Search

Aims This study evaluated the impact of serum uric acid (sUA) on the accuracy of pooled cohort equations (PCE) model, Systematic COronary Risk Evaluation 2 (SCORE2), and SCORE2-older persons. Methods and results We evaluated 19 769 asymptomatic self-referred adults aged 40–79 years free of cardiovascular disease and diabetes who were screened annually in a preventive healthcare setting. sUA levels were expressed as a continuous as well as a dichotomous variable (upper sex-specific tertiles defined as high sUA). The primary endpoint was the composite of death, acute coronary syndrome, or stroke, after excluding subjects diagnosed with metastatic cancer during follow-up. Mean age was 50 ± 8 years and 69% were men. During the median follow-up of 6 years, 1658 (8%) subjects reached the study endpoint. PCE, SCORE2, and high sUA were independently associated with the study endpoint in a multivariable model (P < 0.001 for all). Continuous net reclassification improvement analysis showed a 13% improvement in the accuracy of classification when high sUA was added to either PCE or SCORE2 model (P < 0.001 for both). sUA remained independently associated with the study endpoint among normal-weight subjects in the SCORE2 model (HR 1.3, 95% CI 1.1–1.6) but not among overweight individuals (P for interaction = 0.01). Subgroup analysis resulted in a significant 16–20% improvement in the model performance among normal-weight and low-risk subjects (P < 0.001 for PCE; P = 0.026 and P < 0.001 for SCORE2, respectively). Conclusion sUA significantly improves the classification accuracy of PCE and SCORE2 models. This effect is especially pronounced among normal-weight and low-risk subjects.

Primary sclerosing cholangitis (PSC) is a chronic, progressive liver disease known for its frequent concurrence with inflammatory bowel disease. PSC can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Little is known about the salivary microbiome in PSC and PSC-IBD. This study aimed to evaluate the oral microbiome of patients with PSC, with association to these patient’s fecal microbial composition. Saliva, fecal samples and Food Frequency Questionnaires were collected from 35 PSC patients with or without concomitant inflammatory bowel disease and 30 age- and BMI-matched healthy volunteers. 16S rRNA gene sequencing was performed using Illumina MiSeq platform. The salivary microbial signature of PSC was significantly altered as compared to healthy controls, independent of concomitant IBD, and was comprised of 19 significantly altered species, of which, eight species were consistently overrepresented in both fecal and saliva of patients with PSC, including Veillonella, Scardovia and Streptococcus. PSC is characterized by microbial dysbiosis in the gut and the salivary microbiome, independently from IBD. The PSC dysbiotic signature includes a reduction in autochthonous bacteria and an increased relative abundance of pathogenic bacteria, including an invasion of oral bacteria to the gut. PSC is a strong modulator of the microbial profile, in the gut and the oral microbiome. These results may lead to the development of biomarkers for screening and early diagnosis or the development of personalized medicine in PSC.

Aims Data on the association of cardiorespiratory fitness with survival of cancer patients are limited. This study aimed to evaluate the association between midlife cardiorespiratory fitness and survival after a subsequent cancer diagnosis. Methods We evaluated 19,134 asymptomatic self-referred adults who were screened in preventive healthcare settings. All subjects were free of cardiovascular disease and cancer at baseline and completed a maximal exercise stress test. Fitness was categorised into age-specific and sex-specific quintiles according to the treadmill time and dichotomised to low (quintiles 1–2) and high fitness groups. Results The mean age was 50 ± 8 years and 72% were men. During a median follow-up of 13 years (interquartile range 7–16) 517 (3%) died. Overall, 1455 (7.6%) subjects developed cancer with a median time to cancer diagnosis of 6.4 years (interquartile range 3–10). Death from the time of cancer diagnosis was significantly lower among the high fitness group (Plog rank = 0.03). Time-dependent analysis showed that subjects who developed cancer during follow-up were more likely to die (P Conclusion Higher midlife cardiorespiratory fitness is associated with better survival among cancer patients. Our findings support fitness assessment in preventive healthcare settings.

Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline. To examine whether physical fitness acts as a potential protective mechanism shielding against the negative associations between age and cognition. Specifically, we examined whether physical fitness mediates the relationship between age and processing speed. 114 (M = 63.80, SD = 10.63) senior executives completed a computerized cognitive battery composed of four processing speed tasks. Level of physical fitness was assessed on a treadmill stress test and reported in metabolic equivalents (METs). Older age was associated with slower processing speed (r = 0.25, p = 0.007), whereas greater physical fitness was associated with faster processing speed (r = −0.30, p = 0.001). Path analysis indicated that the association between age and processing speed was fully mediated by the level of physical fitness (Indirect effect: β = 0.10, p = 0.008; Direct effect: β = 0.16, p = 0.20). The findings indicate that physical fitness is a strong mediator of the relationship between age and processing speed and imply that physical fitness makes a major contribution to cognitive reserve during the aging process. The results may suggest that the decrease in physical fitness during aging may partially account for slower cognitive processing.

