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Background Clinical practice guidelines are developed to assist in patient care but the evidence basis for many guidelines has recently been called into question. Methods We conducted a literature review using PubMed and analyzed the overall quality of evidence and made strength of recommendation behind 6 Institute of Health Care (IHI) guidelines for prevention of ventilator associated pneumonia (VAP). Quality of evidence was assessed by the American Thoracic Society levels of evidence (levels I through III) with addition of level IV when evidence existed that the guideline increased VAP. We also examined our own intensive care units (ICUs) for evidence of a correlation between guideline compliance and the development of VAP. Results None of the guidelines could be given more than a moderate recommendation. Only one of the guidelines (head of bed elevation) was graded at level II and could be given a moderate recommendation. One was graded at level IV (stress ulcer disease prophylaxis). The remainder were graded level III and given weak recommendations. In our ICUs compliance with the guidelines did not correlate with a reduction in VAP (p

Background and Purpose: Brain atrophy occurs in the late stage of dementia, yet structural MRI is widely used in the work-up. Atrophy patterns can suggest a diagnosis of Alzheimer disease (AD) or frontotemporal dementia (FTD) but are difficult to assess visually. We hypothesized that the availability of a quantitative volumetric brain MRI report would increase neuroradiologists' accuracy in diagnosing AD, FTD, or healthy controls compared with visual assessment., Materials and Methods: Twenty-two patients with AD, 17 with FTD, and 21 cognitively healthy patients were identified from the electronic health systems record and a behavioral neurology clinic. Four neuroradiologists evaluated T1-weighted anatomic MRI studies with and without a volumetric report. Outcome measures were the proportion of correct diagnoses of neurodegenerative disease versus normal aging ("rough accuracy") and AD versus FTD ("exact accuracy"). Generalized linear mixed models were fit to assess whether the use of a volumetric report was associated with higher accuracy, accounting for random effects of within-rater and within-subject variability. Post hoc within-group analysis was performed with multiple comparisons correction. Residualized volumes were tested for an association with the diagnosis using ANOVA., Results: There was no statistically significant effect of the report on overall correct diagnoses. The proportion of "exact" correct diagnoses was higher with the report versus without the report for AD (0.52 versus 0.38) and FTD (0.49 versus 0.32) and lower for cognitively healthy (0.75 versus 0.89). The proportion of "rough" correct diagnoses of neurodegenerative disease was higher with the report than without the report within the AD group (0.59 versus 0.41), and it was similar within the FTD group (0.66 versus 0.63). Post hoc within-group analysis suggested that the report increased the accuracy in AD (OR = 2.77) and decreased the accuracy in cognitively healthy (OR = 0.25). Residualized hippocampal volumes were smaller in AD (mean difference -1.8; multiple comparisons correction, -2.8 to -0.8; P < .001) and FTD (mean difference -1.2; multiple comparisons correction, -2.2 to -0.1; P = .02) compared with cognitively healthy., Conclusions: The availability of a brain volumetric report did not improve neuroradiologists' accuracy over visual assessment in diagnosing AD or FTD in this limited sample. Post hoc analysis suggested that the report may have biased readers incorrectly toward a diagnosis of neurodegeneration in cognitively healthy adults., (© 2024 by American Journal of Neuroradiology.)

