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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.

Background Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. Methods This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013–2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. Results Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. Conclusions This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

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.

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 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.

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.

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.

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.

Serum lactate dehydrogenase (LDH) is known pathologic marker for a diversity of diseases, including myocardial ischemia. Strenuous and enduring physical activity can transiently induce a greater total LDH level, still within its normal range. To date, however, it has not been determined whether normal-range LDH might be inversely associated with coronary artery disease (CAD) in the low-cardiovascular-risk, physically active, adult population. We conducted a retrospective cohort analysis. A total of 5,519 healthy adults aged 34 to 86 years were followed up for a mean period of 4.2 years. The cohort incidence of CAD was 6.1% (338 cases) from 2001 to 2009. In the present cohort, greater mean LDH levels were significantly associated with a greater number of years, days/week, and minutes/week of leisure time activity (p = 0.02, p = 0.04, and p = 0.01, respectively). These associations were externally validated successfully by analysis of all 5,064 healthy participants aged ≥40 years with normal-range LDH from the 2007 to 2010 National Health and Nutrition Examination Surveys combined. For instance, the mean LDH level was significantly greater in those engaged in 6 to 7 versus 1 to 5 days/wk of vigorous-intensity work activity (138.0 ± 20.7 IU/L vs 133.3 ± 21.7 IU/L, respectively, p = 0.007). In our cohort, the hazard ratio for CAD according to the normal total serum LDH tertiles, adjusted for multiple risk and protective CAD factors in a Cox proportional hazards model, was 0.70 (95% confidence interval 0.54 to 0.92) in the greater versus lower tertile (p for trend = 0.01). In conclusion, we suggest that increased normal-range total serum LDH is associated with reduced short-term risk of CAD outcome in this low-risk, physically active population.

Introduction: Colonic diverticulosis is a common condition with obscure pathogenesis. Obesity, hyperlipidemia and hypertension have been demonstrated to increase the risk of complicated diverticular disease, but the impact of metabolic risk factors on the prevalence of uncomplicated diverticulosis has not been clearly determined. Aims: The aim of the study was to examine the impact of obesity and metabolic syndrome on the prevalence of colonic diverticulosis. Methods: This retrospective case-control study included patients aged 40–85 years who were followed up by the Institute of Medical Screening in Israel and underwent colonoscopy in 2006–2011 for indication of colorectal cancer screening. Patients with diverticulosis as detected by colonoscopy were compared to patients without diverticulosis. The comparison parameters included medical history, biometric parameters, biochemical and lipid profile. Results: The study included 3,175 patients. Diverticulosis was diagnosed in 17.4% of the cohort. On univariate analysis, age, male gender, BMI (continuous variable), obesity, systolic blood pressure, low-density lipoprotein cholesterol level, history of hypertension, ischemic heart disease, hypothyroidism, and absence of diabetes mellitus were associated with an increased risk of colonic diverticulosis. On multivariate analysis, advanced age, male gender, obesity (BMI >30), history of hypothyroidism and absence of diabetes mellitus were associated with an increased risk of diverticulosis. Prevalence of colonic polyps was similar in patients with and without diverticulosis. Conclusion: Colonic diverticulosis was associated with age, male gender, obesity and hypothyroidism. Diabetes mellitus was associated with a decreased risk of colonic diverticulosis.

Background The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle‐aged adults. Methods and Results We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48±9 years and 73% were men. Average baseline resting blood pressure was 120/77±12/7 mm Hg. During a follow‐up of 5±3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new‐onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively; P P P Conclusions In normotensive middle‐aged individuals, blood pressure response to exercise is associated with future development of hypertension.

