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Key Points In developing countries, limited access or adaptation to a healthful, well-balanced diet can cause micronutrient malnutrition, with irreversible health consequences affecting morbidity and mortality Deficiencies in vitamin A and/or iron are prevalent among reproductive-aged women, infants and children in developing countries, with therapeutic doses required for treatment In developing and developed countries, reproductive-aged women or those who are pregnant must ensure adequate intakes of folic acid, iron, calcium and iodine, which might require supplementation In developed countries, adequate nutrient intake can usually be achieved through a well-balanced diet and supplementation might not confer additional health benefits (except among individuals with increased requirements) Postmenopausal women and elderly men could benefit from a combination of low-dose calcium and vitamin D for bone health Use of a multivitamin supplement with low levels of essential vitamins and minerals could be linked to reductions in the incidence of cancer and cataracts among men Dietary supplements are widely used and offer the potential to improve health if appropriately targeted to those in need. This Review summarizes the available data on dietary supplements and health outcomes in both developing and developed countries to help guide decisions about dietary supplement recommendations. Dietary supplements are widely used and offer the potential to improve health if appropriately targeted to those in need. Inadequate nutrition and micronutrient deficiencies are prevalent conditions that adversely affect global health. Although improvements in diet quality are essential to address these issues, dietary supplements and/or food fortification could help meet requirements for individuals at risk of deficiencies. For example, supplementation with vitamin A and iron in developing countries, where women of reproductive age, infants and children often have deficiencies; with folic acid among women of reproductive age and during pregnancy; with vitamin D among infants and children; and with calcium and vitamin D to ensure bone health among adults aged ≥65 years. Intense debate surrounds the benefits of individual high-dose micronutrient supplementation among well-nourished individuals because the alleged beneficial effects on chronic diseases are not consistently supported. Daily low-dose multivitamin supplementation has been linked to reductions in the incidence of cancer and cataracts, especially among men. Baseline nutrition is an important consideration in supplementation that is likely to modify its effects. Here, we provide a detailed summary of dietary supplements and health outcomes in both developing and developed countries to help guide decisions about dietary supplement recommendations.

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.

Background The clinical benefit of aspirin for the primary prevention of cardiovascular disease (CVD) in diabetes remains uncertain. To evaluate the efficacy and safety of aspirin for the primary prevention of cardiovascular outcomes and all-cause mortality events in people with diabetes, we conducted an updated meta-analysis of published randomised controlled trials (RCTs) and a pooled analysis of individual participant data (IPD) from three trials. Methods Randomised controlled trials of aspirin compared with placebo (or no treatment) in participants with diabetes with no known CVD were identified from MEDLINE, Embase, Cochrane Library, and manual search of bibliographies to January 2019. Relative risks with 95% confidence intervals were used as the summary measures of associations. Results We included 12 RCTs based on 34,227 participants with a median treatment duration of 5.0 years. Comparing aspirin use with no aspirin, there was a significant reduction in risk of major adverse cardiovascular events (MACE)0.89 (0.83–0.95), with a number needed to treat (NNT)of 95 (95% CI 61 to 208) to prevent one MACE over 5 years average follow-up. Evidence was lacking of heterogeneity and publication bias among contributing trials for MACE. Aspirin use had no effect on other endpoints including all-cause mortality; however, there was a significant reduction in stroke for aspirin dosage ≤ 100 mg/day 0.75 (0.59–0.95). There were no significant effects of aspirin use on major bleeding and other bleeding events, though some of the estimates were imprecise. Pooled IPD from the three trials (2306 participants) showed no significant evidence of an effect of aspirin on any of the outcomes evaluated; however, aspirin reduced the risk of MACE in non-smokers 0.70 (0.51–0.96) with a NNT of 33 (95% CI 20 to 246) to prevent one MACE. Conclusions Aspirin has potential benefits in cardiovascular primary prevention in diabetes. The use of low dose aspirin may need to be individualised and based on each individual’s baseline CVD and bleeding risk. Systematic review registration PROSPERO: CRD42019122326

