Pathophysiology of Hepatic Encephalopathy: A Framework for Clinicians.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward.

External validation and application of the Diabetes Population Risk Tool (DPoRT) for prediction of type 2 diabetes onset in the US population.

INTRODUCTION: Characterizing diabetes risk in the population is important for population health assessment and diabetes prevention planning. We aimed to externally validate an existing 10-year population risk model for type 2 diabetes in the USA and model the population benefit of diabetes prevention approaches using population survey data. RESEARCH DESIGN AND METHODS: The Diabetes Population Risk Tool (DPoRT), originally derived and validated in Canada, was applied to an external validation cohort of 23 477 adults from the 2009 National Health Interview Survey (NHIS). We assessed predictive performance for discrimination (C-statistic) and calibration plots against observed incident diabetes cases identified from the NHIS 2009-2018 cycles. We applied DPoRT to the 2018 NHIS cohort (n=21 187) to generate 10-year risk prediction estimates and characterize the preventive benefit of three diabetes prevention scenarios: (1) community-wide strategy; (2) high-risk strategy and (3) combined approach. RESULTS: DPoRT demonstrated good discrimination (C-statistic=0.778 (males); 0.787 (females)) and good calibration across the range of risk. We predicted a baseline risk of 10.2% and 21 076 000 new cases of diabetes in the USA from 2018 to 2028. The community-wide strategy and high-risk strategy estimated diabetes risk reductions of 0.2% and 0.3%, respectively. The combined approach estimated a 0.4% risk reduction and 843 000 diabetes cases averted in 10 years. CONCLUSIONS: DPoRT has transportability for predicting population-level diabetes risk in the USA using routinely collected survey data. We demonstrate the model's applicability for population health assessment and diabetes prevention planning. Our modeling predicted that the combination of community-wide and targeted prevention approaches for those at highest risk are needed to reduce diabetes burden in the USA.

Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features Among Commercially Insured Adults in the United States.

BACKGROUND:  The incidence of colorectal cancer (CRC) in patients younger than 50 has been rising over the last several decades, accounting for up to 25% of total cases. Despite the screening age recently being lowered to 45, a significant proportion of cases would still arise at younger ages prior to screening. Nonfamilial early-onset CRC remains a particular concern. Identification of risk factors and clinical features in this age group is needed to improve detection. METHODS: In this retrospective cohort analysis using claims data from the Truven Health MarketScan® Commercial Claims insurance database from 2007 to 2017, patients were identified with colon and rectal cancer, compared across three age groups (ages 18-40, 40-50, and >50), and analyzed for risk factors and clinical features. RESULTS: Female sex was more prevalent in the younger age group compared to age >50 (54% and 51.9% vs. 49.6%), with little change noted between rectal cancer age groups by sex. A higher percentage of younger patients were in the obese age groups compared with older groups for colon cancer, particularly the morbidly obese with BMI >40 (24.94%, 25.75%, and 21.34% in the three age groups). Abdominal pain was a common presenting symptom identified in the age groups <50 compared with age >50 (25% and 19% vs. 14%), along with hematochezia, weight loss, and anemia. CONCLUSIONS: Morbid obesity and female sex may be important risk factors among patients with early-onset CRC. The presence of abdominal pain was more common among the early-onset CRC cohort.

Modelling population-level and targeted interventions of weight loss on chronic disease prevention in the Canadian population.

Obesity is a known risk factor for major chronic diseases. Prevention of chronic disease is a top global priority. The study aimed to model scenarios of population-level and targeted weight loss interventions on 10-year projected risk of chronic disease in Canada using a population-level risk prediction algorithm. The validated Chronic Disease Population Risk Tool (CDPoRT) forecasts 10-year risk of chronic disease in the adult population. We applied CDPoRT to the 2013/14 Canadian Community Health Survey to generate prospective chronic disease estimates for adults 20 years and older in Canada (n = 83,220). CDPoRT was used to model the following scenarios: British Columbia's (BC) and Quebec's (QC) provincial population-level weight reduction targets, a population-level intervention that could achieve weight loss, targeted weight loss interventions for overweight and obese groups, and the combination of a population-level and targeted weight loss intervention. We estimated chronic disease risk reductions and number of cases prevented in each scenario compared with the baseline. At baseline, we predicted an 18.4% risk and 4,151,929 new cases of chronic disease in Canada over the 10-year period. Provincial weight loss targets applied to the Canadian population estimated chronic disease reductions of 0.6% (BC) and 0.1% (QC). The population-level intervention estimated a greater reduction in risk (0.2%), compared to the targeted interventions (0.1%). The combined approach estimated a 0.3% reduction in chronic disease risk. Our modelling predicted that population-level approaches that achieve weight loss in combination with targeted weight loss interventions can substantially decrease the chronic disease burden in Canada.

