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Rationale: Lack of health insurance maybe an independent risk factor for mortality and differential treatment in critical illness.Objectives: To determine whether uninsured critically ill patients had differences in 30-day mortality and critical care service use compared with those with private insurance and to determine if outcome variability could be attributed to patient-level or hospital-level effects.Methods: Retrospective cohort study using Pennsylvania hospital discharge data with detailed clinical risk adjustment, from fiscal years 2005 and 2006, consisting of 167 general acute care hospitals, with 138,720 critically ill adult patients 64 years of age or younger.Measurements and Main Results: Measurements were 30-day mortality and receipt of five critical care procedures. Uninsured patients had an absolute 30-day mortality of 5.7%, compared with 4.6% for those with private insurance and 6.4% for those with Medicaid. Increased 30-day mortality among uninsured patients persisted after adjustment for patient characteristics (odds ratio [OR], 1.25 for uninsured vs. insured; 95% confidence interval [CI], 1.04–1.50) and hospital-level effects (OR, 1.26; 95% CI, 1.05–1.51). Compared with insured patients, uninsured patients had decreased risk-adjusted odds of receiving a central venous catheter (OR, 0.84; 95% CI,0.72–0.97), acute hemodialysis (OR, 0.59; 95% CI, 0.39–0.91), and tracheostomy (OR, 0.43; 95% CI, 0.29–0.64).Conclusions: Lack of health insurance is associated with increased 30-day mortality and decreased use of common procedures for the critically ill in Pennsylvania. Differences were not attributable to hospital-level effects, suggesting that the uninsured have a higher mortality and receive fewer procedures when compared with privately insured patients treated at the same hospitals. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the epidemiology of type 1 diabetes in children in Philadelphia, Pennsylvania, from 1995 through 1999 and compare these data with previous cohorts. RESEARCH DESIGN AND METHODS: This is a report of a retrospective population-based registry maintained since 1985. Hospital records meeting the following criteria were reviewed: newly diagnosed type 1 diabetes, age 0-14 years, residing in Philadelphia at the time of diagnosis, and diagnosed from 1 January 1995 to 31 December 1999. The secondary source of validation was the School District of Philadelphia. Incidence rates by race and age were compared with 1985-1989 and 1990-1994 cohorts. RESULTS: A total of 234 case subjects were identified, and the registry was determined to be 96% complete. The overall age-adjusted incidence rate in Philadelphia was 14.8 per 100,000/year. Incidence rates in Hispanic children (15.5 per 100,000/year) and white children (12.8 per 100,000/year) have been relatively stable over 15 years. The incidence in black children (15.2 per 100,000/year), however, has increased dramatically, rising 64% in children 5-9 years of age (14.9 per 100,000/year) and 37% in the 10- to 14-year age-group (26.9 per 100,000/year). CONCLUSIONS: The overall incidence of type 1 diabetes in Philadelphia is increasing and is similar to other U.S. registries. These are the first data reporting a higher incidence in black children in a registry of children 0-14 years of age. The etiology of the marked increase in incidence in the black population is unknown and underscores the need to establish type 1 diabetes as a reportable disease, so that environmental risk factors may be thoroughly investigated. [ABSTRACT FROM AUTHOR]

Breathing patterns (respiratory kinematics) contain vital prognostic information. This dimension of physiology is not captured by conventional vital signs. We sought to determine the feasibility and utility of quantifying respiratory kinematics. Using inertial sensors, we analyzed upper rib, lower rib, and abdominal motion of 108 patients with respiratory symptoms during a hospital encounter (582 two-minute recordings). We extracted 34 features based on an explainable correspondence with well-established breathing patterns. K-means clustering revealed that respiratory kinematics had three dimensions apart from the respiratory rate. We represented these dimensions using respiratory rate variability, respiratory alternans (rib-predominant breaths alternating with abdomen-predominant ones), and recruitment of accessory muscles (increased upper rib excursion). Latent profile analysis of the kinematic measures revealed two profiles consistent with the established clinical constructs of labored and unlabored breathing. In logistic regression, the labored breathing profile improved model discrimination for critical illness beyond the Sequential Organ Failure Assessment (SOFA) score (AUROC 0.77 v/s 0.72; p = 0.02). These findings quantitatively confirm the prior understanding that the respiratory rate alone does not adequately represent the complexity of respiratory kinematics; they demonstrate that high-dimensional signatures of labored breathing can be quantified in routine practice settings, and they can improve predictions of clinical deterioration., Competing Interests: Declarations Competing interests SMG, WBA, RDW, SJR, and JRM are co-inventors in United States Patent Application Serial No. 18/018,469 for “METHODS, SYSTEMS, AND COMPUTER READABLE MEDIA FOR ANALYZING RESPIRATORY KINEMATICS”. Other authors declare that they have no competing interests. Ethical approval This study was funded by the Ivy foundation COVID-19 translational research fund. It was approved by University of Virginia Health Sciences Institutional Review Board (study number 20844)., (© 2024. The Author(s).)

Background: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 24 0/7 -27 6/7  weeks' gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation., Methods: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24-27 6/7  weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO 2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO 2  ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks' postmenstrual age, discharge, death, or transfer., Discussion: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites., Trial Registration: www., Clinicaltrials: gov , trial identifier NCT05446272 , registered July 6, 2022., (© 2024. The Author(s).)

