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

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.

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

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

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

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

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

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

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

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

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

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

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

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.

Supplemental Digital Content is available in the text., Objectives: 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.

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

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

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

Rationale: Understanding long-term outcomes of critically ill patients may inform shared decision-making in the intensive care unit (ICU).Objectives: To quantify 6-month functional outcomes of general ICU patients, and develop a multivariable model comprising factors present during the first ICU day to predict which patients will return to their baseline function 6 months later.Methods: We conducted a prospective cohort study in three medical ICUs and two surgical ICUs in three hospitals. We enrolled patients who spent at least 3 days in the ICU and received mechanical ventilation for more than 48 hours and/or vasoactive infusions for more than 24 hours.Results: We measured 6-month outcomes including survival, return to original place of residence, and physical and cognitive function. Of 303 enrolled patients, 299 (98.7%) had complete follow-up at 6 months. Among the 169 patients (56.5%) who survived to 6 months, 82.8% returned home, 81.9% were able to toilet, 71.3% were able to ambulate 10 stairs, and 62...

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

This article explores the validity of the Sustained Aeration Inflation for Infant Lungs (SAIL) randomized controlled clinical trial. The SAIL trial enrolled 460 infants out of a planned 600, but the trial was stopped early for harm. We ask here, whether there were any threats to validity in the trial as conducted. We then explore what design elements of the trial could have been improved upon. Finally, we consider what the implications are for future trials in this arena. Clinical Trial Registration: www.clinicaltrials.gov, Identifier: NCT02139800.

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; 33–356/7 weeks; 29–326/7 weeks; 25–286/7 weeks; 22–246/7 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.

OBJECTIVE: To study the relationship between cancer patient/research participants’ perceptions of communication with their research nurse and doctor and 1) participants’ thoughts of dropping out from their cancer clinical trials (CCTs), 2) how informed they felt before and during their clinical trial participation, and 3) trust in their researchers. METHODS: We surveyed 110 adult cancer patients who were enrolled in cancer clinical trials by using 15 modified items from the Medical Communication Competence Scale measuring information exchange and relational communication. Retention was measured by two items: ever thought about dropping out (yes/no) and likelihood of remaining enrolled in the clinical trial (5-point Likert item). We asked how well informed about the trial participants felt at enrollment, at the date they filled out the survey, and about changes in the trial. RESULTS: Patient-participants with thoughts of dropping out from their CCTs rated their communication with research doctors lower than those who did not have thoughts of dropping out (4.14 versus 4.46, t=2.22, p=0.03). Patient-participants’ intention to remain enrolled was correlated with more favorable scores on relational communication (such as contributing to a trusting relationship and showing compassion) with research doctors (r=0.20, p=0.04) and nurses (r=0.25, p=0.01). Communication with doctors was also associated with how informed patient-participants felt during their clinical trials. CONCLUSIONS: Relational communication with research doctors and nurses was significantly related to thoughts about remaining enrolled or dropping out of a clinical trial among adult participants in cancer treatment clinical trials. PRACTICE IMPLICATIONS: Relational skills with cancer patients advances communication in research.

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.

Objective To describe the factors patients and physicians prioritize during first-trimester miscarriage management and assess what drives satisfaction with care. Methods We conducted a mixed-methods study of clinically stable women seeking surgical, medical, or expectant miscarriage treatment. Women with first-trimester fetal demise or anembryonic gestation (N=55) completed demographic and psychosocial surveys. Using purposive sampling, 45 (82%) completed in-depth interviews. Fifteen obstetricians were interviewed. Participants described factors that informed their counseling (physicians) or decision-making (patients). Content analysis used an integrated approach with inductively and deductively derived codes. Patient-derived themes were stratified by treatment choice. Associations between variables and treatment choices were analyzed. Results Thirty-four women (62%) received surgical management, 19 (35%) received medical, and two (4%) received expectant. Physicians expected that women with prior pregnancies have strong management preferences, and indeed, multigravid patients were less likely to change their initial treatment choice after counseling than primigravid patients (12% compared with 42%, odds ratio [OR] 0.18, 95% confidence interval [CI] 0.04-0.81, P=.03). Physicians favored patient-centered decisions and patients chose the treatment that they thought would least affect other responsibilities. Those ultimately receiving surgical management had a higher monthly income (adjusted OR 1.30, 95% CI 1.04-1.63, P=.023) and more social support (adjusted OR 2.45, 95% CI 1.07-5.61, P=.035) than the medical group. The surgical group cited loss acceptance, a favorable perception of surgery, and a desire to expedite the miscarriage as decisive factors. The medical group endorsed control over, and timed completion of, the miscarriage in a more intimate setting, an aversion to surgery or anesthesia, and a perception of improved fertility preservation as decisive factors. Regardless of treatment choice, satisfaction with treatment was linked to a supportive clinical team and expeditious resolution. Conclusion Prior pregnancy experiences, obligations, and sociodemographic factors influence miscarriage management decision-making. Structured counseling, especially for primigravid patients, could improve both the physician and the patient experience with miscarriage care.

