Concordance Between Point-of-Care Urine Ethyl Glucuronide Alcohol Tests and Self-Reported Alcohol Use in Persons with HIV in Uganda.

Screening and assessing alcohol use accurately to maximize positive treatment outcomes remain problematic in regions with high rates of alcohol use and HIV and TB infections. In this study, we examined the concordance between self-reported measures of alcohol use and point-of-care (POC) urine ethyl glucuronide (uEtG) test results among persons with HIV (PWH) in Uganda who reported drinking in the prior 3 months. For analyses, we used the screening data of a trial designed to examine the use of incentives to reduce alcohol consumption and increase medication adherence to examine the concordance between POC uEtG (300 ng/mL cutoff) and six measures of self-reported alcohol use. Of the 2136 participants who completed the alcohol screening, 1080 (50.6%) tested positive in the POC uEtG test, and 1756 (82.2%) self-reported using alcohol during the prior 72 h. Seventy-two percent of those who reported drinking during the prior 24 h had a uEtG positive test, with lower proportions testing uEtG positive when drinking occurred 24-48 h (64.7%) or 48-72 h (28.6%) prior to sample collection. In multivariate models, recency of drinking, number of drinks at last alcohol use, and Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) score were associated with uEtG positivity. The highest area under the curve (AUC) for a uEtG positive test was for recency of drinking. Overall, we concluded that several measures of drinking were associated with POC uEtG positivity, with recency of drinking, particularly drinking within the past 24 h, being the strongest predictor of uEtG positivity.

Traumatic injury and atrial fibrillation among deployed service members.

INTRODUCTION: Atrial fibrillation and atrial flutter (AF/AFL), the most common atrial arrhythmias, have never been examined in combat casualties. In this study, we investigated the impact of traumatic injury on AF/AFL among service members with deployment history. METHODS: Sampled from the Department of Defense (DoD) Trauma Registry (n = 10,000), each injured patient in this retrospective cohort study was matched with a non-injured service member drawn from the Veterans Affairs/DoD Identity Repository. The primary outcome was AF/AFL diagnosis identified using ICD-9-CM and ICD-10-CM codes. Competing risk regressions based on Fine and Gray subdistribution hazards model with were utilized to assess the association between injury and AF/AFL. RESULTS: There were 130 reported AF/AFL cases, 90 of whom were injured and 40 were non-injured. The estimated cumulative incidence rates of AF/AFL for injured was higher compared to non-injured patients (hazards ratio [HR] = 2.04; 95% confidence interval [CI] = 1.44, 2.87). After adjustment demographics and tobacco use, the association did not appreciably decrease (HR = 1.90; 95% CI = 1.23, 2.93). Additional adjustment for obesity, hypertension, diabetes, and vascular disorders, the association between injury and AF/AFL was no longer statistically significant (HR = 1.51; 95% CI = 0.99, 2.52). CONCLUSION: Higher AF/AFL incidence rate was observed among deployed service members with combat injury compared to servicemembers without injury. The association did not remain significant after adjustment for cardiovascular-related covariates. These findings highlight the need for combat casualty surveillance to further understand the AF/AFL risk within the military population and to elucidate the potential underlying pathophysiologic mechanisms.

Clinical prediction of extra-medical use of prescription pain relievers from a representative United States sample.

Use of prescription opioids 'beyond the bounds' of medical guidance can lead to opioid dependence. Yet recent efforts to predict extra-medical use of prescription pain relievers (EMPPR) have relied on electronic medical or pharmacy records. Because peak incidence of EMPPR occurs during adolescence- a time of relative health- administrative data may be inadequate. In this study, with data from a United States (US) population sample, we develop and internally validate an EMPPR prediction model. We analyzed data from 234,593 individuals aged 12-to-17-years, as sampled by the US National Survey of Drug Use and Health, 2004-2018, an annual cross-sectional survey. We encoded 14 predictors with onset prior to EMPPR initiation, including age, sex, and facets of drug and psychiatric history. We ranked these predictors by clinical utility before sequentially adding each to a regularized logistic regression model. On held-out test data (n = 23,685), the model performs well with 14 predictors, with an area under the precision recall curve (AUPRC) is 0.155. The area under the receiver operator curve (AUC) is 0.819, exceeding a recent benchmark on this dataset. Results are robust to survey redesign that occurred in 2015, and are not moderated by past-year use of medical services. In conclusion, while selection of predictors is limited to those with known timing prior to initiation of EMPPR rather than any cross-sectional variable, this model discriminates well. Good classification occurs even with a small set of clinically available predictors- age, a history of depression and alcohol, cigarette, and cannabis use.