Background: Low-intensity shockwave therapy for erectile dysfunction is emerging as a promising treatment option., Aim: This randomized sham-controlled crossover trial assessed the efficacy of low-intensity shockwave therapy in the treatment of erectile dysfunction., Methods: Thirty-three participants with organic erectile dysfunction were enrolled and randomized to shockwave therapy (n = 17) or sham (n = 16). The sham group was allowed to cross over to receive shockwave therapy after 1 month., Outcomes: Primary outcomes were the changes in Sexual Health Inventory for Men (SHIM) score and Erection Hardness Score at 1 month following shockwave therapy vs sham, and secondary outcomes were erectile function measurements at 1, 3, and 6 months following shockwave therapy., Results: At 1 month, mean SHIM scores were significantly increased in the shockwave therapy arm as compared with the sham arm (+3.0 vs -0.7, P  = .024). Participants at 6 months posttreatment (n = 33) showed a mean increase of 5.5 points vs baseline ( P  < .001), with 20 (54.6%) having an increase ≥5. Of the 25 men with an initial Erection Hardness Score <3, 68% improved to a score ≥3 at 6 months. When compared with baseline, the entire cohort demonstrated significant increases in erectile function outcomes at 1, 3, and 6 months after treatment., Clinical Implications: In this randomized sham-controlled crossover trial, we showed that 54.6% of participants with organic erectile dysfunction met the minimal clinically important difference in SHIM scores after treatment with low-intensity shockwave therapy., Strengths and Limitations: Strengths of this study include a sham-controlled group that crossed over to treatment. Limitations include a modest sample size at a single institution., Conclusions: Low-intensity shockwave therapy improves erectile function in men with erectile dysfunction as compared with sham treatment, which persists even 6 months after treatment., Clinical Trial Registration: ClinicalTrials.gov NCT04434352., Competing Interests: None declared., (© Published by Oxford University Press on behalf of The International Society of Sexual Medicine 2023.)

Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C)., Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics., Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy., Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence., Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data., Competing Interests: K.R.B. and S.L. are employees of Palantir Technologies. Y.K. and L.L. are employees of Sema4. M.N.L. is Managing Director of IPQ Analytics, LLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objective: Optimal temporal surgical management of significant carotid stenosis and coronary artery disease remains unknown. Carotid endarterectomy (CEA) and coronary artery bypass (CABG) are performed concurrently (CCAB) or in a staged (CEA-CABG or CABG-CEA) approach. Using the Vascular Quality Initiative-Vascular Implant Surveillance and Interventional Outcomes Coordinated Registry Network-Medicare-linked dataset, this study compared operative and long-term outcomes after CCAB and staged approaches., Methods: The Vascular Quality Initiative-Vascular Implant Surveillance and Interventional Outcomes Coordinated Registry Network dataset was used to identify CEAs from 2011 to 2018 with combined CABG or CABG within 45 days preceding or after CEA. Patients were stratified based on concurrent or staged approach. Primary outcomes were stroke, myocardial infarction (MI), all-cause mortality, stroke and death as composite (SD) and all as composite within 30 days from the last procedure as well as in the long term. Univariate analysis and risk-adjusted analysis using inverse propensity weighting were performed. Kaplan-Meier curves of stroke, MI, and death were created and compared., Results: There were 1058 patients included: 643 CCAB and 415 staged (309 CEA-CABG and 106 CABG-CEA). Compared with staged patients, those undergoing CCAB had a higher preoperative rate of congestive heart failure (24.8% vs 18.4%; P = .01) and decreased renal function (14.9% vs 8.5%; P < .01), as well as fewer prior neurological events (23.5% vs 31.4%; P < .01). Patients undergoing CCAB had similar weighted rate of 30-day stroke (4.6% vs 4.1%; P = .72), death (7.0% vs 5.0%; P = .32), and composite outcomes (stroke and death, 9.8% vs 8.5%; P = .56; stroke, death, and MI, 14.7% vs 17.4%; P = .31), but a lower weighted rate of MI (5.5% vs 11.5%; P < .01) vs the staged cohort. Long-term adjusted risks of stroke (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.54-1.36; P = .51) and mortality (HR, 1.02; 95% CI, 0.76-1.36; P=.91) were similar between groups, but higher risk of MI long-term was seen in those staged (HR, 1.49; 95% CI, 1.07-2.08; P = .02)., Conclusions: In patients undergoing CCAB or staged open revascularization for carotid stenosis and coronary artery disease, the staged approach had an increased risk of postoperative cardiac event, but the short- and long-term rates of stroke and mortality seem to be comparable. Adverse cardiovascular event risk is high between operations when staged and should be a consideration when selecting an approach. Although factors leading to staged sequencing performance need further clarity, CCAB seems to be safe and should be considered an equally reasonable option., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the Pao 2 to the Fio 2 (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously (ratio of the Spo 2 to the Fio 2 [S/F ratio]), but it is affected by skin color and occult hypoxemia can occur in Black patients. Oxygen dissociation curves allow noninvasive estimation of P/F ratios (ePFRs) but remain unproven., Objectives: Measure overt and occult hypoxemia using ePFR., Design Setting and Participants: We retrospectively studied COVID-19 hospital encounters ( n = 5,319) at two academic centers (University of Virginia [UVA] and Emory University)., Main Outcomes and Measures: We measured primary outcomes (death or ICU transfer within 24 hr), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score [NEWS] and Sequential Organ Failure Assessment [SOFA]). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AORs) and area under the receiver operating characteristic curves (AUROCs). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test., Results: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p < 0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (0.70 [both sites]) or SOFA (0.68 [UVA]; 0.65 [Emory]) and similar to S/F ratio (0.76 [UVA]; 0.70 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p < 0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory]; p < 0.01)., Conclusions and Relevance: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models. By accounting for biased oximetry as well as clinicians' real-time responses to it (supplemental oxygen adjustment), ePFRs may reveal racial disparities attributable to occult hypoxemia., Competing Interests: Dr. Moore is supported by the National Institutes of Health (U01AI150508). Dr. Holder is supported by the National Institutes of Health (K23GM37182), and he has received speaker and consulting fees from Baxter International and Philips, respectively. Dr. Kamaleswaran was supported by the National Institutes of Health (R01GM139967). Dr. Clark is an employee of Nihon Kohden Digital Health Solutions (Irvine, CA). Dr. Moorman has equity in Medical Predictive Science Corporation, Charlottesville, VA, and consults for Nihon Kohden Digital Health Solutions, Irvine, CA, with proceeds donated to the University of Virginia Medical Foundation. 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.)