Increased body mass index (BMI) and obesity are associated with increased risk of new-onset atrial fibrillation (AF) among middle-aged adults.The objective of the study is to investigate the association between BMI and the risk for new-onset AF among middle-aged adults.We investigated 18,290 men and women who were annually screened in a tertiary medical center. Participants were divided at baseline into 3 groups: normal weight (BMI ≥18 and25 kg/m(2), n = 7,692), overweight (BMI ≥25 and30 kg/m(2), n = 8,032), and obese (BMI ≥30 kg/m(2), n = 2,566). The primary end point was new-onset AF during follow-up.Mean age of study population was 49 ± 11 years, and 73% were men. A total of 288 incident events (1.6%) occurred during 6 ± 4 years. Kaplan-Meier survival analysis showed that the cumulative probability of AF at 6 years was highest among obese participants, intermediate among overweight participants, and lowest among participants with normal weight (2.1%, 1.7%, and 0.8% respectively, P.001). Multivariable Cox regression analysis showed that overweight and obesity were independently associated with increased AF risk (hazard ratio 1.54 [P = .004] and 2.41 [P.001], respectively). Assessment of BMI change as a time-dependent covariate in the multivariable model showed that each 1 kg/m(2) reduction in BMI during follow-up was associated with a significant 7% reduction in the risk for the occurrence of a first AF event (hazard ratio 0.93, 95% CI 0.88-0.99, P = .019). Consistently, similar analysis showed that each 5-kg weight loss during follow-up was independently associated with a significant 12% reduced risk of new-onset AF (95% CI 0.81-0.98, P = .02).Our findings suggest that overweight and obesity are associated with increased AF risk, whereas weight reduction is independently associated with reduced risk of de novo AF.

Objectives Many features of fibromyalgia syndrome (FMS) resemble those of posttraumatic stress disorder (PTSD). The goal of this study was to investigate the comorbidity of FMS and PTSD in a cohort of men following an intensive, initial, defined traumatic event. Methods One hundred twenty-four males (55 patients with PTSD, 20 patients with major depression, and 49 controls) were evaluated for the presence of FMS. The major traumatic events in all PTSD patients were combat-related. Each individual completed questionnaires characterizing his disease, disabilities, and quality of life. Results Forty-nine percent of PTSD patients, compared to 5% of major depression patients and none of normal controls, fulfilled the American College of Rheumatology criteria for FMS (P

OBJECTIVE To compare long-term lithium patients who developed renal insufficiency (RI) with those who did not, and to examine what characterized these groups. METHOD One hundred fourteen subjects with DSM-IV bipolar, major depressive, or schizoaffective disorder who had been taking lithium for 4 to 30 years from 1968 to 2000 were studied retrospectively. Subjects with blood creatinine levels > or = 1.5 mg/dL were defined as RI patients, and creatinine levels < 1.5 mg/dL indicated no renal insufficiency (NRI). Ninety-four unmedicated subjects, matched for sex and age, served as a comparison group and had 2 measures of creatinine with a mean interval of 11.88 years. RESULTS Twenty-four (21%) of the lithium-treated patients were defined as RI patients. These subjects exhibited the "creeping creatinine" phenomenon as their creatinine levels increased progressively. The NRI subjects showed no increase of creatinine levels in up to 30 years and remained comparable to the comparison group. RI was associated with episodes of lithium intoxication and diseases or medicines that could affect glomerular function, but not with sex, psychiatric diagnosis, age at onset of diagnosed disorder, duration of lithium therapy, serum lithium concentration, and cumulative lithium dose. CONCLUSIONS Long-term lithium therapy did not influence glomerular function in an overwhelming majority of patients. However, about 20% of long-term lithium patients exhibited "creeping creatinine" and developed renal insufficiency.