"Side Effects" Observed Within ~1-90 Days After Cannabis Onset: Epidemiological Estimates for the United States, 2004-2014.

BACKGROUND AND OBJECTIVES: Among newly incident cannabis users, fewer than 4% develop cannabis dependence syndromes within 12 to 24 months, but earlier cannabis side effect (SE) incidence and early syndrome formation remains understudied. We estimate cannabis SE incidence within ~1 to 90 days after first use, and estimate odds ratios (OR) for SE pairs to quantify potential syndromic "running together." METHODS: Each year, 2004 to 2014, the US populations under study consisted of noninstitutionalized civilian residents age 12-years-and-older, sampled for National Surveys on Drug Use and Health. Computerized self-interviews identified 3710 newly incident cannabis users and asked about SEs. Analysis-weighted year-specific SE and SE-SE pair incidence proportions were estimated. Analysis-weighted odds ratio (OR) estimates quantify SE-SE co-occurrences, judged as "greater than chance" when lower bounds (LB) of 95% confidence intervals (CIs) exceed 1.0. Meta-analysis is used to summarize and to check reproducibility. RESULTS: Illustrative of estimates on 17 SEs, roughly 1/2 of cannabis initiates experienced "wanting or trying to cut down or stop using," but 80% of these cut back, such that less than 7% had symptom-like inability to cut back or stop. An estimated 25% had "spent a lot of time getting or using cannabis." The SE-SE paired estimate is 2.8% for those who had spent a lot of time and also had wanted/tried to cut down (95% CI = 2.0, 4.0). OR estimation suggests no syndromic co-occurrence of this SE-SE pair (OR = 0.9; 95% CI = 0.5, 1.6). In contrast, "cannabis causing serious problems at home/work/school" and "continuing to use despite physical problems" were more rare, but had strong SE-SE co-occurrence (OR = 14.8, LB = 2.4). For 78 of 136 possible SE-SE pairs, meta-analysis LB estimates exceeded the 1.0 threshold. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: In these US community samples of cannabis initiates studied soon after first use, the vast majority were free of individual SE experiences counted toward Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition cannabis use disorder diagnoses. For a minority, SE-SE pairs might indicate syndrome formation. These epidemiological meta-analysis estimates might find use in refinement of clinical practice guidelines for fast effective syndrome screens when primary care patients are seen soon after cannabis onset, akin to clinical screening guides designed for newly incident drinkers (Am J Addict 2019;00:1-9).

Patterns of mean age at drug use initiation by race and ethnicity, 2004-2019.

INTRODUCTION: Adolescent drug use can result in clinically significant psychiatric outcomes later in life mitigated by targeted prevention strategies. While mean age of drug initiation has increased over time, there is little research of mean age of drug initiation among adolescents by race/ethnicity. METHODS: The study used the National Survey on Drug Use and Health data (2004-2019). Sample included individuals aged 12 to 21 years. Year-by-year drug use initiation (i.e., first-time use within the past year) trends examined for each drug by race/ethnicity using jointpoint regression. RESULTS: Sample included 95,022 initiates for any of 18 drugs. Year-by-year mean initiation age significantly increased for alcohol (except Non-Hispanic [NH] White, 2004-2012), tobacco cigarettes (except NH American Indian/Alaska Native [AI/AN]), cigars, marijuana (except NH Asian or Pacific Islander, NH Multiracial), cocaine (except NH Black). Significant increase in mean initiation age found for heroin (Hispanic/Latinx only), hallucinogens (NH White, NH Black only), LSD (NH White only), methamphetamines (NH White only), smokeless tobacco (NH White, NH Black only), inhalants (only NH White, NH AI/AN; NH Multiracial, 2004-2011), sedatives (NH White, Hispanic/Latinx only), stimulants (NH White, Hispanic/Latinx only), and ecstasy (NH White, NH Black, Hispanic/Latinx only). Significant decrease in mean initiation age found for alcohol (only NH White, 2013-2019), smokeless tobacco (only Hispanic/Latinx, 2015-2019; NH AI/AN, 2012-2019), and inhalants (only NH Multiracial, 2012-2019). CONCLUSION: Mean initiation age differed widely by race/ethnicity. Mean initiation age in most racial/ethnic groups increased for several drugs including alcohol, marijuana, and tobacco products and decreased for some drugs such as inhalants. These findings could help inform groups to target for future prevention strategies.