Introduction: Peripheral artery disease and cardiac disease are often comorbid conditions. Echocardiography is a diagnostic tool that can be performed preoperatively to risk stratify patients by a functional cardiac test. We hypothesized that ventricular dysfunction and valvular lesions were associated with an increased incidence of expanded major adverse cardiac events (Expanded MACE)., Methods and Materials: Retrospective cohort study from 2011 to 2020 including all patients from a major academic center who had vascular surgery and an echocardiographic study within two years of the index procedure., Results: 813 patients were included in the study; a majority had a history of smoking (86%), an ASA score of 3 (65%), and were male (68%). Carotid endarterectomy was the most common surgery (24%) and the least common surgery was open abdominal aortic aneurysm repair (5%). We found no significant association between the echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction, or valvular lesions and the postoperative development of Expanded MACE., Conclusions: The preoperative echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction and moderate to severe valvular lesions were not predictive of an increased incidence of postoperative Expanded MACE. We identified a significant association between RV dysfunction and post-operative dialysis that should be interpreted carefully due to the small number of outcomes. The transition from open to endovascular surgery and advances in perioperative management may have led to improved cardiovascular outcomes., Trial Registration: Trial Registration: NCT04836702 (clinicaltrials.gov). https://www.google.com/search?client=firefox-b-d&q=NCT04836702., Competing Interests: The authors acknowledge no competing interest related to this manuscript. MJM has patent applications related to perioperative efficiency (wireless suture needles, scrub table item usage analysis), ownership of PeriOp Green Inc., consulted with Dialectica on viscoelastic monitoring of blood clotting, spoke at Takeda Pharmaceutical on sustainability in healthcare. RSB receives a royalty for publication in UpToDate from Wolters-Kluwer., (Copyright: © 2023 Meyer 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.)

In observational studies, the time origin of interest for time-to-event analysis is often unknown, such as the time of disease onset. Existing approaches to estimating the time origins are commonly built on extrapolating a parametric longitudinal model, which rely on rigid assumptions that can lead to biased inferences. In this paper, we introduce a flexible semiparametric curve registration model. It assumes the longitudinal trajectories follow a flexible common shape function with person-specific disease progression pattern characterized by a random curve registration function, which is further used to model the unknown time origin as a random start time. This random time is used as a link to jointly model the longitudinal and survival data where the unknown time origins are integrated out in the joint likelihood function, which facilitates unbiased and consistent estimation. Since the disease progression pattern naturally predicts time-to-event, we further propose a new functional survival model using the registration function as a predictor of the time-to-event. The asymptotic consistency and semiparametric efficiency of the proposed models are proved. Simulation studies and two real data applications demonstrate the effectiveness of this new approach.

Importance: Attrition 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., Objectives: To examine the association between patients' perceived benefits and burdens of research participation and CCT retention., Design, Setting, and Participants: This 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., Exposures: Self-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 Measures: A 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., Results: Among 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 < .001). An increased benefit score was associated with lower composite withdrawal (adjusted OR, 0.40; 95% CI, 0.24-0.66; P < .001). For participants who reported the benefits as being equal to or greater than the burdens, 13.4% withdrew. For those who perceived the benefits as being less than the burdens, 33.3% withdrew (adjusted OR, 3.38; 95% CI, 1.13-10.14; P = .03). The risk of withdrawal was even higher for the composite outcome (adjusted OR, 7.70; 95% CI, 2.76-21.48; P < .001)., Conclusions and Relevance: This 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.

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 2 * (PIVOT), a method that simultaneously quantifies microvascular perfusion, as well as relative oxygenation changes in skeletal muscle and venous oxygen saturation in a large draining vein. The 3-mo exercise intervention was associated with an improvement in peak walking time (64% greater in those randomized to the exercise group at follow-up, P < 0.001). Significant differences were not observed in the MRI measures between the subjects randomized to exercise therapy versus standard medical care based on an intention-to-treat analysis. However, the peak postischemia perfusion averaged across the leg between baseline and follow-up visits increased by 10% ( P = 0.021) in participants that were adherent to the exercise protocol (completed >80% of prescribed exercise visits). In this cohort of adherent exercisers, there was no difference in the time to peak perfusion or oxygenation metrics, suggesting that there was no improvement in microvascular function nor changes in tissue metabolism in response to the 3-mo exercise intervention. NEW & NOTEWORTHY Supervised exercise interventions can improve symptomatology in patients with peripheral artery disease, but the underlying mechanism remains unclear. Here, MRI was used to evaluate perfusion, relative tissue oxygenation, and venous oxygen saturation in response to cuff-induced ischemia. Reactive hyperemia responses were measured before and after 3 mo of randomized supervised exercise therapy or standard medical care. Those participants who were adherent to the exercise regimen had a significant improvement in peak perfusion.