Introduction Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction. Methods To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA. Results Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanine-adenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and intravenous glucose loads. Conclusions FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient to patient. Muscle Nerve 54: 887-894, 2016.

SummaryEliciting knowledge from geographically dispersed experts given their time and scheduling constraints, while maintaining anonymity among them, presents multiple challenges.Describe an innovative, Internet based method to acquire knowledge from experts regarding patients who need post-acute referrals. Compare, 1) the percentage of patients referred by experts to percentage of patients actually referred by hospital clinicians, 2) experts’ referral decisions by disciplines and geographic regions, and 3) most common factors deemed important by discipline.De-identified case studies, developed from electronic health records (EHR), contained a comprehensive description of 1,496 acute care inpatients. In teams of three, physicians, nurses, social workers, and physical therapists reviewed case studies and assessed the need for post-acute care referrals; Delphi rounds followed when team members did not agree. Generalized estimating equations (GEEs) compared experts’ decisions by discipline, region of the country and to the decisions made by study hospital clinicians, adjusting for the repeated observations from each expert and case. Frequencies determined the most common case characteristics chosen as important by the experts.The experts recommended referral for 80% of the cases; the actual discharge disposition of the patients showed referrals for 67%. Experts from the Northeast and Midwest referred 5% more cases than experts from the West. Physicians and nurses referred patients at similar rates while both referred more often than social workers. Differences by discipline were seen in the factors identified as important to the decision.The method for eliciting expert knowledge enabled national dispersed expert clinicians to anonymously review case summaries and make decisions about post-acute care referrals. Having time and a comprehensive case summary may have assisted experts to identify more patients in need of post-acute care than the hospital clinicians. The methodology produced the data needed to develop an expert decision support system for discharge planning.Citation: Bowles KH, Ratcliffe S, Potashnik S, Topaz M, Holmes J, Shih N-W, Naylor MD. Using electronic case summaries to elicit multi-disciplinary expert knowledge about referrals to post-acute care.

Objectives: We aimed to determine the accuracy and validity of the Ultrasonic Cardiac Output Monitor (USCOM) measurements of cardiac output (CO) compared to echocardiography in newborn infants, and the inter-rater agreement of USCOM measurements. Methods: In a single-center study we prospectively evaluated neonates undergoing an echocardiographic evaluation. USCOM measurements of CO were obtained at the pulmonary and aortic valve by 2 physicians blinded to the echocardiographic results. All echocardiographic measurements were performed blinded to USCOM measurements. We first enrolled an ascertainment cohort which was subsequently validated in an independent new cohort. Agreement between echocardiography and USCOM methods was assessed by Bland-Altman analysis. Intra-class correlation coefficients (ICC) assessed the agreement between the 2 operators. The ascertainment cohort correction factors were applied in a second validation cohort and agreement of the calibrated measures evaluated with repeat Bland-Altman comparisons. Results: A total of 50 infants were enrolled in the initial cohort and 15 in the validation cohort. There was a high degree of correlation between the USCOM operators (ICC = 0.975). USCOM measurements of CO were significantly higher compared to echocardiography (left ventricular output bias 95 ± 52 mL/kg/min and right ventricular output bias 64 ± 30 mL/kg/min). There was no difference in the subgroup of infants with and without a ductus arteriosus. After the correction was applied to the validation cohort, there was no longer a significant difference between the measures. Conclusions: CO measured by USCOM consistently overestimated the results obtained from echocardiography. USCOM is not adequate to provide absolute estimates of CO. However, it may allow longitudinal hemodynamic assessment of sick neonates.