Purpose: To determine if language-based disparities in postoperative pain management exist in women undergoing gynecologic surgery., Design: A retrospective cohort study was performed., Methods: The electronic medical records were reviewed of individuals, aged 18 to 80, who underwent an abdominal hysterectomy between 2016 and 2021 at the University of Colorado Anschutz Medical Center. A random sample of 100 patients, 50 categorized as English proficient and 50 categorized as having limited English proficiency (LEP), were compared. The primary outcomes were the number of quantitative pain assessments and the total dose of opioid given in oral morphine milligram equivalents. The secondary outcomes were the average pain scores, the number of qualitative pain assessments, postanesthesia care unit length of stay, regional block use, patient-controlled analgesia, or opioid use after the first 24 hours. Linear and generalized linear modeling was used to assess the relationship between English proficiency and the outcomes of interest., Findings: All patients received at least 1 pain assessment while in the postanesthesia care unit (range 2 to 25). There was no significant difference in the number of objective pain assessments or the total dose of opioid given between the groups. There were no significant differences in any of the secondary outcomes between the groups. On subgroup analysis, the presence of a documented bedside interpreter did not result in a significant difference in endpoints. Fewer LEP patients received patient-controlled analgesia (34% LEP vs 58% English proficient), though the difference did not reach statistical significance., Conclusions: Language barriers may complicate care and impact postoperative recovery. In our population of women in a high-volume, urban, level I, trauma center, there were no observed differences in postoperative pain management practices in patients with LEP compared with English-proficient patients. Standardized nursing protocols may contribute to more equitable care. Ongoing investigations in the identification and prevention of language-related disparities in perioperative care are warranted., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2024 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Osteoarthritis is a significant cause of disability, resulting in increased joint replacement surgeries and health care costs. Establishing benchmarks that more accurately predict surgical duration could help to decrease costs, maximize efficiency, and improve patient experience. We compared the anesthesia-controlled time (ACT) and surgery-controlled time (SCT) of primary total knee (TKA) and total hip arthroplasties (THA) between an academic medical center (AMC) and a community hospital (CH) for 2 orthopedic surgeons., Objective: This study aims to validate and compare benchmarking times for ACT and SCT in a single patient population at both an AMC and a CH., Methods: This retrospective 2-center observational cohort study was conducted at the University of Colorado Hospital (AMC) and UCHealth Broomfield Hospital (CH). Cases with current procedural terminology codes for THA and TKA between January 1, 2019, and December 31, 2020, were assessed. Cases with missing data were excluded. The primary outcomes were ACT and SCT. Primary outcomes were tested for association with covariates of interest. The primary covariate of interest was the location of the procedure (CH vs AMC); secondary covariates of interest included the American Society of Anesthesiologists (ASA) classification and anesthetic type. Linear regression models were used to assess the relationships., Results: Two surgeons performed 1256 cases at the AMC and CH. A total of 10 THA cases and 12 TKA cases were excluded due to missing data. After controlling for surgeon, the ACT was greater at the AMC for THA by 3.77 minutes and for TKA by 3.58 minutes (P<.001). SCT was greater at the AMC for THA by 11.14 minutes and for TKA by 14.04 minutes (P<.001). ASA III/IV classification increased ACT for THA by 3.76 minutes (P<.001) and increased SCT for THA by 6.33 minutes after controlling for surgeon and location (P=.008). General anesthesia use was higher at the AMC for both THA (29.2% vs 7.3%) and TKA (23.8% vs 4.2%). No statistically significant association was observed between either ACT or SCT and anesthetic type (neuraxial or general) after adjusting for surgeon and location (all P>.05)., Conclusions: We observed lower ACT and SCT at the CH for both TKA and THA after controlling for the surgeon of record and ASA classification. These findings underscore the efficiency advantages of performing primary joint replacements at the CH, showcasing an average reduction of 16 minutes in SCT and 4 minutes in ACT per case. Overall, establishing more accurate benchmarks to improve the prediction of surgical duration for THA and TKA in different perioperative environments can increase the reliability of surgical duration predictions and optimize scheduling. Future studies with study populations at multiple community hospitals and academic medical centers are needed before extrapolating these findings., (©Thy B Nguyen, Nathaen Weitzel, Craig Hogan, Rachel M Kacmar, Kayla M Williamson, Jack Pattee, Vesna Jevtovic-Todorovic, Colby G Simmons, Adeel Ahmad Faruki. Originally published in JMIR Perioperative Medicine (http://periop.jmir.org), 26.02.2024.)

