early Inflammatory Markers in Trauma Patients Based on Transfusion Status.

INTRODUCTION: Seven key inflammatory biomarkers were recently found to be associated with the risk of mortality in a multicenter study of massively transfused patients. The aim of this prospective single-center study was to determine which of these early inflammatory markers could predict 30-d mortality among all critically injured trauma patients. METHODS: Serum samples were collected at 6, 24, and 72 h from 238 consecutive patients admitted to the intensive care unit following traumatic injury. Inflammatory markers syndecan-1, eotaxin, IL-1ra, IL-6, IL-8, IL-10, IP-10, and MCP-1 were analyzed via multiplex enzyme-linked immunosorbent assay. Subgroup analysis was performed for patients undergoing massive transfusion (≥5 red blood cells), submassive transfusion (1-4 red blood cells), or no transfusion during the first 4 h postinjury. The primary outcome of 30-d survival was modeled as a function of each biomarker and confounders using repeat measures logistic regression. RESULTS: Patients had a median age of 51.3 y [33.7, 70.2], 70.6% were male, 17.4% experienced penetrating trauma, and had a median injury severity score of 22 [14, 33]. IL-1ra, IL-8, IL-10, and MCP-1 were significantly increased during the first 72 h in nonsurvivors (n = 31). Elevated IL-1ra, IL-8, IL-10, and MCP-1 at 6 h postinjury were associated with 30-d mortality. By contrast, serum syndecan-1 and eotaxin levels were not associated with mortality at any time point. IL-8 and lactate were increased at 6 h in 30-d nonsurvivors for patients receiving submassive transfusion (n = 78). CONCLUSIONS: Early evaluations of IL-1ra, IL-8, IL-10, and IP-10 within 6 h of injury are useful predictors of 30-d mortality. Subgroup analysis suggests that transfusion status does not significantly affect early inflammatory markers. LEVEL OF EVIDENCE: Level III, prognostic/epidemiological.

The Ability of Military Critical Care Air Transport Members to Visually Estimate Percent Systolic Pressure Variation.

INTRODUCTION: Inappropriate fluid management during patient transport may lead to casualty morbidity. Percent systolic pressure variation (%SPV) is one of several technologies that perform a dynamic assessment of fluid responsiveness (FT-DYN). Trained anesthesia providers can visually estimate and use %SPV to limit the incidence of erroneous volume management decisions to 1-4%. However, the accuracy of visually estimated %SPV by other specialties is unknown. The aim of this article is to determine the accuracy of estimated %SPV and the incidence of erroneous volume management decisions for Critical Care Air Transport (CCAT) team members before and after training to visually estimate and utilize %SPV. MATERIAL AND METHODS: In one sitting, CCAT team providers received didactics defining %SPV and indicators of fluid responsiveness and treatment with %SPV ≤7 and ≥14.5 defining a fluid nonresponsive and responsive patient, respectively; they were then shown ten 45-second training arterial waveforms on a simulated Propaq M portable monitor's screen. Study subjects were asked to visually estimate %SPV for each arterial waveform and queried whether they would treat with a fluid bolus. After each training simulation, they were told the true %SPV. Seven days post-training, the subjects were shown a different set of ten 45-second testing simulations and asked to estimate %SPV and choose to treat, or not. Nonparametric limits of agreement for differences between true and estimated %SPV were analyzed using Bland-Altman graphs. In addition, three errors were defined: (1) %SPV visual estimate errors that would label a volume responsive patient as nonresponsive, or vice versa; (2) incorrect treatment decisions based on estimated %SPV (algorithm application errors); and (3) incorrect treatment decisions based on true %SPV (clinically significant treatment errors). For the training and testing simulations, these error rates were compared between, and within, provider groups. RESULTS: Sixty-one physicians (MDs), 64 registered nurses (RNs), and 53 respiratory technicians (RTs) participated in the study. For testing simulations, the incidence and 95% CI for %SPV estimate errors with sufficient magnitude to result in a treatment error were 1.4% (0.5%, 3.2%), 1.6% (0.6%, 3.4%), and 4.1% (2.2%, 6.9%) for MDs, RNs, and RTs, respectively. However, clinically significant treatment errors were statistically more common for all provider types, occurring at a rate of 7%, 10%, and 23% (all P < .05). Finally, students did not show clinically relevant reductions in their errors between training and testing simulations. CONCLUSIONS: Although most practitioners correctly visually estimated %SPV and all students completed the training in interpreting and applying %SPV, all groups persisted in making clinically significant treatment errors with moderate to high frequency. This suggests that the treatment errors were more often driven by misapplying FT-DYN algorithms rather than by inaccurate visual estimation of %SPV. Furthermore, these errors were not responsive to training, suggesting that a decision-making cognitive aid may improve CCAT teams' ability to apply FT-DYN technologies.