Exploring sleep duration and clinical reasoning process in resident physicians: a thematic analysis.

STUDY OBJECTIVES: Connecting resident physician work hours and sleep deprivation to adverse outcomes has been difficult. Our study explores clinical reasoning rather than outcomes. Diagnostic errors are a leading cause of medical error and may result from deficits in clinical reasoning. We used simulated cases to explore relationships between sleep duration and diagnostic reasoning. METHODS: Residents were recruited for a 2-month study (inpatient/outpatient). Each participant's sleep was tracked (sleep diary/actigraphy). At the end of each month, residents watched two brief simulated clinical encounters and performed "think alouds" of their clinical reasoning. In each session, one video was straightforward, and the other video contained distracting contextual factors. Sessions were recorded, transcribed, and interpreted. We conducted a thematic analysis using a constant comparative approach. Themes were compared based on sleep duration and contextual factors. RESULTS: Residents (n=17) slept more during outpatient compared to inpatient months (450.5±7.13 v 425.6±10.78, p=0.02). We found the following diagnostic reasoning themes: uncertainty, disorganized knowledge, error, semantic incompetence, emotional content, and organized knowledge. Themes reflecting suboptimal clinical reasoning (disorganized knowledge, error, semantic incompetence, uncertainty) were observed more in cases with contextual factors (distractors). "Think alouds" from cases with contextual factors following sleep restriction had a greater number of themes concerning for problematic diagnostic reasoning. CONCLUSIONS: Residents obtained significantly more sleep during outpatient compared to inpatient months. Several negative clinical reasoning themes emerged with less sleep combined with cases containing contextual distractors. Our findings reinforce the importance of adequate sleep and supervision in house officers, particularly in cases with distracting elements.

Traumatic Brain Injury and Subsequent Risk of Brain Cancer in US Veterans of the Iraq and Afghanistan Wars.

Importance: While brain cancer is rare, it has a very poor prognosis and few established risk factors. To date, epidemiologic work examining the potential association of traumatic brain injury (TBI) with the subsequent risk of brain cancer is conflicting. Further data may be useful. Objective: To examine whether a history of TBI exposure is associated with the subsequent development of brain cancer. Design, Setting, and Participants: A retrospective cohort study was conducted from October 1, 2004, to September 20, 2019, and data analysis was performed between January 1 and June 26, 2023. The median follow-up for the cohort was 7.2 (IQR, 4.1-10.1) years. Veterans Affairs (VA) and Department of Defense (DoD) administrative data on 1 919 740 veterans from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium were included. Exposure: The main exposure of interest was TBI severity (categorized as mild, moderate or severe [moderate/severe], and penetrating). Main Outcomes and Measures: The outcome of interest was the development of brain cancer based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes in either the DoD/VA medical records or from the National Death Index. Results: After 611 107 exclusions (predominately for no encounter during the study period), a cohort including 1 919 740 veterans was included, most of whom were male (80.25%) and non-Hispanic White (63.11%). Median age at index date was 31 (IQR, 25-42) years. The cohort included 449 880 individuals with TBI (mild, 385 848; moderate/severe, 46 859; and penetrating, 17 173). Brain cancer occurred in 318 individuals without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (≤0.06%). After adjustment, moderate/severe TBI (adjusted hazard ratio [AHR], 1.90; 95% CI, 1.16-3.12) and penetrating TBI (AHR, 3.33; 95% CI, 1.71-6.49), but not mild TBI (AHR, 1.14; 95% CI, 0.88-1.47), were associated with the subsequent development of brain cancer. Conclusions and Relevance: In this cohort study of veterans of the Iraq and Afghanistan wars, moderate/severe TBI and penetrating TBI, but not mild TBI, were associated with the subsequent development of brain cancer.

Unintended Consequences of Code Status in the Intensive Care Unit: What Happens After a Do-Not-Resuscitate Order Is Placed? A Retrospective Cohort Study.