Surgery in Nonalcoholic Cirrhosis: Clinical Outcomes, Healthcare Utilization, and Cost Analysis.

BACKGROUND: Patients with cirrhosis are at increased risk of complications following surgery due to multiple factors, including portal hypertension and alterations in hemostasis. Improvements in perioperative management as well as risk stratification scores have helped improve outcomes, but gaps remain in our understanding of the cost and morbidity of cirrhotic patients who undergo surgery. METHODS: We conducted a case-control study using the IBM Electronic Health Record (EHR) MarketScan Commercial Claims (MSCC) database from January 1, 2007 to December 31, 2017. Nonalcoholic cirrhotic patients who underwent surgery were identified based on International Classification of Diseases, Ninth Revision (ICD-9)/Tenth Revision (ICD-10) codes for multiple surgical categories and matched with controls with cirrhosis who did not undergo surgery in this time period. A total of 115,512 patients were identified with cirrhosis, of whom 19,542 (16.92%) had surgery. Medical history and comorbidities were compiled, and outcomes in the six-month period following surgery were analyzed between matched groups. A cost analysis was performed based on claims data. RESULTS: Nonalcoholic cirrhotic patients who underwent surgery had a higher comorbidity index at baseline compared with controls (1.34 vs. 0.88, P<0.0001). Mortality was increased in the surgery group (4.68% vs. 2.38%, P<0.001) in the follow-up period. The surgical cohort had higher rates of adverse hepatic outcomes, including hepatic encephalopathy (5.00% vs. 2.50%, P<0.0001), spontaneous bacterial peritonitis (0.64% vs. 0.25%, P<0.001), and higher rates of septic shock (0.66% vs. 0.14%, P<0.001), intracerebral hemorrhage (0.49% vs. 0.04%, P<0.001), and acute hypoxemic respiratory failure (7.02% vs. 2.31%, P<0.001). Healthcare utilization analysis revealed increased total claims per patient in the surgical cohort (38.11 vs. 28.64, P<0.0001), higher inpatient admissions (6.05 vs. 2.35, P<0.0001), more outpatient visits (19.72 vs. 15.23, P<0.0001), and prescription claims per patient (11.76 vs. 10.61, P<0.0001) in the postsurgical period. The likelihood of at least one inpatient stay was higher in the surgical cohort (51.63% vs. 22.32%, P<0.0001), and inpatient stays were longer (4.99 days vs. 2.09 days, P<0.0001). The total cost of health services was significantly increased per patient in the postoperative period for patients undergoing surgery ($58,246 vs. $26,842, P<0.0001), largely due to increased inpatient costs ($34,446 vs. $10,789, P<0.0001). CONCLUSION: Nonalcoholic cirrhotics undergoing surgery experienced worse outcomes with respect to adverse hepatic events and complications, including septic shock and intracerebral hemorrhage. Claims and cost analysis showed a significant increase in health expenditure in the surgical group, largely due to the cost of more frequent and longer inpatient admissions.

Diagnosis of Primary Sclerosing Cholangitis Beyond Childhood is Associated with Worse Outcomes.

