Testing for Primary Hyperparathyroidism in 17,491 Patients With Hypercalcemia.

BACKGROUND: Primary hyperparathyroidism (PHPT) is underdiagnosed and associated with many adverse health effects. Historically, many hypercalcemic patients have not received parathyroid hormone (PTH) testing; however, underlying reasons are uncertain. Our goals are to determine the PTH testing rate among hypercalcemic individuals at a large academic health system and to assess for characteristics associated with testing versus not testing for PHPT to inform future strategies for closing testing gaps. METHODS: This retrospective study included adult patients with ≥1 elevated serum calcium result between 2018 and 2022. Based on the presence or absence of a serum PTH result, individuals were classified as "screened" versus "unscreened" for PHPT. Demographic and clinical characteristics of these groups were compared. RESULTS: The sample comprised 17,491 patients: 6567 male (37.5%), 10,924 female (62.5%), mean age 59 y. PTH testing was performed in 6096 (34.9%). Characteristics independently associated with the greatest odds of screening were 5+ elevated calcium results (odds ratio [OR] 5.02, P < 0.0001), chronic kidney disease (OR 3.63, P < 0.0001), maximum calcium >12.0 mg/dL (OR 2.48, P < 0.0001), and osteoporosis (OR 2.42, P < 0.0001). Characteristics associated with lowest odds of screening were age <35 y (OR 0.60, P < 0.0001), death during the study period (OR 0.68, P < 0.0001), age ≥85 y (OR 0.70, P = 0.0007), and depression (OR 0.84; P = 0.0081). CONCLUSIONS: Only 35% of hypercalcemic patients received PTH testing. Although the presence of PHPT-associated morbidity was generally associated with increased rates of screening, hypercalcemic patients with depression were 16% less likely to be tested.

Social Risk Factors Influence Pediatric Emergency Department Utilization and Hospitalizations.

OBJECTIVE: To characterize the association of children's social risk factors with total number of emergency department (ED) visits or hospitalization and time to first subsequent ED or hospitalization. STUDY DESIGN: This was a retrospective cohort study of patients seen at a general pediatric clinic between 2017 and 2021 with documented ≥1 social risk factors screened per visit. Negative binomial or Poisson regression modeled ED utilization and hospitalizations as functions of the total number of risk factors or each unique risk factor. Time-varying Cox models were used to evaluate differences between those who screened positive and those who screened negative, controlling for demographic and clinical covariates. RESULTS: Overall, 4674 patients (mean age, 6.6 years; 49% female; 64% Hispanic; 21% Black) were evaluated across a total of 20 927 visits. Children with risk factors had higher rates of attention-deficit hyperactivity disorder, failure to gain weight, asthma, and prematurity compared with children with no risk (all P < .01). Adjusted models show a positive association between increased total number of factors and ED utilization (incidence rate ratio [IRR], 1.18; 95% CI, 1.12-1.23) and hospitalizations (IRR, 1.36; 95% CI, 1.26-1.47). There were no associations between a positive screen and time to first ED visit (hazard ratio [HR], 0.95; 95% CI, 0.85-1.06; P = .36) or hospitalization (HR, 1.15; 95% CI, 0.84-1.59; P = .40). CONCLUSIONS: Social risk factors were associated with increased ED utilization and hospitalizations at the patient level but were not significantly associated with time to subsequent acute care use. Future research should evaluate the effect of focused interventions on health care utilization, such as those addressing food insecurity and transportation challenges.

Supplemental Nutrition Assistance Program Participation and Health Care Use in Older Adults : A Cohort Study.