Background: On July 1st, 2021, the University of Colorado Hospital (UCH) implemented new sedation protocols in the luminal gastrointestinal (GI) suite. GI proceduralist supervised, Nurse Administered Sedation with fentanyl, midazolam, and diphenhydramine (NAS) sedation was transitioned to Monitored Anesthesia Care with propofol under physician anesthesiologist supervision (MAC)., Objective: To determine if there are statistically significant reductions in Sedation-Start to Scope-In time (SSSI) when using Monitored Anesthesia Care with propofol (MAC) versus Nurse Administered Sedation with fentanyl, midazolam, and diphenhydramine (NAS). Secondary objectives were to determine if statistically significant improvements to other operational times, quality measures, and satisfaction metrics were present., Method: This study was a retrospective analysis of a natural experiment resultant of a change from NAS to MAC sedation protocols. Outcomes for NAS protocols from 1/1/21-6/30/21 were compared to outcomes of MAC protocols from the dates 8/1/21-10/31/21. Results were analyzed using Quasi-Poisson regression analysis and stratified based on upper GI, lower GI, and combined procedures. Patient demographic data including age, biological sex, comorbidities, and BMI, were adjusted for in the analysis. ASA matching was not performed as nursing sedation does not use ASA classifications. Pre-anesthesia co-morbidities were assessed via evaluation of a strict set of comorbidities abstracted from the electronic medical record. Perioperative operational outcomes include Sedation Start to Scope-In (SSSI), In-Room to Scope-In Time (IRSI), Scope Out to Out of Room (SOOR), Total Case Length (TCL), and Post Anesthesia Care Unit Length of Stay (PACU LOS). Quality outcomes include PACU Administered Medications (PAM), and Clinician Satisfaction Scores (CSS)., Results: A total of 5,582 gastrointestinal (GI) endoscopic cases (upper, lower, and combined endoscopies) were observed. Statistically significant decreases in SSSI of 2.5, 2.1, and 2.2 minutes for upper, lower, and dual GI procedures were observed when using MAC protocols. A statistically significant increase in satisfaction scores of 47.0 and 19.6 points were observed for nurses and proceduralists, respectively, when using MAC., Conclusion: MAC protocols for endoscopic GI procedures at UCH led to statistically significant decreases in the time required to complete procedures thus increasing operational efficiency., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mariotti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: CSF-to-venous fistulas contribute to spontaneous intracranial hypotension. CT-guided fibrin occlusion has been described as a minimally invasive treatment strategy; however, its reproducibility across different institutions remains unclear. This multi-institution study evaluated the clinical and radiologic outcomes of CT-guided fibrin occlusion, hypothesizing a correlation among cure rates, fibrin injectate spread, and drainage patterns., Materials and Methods: A retrospective evaluation was conducted on CT-guided fibrin glue treatment in patients with CSF-to-venous fistulas from 6 US and UK institutions from 2020 to 2023. Patient information, procedural characteristics, and injectate spread and drainage patterns were examined. Clinical improvement assessed through medical records served as the primary outcome., Results: Of 119 patients at a mean follow-up of 5.0 months, fibrin occlusion resulted in complete clinical improvement in 59.7%, partial improvement in 34.5%, and no improvement in 5.9% of patients. Complications were reported in 4% of cases. Significant associations were observed between clinical improvement and concordant injectate spread with the fistula drainage pattern ( P = .0089) and pretreatment symptom duration ( P < .001). No associations were found between clinical improvement and cyst puncture, intravascular extension, rebound headache, body mass index, age, or number of treatment attempts., Conclusions: Fibrin occlusion performed across various institutions shows cure when associated with injectate spread matching the CVF drainage pattern and shorter pretreatment symptom duration, emphasizing the importance of accurate injectate placement and early intervention., (© 2023 by American Journal of Neuroradiology.)

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, environmentally persistent chemicals, and prenatal exposures have been associated with adverse child health outcomes. Prenatal PFAS exposure may lead to epigenetic age acceleration (EAA), defined as the discrepancy between an individual's chronologic and epigenetic or biological age., Objectives: We estimated associations of maternal serum PFAS concentrations with EAA in umbilical cord blood DNA methylation using linear regression, and a multivariable exposure-response function of the PFAS mixture using Bayesian kernel machine regression., Methods: Five PFAS were quantified in maternal serum (median: 27 weeks of gestation) among 577 mother-infant dyads from a prospective cohort. Cord blood DNA methylation data were assessed with the Illumina HumanMethylation450 array. EAA was calculated as the residuals from regressing gestational age on epigenetic age, calculated using a cord-blood specific epigenetic clock. Linear regression tested for associations between each maternal PFAS concentration with EAA. Bayesian kernel machine regression with hierarchical selection estimated an exposure-response function for the PFAS mixture., Results: In single pollutant models we observed an inverse relationship between perfluorodecanoate (PFDA) and EAA (-0.148 weeks per log-unit increase, 95% CI: -0.283, -0.013). Mixture analysis with hierarchical selection between perfluoroalkyl carboxylates and sulfonates indicated the carboxylates had the highest group posterior inclusion probability (PIP), or relative importance. Within this group, PFDA had the highest conditional PIP. Univariate predictor-response functions indicated PFDA and perfluorononanoate were inversely associated with EAA, while perfluorohexane sulfonate had a positive association with EAA., Conclusions: Maternal mid-pregnancy serum concentrations of PFDA were negatively associated with EAA in cord blood, suggesting a pathway by which prenatal PFAS exposures may affect infant development. No significant associations were observed with other PFAS. Mixture models suggested opposite directions of association between perfluoroalkyl sulfonates and carboxylates. Future studies are needed to determine the importance of neonatal EAA for later child health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hypotension affects approximately 40% of critically ill patients undergoing emergency intubation and is associated with an increased risk of death. The objective of this study was to examine the association between prophylactic vasopressor administration and the incidence of peri-intubation hypotension and other clinical outcomes., Design: A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors., Setting: Seven emergency departments and 17 ICUs across the United States., Patients: One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021., Interventions: None., Measurements and Main Results: The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66)., Conclusions: The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes., Competing Interests: Dr. Fuchita received a departmental seed grant from the University of Colorado, Department of Anesthesiology, for biostatistical support. Dr. Casey was supported in part by the National Institutes of Health (NIH) (K23HL153584). Dr. Semler was supported in part by the NIH (K23HL143053). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration., Methods: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test., Results: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism., Conclusions: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury., (© 2023. American College of Medical Toxicology.)