The association between diverticular disease and atherosclerotic cardiovascular disease (ASCVD) has been demonstrated previously, mainly in symptomatic subjects.To evaluate 10 years cardiovascular risk, exercise performance and association to ASCVD among subjects with asymptomatic diverticulosis.A retrospective cross-sectional cohort of self-referred participants in a medical screening program, who underwent a screening colonoscopy. Demographics, clinical and laboratory variables, ASCVD score, and metabolic equivalents (METs) during treadmill stress test were compared between subjects with and without diverticulosis as diagnosed on screening colonoscopy.4586 participants underwent screening colonoscopy; 799 (17.4%) had diverticulosis. Among 50-69 yo participants, diverticulosis subjects had a higher ASCVD score compared to non-diverticulosis subjects. Exercise performance was comparable between the groups, across all age groups. Using logistic regression analysis, advanced age group (50-59 yo Adjusted odds ratio (AOR) [95% confidence interval (CI)] 2.57 (1.52-4.34), p 0.001; 60-69 yo, AOR 2.87 (2.09-3.95), p 0.001; ≥ 70 yo AOR 4.81 (3.23-7.15), p 0.001; compared to 50 yo age group), smoking [AOR 1.27 (1.05-1.55), p = 0.016], HTN [AOR 1.27 (1.03-1.56), p = 0.022], obesity [AOR 1.36 (1.06-1.74), p = 0.014] and male sex [AOR 1.29 (1.02-1.64), p = 0.036] were associated with diverticular detection during screening colonoscopy. Among males, achieving METs score ≥ 10 was inversely associated with diverticular detection during screening colonoscopy [AOR 0.64 (0.43-0.95), p = 0.027].Ten years probability for ASCVD estimated by the ASCVD score is higher among subjects with asymptomatic diverticulosis compared to subjects without diverticulosis. Improved exercise performance is demonstrated for the first time to correlate with decreased probability for diverticular disease in screening colonoscopy.

Introduction Cardiorespiratory fitness (CRF) is associated with cardiovascular co-morbidities and is a strong predictor of adverse cardiovascular outcomes. However, data on the natural history of cardiorespiratory fitness among healthy subjects is limited. Purpose This study investigated what are the predictors of deterioration in CRF over time. Methods We investigated 36,239 men and women who were annually screened in a tertiary medical center and completed an exercise stress test in all visits, with a total of 175,596 annual visits. Subjects who failed to complete maximal exercise stress test according to the Bruce protocol at their first baseline visit were excluded. In addition, subjects with less than five visits to the center or those who developed ischemic heart disease during follow-up were excluded. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time. Change in CRF between the first baseline visit and the fifth visit was used to calculate fitness deterioration. The primary study endpoint was defined as the lower sex-specific quintile of change in metabolic equivalents (METS) between visits 1 and 5. Logistic regression models were applied. Results Final study population included 10,841 subjects. The mean age of the study population was 49±10 years, the mean BMI was 26±4, and 8107 (75%) were men. Median METS at baseline were 10.8 (IQR 9–12.6) and 11.1 (IQR 9.4–13) at the first and fifth visit, respectively (p Conclusion Obesity is an independent predictor of future CRF deterioration. The effect of obesity on future CRF deterioration is more pronounced among women as compared to men. Funding Acknowledgement Type of funding sources: None.

Introduction The relationship between ischemic heart disease (IHD) and advanced chronic kidney disease is well established. However, there is a paucity of data regarding the long-term association in between renal function and incidence of IHD. Purpose To study the remote association between point renal function and future incidence of ischemic heart disease among healthy adults. Methods We evaluated asymptomatic self-referred adults who participated in a medical screening program. All subjects were free of IHD at baseline. Glomerular Filtration Rate (GFR) was calculated by CKD-EPI and divided into quartiles (Q1 represents the lowest quartile). Study endpoint was the development of IHD which was externally adjudicated by a physician. Mortality data were available for all subjects from national registry. Cox regression models were applied while adjusting for confounders. Results The final study population included 27,647 subjects (68% men) with a mean age of 47 years. At baseline (first screening visit), median GFR by CKD-EPI was 84 [IQR 74; 95] and 86 [IQR 74.; 101] mL/min per 1.73m2 for men women, respectively. During median follow up of 6 years [IQR 2; 12], 2,286 (8%) of subjects developed IHD, of whom 1,912 (10%) were men and 374 (4%) were women. Incident IHD was in 964 (13.98%), 705 (10.22%), 437 (6.34%) and 171 (2.48%) subjects from GFR Q1-Q4, respectively. Kaplan Meier survival analysis demonstrated a graded increased risk of IHD with decreasing eGFR quartiles (p Log rank Conclusion Mild renal dysfunction even within the normal range is independently associated with remote risk of IHD among young apparently healthy adults. Cardiovascular screening should be considered among young patients with reduced renal function, even within normal reference range. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction While Cardiovascular disease (CVD) and cancer share common risk factors, data on the temporal association between the occurrence of CVD and cancer is limited. Purpose This study investigated the association between incident CVD events future cancer among apparently healthy subjects. Methods We evaluated asymptomatic self-referred adults who participated in a screening program. All subjects were free of CVD and cancer at baseline. CVD was defined as the composite of acute coronary syndrome, percutaneous coronary intervention, or stroke. Study endpoint was the development of cancer during follow up. Cancer and mortality data were available for all subjects from national registries. Cox regression models were applied with CVD as a time-dependent covariate and death as a competing risk event. Results Final study population included 26,574 subjects. Median age was 46 years (Interquartile range [IQR] 40–53) and 69% were men. During median follow up time of 10 years (IQR 3–16) 2,463 (9%) subjects developed CVD, 2,040 (8%) developed cancer and 869 (3%) died. Most common cancer types were prostate among men (N=406, 2.2%) and breast among women (N=283, 3.4%). Compared with patients who were free of CVD and cancer during follow up, risk of death was 5, 34 and 54 times higher for patients who developed CVD event, cancer, or both during follow up, respectively (p Conclusion Incident CVD is independently associated with increased risk of subsequent cancer diagnosis among young adults. Active cancer surveillance should be considered among young patients recovering from a CVD event. Funding Acknowledgement Type of funding sources: None.

