Mixed-effects Cox Proportional Hazards Models Research Articles

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis.

Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies. This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age2, sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group. There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship (p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk. Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

Impact of Social Vulnerability Index on the Development of Severe Visual Impairment or Blindness From Glaucoma

PurposeTo evaluate whether geocoded social risk factor data predict the development of severe visual impairment or blindness due to glaucoma during follow-up using a large electronic health record (EHR) database. DesignCohort study. MethodsPatients diagnosed with open-angle glaucoma (OAG) at a tertiary care institution. All eyes had glaucomatous visual field defects at baseline. Sociodemographic and ocular data were extracted from EHR, including age, gender, self-reported race and ethnicity, insurance status, OAG type, prior glaucoma laser or surgery, baseline disease severity using Hodapp-Anderson-Parrish criteria, mean intraocular pressure (IOP) during follow-up, and central corneal thickness. Social vulnerability index (SVIndex) data at the census tract level were obtained using geocoded patient residences. Mixed-effects Cox proportional hazard models were completed to assess for the development of severe visual impairment or blindness during follow-up, defined as BCVA ≤20/200 at the last two clinic visits or standard automated perimetry (SAP) mean deviation (MD) ≤-22dB confirmed on two tests. ResultsA total of 4,046 eyes from 2,826 patients met inclusion criteria and were followed for an average of 4.3±2.2 years. Severe visual impairment or blindness developed in 79 eyes (2.0%) from 76 patients (2.7%) after an average of 3.4±1.8 years, leading to an incidence rate of severe visual impairment or blindness of 0.5% per year. Older age (adjusted hazards ratio (HR) 1.36 per decade, p=0.007), residence in areas with higher SVIndex (HR 1.56 per 25% increase, p<0.001), higher IOP during follow-up (HR 3.01 per 5 mmHg increase, p<0.001), and moderate or severe glaucoma at baseline (HR 7.31 and 26.87, p<0.001) were risk factors for developing severe visual impairment or blindness. Concordance index of the model was 0.87. Socioeconomic, minority status/language, and housing type/transportation SVIndex themes were key contributors to developing severe visual impairment or blindness. ConclusionsRisk factors for developing glaucoma-related severe visual impairment or blindness included older age, elevated IOP during follow-up, moderate or severe disease at baseline, and residence in areas associated with greater social vulnerability. In addition to ocular risk factors, geocoded EHR data regarding social risk factors could help identify patients at high risk of developing glaucoma-related visual impairment.

Association Between Peritoneal Glucose Absorption, Lipid Metabolism, and Cardiovascular Disease Risk in Nondiabetic Patients on Peritoneal Dialysis

BackgroundExcessive sugar intake increases the energy metabolic burden and the risk of cardiovascular disease (CVD). Patients on peritoneal dialysis (PD) absorb much more glucose than the World Health Organization recommends, but the link to CVD is unclear. ObjectiveTo identify the association between peritoneal glucose absorption, lipid metabolism, and CVD. MethodsWe applied generalized additive mixed-effects and mixed-effects Cox proportional hazard models to evaluate the impact of peritoneal glucose absorption on lipid profiles and CVD risk. We performed subgroup analyses by using protein intake (normalized protein nitrogen appearance [nPNA] and normalized protein catabolic rate [nPCR] were used to assess protein intake) and high-sensitivity C-reactive protein (hs-CRP). ResultsAfter multivariable adjustment, peritoneal glucose absorption per 10 g/d increase was associated with an increase in cholesterol of 0.145 (95% confidence interval [CI]: 0.086–0.204) mmol/L. No link with the total risk of CVD was observed; however, protein intake and hs-CRP levels affected the relationship between glucose absorption and CVD risk. Patients with values for nPNA and nPCR < 1.0 g/(kg∙d) were associated with a lower risk of CVD (hazard ratio [HR] 95% CI 0.68 (0.46–0.98)) with glucose absorption per 10 g/d increase. While patients with hs-CRP levels ≥ 3 mg/d or values for nPNA or nPCR ≥ 1.0 g/(kg∙d) were associated with a higher risk of CVD (HR 95% CI 1.32 (1.07–1.63); 1.31 (1.02–1.68)) for glucose absorption per 10 g/d increase. ConclusionsOur study found a positive correlation between peritoneal glucose absorption and lipid profiles. Increased glucose absorption was associated with a lower risk of CVD in lower protein intake patients, and a higher risk of CVD in higher hs-CRP or protein intake levels in patients on PD.