Aortic valve replacement (AVR) for calcific aortic stenosis is associated with high rates of perioperative stroke and silent cerebral infarcts on diffusion-weighted magnetic resonance imaging (MRI), but cognitive outcomes in elderly AVR patients compared with individuals with cardiac disease who do not undergo surgery are uncertain.One hundred ninety AVR patients (mean age 76 ± 6 years) and 198 non-surgical participants with cardiovascular disease (mean age 74 ± 6 years) completed comprehensive cognitive testing at baseline (preoperatively) and 4 to 6 weeks and 1 year postoperatively. Surgical participants also completed perioperative stroke evaluations, including postoperative brain MRI. Mixed model analyses and reliable change scores examined cognitive outcomes. Stroke outcomes were evaluated in participants with and without postoperative cognitive dysfunction.From reliable change scores, only 12.4% of the surgical group demonstrated postoperative cognitive dysfunction at 4 to 6 weeks and 7.5% at 1 year. Although the surgical group had statistically significantly lower scores in working memory/inhibition 4 to 6 weeks after surgery, the groups did not differ at 1 year. In surgical participants, postoperative cognitive dysfunction was associated with a greater number (p0.01) and larger total volume (p0.01) of acute cerebral infarcts on MRI.In high-risk, aged participants undergoing surgical AVR for aortic stenosis, postoperative cognitive dysfunction was surprisingly limited and was resolved by 1 year in most. Postoperative cognitive dysfunction at 4 to 6 weeks was associated with more and larger acute cerebral infarcts.

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

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

BACKGROUND ICU readmissions are associated with increased mortality and costs; however, it is unclear whether these outcomes are caused by readmissions or by residual confounding by illness severity. An assessment of temporal changes in ICU readmission in response to a specific policy change could help disentangle these possibilities. We sought to determine whether ICU readmission rates changed after 2003 Accreditation Council for Graduate Medical Education Resident Duty Hours reform ("reform") and whether there were temporally corresponding changes in other ICU outcomes. METHODS We used a difference-in-differences approach using Project IMPACT (Improved Methods of Patient Information Access of Core Clinical Tasks). Piecewise regression models estimated changes in outcomes immediately before and after reform in 274,491 critically ill medical and surgical patients in 151 community and academic US ICUs. Outcome measures included ICU readmission, ICU mortality, and in-hospital post-ICU-discharge mortality. RESULTS In ICUs with residents, ICU readmissions increased before reform (OR, 1.5; 95% CI, 1.22-1.84; P P = .03). This abrupt decline in ICU readmissions after reform differed significantly from an increase in readmissions observed in ICUs without residents at this time (difference-in-differences P CONCLUSIONS The changes in ICU readmission rates after reform, without corresponding changes in mortality, suggest that ICU readmissions are not causally related to other untoward patient outcomes. Instead, ICU readmission rates likely reflect operational aspects of care that are not patient-centered, making them less useful indicators of ICU quality.

Context Thyroid nodules are increasingly recognized in children and are associated with a greater risk for thyroid cancer compared with adults. Thyroid ultrasound is the favored tool for evaluation of thyroid nodules; however, there are limited data regarding the accuracy of thyroid ultrasound to confirm features associated with a low risk of thyroid cancer in children. Objectives We examined whether thyroid ultrasound is capable of accurately identifying thyroid nodules at a low risk of malignancy in children. Design and setting Using a retrospective cohort study design, we identified children age ≤18 years with thyroid nodules and adequate follow-up. Ultrasound images were reviewed independently by two blinded expert radiologists, and ultrasound characteristics were analyzed to determine optimal predictive value and reliability. Patients and results A total of 417 subjects were found to have thyroid nodules, and 152 subjects had adequate follow-up; 59 (38.8%) of these were diagnosed with thyroid cancer. We evaluated 236 individual nodules. Features most consistent with benign nodules included small size, isoechoic echogenicity, partially cystic structure, sharp or noninfiltrative margins, absent Doppler flow, and absent calcifications. Significant variability was found between expert interpretations of ultrasound features. Thyroid nodule composition appears to be the most sensitive and reliable feature for stratifying the risk of thyroid cancer. Ultrasound accurately identified benign thyroid nodules in 80.9% of subjects (95% confidence interval, 74-86.6). Conclusions Ultrasonography is useful for the evaluation of thyroid nodules, but we found no combination of ultrasound features sufficient to exclude thyroid cancer without a biopsy.