Background: Some clinicians suspect that patients with do-not-resuscitate (DNR) orders receive less aggressive care. Extrapolation from code status to goals of care could cause significant harm. This study asked the question: Do DNR orders in the intensive care unit (ICU) lead to a decrease in invasive interventions? Methods: This was a retrospective cohort study of ICU patients from three teaching hospitals. All ICU patients were assessed for inclusion. Exclusion criteria were medical futility and death, comfort care, or ICU discharge <48 hours after DNR initiation. Five hundred thirty-six patients met inclusion criteria. One hundred forty-five were included in the final analysis. Primary outcomes were occurrence of invasive interventions after DNR initiation-surgical operation, central line, ventilation, dialysis, or other procedure. Secondary outcomes were antibiotic administration, blood transfusion, mortality, and discharge location. Results: Patients with DNR orders underwent fewer surgical operations (14.5% vs. 31.1%, p = 0.002), but more central lines (42.1% vs. 23.0%, p = 0.009), ventilator use (49.0% vs. 18.9%, p < 0.001), and dialysis (20.0% vs. 4.1%, p = 0.002), compared with patients without DNR orders. Transfusions and antibiotic use decreased similarly over admission for both groups (transfusions: ß = 1.25; p = 0.59; and antibiotics: ß = 1.44; p = 0.27). Mortality and hospice discharges were higher for DNR patients (p < 0.001.). Conclusions: DNR status did not decrease the number of nonoperative interventions patients received as compared with full code counterparts. Although differences in populations existed, patients with DNR orders were likely to receive a similar number of invasive interventions. This finding suggests that providers do not wholesale limit these options for patients with code status limitations.

Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis.

Cell-based therapeutic cancer vaccines use autologous patient-derived tumor cells, allogeneic cancer cell lines or autologous antigen presenting cells to mimic the natural immune process and stimulate an adaptive immune response against tumor antigens. The primary objective of this study is to perform a systematic literature review with an embedded meta-analysis of all published Phase 2 and 3 clinical trials of cell-based cancer vaccines in human subjects. The secondary objective of this study is to review trials demonstrating biological activity of cell-based cancer vaccines that could uncover additional hypotheses, which could be used in the design of future studies. We performed the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final review included 36 studies - 16 single-arm studies, and 20 controlled trials. Our systematic review of the existing literature revealed largely negative trials and our meta-analysis did not show evidence of clinical benefit from cell-based cancer-vaccines. However, as we looked beyond the stringent inclusion criteria of our systematic review, we identified significant examples of biological activity of cell-based cancer vaccines that are worth highlighting. In conclusion, the existing literature on cell-based cancer vaccines is highly variable in terms of cancer type, vaccine therapies and the clinical setting with no overall statistically significant clinical benefit, but there are individual successes that represent the promise of this approach. As cell-based vaccine technology continues to evolve, future studies can perhaps fulfill the potential that this exciting field of anti-cancer therapy holds.

DIAGNOSTIC VALUE OF MITOCHONDRIAL DNA AND PERIPHERAL BLOOD MONONUCLEAR CELL RESPIROMETRY FOR BURN-RELATED SEPSIS.

ABSTRACT: Background: Sepsis is the leading cause of mortality among burn patients that survive acute resuscitation. Clinical criteria have poor diagnostic value for burn-induced sepsis, making it difficult to diagnose. Protein biomarkers (e.g., procalcitonin) have been examined with limited success. We aimed to explore other biomarkers related to mitochondria (mitochondrial DNA [mtDNA]) and mitochondrial function of peripheral blood mononuclear cells (PBMCs) for sepsis diagnosis in burn patients. Methods: We conducted a follow-up analysis of a single center, prospective observational study of subjects (n = 10 healthy volunteers, n = 24 burn patients) to examine the diagnostic value of mtDNA and PBMC respirometry. Patients were enrolled regardless of sepsis status and followed longitudinally. Patient samples were classified as septic or not based on empiric clinical criteria. Isolated PBMCs were loaded into a high-resolution respirometer, and circulating mtDNA was measured with a PCR-based assay. Sequential Organ Failure Assessment (SOFA) criteria were also compared. Results: The SOFA criteria comparing septic versus before/nonseptic patients revealed significantly higher heart rate ( P = 0.012) and lower mean arterial pressure ( P = 0.039) in burn sepsis. MtDNA was significantly elevated in septic burn patients compared with healthy volunteers ( P < 0.0001) and nonseptic patients ( P < 0.0001), with no significant difference between healthy volunteers and nonseptic burn patients ( P = 0.187). The area under the ROC curve (AUC) for mtDNA was 0.685 (95% confidence interval = 0.50-0.86). For PBMC respirometry, burn patients exhibited increased routine and maximal respiration potential compared with healthy volunteers. However, no difference was found between nonseptic and septic patient samples. A subanalysis revealed a significant mortality difference in PBMC respirometry after sepsis diagnosis, wherein survivors had higher routine respiration ( P = 0.003) and maximal respiration ( P = 0.011) compared with nonsurvivors. Conclusion: Our findings reveal that mtDNA may have diagnostic value for burn sepsis, whereas PBMC respirometry is nonspecifically elevated in burns, but may have value in mortality prognosis. A larger, multisite study is warranted for further validity of the diagnostic value of mtDNA and PBMC respirometry as biomarkers for prognosis of sepsis and outcomes in burn patients.