Eight-year nationwide study of the bidirectional association between type 2 diabetes and depression in nearly 8 million German outpatients

IntroductionResearch linking type 2 diabetes and depression mostly relied on hospital-based diagnoses or prescription data, overlooking many outpatient diagnoses. We aimed to quantify the risks of depression in individuals newly...

Long-term exposure to ambient ozone at workplace is positively and non-linearly associated with incident hypertension and blood pressure: longitudinal evidence from the Beijing-Tianjin-Hebei medical examination cohort

BackgroundThere is limited longitudinal evidence on the hypertensive effects of long-term exposure to ambient O3. We investigated the association between long-term O3 exposure at workplace and incident hypertension, diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in general working adults.MethodsWe conducted a cohort study by recruiting over 30,000 medical examination attendees through multistage stratified cluster sampling. Participants completed a standard questionnaire and comprehensive medical examination. Three-year ambient O3 concentrations at each employed participant’s workplace were estimated using a two-stage machine learning model. Mixed-effects Cox proportional hazards models and linear mixed-effects models were used to examine the effect of O3 concentrations on incident hypertension and blood pressure parameters, respectively. Generalized additive mixed models were used to explore non-linear concentration-response relationships.ResultsA total of 16,630 hypertension-free working participants at baseline finished the follow-up. The mean (SD) O3 exposure was 45.26 (2.70) ppb. The cumulative incidence of hypertension was 7.11 (95% CI: 6.76, 7.47) per 100 person-years. Long-term O3 exposure was independently, positively and non-linearly associated with incident hypertension (Hazard ratios (95% CI) for Q2, Q3, and Q4 were 1.77 (1.34, 2.36), 2.06 (1.42, 3.00) and 3.43 (2.46, 4.79), respectively, as compared with the first quartile (Q1)), DBP (β (95% CI) was 0.65 (0.01, 1.30) for Q2, as compared to Q1), SBP (β (95% CI) was 2.88 (2.00, 3.77), 2.49 (1.36, 3.61) and 2.61 (1.64, 3.58) for Q2, Q3, and Q4, respectively), PP (β (95% CI) was 2.12 (1.36, 2.87), 2.03 (1.18, 2.87) and 2.14 (1.38, 2.90) for Q2, Q3, and Q4, respectively), and MAP (β (95% CI) was 1.39 (0.76, 2.02), 1.04 (0.24, 1.84) and 1.12 (0.43, 1.82) for Q2, Q3, and Q4, respectively). The associations were robust across sex, age, BMI, and when considering PM2.5 and NO2.ConclusionsTo our knowledge, this is the first cohort study in the general population that demonstrates the non-linear hypertensive effects of long-term O3 exposure. The findings are particularly relevant for policymakers and researchers involved in ambient pollution and public health, supporting the integration of reduction of ambient O3 into public health interventions.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life

The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

The Accuracy of Nonstandardized MELD/PELD Score Exceptions in the Pediatric Liver Allocation System.

In the United States, over half of pediatric candidates receive exceptions and status upgrades that increase their allocation model of end-stage liver disease/pediatric end-stage liver disease (MELD/PELD) score above their laboratory MELD/PELD score. We determined whether these "nonstandardized" MELD/PELD exceptions accurately depict true pretransplant mortality risk. Using data from the Scientific Registry of Transplant Recipients, we identified pediatric candidates (<18 y of age) with chronic liver failure added to the waitlist between June 2016 and September 2021 and estimated all-cause pretransplant mortality with mixed-effects Cox proportional hazards models that treated allocation MELD/PELD and exception status as time-dependent covariates. We also estimated concordance statistics comparing the performance of laboratory MELD/PELD with allocation MELD/PELD. We then compared the proportion of candidates with exceptions before and after the establishment of the National Liver Review Board. Out of 2026 pediatric candidates listed during our study period, 403 (19.9%) received an exception within a week of listing and 1182 (58.3%) received an exception before delisting. Candidates prioritized by their laboratory MELD/PELD scores had an almost 9 times greater risk of pretransplant mortality compared with candidates who received the same allocation score from an exception (hazard ratio 8.69; 95% confidence interval, 4.71-16.03; P < 0.001). The laboratory MELD/PELD score without exceptions was more accurate than the allocation MELD/PELD score with exceptions (Harrell's c-index 0.843 versus 0.763). The proportion of patients with an active exception at the time of transplant decreased significantly after the National Liver Review Board was implemented (67.4% versus 43.4%, P < 0.001). Nonstandardized exceptions undermine the rank ordering of pediatric candidates with chronic liver failure.

