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Supervised exercise is a common therapeutic intervention for patients with peripheral artery disease (PAD), however, the mechanism underlying the improvement in claudication symptomatology is not completely understood. The hypothesis that exercise improves microvascular blood flow is herein tested via temporally resolved magnetic resonance imaging (MRI) measurement of blood flow and oxygenation dynamics during reactive hyperemia in the leg with the lower ankle-brachial index. One hundred and forty-eight subjects with PAD were prospectively assigned to standard medical care or 3 mo of supervised exercise therapy. Before and after the intervention period, subjects performed a graded treadmill walking test, and MRI data were collected with Perfusion, Intravascular Venous Oxygen saturation, and T

Objective Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 antibodies can enhance initial infection. While cell-culture experiments hinted at this possibility, in-vivo proof remained elusive. Design We used passive immunization in nonhuman primates challenged with simian-human immunodeficiency virus (SHIV), a chimera expressing HIV-1 envelope. We purified IgG from rhesus monkeys with early-stage SHIV infection - before cross-neutralizing anti-HIV-1 antibodies had developed - and screened for maximal complement-mediated antibody-dependent enhancement (C'-ADE) of viral replication with a SHIV strain phylogenetically distinct from that harbored by IgG donor macaques. IgG fractions with maximal C'-ADE but lacking neutralization were combined to yield enhancing anti-SHIV IgG (enSHIVIG). Results We serially enrolled naive macaques (Group 1) to determine the minimal and 50% animal infectious doses required to establish persistent infection after intrarectal SHIV challenge. The first animal was inoculated with a 1:10 virus-stock dilution; after this animal's viral RNA load was >104copies/ml, the next macaque was challenged with 10x less virus, a process repeated until viremia no longer ensued. Group 2 was pretreated intravenously with enSHIVIG 24 hours before SHIV challenge. Overall, Group 2 macaques required 3.4-fold less virus compared to controls (p = 0.002). This finding is consistent with enhanced susceptibility of the passively immunized animals to mucosal SHIV challenge. Conclusion These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure - a potential concern for antibody-based AIDS vaccine development.

Myelodysplastic syndrome (MDS) is a marrow failure disease. As patients often require chronic transfusion, many develop red blood cell (RBC) alloimmunization or immune-mediated platelet refractoriness. MDS represents a spectrum of diseases with specific categorizations and genetic abnormalities, and we set out to determine if these characteristics predispose patients to antibody formation.A natural language search identified MDS patients with pre-transfusion testing from 2015 to 2020. Marrow reports, cytogenetic results, and next-generation sequencing panels were gathered. Transfusion history and testing were collected from the laboratory information system.The group consisted of 226 biopsy-proven MDS patients. The prevalence of RBC alloimmunization was 11.1% (25 of 226). Half (23 of 46) of all RBC alloantibodies were against Rh (C, c, E, e) and Kell (K) antigens. There was a relative enrichment for JAK2 positivity among the RBC alloimmunized group. A total of 7.1% (16 of 226) of patients had immune-mediated platelet refractoriness and had increased transfusion requirements (p ≤ 0.01). No disease type or genetic abnormality was significantly associated with alloimmunization or immune-mediated platelet refractoriness.While JAK2 specific mutations were enriched among RBC alloimmunized patients, this association failed to reach statistical significance in our single-center cohort. Further study using larger patient cohorts is warranted. Overall, this cohort of MDS patients had very similar RBC alloimmunization prevalence and anti-RBC antibody specificities as other recent literature. Our data reinforce the finding that MDS patients are at greater risk for alloimmunization and support the use of extended phenotype matching for these at-risk patients.

While errors can harm patients they remain poorly studied. This study characterized errors in the care of surgical patients and examined the association of errors with morbidity and mortality.Errors have been reported to cause10% or60% of adverse events. Such discordant results underscore the need for further exploration of the relationship between error and adverse events.Patients with operations performed at a single institution and abstracted into the American College of Surgeons National Surgical Quality Improvement Program from January 1, 2018, to December 31, 2018 were examined. This matched case control study comprised cases who experienced a postoperative morbidity or mortality. Controls included patients without morbidity or mortality, matched 2:1 using age (±10 years), sex, and Current Procedural Terminology (CPT) group. Two faculty surgeons independently reviewed records for each case and control patient to identify diagnostic, technical, judgment, medication, system, or omission errors. A conditional multivariable logistic regression model examined the association between error and morbidity.Of 1899 patients, 170 were defined as cases who experienced a morbidity or mortality. The majority of cases (n=93; 55%) had at least 1 error; of the 329 matched control patients, 112 had at least 1 error (34%). Technical errors occurred most often among both cases (40%) and controls (23%). Logistic regression demonstrated a strong independent relationship between error and morbidity (odds ratio=2.67, 95% confidence interval: 1.64-4.35, P0.001).Errors in surgical care were associated with postoperative morbidity. Reducing errors requires measurement of errors.