The collective voice of early phase COVID-19 vaccine trial participants: Insights for improving confidence in novel vaccines.

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

What is the Diagnostic Accuracy of Novel Urine Biomarkers for Urinary Tract Infection?

Background: Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis. Objectives: To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria. Design: A systematic review. Data Sources and Methods: We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics. Results: We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI. Conclusions: There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.

UK consensus definitions for necrotising otitis externa: a Delphi study.

OBJECTIVE: To establish consensus definitions for necrotising otitis externa (NOE) to facilitate the diagnosis and exclusion of NOE in clinical practice and expedite future high-quality study of this neglected condition. DESIGN: The work comprised of a systematic review of the literature, five iterative rounds of consultation via a Delphi process and open discussion within the collaborative. An expert panel analysed the results to produce the final outputs which were shared with and endorsed by national specialty bodies. SETTING: Secondary care in the UK. PARTICIPANTS: UK clinical specialists practising in infection, ear nose and throat (ENT) surgery or radiology. MAIN OUTCOME MEASURES: Definitions and statements meeting the following criteria were accepted: (a) minimum of 70% of respondents in agreement or strong agreement with a definition/statement AND (b) <15% of respondents in disagreement or strong disagreement with a definition/statement. RESULTS: Seventy-four UK clinicians specialising in ENT, Infection and Radiology with a special interest in NOE took part in the work which was undertaken between 2019 and 2021. The minimum response rate for a Round was 76%. Consensus criteria for all proposed case definitions, outcome definitions and consensus statements were met in the fifth round. CONCLUSIONS: This work distills the clinical opinion of a large group of multidisciplinary specialists from across the UK to create practical definitions and statements to support clinical practice and research for NOE. This is the first step in an iterative process. Further work will seek to validate and test these definitions and inform their evolution.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.

Change in country-level COVID-19 lethality is associated with improved testing: no apparent role of medical care or disease-specific knowledge.

AIM: Reductions in the case fatality rate of COVID-19 in the unvaccinated have been credited to improvements in medical care. Here I test whether either of these factors predicts reductions in the case fatality rate, and whether observed reductions are better explicable by improved ascertainment of mild cases. METHODS: Using weighted log-log regression, I compute the association between changes in the case fatality rate and test density between 3 July 2020 and 5 January 2021 in 162 countries; and check whether case fatality rate change is associated with either per capita medical spending (proxy for critical care access) or timing of the pandemic (proxy for COVID-specific knowledge). RESULTS: The median test density increased from 175 tests per thousand population to 1200, while the median case fatality rate dropped from 4.1% to 2.0%. While the case fatality rate was higher at both timepoints in Europe/North America than Africa / Asia, its association with test density was similar across countries. For each doubling in test density, the mean case fatality rate decreased by 18% (P<0.0001) with a median (interquartile rate) country-level decline of 20% (5-30) per doubling of test density. The rate of change of the case fatality rate was not associated with either medical care access or COVID-specific knowledge (all P>0.10). CONCLUSIONS: Declines in the case fatality rate were adequately explained by improved testing, with no effect of either medical knowledge or improvements in care. The true lethality of COVID-19 may not have changed much at the population level. Prevention should remain a priority.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19. In Brief: LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated. Highlights: LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development.

