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Background: Differences in outcomes by indication for venoarterial extracorporeal life support (VA-ECLS) are poorly described. We hypothesized that patients on VA-ECLS for acute pulmonary embolism (PE) have fewer complications and better survival than patients on VA-ECLS for other indications., Methods: All patients ≥18 years on VA-ECLS from the Extracorporeal Life Support Organization global registry (2010-2019) were evaluated (n = 29,842). After excluding patients aged >79 years (n = 729) and those with incomplete indication data (n = 2530), patients were stratified by VA-ECLS indication for PE vs all other indications. The association between being discharged alive and each type of complication with VA-ECLS indication was assessed., Results: Of 26,583 patients included in the analysis, 978 (3.7%) were on VA-ECLS for a primary diagnosis of acute PE. Acute PE patients were younger (53.1 vs 56.7 years, P < .001) and were more likely to be women (52.1% vs 32.3%, P < .001). Patients who underwent VA-ECLS for acute PE were 78% more likely to be discharged alive vs patients supported with VA-ECLS for other reasons (52.8% vs 40.4%; P < .001). Acute PE patients had fewer cardiovascular and renal complications (26.6% vs 38.0% and 31.1% vs 39.4%, respectively; adjusted P < .001). Acute PE patients had higher odds of having clots and mechanical complications (8.7% vs 7.9% and 16.7% vs 14.6%, respectively; adjusted P < .001)., Conclusions: Patients undergoing VA-ECLS for acute PE have higher odds of survival to hospital discharge compared with those supported for other indications. Additionally, VA-ECLS in this population is associated with fewer cardiovascular and renal complications but higher mechanical complications., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Importance: Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials., Objective: To examine cancer clinical trial (CCT) participants' perceptions of informed consent processes and variations in perceptions by cancer type., Design and Setting and Participants: Cross-sectional survey from mixed-methods study at National Cancer Institute-designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or genitourinary, hematologic-lymphatic malignancies, lung cancer, and breast or gynecological cancer ( N  = 334)., Main Outcome Measures: Percentages satisfied with consent process and information provided; and assessing participation's perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type., Results: Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did-47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT., Conclusions and Relevance: Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making.

Objective . Very few predictive models have been externally validated in a prospective cohort following the implementation of an artificial intelligence analytic system. This type of real-world validation is critically important due to the risk of data drift, or changes in data definitions or clinical practices over time, that could impact model performance in contemporaneous real-world cohorts. In this work, we report the model performance of a predictive analytics tool developed before COVID-19 and demonstrate model performance during the COVID-19 pandemic. Approach . The analytic system (CoMETⓇ, Nihon Kohden Digital Health Solutions LLC, Irvine, CA) was implemented in a randomized controlled trial that enrolled 10 422 patient visits in a 1:1 display-on display-off design. The CoMET scores were calculated for all patients but only displayed in the display-on arm. Only the control/display-off group is reported here because the scores could not alter care patterns. Main results. Of the 5184 visits in the display-off arm, 311 experienced clinical deterioration and care escalation, resulting in transfer to the intensive care unit, primarily due to respiratory distress. The model performance of CoMET was assessed based on areas under the receiver operating characteristic curve, which ranged from 0.725 to 0.737. Significance. The models were well-calibrated, and there were dynamic increases in the model scores in the hours preceding the clinical deterioration events. A hypothetical alerting strategy based on a rise in score and duration of the rise would have had good performance, with a positive predictive value more than 10-fold the event rate. We conclude that predictive statistical models developed five years before study initiation had good model performance despite the passage of time and the impact of the COVID-19 pandemic., (Creative Commons Attribution license.)