Background: Evidence linking cardiovascular risk factors to aortic valve sclerosis (AVS) has led to the assumption that the latter is an atherosclerosis-like process. However, triglyceride (TG)-rich lipoproteins, an important risk factor for atherosclerosis, have been rarely investigated in connection with AVS. Methods: A cross-sectional study of 246 healthy individuals (mean age 59±6 years, 77% men) was conducted. Subjects underwent an echocardiographic assessment and extensive blood lipid measurements, including evaluation of TG-related indices, such as serum apolipoprotein (apo) CII and CIII levels, apo CIII levels in VLDL+LDL particles, and apo CIII ratio (CIII level in HDL/CIII level in VLDL+LDL). Results: Twenty-three patients (9.3%) were diagnosed as having AVS. On average, these patients were 5 years older and had higher levels of serum cholesterol, LDL-C and LP(a), compared with non-AVS subjects. In addition, the AVS patients exhibited higher concentrations of serum apo CII, serum apo CIII and apo CIII in VLDL+LDL, and a lower apo CIII ratio. Adjusting for age and gender, a 1 S.D. increment in apo CIII in VLDL+LDL was associated with odds ratio (OR) of 1.76 (95% CI: 1.17–2.65) for AVS. Further adjustment for atherosclerotic risk factors did not alter the association appreciably (OR=1.65, 95% CI: 1.06–2.58). Conclusion: TG-rich lipoproteins may be involved in the early development of AVS. Confirmation in prospective studies is required.

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults.We conducted a historical prospective cohort analysis.A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease.We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults.

Duzli Y, Grossman E, Gaides M, Segev S, Gal N, Ben-Dov I. Do angiotensin-converting enzyme (ACE) inhibitors enhance the effect of exercise rehabilitation in patients with hypertension and ACE DD and DI genotypes? Objective To test whether pharmacologic angiotensin-converting enzyme (ACE) inhibition in carriers of the ACE DD or DI (D, deletion; I, insertion of 287 base pairs) genotypes can simulate the genetic advantage of the II genotype and thereby enhance the conditioning effects of aerobic exercise. Design Nonrandomized controlled trial. Setting Pulmonary institute. Participants Twelve sedentary men with controlled hypertension (5 with DD genotype, 7 with DI genotype; age, 53±7y) treated by ACE inhibitors (study group) and 10 patients (8 men, 2 women; 2 with DD genotype, 8 with DI genotype; age, 54±10y) who were treated by other antihypertensive drugs (controls). Intervention Exercise training. Main Outcome Measures Training effect was measured by maximal oxygen uptake (Vo 2 max) anaerobic threshold (Vo 2AT ), and the corresponding work rates (WR) (in watts)—WRmax and WR AT —before and after 10 weeks of training. Results Vo 2 max increased by a mean of 10% (200mL/min) and WRmax by 14% (25W) in each group ( P 2AT and WR AT tended to increase more in the study group (Vo 2AT : 10% [186±35mL/min] vs 5% [100±1mL/min]; P AT : 19% [19±2W] vs 12% [11±3W]; P Conclusions This study did not show an enhancement of exercise-related conditioning by pharmacologic ACE inhibition among hypertensive patients with ACE DD and DI genotypes, comparable to the advantage conferred by the II genotype.

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 = 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 identified 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 ± 8.82 vs. 48.91 ± 10.60 years, P 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed 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.

Previous studies have demonstrated an association between increased serum uric acid (SUA) levels and incident diabetes. Most clinical and epidemiological investigations, however, focused solely on male populations or did not analyze men and women separately. We assessed the association between SUA levels and diabetes incidence in a large cohort of apparently healthy men and women.Data were retrospectively gathered from 9140 adults who participated in annual medical screening visits during 2000-2009. Mean follow-up time was 4.8 years, and the median age was 50 years. Laboratory test results, data from physical examinations, medical history, and lifestyle information were extracted. The main outcome measure was incident diabetes, defined as two consecutive fasting glucose tests higher than 125 mg/dL. Cox proportional-hazards multivariate models were applied for measuring hazard ratios (HRs) for diabetes according to continuous and categorical levels of uric acid.We identified 499 new cases of diabetes (total, 5.5%: men, 6.2%; women, 3.6%) during the follow-up period. The gender-specific HRs for diabetes, adjusted for age and a set of prespecified multiple risk and protective factors, were 1.57 for each 1 mg/dL increase in SUA (95% confidence interval [CI], 1.32-1.86) in women and 1.08 (95% CI, 0.99-1.17) in men; p for interaction of SUA by gender0.001.SUA is independently associated with diabetes outcome, considerably more in women than in men.

