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PURPOSE: This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. METHODS: Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. RESULTS: The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). CONCLUSION: Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.

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OBJECTIVE: To investigate the association between diabetic ketoacidosis (DKA) and prolonged QTc interval and to assess for correlation between DKA severity and QTc prolongation. STUDY DESIGN: Retrospective observational study in a pediatric hospital. Patients admitted with DKA diagnosed by laboratory criteria and an electrocardiogram (ECG) performed during a period of acidosis were identified using Looking Glass Clinical Analytics. Data including age, sex, pH, electrolytes, anion gap, and ECG variables were collected. Patients were excluded if they had a prior diagnosis of prolonged QTc or were taking QTc prolonging medications. Severity of DKA was classified as mild (pH 7.24-7.3), moderate (pH 7-7.24), or severe (pH <7). ECGs were read by a pediatric electrophysiologist and QTc interval was manually calculated utilizing the Bazett formula. RESULTS: Ninety-six patients were included (mean age 15.2 ± 4.2 years, pH 7.12 ± 0.12, bicarbonate 8.6 ± 3.7 mmol/L, potassium 5.3 ± 1.1 mEq/L). Mean QTc interval for all patients in DKA was 454 ± 32 msec. Mean QTc in the mild group was 441 ± 22 msec, moderate group 460 ± 36 msec, and severe group 461 ± 34 msec. There was a significant difference in QTc interval across DKA severity groups (P = .05). There was a significant association between higher anion gaps and greater QTc intervals (r = 0.21, P = .04). CONCLUSIONS: Thirty-one percent of pediatric patients with DKA demonstrated QTc prolongation on ECG. Severity of DKA and worsening acidosis were associated with increased prolongation of the QTc. Further study is required to evaluate the clinical impact of these findings.

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Many large-bodied marine fishes that form spawning aggregations, such as the Nassau grouper (Epinephelus striatus), have suffered regional overfishing due to exploitation during spawning. In response, marine resource managers in many locations have established marine protected areas or seasonal closures to recover these overfished stocks. The challenge in assessing management effectiveness lies largely in the development of accurate estimates to track stock size through time. For the past 15 y, the Cayman Islands government has taken a series of management actions aimed at recovering collapsed stocks of Nassau grouper. Importantly, the government also partnered with academic and nonprofit organizations to establish a research and monitoring program (Grouper Moon) aimed at documenting the impacts of conservation action. Here, we develop an integrated population model of 2 Cayman Nassau grouper stocks based on both diver-collected mark-resight observations and video censuses. Using both data types across multiple years, we fit parameters for a state-space model for population growth. We show that over the last 15 y the Nassau grouper population on Little Cayman has more than tripled in response to conservation efforts. Census data from Cayman Brac, while more sparse, show a similar pattern. These findings demonstrate that spatial and seasonal closures aimed at rebuilding aggregation-based fisheries can foster conservation success.

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Background: People need to choose from a wide range of foods, and in addition to availability and accessibility, people's values and preferences largely determine their daily food choices. Given the potential adverse health consequences of red and processed meat and the limited knowledge on individuals' health-related values and preferences on the topic, such data would be useful in the development of recommendations regarding meat consumption. Methods and analysis: We will perform an international cross-sectional mixed methods study in four countries across two continents. The study population will consist of adult omnivores currently consuming a minimum of three weekly servings of either unprocessed red meat or processed meat. We will explore participants' willingness to stop or reduce their unprocessed red meat, or their processed meat consumption through a direct-choice exercise. This exercise will consist of presenting a scenario tailored to each individual's average weekly consumption. That is, based on a systematic review and meta-analysis of the best estimate of the risk reduction in overall cancer mortality and cancer incidence, we will ask participants if they would stop their consumption, and/or reduce their average consumption. We will also present the corresponding certainty of the evidence for the potential risk reductions. Finally, for all included participants, we will measure their meat consumption three months after the interview and determine if they have made any changes to their average consumption. Ethics and dissemination: The research protocol was approved by the ethics committees in Canada (Research Ethics Board, Dalhousie University), Spain (Comitè Ètic d'Investigació Clínica de l'IDIAP Jordi Gol), Poland (The Bioethics Committee of the Jagiellonian University), and Brazil (National Research Ethics Commission). The study is based on voluntary participation and informed written consent. Results from this project will be disseminated through publications and presentations.

