A historical cohort study with 27,754 individuals on the association between meat consumption and gastrointestinal tract and colorectal cancer incidence.

In order to explore the association between meat consumption and gastrointestinal/colorectal cancer (CRC) risk and to estimate the Israeli population attributable fraction (PAF), we conducted a collaborative historical cohort study using the individual participant data of seven nutritional studies from the past 6 decades. We included healthy adult men and women who underwent a nutritional interview. Dietary assessment data, using food-frequency or 24-h recall questionnaires, were harmonized. The study file was linked to the National Cancer and death registries. Among 27,754 participants, 1216 (4.4%) were diagnosed with gastrointestinal cancers and 839 (3.0%) with CRC by the end of 2016. Using meta-analysis methods applied to Cox proportional hazard models (adjusted for daily energy intake, sex, age, ethnic origin, education and smoking),100 g/day increments in beef, red meat and poultry consumption, and 50 g/day increment in processed meat consumption were associated with hazard ratios (HRs) and 95% confidence intervals of 1.46 (1.06-2.02), 1.15 (0.87-1.52), 1.06 (0.89-1.26), and 0.93 (0.76-1.12), respectively, for CRC. Similar results were obtained for gastrointestinal cancer, although red meat consumption reached statistical significance (HR = 1.27; 95%CI: 1.02-1.58). The PAFs associated with a reduction to a maximum of 50 g/day in the consumption of red meat were 2.7% (95%CI: -1.9 to 12.0) and 5.2% (0.3-13.9) for CRC and gastrointestinal cancers, respectively. Reduction of beef consumption to a maximum of 50 g/day will result in a CRC PAF reduction of 7.5% (0.7%-24.3%). While beef consumption was associated with gastrointestinal/CRC excess risk, poultry consumption was not. A substantial part of processed meat consumption in Israel is processed poultry, perhaps explaining the lack of association with CRC.

Methodology and challenges for harmonization of nutritional data from seven historical studies.

BACKGROUND: Collection of detailed dietary data is labor intensive and expensive, harmonization of existing data sets has been proposed as an effective tool for research questions in which individual studies are underpowered. METHODS: In this paper, we describe the methodology used to retrospectively harmonize nutritional data from multiple sources, based on the individual participant data of all available studies, which collected nutritional data in Israel between 1963 and 2014. This collaboration was established in order to study the association of red and processed meat with colorectal cancer. Two types of nutritional questionnaires, the Food Frequency Questionnaires (FFQ) and the 24-h dietary recall (24HR recall), and different food composition tables, were used by the participating studies. The main exposure of interest included type of meat (total meat, red meat, and poultry) and level of processing. RESULTS: A total of 29,560 Israeli men and women were enrolled. In studies using FFQ,the weighted mean intakes of total, red, processed meat, and poultry were 95, 27, 37 and 58 gr/day and 92, 25, 10, and 66 gr/day in studies using 24HR recall, respectively.. Despite several methodological challenges, we successfully harmonized nutritional data from the different studies. CONCLUSIONS: This paper emphasizes the significance and feasibility of harmonization of previously collected nutritional data, offering an opportunity to examine associations between a range of dietary exposures and the outcome of interest, while minimizing costs and time in epidemiological studies.

The Reliability and Validity of the OneStep Smartphone Application for Gait Analysis among Patients Undergoing Rehabilitation for Unilateral Lower Limb Disability.

An easy-to-use and reliable tool is essential for gait assessment of people with gait pathologies. This study aimed to assess the reliability and validity of the OneStep smartphone application compared to the C-Mill-VR+ treadmill (Motek, Nederlands), among patients undergoing rehabilitation for unilateral lower extremity disability. Spatiotemporal gait parameters were extracted from the treadmill and from two smartphones, one on each leg. Inter-device reliability was evaluated using Pearson correlation, intra-cluster correlation coefficient (ICC), and Cohen's d, comparing the application's readings from the two phones. Validity was assessed by comparing readings from each phone to the treadmill. Twenty-eight patients completed the study; the median age was 45.5 years, and 61% were males. The ICC between the phones showed a high correlation (r = 0.89-1) and good-to-excellent reliability (ICC range, 0.77-1) for all the gait parameters examined. The correlations between the phones and the treadmill were mostly above 0.8. The ICC between each phone and the treadmill demonstrated moderate-to-excellent validity for all the gait parameters (range, 0.58-1). Only 'step length of the impaired leg' showed poor-to-good validity (range, 0.37-0.84). Cohen's d effect size was small (d < 0.5) for all the parameters. The studied application demonstrated good reliability and validity for spatiotemporal gait assessment in patients with unilateral lower limb disability.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study.