BACKGROUND: The elucidation of differences between adult and pediatric-onset primary sclerosing cholangitis (PSC) may inform clinical decision making, and whether results of adult PSC clinical trials can be extrapolated to pediatric subjects. METHODS: A single-center retrospective analysis of PSC subjects diagnosed during the epoch 2000-13 was conducted. Demographic, clinical, and laboratory data were compared between PSC subjects diagnosed between 0-18 (pediatric) and 19+ (adult) years of age. An adverse outcome was defined as PSC-related death, liver transplant, or malignancy. Survival without any of these was defined as event-free survival. RESULTS: Analyses of 28 pediatric-diagnosed and 59 adult-diagnosed subjects revealed that incidence of early portal hypertension (PHT; P = 0.2), laboratory parameters of liver disease severity, and fibrosis grade at diagnosis were comparable between adult and pediatric PSC subjects. Adult-diagnosed PSC subjects had higher incidences of adverse outcomes compared to pediatric-diagnosed PSC subjects (P = 0.02). The age group 0-18 years (n = 30) had significantly better event-free survival compared to the age group more than 40 years (n = 25; P = 0.03). The prevalence of PHT in adult PSC subjects was 2.6 that of pediatric PSC subjects. PHT adversely affected outcomes in both adult (P < 0.001) and pediatric (P = 0.01) subjects. Adult PSC subjects were more likely to develop biliary complications (BCs; P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult PSC subjects were more likely to have extra-hepatic co-morbidities (P < 0.001). Adult subjects had a longer follow-up duration compared to pediatric subjects (P = 0.06). CONCLUSION: Despite having a comparable clinical, laboratory, and histologic biomarkers of liver disease severity at the time of diagnosis, adult PSC subjects had a worse outcome compared to pediatric PSC subjects. Possible reasons for this finding include higher incidence of PHT, BCs, extra-hepatic co-morbidities, and longer duration of follow-up.

Wilson's Disease: An Analysis of Health Care Use and Cost Burden of Commercially Insured Adults in the United States.

The economic and health care use burdens of Wilson's disease (WD) are unknown. In this study, we aimed to quantify this health care resource use and economic burden. We performed a retrospective case-control analysis of individuals in the Truven Health MarketScan Commercial Claims database (2007-2017). Using propensity scores, 424 WD cases were matched 1:1 to chronic liver disease (CLD) controls without WD. Total and service-specific parameters, expressed in monthly averages, were quantified for the 6-month pre-WD diagnosis versus the 12-month period after diagnosis. Wilcoxon signed-rank tests and McNemar tests were used to examine incremental differences in burden between cases and controls. Adjusted multivariable generalized linear regression models were used to compare health care burdens. Relative to the 6-month pre-WD diagnosis, the 12 months after diagnosis had more claims per patient (2.87 vs. 3.35; P < 0.0001) and increased per patient health care costs (US $2,089 vs. US $3,887; P < 0.0001). WD cases incurred US $1,908 more in total unadjusted costs compared to controls in the 12-month postindex date monthly averages. The increase in claims was primarily due to outpatient visits (1.62 vs. 1.82) and pharmaceutical claims (1.11 vs. 1.37). Cases also had higher health care costs for inpatient admissions (US $559 vs. US $1,264), outpatient visits (US $770 vs. US $1,037), and pharmaceutical claims (US $686 vs. US $1,489). Conclusion: WD is associated with significant health care cost and use burdens driven by increased inpatient admissions, outpatient visits, and pharmaceutical claims.

Acute kidney injury and hepatorenal syndrome in cirrhosis.

Acute kidney injury (AKI) in cirrhosis, including hepatorenal syndrome (HRS), is a common and serious complication in cirrhotic patients, leading to significant morbidity and mortality. AKI is separated into two categories, non-HRS AKI and HRS-AKI. The most recent definition and diagnostic criteria of AKI in cirrhosis and HRS have helped diagnose and prognosticate the disease. The pathophysiology behind non-HRS-AKI and HRS is more complicated than once theorized and involves more processes than just splanchnic vasodilation. The common biomarkers clinicians use to assess kidney injury have significant limitations in cirrhosis patients; novel biomarkers being studied have shown promise but require further studies in clinical settings and animal models. The overall management of non-HRS AKI and HRS-AKI requires a systematic approach. Although pharmacological treatments have shown mortality benefit, the ideal HRS treatment option is liver transplantation with or without simultaneous kidney transplantation. Further research is required to optimize pharmacologic and nonpharmacologic approaches to treatment. This article reviews the current guidelines and recommendations of AKI in cirrhosis.