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: Operative risk for supra-aortic trunk (SAT) surgical revascularization for occlusive disease, particularly transthoracic reconstruction (TR), remains ill-defined. This study sought to describe and compare 30-day outcomes of TR and extra-anatomic (ER) SAT surgical reconstruction for an occlusive indication across the United States over a contemporary 15-year period., Methods: Using the National Surgical Quality Improvement Program, TR and ER performed during 2005-2019 were identified. Procedures performed for nonocclusive indications and those concomitant with coronary or valve operations were excluded. Rates of stroke, death, myocardial infarction (MI) and these as composite outcome (S/D/M) were compared. Logistic regression with stabilized inverse probability weighting (IPW) was used to compare groups via average treatment effect (ATE) while adjusting for covariate imbalances., Results: Over the 15-year period, 166 TR and 1,900 ER patients were identified. The majority of ERs were carotid-subclavian bypass (n = 1,344; 70.7%) followed by carotid-carotid bypass (n = 261; 13.7%) and subclavian/carotid transpositions (n = 123; 6.5%). TR consisted of aorto-SAT bypass (n = 120; 72.3%) and endarterectomy (n = 46; 27.7%). The median age was 64 years for TR and 65 years in ER (P = 0.039). Those undergoing TR were more often women (69.0% vs. 56.9%; P = 0.001) and less likely to have undergone previous cardiac surgery (9.2% vs. 20.8%; P = 0.006). TR were also less frequently hypertensive (68.1% vs. 75.4%; P = 0.038) and had statistically lower preoperative creatinine levels (0.86 vs 0.91; P = 0.002). Unadjusted rates of MI (0.6% vs. 1.3%; P = 0.72) and stroke (3.6% vs. 1.9%; P = 0.15) were similar between groups with mortality (3.6% vs. 1.5%; P = 0.05) and S/D/M (6.6% vs. 3.9%; P = 0.10) trending higher with TR. IPWs could be calculated for 1,754 patients (148 TR; 1,606 ER). The estimated probability of S/D/M was 3.8% in the ER group and 6.2% in TR; no difference was seen in ATE (2.4%; 95% confidence interval [CI]: -1.5 to 6.2; P = 0.23). No differences were seen in individual component ATEs (stroke: 3.0% vs. 1.7%; ATE = 1.3%; 95% CI: -3.9 to 1.3; P = 0.32; mortality: 3.8% vs. 1.4%; ATE = 2.4%; 95% CI: -5.6 to 0.7; P = 0.13). Secondary outcomes showed TR patients were more likely to have non-home discharge (18.7% vs. 6.6%; ATE = 12.1%; 95% CI: 5.0-19.2; P < 0.001) and longer lengths of stay (6.1 vs. 4.0; ATE = 2.2 days; 95% CI: 0.9-3.4; P < 0.001). Moreover, TR patients were more likely to require transfusion (22.7% vs. 5.0%; ATE = 17.7%; 95% CI: 10.2-25.2; P < 0.001) and develop sepsis (2.7% vs. 0.2%; ATE = 2.5%; 95% CI: 0.1-5.0; P = 0.04)., Conclusions: Transthoracic and extra-anatomic surgical reconstruction of the SATs for occlusive disease have similar operative cardiovascular risk. However, morbidity tends to be higher with TR due to higher transfusion requirements, sepsis risk, and need for facility stay. These results suggest ER as a first-line approach in those with proper disease anatomy is reasonable with lower morbidity, while TR remains justified in appropriate patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life., Methods: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation., Results: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing., Conclusions: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation., Impact: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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.)