Abstract 143: Sepsis And Risk Of Major Postoperative Vascular Complications

Introduction: Stroke, myocardial infarction (MI), and pulmonary embolism (PE) greatly increase postoperative morbidity and mortality. Sepsis has been linked to increased risk of major vascular events, but the risk related to sepsis exposure throughout the postoperative period is uncertain. Hypothesis: Perioperative sepsis exposure increases the 30-day risk of postoperative stroke, myocardial infarction (MI), and pulmonary embolism (PE). Methods: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP), a formulaic sampling of surgical cases from participating United States institutions that prospectively collects demographic, clinical, surgical and 30-day outcome data. Sepsis was defined by systemic inflammatory response syndrome with either positive blood culture or evidence for infection found intraoperatively, and severe sepsis/shock as sepsis with evidence of organ dysfunction or circulatory dysfunction. We used mixed-effects Cox proportional hazard models, treating type of surgery as a random effect, to estimate the hazard ratios for major vascular complications due to sepsis and severe sepsis/shock exposure, adjusting for otherrisk factors. Results: We studied 6,614,937 surgical procedures. There were 201,230 cases with sepsis and an additional 78,052 cases of severe sepsis/shock. Outcomes included 13,939 strokes, 23,600 MIs, 21,893 PEs, and 1690 cases with multiple major vascular complications. Exposure to sepsis (HR 1.98, 95% confidence interval 1.91 to 2.06) or severe sepsis/shock (HR 3.27, 3.14 to 3.40) increased the risk of major vascular complications with larger effect than other established risks. Sepsis improvement within the preoperative period was associated with reduced risk (HR 0.82, 0.77 to 0.88). These findings were consistent in separate models for each complication. Conclusions: Sepsis approximately doubles and severe sepsis or shock triples the 30-day postoperative risk of major vascular complications. Improvement in sepsis severity prior to operation is associated with a 20% risk reduction.

Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension.

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or other factors is incompletely understood. We sought to examine the association between race/ethnicity and socioeconomic status and time-to-PAH treatment. We conducted a retrospective cohort study of Veterans diagnosed with incident PAH between 2006 and 2019 and treated with PAH therapy. Our outcome was time-to-PAH treatment. Our primary exposures were race/ethnicity, annual household income, health insurance status, education, and housing insecurity. We calculated time-to-treatment using multivariable mixed-effects Cox proportional hazard models. Of 1827 Veterans with PAH, 27% were Black, 4% were Hispanic, 22.1% had an income < $20,000, 53.3% lacked non-VA insurance, 25.5% had <high school education, and 3.9% had housing insecurity. Median time-to-treatment was 114 days (interquartile range [IQR] 21-336). Our multivariable models demonstrated increased time-to-treatment among patients with lower household income (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.60-0.91 for < $20,000 vs. ≥ $100,000) and those without non-VA insurance (HR 0.90, 95% CI 0.82-1.00). Race/ethnicity, education, and housing insecurity were not associated with time-to-treatment. Veterans with PAH experienced substantial and potentially harmful treatment delays, with median time-to-treatment of 16 weeks after diagnosis. Those with lower income and those without non-VA health insurance experienced even greater treatment delays. Additional research is urgently needed to develop interventions to improve timely PAH treatment and mitigate economic disparities in treatment.