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)., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Telemedicine has been rapidly adopted in the wake of the COVID-19 pandemic. There is limited work surrounding demographic and socioeconomic disparities that may exist in telemedicine utilization. This study aimed to examine demographic and socioeconomic differences in surgical patient telemedicine usage during the COVID-19 pandemic., Methods: Department of Surgery outpatients seen from July 1, 2019 to May 31, 2020 were stratified into three visit groups: pre-COVID-19 in-person, COVID-19 in-person, or COVID-19 telemedicine. Generalized linear models were used to examine associations of sex, race/ethnicity, Distressed Communities Index (DCI) scores, MyChart activation, and insurance status with telemedicine usage during the COVID-19 pandemic., Results: 14,792 patients (median age 60, female [57.0%], non-Hispanic White [76.4%]) contributed to 21,980 visits. Compared to visits before the pandemic, telemedicine visits during COVID-19 were more likely to be with patients from the least socioeconomically distressed communities (OR, 1.31; 95% CI, 1.08,1.58; P = 0.005), with an activated MyChart (OR, 1.38; 95% CI, 1.17-1.64; P < .001), and with non-government or commercial insurance (OR, 2.33; 95% CI, 1.84-2.94; P < .001). Adjusted comparison of telemedicine visits to in person visits during COVID-19 revealed telemedicine users were more likely to be female (OR, 1.38, 95% CI, 1.10-1.73; P = 0.005) and pay with non-government or commercial insurance (OR, 2.77; 95% CI, 1.85-4.16; P < .001)., Conclusions: During the first three months of the COVID-19 pandemic, telemedicine was more likely utilized by female patients and those without government or commercial insurance compared to patients who used in-person visits. Interventions using telemedicine to improve health care access might consider such differences in utilization., Competing Interests: The authors have declared that no competing interests exist.

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 <0.001). Comparable results were seen in a subgroup that had inflammatory marker elevations at baseline. Atorvastatin treatment did not significantly alter monocyte gene expression or normalize aberrant baseline transcriptional patterns., Conclusions: In this study of aviremic HIV+ individuals at high risk of non-AIDS events, 12 weeks of atorvastatin did not normalize monocyte gene expression patterns nor lead to significant changes in monocyte surface markers or plasma mediators linked to non-AIDS comorbidities., Competing Interests: The authors declare no competing financial or other conflicts of interest., (Copyright © Pathogens and Immunity 2021.)

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 IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, 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, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization via systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before - and all i.r. dIgA doses 30 min before - i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) - consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition., Competing Interests: AL, DC and EC are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. The remaining 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 © 2021 Gong, Lakhashe, Hariraju, Scinto, Lanzavecchia, Cameroni, Corti, Ratcliffe, Rogers, Xiao, Fontenot, Villinger and Ruprecht.)

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.

Background: Patients 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., Objective: The 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., Methods: We 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., 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 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 Registration: ClinicalTrials.gov NCT04359641; https://clinicaltrials.gov/ct2/show/NCT04359641., International Registered Report Identifier (irrid): DERR1-10.2196/29631., (©Jessica Keim-Malpass, Sarah J Ratcliffe, Liza P Moorman, Matthew T Clark, Katy N Krahn, Oliver J Monfredi, Susan Hamil, Gholamreza Yousefvand, J Randall Moorman, Jamieson M Bourque. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.07.2021.)

Background: Continuous heart rate (HR) and oxygenation (SpO 2 ) 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 SpO 2 . 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 SpO 2 metrics were similar at the three NICUs, with mean HR rising by ~10 beats/min over the first 2 weeks and mean SpO 2 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 SpO 2 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 SpO 2 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 SpO 2 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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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 (<0.2 μg/mL) at 96 hours in all patients. There was significant variability in reported pain scores and rescue opioid medication across the 15 patients. More than 50% of patients had return of normal chest wall sensation at 48 hours. All patients had resolution of nerve blockade at 96 hours. No patients developed local anesthetic toxicity., Conclusions: This study of the pharmacokinetics of liposomal bupivacaine following multilevel intercostal nerve blockade demonstrates significant variability and delay in systemic absorption of the drug. Peak serum concentration occurred at 48 hours or sooner in all patients. The serum bupivacaine concentration always remained well below the described toxicity threshold (2 μg/mL) during the 96-hour study period.

Objective: Trajectories of physiomarkers over time can be useful to define phenotypes of disease progression and as predictors of clinical outcomes. The aim of this study was to identify phenotypes of the time course of late-onset sepsis in premature infants in Neonatal Intensive Care Units., Methods: We examined the trajectories of a validated continuous physiomarker, abnormal heart rate characteristics, using functional data analysis and clustering techniques., Participants: We analyzed continuous heart rate characteristics data from 2989 very low birth weight infants (<1500 grams) from nine NICUs from 2004-2010., Result: Despite the relative homogeneity of the patients, we found extreme variability in the physiomarker trajectories. We identified phenotypes that were indicative of seven and 30 day mortality beyond that predicted by individual heart rate characteristics values or baseline demographic information., Conclusion: Time courses of a heart rate characteristics physiomarker reveal snapshots of illness patterns, some of which were more deadly than others., (© The Author(s) 2020.)

It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system., (Copyright © 2020 Shinde, Howie, Stegmann, Hay, Waterman, Szittner, Bentlage, Kapp, Lissenberg-Thunnissen, Dekkers, Schasfoort, Ratcliffe, Smolkin, Vidarsson, Schoot, Hudson and Zimring.)