Purpose of ReviewTesticular cancer (TC) is the leading cancer in men between 18 and 39 years of age. Current treatment involves tumor resection followed by surveillance and/or one or more lines of cisplatin-based chemotherapy (CBCT) and/or bone marrow transplant (BMT). Ten years after treatment, CBCT has been associated with significant atherosclerotic cardiovascular disease (CVD) including myocardial infarction (MI), stroke, and heightened rates of hypertension, dyslipidemia, diabetes mellitus, and metabolic syndrome (MetS). Additionally, low testosterone levels and hypogonadism contribute to MetS and may further drive CVD.Recent FindingsCVD in TCS has been associated with worse physical functioning accompanied by role limitations, decreased energy, and decreased overall health. Exercise may play a role in ameliorating these effects.SummarySystematic CVD screening practices are needed at TC diagnosis and in survivorship. We encourage a multidisciplinary partnership between primary care physicians, cardiologists, cardio-oncologists, medical oncologists, and survivorship providers to address these needs.

Micronutrient deficiencies occur in segments of the adult population in the United States. Multivitamin/multimineral supplements (MVMS) are widely used by this population, which reduces inadequacies in micronutrient intake, but the potential for exceeding tolerable upper intake levels in others should be considered. There are concerns associated with the excessive intake of certain nutrients, particularly folic acid, and potential untoward consequences. The advent of nutrigenomics and the enhanced ability to directly study the interactions between nutrition and genetic variants and expression will allow for the conduct of more targeted studies with specific endpoints and may ultimately lead to progress in the field of personalized nutrition. The role of MVMS in health maintenance and chronic disease prevention remains controversial. Conducting studies in this area has been hampered by, among other factors, inconsistent definitions of MVMS, ranging from as few as three vitamins to broad-spectrum products containing more than two dozen vitamins and minerals. Results from some observational studies and large-scale, randomized, controlled trials suggest that MVMS may reduce the risk of some forms of cancer and, potentially, cardiovascular disease. The ongoing COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is expected to build on this research and provide additional insights into these areas.

Identification of risk biomarkers may enhance early detection of smoking-related lung cancer. We measured between 392 and 1,162 proteins in blood samples drawn at most three years before diagnosis in 731 smoking-matched case-control sets nested within six prospective cohorts from the US, Europe, Singapore, and Australia. We identify 36 proteins with independently reproducible associations with risk of imminent lung cancer diagnosis (all p  < 4 × 10 −5 ). These include a few markers (e.g. CA-125/MUC-16 and CEACAM5/CEA) that have previously been reported in studies using pre-diagnostic blood samples for lung cancer. The 36 proteins include several growth factors (e.g. HGF, IGFBP-1, IGFP-2), tumor necrosis factor-receptors (e.g. TNFRSF6B, TNFRSF13B), and chemokines and cytokines (e.g. CXL17, GDF-15, SCF). The odds ratio per standard deviation range from 1.31 for IGFBP-1 (95% CI: 1.17–1.47) to 2.43 for CEACAM5 (95% CI: 2.04–2.89). We map the 36 proteins to the hallmarks of cancer and find that activation of invasion and metastasis, proliferative signaling, tumor-promoting inflammation, and angiogenesis are most frequently implicated. Lung cancer screening could enhance early diagnosis and treatment. Here, the authors used proteomic analysis of pre-diagnosis samples across 6 cohorts to identify 36 proteins associated with imminent lung cancer diagnosis.