Training of computational algorithms to predict NAFLD activity score and fibrosis stage from liver histopathology slides.

BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), has been increasing for decades. Since the mainstay is lifestyle modification in this mainly asymptomatic condition, there is a need for accurate diagnostic methods. OBJECTIVES: This study proposes a method with a computer-aided diagnosis (CAD) system to predict NAFLD Activity score (NAS scores-steatosis, lobular inflammation, and ballooning) and fibrosis stage from histopathology slides. METHODS: A total of 87 pathology slides pairs (H&E and Trichrome-stained) were used for the study. Ground-truth NAS scores and fibrosis stages were previously identified by a pathologist. Each slide was split into 224 × 224 patches and fed into a feature extraction network to generate local features. These local features were processed and aggregated to obtain a global feature to predict the slide's scores. The effects of different training strategies, as well as training data with different staining and magnifications were explored. Four-fold cross validation was performed due to the small data size. Area Under the Receiver Operating Curve (AUROC) was utilized to evaluate the prediction performance of the machine-learning algorithm. RESULTS: Predictive accuracy for all subscores was high in comparison with pathologist assessment. There was no difference among the 3 magnifications (5x, 10x, 20x) for NAS-steatosis and fibrosis stage tasks. A larger magnification (20x) achieved better performance for NAS-lobular scores. Middle-level magnification was best for NAS-ballooning task. Trichrome slides are better for fibrosis stage prediction and NAS-ballooning score prediction task. NAS-steatosis prediction had the best performance (AUC 90.48%) in the model. A good performance was observed with fibrosis stage prediction (AUC 83.85%) as well as NAS-ballooning prediction (AUC 81.06%). CONCLUSIONS: These results were robust. The method proposed proved to be effective in predicting NAFLD Activity score and fibrosis stage from histopathology slides. The algorithms are an aid in having an accurate and systematic diagnosis in a condition that affects hundreds of millions of patients globally.

The Brain-Gut-Microbiotal Axis: A framework for understanding functional GI illness and their therapeutic interventions.

Functional gastrointestinal disorders (FGIDs), characterized by chronic abdominal complaints without a structural or biochemical cause, are common diseases that are frequently encountered by specialists in internal medicine. Collectively, irritable bowel syndrome (IBS) and functional dyspepsia are estimated to affect up to 22% of the population, and are often associated with additional somatic and pain complaints, all without an obvious structural source [1,2]. An appreciation of the current understanding of the mechanistic basis for these disorders is key to developing treatment goals and optimization of patient management strategies. In recent years, the brain-gut axis increasingly has been recognized as a central factor in the experience of functional abdominal pain disorders, including the most recent Rome IV guidelines which identify FGIDs as disorders of gut-brain interaction [3]. The brain-gut axis (BGA), simply defined, is a complex network of bidirectional communication between the central and enteric nervous systems. This axis broadly includes all the systems involved with communication between the GI tract and central nervous system (CNS), with principle inputs into this network occurring between the CNS, enteric nervous system (ENS), and autonomic nervous systems (ANS), but also includes interfaces with numerous other factors, including endocrine hormones and immune effector cells as well as interactions with the gut microbiota. Perturbances to this system have been found to play a critical role in the development of visceral hypersensitivity, bowel dysregulation, and mood. This review will summarize the principle processes involved in the neurologic and biologic function of the brain-gut axis, our current understanding of its role in functional GI disorders, and potential targets for therapeutic intervention.

COVID-19 status quo: Emphasis on gastrointestinal and liver manifestations.