Outcomes Associated With Intensive Care and Organ Support Among Patients With COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Accurate accounting of coronavirus disease 2019 (COVID-19) critical care outcomes has important implications for health care delivery. RESEARCH QUESTION: We aimed to determine critical care and organ support outcomes of intensive care unit (ICU) COVID-19 patients and whether they varied depending on the completeness of study follow-up or admission time period. STUDY DESIGN AND METHODS: We conducted a systematic review and meta-analysis of reports describing ICU, mechanical ventilation (MV), renal replacement therapy (RRT), and extracorporeal membrane oxygenation (ECMO) mortality. A search was conducted using PubMed, Embase, and Cochrane databases.We included English language observational studies of COVID-19 patients, reporting ICU admission, MV, and ICU case fatality, published from December 1, 2019 to December 31, 2020. We excluded reports of less than 5 ICU patients and pediatric populations. Study characteristics, patient demographics, and outcomes were extracted from each article. Subgroup meta-analyses were performed based on the admission end date and the completeness of data. RESULTS: Of 6,778 generated articles, 145 were retained for inclusion (n = 60,357 patients). Case fatality rates across all studies were 34.0% (95% CI = 30.7%, 37.5%, P < 0.001) for ICU deaths, 47.9% (95% CI = 41.6%, 54.2%, P < 0.001) for MV deaths, 58.7% (95% CI = 50.0%, 67.2%, P < 0.001) for RRT deaths, and 43.3% (95% CI = 31.4%, 55.4%, P < 0.001) for extracorporeal membrane oxygenation deaths. There was no statistically significant difference in ICU and organ support outcomes between studies with complete follow-up versus studies without complete follow-up. Case fatality rates for ICU, MV, and RRT deaths were significantly higher in studies with patients admitted before April 31st 2020. INTERPRETATION: Coronavirus disease 2019 critical care outcomes have significantly improved since the start of the pandemic. Intensive care unit outcomes should be evaluated contextually (study quality, data completeness, and time) for the most accurate reporting and to effectively guide mortality predictions.

Suicide attempts and mental health diagnoses in combat-injured service members: A retrospective cohort study.

INTRODUCTION: Examinations of risk factors for suicide attempt in United States service members at high risk of mental health diagnoses, such as those with combat injuries, are essential to guiding prevention and intervention efforts. METHODS: Retrospective cohort study of 8727 combat-injured patients matched to deployed, non-injured patients utilizing Department of Defense and Veterans Affairs administrative records. RESULTS: Combat injury was positively associated with suicide attempt in the univariate model (HR = 1.75, 95% CI 1.5-2.1), but lost significance after adjustment for mental health diagnoses. Utilizing Latent Transition Analysis in the combat-injured group, we identified five mental/behavioral health profiles: (1) Few mental health diagnoses, (2) PTSD and depressive disorders, (3) Adjustment disorder, (4) Multiple mental health comorbidities, and (5) Multiple mental health comorbidities with alcohol use disorder (AUD). Multiple mental health comorbidities with AUD had the highest suicide attempt rate throughout the study and more than four times that of Multiple mental health comorbidities in the first study year (23.4 vs. 5.1 per 1000 person years, respectively). CONCLUSION: Findings indicate that (1) combat injury's impact on suicide attempt is attenuated by mental health and (2) AUD with multiple mental health comorbidities confers heightened suicide attempt risk in combat-injured service members.

Long-Term Health Care Costs for Service Members Injured in Iraq and Afghanistan.