BACKGROUND: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. METHODS: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). RESULTS: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51-68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 - 487.3] vs adj.ROR = 250.2 [79.3 - 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 - 58.8] vs adj.ROR = 88.0 [27.0 - 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 - 34.8] vs adj.ROR = 23.3 [19.2 - 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 - 11.2] vs adj.ROR = 8.6 [7.2 - 10.3]), nocturia (adj.ROR = 5.5 [3.7 - 8.2] vs adj.ROR = 6.7 [2.8 - 15.7]), dehydration (adj.ROR = 2.5 [2.3 - 2.8] vs adj.ROR = 2.6 [2.1 - 3.3]), and fractures (adj.ROR = 1.7 [1.4 - 2.1] vs adj.ROR = 1.5 [1.02 - 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 - 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 - 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. CONCLUSION: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Metformin Treatment Among Men With Diabetes and the Risk of Prostate Cancer: A Population-Based Historical Cohort Study.

There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in a population-based Israeli cohort of 145,617 men aged 21-89 years with incident diabetes who were followed over the period 2002-2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for use of other glucose-lowering medications, age, ethnicity, and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years of follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (per defined daily dose; without adjustment for glucose control, hazard ratio (HR) = 1.53 (95% confidence interval (CI): 1.19, 1.96); with adjustment, HR = 1.42 (95% CI: 1.04, 1.94)). However, exposure during the previous 2-7 years was negatively associated with risk (without adjustment for glucose control, HR = 0.58 (95% CI: 0.37, 0.93); with adjustment, HR = 0.60 (95% CI: 0.33, 1.09)). These positive and negative associations with previous-year and earlier metformin exposure, respectively, need to be confirmed and better understood.

Is health-related quality of life 1-year after coronary artery bypass graft surgery associated with living in a greener environment?

INTRODUCTION: Greenery in the residential environment and in the hospital has been associated with improved surgical outcomes and recovery. We investigated the association between the level of residential greenness of patients with coronary disease and their heart disease-related Quality of Life (HRQoL) 1-year after a coronary artery bypass grafting (CABG) surgery. METHODS: Participants in a prospective cohort study who underwent CABG surgery at seven cardiothoracic units throughout Israel during the years 2004-2007 filled in the MacNew HRQoL one day before and one year after surgery. Successful recovery was defined as ≥0.5 increase in the MacNew score between baseline and follow-up. Exposure to residential greenness in 90 m and 300 m buffers around the patient's home was assessed with Linear Spectral Unmixing analysis of Landsat 30 m imagery. RESULTS: The cohort comprised of 861 patients (22% female) with a mean age of 65.5 years, and 59.2% classified as low-income. In the total cohort, higher residential greenness was associated with an improvement in emotional HRQoL (OR = 1.33 (95%CI: 0.99-1.79)), adjusting for demographic and socio-economic factors, living in the periphery/center, presence of diabetes, attending cardiac rehabilitation following surgery, BMI, and change in physical fitness and depression over the 1-year follow-up. Although no association was found between greenness and change in the physical or social subscales, a positive association was specifically observed among the low-income patients for the global HRQoL score, OR = 1.42 (95%CI: 0.97-2.10), as compared to the higher-income patients, p for interaction = 0.03. CONCLUSIONS: Residential greenness is associated with improvement in HRQoL 1-year after CABG surgery, but not the physical and social scales, only in low-income patients. Ensuring greenery in the living environment may act as a social intervention that supports human health and disease recovery.

[PREDICTION MODEL FOR ASSESSING PHYSICAL FITNESS IN CARDIAC PATIENTS].