Clinical and experimental data support a critical role for inflammation in cardiovascular disease. The purpose of the current study was to examine the relation between an inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), and incident atrial fibrillation (AF) in asymptomatic adults. We investigated 21,118 self-referred men and women who were annually screened in a tertiary medical center. All subjects were free of AF at baseline and had their serum NLR calculated at the first annual visit. Subjects were divided into 2 groups based on their baseline NLR: Low (2.83; n = 17,524) and high (≥2.83; n = 3,594; Upper Sextile). The primary endpoint was new onset AF during follow-up. Mean age of study population was 48 ± 10 years and 72% were men. A total of 563 (2.7%) incident events occurred during an average follow-up of 7.5 ± 5 years. Unadjusted Cox regression analysis demonstrated that each 1 unit increase in NLR was associated with a significant 14% increase in risk of occurrence of a first AF event (95% confidence interval 1.06 to 1.23, p0.001) and 20% increased risk of death. Kaplan-Meier's survival analysis showed that the cumulative probability of incident AF was significantly higher among subjects with high NLR compared with low NLR group (p = 0.006). Interaction analysis with adjustment to clinical parameters showed that NLR-related risk was age-dependent, such that in the younger age-group (=50 years) high NLR group had two folds increased risk for AF event compared with low NLR group (95% confidence interval 1.08 to 3.51; p = 0.027) whereas among older subjects the rate of events was similar between both NLR groups (p = NS; p for interaction = 0.024). In conclusion, our findings suggest that high NLR is associated with increased risk of new onset AF. This finding is more pronounced among young adults.

Background Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. Methods Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. Results Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. Conclusions The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.

Introduction The current categorization of cardiovascular (CV) disease based on the Pooled Cohort Equations Risk (PCE) broadened the scope of candidates eligible for statin therapy. Coronary artery calcium score (CCS) identifies those who are most likely to benefit from statin therapy for primary prevention. The Multi-Ethnic Study of Atherosclerosis (MESA) score is the first that includes CCS for CV risk calculation. Aim To find whether MESA score can better predicts CV events than the PCE score and better allocates asymptomatic subjects for statin treatment Methods 632 consecutive subjects free of CV disease, mean age 56±7 years, 84% male, underwent clinical evaluation and CCS measuring. PCE and MESA risk scores were calculated for each subject. Patients were divided according to the 4 PCE categories of 10 years CV risk, and further analyzed according to a higher or lower risk groups than 7.5%, the cutoff above which statin is definitely indicated. Results During mean follow-up of 6.5±3.3 years, 54 subjects experienced a first CV event. Those with MESA risk score ≤7.5% had a favorable outcome even when the PCE indicated a risk of >7.5%. The MESA risk improves the discrimination, ROC curves C-statistics increased from 0.653 for the PCE risk to 0.770. 84% (99/118) of those with borderline risk (5 to ≤7.5%) according to the PCE score, were re-allocated by the MESA risk into an higher (>7.5%) or lower risk category ( Conclusion The MESA risk score better predicts CV events than the PCE score in asymptomatic, and contributes to better allocate them to statin treatment. Funding Acknowledgement Type of funding source: None

Background Cardiovascular disease (CVD) and cancer share common risk factors. This study investigated the association of CVD diagnosis and the risk of future cancer. Methods We evaluated asymptomatic self-referred adults aged 40–79 years who participated in a screening program. All subjects were free of CVD and cancer at baseline. CVD was defined as the composite of acute coronary syndrome, percutaneous coronary intervention or stroke. Cancer and mortality data were available for all subjects from national registries. Primary end-point was development of cancer during follow up. Cox regression models were applied with CVD as a time-dependent covariate and death as a competing risk event. Results Final study population included 15,486 subjects. Median age was 50 years (Interquartile range [IQR] 44–55) and 72% were men. During median follow up time of 11 years (IQR 6–15) 1,028 (7%) subjects developed CVD, 1,281 (8%) developed cancer and 499 (3%) died. Most common cancer types were prostate among men (N=277, 1.8%) and breast among women (N=187, 1.2%). Time dependent survival analysis showed that subjects who developed CVD during follow up were 60% more likely to develop cancer (95% Confidence Interval [CI] 1.3–1.95, p Conclusions Incident CVD is independently associated with 2-fold increased risk of subsequent cancer diagnosis among young adults. Our analysis underscores the importance of cancer surveillance among young patients following a CVD event. Figure 1 Funding Acknowledgement Type of funding source: None