Non-mortality septic shock outcomes (e.g., Sequential Organ Failure Assessment score) are important clinical endpoints in pivotal sepsis trials. However, comparisons of observed longitudinal non-mortality outcomes between study groups can be biased if death is unequal between study groups or is associated with an intervention (i.e., informative censoring). We compared the effects of vasopressin versus norepinephrine on the Sequential Organ Failure Assessment score in the Vasopressin and Septic Shock Trial to illustrate the use of joint modeling to help minimize potential bias from informative censoring., Design: Secondary analysis of the Vasopressin and Septic Shock Trial data., Setting: Twenty-seven ICUs in Canada, Australia, and United States., Subjects: Seven hundred sixty-three participants with septic shock who received blinded vasopressin ( n = 389) or norepinephrine infusions ( n = 374)., Measurements and Main Results: Sequential Organ Failure Assessment scores were calculated daily until discharge, death, or day 28 after randomization. Mortality was numerically higher in the norepinephrine arm (28 d mortality of 39% vs 35%; p = 0.25), and there was a positive association between higher Sequential Organ Failure Assessment scores and patient mortality, characteristics that suggest a potential for bias from informative censoring of Sequential Organ Failure Assessment scores by death. The best-fitting joint longitudinal (i.e., linear mixed-effects model) and survival (i.e., Cox proportional hazards model for the time-to-death) model showed that norepinephrine was associated with a more rapid improvement in the total Sequential Organ Failure Assessment score through day 4, and then the daily Sequential Organ Failure Assessment scores converged and overlapped for the remainder of the study period., Conclusions: Short-term reversal of organ dysfunction occurred more rapidly with norepinephrine compared with vasopressin, although differences between study arms did not persist after day 4. Joint models are an accessible methodology that could be used in critical care trials to assess the effects of interventions on the longitudinal progression of key outcomes (e.g., organ dysfunction, biomarkers, or quality of life) that may be informatively truncated by death or other censoring events., Competing Interests: Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of proprotein convertase subtilisin/kexin type 9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock. He is an inventor on these patents. He was a founder, Director, and shareholder in Cyon Therapeutics and is a shareholder in Molecular You. He reports receiving consulting fees in the last 3 years from: 1) Asahi Kesai Pharmaceuticals of America (developing recombinant thrombomodulin in sepsis); 2) SIB Therapeutics LLC (developing a sepsis drug); and 3) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). He is no longer actively consulting for the following: 1) La Jolla Pharmaceuticals (developing angiotensin II; he chaired the Data and Safety Monitoring Board of a trial of angiotensin II from 2015 to 2017), no longer actively consulting; 2) Grifols (sells albumin), no longer actively consulting; and 3) PAR Pharma (sells prepared bags of vasopressin), no longer actively consulting. He reports having received an investigator-initiated grant from Grifols (entitled “Is [heparin binding protein] a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: People living with HIV on antiretroviral therapy (HIV/ART) experience excess non-AIDS comorbidities, and also remain at increased risk for certain infections and viral malignancies. Monocytes/macrophages are central to many of these comorbidities, and elevated plasma cytokines and immune activation during untreated infection are often incompletely reversed by ART and are also associated with comorbidities., Methods: We investigated monocyte surface markers, gene expression, and plasma cytokines in 11 HIV-infected older individuals (median 53 years) who started therapy with low CD4 counts (median 129 cells/µl), with elevated hsCRP (≥ 2mg/L) despite long-term ART (median 7.4 years), along with matched controls., Results: Frequency of monocyte subsets (based on CD14/CD16/CD163), were not different from controls, but surface expression of CD163 was increased ( P = 0.021) while PD1 was decreased ( P = 0.013) along with a trend for higher tissue factor ( P = 0.096). As a group, HIV/ART participants had elevated plasma CCL2 (MCP-1; P = 0.0001), CXCL9 (MIG; P = 0.04), and sIL2R ( P = 0.015), which were correlated, while sCD14 was not elevated. Principal component analysis of soluble markers revealed that 6/11 HIV/ART participants clustered with controls, while 5 formed a distinct group, driven by IL-10, CCL11, CXCL10, CCL2, CXCL9, and sIL2R. These individuals were significantly older than those clustering with controls. Transcriptomic analysis revealed multiple genes linked to immune functions including inflammation, immune cell development, and cell-cell signaling that were downregulated in HIV/ART monocytes and distinct from patterns in untreated subjects., Conclusions: Long-term ART-treated individuals normalize monocyte subsets but exhibit immune dysregulation involving both aberrant inflammation and monocyte dysfunction, as well as inter-individual heterogeneity, suggesting complex mechanisms linking monocytes and HIV/ART comorbidities., Competing Interests: The authors declare no competing financial or other conflicts of interest., (© Pathogens and Immunity 2019.)

Background: Aortic valve replacement (AVR) for calcific aortic stenosis is associated with high rates of perioperative stroke and silent cerebral infarcts on diffusion-weighted magnetic resonance imaging (MRI), but cognitive outcomes in elderly AVR patients compared with individuals with cardiac disease who do not undergo surgery are uncertain., Methods: One hundred ninety AVR patients (mean age 76 ± 6 years) and 198 non-surgical participants with cardiovascular disease (mean age 74 ± 6 years) completed comprehensive cognitive testing at baseline (preoperatively) and 4 to 6 weeks and 1 year postoperatively. Surgical participants also completed perioperative stroke evaluations, including postoperative brain MRI. Mixed model analyses and reliable change scores examined cognitive outcomes. Stroke outcomes were evaluated in participants with and without postoperative cognitive dysfunction., Results: From reliable change scores, only 12.4% of the surgical group demonstrated postoperative cognitive dysfunction at 4 to 6 weeks and 7.5% at 1 year. Although the surgical group had statistically significantly lower scores in working memory/inhibition 4 to 6 weeks after surgery, the groups did not differ at 1 year. In surgical participants, postoperative cognitive dysfunction was associated with a greater number (p < 0.01) and larger total volume (p < 0.01) of acute cerebral infarcts on MRI., Conclusions: In high-risk, aged participants undergoing surgical AVR for aortic stenosis, postoperative cognitive dysfunction was surprisingly limited and was resolved by 1 year in most. Postoperative cognitive dysfunction at 4 to 6 weeks was associated with more and larger acute cerebral infarcts., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Build and validate a clinical decision support (CDS) algorithm for discharge decisions regarding referral for post-acute care (PAC) and to what site of care. Materials and Methods: Case studies derived from EHR data were judged by 171 interdisciplinary experts and prediction models were generated. Results: A two-step algorithm emerged with area under the curve (AUC) in validation of 91.5% (yes/no refer) and AUC 89.7% (where to refer). Discussion: CDS for discharge planning (DP) decisions may remove subjectivity, and variation in decision-making. CDS could automate the assessment process and alert clinicians of high need patients earlier in the hospital stay. Conclusion: Our team successfully built and validated a two-step algorithm to support discharge referral decision-making from EHR data. Getting patients the care and support they need may decrease readmissions and other adverse events. Further work is underway to test the effects of the CDS on patient outcomes in two hospitals.