BACKGROUND: Older adults dually eligible for Medicare and Medicaid have particularly high food insecurity prevalence and health care use. OBJECTIVE: To determine whether participation in the Supplemental Nutrition Assistance Program (SNAP), which reduces food insecurity, is associated with lower health care use and cost for older adults dually eligible for Medicare and Medicaid. DESIGN: An incident user retrospective cohort study design was used. The association between participation in SNAP and health care use and cost using outcome regression was assessed and supplemented by entropy balancing, matching, and instrumental variable analyses. SETTING: North Carolina, September 2016 through July 2020. PARTICIPANTS: Older adults (aged ≥65 years) dually enrolled in Medicare and Medicaid but not initially enrolled in SNAP. MEASUREMENTS: Inpatient admissions (primary outcome), emergency department visits, long-term care admissions, and Medicaid expenditures. RESULTS: Of 115 868 persons included, 5093 (4.4%) enrolled in SNAP. Mean follow-up was approximately 22 months. In outcome regression analyses, SNAP enrollment was associated with fewer inpatient hospitalizations (-24.6 [95% CI, -40.6 to -8.7]), emergency department visits (-192.7 [CI, -231.1 to -154.4]), and long-term care admissions (-65.2 [CI, -77.5 to -52.9]) per 1000 person-years as well as fewer dollars in Medicaid payments per person per year (-$2360 [CI, -$2649 to -$2071]). Results were similar in entropy balancing, matching, and instrumental variable analyses. LIMITATION: Single state, no Medicare claims data available, and possible residual confounding. CONCLUSION: Participation in SNAP was associated with fewer inpatient admissions and lower health care costs for older adults dually eligible for Medicare and Medicaid. PRIMARY FUNDING SOURCE: National Institutes of Health.

Correction: Benefit and harm of intensive blood pressure treatment: Derivation and validation of risk models using data from the SPRINT and ACCORD trials.

[This corrects the article DOI: 10.1371/journal.pmed.1002410.].

Examining differences between overweight women and men in 12-month weight loss study comparing healthy low-carbohydrate vs. low-fat diets.

BACKGROUND/OBJECTIVES: Biological sex factors and sociocultural gender norms affect the physiology and behavior of weight loss. However, most diet intervention studies do not report outcomes by sex, thereby impeding reproducibility. The objectives of this study were to compare 12-month changes in body weight and composition in groups defined by diet and sex, and adherence to a healthy low carbohydrate (HLC) vs. healthy low fat (HLF) diet. PARTICIPANTS/METHODS: This was a secondary analysis of the DIETFITS trial, in which 609 overweight/obese nondiabetic participants (age, 18-50 years) were randomized to a 12-month HLC (n = 304) or HLF (n = 305) diet. Our first aim concerned comparisons in 12-month changes in weight, fat mass, and lean mass by group with appropriate adjustment for potential confounders. The second aim was to assess whether or not adherence differed by diet-sex group (HLC women n = 179, HLC men n = 125, HLF women n = 167, HLF men n = 138). RESULTS: 12-month changes in weight (p < 0.001) were different by group. HLC produced significantly greater weight loss, as well as greater loss of both fat mass and lean mass, than HLF among men [-2.98 kg (-4.47, -1.50); P < 0.001], but not among women. Men were more adherent to HLC than women (p = 0.02). Weight loss estimates within group remained similar after adjusting for adherence, suggesting adherence was not a mediator. CONCLUSIONS: By reporting outcomes by sex significant weight loss differences were identified between HLC and HLF, which were not recognized in the original primary analysis. These findings highlight the need to consider sex in the design, analysis, and reporting of diet trials.

Interfacility Transfer of Medicare Beneficiaries With Acute Type A Aortic Dissection and Regionalization of Care in the United States.