Background and Objectives: Existing tools to diagnose spontaneous intracranial hypotension (SIH), namely spinal opening pressure (OP) and brain MRI, have limited sensitivity. We investigated whether evaluation of brain MRI using the Bern score, combined with calculated craniospinal elastance, would aid in diagnosing SIH and provide insight into its pathophysiology., Methods: A retrospective chart review was performed of patients who underwent brain MRI and pressure-augmented dynamic CT myelography (dCTM) for suspicion of SIH. Two blinded neuroradiologists assigned Bern scores for each brain MRI. OP and incremental pressure changes after intrathecal saline infusion were recorded to calculate craniospinal elastance. The relationship between Bern score, OP, and elastance and whether a leak was found were analyzed., Results: Seventy-two consecutive dCTMs were performed in 53 patients. Twelve CSF-venous fistulae, 2 ruptured meningeal diverticula, 2 dural defects, and 1 dural bleb were found (17/53, 32%). Among patients with imaging-proven CSF leak/fistula, OP was normal in all but 1 patient and was not significantly different in those with a leak compared with those without (15.1 vs 13.6 cm H 2 O, p = 0.24, A = 0.40). The average Bern score in individuals with a leak was significantly higher than that in those without (5.35 vs 1.85, p < 0.001, A = 0.85), even when excluding pachymeningeal enhancement from the score (3.77 vs 1.57, p = 0.001, A = 0.78). The average elastance in those with a leak was higher than that in those without, but this difference was not statistically significant (2.05 vs 1.20 mL/cm H 2 O, p = 0.19, A = 0.40). Increased elastance was significantly associated with an increased Bern score (95% CI -0.55 to 0.12, p < 0.01) and was significantly associated with venous distention, pachymeningeal enhancement, prepontine narrowing, and subdural collections, but not a narrowed mamillopontine or suprasellar distance., Discussion: OP is not an effective predictor for diagnosing CSF leak and if used in isolation would result in misdiagnosis of 94% of patients in our cohort. The Bern score was associated with a higher diagnostic yield of dCTM. Elastance was significantly associated with certain components of the Bern score., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The use of hyperoxemia during cardiac surgery remains controversial. We hypothesized that intraoperative hyperoxemia during cardiac surgery is associated with an increased risk of postoperative pulmonary complications., Design: Retrospective cohort study., Setting: We analyzed intraoperative data from five hospitals within the Multicenter Perioperative Outcomes Group between January 1, 2014, and December 31, 2019. We assessed intraoperative oxygenation of adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Hyperoxemia pre and post CPB was quantified as the area under the curve (AUC) of Fio 2 above 0.21 in minutes when the corresponding peripheral oxygen saturation was greater than 92% measured by pulse oximetry. We quantified hyperoxemia during CPB as the AUC of Pao 2 greater than 200 mm Hg measured by arterial blood gas. We analyzed the association of hyperoxemia during all phases of cardiac surgery with the frequency of postoperative pulmonary complications within 30 days, including acute respiratory insufficiency or failure, acute respiratory distress syndrome, need for reintubation, and pneumonia., Patients: Twenty-one thousand six hundred thirty-two cardiac surgical patients., Interventions: None., Measurements and Main Results: During 21,632 distinct cardiac surgery cases, 96.4% of patients spent at least 1 minute in hyperoxemia (99.1% pre-CPB, 98.5% intra-CPB, and 96.4% post-CPB). Increasing exposure to hyperoxemia was associated with an increased risk of postoperative pulmonary complications throughout three distinct surgical periods. During CPB, increasing exposure to hyperoxemia was associated with an increased odds of developing postoperative pulmonary complications ( p < 0.001) in a linear manner. Hyperoxemia before CPB ( p < 0.001) and after CPB ( p = 0.02) were associated with increased odds of developing postoperative pulmonary complications in a U-shaped relationship., Conclusions: Hyperoxemia occurs almost universally during cardiac surgery. Exposure to hyperoxemia assessed continuously as an AUC during the intraoperative period, but particularly during CPB, was associated with an increased incidence of postoperative pulmonary complications., Competing Interests: Dr. Douin received research grant funding from the National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) T32GM135169. Dr. Clendenen received research grant funding from the NIH/NHLBI K23HL151882 (principal investigator: to Dr. Clendenen). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Rationale and Objectives: Recent decades have seen a steady increase in noncontrast head CT utilization in the emergency department with a concurrent rise in the practice of physician assistants (PAs) and nurse practitioners (NPs). The goal of this study was to identify ordering and patient characteristics predictive of positive noncontrast head CTs in the ED. We hypothesized NP/PAs would have lower positivity rates compared to physicians, suggestive of relative overutilization., Materials and Methods: We retrospectively identified ED patients who underwent noncontrast head CTs at a single institution: a nonlevel 1 trauma center, during a 7-year period, recording examination positivity, ordering provider training/experience, and multiple additional ordering/patient attributes. Exam positivity was defined as any intracranial abnormality necessitating a change in acute management, such as acute hemorrhage, hydrocephalus, herniation, or worsening prior findings., Results: 6624 patients met inclusion criteria. 4.6% (280/6107) of physician exams were positive while 3.7% (19/517) of NP/PA exams were positive; however, differences were not significant. Increasing provider experience was not associated with positivity. Attributes with increased positivity were patient age (p < 0.001), daytime exam (p < 0.05), and indications regarding malignancy (p < 0.001) or focal neurologic deficit (p = 0.001). Attributes with decreased positivity were indications of trauma (p < 0.001) or vertigo/dizziness (p < 0.05)., Conclusion: We found no significant difference in rates of exam positivity between physicians and NP/PAs, even accounting for years of experience. This suggests increasing utilization of head CTs in the ED is not due to the increasing presence of NP/PAs, and may be reflective of general practice trends and clear diagnostic algorithms leading to head CT., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