Background Continuous heart rate (HR) and oxygenation (SpO2) metrics can be useful for predicting adverse events in very low birth weight (VLBW) infants. To optimize the utility of these tools, inter-site variability must be taken into account. Methods For VLBW infants at three neonatal intensive care units (NICUs), we analyzed the mean, standard deviation, skewness, kurtosis, and cross-correlation of electrocardiogram HR, pulse oximeter pulse rate, and SpO2. The number and durations of bradycardia and desaturation events were also measured. Twenty-two metrics were calculated hourly, and mean daily values were compared between sites. Results We analyzed data from 1168 VLBW infants from birth through day 42 (35,238 infant-days). HR and SpO2 metrics were similar at the three NICUs, with mean HR rising by ~10 beats/min over the first 2 weeks and mean SpO2 remaining stable ~94% over time. The number of bradycardia events was higher at one site, and the duration of desaturations was longer at another site. Conclusions Mean HR and SpO2 were generally similar among VLBW infants at three NICUs from birth through 6 weeks of age, but bradycardia and desaturation events differed in the first 2 weeks after birth. This highlights the importance of developing predictive analytics tools at multiple sites. Impact HR and SpO2 analytics can be useful for predicting adverse events in VLBW infants in the NICU, but inter-site differences must be taken into account in developing predictive algorithms. Although mean HR and SpO2 patterns were similar in VLBW infants at three NICUs, inter-site differences in the number of bradycardia events and duration of desaturation events were found. Inter-site differences in bradycardia and desaturation events among VLBW infants should be considered in the development of predictive algorithms.

Individualized prediction is a hallmark of clinical medicine and decision making. However, most existing prediction models rely on biomarkers and clinical outcomes available at a single time. This is in contrast to how health states progress and how physicians deliver care, which relies on progressively updating a prognosis based on available information. With the use of joint models of longitudinal and survival data, it is possible to dynamically adjust individual predictions regarding patient prognosis. This article aims to introduce the reader to the development of dynamic risk predictions and to provide the necessary resources to support their implementation and assessment, such as adaptable R code, and the theory behind the methodology. Furthermore, measures to assess the predictive performance of the derived predictions and extensions that could improve the predictions are presented. We illustrate personalized predictions using an online dataset consisting of patients with chronic liver disease (primary biliary cirrhosis).

BackgroundProgressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously, but occult hypoxemia can occur in Black patients because the technique is affected by skin color. Oxygen dissociation curves allow non-invasive estimation of P/F ratios (ePFR) but this approach remains unproven.Research QuestionCan ePFRs measure overt and occult hypoxemia?Study Design and methodsWe retrospectively studied COVID-19 hospital encounters (n=5319) at two academic centers (University of Virginia [UVA] and Emory University). We measured primary outcomes (death or ICU transfer within 24 hours), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score (NEWS) and Sepsis-3). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AOR) and area under receiver operating characteristics curves (AUROC). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test.ResultsOvert hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; pInterpretationThe ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models like NEWS and Sepsis-3. By accounting for biased oximetry as well as clinicians’ real-time responses to it (supplemental oxygen adjustment), ePFRs may enable statistical modelling of racial disparities in outcomes attributable to occult hypoxemia.

BACKGROUND Intercostal nerve blocks with liposomal bupivacaine are commonly used for thoracic surgery pain management. However, dose scheduling is difficult because the pharmacokinetics of a single-dose intercostal injection of liposomal bupivacaine has never been investigated. The primary aim of this study was to assess the median time to peak plasma concentration (Tmax) following a surgeon-administered, single-dose infiltration of 266 mg of liposomal bupivacaine as a posterior multilevel intercostal nerve block in patients undergoing posterolateral thoracotomy. METHODS We chose a sample size of 15 adults for this prospective observational study. Intercostal injection of liposomal bupivacaine was considered time 0. Serum samples were taken at the following times: 5, 15, and 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours. The presence of sensory blockade, rescue pain medication, and pain level were recorded after the patient was able to answer questions. RESULTS Forty patients were screened, and 15 patients were enrolled in the study. Median (interquartile range [IQR]) Tmax was 24 (12) hours (confidence interval [CI], 19.5-28.5 hours) with a range of 15 minutes to 48 hours. The median (IQR) peak plasma concentration (Cmax) was 0.6 (0.3) μg/mL (CI, 00.45-0.74 μg/mL) in a range of 0.3-1.2. The serum bupivacaine concentration was undetectable (

OBJECTIVES Compare patient characteristics by hospital discharge disposition (home without services, home with home healthcare (HHC) services, or post-acute care (PAC) facilities). Examine timing and rates of 30-day healthcare utilization (rehospitalization, emergency department (ED) visit, or observation (OBS) visit) and patient characteristics associated with rehospitalization by discharge location. DESIGN Retrospective analysis of hospital administrative and clinical data. SETTING AND PARTICIPANTS A total of 3,294 older adult inpatients discharged home with or without HHC services or to a PAC facility. MEASUREMENTS Patient-level sociodemographic and clinical characteristics. Number of and time to occurrences of rehospitalization or ED/OBS visit within 30 days of hospital discharge. RESULTS Most rehospitalizations and ED/OBS visits occurred within 14 days from hospital discharge. Patients who returned within 24 hours came mostly from inpatient rehabilitation facilities (IRFs). More intense levels of PAC services were linked with higher rehospitalization risk. However, specific predictors differed by discharge location. Being unemployed, being single, and having more comorbidities were most associated with rehospitalization in those who went home with or without services, whereas patients rehospitalized from IRFs were younger, with less chronic illness burden, but greater and recent functional decline. Those discharged with HHC services had more return ED/OBS visits. CONCLUSIONS Although sicker patients were referred for more intense levels of PAC services, patients with greater chronic illness burden were still most often rehospitalized. In addition to unique patient differences, rehospitalizations from IRF within 24 hours suggest systems factors are contributory. Most return acute healthcare utilization occurred within 14 days; therefore, interventions should focus on smoothing transitions to all discharge locations. Because predictors of rehospitalization risk differed by discharge disposition, future research is necessary to study approaches aimed at matching patients' care needs with the most suitable PAC services at the right time. J Am Geriatr Soc 68:2279-2287, 2020.