Development of hepatocellular carcinoma in patients with cirrhosis is associated with alterations in intestinal microbiota, including an escalation of dysbiosis and reduced bacterial richness. This study demonstrates that reduced bacterial richness and dysbiosis escalate with the progression of cirrhosis from compensated to decompensated cirrhosis and to HCC-associated cirrhosis (HCC-cirrhosis). Moreover, we report for the first time the effect of environmental factors on HCC-cirrhosis. Excess weight was associated with increased dysbiosis in patients with HCC compared to their normal-weight counterparts. Moreover, fatty liver, consumption of artificial sweeteners, and high-sugar foods were associated with altered microbial composition, including altered levels of Akkermansia muciniphila in HCC-cirrhosis. We have successfully determined that levels of Alphaproteobacteria and the two genera CF231 and Clostridium are significantly altered in cirrhotic patients who develop hepatocellular carcinoma, independently of cirrhosis severity and dietary habits., Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. While cirrhosis is the main risk factor for HCC, the factors influencing progression from cirrhosis to HCC remain largely unknown. Gut microbiota plays a key role in liver diseases; however, its association with HCC remains elusive. This study aimed to elucidate microbial differences between patients with HCC-associated cirrhosis (HCC-cirrhosis) and cirrhotic patients without HCC and healthy volunteers and to explore the associations between diet, lifestyle, and the microbiome of these patients. Fecal samples and food frequency questionnaires were collected from 95 individuals (30 HCC-cirrhosis patients, 38 cirrhotic patients without HCC, and 27 age- and body mass index [BMI]-matched healthy volunteers). 16S rRNA gene sequencing was performed. Bacterial richness in cirrhosis and HCC-cirrhosis patients was significantly lower than in healthy controls. The HCC-cirrhosis group was successfully classified with an area under the curve (AUC) value of 0.9 based on the dysbiotic fecal microbial signature. The HCC-cirrhosis group had a significant overrepresentation of Clostridium and CF231 and reduced Alphaproteobacteria abundance compared to cirrhotic patients without HCC. Patients with HCC-cirrhosis who were overweight displayed significantly decreased bacterial richness and altered microbiota composition compared to their normal-weight counterparts. There was a significant correlation in the HCC-cirrhosis group between intake of artificial sweeteners and the presence of Akkermansia muciniphila. A unique microbial signature was observed in patients with HCC-cirrhosis, irrespective of cirrhosis stage, diet, or treatment. BMI, dietary sugar, and artificial sweeteners were significantly associated with alterations in the microbiome of HCC-cirrhosis patients. However, the increased abundance of Clostridium and CF231 observed in HCC-cirrhosis patients was not influenced by environmental factors, implying that this change was due to development of HCC. IMPORTANCE Development of hepatocellular carcinoma in patients with cirrhosis is associated with alterations in intestinal microbiota, including an escalation of dysbiosis and reduced bacterial richness. This study demonstrates that reduced bacterial richness and dysbiosis escalate with the progression of cirrhosis from compensated to decompensated cirrhosis and to HCC-associated cirrhosis (HCC-cirrhosis). Moreover, we report for the first time the effect of environmental factors on HCC-cirrhosis. Excess weight was associated with increased dysbiosis in patients with HCC compared to their normal-weight counterparts. Moreover, fatty liver, consumption of artificial sweeteners, and high-sugar foods were associated with altered microbial composition, including altered levels of Akkermansia muciniphila in HCC-cirrhosis. We have successfully determined that levels of Alphaproteobacteria and the two genera CF231 and Clostridium are significantly altered in cirrhotic patients who develop hepatocellular carcinoma, independently of cirrhosis severity and dietary habits.

Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline.To examine whether physical fitness acts as a potential protective mechanism shielding against the negative associations between age and cognition. Specifically, we examined whether physical fitness mediates the relationship between age and processing speed.114 (M = 63.80, SD = 10.63) senior executives completed a computerized cognitive battery composed of four processing speed tasks. Level of physical fitness was assessed on a treadmill stress test and reported in metabolic equivalents (METs).Older age was associated with slower processing speed (r = 0.25, p = 0.007), whereas greater physical fitness was associated with faster processing speed (r = -0.30, p = 0.001). Path analysis indicated that the association between age and processing speed was fully mediated by the level of physical fitness (Indirect effect: β = 0.10, p = 0.008; Direct effect: β = 0.16, p = 0.20).The findings indicate that physical fitness is a strong mediator of the relationship between age and processing speed and imply that physical fitness makes a major contribution to cognitive reserve during the aging process. The results may suggest that the decrease in physical fitness during aging may partially account for slower cognitive processing.

Although cardiorespiratory fitness (CRF) is a strong independent predictor of adverse cardiovascular outcomes, it is not considered as a risk enhancer by current guidelines.We evaluated asymptomatic self-referred adults aged 40 to 79 years of age, free of cardiovascular disease at baseline, who were screened annually and completed baseline exercise stress test. Baseline CRF was dichotomized into 2 groups: low (metabolic equivalents8) and high. The primary endpoint was the composite of death, nonfatal acute coronary syndrome, and stroke after excluding subjects diagnosed with metastatic cancer during follow-up.Study population included 15,445 subjects with median age of 49 years (interquartile range: 44-55). During median follow-up of 8 years 1362 (9%) subjects developed the study endpoint. Kaplan-Meier survival analysis showed that both fitness and atherosclerotic cardiovascular disease (ASCVD) were associated with developing of the study endpoint (P0.001 for both). Cox regression model with adjustment for ASCVD risk consistently showed that lower fitness was associated with a significant 23% higher risk to develop the study endpoint (P = 0.001). Continuous net reclassification improvement analysis showed an overall improvement of 11.4% (95% confidence interval, 8%-14.6%; P value0.001) in the accuracy of classification when fitness was added to the ASCVD model.Low CRF is a strong independent predictor of the cardiovascular morbidity and mortality in asymptomatic adults. Addition of fitness to the pooled cohort ASCVD risk significantly improves the accuracy of the model.