The coronavirus disease 2019 (COVID-19) has caused one of the worst public health crises in modern history. Even though severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory tract, gastrointestinal manifestations are well described in literature. This review will discuss the epidemiology, virology, manifestations, immunosuppressant states, and lessons learned from COVID-19. Observations: At the time of writing, COVID-19 had infected more than 111 million people and caused over 2.5 million deaths worldwide. Multiple medical comorbidities including obesity, pre-existing liver condition and the use of proton pump inhibitor have been described as risk factor for severe COVID-19. COVID-19 most frequently causes diarrhea (12.4%), nausea/vomiting (9%) and elevation in liver enzymes (15%-20%). The current data does not suggest that patients on immunomodulators have a significantly increased risk of mortality from COVID-19. The current guidelines from American Gastroenterological Association and American Association for the Study of Liver Diseases do not recommend pre-emptive changes in patients on immunosuppression if the patients have not been infected with COVID-19. Conclusions and relevance: The COVID-19 pandemic has prompted a change in structure and shape of gastroenterology departmental activities. Endoscopy should be performed only when necessary and with strict protective measures. Online consultations in the form of telehealth services and home drug deliveries have revolutionized the field.

International population-based health surveys linked to outcome data: A new resource for public health and epidemiology.

BACKGROUND: National health surveys linked to vital statistics and health care information provide a growing source of individual-level population health data. Pooling linked surveys across jurisdictions would create comprehensive datasets that are larger than most existing cohort studies, and that have a unique international and population perspective. This paper's objectives are to examine the feasibility of pooling linked population health surveys from three countries, facilitate the examination of health behaviours, and present useful information to assist in the planning of international population health surveillance and research studies. DATA AND METHODS: The design, methodologies and content of the Canadian Community Health Survey (2003 to 2008), the United States National Health Interview Survey (2000, 2005) and the Scottish Health Survey (SHeS) (2003, 2008 to 2010) were examined for comparability and consistency. The feasibility of creating common variables for measuring smoking, alcohol consumption, physical activity and diet was assessed. Sample size and estimated mortality events were collected. RESULTS: The surveys have comparable purposes, designs, sampling and administration methodologies, target populations, exclusions, and content. Similar health behaviour questions allow for comparable variables to be created across the surveys. However, the SHeS uses a more detailed risk factor evaluation for alcohol consumption and diet data. Therefore, comparisons of alcohol consumption and diet data between the SHeS and the other two surveys should be performed with caution. Pooling these linked surveys would create a dataset with over 350,000 participants, 28,424 deaths and over 2.4 million person-years of follow-up. DISCUSSION: Pooling linked national population health surveys could improve population health research and surveillance. Innovative methodologies must be used to account for survey dissimilarities, and further discussion is needed on how to best access and analyze data across jurisdictions.

Did the UN convention on the rights of the child reduce child mortality around the world? An interrupted time series analysis.

BACKGROUND: Child mortality has been reduced by more than 50 % over the past 30 years. A range of secular economic and social developments have been considered to explain this phenomenon. In this paper, we examine the association between ratification of the Convention on the Rights of the Child (CRC), which was specifically put in place to ensure the well-being of children, and declines in child mortality. METHODS: Data come from three sources: the United Nations Treaty Series Database, the World Bank World Development Indicators database and, the Polity IV database. Because CRC was widely ratified, leaving few control cases, we used interrupted times series analyses, which uses the trend in the health outcome before policy exposure to mathematically determine what the trend in the health outcome would have been after the policy exposure, if it had continued 'as is' - meaning, if the policy exposure had not occurred. RESULTS: CRC ratification was associated with declining child mortality. CRC ratification was associated with a significant change in shorter-term child mortality trends in all groups except high-income, non-democratic countries and low-imcome democratic countries. CRC ratification was associated with long-term child mortality trends in all groups except middle-income, non-democratic countries. CONCLUSIONS: Child mortality rates would likely have declined even in the absence of CRC ratification, but CRC is associated with a larger decline. Our findings provide a way to assess the effects of widely-held societal norms on health and demonstrate the moderating effects of democracy and income level.

Adherence to Predefined Dietary Patterns and Risk of Developing Type 2 Diabetes in the Canadian Adult Population.