AIMS: To develop and validate a readily-available tool for the evaluation of the fitness of cardiac patients. BACKGROUND: Physical fitness is an important factor in the tertiary prevention for cardiac patients. METHODS: In this cross-sectional study, 154 cardiac patients: 119 men and 35 women, mean age 63.1±11.2 years, entering the cardiac-rehabilitation program at the Sheba Medical Center, gave informed consent and completed a 24-hour recall physical activity questionnaire. Information on BMI, medication use and on their performance on a symptom-free limited treadmill test, i.e. measured estimated VO2 (ml/kg/min) and resting heart rate (bpm), were obtained from the medical chart. RESULTS: A linear-regression equation for predicting the measured estimated VO2 includes the overall physical activity index calculated from the physical activity questionnaire, sex, age, BMI, type of coronary heart disease (acute myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention), duration of illness, resting heart rate, use of beta-blockers and level of education. The correlation coefficient between measured VO2 values and calculated values is r=0.6. Upon categorizing patients to high and low physical fitness according to the VO2 median value, the validity of the equation was found to be good: sensitivity=61.2%, specificity=65.2%, positive predictive value=68.4%, negative predictive value=57.7%. CONCLUSIONS: The prediction equation for assessing VO2 in cardiac patients is a simple, inexpensive tool, which may be used for monitoring changes in the patients' physical fitness. It may assist the physician in following a cardiac patient's response to physical activity recommendations and improving fitness when the ergometric stress-test availability is low.

The association between insulin sensitivity indices, ECG findings and mortality: a 40-year cohort study.

BACKGROUND: Type 2 Diabetes is a major risk factor for cardiovascular (CV) mortality. Insulin resistance can be evaluated non-invasively by insulin sensitivity indices (ISI) such as the Mcauley index (MCAi), which is a function of the fasting insulin and triglycerides. Currently, the association between ISIs and ECG findings and all-cause and CV mortality is still not established in a large scale and heterogeneous population. METHOD: In a prospective study of the Israel cohort on Glucose Intolerance, Obesity and Hypertension (GOH) second phase (1979-1982) 1830 men and women were followed until December-2016 for CV-mortality and December-2019 for all-cause mortality. ECGs were recorded and OGTTs performed during baseline. ISIs were categorized into quartiles and evaluated against ECG findings and all-cause and CV-mortality. RESULTS: Mean age at baseline was 52.0 ± 8.1 years, and 75 (15.2%) and 47 (25.3%) participants in the upper quartiles (Q2-4) and the lower quartile (Q1) of the MCAi, presented with Ischemic changes on ECG respectively (p = 0.02). Multivariable analysis showed higher odds for ECG ischemic changes, for individuals in Q1-MCAi (adjusted-OR = 1.7, 95% CI 1.02-2.8), compared with Q2-4-MCAi, which attenuated when excluding individuals with diabetes (adjusted-OR = 1.6, 95% CI 0.9-2.7, p = 0.09). Median follow up for all-cause and for cardiovascular mortality was 31 years and 37 years, respectively. Cox proportional-hazards regression showed an increased risk for all-cause mortality for individuals in Q1-MCAi (HR = 1.2, 95% CI 1.02-1.3) as well as an increased risk for CV-mortality (HR = 1.4, 95%CI 1.1-1.8) compared with Q2-4-MCAi. Individuals in Q4-Ln Homeostatic model assessment- Insulin Resistance (HOMA-IR) and Q1- Quantitative Insulin Sensitivity Check Index (QUICKI) also presented with increased risk for all-cause-mortality (HR = 1.2, 95%CI 1.04-1.4; and HR = 1.2, 95% CI 1.04-1.4, respectively). Other ISIs did not show significant associations with CV-mortality. CONCLUSION: Higher insulin-resistance, according to the MCAi, associated with ECG-changes, and with greater risk for all-cause and CV-mortality over a 40-year follow-up. The MCAi may be considered as an early predictive and prognostic biomarker for CV-morbidity and mortality in adults.

Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre-COVID-19 reports.