BACKGROUND: The feasibility and effectiveness of delaying surgery to transfer patients with acute type A aortic dissection-a catastrophic disease that requires prompt intervention-to higher-volume aortic surgery hospitals is unknown. We investigated the hypothesis that regionalizing care at high-volume hospitals for acute type A aortic dissections will lower mortality. We further decomposed this hypothesis into subparts, investigating the isolated effect of transfer and the isolated effect of receiving care at a high-volume versus a low-volume facility. METHODS: We compared the operative mortality and long-term survival between 16 886 Medicare beneficiaries diagnosed with an acute type A aortic dissection between 1999 and 2014 who (1) were transferred versus not transferred, (2) underwent surgery at high-volume versus low-volume hospitals, and (3) were rerouted versus not rerouted to a high-volume hospital for treatment. We used a preference-based instrumental variable design to address unmeasured confounding and matching to separate the effect of transfer from volume. RESULTS: Between 1999 and 2014, 40.5% of patients with an acute type A aortic dissection were transferred, and 51.9% received surgery at a high-volume hospital. Interfacility transfer was not associated with a change in operative mortality (risk difference, -0.69%; 95% CI, -2.7% to 1.35%) or long-term mortality. Despite delaying surgery, a regionalization policy that transfers patients to high-volume hospitals was associated with a 7.2% (95% CI, 4.1%-10.3%) absolute risk reduction in operative mortality; this association persisted in the long term (hazard ratio, 0.81; 95% CI, 0.75-0.87). The median distance needed to reroute each patient to a high-volume hospital was 50.1 miles (interquartile range, 12.4-105.4 miles). CONCLUSIONS: Operative and long-term mortality were substantially reduced in patients with acute type A aortic dissection who were rerouted to high-volume hospitals. Policy makers should evaluate the feasibility and benefits of regionalizing the surgical treatment of acute type A aortic dissection in the United States.

Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease.

BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors. METHODS: A multitiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison among >500 000 British adults in the UK Biobank. ACHD diagnoses were subclassified as isolated aortic valve and noncomplex defects. Time-to-event analyses were conducted for the primary end points of fatal or nonfatal acute coronary syndrome, ischemic stroke, heart failure, and atrial fibrillation and a secondary combined end point for major adverse cardiovascular events. Maximum follow-up time for the study period was 22 years with retrospectively and prospectively collected data from the UK Biobank. RESULTS: We identified 2006 individuals with lower-complexity ACHD and 497 983 unexposed individuals in the UK Biobank (median age at enrollment, 58 [interquartile range, 51-63] years). Of the ACHD-exposed group, 59% were male, 51% were current or former smokers, 30% were obese, and 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes mellitus, respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary end points, with hazard ratios ranging from 2.0 (95% CI, 1.5-2.8; P<0.001) for acute coronary syndrome to 13.0 (95% CI, 9.4-18.1; P<0.001) for heart failure. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of major adverse cardiovascular events, in contrast to 13% in individuals without ACHD with ≥5 risk factors. CONCLUSIONS: Individuals with lower-complexity ACHD had a higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

Impact of Rapid Antimicrobial Susceptibility Testing in Gram-Negative Rod Bacteremia: a Quasi-experimental Study.

Clinical justification for rapid antimicrobial susceptibility testing (AST) in Gram-negative rod (GNR) bacteremia is compelling; however, evidence supporting its value is sparse. We investigated the impact of rapid AST on clinical and antimicrobial stewardship outcomes in real-world practice. We performed a before-and-after quasi-experimental study from February 2018 to July 2019 at a tertiary hospital of the 24-h/day, 7-day/week implementation of the direct Vitek 2 AST method from positive blood culture broth for GNR bacteremia with electronic isolate-specific de-escalation comments and daytime antibiotic stewardship program (ASP) intervention. The primary outcome was time to appropriate antibiotic escalation or de-escalation, and secondary outcomes included time to oral antibiotic stepdown, hospital length of stay (LOS), all-cause 30-day mortality, 7-day incidence of acute kidney injury (AKI), and 30-day incidence of Clostridioides difficile infection (CDI). A total of 671 GNR isolates were included from 643 adult patients. Among patients for whom antibiotic change occurred after rapid AST result, rapid AST was associated with a trend in decreased time to escalation or de-escalation (hazard ratio, 1.22; 95% confidence interval [CI], 0.99 to 1.51; P = 0.06), with median times of 52.3 versus 42.2 h. Secondary outcomes were similar in both groups and include median time to oral antibiotic stepdown, LOS, all-cause mortality, and incidence of AKI and CDI. Rapid AST led to improved stewardship measures but did not impact clinical patient outcomes. These results highlight that multiple variables in addition to the timing of the AST result contribute to clinical outcome and that further intervention may be required to clinically justify rapid AST implementation.