INTRODUCTION: Over the last two decades, the conflicts in Iraq and Afghanistan have cost the United States significantly in terms of lives lost, disabling injuries, and budgetary expenditures. This manuscript calculates the differences in costs between veterans with combat injuries vs veterans without combat injuries. This work could be used to project future costs in subsequent studies. MATERIALS AND METHODS: In this retrospective cohort study, we randomly selected 7,984 combat-injured veterans between February 1, 2002, and June 14, 2016, from Veterans Affairs Health System administrative data. We matched injured veterans 1:1 to noninjured veterans on year of birth (± 1 year), sex, and first service branch. We observed patients for a maximum of 10 years. This research protocol was reviewed and approved by the David Grant USAF Medical Center institutional review board (IRB), the University of Utah IRB, and the Research Review Committee of the VA Salt Lake City Health Care System in accordance with all applicable Federal regulations. RESULTS: Patients were primarily male (98.1% in both groups) and White (76.4% for injured patients, 72.3% for noninjured patients), with a mean (SD) age of 26.8 (6.6) years for the injured group and 27.7 (7.0) years for noninjured subjects. Average total costs for combat-injured service members were higher for each year studied. The difference was highest in the first year ($16,050 compared to $4,135 for noninjured). These differences remained significant after adjustment. Although this difference was greatest in the first year (marginal effect $12,386, 95% confidence interval $9,736-$15,036; P < 0.001), total costs continued to be elevated in years 2-10, with marginal effects ranging from $1,766 to $2,597 (P < 0.001 for all years). More severe injuries tended to increase costs in all categories. CONCLUSIONS: Combat injured patients have significantly higher long-term health care costs compared to their noninjured counterparts. If this random sample is extrapolated to the 53,251 total of combat wounded service members, it implies a total excess cost of $1.6 billion to date after adjustment for covariates and a median follow-up time of 10 years. These costs are likely to increase as injured veterans age and develop additional chronic conditions.

Factors Associated with Child Removal Among American Indian and Alaska Native People in an Alcohol Intervention Study.

This study was a secondary data analysis of factors associated with alcohol-related child removal among American Indian/Alaska Native (AI/AN) adults enrolled in a clinical trial of an alcohol intervention. Among 326 parent participants, 40% reported ever having a child removed from their care in part because of the parent's alcohol use, defined here as alcohol-related child removal. Seventy-five percent of parents reported at least one separation during their own childhood (M = 1.3, SD = 1.0). In a multivariable analysis, alcohol-related child removal was associated with parental boarding school attendance. No relationship was found between alcohol-related child removal and alcohol intervention outcomes. Results may provide evidence of multigenerational child removal impacts of boarding schools on AI/AN adults receiving an alcohol use disorder intervention. Assessment of parental history of child removal by practitioners, strategies to prevent alcohol-related separation and to support reunification should be integrated into addiction treatment in AI/AN communities.

Intensive Care and Organ Support Related Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis.

To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support. DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021. STUDY SELECTION: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients. DATA EXTRACTION: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included. DATA SYNTHESIS: One hundred fifty-seven studies evaluating 948,309 patients were included. The CFR for in-hospital mortality, ICU mortality, MV, RRT, and ECMO were 25.9% (95% CI: 24.0-27.8%), 37.3% (95% CI: 34.6-40.1%), 51.6% (95% CI: 46.1-57.0%), 66.1% (95% CI: 59.7-72.2%), and 58.0% (95% CI: 46.9-68.9%), respectively. MV (52.7%, 95% CI: 47.5-58.0% vs 31.3%, 95% CI: 16.1-48.9%; p = 0.023) and RRT-related mortality (66.7%, 95% CI: 60.1-73.0% vs 50.3%, 95% CI: 42.4-58.2%; p = 0.003) decreased from 2020 to 2021. CONCLUSIONS: We present updated estimates of CFR for patients hospitalized and requiring intensive care for the management of COVID-19. Although mortality remain high and varies considerably worldwide, we found the CFR in patients supported with MV significantly improved since 2020.

SARS-CoV-2 Antibody Longitudinal Profile of Immune Globulin Preparations.