AIM: There is a clinical need for safety data regarding hydroxychloroquine (HCQ) and chloroquine (CQ) during the coronavirus (COVID-19) pandemic. We analysed real-world data using the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) database to assess HCQ/CQ-associated cardiovascular adverse events (CVAEs) in pre-COVID-19 reports. METHODS: We conducted disproportionality analysis of HCQ/CQ in the FAERS database (07/2014-9/2019), using reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 ). RESULTS: The full database contained 6 677 225 reports with a mean (±SD) age of 53 (±17) years and 74% females. We identified 4895 reports of HCQ/CQ related adverse events, of which 696 (14.2%) were CVAEs. Compared with the full database, HCQ/CQ use was associated with a higher reporting rate of major CVAEs, including cardiomyopathy (n = 86 [1.8%], ROR = 29.0 [23.3-35.9]), QT prolongation (n = 43 [0.9%], ROR = 4.5 [3.3-6.1]), cardiac arrhythmias (n = 117 [2.4%], ROR = 2.2 [1.8-2.7]) and heart failure (n = 136 [2.8%], ROR = 2.2 [1.9-2.7], all IC025 > 0). No statistically significant differences were observed between sex and age groups. CVAEs were reported more often in patients with systemic lupus erythematosus and Sjogren's syndrome. HCQ/CQ-associated CVAEs demonstrated subsequent hospitalization and mortality rates of 39% and 8%, respectively. Overdose reports demonstrated an increased frequency of QT prolongation and ventricular arrhythmias (35% and 25%, respectively). CONCLUSION: In a real-world setting, HCQ/CQ treatment is associated with higher reporting rates of various CVAEs, particularly cardiomyopathy, QT prolongation, cardiac arrhythmias and heart failure. HCQ/CQ-associated CVAEs result in high rates of severe outcomes and should be carefully considered as an off-label indication, especially for patients with cardiac disorders.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Associations of dietitian follow-up counselling visits and physical exercise with weight loss one year after sleeve gastrectomy.

PURPOSE: To examine associations of patients' attendance to follow-up meetings with a registered dietitian (RD) and physical exercise practices with weight loss during the 1 year following laparoscopic sleeve gastrectomy (SG). METHODS: Of 241 patients with obesity who underwent SG during 2012, 184 (76.3%) participated in a 1-year follow-up telephone interview and had information on number of RD follow-up meetings. Clinical information was available from computerized patient files. Multiple logistic regression analysis, adjusting for propensity score, was computed to reveal factors associated with greater weight loss. RESULTS: The mean %TWL was 31.4 ± 6.1 and the mean number of reported RD meetings during the year following SG was 4.6. The proportion of physically active patients increased by 15% (from 23 to 42) among those who attended at least 3 RD follow-up meetings (n = 123), and by 5% (from 18 to 23) among those who attended fewer than 3 meetings (n = 61) (p = 0.05). Patients conducting physical exercise reported a lower level of pain/discomfort on the EQ5D quality-of-life questionnaire (p = 0.03). The adjusted regression model revealed no association between the number of RD follow-up meetings and weight-reduction success, but physical exercise during the year following SG conferred a 2.6 times greater odds of belonging to the upper two tertiles of the % excess body weight loss ( 95% CI 1.2-5.3). CONCLUSIONS: Patients with better adherence to RD follow-up meetings were also more physically active. Patients on physical exercise also achieved greater weight reduction following SG, and reported less pain or discomfort. Nutritional counselling and physical exercise are necessary to ensure maximal and sustainable benefits from SG.  LEVEL OF EVIDENCE: Level III, Cohort study.

Metformin Treatment and Cancer Risk: Cox Regression Analysis, With Time-Dependent Covariates, of 320,000 Persons With Incident Diabetes Mellitus.

There is conflicting evidence regarding the association between metformin use and cancer risk in diabetic patients. During 2002-2012, we followed a cohort of 315,890 persons aged 21-87 years with incident diabetes who were insured by the largest health maintenance organization in Israel. We used a discrete form of weighted cumulative metformin exposure to evaluate the association of metformin with cancer incidence. This was implemented in a time-dependent covariate Cox model, adjusting for treatment with other glucose-lowering medications, as well as age, sex, ethnic background, socioeconomic status, smoking (for bladder and lung cancer), and parity (for breast cancer). We excluded from the analysis metformin exposure during the year before cancer diagnosis in order to minimize reverse causation of cancer on changes in medication use. Estimated hazard ratios associated with exposure to 1 defined daily dose of metformin over the previous 2-7 years were 0.98 (95% confidence interval (CI): 0.82, 1.18) for all-sites cancer (excluding prostate and pancreas), 1.05 (95% CI: 0.67, 1.63) for colon cancer, 0.98 (95% CI: 0.49, 1.97) for bladder cancer, 1.02 (95% CI: 0.59, 1.78) for lung cancer, and 0.88 (95% CI: 0.56, 1.39) for female breast cancer. Our results do not support an association between metformin treatment and the incidence of major cancers (excluding prostate and pancreas).