Demographic and psychosocial factors associated with hair cortisol concentrations in preschool children.

BACKGROUND: Early life stress has enduring effects on physical and mental health. Hair cortisol concentrations (HCCs) reflect exposures to contextual stressors in early life, but are understudied in preschool children. METHODS: Hair samples from children (N = 693) during clinic visits (CVs) scheduled at 1-4 years (CV1-CV4) were measured using validated assay methods for HCC. RESULTS: HCCs were highest at CV1 and decreased at CV2-CV4, with no sex differences. Black children had higher HCC than White/other children; these differences persisted even after adjusting for socioeconomic factors. Bivariable analyses showed significant effects on HCC for Black race, with specific demographic and psychosocial factors at different ages. Multivariable analyses showed that higher HCC at CV1 were associated with Black race and male sex; at CV2 with Black race, lower maternal self-esteem, socioeconomic adversity, and the child's risk for developmental delay; at CV3 with Black race; at CV4 with maternal depression and the child's prior HCC values. CONCLUSIONS: HCCs were higher in Black children than White/other races; differences were related to maternal factors, socioeconomic adversity, and the child's risk for developmental delay. Public health measures to reduce disparities between Blacks and other races must also consider the long-term effects of chronic stress in early life.

Direct measurement of atrioventricular valve regurgitant jets using 4D flow cardiovascular magnetic resonance is accurate and reliable for children with congenital heart disease: a retrospective cohort study.

BACKGROUND: 3D-time resolved flow (4DF) cardiovascular magnetic resonance (CMR) with retrospective analysis of atrioventricular valve regurgitation (AVVR) allows for internal validation by multiple direct and indirect methods. Limited data exist on direct measurement of AVVR by 4DF CMR in pediatric congenital heart disease (CHD). We aimed to validate direct measurement of the AVVR jet as accurate and reliable compared to the volumetric method (clinical standard by 2D CMR) and as a superior method of internal validation than the annular inflow method. METHODS: We identified 44 consecutive patients with diverse CHD referred for evaluation of AVVR by CMR. 1.5 T or 3 T scanners, intravenous contrast, and a combination of parallel imaging and compressed sensing were used. Four methods of measuring AVVR volume (RVol) were used: volumetric method (VOL; the clinical standard) = stroke volume by 2D balanced steady-state free precession - semilunar valve forward flow (SLFF); annular inflow method (AIM) = atrioventricular valve forward flow [AVFF] - semilunar valve net flow (SLNF); and direct measurement (JET). AVFF was measured using static and retrospective valve tracking planes. SLFF, SLNF, AVFF, and JET were measured by 4DF phase contrast. Regurgitant fraction was calculated as [RVol/(RVol+SLNF)]× 100. Statistical methods included Spearman, Wilcoxon rank sum test/Student paired t-test, Bland Altman analysis, and intra-class coefficient (ICC), where appropriate. RESULTS: Regurgitant fraction by JET strongly correlated with the indirect methods (VOL and AIM) (ρ = 0.73-0.80, p < 0.001) and was similar to VOL with a median difference (interquartile range) of - 1.5% (- 8.3-7.2%; p = 0.624). VOL had weaker correlations with AIM and JET (ρ = 0.69-0.73, p < 0.001). AIM underestimated RF by 3.6-6.9% compared to VOL and JET, p < 0.03. Intra- and inter- observer reliability were excellent for all methods (ICC 0.94-0.99). The mean (±standard deviation) inter-observer difference for VOL was 2.4% (±5.1%), p < 0.05. CONCLUSIONS: In a diverse cohort of pediatric CHD, measurement of AVVR using JET is accurate and reliable to VOL and is a superior method of internal validation compared to AIM. This study supports use of 4DF CMR for measurement of AVVR, obviating need for expert prospective prescription during image acquisition by 2D CMR.