Long-term incidence of posterior capsular opacification in patients with non-infectious uveitis

Little is known about the long-term incidence of posterior capsule opacification (PCO) after cataract surgery in patients with uveitis. This retrospective study included 211 eyes of 146 patients with non-infectious uveitis who underwent cataract surgery and implantation of an Acrysof SN60WF (Surface: plasma-treated, Optic and Haptic: hydrophobic acrylic), iSert XY-1 (Surface: UV-ozone-treated, Optic and Haptic: hydrophobic acrylic), or iSert 251/255 (Surface: UV-ozone-treated, Optics: hydrophobic acrylic, Haptic: polymethyl methacrylate). The cumulative incidences of PCO and subsequent yttrium–aluminum-garnet (Nd:YAG) capsulotomy over the 5-year follow-up were analyzed, and patients who were implanted with different intraocular lenses (IOLs) were compared. Mixed-effects Cox proportional hazard models showed that, compared with the Acrysof group, the iSert XY-1 group had higher risks of PCO (adjusted HR, 7.26; 95% CI, 1.82–28.8) and Nd:YAG capsulotomy (adjusted HR, 6.50; 95% CI, 1.55–27.2). Similar results were obtained when the Acrysof group was compared with the iSert 251/255 group for PCO (adjusted HR, 8.22; 95% CI, 2.35–28.7) and Nd:YAG capsulotomy (adjusted HR, 8.26; 1.90–36.0). These data suggest that a plasma-treated surface, hydrophobic acrylic optic and hydrophobic acrylic haptic, of the IOL could enhance biocompatibility even under inflammatory conditions, thus suppressing PCO development.

Association of Thiamine Use with Outcomes in Patients with Sepsis and Alcohol Use Disorder: An Analysis of the MIMIC-III Database.

IntroductionThe association between thiamine use and clinical outcomes among patients with sepsis and alcohol use disorder (AUD) is unclear.MethodsIn this retrospective cohort study of patients from Medical Information Mart for Intensive Care III (MIMIC-III, version 1.4), we evaluated the association of thiamine use with clinical outcomes in patients with AUD and sepsis. The primary outcome was 28-day survival, and secondary outcomes included ICU, in-hospital, and 90-day mortality, ICU and hospital length of stay, duration of vasopressor use, need and duration of continuous renal replacement therapy (CRRT), and dynamic changes for variables up to day 7 after ICU admission.ResultsA total of 944 patients with sepsis and AUD were included in this cohort [median age, 53.1 years; women, 26.0% (245 of 944)]. Among all patients, 24.6% (233 of 944) received thiamine with a dose of 200 mg (IQR 100–345 mg). The 28-day mortality was 11.2% (26 of 233) in the thiamine use group compared with 18.6% (132 of 711) in the no thiamine use group (P = 0.009). After adjustment for a series of confounders, the mixed-effects Cox proportional hazards models showed that administration of thiamine was associated with a lower risk of 28-day mortality compared with no administration of thiamine.ConclusionsIn critically ill patients with alcohol use disorder admitted for sepsis, treatment with thiamine may be associated with a decreased risk of death. However, the present results should be interpreted with caution due to the limitations of retrospective design. Additional larger, multicenter randomized controlled trials are needed to confirm our findings.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00603-1.

Long-term exposure to objective and perceived residential greenness and diabetes mortality: A census-based cohort study