Background Symptoms drive healthcare use among adults with atrial fibrillation, but limited data are available regarding which symptoms are most problematic and which patients are most at‐risk. The purpose of this study was to: (1) identify clusters of patients with similar symptom profiles, (2) characterize the individuals within each cluster, and (3) determine whether specific symptom profiles are associated with healthcare utilization. Methods We conducted a cross‐sectional secondary data analysis of 1,501 adults from the Vanderbilt Atrial Fibrillation Registry. Participants were recruited from Vanderbilt cardiology clinics, emergency department, and in‐patient services. Subjects included in our analysis had clinically verified atrial fibrillation and a completed symptom survey. Symptom and healthcare utilization data were collected with the University of Toronto Atrial Fibrillation Severity Scale. Latent class regression analysis was used to identify symptom clusters, with clinical and demographic variables included as covariates. We used Poisson regression to examine the association between latent class membership and healthcare utilization. Results Participants were predominantly male (67%) with a mean age of 58.4 years (±11.9). Four latent classes were evident, including an Asymptomatic cluster (N = 487, 38%), Highly Symptomatic cluster (N = 142, 11%), With Activity cluster (N = 326, 25%), and Mild Diffuse cluster (N = 336, 26%). Highly Symptomatic membership was associated with the greatest rate of emergency department visits and hospitalizations (incident rate ratio 2.4, P < 0.001). Conclusions Clinically meaningful atrial fibrillation symptom profiles were identified that were associated with increased rates of emergency department visits and hospitalizations.

Background: Lipid mediators are complex molecules that demonstrate an association to inflammatory states including atherosclerotic vascular disease. Peripheral artery disease (PAD) is an atherosclerotic disease of the distal aorta and lower extremity arteries. Supervised walking therapy (SWT) is the mainstay of treatment for PAD and is hypothesized to improve claudication by suppressing inflammatory activation. Objectives: We sought to examine how lipid mediators were impacted by treadmill testing in PAD, and to identify lipid mediators that were altered by SWT. Methods: Plasma samples were collected before and after Gardner treadmill testing (GTT) in individuals with PAD; participants underwent 12 weeks of SWT and were retested. Lipid mediators were isolated using Ostro Sample Preparation Plates (Waters; Milford, MA) and quantified by UPLC-MS/MS. Results: Thirty-six participants had complete sets of plasma for analysis. The median age was 67 years (IQR: 62 - 71); there were 55 men (73%) and the median ABI was 0.64 (IQR: 0.55 - 0.76). The median peak walking time prior to SWT was 7.4 min (IQR: 4.8 - 10.3 min), which increased to 11.9 min (IQR: 8.4 - 17.1) after SWT (p < 10 -4 ). Discriminant analysis showed clear separation of pre- and post- GTT and pre- and post- SWT samples based on global lipid profiles (Figure 1). Cluster analysis demonstrated 13 distinct clusters of lipid mediators; those clusters containing carbon and arachidonic acid epoxides, and vicinal diols were significantly (FDR Conclusions: Lipid mediator profiles manifested unique response patterns to treadmill testing and were modified by supervised walking therapy. These data suggest that lipid mediators play an active role in the biology underlying improvements in lower extremity symptoms associated with SWT and may offer a novel target for therapeutic manipulation.

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 (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.