Performance of Matching Methods as Compared With Unmatched Ordinary Least Squares Regression Under Constant Effects.

Matching methods are assumed to reduce the likelihood of a biased inference compared with ordinary least squares (OLS) regression. Using simulations, we compared inferences from propensity score matching, coarsened exact matching, and unmatched covariate-adjusted OLS regression to identify which methods, in which scenarios, produced unbiased inferences at the expected type I error rate of 5%. We simulated multiple data sets and systematically varied common support, discontinuities in the exposure and/or outcome, exposure prevalence, and analytical model misspecification. Matching inferences were often biased in comparison with OLS, particularly when common support was poor; when analysis models were correctly specified and common support was poor, the type I error rate was 1.6% for propensity score matching (statistically inefficient), 18.2% for coarsened exact matching (high), and 4.8% for OLS (expected). Our results suggest that when estimates from matching and OLS are similar (i.e., confidence intervals overlap), OLS inferences are unbiased more often than matching inferences; however, when estimates from matching and OLS are dissimilar (i.e., confidence intervals do not overlap), matching inferences are unbiased more often than OLS inferences. This empirical "rule of thumb" may help applied researchers identify situations in which OLS inferences may be unbiased as compared with matching inferences.

Dual blockade of the PI3K/Akt/mTOR pathway inhibits posttransplant Epstein-Barr virus B cell lymphomas and promotes allograft survival.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation that often manifests as Epstein-Barr virus (EBV)-associated B cell lymphomas. Current treatments for PTLD have limited efficacy and can be associated with graft rejection or systemic toxicities. The mTOR inhibitor, rapamycin, suppresses tumor growth of EBV+ B cell lymphoma cells in vitro and in vivo; however, the efficacy is limited and clinical benefits of mTOR inhibitors for PTLD are variable. Here, we show constitutive activation of multiple nodes within the PI3K/Akt/mTOR pathway in EBV+ PTLD-derived cell lines. Inhibition of either PI3K or Akt, with specific inhibitors CAL-101 and MK-2206, respectively, diminished growth of EBV+ B cell lines from PTLD patients in a dose-dependent manner. Importantly, rapamycin combined with CAL-101 or MK-2206 had a synergistic effect in suppressing cell growth as determined by IC50 isobolographic analysis and Loewe indices. Moreover, these combinations were significantly more effective than rapamycin alone in inhibiting tumor xenograft growth in NOD-SCID mice. Finally, both CAL-101 and MK-2206 also prolonged survival of heterotopic cardiac allografts in C57BL/6 mice. Thus, combination therapy with rapamycin and a PI3K inhibitor, or an Akt inhibitor, can be an efficacious treatment for EBV-associated PTLD, while simultaneously promoting allograft survival.

Measuring socioeconomic adversity in early life.

AIM: Early life adversity leads to enduring effects on physical and mental health, school performance and other outcomes. We sought to identify potentially modifiable factors associated with socioeconomic adversity in early life. METHODS: We enrolled 1503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial and economic variables were analysed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state and national levels. RESULTS: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education and health insurance. Significantly worse health and social outcomes occurred in the lower versus higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles. CONCLUSION: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes.

Birth Location of Infants with Critical Congenital Heart Disease in California.