INTRODUCTION: Intravenous immunoglobulin (IVIG) preparations, used for the treatment of antibody deficiencies, provide a glimpse of the general population's antibody profile as each preparation is generated from a pool of thousands of donors. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 (Covid-19) pandemic, and a vaccine for the prevention of Covid-19 was authorized for emergency use in December 2020. We completed a longitudinal analysis of SARS-CoV-2 antibody levels in commercial IVIG preparations. MATERIALS AND METHODS: We collected IVIG samples from our infusion clinic. IVIG product lot number, product name, and manufacturer information were recorded, with the date of preparation verified from the manufacturer. SARS-CoV-2 antibody titers as well as total immunoglobulin levels were measured using commercially available assays. The study received Institutional Review Board approval. RESULTS: We found no SARS-CoV-2 antibodies in preparations generated on or before January 2020. Overall, SARS-CoV-2 antibody levels in IVIG preparations tended to increase with progressing preparation date. We observed a dramatic and continual rise of SARS-CoV-2 antibody levels in IVIG preparations made in the beginning after January 2021, coinciding with the peak in incidence of confirmed cases and availability of Covid-19 vaccines in the United States. CONCLUSION: SARS-CoV-2 antibody levels in IVIG mirror case prevalence, and vaccination resulted in a far more rapid rate of rise in antibody levels. IVIG preparations or serum repositories can provide an accessible way to model a population's evolving novel pathogen exposure, immunity, and vaccine response.

A Prospective Observational Study Comparing Clinical Sepsis Criteria to Protein Biomarkers Reveals a Role for Vascular Dysfunction in Burn Sepsis.

OBJECTIVES: To compare the diagnostic value of clinical sepsis criteria to novel protein biomarkers in the burn patient. DESIGN: Prospective observational study. SETTING: American Burn Association verified Burn Center ICU. PATIENTS: Burn patients (n = 24) and healthy volunteers (n = 10). INTERVENTIONS: Enrolled burn patients (n = 24) were stratified based on whether or not they met a clinical definition of sepsis. Four separate clinical criteria for sepsis were analyzed for their diagnostic sensitivity and specificity, which were compared to a panel of protein biomarkers. The most significant protein biomarkers were further analyzed via the area under the receiver operating characteristic curves (AUROCs). MEASUREMENTS AND MAIN RESULTS: Of the clinical criteria, SEPSIS-2 criteria led to the highest AUROC (0.781; p < 0.001), followed by the quick Sequential Organ Failure Assessment score (AUROC = 0.670; p = 0.022). Multiplexing revealed a number of inflammatory proteins (complement C5) and matrix metalloproteinases (MMP1, MMP7) that were significantly elevated in septic samples compared with both healthy controls and nonseptic burn samples. Furthermore, three proteins associated with endothelial dysfunction and glycocalyx shedding revealed diagnostic potential. Specifically, syndecan-1, p-selectin, and galectin-1 were all significantly elevated in sepsis, and all resulted in an AUROC greater than 0.7; analyzing the sum of these three markers led to an AUROC of 0.808. CONCLUSIONS: These data reveal several potential biomarkers that may help with sepsis diagnosis in the burn patient. Furthermore, the role of endotheliopathy as a mechanistic etiology for sepsis after burns warrants further investigation.

Post-Combat-Injury Opioid Prescription and Alcohol Use Disorder in the Military.

INTRODUCTION: Previous studies have identified combat exposure and combat traumatic experience as problematic drinking risk factors. Increasing evidence suggests that opioid use increases the risk of alcohol use disorder. This study investigated the association between opioid prescription use after injury and (1) alcohol use disorder and (2) severity of alcohol use disorder among deployed military servicemembers. METHODS: Deidentified health records data of 9,029 deployed servicemembers from a retrospective cohort study were analyzed. Data were randomly selected from the Department of Defense Trauma Registry and included servicemembers with combat injuries during deployment in Iraq or Afghanistan (2002-2016). Pharmacy records and International Classification of Diseases, Ninth and Tenth Revision diagnosis codes were used. Three groups were identified (no opioid prescription use, nonpersistent opioid prescription use, and persistent opioid prescription use) and were compared on the basis of alcohol use disorder risk using Cox proportional hazard models. Data analyses were performed in 2021. RESULTS: Of the 9,029 servicemembers with combat injury, 2,262 developed alcohol use disorder (1,322 developed severe alcohol use disorder). Compared with no opioid prescription use, increased alcohol use disorder risk was associated with persistent opioid prescription use, with a hazard ratio of 1.13 (95% CI=1.02, 1.26). After covariate adjustment, increased risk remained statistically significant (hazards ratio=1.24; 95% CI=1.10, 1.39). There was no significant difference in alcohol use disorder risk between no opioid prescription use and nonpersistent opioid prescription use. The risk of severe alcohol use disorder did not vary by opioid use among servicemembers with alcohol use disorder diagnosis. CONCLUSIONS: The findings of the study suggest that the incidence of alcohol use disorder was higher among injured servicemembers with persistent opioid prescription use than among those without opioid use. If replicated in prospective studies, the findings highlight the need for clinicians to consider the current and history of alcohol use of patients in initiating treatment involving opioids.