BACKGROUND. SARS-CoV-2 infection is associated with acute stroke, possibly caused by viral tropism to the vascular endothelium. Whether cerebrovascular endothelial dysfunction and inflammation persist after acute infection is poorly understood. OBJECTIVE. The purposes of this study were to assess the association between prior SARS-CoV-2 infection and cerebrovascular reactivity (CVR) and vessel wall imaging (VWI) abnormalities and to explore the association between CVR impairment and post-COVID neurologic conditions. METHODS. This prospective study included 15 participants with prior SARS-CoV-2 infection (11 women, four men; mean age, 43 years; mean time since infection, 238 days; three with prior critical illness, 12 with prior mild illness; seven with post-COVID neurologic conditions) and 10 control participants who had never had SARS-CoV-2 infection (two women, two men; mean age, 44 years) from July 1, 2021, to February 9, 2022. Participants underwent research MRI that included arterial spin labeling perfusion imaging with acetazolamide stimulus to measure cerebral blood flow (CBF) and calculate CVR. Examinations also included VWI, performed with a contrast-enhanced black-blood 3D T1-weighted sequence. An age- and sex-adjusted linear model was used to assess associations between CVR and prior infection. A t test was used to assess associations between CVR and post-COVID neurologic conditions in participants with previous infection. A difference of proportions test was used to assess associations between VWI abnormalities and infection status. RESULTS. Mean whole-cortex CBF after acetazolamide administration was greater in participants without previous infection than in participants with previous infection (73.8 ± 13.2 [SD] vs 60.5 ± 15.8 mL/100 gm/min; p = .04). Whole-brain CVR was lower in participants with previous infection than those without previous infection (difference, -8.9 mL/100 g/min; p < .001); significantly lower CVR was also observed in participants with previous infection after exclusion of those with prior critical illness. Among participants with previous infection, CVR was lower in those with than those without post-COVID neurologic conditions, although this difference was not significant (16.9 vs 21.0 mL/100 g/min; p = .22). Six of 15 (40%) participants with previous infection versus 1 of 10 (10%) participants without previous infection had at least one VWI abnormality ( p = .18). All VWI abnormalities were consistent with atherosclerosis. CONCLUSION. SARS-CoV-2 infection is associated with chronic impairment of CVR. The mechanism is unknown from this study. CLINICAL IMPACT. Future studies are needed to determine the clinical implications of SARS-CoV-2-associated CVR impairment.