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BACKGROUND: Cardiac surgeries are complex procedures aiming to re-establish coronary flow and correct valvular defects. Oxidative stress, caused by inflammation and ischemia-reperfusion injury, is associated with these procedures, increasing the risk of adverse outcomes. N-acetylcysteine (NAC) acts as an antioxidant by replenishing the glutathione stores, and emerging evidence suggests that NAC may reduce the risk of adverse perioperative outcomes. We conducted a systematic review and meta-analysis to investigate the addition of NAC to a standard of care among adult patients undergoing cardiac surgery. METHODS: We searched four databases (PubMed, EMBASE, CENTRAL, LILACS) from inception to October 2018 and the grey literaure for randomized controlled trials (RCTs) investigating the effect of NAC on pre-defined outcomes including mortality, acute renal insufficiency (ARI), acute cardiac insufficiency (ACI), hospital length of stay (HLoS), intensive care unit length of stay (ICULoS), arrhythmia and acute myocardial infarction (AMI). Reviewers independently screened potentially eligible articles, extracted data and assessed the risk of bias among eligible articles. We used the GRADE approach to rate the overall certainty of evidence for each outcome. RESULTS: Twenty-nine RCTs including 2,486 participants proved eligible. Low to moderate certainty evidence demonstrated that the addition of NAC resulted in a non-statistically significant reduction in mortality (Risk Ratio (RR) 0.71; 95% Confidence Interval (CI) 0.40 to 1.25), ARI (RR 0.92; 95% CI 0.79 to 1.09), ACI (RR 0.77; 95% CI 0.44 to 1.38), HLoS (Mean Difference (MD) 0.21; 95% CI -0.64 to 0.23), ICULoS (MD -0.04; 95% CI -0.29 to 0.20), arrhythmia (RR 0.79; 95% CI 0.52 to 1.20), and AMI (RR 0.84; 95% CI 0.48 to 1.48). LIMITATIONS: Among eligible trials, we observed heterogeneity in the population and interventions including patients with and without kidney dysfunction and interventions that differed in route of administration, dosage, and duration of treatment. This observed heterogeneity was not explained by our subgroup analyses. CONCLUSIONS: The addition of NAC during cardiac surgery did not result in a statistically significant reduction in clinical outcomes. A large randomized placebo-controlled multi-centre trial is needed to determine whether NAC reduces mortality. REGISTRATION: PROSPERO CRD42018091191.

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CONTEXT: Ankle injury is one of the most common conditions in athletics and military activities. Strength asymmetry (SA) and imbalance may represent a risk factor for injury, but past investigations have produced ambiguous conclusions. Perhaps one explanation for this ambiguity is the fact that these authors used univariate models to predict injury. OBJECTIVE: To evaluate the predictive utility of SA and imbalance calculations for ankle injury in univariate and multivariate prediction models. DESIGN: Prospective cohort study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 140 male US Air Force Special Forces. MAIN OUTCOME MEASURE(S): Baseline testing consisted of body composition, isometric strength, and aerobic and anaerobic capacity. A clinician conducted medical chart reviews 365 days posttesting to document the incidence of ankle injury. Strength asymmetries were calculated based on the equations most prevalent in the literature along with known physiological predictors of injury in the military: age, height, weight, body composition, and aerobic capacity. Simple logistic regression was conducted using each predictor, and backward stepwise logistic regression was conducted with each equation method and the physiological predictors entered initially into the model. RESULTS: Strength asymmetry or imbalance or both, as a univariate predictor, was not able to predict ankle injury 365 days posttesting. Body mass (P = .01) and body mass index (P = .01) significantly predicted ankle injury. Strength asymmetry or imbalance or both significantly predicted ankle injury when considered with body mass (P = .002-.008). CONCLUSIONS: As a univariate predictor, SA did not predict ankle injury. However, SA contributed significantly to predicting ankle injury in a multivariate model using body mass. Interpreting SA and imbalance in the presence of other physiological variables can help elucidate the risk of ankle injury.

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INTRODUCTION: Musculoskeletal injury rates in military personnel remain unacceptably high. Application of machine learning algorithms could be useful in multivariate models to predict injury in this population. The purpose of this study was to investigate if interaction between individual predictors, using a decision tree model, could be used to develop a population-specific algorithm of lower-extremity injury (LEI) risk. METHODS: One hundred forty Air Force Special Forces Operators (27.4 ± 5.0 yr, 177.6 ± 5.8 cm, 83.8 ± 8.4 kg) volunteered for this prospective cohort study. Baseline testing included body composition, isokinetic strength, flexibility, aerobic/anaerobic capacity, anaerobic power, and landing biomechanics. To evaluate unilateral landing patterns, subjects jumped off two-feet from a distance (40% of their height) over a hurdle and landing single-legged on a force plate. Medical chart reviews were conducted 365 d postbaseline. χ automatic interaction detection (CHAID) was used, which compares predictor variables to LEI and assigns a population-specific "cut-point" for the most relevant predictors. RESULTS: Twenty-seven percent of operators (n = 38) suffered LEI. A maximum knee flexion angle difference of 25.1% had the highest association with injury in this population (P = 0.006). Operators with >25.1% differences in max knee flexion angle (n = 13) suffered LEI at a 69.2% rate. Seven of the 13 Operators with >25.1% difference in max knee flexion angle weighed >81.8 kg, and 100% of those operators suffered LEI (P = 0.047; n = 7). Only 33% of operators with >25.1% difference in max knee flexion angle that weighed <81.8 kg suffered LEI. CONCLUSIONS: This study demonstrated increased risk of LEI over a 365-d period in Operators with greater differences in single-leg landing strategies and higher body mass. The CHAID approach can be a powerful tool to analyze population-specific risk factors for injury, along with how those factors may interact to enhance risk.