A Multicenter Evaluation of the Seraph 100 Microbind Affinity Blood Filter for the Treatment of Severe COVID-19.

The Seraph100 Microbind Affinity Blood Filter (Seraph 100) (ExThera Medical, Martinez, CA) is an extracorporeal therapy that can remove pathogens from blood, including severe acute respiratory syndrome coronavirus 2. The aim of this study was to evaluate safety and efficacy of Seraph 100 treatment for COVID-19. DESIGN: Retrospective cohort study. SETTING: Nine participating ICUs. PATIENTS: COVID-19 patients treated with Seraph 100 (n = 53) and control patients matched by study site (n = 53). INTERVENTION: Treatment with Seraph 100. MEASUREMENTS AND MAIN RESULTS: At baseline, there were no differences between the groups in terms of sex, race/ethnicity, body mass index, and need for mechanical ventilation. However, patients in the Seraph 100 group were younger (median age, 54 yr; interquartile range [IQR], 41-65) compared with controls (median age, 64 yr; IQR, 56-69; p = 0.009). Charlson comorbidity index scores were lower in the Seraph 100 group (2; IQR, 0-3) compared with the control group (3; IQR, 2-4; p = 0.006). Acute Physiology and Chronic Health Evaluation II scores were also lower in Seraph 100 subjects (12; IQR, 9-17) compared with controls (16; IQR, 12-21; p = 0.011). The Seraph 100 group had higher vasopressor-free days with an incidence rate ratio of 1.30 on univariate analysis. This difference was not significant after adjustment. Seraph 100-treated subjects were less likely to die compared with controls (32.1% vs 64.2%; p = 0.001), a difference that remained significant after adjustment. However, no difference in mortality was observed in a post hoc analysis utilizing an external control group. In the full cohort of 86 treated patients, there were 177 total treatments, in which only three serious adverse events were recorded. CONCLUSIONS: Although this study did not demonstrate consistently significant clinical benefit across all endpoints and comparisons, the findings suggest that broad spectrum, pathogen agnostic, blood purification can be safely deployed to meet new pathogen threats while awaiting targeted therapies and vaccines.

Development and Validation of a Prediction Model of Prescription Tranquilizer Misuse Based on a Nationally Representative United States Sample.

BACKGROUND: Prescription tranquilizer misuse is a risky behavior associated with fatal drug poisonings. Although various predictors have been examined, there is no published prediction model for tranquilizer misuse. This study develops and internally validates a tranquilizer misuse prediction model based primarily on drug histories of participants in a national cross-sectional survey. Predictors also include psychiatric, behavioral and demographic variables. METHODS: We analyzed data from 471,097 individuals aged 14-to-29-years in the United States, as sampled by the National Survey of Drug Use and Health, 2004-2018, an annual cross-sectional survey. We encoded 21 predictors with known or likely onset prior to tranquilizer misuse initiation, (e.g., early onset of cannabis use). With this dataset, we trained a neural network and regularized logistic regression model. While the assessment for tranquilizer misuse changed slightly in 2015, by pooling all years of survey data, predictions are robust to this source of variation. RESULTS: 1.44% of the pooled sample, 2004-2018, recently initiated tranquilizer misuse (unweighted estimate). On held-out test data (n = 43,714), logistic regression and the neural network performed equally well, with an area under the receiver operating characteristic curve (AUC) of ∼0.83 on the primary model, containing 12 variables known to occur before tranquilizer misuse. CONCLUSION: Built for case prediction rather than case detection, this model restricted predictors to those with known timing prior to initiation of tranquilizer misuse. Yet its performance supersedes commonly accepted criteria for clinical prediction models (AUC > 0.80). Future work should incorporate survey analysis weights into the prediction model to minimize possible bias.