Clinical thyroid disease is associated with changes in the cardiovascular system, including changes in heart rate during exercise. However, data on the relation between subclinical thyroid disease (SCTD) and heart rate during exercise are limited.We investigated 3799 apparently healthy subjects who were evaluated in the Institute for Preventive Medicine at the Sheba Medical Center. All subjects answered standard health questionnaires; were examined by a physician; completed routine blood tests including thyrotropin, free triiodothyronine, and free thyroxine levels; and underwent a treadmill exercise according to the Bruce protocol. Subjects with known thyroid disease or those who were taking thyroid-related drugs were excluded from the analysis. Heart rate profile was compared between patients with subclinical hypothyroidism (SCHypoT), patients with normal thyroid function, and patients with subclinical hyperthyroidism (SCHyperT) using propensity score matching.Seventy patients had SCHyperT and 273 had SCHypoT. Compared with age- and sex-matched normal subjects, SCHyperT subjects had a higher resting heart rate (83±17 vs. 76±12 beats per minute [bpm], p=0.006), a significantly higher recovery heart rate (94±12 vs. 90±12 bpm, p=0.045), and a significantly lower heart rate reserve (80±20 vs. 87±18 bpm, p=0.006). Subjects with SCHypoT showed a trend toward a lower resting heart rate (75±13 vs. 77±15 bpm, p=0.09) and had a significantly lower recovery heart rate (88±12 vs. 90±13 bpm, p=0.035). There was no significant difference in exercise duration or blood pressure between subjects with SCTD and their matched normal controls.Subjects with SCTD have a significantly different heart rate profile during rest, exercise, and recovery.

Both resting blood pressure (BP) variability and exercise BP previously showed association with incident hypertension. The aim of the present study was to examine whether visit-to-visit variability in exercise systolic blood pressure (SBP) can predict the risk for new-onset hypertension among normotensive adults. We investigated 6546 normotensive men and women who were annually screened in a tertiary medical center and completed treadmill exercise tests at each visit. Based on the initial three baseline annual visits, long-term intervisit variability of exercise SBP among the three tests was measured using standard deviation (SD) and coefficient of variation for each participant. The rate of newly diagnosed hypertension was measured in different variability levels during 6 ± 3 years of follow-up. Multivariate analysis adjusted for various clinical factors, including resting BP, showed that each 5 mm Hg rise in the SD of exercise SBP resulted in a significant 5% increase in the risk for the development of future hypertension (P = .015). Subjects in the upper exercise SBP SD variability tertile had a 28% (P = .007) increased risk for hypertension during follow-up, as compared with those in the lowest tertile. Similar results were achieved for the assessment of coefficient of variation of exercise SBP. In conclusion, visit-to-visit variability in exercise SBP can predict the development of future hypertension among normotensive individuals.

While moderate and severe chronic kidney disease is an established independent risk factor for cardiovascular disease (CVD), the association of estimated glomerular filtration rate (eGFR) differences within the normal to mildly reduced range (from 60 to90 ml/min/1.73 m(2)) and CVD is less clear. Our aim was to examine the association of eGFR with incident CVD in a cohort of predominantly healthy subjects with normal to mildly reduced renal function.Retrospective cohort study.We collected demographic, clinical, and laboratory parameters of subjects free of diabetes mellitus or CVD who attended annual medical screening examinations between 2001 and 2009. Main outcome measures were a new diagnosis of coronary artery disease (CAD) or cerebrovascular events (CVE).During a median follow up of 4.3 years, among 10,909 subjects (mean eGFR 78.5 ± 12.2 ml/min/1.73 m(2)), 10.3% were diagnosed with CAD (n = 1025) or CVE (n = 94). Compared with subjects in the highest eGFR quintile (≥ 88.8 ml/min/1.73 m(2)), subjects in the lowest quintile (≤ 68.2 ml/min/1.73 m(2)) had a hazard ratio (HR) of 1.64 (95% CI 1.35-2.00; p0.001) for a CAD outcome, but this association was no longer significant after adjustment for age and other confounders (adjusted HR 1.08; p = 0.55). Similar findings were obtained for the association of eGFR with CVE.In a predominantly healthy population with normal to mildly reduced renal function, lower eGFR is associated with higher risk for CVD; however, this association is not independent but merely reflects the association of age and other cardiovascular risk factors with reduced eGFR.

Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.

The most common ophthalmologic manifestation of hypertension is hypertensive retinopathy. Our study was designed to evaluate the factors that determine retinal vessel caliber in hypertensive subjects.During a 6-month period, retinal photographs were taken of participants during a routine yearly check-up. The photographs were evaluated by an ophthalmologist and the diameters of the individual retinal vessels were measured and summarized by a computer program. Data including patient's medical history, physical examination and laboratory evaluations were collected. The findings of the ophthalmologic examinations were analyzed with respect to the relevant systemic data.We evaluated 285 subjects (43 women) with an average age of 62 ± 9 years (range 33-87). Hypertension was reported in 204 (71.6%) subjects and diabetes mellitus in 60 subjects (21%). The arteriolar calibers were inversely related to age (R = - 017; p = 0.01). Retinal arteriolar and venular calibers were wider in smokers and in subjects with dyslipidemia. History of hypertension was not associated with any vascular changes. However, retinal arteriolar caliber was inversely related to blood pressure levels. Diuretic treatment was associated with narrow retinal venular caliber.The association between different cardiovascular risk factors and hypertensive retinopathy is complex. Effective blood pressure control has a beneficial effect on the vascular changes in the retina.

High values of resting heart rate were found to be correlated with adverse outcomes in various patient groups. Heart rate variability (HRV) is a reliable technique in determining autonomic nervous system function. Our aim was to evaluate whether a 10-second resting heart rate obtained from a resting electrocardiogram (ECG), could be used as a reliable evaluation of short-term HRV.Seventy-nine healthy volunteers were included in the study. All participants underwent a 10-second ECG, and 5-minute HRV measurement under strict criteria.A significantly negative correlation was found between resting heart rate and 5-minute max-RR, min-RR, standard deviation of normal RR intervals (SDNN), root mean square of successive differences of RR intervals (RMSSD), HRV triangular index, number of intervals differing by 50 milliseconds from the preceding interval (NN50), pNN50, standard deviation of the points perpendicular to the line of identity (SD1), standard deviation along the line of identity (SD2), and high frequency spectral component (HF). A significant positive correlation was found between resting heart rate and a 5-minute low frequency spectral component (LF) and LF/HF ratio. Specifically, max-RR and min-RR were found to have the best correlation with resting heart rate.Resting heart rate obtained from a 10-second ECG can be used for crude estimation of all HRV results in healthy individuals who do not take medications, with variable efficacy depending on the measured parameter. Resting heart rate was especially efficient in predicting max-RR and min-RR. Further research should focus on assessing the reliability of a resting heart rate for HRV evaluation, in patients with autonomic dysfunction and high-risk cardiac patients.

Background: Heart rate variability (HRV) is an accepted and reliable means for assessing autonomic nervous system dysfunction. A 5‐minute measurement of HRV is considered methodologically adequate. Several studies have attempted to use shorter recordings of 1–2 minutes or 10 seconds. The aim of this study was to determine the reliability of HRV parameters calculated from ultra‐short electrocardiogram recordings. Methods: Seventy healthy volunteers were recruited for the study. HRV was evaluated for 5 minutes according to accepted procedures. Thereafter, HRV parameters were recalculated from randomly selected 1‐minute and 10‐second intervals. The standard and ultra‐short measurements were correlated using intraclass correlation coefficients. Results: Good correlations between the 5‐minute electrocardiograms (ECGs) and both the 1‐minute and 10‐second ECGs were noted for average RR interval, and root mean square of successive differences in RR intervals (RMSSD). No correlation was noted for standard deviation of the RR interval (SDNN) and several other HRV parameters. Conclusions: RMSSD, but not SDNN, seem a reliable parameter for assessing HRV from ultra‐short (1 minute or 10 seconds) resting electrocardiographic recordings. Power spectral analysis and evaluation of other HRV parameters require longer recording periods. Further research is required to evaluate the importance of ultra‐short RMSSD for cardiovascular risk stratification. Ann Noninvasive Electrocardiol 2011;16(2):117–122