BackgroundResiding close to green spaces might reduce diabetes mellitus (DM) risk; however, evidence for diabetes mortality is limited. Moreover, individual and neighbourhood social factors may determine DM risk. Exposure to green spaces may also depend on socioeconomic position (SEP). This study examined the associations between residential greenness and diabetes-related mortality, and the role of the social environment in these associations. MethodsWe used the 2001 Belgian census linked to mortality register data for the period 2001–2014. We included individuals aged 40–79 years old and residing in the five largest Belgian urban areas at baseline. Exposure to residential greenness was assessed with surrounding greenness using the Normalized Difference Vegetation Index (NDVI) within 500-m of residence (objective indicator), and perceived neighbourhood greenness (subjective indicator). We conducted mixed-effects Cox proportional hazards models to obtain hazard ratios (HR) for diabetes-related mortality per interquartile range (IQR) increments of residential greenness. We assessed effect modification by social factors through stratification. ResultsFrom 2,309,236 individuals included at baseline, 1.2% died from DM during follow-up. Both residential greenness indicators were inversely associated with diabetes-related mortality after adjustment for individual social factors. After controlling for neighbourhood SEP, the beneficial association with surrounding greenness disappeared [HR 1.02 (95%CI:0.99,1.06)], but persisted with perceived neighbourhood greenness [HR 0.93 (95%CI:0.91,0.95)]. After stratification the inverse associations with perceived neighbourhood greenness were strongest for women, the lowest educated, and individuals residing in least deprived neighbourhoods. ConclusionsOur findings suggest that an overall positive perception of neighbourhood green spaces reduces independently the risk of diabetes-related mortality, regardless of the neighbourhood social environment. Nevertheless, neighbourhood SEP may be a strong confounder in the associations between diabetes-related mortality and greenness indicators derived from satellite images. Perception factors not captured by objective measurements of green spaces are potentially relevant in the association with DM, especially among disadvantaged groups.

Impact of County Health Rankings on Nationwide Liver Transplant Outcomes.

There is limited information concerning whether social determinants of health affect postliver transplant (LT) outcomes. This study aims to understand to what extent the health of LT recipients' counties of residence influence long-term LT outcomes. We used the United Network for Organ Sharing data to identify adult LT recipients transplanted between January 2010 and June 2018. Patient-level data were matched to county-level County Health Ranking (CHR) data using transplant recipient zip code, and nationwide CHRs were created. Mixed-effects Cox proportional hazards models were used to examine associations between CHRs and graft and patient survival post-LT. Health outcomes rank was significantly associated with posttransplant graft and patient survival, with worst tertile counties showing a 13% increased hazard of both graft failure and patient mortality compared to the best tertile counties. Although county health is associated with LT outcomes, it also appears that LT recipient selection is effective at mitigating major disparities based on county of residence and helps yield equitable outcomes in this respect.

Extreme hyponatremia as a risk factor for early mortality after liver transplantation in the MELD-sodium era.

The impact of hyponatremia on waitlist and post-transplant outcomes following the implementation of MELD-Na-based liver allocation remains unclear. We investigated waitlist and postliver transplant (LT) outcomes in patients with hyponatremia before and after implementing MELD-Na-based allocation. Adult patients registered for a primary LT between 2009 and 2021 were identified in the OPTN/UNOS database. Two eras were defined; pre-MELD-Na and post-MELD-Na. Extreme hyponatremia was defined as a serum sodium concentration ≤120mEq/l. Ninety-day waitlist outcomes and post-LT survival were compared using Fine-Gray proportional hazard and mixed-effects Cox proportional hazard models. A total of 118487 patients were eligible (n=64940: pre-MELD-Na; n=53547: post-MELD-Na). In the pre-MELD-Na era, extreme hyponatremia at listing was associated with an increased risk of 90-day waitlist mortality ([ref: 135-145] HR: 3.80; 95% CI: 2.97-4.87; P<0.001) and higher transplant probability (HR: 1.67; 95% CI: 1.38-2.01; P<0.001). In the post-MELD-Na era, patients with extreme hyponatremia had a proportionally lower relative risk of waitlist mortality (HR: 2.27; 95% CI 1.60-3.23; P<0.001) and proportionally higher transplant probability (HR: 2.12; 95% CI 1.76-2.55; P<0.001) as patients with normal serum sodium levels (135-145). Extreme hyponatremia was associated with a higher risk of 90, 180, and 365-day post-LT survival compared to patients with normal serum sodium levels. With the introduction of MELD-Na-based allocation, waitlist outcomes have improved in patients with extreme hyponatremia but they continue to have worse short-term post-LT survival.

Is a higher altitude associated with shorter survival among at-risk neonates?