The metabolic syndrome and its components are differentially associated with chronic diseases in a high-risk population of 350 000 adults: A cross-sectional study.

AIMS: We compared strengths of associations conferred by the metabolic syndrome (MetS) and its components across four chronic disease categories (cancer, cardiovascular diseases [CVDs], chronic kidney disease [CKD], and chronic obstructive pulmonary disease [COPD]) in a community-dwelling high-risk population. METHODS: This is a cross-sectional analysis of Israeli adults insured in a single health maintenance organization during 2010 to 2013 and having greater than or equal to two MetS components (hypertension, dysglycemia, low high-density lipoprotein level, high plasma triglyceride level, and obesity). Data regarding MetS components, chronic disease prevalence, and sociodemographic variables were retrieved from electronic health records and disease registries. RESULTS: Among 347 244 eligible members, 54.2% had MetS. MetS was negatively associated with cancer, (prevalence ratio [PR] = 0.86; 95% confidence interval, 0.79-0.93) and positively associated with CKD (PR = 1.07, [1.01-1.13]). Some MetS components conferred different associations across the chronic diseases: a high triglyceride level was positively associated with cancer (PR = 1.15, 1.12-1.18) and CKD (PR = 1.37, 1.32-1.41) but negatively associated with CVD (PR = 0.88, 0.86-0.90) and COPD (PR = 0.93, 0.88-0.98). In the presence of MetS, those with dysglycemia had higher cancer prevalence than those with normoglycemia (PR-interaction MetS*dysglycemia on cancer = 1.14, 1.06-1.22). Likewise, in the presence of MetS, men were more likely than women to present with CVD (PR-interaction MetS*sex on CVD = 1.12, [1.05-1.20]). CONCLUSIONS: Prevalences of the MetS and MetS components distribute unequally across four chronic diseases. MetS including dysglycemia may warrant screening for cancer, and MetS in males may indicate the presence of CVD. Longitudinal studies may reveal if MetS is associated with different risks or merely indicates better prognosis once having a chronic illness.

Reuniting overnutrition and undernutrition, macronutrients, and micronutrients.

Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.

Newly diagnosed type 2 diabetes may serve as a potential marker for pancreatic cancer.

Pancreatic cancer has an extremely highly case fatality. Diabetes is a well-established strong risk factor for pancreatic cancer. Compared with a nondiabetic population, we previously reported a 15- and 14-fold greater risk for detecting pancreatic cancer during the first year after diagnosing diabetes in adult women and men, respectively, which dropped during the second year to 5.4-fold and 3.5-fold, respectively, and stabilized around 3-fold for the rest of the 11-year follow-up in our historical cohort. The population attributable risk during the 11-year period was 13.3% and 14.1% in prevalent diabetic women and men, respectively. This means that one out of about every 8 patients diagnosed with pancreatic cancer has been previously diagnosed with diabetes. The globally high prevalence of diabetes and the aggravating implications of a delayed pancreatic cancer diagnosis call for newly-onset diabetes to be considered a potential marker for an underlying pancreatic cancer and addressed accordingly.

Lessons learned from the 1-hour post-load glucose level during OGTT: Current screening recommendations for dysglycaemia should be revised.

This perspective covers a novel area of research describing the inadequacies of current approaches for diagnosing dysglycaemia and proposes that the 1-hour post-load glucose level during the 75-g oral glucose tolerance test may serve as a novel biomarker to detect dysglycaemia earlier than currently recommended screening criteria for glucose disorders. Considerable evidence suggests that a 1-hour post-load plasma glucose value ≥155 mg/dl (8.6 mmol/L) may identify individuals with reduced ß-cell function prior to progressing to prediabetes and diabetes and is highly predictive of those likely to progress to diabetes more than the HbA1c or 2-hour post-load glucose values. An elevated 1-hour post-load glucose level was a better predictor of type 2 diabetes than isolated 2-hour post-load levels in Indian, Japanese, and Israeli and Nordic populations. Furthermore, epidemiological studies have shown that a 1-hour PG ≥155 mg/dl (8.6 mmol/L) predicted progression to diabetes as well as increased risk for microvascular disease and mortality when the 2-hour level was <140 mg/dl (7.8 mmol/L). The risk of myocardial infarction or fatal ischemic heart disease was also greater among subjects with elevated 1-hour glucose levels as were risks of retinopathy and peripheral vascular complications in a Swedish cohort. The authors believe that the considerable evidence base supports redefining current screening and diagnostic recommendations with the 1-hour post-load level. Measurement of the 1-hour PG level would increase the likelihood of identifying a larger, high-risk group with the additional practical advantage of potentially replacing the conventional 2-hour oral glucose tolerance test making it more acceptable in a clinical setting.

Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

New onset diabetes in adulthood is associated with a substantial risk for mortality at all ages: a population based historical cohort study with a decade-long follow-up.

BACKGROUND: Diabetes has been reported to be associated with an increased relative risk for mortality, with estimates ranging from 1.1 to 2.1. Findings are inconsistent regarding modification of the risk by gender and by age. The aim of this study was to estimate the mortality risk associated with new-onset diabetes in adulthood, by age group and gender. METHODS: From the database of a large health care provider, we identified 31,987 individuals diagnosed with diabetes during 2003-2005; and 162,656 individuals without diabetes, group-matched by age. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall mortality adjusted for age, gender, socioeconomic (SE) level, obesity, smoking and comorbidities at baseline. RESULTS: During a median follow-up of 9.5 years, 4464 (14%) of persons with diabetes and 13,327 (8.2%) of those without died. Among persons with incident diabetes, the proportion of men, smokers, obese and patients of low SE level was higher, as was the prevalence of cardiovascular disease and renal impairment at baseline. Incident diabetes was associated with an adjusted HR for mortality of 1.38 (95% CI 1.32-1.43). Mortality HR for DM was comparable with hypertension (1.42; 1.37-1.46), smoking (1.65; 1.58-1.71) and atherosclerosis (1.40; 1.35-1.46). Diabetes associated mortality HR was somewhat higher among women 1.78 (95% CI 1.58-2.08) as compared with men 1.51 (95% CI 1.41-1.62). CONCLUSIONS: Incident diabetes in adults is associated with a substantial risk for mortality, especially in younger adults. Further efforts should be allocated to diabetes primary prevention.

Diabetes, prostate cancer screening and risk of low- and high-grade prostate cancer: an 11 year historical population follow-up study of more than 1 million men.

AIMS/HYPOTHESIS: An inverse association has consistently been shown between diabetes and prostate cancer incidence. We investigated whether lower prostate cancer incidence among men with diabetes is attributable to lower detection due to prostate cancer screening patterns. METHODS: We studied a population-based historical cohort of 1,034,074 Israeli men aged 21-90 years, without a previous history of cancer. The cohort was followed-up from 2002 to 2012, according to diabetes morbidity, for frequency of prostate-specific antigen (PSA) testing, mean PSA values and detection of prostate cancer, after adjustment for age, ethnic origin, socioeconomic status and PSA testing. RESULTS: In January 2002, 74,756 men had prevalent diabetes. During the 11 year follow-up, 765,483 (74%) remained diabetes-free and 193,835 developed diabetes. Approximately 10% more PSA screening was performed in men with than without diabetes, but the rate of PSA positivity (>4 µg/l) was 20% lower in men with diabetes. PSA values were already significantly lower in men who developed diabetes than in those who did not, 3 years before diabetes diagnosis. Reduced prostate cancer risk was observed among men with incident diabetes only for low-moderate grade tumours (Gleason score 2-6: adjusted HR 0.83; 95% CI 0.77, 0.89). No association was observed for high-grade tumours (Gleason score 7-10: HR 0.99; 95% CI 0.88, 1.11). CONCLUSIONS/INTERPRETATION: Our findings suggest that diabetes comorbidity is a factor to be considered in prostate cancer screening strategies, and specifically in the interpretation of PSA levels. Furthermore, our demonstration of reduced incidence of low-moderate grade but not high-grade prostate cancer tumours among men with diabetes supports the possibility that low PSA levels, rather than lower tumour risk, explains the observed reduced incidence of prostate cancer in men with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02072902.