High levels of plasma homocysteine constitute a risk for cardiovascular disease. Physical activity, known to reduce CVD risk, has been related to levels of Hcy. Recently, higher Hcy was shown to be associated with lower cardiovascular fitness in women but not in men.To further explore the relationship between cardiorespiratory fitness and plasma total homocysteine levels in a large cohort of adult males and females.This cross-sectional study included 2576 fitness and Hcy examinations in adults (62% males) aged 30-59 years randomly drawn from a population undergoing a periodic health examination in the Sheba Medical Center's Executive Screening Survey. Blood tests were collected for tHcy and a sub-maximal exercise test was performed to estimate cardiorespiratory fitness. Information on CVD/CVD risk factors (coronary heart disease, cerebrovascular accident, diabetes, hypertension or dyslipidemia) was self-reported.Mean tHcy plasma levels were 14.4 +/- 7.7 and 10.2 +/- 3.0 micromol/ml, and mean maximal oxygen uptake 36.5 +/- 11.7 and 292 +/- 9.5 ml/kg/min for males and females, respectively. A multiple regression analysis, adjusting for age, body mass index and CVD/CVD risk factors, showed no association between cardiorespiratory fitness and level of tHcy in males (P = 0.09) or in females (P = 0.62).In this sample no association was found between level of cardiorespiratory fitness and plasma tHcy in men or women. The inconsistency of findings and the small number of studies warrant further research of the association between cardiorespiratory fitness and tHcy, an association that may have clinical implications for the modifications of cardiovascular risk factors.

Soft tissue infections in compromised patients are frequently caused by Gram-negative organisms and particularly by Pseudomonas aeruginosa. These pathogens are effectively eradicated by pefloxacin as well as by ceftazidime. The effectiveness and safety of these two agents were compared in a prospective randomized study in 67 patients with soft tissue infections. Underlying conditions included malignant diseases, diabetes mellitus and chronic renal failure. The infections included: post operative infection, septic foot, soft tissue abscess and cellulitis. Thirty-three patients were treated with intravenous ceftazidime for a mean duration of ten days. More than half the 34 patients given pefloxacin were treated only orally for a mean period of 13 days. The clinical and bacteriological outcomes were similar in both groups. There was clinical cure or improvement in 26 pefloxacin cases and in 23 ceftazidime cases, failure in six pefloxacin cases and in seven ceftazidime and relapse in two pefloxacin and in three ceftazidime patients. The bacteriological responses were eradication in 23 pefloxacin cases and in 22 ceftazidime cases, persistence in five pefloxacin cases and in six ceftazidime cases, relapse in one pefloxacin case and in none of the ceftazidime group, reinfection in four pefloxacin cases and in three ceftazidime cases and there was one unassessed patient in the pefloxacin group and two in the ceftazidime group. Nausea and vomiting occurred in three patients and elevation of liver enzymes in another patient; all side effects were observed only in the pefloxacin treated patients. These results suggest that oral pefloxacin could offer an alternative to intravenous ceftazidime in half the compromised patients with tissue infections. However, adverse reactions due to pefloxacin administration should be watched for during such therapy.