Objective To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered noninvasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms. Study design We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups. Results Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mL/kg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mL/kg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation. Conclusion Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup. Trial Registration Clinicaltrials.gov : NCT02139800 .

ImportanceAttrition in cancer clinical trials (CCTs) can lead to systematic bias, underpowered analyses, and a loss of scientific knowledge to improve treatments. Little attention has focused on retention, especially the role of perceived benefits and burdens, after participants have experienced the trial.ObjectivesTo examine the association between patients’ perceived benefits and burdens of research participation and CCT retention.Design, Setting, and ParticipantsThis survey study was conducted at a National Cancer Institute–designated comprehensive cancer center in the Northeast region of the US. The sample included adult patients with a cancer diagnosis participating in cancer therapeutic trials. Data were collected from September 2015 to June 2019. Analysis of study data was ongoing since November 2019 through October 2022.ExposuresSelf-reported validated survey instrument with a list of 22 benefits and 23 burdens of research participation that can be rated by patients with a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree).Main Outcomes and MeasuresA primary outcome was actual withdrawal from the CCT, and a composite outcome was composite withdrawal that included both actual withdrawal and thoughts of withdrawing. Bivariate and multivariable logistic regressions were used.ResultsAmong the 334 participants in the sample, the mean (SD) age was 61.9 (11.5) years and 174 women (52.1%) were included. Top-cited benefits included both aspirational and action-oriented goals, including helping others (94.2%), contributing to society (90.3%), being treated respectfully (86.2%), and hoping for a cure (86.0%). Worry over receiving a placebo (61.3%), rearranging one’s life (41.9%), and experiencing bothersome adverse effects (41.6%) were notable burdens. An increased burden score was associated with a higher probability of actual withdrawal (adjusted odds ratio [OR], 1.86; 95% CI, 1.1-3.17; P = .02) or composite withdrawal (adjusted OR, 3.44; 95% CI, 2.09-5.67; P P P = .03). The risk of withdrawal was even higher for the composite outcome (adjusted OR, 7.70; 95% CI, 2.76-21.48; P Conclusions and RelevanceThis survey study found that patients perceived important benefits from CCT participation, and this perception was associated with trial retention, even among those who also perceived substantial burdens. A broader dialogue among stakeholders can inform an ethical and patient-centric focus on benefits throughout the course of a CCT to increase retention.

RationaleBreathing motion (respiratory kinematics) can be characterized by the interval and depth of each breath, and by magnitude-synchrony relationships between locations. Such characteristics and their breath-by-breath variability might be useful indicators of respiratory health.ObjectivesTo enable breath-by-breath characterization of respiratory kinematics, we developed a method to detect breaths using motion sensor signals.MethodsIn 34 volunteers who underwent maximal exercise testing, we used 8 motion sensors to record upper rib, lower rib and abdominal kinematics at 3 exercise stages (rest, lactate threshold and exhaustion). We recorded volumetric air flow signals using clinical exercise laboratory equipment and synchronized them with kinematic signals. Using instantaneous phase landmarks from the analytic representation of kinematic and flow signals, we identified individual breaths and derived respiratory rate signals at 1Hz. To evaluate the fidelity of kinematics-derived respiratory rate signals, we calculated their cross-correlation with the flow-derived respiratory rate signals. To identify coupling between kinematics and flow, we calculated the Shannon entropy of the relative frequency with which kinematic phase landmarks were distributed over the phase of the flow cycle.Measurements and Main ResultsWe found good agreement in the kinematics-derived and flow-derived respiratory rate signals, with cross-correlation coefficients as high as 0.94. In some individuals, the kinematics and flow were significantly coupled (Shannon entropy < 2) but the relationship varied within (by exercise stage) and between individuals. The final result was that the phase landmarks from the kinematic signal were uniformly distributed over the phase of the air flow signals (Shannon entropy close to the theoretical maximum of 3.32).ConclusionsThe Analysis of Respiratory Kinematics method can yield highly resolved respiratory rate signals by separating individual breaths. This method will facilitate characterization of clinically significant breathing motion patterns on a breath-by-breath basis. The relationship between respiratory kinematics and flow is much more complex than expected, varying between and within individuals.

Study Objective To identify preoperative and intraoperative risk factors for adnexal torsion after hysterectomy, and to estimate the incidence of the disease in the modern-day era of laparoscopic surgery. Design Retrospective nested case-control study. Setting Large urban medical system. Patients Eighty-nine female patients ages 17 to 51. Interventions Patients underwent ovarian-sparing hysterectomy. Measurements and Main Results The estimated incidence of ovarian torsion after hysterectomy was 0.5% (46/8538 ovarian-sparing hysterectomies). The following variables were found to be associated with adnexal torsion after hysterectomy in an adjusted logistic regression: laparoscopic or laparoscopic-assisted approach to hysterectomy vs any other approach (odds ratio [OR], 3.36; 95% confidence interval [CI], 0.86–13.23); younger age at the time of hysterectomy (17–40 years) vs older age (41–51 years) (OR, 3.45; 95% CI, 1.33–8.97); and a gynecologic history significant for endometriosis (OR, 4.07; 95% CI, 1.04–15.88). Conclusion There is an association between laparoscopic approach to hysterectomy, younger age at time of hysterectomy, and a history of endometriosis with subsequent risk of adnexal torsion. Providers should have a heightened index of suspicion for adnexal torsion after hysterectomy in patients presenting with acute-onset abdominal pain who underwent laparoscopic hysterectomy at a younger age.