BACKGROUND Data on the association between AF and fitness are conflicting. OBJECTIVES The aim of this analysis was to investigate the association between fitness, obesity and incidence of atrial fibrillation (AF) among apparently healthy non-athlete adults. METHODS We investigated 20 410 self-referred subjects who were annually screened in a tertiary medical centre. All subjects were free of AF and completed maximal exercise stress test according to the Bruce protocol at baseline. Fitness was categorised into age- and sex-specific quintiles (Q) according to the treadmill time. Subjects were categorised to low (Q1-Q2) and high fitness (Q3-5) groups. The primary end point was new-onset AF during follow-up. RESULTS Mean age was 48 ± 10 years and 72% were men. A total of 463 (2.3%) events occurred during an average follow-up of 8 ± 5 years corresponding to an AF event rate of 0.3% per person year. Univariate and multivariate models showed that AF risk was similar in both fitness groups. However, AF event rate was 0.55% per person year among high fitness obese subjects, compared with 0.31% for low fitness obese subjects (P

Population screening of three common BRCA1/BRCA2 mutations in Ashkenazi Jews (AJ) apparently fulfills screening criteria. We compared streamlined BRCA screening via self-referral with proactive recruitment in medical settings.Unaffected AJ, age ≥25 years without known familial mutations, were either self-referred or recruiter-enrolled. Before testing, participants received written information and self-reported family history (FH). After testing, both non-carriers with significant FH and carriers received in-person genetic counseling. Psychosocial questionnaires were self-administered 1 week and 6 months after enrollment.Of 1,771 participants, 58% were recruiter-enrolled and 42% were self-referred. Screening uptake was 67%. Recruited enrollees were older (mean age 54 vs. 48, P0.001) and had less suggestive FH (23 vs. 33%, P0.001). Of 32 (1.8%) carriers identified, 40% had no significant FH. Post-test counseling compliance was 100% for carriers and 89% for non-carrier women with FH. All groups expressed high satisfaction (90%). At 6 months, carriers had significantly increased distress and anxiety, greater knowledge, and similar satisfaction; 90% of participants would recommend general AJ BRCA screening.Streamlined BRCA screening results in high uptake, very high satisfaction, and no excess psychosocial harm. Proactive recruitment captured older women less selected for FH. Further research is necessary to target younger women and assess other populations.Genet Med advance online publication 08 December 2016.

Background Data on the functional impact of anemia on cardiorespiratory fitness (CRF) and survival in healthy individuals are limited. Our aim was to evaluate the association between anemia thresholds, low CRF, and survival in otherwise healthy adults. Methods Study population included 16 334 apparently healthy subjects attending annual periodic health screening examinations (71 200 annual visits), including exercise stress testing (EST). Anemia was defined by the World Health Organization (WHO) or Beutler and Waalens’ (BW) criteria. Low CRF was defined as the lowest fitness quintile according to the Bruce protocol. Results The mean age was 46±10 years, and 70% were men. Mean Hb levels were 13±1 and 15±1 among women and men, respectively, with higher proportion of anemia among women. The majority of anemic subjects had mild anemia. When analyzing repeated annual visits, anemia was associated with a significant 39% and 64% increased risk of low CRF according the WHO and BW criteria only in women (n=18 672). Baseline anemia at first visit was associated with 2.6- and 1.9-fold increased risk of all-cause mortality using the WHO and BW criteria, exclusively in men (n=11 511). Conclusions Overall, the functional and prognostic impact of anemia is gender dependent, based on the WHO and BW arbitrary criteria, suggesting differing mechanism and responses.

Background Cardio-respiratory fitness (CRF) is a known predictor of cardiovascular morbidity and mortality. However, data on the association of CRF with survival following a diagnosis of cancer is limited. Purpose To evaluate the association between CRF in a large cohort of asymptomatic adults and a probability of survival after subsequent cancer diagnosis. Methods We evaluated asymptomatic self-referred adults aged 40–79 years who were screened annually at a tertiary medical center. All subjects were free of cardiovascular disease and cancer at baseline and completed maximal exercise stress test according to the Bruce protocol. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1-Q2 defined as low fitness and Q3-Q5 as higher fitness. Cancer data was available from a national cancer registry. The primary end point was all-cause mortality. Results Final study population in included 15,800 subjects. Mean age was 51±8 years and 72% were men. During median follow up of 13 years (IQR 7–16) 1,312 (8%) subjects developed cancer and 486 (3%) died. Most common cancer types were prostate in 302 (23%) and breast cancer in 189 (14%) patients. No difference was found in distribution of major cancer types between different fitness categories. Univariate Cox regression with cancer as a time dependent covariate showed that subjects who developed cancer during follow up were 19 times more likely to die (95% CI 15.5–22.5, p Conclusions Low CRF is associated with worse survival among subjects diagnosed as having cancer during follow up. These findings support the effectiveness of fitness assessment in preventive health care settings.

Background Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. Methods A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. Results A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. Conclusion In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

To investigate the association between heart rate recovery (HRR) and new-onset atrial fibrillation (AF) in middle-aged adults.Heart rate recovery was calculated using the exercise stress test in 15,729 apparently healthy self-referred men and women who attended periodic health screening examinations between January 2000, and December 2015. All participants completed the maximal exercise stress test according to the Bruce protocol and were followed clinically on a yearly basis for a median of 6.4±4 years. The primary end point was new-onset AF. Participants were grouped according to HRR at 5 minutes, dichotomized at the median value (73 beats/min).Participants with low HRR were older, were more commonly men, had a higher rate of comorbidities, and were less fit. Kaplan-Meier survival analysis revealed that the cumulative probability of AF at 6 years was higher in participants with low HRR (2.1%) than in those with high HRR (0.6%) (log-rank, P.001). Older age, male sex, obesity resting heart rate, and ischemic heart disease were all associated with increased AF risk in a univariate Cox regression model (P.05 for all). Multivariate Cox regression analysis revealed that low HRR was independently associated with increased AF risk (hazard ratio, 1.92; 95% CI, 1.3-2.8; P.001) after adjustment for multiple confounders.Lower HRR is independently associated with the development of new-onset AF during long-term follow-up in middle-aged adults.