Estimating total morbidity burden of COVID-19: relative importance of death and disability.

OBJECTIVE: Calculations of disease burden of COVID-19, used to allocate scarce resources, have historically considered only mortality. However, survivors often develop postinfectious 'long-COVID' similar to chronic fatigue syndrome; physical sequelae such as heart damage, or both. This paper quantifies relative contributions of acute case fatality, delayed case fatality, and disability to total morbidity per COVID-19 case. STUDY DESIGN AND SETTING: Healthy life years lost per COVID-19 case were computed as the sum of (incidence*disability weight*duration) for death and long-COVID by sex and 10-year age category in three plausible scenarios. RESULTS: In all models, acute mortality was only a small share of total morbidity. For lifelong moderate symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of morbidity; if survivors' later mortality increased, morbidity increased most in young people of both sexes. CONCLUSIONS: Under most conditions most COVID-19 morbidity was in survivors. Future research should investigate incidence, risk factors, and clinical course of long-COVID to elucidate total disease burden, and decisionmakers should allocate scarce resources to minimize total morbidity.

Vaccine nationalism and internationalism: perspectives of COVID-19 vaccine trial participants in the United Kingdom.

BACKGROUND: Vaccine nationalism has become a key topic of discussion during the development, testing, and rollout of COVID-19 vaccines. Media attention has highlighted the ways that global, coordinated access to vaccines has been limited during the pandemic. It has also exposed how some countries have secured vaccine supply, through bilateral purchase agreements and the way pharmaceutical companies have priced, negotiated, and delivered these supplies. Much of the focus of this debate has been on the vaccine supply 'winners' and 'losers', but the voices of public opinion have been more limited. METHODS: We explore the concepts of vaccine nationalism and internationalism from the perspective of vaccine trial participants, using an empirical perspectives study that involved interviews with phase I/II COVID-19 vaccine trial participants in Oxford, UK. We surveyed and interviewed participants between September and October 2020 about their views, motivations and experiences in taking part in the trial. RESULTS: First, we show how trial participants describe national and international ideas about vaccination as intertwined and challenge claims that these positions are mutually exclusive or oppositional. Second, we analyse these viewpoints further to show that vaccine nationalism is closely connected with national pride and metaphors of a country's scientific achievements. Participants held a global outlook and were highly supportive of the prioritisation of vaccines by global need, but many were also pessimistic that such a solution could be possible. CONCLUSION: Trial participants constitute an informed public group, with situated public expertise that the global community could draw on as an expert opinion. We argue that vaccine nationalism is strongly attached to national character and, therefore, it is more difficult for ownership of a vaccine to be though of as international.

Cardioprotective effects of resistance training add to those of total activity in Americans.

BACKGROUND: Resistance training is cardioprotective independent of total activity in experimental research and is prescribed to clinical populations, but is often largely neglected at population scale. Here we determine whether these benefits are relevant to general practice. METHODS: A total of 6947 Americans over 20 years old (51% male) from NHANES 2003-2006 reported resistance training and objectively tracked 1-week total activity. Activity measures were modeled as five-level predictors of objectively measured binary heart-disease risks (hypertension, dyslipidemia, overweight, and diabetes) corrected for age, ethnicity, gender, and smoking. Significance was defined as Pfor trend less than .10 that the lowest activity category differed from the average of all others. If both activity measures predicted the same risk, mutually corrected models were run. RESULTS: Average total activity was 20 minutes/day (SD 24). About 30% of subjects had resistance trained in the past month, reporting up to 7 sessions/day. Prevalences of hypertension, dyslipidemia, overweight, and diabetes were 32%, 46%, 68%, and 7.2%, respectively. All significant associations for resistance training (but not total activity) exhibited a threshold in dose-response curve, with comparable benefits from any dose above "none." Resistance trainers had significantly lower odds of hypertension (ORs, 0.55-0.85), overweight (ORs, 0.55-0.74), and diabetes (ORs, 0.51-0.80), but not dyslipidemia (ORs, 0.55-0.74). For total activity there was no significant trend in risk of either hypertension or dyslipidemia, but there were for overweight (ORs for each quintile above the lowest 1.04, 0.89, 0.78, and 0.49) and diabetes (ORs, 0.83, 0.68, 0.50, and 0.23; all Pfor trend <.01). Associations of resistance training with diabetes and obesity attenuated only slightly after correction for total activity, and vice versa. CONCLUSIONS: Cardioprotective associations of resistance training were comparable to those of total activity and clinically relevant at low doses. Largest benefits accrued to those who combined any dose of resistance training with high total activity.