Continuous heart rate (HR) and oxygenation (SpOFor VLBW infants at three neonatal intensive care units (NICUs), we analyzed the mean, standard deviation, skewness, kurtosis, and cross-correlation of electrocardiogram HR, pulse oximeter pulse rate, and SpOWe analyzed data from 1168 VLBW infants from birth through day 42 (35,238 infant-days). HR and SpOMean HR and SpOHR and SpO

BackgroundPatients in acute care wards who deteriorate and are emergently transferred to intensive care units (ICUs) have poor outcomes. Early identification of patients who are decompensating might allow for earlier clinical intervention and reduced morbidity and mortality. Advances in bedside continuous predictive analytics monitoring (ie, artificial intelligence [AI]–based risk prediction) have made complex data easily available to health care providers and have provided early warning of potentially catastrophic clinical events. We present a dynamic, visual, predictive analytics monitoring tool that integrates real-time bedside telemetric physiologic data into robust clinical models to estimate and communicate risk of imminent events. This tool, Continuous Monitoring of Event Trajectories (CoMET), has been shown in retrospective observational studies to predict clinical decompensation on the acute care ward. There is a need to more definitively study this advanced predictive analytics or AI monitoring system in a prospective, randomized controlled, clinical trial. ObjectiveThe goal of this trial is to determine the impact of an AI-based visual risk analytic, CoMET, on improving patient outcomes related to clinical deterioration, response time to proactive clinical action, and costs to the health care system. MethodsWe propose a cluster randomized controlled trial to test the impact of using the CoMET display in an acute care cardiology and cardiothoracic surgery hospital floor. The number of admissions to a room undergoing cluster randomization was estimated to be 10,424 over the 20-month study period. Cluster randomization based on bed number will occur every 2 months. The intervention cluster will have the CoMET score displayed (along with standard of care), while the usual care group will receive standard of care only. ResultsThe primary outcome will be hours free from events of clinical deterioration. Hours of acute clinical events are defined as time when one or more of the following occur: emergent ICU transfer, emergent surgery prior to ICU transfer, cardiac arrest prior to ICU transfer, emergent intubation, or death. The clinical trial began randomization in January 2021. ConclusionsVery few AI-based health analytics have been translated from algorithm to real-world use. This study will use robust, prospective, randomized controlled, clinical trial methodology to assess the effectiveness of an advanced AI predictive analytics monitoring system in incorporating real-time telemetric data for identifying clinical deterioration on acute care wards. This analysis will strengthen the ability of health care organizations to evolve as learning health systems, in which bioinformatics data are applied to improve patient outcomes by incorporating AI into knowledge tools that are successfully integrated into clinical practice by health care providers. Trial RegistrationClinicalTrials.gov NCT04359641; https://clinicaltrials.gov/ct2/show/NCT04359641 International Registered Report Identifier (IRRID)DERR1-10.2196/29631

Statins, a common drug class for treatment of dyslipidemia, may be neuroprotective for spontaneous intracerebral hemorrhage (ICH) by targeting secondary brain injury pathways in the surrounding brain parenchyma. Statin-mediated neuroprotection may stem from downregulation of mevalonate and its derivatives, targeting key cell signaling pathways that control proliferation, adhesion, migration, cytokine production, and reactive oxygen species generation. Preclinical studies have consistently demonstrated the neuroprotective and recovery enhancement effects of statins, including improved neurologic function, reduced cerebral edema, increased angiogenesis and neurogenesis, accelerated hematoma clearance, and decreased inflammatory cell infiltration. Retrospective clinical studies have reported reduced perihematomal edema, lower mortality rates, and improved functional outcomes in patients who were taking statins before ICH. Several clinical studies have also observed lower mortality rates and improved functional outcomes in patients who were continued or initiated on statins after ICH. Subgroup analysis of a previous randomized trial has raised concerns of a potentially elevated risk of recurrent ICH in patients with previous hemorrhagic stroke who are administered statins. However, most statin trials failed to show an association between statin use and increased hemorrhagic stroke risk. Variable statin dosing, statin use in the pre-ICH setting, and selection biases have limited rigorous investigation of the effects of statins on post-ICH outcomes. Future prospective trials are needed to investigate the association between statin use and outcomes in ICH.