OBJECTIVE: Diet quality indices are increasingly being used in epidemiologic research. However, no studies have addressed whether adherence to Canadian dietary guidelines is longitudinally associated with decreased risk of type 2 diabetes in a population-based sample. The objective of this study is to examine the association between the Healthy Eating Index (HEI) and incident type 2 diabetes in the Canadian population. METHODS: We used data from Ontario respondents to the 2004 Canadian Community Health Survey linked to health administrative data (n=4,755). Adherence to the HEI was analyzed with a 24-hour dietary recall. Type 2 diabetes was ascertained through the Ontario Diabetes Database, and tracked up to 12.1 years from baseline. Cox proportional hazards models were used to estimate type 2 diabetes risk as a function of HEI score. Given obesity's potential role as a mediator, we explored the effects of removing body mass index from the final model. RESULTS: High HEI adherence was not associated with a reduction in diabetes risk overall (hazard ratio [HR], 0.97; 95% confidence interval, 0.62 to 1.50), nor in separate strata of men (HR, 0.94) or women (HR, 1.03). Additional adjustment for body mass index attenuated the multivariable adjusted hazard ratios toward the null. CONCLUSIONS: This is the first study to prospectively explore the relationship between adherence to the dietary recommendations of the HEI and diabetes risk in a representative, population-based sample. Our analyses challenge previous findings and highlight the utility of linked data to evaluate the role of healthy dietary patterns in relation to population-level morbidity.

Generalization of the time-to-event continual reassessment method to bivariate outcomes.

This article considers the problem of designing Phase I-II clinical trials with delayed toxicity and efficacy outcomes. The proposed design is motivated by a Phase I-II study evaluating all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The primary objective of the study is to identify a dose that maximizes efficacy and has an acceptable level of toxicity. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not practical to wait until both outcomes for each patient have been fully observed before sequentially assigning the dose of a newly eligible patient. In order to avoid delays in treatment for newly enrolled patients and to accelerate trial progress, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes. Simulation studies are conducted to evaluate the proposed method, and we found that the proposed design is able to accurately select doses that maximize efficacy and have acceptable toxicity, while using all available information in allocating patients at the time of dose assignment. We compare the proposed methodology to two existing methods in the area.

Can the health effects of widely-held societal norms be evaluated? An analysis of the United Nations convention on the elimination of all forms of discrimination against women (UN-CEDAW).

BACKGROUND: Female life expectancy and mortality rates have been improving over the course of many decades. Many global changes offer potential explanations. In this paper, we examined whether the United Nations Convention on the Elimination of All Forms of Discrimination Against Women (CEDAW) has, in part, been responsible for the observed improvements in these key population metrics of women's health. METHODS: Data were obtained from the United Nations Treaty Series Database, the World Bank World Development Indicators database and, the Polity IV database. Because CEDAW is nearly universally ratified, it was not feasible to compare ratifying countries to non-ratifying countries. We therefore applied interrupted times series analyses, which creates a comparator (counterfactual) scenario by using the trend in the health outcome before the policy exposure to mathematically determine what the trend in the health outcome would have been after the policy exposure, had the policy exposure not occurred. Analyses were stratified by country-level income and democratization. RESULTS: Among low-income countries, CEDAW improved outcomes in democratic, but not non-democratic countries. In middle-income countries, CEDAW largely had no effect and, among high-income countries, had largely positive effects. CONCLUSIONS: While population indicators of women's health have improved since CEDAW ratification, the impact of CEDAW ratification itself on these improvements varies across countries with differing levels of income and democratization.

The association between food insecurity and incident type 2 diabetes in Canada: A population-based cohort study.

BACKGROUND: A pervasive and persistent finding is the health disadvantage experienced by those in food insecure households. While clear associations have been identified between food insecurity and diabetes risk factors, less is known about the relationship between food insecurity and incident type 2 diabetes. The objective of this study is to investigate the association between household food insecurity and the future development of type 2 diabetes. METHODS: We used data from Ontario adult respondents to the 2004 Canadian Community Health Survey, linked to health administrative data (n = 4,739). Food insecurity was assessed with the Household Food Security Survey Module and incident type 2 diabetes cases were identified by the Ontario Diabetes Database. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes as a function of food insecurity. RESULTS: Canadians in food insecure households had more than 2 times the risk of developing type 2 diabetes compared to those in food secure households [HR = 2.40, 95% CI = 1.17-4.94]. Additional adjustment for BMI attenuated the association between food insecurity and type 2 diabetes [HR = 2.08, 95% CI = 0.99, 4.36]. CONCLUSIONS: Our findings indicate that food insecurity is independently associated with increased diabetes risk, even after adjustment for a broad set of measured confounders. Examining diabetes risk from a broader perspective, including a comprehensive understanding of socioeconomic and biological pathways is paramount for informing policies and interventions aimed at mitigating the future burden of type 2 diabetes.