The American Academy of Pediatrics classifies neonatal intensive care units (NICUs) from level I to IV based on the acuity of care each unit can provide. Birth in a higher level center is associated with lower morbidity and mortality in high-risk populations. Congenital heart disease accounts for 25-50% of infant mortality related to birth defects in the U.S., but recent data are lacking on where infants with critical congenital heart disease (CCHD) are born. We used a linked dataset from the Office of Statewide Health Planning and Development to access ICD-9 diagnosis codes for all infants born in California from 2008 to 2012. We compared infants with CCHD to the general population, identified where infants with CCHD were born based on NICU level of care, and predicted level IV birth among infants with CCHD using logistic regression techniques. From 2008 to 2012, 6325 infants with CCHD were born in California, with 23.7% of infants with CCHD born at a level IV NICU compared to 8.4% of the general population. Level IV birth for infants with CCHD was associated with lower gestational age, higher maternal age and education, the presence of other congenital anomalies, and the diagnosis of a single ventricle lesion. More infants with CCHD are born in a level IV NICU compared to the general population. Future studies are needed to determine if birth in a lower level of care center impacts outcomes for infants with CCHD.

Near-Far Matching in R: The nearfar Package.

Estimating the causal treatment effect of an intervention using observational data is difficult due to unmeasured confounders. Many analysts use instrumental variables (IVs) to introduce a randomizing element to observational data analysis, potentially reducing bias created by unobserved confounders. Several persistent problems in the field have served as limitations to IV analyses, particularly the prevalence of "weak" IVs, or instrumental variables that do not effectively randomize individuals to the intervention or control group (leading to biased and unstable treatment effect estimates), as well as IV-based estimates being highly model dependent, requiring parametric adjustment for measured confounders, and often having high mean squared errors in the estimated causal effects. To overcome these problems, the study design method of "near-far matching" has been devised, which "filters" data from a cohort by simultaneously matching individuals within the cohort to be "near" (similar) on measured confounders and "far" (different) on levels of an IV. To facilitate the application of near-far matching to analytical problems, we introduce the R package nearfar and illustrate its application to both a classical example and a simulated dataset. We illustrate how the package can be used to "strengthen" a weak IV by adjusting the "near-ness" and "far-ness" of a match, reduce model dependency, enable nonparametric adjustment for measured confounders, and lower mean squared error in estimated causal effects. We additionally illustrate how to utilize the nearfar package when analyzing either continuous or binary treatments, how to prioritize variables in the match, and how to calculate F statistics of IV strength with or without adjustment for measured confounders.

Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial.

Importance: Dietary modification remains key to successful weight loss. Yet, no one dietary strategy is consistently superior to others for the general population. Previous research suggests genotype or insulin-glucose dynamics may modify the effects of diets. Objective: To determine the effect of a healthy low-fat (HLF) diet vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin secretion are related to the dietary effects on weight loss. Design, Setting, and Participants: The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized clinical trial included 609 adults aged 18 to 50 years without diabetes with a body mass index between 28 and 40. The trial enrollment was from January 29, 2013, through April 14, 2015; the date of final follow-up was May 16, 2016. Participants were randomized to the 12-month HLF or HLC diet. The study also tested whether 3 single-nucleotide polymorphism multilocus genotype responsiveness patterns or insulin secretion (INS-30; blood concentration of insulin 30 minutes after a glucose challenge) were associated with weight loss. Interventions: Health educators delivered the behavior modification intervention to HLF (n = 305) and HLC (n = 304) participants via 22 diet-specific small group sessions administered over 12 months. The sessions focused on ways to achieve the lowest fat or carbohydrate intake that could be maintained long-term and emphasized diet quality. Main Outcomes and Measures: Primary outcome was 12-month weight change and determination of whether there were significant interactions among diet type and genotype pattern, diet and insulin secretion, and diet and weight loss. Results: Among 609 participants randomized (mean age, 40 [SD, 7] years; 57% women; mean body mass index, 33 [SD, 3]; 244 [40%] had a low-fat genotype; 180 [30%] had a low-carbohydrate genotype; mean baseline INS-30, 93 µIU/mL), 481 (79%) completed the trial. In the HLF vs HLC diets, respectively, the mean 12-month macronutrient distributions were 48% vs 30% for carbohydrates, 29% vs 45% for fat, and 21% vs 23% for protein. Weight change at 12 months was -5.3 kg for the HLF diet vs -6.0 kg for the HLC diet (mean between-group difference, 0.7 kg [95% CI, -0.2 to 1.6 kg]). There was no significant diet-genotype pattern interaction (P = .20) or diet-insulin secretion (INS-30) interaction (P = .47) with 12-month weight loss. There were 18 adverse events or serious adverse events that were evenly distributed across the 2 diet groups. Conclusions and Relevance: In this 12-month weight loss diet study, there was no significant difference in weight change between a healthy low-fat diet vs a healthy low-carbohydrate diet, and neither genotype pattern nor baseline insulin secretion was associated with the dietary effects on weight loss. In the context of these 2 common weight loss diet approaches, neither of the 2 hypothesized predisposing factors was helpful in identifying which diet was better for whom. Trial Registration: clinicaltrials.gov Identifier: NCT01826591.