BackgroundChocolate intake has shown cardiometabolic health benefits. Whether chocolate has any effect on cellular aging remains unknown. We aimed to test the hypothesis that higher chocolate intake is associated with longer leukocyte telomere length (LTL) in adolescents.MethodsA total of 660 adolescents (aged 14–18 years) were included in the analysis. The chocolate intake was assessed by 7-day, 24-h dietary recalls and split into three groups, which were none, <2 servings/week, and 2 servings/week or more. LTL (T/S ratio) was determined by a modified quantitative polymerase chain reaction-based assay.ResultsAmong the 660 adolescents, 58% did not take any chocolate, 25% consumed <2 servings/week, and 17% consumed ≥2 servings/week. Compared to non-consumers, adolescents who consumed chocolate of ≥2 servings/week had 0.27 standard deviation (SD) longer LTL (p = 0.014). Higher chocolate consumption was associated with increased apolipoprotein A1 (ApoA1) (p = 0.038) and ApoA1/high-density lipoprotein (HDL) (p = 0.046). Moreover, higher ApoA1/HDL levels were correlated with longer LTL (p = 0.026).ConclusionAdolescents who consume 2 servings/week or more of chocolate candy have longer LTL compared with non-consumers, and ApoA1/HDL pathway may be involved in this relationship.

Aims/hypothesisInterventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes.MethodsThis study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years.ResultsA total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index.Conclusions/interpretationAmong adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years.Trial registrationClinicalTrials.gov NCT01684722FundingThe study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases.

PurposePhysical activity (PA) can improve cancer survival; however, whether the timing of PA differentially affects mortality risk is unclear. We evaluated the association between PA levels pre- and post-diagnosis and mortality risk in the Women’s Health Study (WHS), Physicians’ Health Study (PHS)-I, and PHS-II prospective cohorts.MethodsWe categorized PA pre- and post-diagnosis as active (WHS: ≥ 7.5 metabolic equivalent (MET)-h/week; PHS: vigorous PA ≥ 2–4 times/week) or inactive. We analyzed changes in pre- and post-diagnosis PA levels as four joint categories: (1) Inactive → Inactive, (2) Active → Inactive, (3) Inactive → Active, and (4) Active → Active, on mortality risk using multivariable Cox proportional hazards regression.ResultsWe identified 10,541 participants with incident cancer and 3,696 deaths during follow-up. Compared to maintaining inactivity in both periods, remaining active pre- and post-diagnosis observed lower all-cause (Hazard Ratio [95% confidence interval]: WHS: 0.55 [0.47–0.64]; PHS-I: 0.77 [0.67–0.88]), cancer (WHS: 0.55 [0.45–0.67]; PHS-I: 0.75; [0.61–0.92]) and non-cancer/cardiovascular disease (CVD) mortality risks (WHS: 0.49 [0.38–0.65]). Similarly, becoming active post-diagnosis was associated with lower all-cause (WHS: 0.60 (0.48–0.75]; PHS-I: 0.72 [0.61–0.88]), cancer (WHS: 0.65 [0.49–0.86]; PHS-I: 0.64 [0.49–0.84]), and non-cancer/CVD mortality risk (WHS: 0.49 [0.33–0.75]). Being active pre- and post-diagnosis was associated with lower mortality risks in separate analyses, although significance differed by cohort and outcome.ConclusionsRemaining active pre- and post-diagnosis and becoming active post-diagnosis may be associated with improvements in cancer survival, however, research is needed across diverse cancer populations.

Purpose Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors. Methods Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher’s exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. Results Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia ( P  = 0.008), and difficulty hearing ( P  < .001). Tinnitus was also significantly related to age at survey completion (OR = 1.79; P  = 0.003) and cumulative cisplatin dose (OR = 5.17; P  < 0.001). TC survivors with hearing loss were more likely to report diabetes ( P  = 0.042), hypertension ( P  = 0.007), hypercholesterolemia ( P  < 0.001), and family history of hearing loss ( P  = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P  = 0.036), hypercholesterolemia (OR = 3.45; P  = 0.007), cumulative cisplatin dose (OR = 1.94; P  = 0.049), and family history of hearing loss (OR = 2.87; P  = 0.071). Conclusions Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. Implications for Cancer Survivors Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.