To the Editor: With rising demand for critical care, intensivists’ time must increasingly be divided among patients (1–6). Recent studies suggest that increased strain at intensive care unit (ICU) admission leads to higher mortality in closed ICUs (7) and that increased strain at discharge leads to increases in ICU readmissions (8). These relationships between strain and outcomes could be mediated by strain-induced changes in the time intensivists devote to patients during patient care rounds (7–9). We therefore examined how the allocation of intensivists’ time during rounds changes at times of low versus high ICU strain and whether intensivists preferentially allocate time away from certain patient groups as strain increases. Some results have been previously reported in the form of an abstract (10). Methods We conducted a prospective study of patient care rounds in the 24-bed medical ICU of the Hospital of the University of Pennsylvania in 2012. Time spent performing various rounding activities was recorded in real time by trained data collectors, using a tablet computer. Methods for assessing interrater reliability can be found in the online supplement. Data collection was randomly assigned to one of two intensivist-led medical ICU teams each day and was not performed on weekends. Variables describing patient characteristics, staffing, and ICU strain were obtained from the electronic medical record and as part of a separate clinical trial (11). Our analysis focused on “cognitive rounding time” (time spent on the patient’s assessment and plan) and on total rounding time (presentation of events and data, assessment and plan, and teaching related to that patient). Three validated strain variables (5) were considered: team census (“census”), representing the number of patients rounded on by the observed team each day; number of new admissions (“admissions”) since the end of rounds the previous day; and average severity of illness (“acuity”) of patients on the team, using Acute Physiology and Chronic Health Evaluation III (APACHE III) scores (12). We constructed explanatory linear mixed-effects models for cognitive and total rounding time for each patient-day. Patients were treated as random clusters, cumulative days hospitalized in the ICU were included as a random slope and as a linear term, and attending was treated as an indicator variable (13). Patient race was obtained from the electronic medical record and could be reported by either patient or provider. We considered three race categories: black, nonblack (white or Asian), and unknown. Table 1 and Table E1 in the online supplement describe all evaluated covariates. Table 1. Descriptive Statistics We constructed separate models to determine whether time was allocated away from specific patient groups as strain increased by exploring interactions between the three strain variables and the following six patient variables: admission status (new admission vs. follow-up), patient race (black vs. nonblack), age (continuous), severity of illness (continuous), family presence on rounds, and patient sex. We then constructed a fully adjusted model with all interactions having a P value < 0.2 and used backward selection, removing nonsignificant terms (14). We used Holm tests of conditional significance given the multiple comparisons made (15). Additional details regarding the statistical analyses are available in the online supplement. Results Rounds were observed for 566 patients over the course of 114 noncontiguous weekdays, for a total of 1,295 patient-days. Intensivists rounded on a median of 11 patients (interquartile range [IQR], 10–13) each day, including two new admissions (IQR, 1–3). Median daily rounding time was 188.6 minutes (IQR, 164.8–212.6 min); 91.9 minutes (IQR, 77.9–107.3 min) were spent on cognitive rounding time (Table 1). Daily rounding time increased as census (6.3 min; 95% confidence interval [CI], 2.4–10.1 min; P = 0.002) and admissions (6.0 min; 95% CI, 0.6–11.4 min; P = 0.031) increased (Figure E1 in the online supplement); cognitive rounding time increased as census increased (2.5 min; 95% CI, 0.1–4.9 min; P = 0.045). In fully adjusted models, with increasing daily admissions, newly admitted patients received 1.38 fewer minutes (95% CI, −2.43 to −0.33 min; PHolm = 0.002) total rounding time (interaction P value = 0.01) and 0.73 fewer minutes (95% CI, −1.42 to −0.07 min; PHolm = 0.0113) cognitive rounding time per additional admission. No significant changes occurred among follow-up patients (interaction P value = 0.030; Figure E2). As census increased, each unit increase led to a 0.5-minute (95% CI, 0.87–0.13 min; PHolm = 0.0135) decrease in cognitive rounding time among new admissions, with no decrement among follow-ups (interaction P value = 0.028). The effect of census on total rounding time was modified by new admission status and race. A three-way interaction (P = 0.04) revealed that among follow-ups, nonblack patients received 3.4 minutes (95% CI, −5.6 to −1.2 min; PHolm = 0.02) more than blacks at low census (eight patients); however, the excess time spent with nonblacks disappeared as census increased (P < 0.01). In contrast, no significant differences in strain-induced decrements in rounding time were observed between black and nonblack new admissions (P = 0.22; Figure 1). These relationships persisted in two sensitivity analyses, excluding patients of indeterminate race or excluding Asians from the nonblack group (Table E2). Figure 1. Total rounding time. Models are adjusted for acuity, severity of illness measured on Day 1 of the first intensive care unit (ICU) stay, day number in ICU course, attending, data collector, order patient was rounded on (inverse), maximum team size, attending’s ... Neither patient age, sex, acuity, and severity of illness nor the presence of family on rounds affected the allocation of rounding time. Discussion This study provides the first description of how ICU physicians allocate rounding time among patients and how this allocation changes as ICUs become strained. Daily rounding time increased with increases in census and admissions, but less time was spent per patient, primarily affecting new admissions and nonblack follow-up patients. These findings are consistent with studies showing that clinicians perceive their time to be highly constrained (1, 5, 6). The observation that strain preferentially affected new admissions and nonblack follow-ups may reflect the fact that these patients received more time in general, such that further reductions were challenging. Importantly, we found that increases in ICU strain did not result in disproportionate decreases in the time allocated to other patient subgroups, suggesting that ICU physicians generally ration their time equitably. Although total rounding time was allocated away from nonblack follow-ups as census increased, the facts that nonblacks received more time overall and that similar patterns were not observed among new admissions casts doubt on this finding, representing a true racial disparity. This study had several limitations. First, data were not collected outside of morning rounds, and therefore we could not assess how strain affected time allocation at other times. Second, although a differential effect of census on time allocation was not found between newly admitted black and nonblack patients, future research should determine whether a larger sample would reveal a significant disparity. Third, severity of illness was assessed only at ICU admission, limiting severity adjustment on subsequent days; however, bias introduced by inadequate severity adjustment is unlikely to be differential across different levels of census, and therefore it is unlikely to have affected the results. Residual confounding could still be present, as severity of illness may be indirectly affected by census. Finally, data capture was not formally evaluated; however, interrater reliability was excellent. In summary, this study provides a description of how intensivists allocate their time among patients as their workloads increase, providing objective confirmation of the common perception that time is a scarce resource. However, as a single-center study, these results may not generalize to other ICUs. In addition, because we often lacked data on rounding time on the same patient over contiguous days, we could not address whether observed decreases in rounding time mediated previously observed relationships between strain and outcomes or whether they represent improved efficiency. Future research is needed to explore these questions (7, 8).