Introduction: The prevalence of HIV-associated neurocognitive disorders continues to rise despite the widespread use of antiretroviral therapy. We aimed to define the risk of neurocognitive dysfunction among smokers relative to nonsmokers., Methods: We conducted a retrospective cohort study including HIV-infected adults ages 21 to 65 years. The Mental Alternation Test (MAT) was the primary outcome. The odds of cognitive impairment were compared using random-effects logistic regression to adjust for potential confounders., Results: Of 3033, 1486 (49%) were smokers. The odds ratio for the association between smoking and cognitive impairment was 1.12 (95% confidence interval: 0.85-1.49). Nonsmokers had a higher median MAT score relative to smokers ( P = .01)., Conclusion: There was no evidence that HIV-infected smokers had greater neurocognitive dysfunction relative to HIV-infected nonsmokers. While tobacco use remains an important health risk issue to address in the HIV population, it may not represent a risk factor for neurocognitive impairment.

Clinical endpoints measured in terms of duration, such as intensive care unit (ICU) length of stay (LOS), are widely used in randomized clinical trials (RCTs) and observational research. In analyses of patient-level data from a recent RCT, in which ICU LOS was the primary endpoint, and in administrative data, we showed that additional ICU time is often accrued by patients after they are deemed ready for discharge. This "immutable" time (which cannot plausibly be altered by interventions under study) varies by day, week, and year, adding on average one-third of a day to total LOS. We then used statistical simulations, informed by the administrative data and RCT, to assess the impact of immutable time on the measurement and statistical comparison of patients' ICU LOS. These simulations demonstrated that immutable time combines with clinically necessary ICU time (neither of which is likely to be normally distributed) to produce overall LOS distributions that might either mask true treatment effects or suggest false treatment effects relative to analyses of time to discharge readiness. The extent and direction of bias were complex functions of the statistical method used, mortality rates and distributions, and the magnitude of immutable time relative to intervention-associated reductions in LOS., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.

Background and Purpose: Stroke is a potentially devastating complication of cardiac surgery. Identifying predictors of radiographic infarct may lead to improved stroke prevention for surgical patients., Methods: We reviewed 129 postoperative brain magnetic resonance imagings from a prospective study of patients undergoing surgical aortic valve replacement. Acute infarcts were classified as watershed or embolic using prespecified criteria., Results: Acute infarct on magnetic resonance imaging was seen in 79 of 129 patients (61%), and interrater reliability for stroke pathogenesis was high (κ=0.93). Embolic infarcts only were identified in 60 patients (46%), watershed only in 2 (2%), and both in 17 (13%). In multivariable logistic regression, embolic infarct was associated with aortic arch atheroma (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.0-12.0; P=0.055), old subcortical infarcts (OR, 5.5; 95% CI, 1.1-26.6; P=0.04), no history of percutaneous transluminal coronary angioplasty or coronary artery bypass graft (OR, 4.0; 95% CI, 1.2-13.7; P=0.03), and higher aortic valve gradient (OR, 1.3 per 5 mm Hg; 95% CI, 1.09-1.6; P=0.004). Watershed infarct was associated with internal carotid artery stenosis ≥70% (OR, 11.7; 95% CI, 1.8-76.8; P=0.01) and increased left ventricular ejection fraction (OR, 1.6 per 5% increase; 95% CI, 1.08-2.4; P=0.02)., Conclusions: The principal mechanism of acute cerebral infarction after aortic valve replacement is embolism. There are distinct factors associated with watershed and embolic infarct, some of which may be modifiable., (© 2016 American Heart Association, Inc.)

Background: Endothelial dysfunction present in patients with peripheral artery disease may be better understood by measuring the temporal dynamics of blood flow and oxygen saturation during reactive hyperemia than by conventional static measurements., Methods and Results: Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), a recently developed MRI technique, was used to measure the response to an ischemia-reperfusion paradigm in 96 patients with peripheral artery disease of varying severity and 10 healthy controls. Perfusion, venous oxygen saturation SvO2, and T2* were each quantified in the calf at 2-s temporal resolution, yielding a dynamic time course for each variable. Compared with healthy controls, patients had a blunted and delayed hyperemic response. Moreover, patients with lower ankle-brachial index had (1) a more delayed reactive hyperemia response time, manifesting as an increase in time to peak perfusion in the gastrocnemius, soleus, and peroneus muscles, and in the anterior compartment, (2) an increase in the time to peak T2* measured in the soleus muscle, and (3) a prolongation of the posterior tibial vein SvO2 washout time. Intrasession and intersession repeatability were also assessed. Results indicated that time to peak perfusion and time to peak T2* were the most reliable extracted time course metrics., Conclusions: Perfusion, dynamic SvO2, and T2* response times after induced ischemia are highly correlated with peripheral artery disease severity. Combined imaging of peripheral microvascular blood flow and dynamics of oxygen saturation with Perfusion, intravascular SvO2, and T2* may be a useful tool to investigate the pathophysiology of peripheral artery disease., (© 2015 American Heart Association, Inc.)