Aims The SCORE risk estimation system is used for cardiovascular risk stratification in apparently healthy adults and is based on known cardiovascular risk factors. The purpose of the current study was to evaluate whether exercise capacity can improve the accuracy of the SCORE overall survival risk estimation. Methods and results We investigated 22 878 asymptomatic men and women who were annually screened in a tertiary medical centre. All subjects were free of known ischaemic heart disease, and had completed maximal exercise stress test according to the Bruce protocol. The SCORE risk estimation system was used to evaluate individual cardiovascular risk for all subjects. The primary endpoint was mortality, after exclusion of patients with metastatic cancer during follow-up. The incremental contribution of exercise capacity in predicting the risk of death was evaluated by net reclassification improvement (NRI) and area under the receiver operating curve (AUROC). Mean age of the study population was 47.4 ± 10.3, and 71.6% were men. There were 505 (2.21%) deaths during a mean follow-up of 9.2 ± 4.1 years. Kaplan–Meier survival analysis showed that both SCORE and low exercise capacity were associated with reduced survival. When added to the SCORE risk prediction, exercise capacity allowed more accurate risk stratification: NRI analysis showed an overall improvement of 56.8% in the accuracy of classification and the AUROC increased (0.782 vs. 0.766). Conclusion Both SCORE and exercise capacity are strong independent predictors of all-cause mortality. The addition of exercise capacity to the SCORE risk model can improve the accuracy of the model.

Population screening of three common BRCA1/BRCA2 mutations in Ashkenazi Jews (AJ) apparently fulfills screening criteria. We compared streamlined BRCA screening via self-referral with proactive recruitment in medical settings. Unaffected AJ, age ≥25 years without known familial mutations, were either self-referred or recruiter-enrolled. Before testing, participants received written information and self-reported family history (FH). After testing, both non-carriers with significant FH and carriers received in-person genetic counseling. Psychosocial questionnaires were self-administered 1 week and 6 months after enrollment. Of 1,771 participants, 58% were recruiter-enrolled and 42% were self-referred. Screening uptake was 67%. Recruited enrollees were older (mean age 54 vs. 48, P 90%). At 6 months, carriers had significantly increased distress and anxiety, greater knowledge, and similar satisfaction; 90% of participants would recommend general AJ BRCA screening. Streamlined BRCA screening results in high uptake, very high satisfaction, and no excess psychosocial harm. Proactive recruitment captured older women less selected for FH. Further research is necessary to target younger women and assess other populations. Genet Med advance online publication 08 December 2016

Pharmacological approaches to increase HDL Cholesterol (HDL-C) failed to improve cardiovascular outcomes. The current analysis investigated the association of non-pharmacological increase in HDL-C with cardiovascular events in preventive healthcare settings. We assessed asymptomatic, self-referred

While serum uric acid (SUA) is associated with adverse cardiovascular outcome, it has been excluded from cardiovascular risk models. This study evaluated the impact of SUA on the accuracy of atherosclerotic cardiovascular disease (ASCVD) pooled cohort equations (PCE) model. We evaluated 15,095

To investigate the nature of the association of normal levels of total cholesterol with cognitive function and the contribution of age to this association.A sample of 61 senior executives, who were summoned for an annual medical examination with approximately four measurements of total cholesterol during 4 years, were examined with a computerized cognitive battery assessing mental processing speed as a sensitive measure of cognitive decline. We examined the association of total cholesterol with processing speed and the moderating effect of age on this association.A multiple regression analysis yielded a significant interaction between cholesterol and age for processing speed (p = .045). In order to examine the source of the interaction, simple slope analysis was performed. A significant negative high correlation was found for young subjects (p = .021), while no significant correlation was observed at middle (p = .286) or older (p = .584) age. The difference in slopes was robust to adjustment for potential confounding factors, including body mass index, and fasting glucose.Within the normal range, higher total cholesterol levels were associated with better processing speed in younger ages and this association diminished with increasing age. Our findings highlight the important role of brain cholesterol in good cognitive functioning.

We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (

Despite ample research on the dysplasia to carcinoma risk in ulcerative colitis, there are scant data on the prevalence of adenomatous polyps in this population.The number and histology of all polyps detected at colonoscopies of ulcerative colitis patients aged 50 during 2006 - 2012 were compared with similarly aged controls undergoing screening colonoscopy.There were 206 patients with ulcerative colitis and 624 controls included in the study (mean age 61.7 ± 8.7 vs. 60.8 ± 6.1, respectively; P = 0.15). Adenomatous polyps were detected in only 13/206 colonoscopies for ulcerative colitis compared with 162 /624 controls (6.3 % vs. 25.9 %, respectively; odds ratio [OR] 0.19, 95 % confidence interval [CI] 0.1 - 0.34; P 0.0001). When also considering all prior colonoscopies performed over 7.7 ± 4.6 years of follow-up (mean 4.1 ± 2.9 colonoscopies/patient, range 1 - 15, total 832 colonoscopies), the risk of ever finding an adenoma in ulcerative colitis patients was still significantly lower compared with controls (14.1 % vs. 25.9 %, respectively; OR 0.47, 95 %CI 0.3 - 0.72; P = 0.0005). On multivariable analysis, adenomas were positively associated with advanced age (OR 1.07/year, 95 %CI 1.03 - 1.1; P 0.0001) and with increasing body mass index (BMI; OR 1.06/kg/m(2), 95 %CI 1.01 - 1.1; P = 0.01) and negatively associated with having ulcerative colitis (OR 0.15, 95 %CI 0.09 - 0.44; P = 0.0005). Among 115 Crohn's disease patients aged 50 years, the rate of ever-adenomas in small-bowel Crohn's disease was similar to the controls (P = 0.8) and not influenced by 5-aminosalicylic acid use, whereas patients with colonic Crohn's disease had a significantly lower rate of adenomas compared with the controls (3.9 % vs. 25.9 %; P = 0.002).Unlike patients with small-bowel Crohn's disease, patients with ulcerative colitis or with colonic Crohn's disease seldom develop sporadic adenomatous polyps. These data may provide novel clues to a possible role for colonic immune activation in restricting the adenoma to carcinoma sequence while propagating the dysplasia to carcinoma pathway.