We aimed to evaluate whether reduced cardiovascular fitness has a direct or indirect effect for the development of cardiovascular disease.We investigated 15,595 men and women who were annually screened in a tertiary medical center. All subjects were free of ischemic heart disease and had completed maximal exercise stress test according to the Bruce protocol at their first visit. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1 as lowest fitness. Subjects were categorized at baseline into 3 groups: low fitness (Q1), moderate fitness (Q2-Q4), and high fitness (Q5). The primary end point of the current analysis was the development of a first cardiovascular event during follow-up.Mean age of study patients was 48 ± 10 years, and 73% were men. A total of 679 events occurred during 92,092 person-years of follow-up. Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was significantly higher among subjects with low fitness (P.001). Low fitness was associated with known cardiovascular risk factors, including hypercholesterolemia (odds ratio [OR] 1.58, 95% CI 1.31-1.89), diabetes mellitus (OR 2.32, 95% CI 1.58-3.41), and obesity (OR 10.46, 95% CI 8.43-12.98). The effect of low fitness on cardiovascular events was no longer significant when including diabetes mellitus, hypercholesterolemia, and obesity as mediators (hazard ratio 0.99, 95% CI 0.82-1.19).The association between cardiovascular fitness and adverse cardiovascular outcomes may be modulated through traditional cardiovascular risk factors. These findings need to be further validated in prospective clinical trials.

The physical activity questionnaire is typically chosen for population studies because it is practical and does not interfere with the behavior of the surveyed individual. This instrument can be adapted for the particular studied population, and in terms of accuracy it is both reliable and valid.To develop a valid and appropriate measure to assess physical fitness according to the level of physical activity throughout the day, and to estimate the relation between a subjective questionnaire measurement evaluating physical activity, to predicted VO2max, as an objective measure of physical fitness.Three hundred healthy subjects, 150 men and 150 women, aged 25-65 years old participated in this study. All subjects were routinely examined in the Sheba Medical Center Executive Screening Survey. They were asked to complete a self-administered questionnaire and report on the level of physical activity at work, the level of sports activity and the level of leisure time non-sport activity. The index calculated from the questionnaire was compared to the result from a sub-maximal exercise test, which they performed in The Executive Screening Survey, to composite a valid questionnaire to estimate physical fitness.A high and statistically significant correlation (r = 0.64, P0.01) was found between the indexes of physical activity calculated from the questionnaire to the predicted VO2max, measured from the sub-maximal exercise test. The reliability of the questionnaire was examined by test-retest and a high and statistically significant correlation (r = 0.89, P0.01) was found between the first and the proceeding one month administration of the questionnaire. The final modal to predict VO2max included a total index of physical activity, gender, BMI, age and resting heart rate. Overall this model predicted 58% of the VO2max.The self-administered questionnaire developed in this study has high construct validity and a significant correlation to predicted VO2max, with high sensitivity in both sexes and among active and non-active subjects. It is therefore an appropriate tool to be used in epidemiological studies.

Background Triglycerides (TG) are carried in the circulation by diverse lipoprotein particles, which vary in their lipid and protein content, metabolism, and atherogenicity. Several indices related to apolipoproteins (apo) CII and CIII blood concentration have been proposed to reflect TG metabolism more accurately than the blood level of TG. In the present study we compared the distribution of those indices in coronary heart disease (CHD) patients and controls. Methods Ninety consecutively discharged patients with CHD and 209 healthy controls were included in the analysis. Demographic, clinical, and laboratory characteristics were obtained. Results The CHD patients differed appreciably from controls in several TG-related variables. After adjusting for cardiovascular risk factors, significant associations were found between CHD and the following: TG, VLDL-C, apo CIII, apo CIII in HDL, apo CIII in VLDL + LDL, apo CII- to- TG ratio, and apo CIII ratio (CIII in HDL/CIII in VLDL + LDL). Further adjustment for HDL-C substantially attenuated the above associations, except for those regarding apo CIII in VLDL + LDL (odds ratio (OR): 1.69 per 1 SD increment, 95%CI: 1.03–2.77) and apo CIII ratio (OR: 0.40 per 1 SD increment, 95%CI: 0.15–1.00). Conclusion Our results add to the growing evidence which links apo CIII concentration in VLDL + LDL to CHD. Further confirmation in prospective studies would be required before considering this measurement as a screening tool.