Background: Extremely preterm infants require assistance recruiting the lung to establish a functional residual capacity after birth. Sustained inflation (SI) combined with positive end expiratory pressure (PEEP) may be a superior method of aerating the lung compared with intermittent positive pressure ventilation (IPPV) with PEEP in extremely preterm infants. The Sustained Aeration of Infant Lungs (SAIL) trial was designed to study this question., Methods/design: This multisite prospective randomized controlled unblinded trial will recruit 600 infants of 23 to 26 weeks gestational age who require respiratory support at birth. Infants in both arms will be treated with PEEP 5 to 7 cm H2O throughout the resuscitation. The study intervention consists of performing an initial SI (20 cm H20 for 15 seconds) followed by a second SI (25 cm H2O for 15 seconds), and then PEEP with or without IPPV, as needed. The control group will be treated with initial IPPV with PEEP. The primary outcome is the combined endpoint of bronchopulmonary dysplasia or death at 36 weeks post-menstrual age., Trial Registration: www.clinicaltrials.gov , Trial identifier NCT02139800 , Registered 13 May 2014.

Although commonly observed in clinical practice, the heterogeneity of obstructive sleep apnoea (OSA) clinical presentation has not been formally characterised. This study was the first to apply cluster analysis to identify subtypes of patients with OSA who experience distinct combinations of symptoms and comorbidities. An analysis of baseline data from the Icelandic Sleep Apnoea Cohort (822 patients with newly diagnosed moderate-to-severe OSA) was performed. Three distinct clusters were identified. They were classified as the "disturbed sleep group" (cluster 1), "minimally symptomatic group" (cluster 2) and "excessive daytime sleepiness group" (cluster 3), consisting of 32.7%, 24.7% and 42.6% of the entire cohort, respectively. The probabilities of having comorbid hypertension and cardiovascular disease were highest in cluster 2 but lowest in cluster 3. The clusters did not differ significantly in terms of sex, body mass index or apnoea-hypopnoea index. Patients with OSA have different patterns of clinical presentation, which need to be communicated to both the lay public and the professional community with the goal of facilitating care-seeking and early identification of OSA. Identifying distinct clinical profiles of OSA creates a foundation for offering more personalised therapies in the future., (©ERS 2014.)

Unlabelled: The possibility that vaccination with adenovirus (AdV) vectors increased mucosal T cell activation remains a central hypothesis to explain the potential enhancement of HIV acquisition within the Step trial. Modeling this within rhesus macaques is complicated because human adenoviruses, including human adenovirus type 5 (HAdV-5), are not endogenous to macaques. Here, we tested whether vaccination with a rhesus macaque-derived adenoviral vector (simian adenovirus 7 [SAdV-7]) enhances mucosal T cell activation within rhesus macaques. Following intramuscular SAdV-7 vaccination, we observed a pronounced increase in SAdV-7-specific CD4(+) T cell responses in peripheral blood and, more dramatically, in rectal mucosa tissue. Vaccination also induced a significant increase in the frequency of activated memory CD4(+) T cells in SAdV-7- and HAdV-5-vaccinated animals in the rectal mucosa but not in peripheral blood. These fluctuations within the rectal mucosa were also associated with a pronounced decrease in the relative frequency of naive resting CD4(+) T cells. Together, these results indicate that peripheral vaccination with an AdV vector can increase the activation of mucosal CD4(+) T cells, potentially providing an experimental model to further evaluate the role of host-vector interactions in increased HIV acquisition after AdV vector vaccination., Importance: The possibility that vaccination with a human adenovirus 5 vector increased mucosal T cell activation remains a central hypothesis to explain the potential enhancement of human immunodeficiency virus (HIV) acquisition within the Step trial. In this study, we tested whether vaccination with a rhesus macaque-derived adenoviral vector in rhesus macaques enhances mucosal CD4(+) T cell activation, the main cell target of simian immunodeficiency virus (SIV)/HIV. The results showed that vaccination with an adenoviral vector indeed increases activation of mucosal CD4(+) T cells and potentially increases susceptibility to SIV infection., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Rationale: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits., Objectives: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials., Methods: One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied., Measurement and Main Results: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%., Conclusions: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.

Background: The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized., Methods and Results: We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1-9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay., Conclusions: Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality., (© 2014 American Heart Association, Inc.)

Rationale: The aging population may strain intensive care unit (ICU) capacity and adversely affect patient outcomes. Existing fluctuations in demand for ICU care offer an opportunity to explore such relationships., Objectives: To determine whether transient increases in ICU strain influence patient mortality, and to identify characteristics of ICUs that are resilient to surges in capacity strain., Methods: Retrospective cohort study of 264,401 patients admitted to 155 U.S. ICUs from 2001 to 2008. We used logistic regression to examine relationships of measures of ICU strain (census, average acuity, and proportion of new admissions) near the time of ICU admission with mortality., Measurements and Main Results: A total of 36,465 (14%) patients died in the hospital. ICU census on the day of a patient's admission was associated with increased mortality (odds ratio [OR], 1.02 per standardized unit increase; 95% confidence interval [CI]: 1.00, 1.03). This effect was greater among ICUs employing closed (OR, 1.07; 95% CI: 1.02, 1.12) versus open (OR, 1.01; 95% CI: 0.99, 1.03) physician staffing models (interaction P value = 0.02). The relationship between census and mortality was stronger when the census was composed of higher acuity patients (interaction P value < 0.01). Averaging strain over the first 3 days of patients' ICU stays yielded similar results except that the proportion of new admissions was now also associated with mortality (OR, 1.04 for each 10% increase; 95% CI: 1.02, 1.06)., Conclusions: Several sources of ICU strain are associated with small but potentially important increases in patient mortality, particularly in ICUs employing closed staffing models. Although closed ICUs may promote favorable outcomes under static conditions, they are susceptible to being overwhelmed by patient influxes.