A systematic review and meta-analysis of the association between childhood infections and the risk of childhood acute lymphoblastic leukaemia.

BACKGROUND: To determine whether childhood infections were associated with the development of childhood acute lymphoblastic leukaemia (ALL). METHODS: We included studies that assessed any infection in childhood prior to the diagnosis of ALL in children aged 0-19 years compared to children without cancer. The primary analysis synthesised any infection against the odds of ALL, and secondary analyses assessed the frequency, severity, timing of infections, and specific infectious agents against the odds of ALL. Subgroup analyses by data source were investigated. RESULTS: In our primary analysis of 12 496 children with ALL and 2 356 288 children without ALL from 38 studies, we found that any infection was not associated with ALL (odds ratio (OR)=1.10, 95% CI: 0.95-1.28). Among studies with laboratory-confirmed infections, the presence of infections increased the odds of ALL by 2.4-fold (OR=2.42, 95% CI: 1.54-3.82). Frequency, severity, and timing of infection were not associated with ALL. CONCLUSIONS: The hypothesis put forward by Greaves and others about an infectious aetiology are neither confirmed nor refuted and the overall evidence remains inadequate for good judgement. The qualitative difference in the subgroup effects require further study, and future research will need to address the challenges in measuring infectious exposures.

Prevalence of behavioural risk factors for cardiovascular disease in adolescents in low-income and middle-income countries: an individual participant data meta-analysis.

BACKGROUND: Although overt manifestations of cardiovascular disease (CVD) rarely emerge before adulthood, CVD risk factors are often present in adolescents. However, the prevalence and magnitude of behavioural CVD risk factors in adolescents in low-income and middle-income countries remains unclear. We estimated the magnitude and co-occurrence of behavioural CVD risk factors in adolescents aged 12-15 years for 65 low-income and middle-income countries between 2003 and 2011. METHODS: We extracted Global School-Based Student Health Surveys (GSHS) datasets from the Centers for Disease Control and Prevention (CDC) website. Pooled prevalence estimates of current tobacco use, alcohol use, low fruit and vegetable intake, low physical activity, obesity and co-occurrence of CVD risk factors for WHO regions and overall, was calculated with random-effects meta-analysis. We explored potential sources of heterogeneity for each CVD risk factor through random-effects meta-regression analysis. FINDINGS: Between 2003 and 2011, of 169 369 adolescents, 12·1% (95% CI 10·2-14·1) used tobacco, 15·7% (12·3-19·5) used alcohol, 74·3% (71·9 -76·5) had low fruit and vegetable intake, 71·4% (69·5-73·3) reported low physical activity and 7·1% (5·6-8·7) were obese. The pooled regional prevalence of exposure to three or more CVD risk factors was lowest in the southeast Asian region (3·8%, 95% CI 1·2-7·5) and highest in the western Pacific region (18·6%, 12·8-25·3). Substantial heterogeneities within and across regions were not fully explained by major study characteristics. INTERPRETATION: In low-income and middle-income countries, adolescents carry a substantial burden of behavioural CVD risk factors, which tend to co-occur. Surveillance, prevention, detection, and control initiatives are a global health priority. FUNDING: None.

Seamless Phase I/II Adaptive Design for Oncology Trials of Molecularly Targeted Agents.

In dose-finding trials of chemotherapeutic agents, the goal of identifying the maximum tolerated dose is usually determined by considering information on toxicity only, with the assumption that the highest safe dose also provides the most promising outlook for efficacy. Trials of molecularly targeted agents challenge accepted dose-finding methods because minimal toxicity may arise over all doses under consideration and higher doses may not result in greater response. In this article, we propose a new early-phase method for trials investigating targeted agents. We provide simulation results illustrating the operating characteristics of our design.