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Concussions are common in military personnel and may result in increased risk of musculoskeletal injury. One plausible explanation for this risk could be that neuromotor deficiencies enhance injury risk after a concussion through altered muscular activation/contraction timing. PURPOSE: To compare military personnel with at least one concussion during the past 1 month to 2 yr (CONCUSSED) to military branch-matched, age-matched, and Special Operations Forces group-matched controls (CONTROL) on physiological, musculoskeletal, and biomechanical performance. METHODS: A total of 48 (24 CONCUSSED, 24 CONTROL) male Air Force and Naval Special Warfare Operators age 19 to 34 yr participated in the study. Participants self-reported demographics/injury history and completed the following assessments: 1) physiological-body composition, anaerobic power and capacity, aerobic capacity and lactate threshold; 2) musculoskeletal-lower extremity isokinetic strength testing, including time to peak torque; and 3) biomechanical-single-leg jump and landing task, including landing kinematics of the hip, knee and ankle. A machine learning decision tree algorithm (C5.0) and one-way ANOVA were used to compare the two groups on these outcomes. RESULTS: Despite nonsignificant differences using ANOVA, the C5.0 algorithm revealed CONCUSSED demonstrated quicker time to peak knee flexion angle during the single-leg landing task (≤0.170 s; CONCUSSED: n = 22 vs CONTROL: n = 14), longer time to peak torque in knee extension isokinetic strength testing (>500 ms; CONCUSSED: n = 18 vs CONTROL: n = 4) and larger knee flexion angle at initial contact (>7.7°; CONCUSSED: n = 18 vs CONTROL: n = 2). CONCLUSION: The findings supported the hypothesis that CONCUSSED military personnel would demonstrate altered neuromuscular control in landing strategies and muscular activation. Future research should assess prospectively neuromuscular changes after a concussion and determine if these changes increase risk of subsequent musculoskeletal injuries.

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In a retrospective study of 501 neonates with potential in utero substance exposure, the drug detection performance of a commercially available umbilical cord tissue toxicology test was evaluated against a commercially available gold standard meconium toxicology test. Drugs detected in paired meconium and umbilical cord tissue samples were often discordant.

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BACKGROUND: Cholangitis in dogs appears to be more common than previously thought, but understanding of the disease remains incomplete. OBJECTIVE: To describe a population of dogs with cholangitis or cholangiohepatitis. ANIMALS: Fifty-four client-owned dogs with cholangitis or cholangiohepatitis. METHODS: Medical records of dogs with cholangitis or cholangiohepatitis confirmed by histopathology between January 2004 and December 2014 were identified using a computer-based search and retrospectively reviewed. RESULTS: Clinical signs included vomiting (72.2%), lethargy (70.4%), and inappetence (64.8%). Most dogs (49/50) had increased liver enzyme activities, hyperbilirubinemia (32/50), and hypercholesterolemia (24/43). Ultrasonographic abnormalities of the hepatobiliary system were seen in 84% of cases. On histopathology, 53 of 54 affected dogs had neutrophilic cholangitis (NC) or cholangiohepatitis, whereas 1 dog had lymphocytic cholangitis. Most cases (42/54) were chronic. Evidence of concurrent biliary disease (46.2%) and biliary tract obstruction (42.6%) was common. Seventeen of 36 biliary and 11 of 25 liver cultures were positive for bacterial growth; Escherichia coli and Enterococcus spp. were most common. Median patient survival was 671 days (95% confidence interval [CI]: 114-1,426). On Cox regression, dogs that did not have a cholecystectomy performed had a 2.1 greater hazard for death (P = 0.037; 95% CI: 1.0-4.3) compared to cholecystectomized dogs. Dogs >13 years old had a 5.0 greater hazard for death (P = 0.001; 95% CI: 1.9-13.2) compared to younger dogs. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Chronic NC or cholangiohepatitis was most common. Cholecystitis and biliary tract obstruction often occurred in conjunction with cholangitis. Cholecystectomized dogs had decreased risk of death; thus, cholecystectomy may improve patient outcome.