Introduction: Deep sternal wound infection (DSWI) is a rare complication associated with high mortality. Seasonal variability in surgical site infections has been demonstrated, however, these patterns have not been applied to DSWI. The purpose of this study was to assess temporal clustering of DSWIs., Methods: All cardiac surgery patients who underwent sternotomy were queried from a regional Society of Thoracic Surgeons database from 17 centers from 2001 to 2019. All patients with the diagnosis of DSWI were then identified. Cluster analysis was performed at varying time intervals (monthly, quarterly, and yearly) at the hospital and regional level. DSWI rates were calculated by year and month, and compared using mixed-effects negative binomial regression., Results: A total of 134,959 patients underwent a sternotomy for cardiac surgery, of whom 469 (0.35%) developed a DSWI. Rates of DSWI per hospital across all years ranged from 0.12% to 0.69%. Collaborative-level rates of DSWIs were the greatest in September (0.44%) and the lowest in January (0.30%). Temporal clustering was not seen across seasonal quarters (high rate in preceeding quarter was not associated with a high rate in the next quarter) (P = 0.39). There were yearly differences across all institutions in the DSWI rates. A downward trend in DSWI rates was seen from 2001 to 2019 (P < 0.001). A difference among hospitals in the cohort was observed (P < 0.001)., Conclusions: DSWI are a rare event within our region. Unlike other surgical site infection, there does not appear to be a seasonal pattern associated with DSWI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Medicaid expansion's (ME) impact on postoperative outcomes after abdominal surgery remains poorly defined. We aimed to evaluate ME's effect on surgical morbidity, mortality, and readmissions in a state that expanded Medicaid (Virginia) compared to a state that did not (Tennessee) over the same time period., Methods: Virginia Surgical Quality Collaborative (VSQC) American College of Surgeons National Surgical Quality Improvement Program data for Medicaid, uninsured, and private insurance patients undergoing abdominal procedures before Virginia's ME (3/22/18-12/31/18) were compared with post-ME (1/1/19-12/31/19), as were corresponding non-ME state Tennessee Surgical Quality Collaborative (TSQC) data for the same 2018 and 2019 time periods. Postexpansion odds ratios for 30-d morbidity, 30-d mortality, and 30-d unplanned readmission were estimated using propensity score-adjusted logistic regression models., Results: In Virginia, 4753 abdominal procedures, 2097 pre-ME were compared to 2656 post-ME. In Tennessee, 5956 procedures, 2484 in 2018 were compared to 3472 in 2019. VSQC's proportion of Medicaid population increased following ME (8.9% versus 18.8%, P < 0.001) while uninsured patients decreased (20.4% versus 6.4%, P < 0.001). Post-ME VSQC had fewer 30-d readmissions (12.2% versus 6.0%, P = 0.013). Post-ME VSQC Medicaid patients had significantly lower probability of morbidity (-8.18, 95% confidence interval: -15.52 ∼ -0.84, P = 0.029) and readmission (-6.92, 95% confidence interval: -12.56 ∼ -1.27, P = 0.016) compared to pre-ME. There were no differences in probability of morbidity or readmission in the TSQC Medicaid population between study periods (both P > 0.05); there were no differences in mortality between study periods in VSQC and TSQC patient populations (both P > 0.05)., Conclusions: ME was associated with decreased 30-d morbidity and unplanned readmissions in the VSQC. Data-driven policies accounting for ME benefits should be considered., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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: To compare comprehensive continence outcomes in patients receiving pelvic floor muscle training (PFMT) vs standard unsupervised home pelvic floor exercise therapy (UPFE)., Methods: As part of the UVA prostatectomy functional outcomes program, participating patients complete a 12-month PFMT program under FPMRS specialist supervision. We performed a retrospective review of prospectively collected longitudinal outcomes in patients receiving PFMT vs UPFE through 12-month follow-up. Primary study outcome was ICIQ-MLUTS SUI domain score (SDS). Secondary outcomes included daily pad use (PPD), SUI Cure (SDS=0), and quality of life score (IIQ-7). Multilevel mixed effects linear regression was used to model SDS over time., Results: Analysis included 40 men. No difference in patient characteristics was seen in comparison of PFMT vs UPFE cohorts (P = NS, all comparisons). Mean predicted SDS was significantly better in the PFMT vs UPFE cohorts at 6-month (0.81 ± 0.21 vs 1.75 ± 0.34, respectively) (P = .014) and 12-month (0.72 ± 0.17 vs 1.67 ± 0.30, respectively) (P = .004) time points. At 12-month follow-up, 11 (55%) vs 4 (20%) patients reported absence of SUI in PFMT vs UPFE cohorts, respectively. Predicted probabilities of SUI cure in PFMT vs UPFE cohorts at 12months were 0.52 ± 0.14 vs 0.23 ± 0.13, respectively (P = .14). At 12-month follow-up, the mean predicted PPD and IIQ score was 0.19 ± 0.10 vs 0.79 ± 0.33 and 2.86 ± 0.86 vs 2.55 ± 1.07 in PFMT vs UPFE cohorts, respectively (P = NS)., Conclusion: In-person, FMPRS-directed PFMT is associated with improved SUI domain scores following robotic-assisted laparoscopic prostatectomy, a finding durable through 12-month follow-up., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O 2 /support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O 2 /support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

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.

Background: 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., Study Design and Methods: 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., Results: 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., Discussion: 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., (© 2022 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

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.