Benefit and harm of intensive blood pressure treatment: Derivation and validation of risk models using data from the SPRINT and ACCORD trials.

BACKGROUND: Intensive blood pressure (BP) treatment can avert cardiovascular disease (CVD) events but can cause some serious adverse events. We sought to develop and validate risk models for predicting absolute risk difference (increased risk or decreased risk) for CVD events and serious adverse events from intensive BP therapy. A secondary aim was to test if the statistical method of elastic net regularization would improve the estimation of risk models for predicting absolute risk difference, as compared to a traditional backwards variable selection approach. METHODS AND FINDINGS: Cox models were derived from SPRINT trial data and validated on ACCORD-BP trial data to estimate risk of CVD events and serious adverse events; the models included terms for intensive BP treatment and heterogeneous response to intensive treatment. The Cox models were then used to estimate the absolute reduction in probability of CVD events (benefit) and absolute increase in probability of serious adverse events (harm) for each individual from intensive treatment. We compared the method of elastic net regularization, which uses repeated internal cross-validation to select variables and estimate coefficients in the presence of collinearity, to a traditional backwards variable selection approach. Data from 9,069 SPRINT participants with complete data on covariates were utilized for model development, and data from 4,498 ACCORD-BP participants with complete data were utilized for model validation. Participants were exposed to intensive (goal systolic pressure < 120 mm Hg) versus standard (<140 mm Hg) treatment. Two composite primary outcome measures were evaluated: (i) CVD events/deaths (myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or CVD death), and (ii) serious adverse events (hypotension, syncope, electrolyte abnormalities, bradycardia, or acute kidney injury/failure). The model for CVD chosen through elastic net regularization included interaction terms suggesting that older age, black race, higher diastolic BP, and higher lipids were associated with greater CVD risk reduction benefits from intensive treatment, while current smoking was associated with fewer benefits. The model for serious adverse events chosen through elastic net regularization suggested that male sex, current smoking, statin use, elevated creatinine, and higher lipids were associated with greater risk of serious adverse events from intensive treatment. SPRINT participants in the highest predicted benefit subgroup had a number needed to treat (NNT) of 24 to prevent 1 CVD event/death over 5 years (absolute risk reduction [ARR] = 0.042, 95% CI: 0.018, 0.066; P = 0.001), those in the middle predicted benefit subgroup had a NNT of 76 (ARR = 0.013, 95% CI: -0.0001, 0.026; P = 0.053), and those in the lowest subgroup had no significant risk reduction (ARR = 0.006, 95% CI: -0.007, 0.018; P = 0.71). Those in the highest predicted harm subgroup had a number needed to harm (NNH) of 27 to induce 1 serious adverse event (absolute risk increase [ARI] = 0.038, 95% CI: 0.014, 0.061; P = 0.002), those in the middle predicted harm subgroup had a NNH of 41 (ARI = 0.025, 95% CI: 0.012, 0.038; P < 0.001), and those in the lowest subgroup had no significant risk increase (ARI = -0.007, 95% CI: -0.043, 0.030; P = 0.72). In ACCORD-BP, participants in the highest subgroup of predicted benefit had significant absolute CVD risk reduction, but the overall ACCORD-BP participant sample was skewed towards participants with less predicted benefit and more predicted risk than in SPRINT. The models chosen through traditional backwards selection had similar ability to identify absolute risk difference for CVD as the elastic net models, but poorer ability to correctly identify absolute risk difference for serious adverse events. A key limitation of the analysis is the limited sample size of the ACCORD-BP trial, which expanded confidence intervals for ARI among persons with type 2 diabetes. Additionally, it is not possible to mechanistically explain the physiological relationships explaining the heterogeneous treatment effects captured by the models, since the study was an observational secondary data analysis. CONCLUSIONS: We found that predictive models could help identify subgroups of participants in both SPRINT and ACCORD-BP who had lower versus higher ARRs in CVD events/deaths with intensive BP treatment, and participants who had lower versus higher ARIs in serious adverse events.