Purpose: To develop and validate a non-contrast free-breathing whole-heart 3D cine steady-state free precession (SSFP) sequence with a novel 3D radial leaf trajectory., Methods: We used a respiratory navigator to trigger acquisition of 3D cine data at end-expiration to minimize respiratory motion in our 3D cine SSFP sequence. We developed a novel 3D radial leaf trajectory to reduce gradient jumps and associated eddy-current artifacts. We then reconstructed the 3D cine images with a resolution of 2.0mm 3 using an iterative nonlinear optimization algorithm. Prospective validation was performed by comparing ventricular volumetric measurements from a conventional breath-hold 2D cine ventricular short-axis stack against the non-contrast free-breathing whole-heart 3D cine dataset in each patient (n = 13)., Results: All 3D cine SSFP acquisitions were successful and mean scan time was 07:09 ± 01:31 min. End-diastolic ventricular volumes for left ventricle (LV) and right ventricle (RV) measured from the 3D datasets were smaller than those from 2D (LV: 159.99 ± 42.99 vs. 173.16 ± 47.42; RV: 180.35 ± 46.08 vs. 193.13 ± 49.38; p-value≤0.044; bias<8%), whereas ventricular end-systolic volumes were more comparable (LV: 79.12 ± 26.78 vs. 78.46 ± 25.35; RV: 97.18 ± 32.35 vs. 102.42 ± 32.53; p-value≥0.190, bias<6%). The 3D cine data had a lower subjective image quality score., Conclusion: Our non-contrast free-breathing whole-heart 3D cine sequence with novel leaf trajectory was robust and yielded smaller ventricular end-diastolic volumes compared to 2D cine imaging. It has the potential to make examinations easier and more comfortable for patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined., Methods: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome., Results: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1 , the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort., Conclusion: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Background: Animal studies have shown that midazolam can increase vulnerability to cardiac ischemia, potentially via circadian-mediated mechanisms. We hypothesized that perioperative midazolam administration is associated with an increased incidence of myocardial injury in patients undergoing non-cardiac surgery (MINS) and that circadian biology may underlie this relationship., Methods: We analyzed intraoperative data from the Multicenter Perioperative Outcomes Group for the occurrence of MINS across 50 institutions from 2014 to 2019. The primary outcome was the occurrence of MINS. MINS was defined as having at least one troponin-I lab value ≥0.03 ng/ml from anesthesia start to 72 h after anesthesia end. To account for bias, propensity scores and inverse probability of treatment weighting were applied., Results: A total of 1,773,118 cases were available for analysis. Of these subjects, 951,345 (53.7%) received midazolam perioperatively, and 16,404 (0.93%) met criteria for perioperative MINS. There was no association between perioperative midazolam administration and risk of MINS in the study population as a whole (odds ratio (OR) 0.98, confidence interval (CI) [0.94, 1.01]). However, we found a strong association between midazolam administration and risk of MINS when surgery occurred overnight (OR 3.52, CI [3.10, 4.00]) or when surgery occurred in ASA 1 or 2 patients (OR 1.25, CI [1.13, 1.39])., Conclusion: Perioperative midazolam administration may not pose a significant risk for MINS occurrence. However, midazolam administration at night and in healthier patients could increase MINS, which warrants further clinical investigation with an emphasis on circadian biology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prin, Pattee, Douin, Scott, Ginde and Eckle.)