BACKGROUND: In randomized clinical trials (RCTs) among critically ill patients, it is uncertain how choices regarding the measurement and analysis of nonmortal outcomes measured in terms of duration, such as intensive care unit (ICU) length of stay (LOS), affect studies’ conclusions. OBJECTIVES: Assess the definitions and analytic methods used for ICU LOS analyses in published RCTs. RESEARCH DESIGN: Systematic review and statistical simulation study. RESULTS: Among the 80 of 150 trials providing sufficient information regarding the chosen definition of ICU LOS, three different start-times (ICU admission, trial enrollment/randomization, receipt of intervention) and two end-times (discharge readiness, actual discharge) were used. In roughly three-quarters of these studies, ICU LOS was compared using approaches that did not explicitly account for death, either by ignoring it entirely or stratifying the analyses by survival status. The remaining studies used time-to-event (discharge) models censoring at death or applied a fixed LOS value to patients who died. In statistical simulations, we showed that each analytic approach tested a different question regarding ICU LOS, and that approaches that do not explicitly account for death often produce misleading or ambiguous conclusions when treatments produce small effects on mortality, even if those are not detected as significant in the trial. CONCLUSIONS: There is considerable variability in how ICU LOS is measured and analyzed which impairs the ability to compare results across trials and can produce spurious conclusions. Analyses of duration-based outcomes such as LOS should jointly assess the impact of the intervention on mortality to yield correct interpretations.

Background: Many people living with HIV have persistent monocyte activation despite viral suppression by antiretroviral therapy (ART), which contributes to non-AIDS complications including neurocognitive and other disorders. Statins have immunomodulatory properties that might be beneficial by reducing monocyte activation. Methods: We previously characterized monocyte gene expression and inflammatory markers in 11 HIV-positive individuals on long-term ART (HIV/ART) at risk for non-AIDS complications because of low nadir CD4+ counts (median 129 cells/uL) and elevated hsCRP. Here, these individuals participated in a double-blind, randomized, placebo-controlled crossover study of 12 weeks of atorvastatin treatment. Monocyte surface markers were assessed by flow cytometry, plasma mediators by ELISA and Luminex, and monocyte gene expression by microarray analysis. Results: Among primary outcome measures, 12 weeks of atorvastatin treatment led to an unexpected increase in CCR2+ monocytes (P=0.04), but did not affect CD16+ or CD163+ monocytes, nor levels in plasma of CCL2/MCP-1 or sCD14. Among secondary outcomes, atorvastatin treatment was associated with decreased plasma hsCRP (P=0.035) and IL-2R (P=0.012). Treatment was also associated with increased total CD14+ monocytes (P=0.015), and increased plasma CXCL9 (P=0.003) and IL-12 (P

Following the COVID-19 pandemic, safe and effective vaccines were developed and authorized for use in the general population. Studying factors that encourage community acceptance of these vaccines is needed to prevent proliferation of SARS-CoV-2 variants, to safely relax local restrictions, and to return to pre-pandemic living conditions. To our knowledge, United States (US) county-level disparities in vaccination are yet to be investigated. Our data span February - May 2021 across 3138 US counties. We consider percentage of residents with at least one dose of an authorized COVID vaccine as the outcome. Spatio-temporal models were used to determine associations of vaccination rates with time-fixed and time-varying covariates. Spatial variability was modelled via Conditional Auto-regressive models; county trajectories over time were specified using random slopes. Greater vaccination rates occur in counties with older residents, high educational attainment, and high proportion of minority residents. Vaccination rates change with COVID risk metrics, suggesting continued slowing of vaccine uptake due to decreasing incidence and infection rates. County effects reveal strong regional patterns in average vaccination rates and trajectories. Although local herd immunity can be expected in August 2021 for counties with typical uptake rates, these counties are clustered in relatively few areas of the country.

Maximizing liver graft volume benefits the living donor liver recipient. Whether maximizing graft volume negatively impacts living donor recovery and outcomes remains controversial. Patient randomization between right and left hepatectomy has not been possible due to anatomic constraints; however, a number of published, nonrandomized observational studies summarize donor outcomes between 2 anatomic living donor hepatectomies. This meta-analysis compares donor-specific outcomes after right versus left living donor hepatectomy. Systematic searches were performed via PubMed, Cochrane, ResearchGate, and Google Scholar databases to identify relevant studies between January 2005 and November 2019. The primary outcomes compared overall morbidity and incidence of severe complications (Clavien-Dindo >III) between right and left hepatectomy in donors after liver donation. Random effects meta-analysis was performed to derive summary risk estimates of outcomes. A total of 33 studies (3 prospective and 30 retrospective cohort) were used to identify 7649 pooled patients (5993 right hepatectomy and 1027 left hepatectomy). Proportion of donors who developed postoperative complications did not significantly differ after right hepatectomy (0.33; 95% confidence interval [CI], 0.27-0.40) and left hepatectomy (0.23; 95% CI, 0.17-0.29; P = 0.19). The overall risk ratio (RR) did not differ between right and left hepatectomy (RR, 1.16; 95% CI, 0.83-1.63; P = 0.36). The relative risk for a donor to develop severe complications showed no differences by hepatectomy side (Incidence rate ratio, 0.97; 95% CI, 0.67-1.40; P = 0.86). There is no evidence that the overall morbidity differs between right and left lobe donors. Publication bias reflects institutional and surgeon variation. A prospective, standardized, multi-institutional study would help quantify the burden of donor complications after liver donation.