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OBJECTIVES: To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. STUDY DESIGN: A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. RESULTS: We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). CONCLUSION: Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

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OBJECTIVE: To investigate how food commercials influence children's food choices. STUDY DESIGN: Twenty-three children ages 8-14 years provided taste and health ratings for 60 food items. Subsequently, these children were scanned with the use of functional magnetic resonance imaging while making food choices (ie, "eat" or "not eat") after watching food and nonfood television commercials. RESULTS: Our results show that watching food commercials changes the way children consider the importance of taste when making food choices. Children did not use health values for their food choices, indicating children's decisions were largely driven by hedonic, immediate rewards (ie, "tastiness"); however, children placed significantly more importance on taste after watching food commercials compared with nonfood commercials. This change was accompanied by faster decision times during food commercial trials. The ventromedial prefrontal cortex, a reward valuation brain region, showed increased activity during food choices after watching food commercials compared with after watching nonfood commercials. CONCLUSION: Overall, our results suggest watching food commercials before making food choices may bias children's decisions based solely on taste, and that food marketing may systematically alter the psychological and neurobiologic mechanisms of children's food decisions.

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BACKGROUND: The 2012 American College of Chest Physicians' Evidence-Based Clinical Practice (CHEST), the 2012 European Society of Cardiology, and the 2014 American Heart Association guidelines and published decision tools by LaHaye and Casciano offer oral anticoagulant (OAC) recommendations for patients with atrial fibrillation (AF). The aim of our study was to compare the net clinical benefit (NCB) of OAC prescribing that was concordant with these decision aids. METHODS: A cohort study of the 2001-2013 LifeLink claims data was used. NCB in concordance with each decision aid was defined as adverse events (thromboembolic and major bleed events) prevented per 10,000 person-years. Cox proportional hazard models were used to assess the relative risk of AF adverse events associated in concordance with each decision aid adjusted for potential confounders. FINDINGS: The study included 15,129 patients with AF, contributing 33,512 person-years. The NCB of the CHEST guidelines was the highest (NCB = 30.07; 95% confidence interval [CI] = 28.66, 31.49) and the European Society of Cardiology guidelines the lowest (NCB = 7.38; 95% CI = 5.97, 8.80). Significant unadjusted decreases in the risk of AF adverse events associated with concordant OAC use/nonuse were found for the CHEST guidelines (hazard ratio [HR] = .825; 95% CI = .695, .979), Casciano tool (HR = .838; 95% CI = .706, .995), and LaHaye tool (HR = .841; 95% CI = .709, .999); however, none were significant after multivariate adjustment. CONCLUSION: Concordant OAC use with any of the decision aids except for the aggressive LaHaye tool led to a positive NCB. The decision aids based on the CHA2DS2-VASc algorithm did not consistently improve the NCB compared to CHADS2-based aids. Recommending OAC use when CHA2DS2-VASc score = 1 resulted in a lower NCB when all other factors guiding recommendations were held constant.

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K2 is a synthetic cannabinoid that has potential cardiovascular side effects, including myocardial ischemia, myocardial infarction, and arrhythmias. Cardiac testing of pediatric patients is often not performed owing to a lack of symptomatology. We report a series of pediatric patients with concern for myocardial ischemia temporally associated with K2 exposure.

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OBJECTIVE: To examine the proportion of diabetic peripheral neuropathy (DPN) patients receiving pharmacologic DPN treatments and specifically to identify the rates and factors associated with opioid use and first-line opioid use. METHODS: A 10% sample of IMS-LifeLink claims data from 1998 through 2008 was used. The study population consisted of diabetic patients who met DPN criteria using a validated DPN algorithm. Multivariable logistic regression controlling for demographics, comorbidities, and other clinical characteristics was used to identify factors associated with any DPN pharmacologic treatment, any opioid use, and first-line opioid treatment. Sensitivity analyses were conducted to explore variations in exclusion criteria as well as opioid use definitions. RESULTS: A total of 666 DPN patients met inclusion criteria and pharmacologic treatment was received by 288 patients (43.24%) and of those, 154 (53.47%) had DPN-related opioid use and 96 (33.33%) received opioid as first-line treatment. Persons with diabetic complications were more likely to use opioids (odds ratio=4.53; 95% confidence interval, 1.09-18.92). Food and Drug Administration-approved DPN agents duloxetine 1.04% (n=3) and pregabalin 5.56% (n=16) had much lower rates of use. DPN-related drug use and DPN-related opioid usage increased as we used less restrictive samples in sensitivity analyses. CONCLUSIONS: Opioids were the most frequently prescribed first-line agents for DPN. More than 50% of DPN patients remained untreated with pharmacologic agents 1 year after a DPN diagnosis.

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