The Hybrid Rat Diversity Panel (HRDP) is a stable and well-characterized set of more than 90 inbred rat strains that can be leveraged for systems genetics approaches to understanding the genetic and genomic variation associated with complex disease. The HRDP exhibits substantial between-strain diversity while retaining substantial within-strain isogenicity, allowing for the precise mapping of genetic variation associated with complex phenotypes and providing statistical power to identify associated variants. In order to robustly identify associated genetic variants, it is important to account for the population structure induced by inbreeding. To this end, we investigate the performance of four plausible approaches towards modeling quantitative traits in the HRDP and quantify their operating characteristics. In particular, we investigate three approaches based on genome-wide mixed model analysis, and one approach based on ordinary least squares linear regression. Towards facilitating study planning and design, we conduct extensive simulations to investigate the power of genetic association analyses in the HRDP, and characterize the impressive attained power. In simulation of eQTL data in the HRDP, we find that a mixed model approach that leverages leave-one-chromosome-out kinship estimation attains the highest power while controlling type I error., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pattee, Vanderlinden, Mahaffey, Hoffman, Tabakoff and Saba.)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused high inpatient mortality and morbidity throughout the world. COVID-19 convalescent plasma (CCP) has been utilized as a potential therapy for patients hospitalized with coronavirus disease 2019 (COVID-19) pneumonia. This study evaluated the outcomes of hospitalized patients with COVID-19 treated with CCP in a prospective, observational, multicenter trial., Methods: From April through August 2020, hospitalized patients with COVID-19 at 16 participating hospitals in Colorado were enrolled and treated with CCP and compared with hospitalized patients with COVID-19 who were not treated with convalescent plasma. Plasma antibody levels were determined following the trial, given that antibody tests were not approved at the initiation of the trial. CCP-treated and untreated hospitalized patients with COVID-19 were matched using propensity scores followed by analysis for length of hospitalization and inpatient mortality., Results: A total of 542 hospitalized patients with COVID-19 were enrolled at 16 hospitals across the region. A total of 468 hospitalized patients with COVID-19 were entered into propensity score matching with 188 patients matched for analysis in the CCP-treatment and control arms. Fine-Gray models revealed increased length of hospital stay in CCP-treated patients and no change in inpatient mortality compared with controls. In subgroup analysis of CCP-treated patients within 7 days of admission, there was no difference in length of hospitalization and inpatient mortality., Conclusions: These data show that treatment of hospitalized patients with COVID-19 treated with CCP did not significantly improve patient hospitalization length of stay or inpatient mortality., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer., Objectives: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach., Methods: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing., Results: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 -8 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 -4 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels., Conclusion: This work provides new evidence for a role of FGL1 in hemostasis., (© 2021 International Society on Thrombosis and Haemostasis. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Polygenic scores quantify the genetic risk associated with a given phenotype and are widely used to predict the risk of complex diseases. There has been recent interest in developing methods to construct polygenic risk scores using summary statistic data. We propose a method to construct polygenic risk scores via penalized regression using summary statistic data and publicly available reference data. Our method bears similarity to existing method LassoSum, extending their framework to the Truncated Lasso Penalty (TLP) and the elastic net. We show via simulation and real data application that the TLP improves predictive accuracy as compared to the LASSO while imposing additional sparsity where appropriate. To facilitate model selection in the absence of validation data, we propose methods for estimating model fitting criteria AIC and BIC. These methods approximate the AIC and BIC in the case where we have a polygenic risk score estimated on summary statistic data and no validation data. Additionally, we propose the so-called quasi-correlation metric, which quantifies the predictive accuracy of a polygenic risk score applied to out-of-sample data for which we have only summary statistic information. In total, these methods facilitate estimation and model selection of polygenic risk scores on summary statistic data, and the application of these polygenic risk scores to out-of-sample data for which we have only summary statistic information. We demonstrate the utility of these methods by applying them to GWA studies of lipids, height, and lung cancer., Competing Interests: The authors have declared that no competing interests exist.

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22-49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio-functionally. Compared with normal BOEC, abnormal BOEC released 13±3-fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow-up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high- HMGB1 and low- LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.

Genome-wide association studies (GWAS) have successfully identified many genetic variants associated with complex traits. However, GWAS experience power issues, resulting in the failure to detect certain associated variants. Additionally, GWAS are often unable to parse the biological mechanisms of driving associations. An existing gene-based association test framework, Transcriptome-Wide Association Studies (TWAS), leverages expression quantitative trait loci data to increase the power of association tests and illuminate the biological mechanisms by which genetic variants modulate complex traits. We extend the TWAS methodology to incorporate somatic information from tumors. By integrating germline and somatic data we are able to leverage information from the nuanced somatic landscape of tumors. Thus we can augment the power of TWAS-type tests to detect germline genetic variants associated with cancer phenotypes. We use somatic and germline data on lung adenocarcinomas from The Cancer Genome Atlas in conjunction with a meta-analyzed lung cancer GWAS to identify novel genes associated with lung cancer., (© 2019 Wiley Periodicals, Inc.)