Human adenovirus (AdHu)-based candidate AIDS vaccine can provide protection from simian immunodeficiency virus (SIV) transmission and disease progression. However, their potential use may be limited by widespread preexisting immunity to the vector. In contrast, preexisting immunity to chimpanzee adenoviruses (AdC) is relatively rare. In this study, we utilized two regimens of prime-boost immunizations with AdC serotype SAd-V23 (also called AdC6) and SAd-V24 (also called AdC7) expressing SIV Gag/Tat to test their immunogenicity and ability to protect rhesus macaques (RMs) from a repeated low-dose SIVmac239 challenge. Both AdC6 followed by AdC7 (AdC6/7) and AdC7 followed by AdC6 (AdC7/6) induced robust SIV Gag/Tat-specific T cell responses as measured by tetramer staining and functional assays. However, no significant protection from SIV transmission was observed in either AdC7/6- or AdC7/6-vaccinated RMs. Interestingly, in the RMs showing breakthrough infections, AdC7/6-SIV immunization was associated with a transient but significant (P = 0.035 at day 90 and P = 0.033 at day 120 postinfection) reduction in the setpoint viral load compared to unvaccinated controls. None of the measured immunological markers (i.e., number or functionality of SIV-specific CD8(+) and CD4(+) T cell responses and level of activated and/or CCR5(+) CD4(+) target cells) at the time of challenge correlated with protection from SIV transmission in the AdC-SIV-vaccinated RMs. The robust immunogenicity observed in all AdC-immunized RMs and the transient signal of protection from SIV replication exhibited by AdC7/6-vaccinated RMs even in the absence of any envelope immunogen suggest that AdC-based vectors may represent a promising platform for candidate AIDS vaccines.

Objective: To assess whether women with polycystic ovary syndrome (PCOS) follow the same age-related decline in IVF outcomes as women with tubal factor infertility over the reproductive life span. PCOS is characterized by increased ovarian reserve as assessed by antral follicle counts and anti-Müllerian hormone levels. It is unclear whether these surrogate markers of ovarian reserve reflect a true lengthening of the reproductive window., Design: Retrospective cohort., Setting: Not applicable., Patient(s): Women with PCOS and tubal factor infertility (42,286 cycles)., Intervention(s): IVF., Main Outcome Measure(s): Pregnancy and live-birth rates., Result(s): The mean number of oocytes retrieved was higher in women with PCOS compared with in women with tubal factor (16.4 vs. 12.8; odds ratio [OR], 1.27; 95% confidence interval [CI], 1.25-1.29). The clinical pregnancy (42.5% vs. 35.8%; OR, 1.32; 95% CI, 1.27-1.38) and live-birth rates were also increased in women with PCOS (34.8% vs. 29.1%; OR, 1.30; 95% CI, 1.24-1.35). A similar rate of decline in clinical pregnancy and live-birth rates was noted in both groups (20-44 years). The implantation, clinical pregnancy, miscarriage, and live-birth rates were not significantly different for each year after age 40 in the two groups., Conclusion(s): Despite a higher oocyte yield in all age groups, women with PCOS over age 40 had similar clinical pregnancy and live-birth rates compared with women with tubal factor infertility. These findings suggest that the reproductive window may not be extended in PCOS and that patients with infertility should be treated in a timely manner despite indicators of high ovarian reserve., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000-2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes., Research Design and Methods: Diabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period., Results: The overall age-adjusted incidence rate in 2000-2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0-4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children., Conclusions: The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985-1989 cohort. The most marked increases were among white children ages 10-14 years and black children ages 0-4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.

In this study, we compared the immunogenicity and protection from repeated low-dose intrarectal SIVmac251 challenge in two groups of vaccinated RMs. Animals were immunized with live SIVmac239, which had been attenuated by a deletion of the nef sequence, or they were vaccinated twice with an E1-deleted AdHu5, expressing SIVmac239gag. The vaccinated animals and a cohort of unvaccinated control animals were then challenged 10 times in weekly intervals with low doses of SIVmac251 given rectally. Our results confirm previous studies showing that whereas SIVΔnef provides some degree of protection against viral acquisition after repeated low-dose rectal SIVmac251 challenges, vaccination with an AdHu5gag vaccine designed to induce only antiviral T cell responses is ineffective. As immunological analyses of prechallenge, vaccine-induced T and B cell responses failed to reveal correlates of protection that distinguished the more susceptible from the more resistant vaccinated animals, we carried out RNA-Seq studies of paired pre- and postvaccination samples to identify transcriptional patterns that correlated with the differences in response. We show that gene expression signatures associated with the delayed SIV infection seen in some AdHu5gag recipients were largely present in prevaccination samples of those animals. In contrast, the responding SIVΔnef-immunized animals showed a predominance of vaccine-induced changes, thus enabling us to define inherited and vaccine-induced gene expression signatures and their associated pathways that may play a role in preventing SIV acquisition.