Objective: 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., Background: Errors have been reported to cause <10% or >60% of adverse events. Such discordant results underscore the need for further exploration of the relationship between error and adverse events., Methods: 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., Results: 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, P <0.001)., Conclusion: Errors in surgical care were associated with postoperative morbidity. Reducing errors requires measurement of errors., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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). 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. A total of 3283 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 < 0.001), recent pneumonia (46% vs 31%, P < 0.001), dialysis-dependent renal failure (57% vs 31%, P < 0.001) or reoperative status (41% vs 31%, P < 0.001) were more likely to experience prolonged ICU stays. A prediction model utilizing preoperative and intraoperative variables correctly predicted prolonged ICU stay 76% of the time. A preoperative variable-only model exhibited 74% prediction accuracy. Excellent prediction of prolonged ICU stay can be achieved using STS data. Moreover, there is limited loss of predictive ability when restricting models to preoperative variables. This novel model can be applied to aid patient counseling, resource allocation, and staff utilization., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective. Breathing 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. To enable breath-by-breath characterization of respiratory kinematics, we developed a method to detect breaths using motion sensors. Approach. In 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 (RR) signals at 1 Hz. To evaluate the fidelity of kinematics-derived RR, we calculated bias, limits of agreement, and cross-correlation coefficients (CCC) relative to flow-derived RR. To identify coupling between kinematics and flow, we calculated the Shannon entropy of the relative frequency with which flow landmarks were distributed over the phase of the kinematic cycle. Main Results. We found good agreement in the kinematics-derived and flow-derived RR signals [bias (95% limit of agreement) = 0.1 (± 7) breaths/minute; CCC median (IQR) = 0.80 (0.48-0.91)]. In individual signals, kinematics and flow were well-coupled (entropy 0.9-1.4 across sensors), but the relationship varied within (by exercise stage) and between individuals. The final result was that the flow landmarks did not consistently localize to any particular phase of the kinematic signals (entropy 2.2-3.0 across sensors). Significance. The 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., (Creative Commons Attribution license.)

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., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

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 h 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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

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.

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., (© 2020 The American Geriatrics Society.)

Background: Allergic asthmatic subjects are uniquely susceptible to acute wheezing episodes provoked by rhinovirus. However, the underlying immune mechanisms and interaction between rhinovirus and allergy remain enigmatic, and current paradigms are controversial., Objective: We sought to perform a comprehensive analysis of type 1 and type 2 innate and adaptive responses in allergic asthmatic subjects infected with rhinovirus., Methods: Circulating virus-specific T H 1 cells and allergen-specific T H 2 cells were precisely monitored before and after rhinovirus challenge in allergic asthmatic subjects (total IgE, 133-4692 IU/mL; n = 28) and healthy nonallergic controls (n = 12) using peptide/MHCII tetramers. T cells were sampled for up to 11 weeks to capture steady-state and postinfection phases. T-cell responses were analyzed in parallel with 18 cytokines in the nose, upper and lower airway symptoms, and lung function. The influence of in vivo IgE blockade was also examined., Results: In uninfected asthmatic subjects, higher numbers of circulating virus-specific PD-1 + T H 1 cells, but not allergen-specific T H 2 cells, were linked to worse lung function. Rhinovirus infection induced an amplified antiviral T H 1 response in asthmatic subjects versus controls, with synchronized allergen-specific T H 2 expansion, and production of type 1 and 2 cytokines in the nose. In contrast, T H 2 responses were absent in infected asthmatic subjects who had normal lung function, and in those receiving anti-IgE. Across all subjects, early induction of a minimal set of nasal cytokines that discriminated high responders (G-CSF, IFN-γ, TNF-α) correlated with both egress of circulating virus-specific T H 1 cells and worse symptoms., Conclusions: Rhinovirus induces robust T H 1 responses in allergic asthmatic subjects that may promote disease, even after the infection resolves., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Patients at greatest risk for fall-related injuries are older adults with orthostatic hypotension (OH), a condition which drops blood pressure. This study sought to determine salient demographic and patient-level factors increasing risk for OH among a sample of elderly fallers., Methods: Data analysis for this retrospective study sought to assess the relationship between various demographic and clinical risk factors and the likelihood of OH. Because fallers could experience multiple falls, generalized estimating equations were used to account for patient-level correlations., Results: One hundred seventeen falls occurred in 47 patients, who were primarily female with a mean age of 90.7 years. Falls resulted in 18 cases of OH. Orthostatic hypotension cases were less likely to have a gait in a steady line (5.6% vs 55.6%, P = 0.001). Patients with decreased muscular coordination were almost 5 times more likely to experience OH than those with no coordination problems (odds ratio = 4.86, P = 0.02). Patients with gait in a steady line were less likely to experience OH after a fall (OR = 0.06, P = 0.006)., Conclusions: Orthostatic hypotension is potentially modifiable once detected. Evidenced-based protocol for assessment and management of OH among patients with gait and balance impairment is presented.