BACKGROUND Patients on acute care wards who deteriorate and are emergently transferred to intensive care units have poor outcomes. Early identification of decompensating patients might allow for earlier clinical intervention and reduced morbidity and mortality. Advances in bedside continuous predictive analytics monitoring (i.e., artificial intelligence (AI)-based risk prediction) make complex data easily available to healthcare providers, and can provide early warning of potentially catastrophic clinical events. We present a dynamic, visual predictive analytics monitoring tool that integrates real-time bedside telemetric physiologic data into robust clinical models to estimate and communicate risk of imminent events. This tool, CoMET (Continuous Monitoring of Event Trajectories), has been shown in retrospective observational studies to predict clinical decompensation on the acute care ward. There is a need to more definitively study this advanced predictive analytics or AI monitoring system in a prospective, randomized controlled clinical trial. OBJECTIVE The goal of this trial is to determine the impact of an AI-based visual risk analytic, CoMET, on: (1) improving patient outcomes related to clinical deterioration, (2) response time to proactive clinical action, and (3) costs to the healthcare system. METHODS We propose a cluster randomized controlled trial (NCT04359641) to test the impact of displaying CoMET on an acute care cardiology and cardiothoracic surgery hospital floor. The number of admissions to a room undergoing cluster-randomization is estimated to be 10,424 over the 20-month study period. Cluster randomization based on bed number occurs every 2 months. The intervention cluster will have the CoMET score displayed (along with standard of care), while the usual care group receives standard of care only. RESULTS The primary outcome will be hours free from events of clinical deterioration. Hours of acute clinical events are defined as time when one or more of the following occur: emergent ICU transfer, emergent surgery prior to ICU transfer, cardiac arrest prior to ICU transfer, emergent intubation, or death. The clinical trial began randomization in January 2021. CONCLUSIONS Very few AI-based health analytics are translated from algorithm to real-world use. This study will use robust prospective, randomized controlled clinical trial methodology to assess the effectiveness of an advanced AI predictive analytics monitoring system incorporating real-time telemetric data for identifying clinical deterioration on acute care wards. This analysis will strengthen the ability of healthcare organizations to evolve as learning health systems, which apply bioinformatics data to improve patient outcomes by incorporating AI into knowledge tools that are successfully integrated into clinical practice by healthcare providers. CLINICALTRIAL Clinical trials identifier: NCT04359641

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases., Summary: IL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronan’s receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.

Background: Sudden cardiac death (SCD) is a major driver of mortality in patients with end-stage renal disease (ESRD) on hemodialysis (HD). The degree to which ventricular arrhythmias (VA) play a role in SCD in ESRD patients is unclear. Objective: Use cardiac implantable electronic devices (CIEDs) to clarify VA burden in ESRD patients overall and in relation to interdialytic cycle. Methods: We identified 44 patients at a single academic center with CIEDs, 22 on HD, along with 22 age- and sex-matched controls. Device interrogations from 11/13/14 – 4/8/19 were reviewed. Results: Overall, there were no differences in HD patients and controls in adjusted overall event rate (HD 9.81 x 10-5 ± 1.5 x 10-3 events/patient-hours vs control 3.71 x 10-5 ± 9.1 x 10-4 events/patient-hours, p = 0.902), or proportion of patients experiencing VA event (HD 45.4% vs control 63.6%, p = 0.226). There was no difference in ventricular pacing burden. Controls were more likely to require device therapy for VT/VF episodes (total ATP episodes 2/38 in HD vs 10/22 in controls, p < 0.01, total ICD shocks 10/38 in HD vs 17/22 in controls, p < 0.01). HD patients were most likely to experience VA within 12-hours of HD completion (p < 0.01), and the vast majority of events were NSVT. Conclusion: VA and ventricular pacing burden was similar by CIED analysis between groups. In HD patients, VA were likely to occur within the first 12 hours post-dialysis, were primarily NSVT, and were unlikely to require device therapy.

BACKGROUND: In premature infants, clinical changes frequently occur due to sepsis or non-infectious conditions, and distinguishing between these is challenging. Baseline risk factors, vital signs, and clinical signs guide decisions to culture and start antibiotics. We sought to compare heart rate (HR) and oxygenation (SpO2) patterns as well as baseline variables and clinical signs prompting sepsis work-ups ultimately determined to be late-onset sepsis (LOS) and sepsis ruled out (SRO). METHODS: At three NICUs, we reviewed records of very low birth weight (VLBW) infants around their first sepsis work-up diagnosed as LOS or SRO. Clinical signs prompting the evaluation were determined from clinician documentation. HR-SpO2 data, when available, were analyzed for mean, standard deviation, skewness, kurtosis, and cross-correlation. We used LASSO and logistic regression to assess variable importance and associations with LOS compared to SRO. RESULTS: We analyzed sepsis work-ups in 408 infants (173 LOS, 235 SRO). Compared to infants with SRO, those with LOS were of lower GA and BW, and more likely to have a central catheter and mechanical ventilation. Clinical signs cited more often in LOS included hypotension, acidosis, abdominal distension, lethargy, oliguria, and abnormal CBC or CRP (p

OBJECTIVES: Intensive care unit (ICU) costs comprise a significant proportion of the total inpatient charges for cardiac surgery. No reliable method for predicting intensive care unit length of stay following cardiac surgery exists, making appropriate staffing and resource allocation challenging. We sought to develop a predictive model to anticipate prolonged ICU length of stay (LOS). METHODS: All patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery with a Society of Thoracic Surgeons (STS) predicted risk score were evaluated from an institutional STS database. Models were developed using 2014–2017 data; validation used 2018–2019 data. Prolonged ICU LOS was defined as requiring ICU care for at least three days postoperatively. Predictive models were created using lasso regression and relative utility compared. RESULTS: A total of 3,283 patients were included with 1669 (50.8%) undergoing isolated CABG. Overall, 32% of patients had prolonged ICU LOS. Patients with comorbid conditions including severe COPD (53% vs. 29%, p

ObjectiveTo determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGGs, WHO grades II–III) and to stratify the risk of VTE by molecular subtype in gliomas grade II–IV, we performed a retrospective review of a large cohort of patients with glioma.MethodsWe performed a retrospective analysis of a cohort of 635 adult patients with glioma with molecular testing seen at the University of Virginia with a diagnosis of diffuse glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model.ResultsOf 256 patients with LGG, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II–IV patients, absence of an IDH mutation was associated with a threefold increase in VTE risk when compared to IDH-mutant patients (hazard ratio 3.06, 95% confidence interval 2.03–4.64). In patients with glioblastoma, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.ConclusionPatients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in glioblastoma does not affect the incidence of VTE.