We hypothesize that high altitudes could have an adverse effect on neonatal health outcomes, especially among at-risk neonates. The current study aims to assess the association between higher altitudes on survival time among at-risk neonates. Retrospective survival analysis. Setting: Ecuadorian neonates who died at ≤28 days of life. Patients: We analyzed the nationwide dataset of neonatal deaths from the Surveillance System of Neonatal Mortality of the Ministry of Public Health of Ecuador, registered from 126 public and private health care facilities, between January 2014 to September 2017. Main outcome measures: We retrospectively reviewed 3016 patients. We performed a survival analysis by setting the survival time in days as the primary outcome and fixed and mixed-effects Cox proportional hazards models to estimate hazard ratios (HR) for each altitude stratum of each one of the health care facilities in which those neonates were attended, adjusting by individual variables (i.e., birth weight, gestational age at birth, Apgar scale at 5 minutes, and comorbidities); and contextual variables (i.e., administrative planning areas, type of health care facility, and level of care). Altitudes of health care facilities ranging from 80 to <2500 m, 2500 to <2750m, and ≥2750 m were associated respectively with 20% (95% CI: 1% to 44%), 32% (95% CI:<1% to 79%) and 37% (95% CI: 8% to 75%) increased HR; compared with altitudes at <80 m. Higher altitudes are independently associated with shorter survival time, as measured by days among at-risk neonates. Altitude should be considered when assessing the risk of having negative health outcomes during neonatal period.

Residential Greenspace in Childhood Reduces Risk of Pediatric Inflammatory Bowel Disease: A Population-Based Cohort Study.

Environmental factors related to urbanization and industrialization are believed to be involved in inflammatory bowel disease (IBD) development, but no study has looked at the association between greenspace and IBD. We conducted a retrospective cohort study using linked population-based health administrative and environmental data sets. The study population comprised 2,715,318 mother-infant pairs from hospital births in Ontario, Canada, between April 1, 1991, and March 31, 2014. We measured the exposure to residential greenspace using the normalized difference vegetation index derived using remote-sensing methods. Average greenspace was estimated for the pregnancy and childhood periods. We used mixed-effects Cox proportional hazard models to assess potential associations between residential greenspace and the risk of developing IBD before 18 years while adjusting for covariates including sex, maternal IBD, rural/urban residence at birth, and neighborhood income. There were 3,444 IBD diagnoses that occurred during follow-up. An increase in the interquartile range of residential greenspace during the childhood period was associated with a lower risk of developing pediatric-onset IBD (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.74-0.81). This relationship was significant for both ulcerative colitis (HR 0.72 95% CI 0.67-0.78) and Crohn's disease (HR 0.81, 95% CI 0.76-0.87). There was a linear dose response across increasing quartiles of greenspace (P < 0.0001). No consistent association was detected between maternal intrapartum greenspace exposure and pediatric-onset IBD. Higher exposure to residential greenspace during childhood was associated with a reduced risk of IBD, suggesting a novel avenue to prevent IBD in children.

Bacterial Pneumonia in Brain-Dead Patients: Clinical Features and Impact on Lung Suitability for Donation.

To appraise the epidemiological features of bacterial pneumonia and its impact on lung suitability for donation in brain-dead patients managed with protective ventilatory settings. Retrospective observational study. Six ICUs from two university-affiliated hospitals. Brain-dead adult patients managed in the participating ICUs over a 4-year period. None. Among the 231 included patients, 145 (62.8%) were classified as ideal or extended-criteria potential lung donors at ICU admission and the remaining 86 patients having baseline contraindication for donation. Culture-proven aspiration pneumonia and early-onset ventilator-associated pneumonia occurred in 54 patients (23.4%) and 15 patients (6.5%), respectively (overall pneumonia incidence, 29.9%). Staphylococcus aureus and Enterobacterales were the most common pathogens. Using mixed-effects Cox proportional hazard models, age (adjusted hazard ratio, 0.98; 95% CI [0.96-0.99]), anoxic brain injury (3.55 [1.2-10.5]), aspiration (2.29 [1.22-4.29]), and not receiving antimicrobial agents at day 1 (3.56 [1.94-6.53]) were identified as independent predictors of pneumonia occurrence in the whole study population. Analyses restricted to potential lung donors yielded similar results. Pneumonia was associated with a postadmission decrease in the PaO2/FIO2 ratio and lower values at brain death, in the whole study population (estimated marginal mean, 294 [264-323] vs 365 [346-385] mm Hg in uninfected patients; p = 0.0005) as in potential lung donors (299 [248-350] vs 379 [350-408] mm Hg; p = 0.04; linear mixed models). Lungs were eventually retrieved in 31 patients (34.4%) among the 90 potential lung donors with at least one other organ harvested (pneumonia prevalence in lung donors (9.7%) vs nondonors (49.2%); p = 0.0002). Pneumonia occurs in one-third of brain-dead patients and appears as the main reason for lung nonharvesting in those presenting as potential lung donors. The initiation of antimicrobial prophylaxis upon the first day of the ICU stay in comatose patients with severe brain injury could enlarge the pool of actual lung donors.