Obesity and overweight are strongly associated with cardiovascular morbidity and mortality. However, there are limited data on the association between excess weight and the risk of ectopic ventricular activity.We investigated the association between body mass index (BMI) and the risk for ectopic ventricular activity (defined as multiple ventricular premature beats (≥3), ventricular bigeminy, nonsustained ventricular tachycardia or sustained ventricular tachycardia) during exercise stress testing among 22,516 apparently healthy men and women who attended periodic health screening examinations between the years 2000 and 2014. All subjects had completed maximal exercise stress testing annually according to the Bruce protocol. Subjects were divided at baseline into three groups: normal weight (BMI ≥ 18.5 kg/m(2) and25; N = 9,994), overweight (BMI ≥ 25 and 30; N = 9,613) and obese (BMI ≥ 30; N = 2,906).The mean age of study subjects was 47 ± 10 years and 72% were men. Kaplan-Meier survival analysis showed that the cumulative probability for the development of exercise-induced ectopic ventricular activity arrhythmias was highest among obese subjects, intermediate among overweight subjects and lowest among subjects with normal weight (3.4%, 2.7% and 2.2% respectively; p 0.001). Multivariate binary logistic regression with repeated measures of 92,619 ESTs, showed that obese subjects were 33% more likely to have ectopic ventricular arrhythmias during exercise compared with subjects with normal weight (p = 0.005), and that each 1 kg/m(2) increase in BMI was associated with a significant 4% (p = 0.002) increased adjusted risk for exercise-induced ventricular arrhythmias.Obesity is independently associated with increased likelihood of ectopic ventricular arrhythmia during exercise.

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n 5 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identi- fied 28 subjects (24 males) who developed PD at follow- up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 6 8.82 vs. 48.91 6 10.60 years, P < 0.001). The time between the first ergometri ct est and motor symptoms onset was 4.64 6 2.86 years. Patients who later devel- oped PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD. V C 2014 International Parkinson and Movement Disorder Society

Smoking is an independent cardiovascular risk factor and correlates with reduced exercise tolerance. However, data on the time dependent effect of smoking cessation on exercise tolerance are limited.We investigated 17,115 men and women who were annually screened at the Institute for Medical Screening of the Chaim Sheba Medical Centre. All subjects had their smoking status documented and performed an exercise stress testing (EST) according to Bruce protocol at each visit. Subjects were divided at baseline into four groups: active smokers (N = 2858), recent quitters (smoking cessation ≤2 years before baseline EST; N = 861), remote quitters (smoking cessation2 years before the baseline EST; N = 3856) and never smokers (N = 9810). Baseline and follow up EST duration were compared among the four groups.Recent quitters demonstrated a 2.4-fold improvement in their EST duration compared with active smokers (improvement of 24 ± 157 vs. 10 ± 157 s, respectively, p = 0.02). Multivariate logistic regression showed that recent quitters were 26% more likely to improve their exercise tolerance compared with active smokers (95% confidence interval (CI) 1.08-1.47, p = 0.003). Assessing smoking status as a time-dependent covariate during four consecutive visits demonstrated that recent quitters were 17% more likely to improve their exercise tolerance compared with active smokers (95% CI 1.02-1.34, p = 0.02), with a less pronounced benefit among remote quitters (hazard ratio = 1.11, 95% CI 1.02-1.21; p = 0.01).Smoking cessation is independently associated with improved exercise tolerance. The benefits of smoking cessation are evident within the first two years of abstinence.

High-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular events. The aim of the current study was to evaluate the correlation between changes in HDL-C and subsequent cardiovascular events.Study population comprised 13,037 subjects free of cardiovascular disease with a mean follow up of 6 ± 3 years. Low HDL-C was defined as40 mg/dl for men and50mg/dl for women. Participants were divided into three groups based on HDL-C levels at the first and second baseline visits: persistently-low HDL-C (LL); persistently-high HDL-C (HH); and those with high HDL-C in a one visit only: intermittently high HDL-C (LH/HL). The primary endpoint was the first occurrence of a cardiovascular event.A total of 529 (4.1%) incident events occurred during follow-up. HDL-C levels increased significantly between the two landmark visits (47.5 ± 12.6 vs. 48.1 ± 12.2, p0.001). Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was highest among subjects in the LL group (7.6%), and similar among LH/HL and HH groups (3.3% and 4%, respectively; log-rank p=0.001). Multivariate Cox regression analysis, with HDL-C as time-dependent covariate, showed that subjects with persistently low HDL-C during follow up experienced a 51% increased cardiovascular risk compared with subjects with persistently high HDL-C (p=0.026). Subjects with intermittently high HDL-C during follow up experienced similar risk to those with persistently high HDL-C (HR=1.02; p=0.89).Variations in HDL-C levels during follow-up are associated with subsequent cardiovascular risk. Patients who retain low HDL-C levels are at the cardiovascular highest risk.