Background. Patients may find clinical prediction models more useful if those models accounted for preferences for false-positive and false-negative predictive errors and for other model characteristics. Methods. We conducted a discrete choice experiment to compare preferences for characteristics of a hypothetical mortality prediction model among community-dwelling patients with chronic lung disease recruited from 3 clinics in Philadelphia. This design was chosen to allow us to quantify “exchange rates” between different characteristics of a prediction model. We provided previously validated educational modules to explain model attributes of sensitivity, specificity, confidence intervals (CI), and time horizons. Patients reported their interest in using prediction models themselves or having their physicians use them. Patients then chose between 2 hypothetical prediction models each containing varying levels of the 4 attributes across 12 tasks. Results. We completed interviews with 200 patients, among whom 95% correctly chose a strictly dominant model in an internal validity check. Patients’ interest in predictive information was high for use by themselves ( n = 169, 85%) and by their physicians ( n = 184, 92%). Interest in maximizing sensitivity and specificity were similar (0.88 percentage points of specificity equivalent to 1 point of sensitivity, 95% CI 0.72 to 1.05). Patients were willing to accept a reduction of 6.10 months (95% CI 3.66 to 8.54) in the predictive time horizon for a 1% increase in specificity. Discussion. Patients with chronic lung disease can articulate their preferences for the characteristics of hypothetical mortality prediction models and are highly interested in using such models as part of their care. Just as clinical care should become more patient centered, so should the characteristics of predictive models used to guide that care.

Importance Most preterm infants require respiratory support to establish lung aeration after birth. Intermittent positive pressure ventilation and continuous positive airway pressure are standard therapies. An initial sustained inflation (inflation time >5 seconds) is a widely practiced alternative strategy. Objective To conduct a systematic review and meta-analysis of sustained inflation vs intermittent positive pressure ventilation and continuous positive airway pressure for the prevention of hospital mortality and morbidity for preterm infants. Data Sources MEDLINE (through PubMed), Embase, the Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Central Register of Controlled Trials were searched through June 24, 2019. Study Selection Randomized clinical trials of preterm infants born at less than 37 weeks’ gestation that compared sustained inflation (inflation time >5 seconds) vs standard resuscitation with either intermittent positive pressure ventilation or continuous positive airway pressure were included. Studies including other cointerventions were excluded. Data Extraction and Synthesis Two reviewers assessed the risk of bias of included studies. Meta-analysis of pooled outcome data used a fixed-effects model specific to rarer events. Subgroups were based on gestational age and study design (rescue vs prophylactic sustained inflation). Main Outcomes and Measures Death before hospital discharge. Results Nine studies recruiting 1406 infants met inclusion criteria. Death before hospital discharge occurred in 85 of 736 infants (11.5%) treated with sustained inflation and 62 of 670 infants (9.3%) who received standard therapy for a risk difference of 3.6% (95% CI, −0.7% to 7.9%). Although analysis of the primary outcome identified important heterogeneity based on gestational age subgroups, the 95% CI for the risk difference included 0 for each individual gestational age subgroup. There was no difference in the primary outcome between subgroups based on study design. Sustained inflation was associated with increased risk of death in the first 2 days after birth (risk difference, 3.1%; 95% CI, 0.9%-5.3%). No differences in the risk of other secondary outcomes were identified. The quality-of-evidence assessment was low owing to risk of bias and imprecision. Conclusions and Relevance There was no difference in the risk of the primary outcome of death before hospital discharge, and there was no evidence of efficacy for sustained inflation to prevent secondary outcomes. These findings do not support the routine use of sustained inflation for preterm infants after birth.

Background: Symptom clusters among adults with atrial fibrillation have previously been identified but no study has examined the relationship between symptom clusters and outcomes. Aims: The purpose of this study was to identify atrial fibrillation-specific symptom clusters, characterize individuals with each cluster, and determine whether symptom cluster membership is associated with healthcare utilization. Methods: This was a cross-sectional secondary data analysis of 1501 adults from the Vanderbilt Atrial Fibrillation Registry with verified atrial fibrillation. Self-reported symptoms were measured with the University of Toronto Atrial Fibrillation Severity Scale. We used hierarchical cluster analysis (Ward’s method) to identify clusters and dendrograms, pseudo F, and pseudo T-squared to determine the ideal number of clusters. Next, we used regression analysis to examine the association between cluster membership and healthcare utilization. Results: Males predominated (67%) and the average age was 58.4 years. Two symptom clusters were identified, a Weary cluster (3.7%, n=56, fatigue at rest, shortness of breath at rest, chest pain, and dizziness) and an Exertional cluster (32.7%, n=491, shortness of breath with activity and exercise intolerance). Several sociodemographic and clinical characteristics varied by symptom cluster group membership, including age, gender, atrial fibrillation type, body mass index, comorbidity status, and treatment strategy. Women were more likely to experience either cluster ( pConclusion: We identified two symptom clusters. The Weary cluster was associated with a significantly increased rate of healthcare utilization.