Objective: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study., Methods: ARIC identified 408 clinically diagnosed AAAs among 8 962 individuals of European ancestry during a median of 22 years of follow up. The Greek case control study included 341 AAAs of European ancestry recruited in a tertiary referral centre and 292 geographically and ethnically matched controls recruited from the same institution. A Cox proportional hazards model was used to analyse the ARIC data and logistic regression to analyse the Greek data., Results: In ARIC, rs9316871 and rs3827066 were significantly associated with AAA risk (HR [p] was 0.77 [.004] and 1.22 [.03], respectively), rs2836411 was associated at borderline significance (1.13 [.08]), whereas rs1795061 was not associated (p = .55). In the Greek case control study, rs1795061 and rs2836411 were significantly associated with AAA (OR [p] was 1.66 [< .001] and 1.29 [.04], respectively), whereas rs9316871 was not (p = .81). Genotyping of rs3827066 did not succeed. In the meta-analysis of the two studies, the association for rs9316871and rs2836411 was statistically significant and consistent between the two studies: p = .02 and .007, respectively., Conclusions: Associations between rs9316871and rs2836411 and AAA risk were replicated in the meta-analysis of the two independent cohorts, providing further support for the importance of these loci in the aetiology of AAA., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to learn from 29 Black women how to develop effective Type 2 diabetes programming. Three focus groups were held in Des Moines, Iowa, during fall 2012. Results highlighted themes related to diabetes knowledge, diabetes management and prevention, physical activity, diet, and diabetes management programming. Opinions were shared as to whether family members should be included in programs for supporting those diagnosed with diabetes. These results provided guidance and ideas to scholars and health care professionals aiming to improve effectiveness of diabetes programs for Black women and families., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Federal regulations that were published in 1974 required a physician to be employed full or part time as the medical directory by a skilled nursing facilities. Negotiation was needed in each facility to reconcile the traditional role of the physician who care for individual patients with the new role of the physician who would be involved in decisions regarding the care of groups of residents. Professional and provider organizations attempted to define the new role, which developed through experience, networking, and educational opportunities. A consensus conference held in January 1988 identified the functions and tasks associated with medical direction, and, subsequently, educational opportunities focusing on the competencies associated with performing these tasks and functions were developed. This article traces the history and evolution of the formalization of the medical director's role.

We studied the frequency with which cardiopulmonary resuscitation (CPR) is attempted on residents of American nursing homes. Each author (all members of the Clinical Practice Committee of the American Geriatrics Society) completed a questionnaire in 1989 about policy and practice regarding CPR during 1988 in each of three to seven nursing homes, by questioning the medical or nursing director or the administrator. Because of the vagaries of nursing home record-keeping, data from some homes were allowed when they were "accurate to within 10%." Data from 58 nursing homes, totalling 10,836 bed-years were available. In 33 of these homes, accounting for 5,425 bed-years, CPR was never attempted. CPR was more likely to be foregone in nursing homes with religious affiliation than in nursing homes without (13 of 17 vs 18 of 38; chi 2 = 4.0; P less than 0.05). Religious affiliation was unknown for three nursing homes. Academic affiliation (10 of 16 vs 20 of 37 in non-affiliated nursing homes) and non-profit status (14 of 19 vs 16 of 23 in for-profit nursing homes) did not significantly affect the likelihood that CPR would never be used. In 31 of 54 nursing homes with explicit do not resuscitate (DNR) policies, CPR was never performed, compared to 2 of 4 homes without such policies. For nursing homes with complete data, there were 1,196 deaths in 32 facilities where CPR was never attempted compared to 1,294 deaths for 24 nursing homes with CPR. For 22 nursing homes without CPR, there were 2,172 emergency room transfers compared to 1,363 emergency room transfers in 18 nursing homes where CPR was attempted.(ABSTRACT TRUNCATED AT 250 WORDS)

The Department of Family Practice and Community Health of the University of Minnesota Medical School is composed of six affiliated units. Each unit is allied with a hospital complex and operates an independent family practice clinic. Since each unit has unique demographic characteristics, general objectives for training residents in geriatric medicine have been developed. Cognitive, attitudinal and skill objectives also have been identified. The unit director implements the general objectives by using the special strengths of that particular unit.

In fulfilling the need for physician involvement in the care of the elderly in long-term facilities, family physicians can function in three roles. First, they can apply their knowledge and skills to the complex multisystemic problems they encounter as attending physicians. Second, they can develop and organize services as medical directors. Third, they can help to assure quality of care through service on utilization review committees.

Data from a Minneapolis Professional Standards Review Organization (PSRO) are used to explore the frequency of global brain failure, a group of diseases, in a population of nursing home residents. Findings are related to three other studies of the same or similar phenomena. Approximately 15 per cent of all patients in the Minnesota database exhibit global brain failure as measured by functional impairment on mental and physical indices. Thirty per cent of the patients in the database are incontinent. These findings raise ethical issues concerning the care management of the global brain failure patient who has an irreversible and gradually fatal disease.