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

Summary Our objective was to determine tuberculin skin test conversion rate of health care workers traveling to Botswana. The rate of tuberculin skin test conversion was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87–17.60). Background International travel by health care workers traveling from low incidence countries to areas of the world where tuberculosis is highly endemic places the health care worker at an increased risk of acquiring tuberculosis. Objectives To determine the tuberculin skin test conversion rate of health care workers living in the United States with previously negative tuberculin skin test results working for less than 1 year in a hospital in Botswana where tuberculosis is highly endemic. Methods We performed a cross-sectional survey among health care workers affiliated with the University of Pennsylvania School of Medicine who participated in patient care in Botswana between July 1st 2004 and June 30th 2009. We recruited health care workers after returning from Botswana who had a documented negative tuberculin skin test in the year prior to travel, who spent at least 2 weeks but not more than 1 year and who had a documented tuberculin skin test 2–3 months post travel. The main study outcome was a positive tuberculin skin test 6–12 weeks after returning from Botswana, defined by an area of at least 10 mm induration 48–72 h after placement of the tuberculin skin test. Results 95 Subjects participated in the study and there were 4 tuberculin skin test conversions. The rate of tuberculin skin test conversion in our study population was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87–17.60). Conclusions The tuberculin skin test conversion rate was higher than the reported conversion rates for those not working in a health care setting.

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

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

BackgroundMedical management of early pregnancy loss is an alternative to uterine aspiration, but standard medical treatment with misoprostol commonly results in treatment failure. We compared the efficacy and safety of pretreatment with mifepristone followed by treatment with misoprostol with the efficacy and safety of misoprostol use alone for the management of early pregnancy loss.MethodsWe randomly assigned 300 women who had an anembryonic gestation or in whom embryonic or fetal death was confirmed to receive pretreatment with 200 mg of mifepristone, administered orally, followed by 800 μg of misoprostol, administered vaginally (mifepristone-pretreatment group), or 800 μg of misoprostol alone, administered vaginally (misoprostol-alone group). Participants returned 1 to 4 days after misoprostol use for evaluation, including ultrasound examination, by an investigator who was unaware of the treatment-group assignments. Women in whom the gestational sac was not expelled were offered expectant management, a second dose of misoprostol, or uterine aspiration. We followed all participants for 30 days after randomization. Our primary outcome was gestational sac expulsion with one dose of misoprostol by the first follow-up visit and no additional intervention within 30 days after treatment.ResultsComplete expulsion after one dose of misoprostol occurred in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8 to 89.3) in the mifepristone-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the misoprostol-alone group (relative risk, 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; relative risk, 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P=0.31); pelvic infection was diagnosed in 1.3% of the women in each group.ConclusionsPretreatment with mifepristone followed by treatment with misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. (Funded by the National Institute of Child Health and Human Development; PreFaiR ClinicalTrials.gov number, NCT02012491 .).