Purpose To prospectively compare survival between human immunodeficiency virus (HIV)-infected versus HIV-uninfected cervical cancer patients who initiated curative chemoradiation therapy (CRT) in a limited-resource setting. Methods and Materials Women with locally advanced cervical cancer with or without HIV infection initiating radical CRT in Botswana were enrolled in a prospective, observational, cohort study from July 2013 through January 2015. Results Of 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122 of 143) had stage II/III cervical cancer, and 67% (96 of 143) were HIV-infected. All HIV-infected patients were receiving antiretroviral therapy (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The 2-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54%-74%) and 66% for HIV-uninfected women (95% CI 49%-79%) (P = .70). Factors associated with better 2-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, P = .003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, P = .04), and age Conclusions Human immunodeficiency virus status had no effect on 2-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status.

Physicians are increasingly being held accountable for patient outcomes, yet their specific contribution to the outcomes remains uncertain.To determine variation in outcomes of mechanically ventilated patients among intensivists, as well as associations between intensivist experience and patient outcomes.We performed a retrospective cohort study of mechanically ventilated Medicare fee-for-service patients in acute care hospitals in Pennsylvania using administrative, clinical, and physician data from Centers for Medicare and Medicaid Services and the American Medical Association from 2008 and 2009. We identified intensivists by training background, board certification, and claims for services provided to patients admitted to an intensive care unit. We assigned patients to intensivists for outcome attribution based on submitted claims for critical care and in-patient services. We estimated the physician-specific adjusted odds ratios (ORs) for 30-day mortality using a hierarchical model with a random effect for physician, adjusted for patient and hospital characteristics. We tested for independent association of physician experience with patient outcomes using mixed-effects regression for the primary outcome of 30-day mortality. We defined physician experience in two ways: years since training completion ("duration") and annual number of mechanically ventilated patients ("volume").We assigned 345 physicians to 11,268 patients. The 30-day mortality was 43% and median hospital length of stay was 11 days (interquartile range = 6-18). The physician adjusted OR varied from 0.72 to 1.64 (median = 0.99; interquartile range = 0.92-1.09). A total of 48% of physicians was outliers, with an adjusted OR significantly different from 1. However, among intensivists, physician experience was not associated with 30-day mortality (duration OR = 1.00 per additional year; 95% confidence interval = 1.00-1.01; volume OR = 1.00 per additional patient; 95% confidence interval = 1.00-1.00).Intensivists independently contribute to outcomes of Medicare patients who undergo mechanical ventilation, as evidenced by the variation in risk-adjusted mortality across intensivists. However, physician experience does not underlie this relationship between intensivists, suggesting the need to identify modifiable physician factors to improve outcomes.

Importance Cancer clinical trials (CCTs) provide patients an opportunity to receive experimental drugs, tests, and/or procedures that can lead to remission. For some, a CCT may seem like their only option. Little is known about experiences of patient-participants who withdraw or are withdrawn from CCTs. Objective To examine patient-participants' experiences during withdrawal from CCTs. Design, setting, and participants This qualitative, descriptive study used a semistructured interview designed specifically for it, with open-ended and probing questions. The study took place at a National Cancer Institute-designated comprehensive cancer center affiliated with the University of Pennsylvania. The need for a sample of 20 interviewees was determined by code and meaning saturation (ie, no new themes revealed and identified themes fully elaborated). Interviews were transcribed verbatim and analyzed with a qualitative software program. Data coded with the software were refined into categories reflecting broad themes. A criterion-based sampling approach was used to select a subset of adult patients with cancer who were former CCT participants and who agreed on exit from those CCTs to a later interview about withdrawal experiences. They were contacted one by one by telephone from September 2015 through June 2019 until 20 agreed. Data analysis was completed in October 2020. Main outcomes and measures Themes characterizing patient-participants' perceptions of their withdrawal experiences. Results Respondents' mean (SD) age was 64.42 (8.49) years; 12 (63.2%) were men. Most respondents were White (18 respondents [94.7%]) and college educated (11 respondents [55.0%]). Cancer stage data were available for 17 participants, 11 of whom (64.7%) had stage IV cancer at CCT enrollment. Thirteen respondents reported withdrawal as a result of disease progression, and 5 withdrew because of adverse effects. Other reasons for withdrawal included acute illness and participant uncertainty about the reason. Analysis of interview data yielded 5 themes: posttrial prognostic awareness, goals of care discussions, emotional coping, burden of adverse effects, and professional trust and support. Subthemes included regrets or hindsight, urgency to start next treatment, and weighing benefits and burdens of treatment. Limited discussions about patient-participants' immediate posttrial care needs left many feeling that there was no clear path forward. Conclusions and relevance Patient-participants transitioning from a CCT described feeling intense symptoms and emotions and awareness that their life span was short and options seemed to be limited. Communication that includes attention to posttrial needs is needed throughout the CCT to help patient-participants navigate posttrial steps. Research should focus on components of responsible and ethical CCT transitions, including types and timing of discussions and who should begin these discussions with patient-participants and their families.