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.)

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.

Aims: Survival after delivery room cardiopulmonary resuscitation (DR-CPR) is not well characterized in full-term infants, and survival outcomes after DR-CPR have not been defined across the spectrum of gestation. The study objectives were to define gestational age (GA) specific survival following DR-CPR and to assess the association between GA and DR-CPR characteristics and survival outcomes., Methods: Retrospective cohort study of prospectively collected data in the American Heart Association Get With the Guidelines-Resuscitation registry. Newborn infants without congenital abnormalities who received greater than 1 min of chest compressions for DR-CPR were included. GA was stratified by categorical subgroups: ≥36 weeks; 33-35 6/7 weeks; 29-32 6/7 weeks; 25-28 6/7 weeks; 22-24 6/7 weeks. The primary outcome was survival to hospital discharge; the secondary outcome was return of circulation (ROC)., Results: Among 1022 infants who received DR-CPR, 83% experienced ROC and 64% survived to hospital discharge. GA-stratified hospital survival rates were 83% (≥36 weeks), 66% (33-35 weeks), 60% (29-32 weeks), 52% (25-28 weeks), and 25% (22-24 weeks). Compared with GA ≥ 36 weeks, lower GA was independently associated with decreasing odds of survival (33-35 weeks: adjusted Odds Ratio [aOR] 0.46, 95% Confidence Interval [CI] 0.26-0.81; 29-32 weeks: aOR 0.40, 95% CI 0.23-0.69; 25-28 weeks: aOR 0.21, 95% CI 0.11-0.41; 22-24 weeks: aOR 0.06, 95% CI 0.03-0.10)., Conclusions: In this national registry of infants who received delivery room cardiopulmonary resuscitation (DR-CPR), 83% survived the event and two-thirds survived to hospital discharge. These results contribute to defining survival outcomes following DR-CPR across the continuum of gestation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Infants with congenital diaphragmatic hernia (CDH) often experience hypoxaemia with acidosis immediately after birth. The traditional approach in the delivery room is immediate cord clamping followed by intubation. Initiating resuscitation prior to umbilical cord clamping (UCC) may support this transition., Objectives: To establish the safety and feasibility of intubation and ventilation prior to UCC for infants with CDH. To compare short-term outcomes between trial participants and matched controls treated with immediate cord clamping before intubation and ventilation., Design: Single-arm, single-site trial of infants with CDH and gestational age ≥36 weeks. Infants were placed on a trolley immediately after birth and underwent intubation and ventilation, with UCC performed after qualitative CO 2 detection. The primary feasibility endpoint was successful intubation prior to UCC. Prespecified safety and physiological outcomes were compared with historical controls matched for prognostic variables using standard bivariate tests., Results: Of 20 enrolled infants, all were placed on the trolley, and 17 (85%) infants were intubated before UCC. The first haemoglobin and mean blood pressure at 1 hour of life were significantly higher in trial participants than controls. There were no significant differences between groups for subsequent blood pressure values, vasoactive medications, inhaled nitric oxide or extracorporeal membrane oxygenation. Blood gas and oxygenation index values did not differ between groups at any point., Conclusions: Intubation and ventilation prior to UCC is safe and feasible among infants with CDH. The impact of this approach on clinically relevant outcomes deserves investigation in a randomised trial., Competing Interests: Competing interests: EEF is an unpaid member of the Scientific Advisory board for Concord Neonatal. NN receives research support from Draeger, Aerogen, Smiths Medical, Actuated Medical and Vero Biotech. No other competing interests are declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

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.