Role of Ascertainment Bias in Determining Case Fatality Rate of COVID-19.

Case fatality rate (CFR) is used to calculate mortality burden of COVID-19 under different scenarios, thus informing risk-benefit balance of interventions both pharmaceutical and nonpharmaceutical. However, observed CFR is driven by testing: as more low-risk cases are identified, observed CFR will decline. This report quantifies test bias by modeling observed CFR as log-log-linear function of test density (tests per population) in 163 countries. CFR declined almost 20% (e.g. from 5% to 4%) for each doubling of test density (p < 0.0001); this association did not vary by continent (interaction p > 0.10) although at any given test density CFR was higher in Europe or North America than in Asia or Africa. This effect of test density on observed CFR is adequate to hide all but the largest true differences in case survivorship. Published estimates of CFR should specify test density, and comparisons should correct for it such as by applying the provided model.

The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour-1 kg-1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

Self-estimated BMI, but not self-perceived body size, accurately identifies unhealthy weight in US adults.

BACKGROUND: Self-perceptions of health and disease can be a major driver of health behaviors. Improving accuracy of self-ascertainment of obesity may prompt uptake of weight-control behaviors in those with obesity. METHODS: We assess performance of self-perceived body size ('too small', 'about right' or 'too large'), self-estimated BMI in kg/m2, and sociodemographics in detecting measured BMI category (under-, normal-, overweight and obese; BMI cutpoints 18.5, 25 and 30) in first bivariate and then multivariable models. RESULTS: Of 37,281 adults in the US from NHANES, 2, 34, 33 and 32% were under-, normal-, overweight and obese. Respectively 56, 73, 60 and 91% self-perceived as 'too small', 'about right', 'too large' and 'too large.' Of those who self-perceived as 'too small', 22% were underweight and 10% were overweight or obese. 99.7% of obese participants self-estimated a BMI in the overweight/obese range, including many who did not self-perceive as 'too large'. Among obese participants, self-perception as either 'about right' or 'too small' was more likely for those who were younger (OR for perception as 'too large' 1.01 per year, 95% confidence interval 1.00-1.01) male (OR 0.33, (0.28-0.39)) nonwhite (ORs 0.36-0.79 for different ethnicities), low-income (ORs 0.61 and 1.8 for the lowest and highest of six categories, vs. the third) or measured recently (OR 0.98 (0.96-1.0) per year since 1999). Misperception was less common, but still existed, for participants with moderate or severe obesity (ORs 2.9 (2.3-3.5) and 7.9 (5.4-12), vs. 'mild.') (all p < 0.01.) CONCLUSIONS: A tenth of adults in the US with obesity, especially those from overweight peer groups, self-perceive as normal or underweight and thus may not be motivated to control their weight. However, virtually all self-estimate an overweight or obese BMI. If measured BMI is not available, self-estimates are sufficiently accurate that interventions may rely on it to identify obesity.

LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection.

SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection. ONE SENTENCE SUMMARY: LY-CoV555, an anti-spike antibody derived from a convalescent COVID-19 patient, potently neutralizes SARS-CoV-2 and protects the upper and lower airways of non-human primates against SARS-CoV-2 infection.