Falls disproportionately burden frail older adults in long-term care, which is evidenced by the 60% fall rate annually in this setting. Our health systems improvement model, framed by the Health Outcomes Model for falls prevention, is targeted to achieve the triple aim of better health, better care, and better value. Highlighting evidence from three inter-related studies, this presentation describes the impact of a practice change model and its impact on patient, unit/staff, and organizational level factors as related to facility-wide falls prevention. In study one, we used an evidenced-based practice approach and assessment tool to achieve total and recurrent falls reduction over one year by 32% and 25%, respectively (p

The aging population may strain intensive care unit (ICU) capacity and adversely affect patient outcomes. Existing fluctuations in demand for ICU care offer an opportunity to explore such relationships.To determine whether transient increases in ICU strain influence patient mortality, and to identify characteristics of ICUs that are resilient to surges in capacity strain.Retrospective cohort study of 264,401 patients admitted to 155 U.S. ICUs from 2001 to 2008. We used logistic regression to examine relationships of measures of ICU strain (census, average acuity, and proportion of new admissions) near the time of ICU admission with mortality.A total of 36,465 (14%) patients died in the hospital. ICU census on the day of a patient's admission was associated with increased mortality (odds ratio [OR], 1.02 per standardized unit increase; 95% confidence interval [CI]: 1.00, 1.03). This effect was greater among ICUs employing closed (OR, 1.07; 95% CI: 1.02, 1.12) versus open (OR, 1.01; 95% CI: 0.99, 1.03) physician staffing models (interaction P value = 0.02). The relationship between census and mortality was stronger when the census was composed of higher acuity patients (interaction P value0.01). Averaging strain over the first 3 days of patients' ICU stays yielded similar results except that the proportion of new admissions was now also associated with mortality (OR, 1.04 for each 10% increase; 95% CI: 1.02, 1.06).Several sources of ICU strain are associated with small but potentially important increases in patient mortality, particularly in ICUs employing closed staffing models. Although closed ICUs may promote favorable outcomes under static conditions, they are susceptible to being overwhelmed by patient influxes.

BACKGROUND:: Intensive care unit (ICU) readmission rates are commonly viewed as indicators of ICU quality. However, definitions of ICU readmissions vary, and it is unknown which, if any, readmissions are associated with ICU quality. OBJECTIVE:: Empirically derive the optimal interval between ICU discharge and readmission for purposes of considering ICU readmission as an ICU quality indicator. RESEARCH DESIGN:: Retrospective cohort study. SUBJECTS:: A total of 214,692 patients discharged from 157 US ICUs participating in the Project IMPACT database, 2001-2008. MEASURES:: We graphically examined how patient characteristics and ICU discharge circumstances (eg, ICU census) were related to the odds of ICU readmissions as the allowable interval between ICU discharge and readmission was lengthened. We defined the optimal interval by identifying inflection points where these relationships changed significantly and permanently. RESULTS:: A total of 2242 patients (1.0%) were readmitted to the ICU within 24 hours; 9062 (4.2%) within 7 days. Patient characteristics exhibited stronger associations with readmissions after intervals >48-60 hours. By contrast, ICU discharge circumstances and ICU interventions (eg, mechanical ventilation) exhibited weaker relationships as intervals lengthened, with inflection points at 30-48 hours. Because of the predominance of afternoon readmissions regardless of time of discharge, using intervals defined by full calendar days rather than fixed numbers of hours produced more valid results. DISCUSSION:: It remains uncertain whether ICU readmission is a valid quality indicator. However, having established 2 full calendar days (not 48 h) after ICU discharge as the optimal interval for measuring ICU readmissions, this study will facilitate future research designed to determine its validity. Copyright © 2013 by Lippincott Williams & Wilkins.

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