The Pooled Cohort Equations (PCE) are used for atherosclerotic cardiovascular disease (ASCVD) risk stratification. The purpose of the current study was to evaluate whether cardiorespiratory fitness could be used to improve the accuracy of the risk model. We evaluated 15,596 asymptomatic self

Attenuated heart rate (HR) response during exercise is associated with adverse cardiovascular outcome. The acceptable value for HR response is 85% of the age-predicted maximal HR (APMHR). This study hypothesized that mild attenuation of HR response during exercise among healthy subjects is associated with increased cardiovascular risk. The study population comprised 10,323 healthy men and women without known cardiovascular disease (CVD) or diabetes mellitus who underwent a yearly screening program and were followed up during a mean period of 4.3 years. Participants were grouped to 3 tertiles based on the percentage of their APMHR reached at the baseline stress test. The primary end point was the occurrence of CVD or cerebrovascular disease. A total of 1,015 incident cases of CVD occurred during follow-up. A multivariate Cox proportional hazards regression model showed that the CVD risk of subjects who reached 60% to 96% of their APMHR was 35% greater compared with those who reached their APMHR (p = 0.001). A subgroup analysis among subjects who reached 85% of their APMHR showed that even mildly attenuated heart response (in the range of 85% to 96% APMHR) was independently associated with 36% increase in CVD risk (p0.001). In conclusion, attenuated HR response during exercise is a powerful and independent predictor of adverse cardiovascular events during long-term follow-up among healthy men and women. The prognostic implications of attenuated HR response in this population are apparent even with a minor decrease of the maximal HR to96% of the APMHR.

Background Metabolic syndrome and its components are severe global health issues that are increasing in frequency as the prevalence of obesity increases. Various studies have established a correlation between metabolic syndrome and diseases including, diabetes mellitus, non-alcoholic fatty liver disease, cirrhosis, and cardiovascular disease. In recent years, correlations have also been detected between obesity and metabolic syndrome and the prevalence of certain types of cancer. The current study examines whether obesity and metabolic syndrome components are risk factors for cancer among the adult population in Israel. Methods A cohort study analysis was performed of 24,987 initially healthy men and women who underwent yearly medical assessments at the Institute for Medical Screening in the Sheba Medical Center. Data from the Institute for Medical Screening database was correlated with that from the Israel Cancer Center in the Ministry of Health updated to December 2013. The correlation between metabolic syndrome, obesity, and the overall risk of cancer as well as the risks of specific types of cancer were examined. Results Of 20,444 subjects for whom complete data were available, 1535 were diagnosed with cancer during the mean follow-up time of 104.3 months. In a multi-variant analysis, no significant correlation was found between metabolic syndrome or obesity and the incidence of cancer. When the data were stratified by gender and cancer type, however, a significant association between metabolic syndrome and breast cancer in women was observed (P = 0.03, HR = 1.67, 95% CI = 1.05–2.67). Conclusion Metabolic syndrome correlates with higher than expected breast cancer incidence in women.

Men tend to develop cardiovascular disease (CVD) earlier in life than women. Whether this difference is attributable only to gender is a matter of debate. The purpose of this study was to evaluate gender differences in cardiovascular risk in a large cohort of asymptomatic men and women and explore gender-related risk in prespecified risk factor subgroups. We investigated 14,966 asymptomatic men and women free of diabetes, hypertension, or ischemic heart disease who were annually screened. The primary end point of the present study was the occurrence of ischemic or cerebrovascular disease as composite end point. Multivariate Cox proportional hazards regression modeling was used to assess the gender difference regarding CVD and to examine the association between CVD risk factors and gender. Mean age of the study population was 47 ± 10 years and 30% were women. Kaplan-Meier survival analysis showed that at 6.2 ± 3.9 years' follow-up, the rate of CVD events was 6.1% among men compared with 1.8% among women (log-rank p0.001). Consistently, multivariate analysis demonstrated that male gender was independently associated with a significant threefold increased risk for development of CVD events (hazard ratio 3.05, CI 2.25 to 4.14). The CVD risk associated with male gender was consistent in each risk subset analyzed, including older age, low high-density lipoprotein, impaired fasting glucose, and positive family history for ischemic heart disease (all p values for gender-by-risk factor interactions0.05). Higher performance on treadmill test had a protective effect regarding CVD development in both men and women. In conclusions, healthy middle-aged men experienced increased risk for the development of CVD events compared with women independently of traditional CVD risk factors. However, better exercise capacity is associated with a protective effect.

BACKGROUND Hypertension (HTN) is associated with coronary artery calcification (CAC). We hypothesized that preexisting CAC is associated with the development of HTN. METHODS This study included 483 normotensive subjects (mean age 54 years, 83% males) who underwent a baseline evaluation of their CAC score with ungated dual-section computed tomography during 2001-2002 and returned for at least the first annual follow-up. All subjects underwent an annual examination and were followed for a mean period of 6.6 ± 3.2 years to identify newly developed HTN. Data on the patient's medical history, physical examination and laboratory evaluations were collected. RESULTS During the follow-up, 104 subjects developed HTN. The rate of newly developed HTN was significantly higher among those with CAC (60 of 223 subjects; 27%) than among those without CAC (44 of 260; 17%) (P < 0.01). The presence of CAC predicted the development of HTN with a hazard ratio of 1.73 (95% confidence interval, 1.17-2.56; P < 0.01). After adjustment for age, sex, body mass index, smoking, baseline systolic blood pressure, and levels of glucose, triglycerides, and low-density lipoprotein cholesterol, the presence of CAC still predicted the development of HTN with a hazard ratio of 1.63 (95% confidence interval, 1.02-2.60; P = 0.04). CONCLUSIONS Preexisting CAC is associated with the development of HTN.