Statistical analysis plan for the Balanced Solution versus Saline in Intensive Care Study (BaSICS).

ObjectiveTo report the statistical analysis plan (first version) for the Balanced Solutions versus Saline in Intensive Care Study (BaSICS).MethodsBaSICS is a multicenter factorial randomized controlled trial that will assess the effects of Plasma-Lyte 148 versus 0.9% saline as the fluid of choice in critically ill patients, as well as the effects of a slow (333mL/h) versus rapid (999mL/h) infusion speed during fluid challenges, on important patient outcomes. The fluid type will be blinded for investigators, patients and the analyses. No blinding will be possible for the infusion speed for the investigators, but all analyses will be kept blinded during the analysis procedure.ResultsBaSICS will have 90-day mortality as its primary endpoint, which will be tested using mixed-effects Cox proportional hazard models, considering sites as a random variable (frailty models) adjusted for age, organ dysfunction and admission type. Important secondary endpoints include renal replacement therapy up to 90 days, acute renal failure, organ dysfunction at days 3 and 7, and mechanical ventilation-free days within 28 days.ConclusionThis manuscript provides details on the first version of the statistical analysis plan for the BaSICS trial and will guide the study’s analysis when follow-up is finished.

Differential Effect of Rituximab on Relapse-Free Survival in De Novo and Relapsed Immune Thrombotic Thrombocytopenic Purpura in African-American and Caucasian Populations

Differential Effect of Rituximab on Relapse-Free Survival in De Novo and Relapsed Immune Thrombotic Thrombocytopenic Purpura in African-American and Caucasian Populations

The Effect of Abnormal Reproductive Tract Discharge on the Calving to Conception Interval of Dairy Cows.

Prolonged calving-to-conception interval (CCI) can increase economic loss in cattle. We investigated the effect of post-calving abnormal reproductive tract discharge (ARTD) on CCI in dairy cows and quantified the relationship of ARTD and associated risk factors with CCI. The source population was dairy cows that calved in the study period on three pasture-based, year-round calving farms in the Riverina, NSW, Australia. Farm records and records from veterinarians' visits were analyzed. ARTD was defined as the presence of reproductive tract discharge according to the following classification: per vaginum purulent discharge ≥21 days post-calving or mucopurulent discharge >26 days post-calving. The incidence of ARTD was calculated. A Kaplan-Meier survivor function was used to estimate median time to conception post-calving dependent on the presence or absence of ARTD. Mixed effects Cox-proportional hazard models were used to estimate the direct and indirect effects of ARTD, and other potential risk factors on CCI such as body condition score (BCS), ambient temperature, and milk yield. Model structures were guided by a directed acyclic graph of potential risk factors for ARTD. The incidence of ARTD in lactations was 16% (95% CI 13.8–18.5%) and did not differ significantly between the three farms (P > 0.05). The median CCI was 176 and 118 days for lactations with and without ARTD, respectively (P < 0.01). The rate of pregnancy following calving in cows with ARTD was significantly decreased relative to the rate of pregnancy in cows without (total effect hazard ratio = 0.62, se = 0.18, P = 0.01). High peak milk yield (>32 L) and parity >2 also significantly extended CCI. We did not observe an effect of BCS or ambient temperature on CCI. The incidence of ARTD in the current study was consistent with clinical endometritis (considered a major source of ARTD) reported in other studies. In contrast—and despite regular veterinary assessment and treatment of on the farms in this study—ARTD extended CCI. Evaluation of the economic impact of ARTD on dairy farms in this region is warranted, and methods to identify high risk cows and develop effective interventions are required.