Teamwork in the NICU Setting and Its Association with Health Care-Associated Infections in Very Low-Birth-Weight Infants.

Background and Objective Teamwork may affect clinical care in the neonatal intensive care unit (NICU) setting. The objective of this study was to assess teamwork climate across NICUs and to test scale-level and item-level associations with health care-associated infection (HAI) rates in very low-birth-weight (VLBW) infants. Methods Cross-sectional study of the association between HAI rates, defined as any bacterial or fungal infection during the birth hospitalization, among 6,663 VLBW infants cared for in 44 NICUs between 2010 and 2012. NICU HAI rates were correlated with teamwork climate ratings obtained in 2011 from 2,073 of 3,294 eligible NICU health professionals (response rate 63%). The relation between HAI rates and NICU teamwork climate was assessed using logistic regression models including NICU as a random effect. Results Across NICUs, 36 to 100% (mean 66%) of respondents reported good teamwork. HAI rates were significantly and independently associated with teamwork climate (odds ratio, 0.82; 95% confidence interval, 0.73-0.92, p = 0.005), such that the odds of an infant contracting a HAI decreased by 18% with each 10% rise in NICU respondents reporting good teamwork. Conclusion Improving teamwork may be an important element in infection control efforts.

Obstetric Ultrasound Efficiency and Accuracy Using a Protocol-Based Examination.

OBJECTIVES: Obstetric ultrasound imaging requires the acquisition of a standard set of maternal and fetal images. Our objective was to evaluate the impact of implementation of a protocol-based ultrasound examination on the duration of ultrasound examinations, examination completion, and accuracy of documentation. METHODS: We conducted a case-cohort study. Obstetric ultrasound examinations performed in the first, second, and third trimesters were reviewed before and after implementation of a protocol-based ultrasound examination. The duration of the ultrasound examination, number of missing required images, and documentation of missing images were abstracted from an image archival system. To account for clustering by sonographer, 3 mixed effects models with a fixed effect for protocol and a random intercept for sonographer were used to evaluate the effect on the total time of the examination, number of missing images, and whether missing images were documented. RESULTS: A total of 100 ultrasound examinations were compared: 50 before and 50 after implementation of the protocol. Statistically significant differences between outcomes before and after protocol implementation were observed for all outcomes. After implementation of the protocol, the average duration of ultrasound examinations decreased by 7.62 minutes (95% confidence interval [CI], 3.57-11.68 minutes); the number of missing images was reduced by 5.81 per examination (95% CI, 4.24-7.39); and proper documentation of missing images increased by 40.24% (95% CI, 22.77%-57.71%). CONCLUSIONS: Implementation of a software protocol-based ultrasound examination significantly improved the efficiency and accuracy of obstetric ultrasound examinations in this study.

Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer.

INTRODUCTION: Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment. METHODS: We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS. RESULTS: We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013). CONCLUSIONS: CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.