The intestinal trans-epithelial elimination of moxifloxacin was measured in the jejunum, ileum, caecum and in the bile in a rabbit model. Over a 120 min period following a single parenteral administration of moxifloxacin 15 mg/kg, peak serum concentration was 3.1 (+/- 1.1) mg/L. The elimination constants were: 0.019 (+/- 0. 017) microg/cm(2)/min, 0.011 (+/- 0.014) microg/cm(2)/min and 0.002 (+/- 0.002) microg/cm(2)/min in the jejunum, ileum and caecum, respectively. Per loop, over 120 min, the respective eliminated quantities were: 9.59 (+/- 9.37) microg, 8.26 (+/- 6.74) microg and 1.92 (+/- 1.86) microg. Biliary moxifloxacin concentrations varied between 1.30 and 5.16 mg/L and exceeded serum levels from 45 min onwards. Intestinal concentrations paralleled serum moxifloxacin levels. Altogether, approximately 4.5% of the moxifloxacin dose was eliminated trans-epithelially in the digestive tract over the 120 min experimental period.

The treatment of community-acquired pneumonia is empirical in most cases and must cover a wide range of potential pathogens, such as Streptococcus pneumoniae, including penicillin-resistant strains, Haemophilus influenzae and intracellular microorganisms. The objective of this double-blind, randomized, parallel group study was to compare the efficacy and safety of sparfloxacin (400 mg loading dose, followed by 200 mg o.d.) with that of oral amoxycillin-clavulanic acid (500/125 mg t.i.d.) or oral erythromycin (1 g b.i.d.), during 7-14 days in 808 patients with confirmed community-acquired pneumonia. The overall success rates for sparfloxacin (87%), amoxycillin-clavulanic acid (80%) and erythromycin (85%) were similar in evaluable patients, and the equivalence hypothesis used for the statistical analysis showed at least an equivalent efficacy for the three antibiotics tested. The analysis of microbiologically documented infections (40% of the patients) showed that overall success rates were similar for S. pneumoniae and H. influenzae infections. Treatment withdrawal was necessary in 3.5, 2.5 and 7.7% of the patients treated with sparfloxacin, amoxycillin-clavulanic acid and erythromycin, respectively. This study indicates that sparfloxacin was at least as effective as amoxycillin-clavulanic acid or erythromycin in the treatment of mild-to-moderate community-acquired pneumonia and that the adverse effects were similar in the three groups.

In a multicentre, double-blind, randomized study involving four general hospitals in Israel, the efficacy and safety of ceftriaxone 1 g/day i.v. was compared to that of 2 g/day i.v. in the treatment of moderate to severe community-acquired infections requiring hospitalization. Two hundred and twenty-two patients were enrolled; 112 received intravenous ceftriaxone 1 g/day, and 110 received 2 g/day. The two groups were matched demographically, and their mean APACHE II score (10 points) and mean duration of successful therapy (7 days) were identical. The sites of infection in the 1 g and 2 g groups respectively were lower respiratory tract in 57 versus 51 patients, urinary tract in 31 versus 40 patients, and soft tissue in 24 versus 19 patients. There were no significant differences in clinical outcome between the 1 g and 2 g groups, the outcome being cure in 91% versus 86% of patients, improvement in 3% versus 3% of patients, failure in 3% versus 8% of patients, and relapse in 3% versus 3% of patients. The findings of this study indicate that ceftriaxone 1 g/day is as effective as 2 g/day in the treatment of moderate to severe community-acquired infections. The low-dose form is a more economical means of treating these infections.

Sixteen patients with acute meningitis caused by Gram-negative bacteria were treated with pefloxacin intravenously. The age range of the patient group was six months to 85 years with a mean age of 40 years; three patients were children. In all but two patients meningitis was a complication of neurosurgical operations and fourteen of the sixteen had received prior therapy which was not successful. The causative organisms were: Pseudomonas aeruginosa (5), Acinetobacter calcoaceticus (4), Klebsiella pneumoniae (3), Enterobacter cloacae (2), Citrobacter diversus (1) and Salmonella group C (1). Pefloxacin was administered intravenously 800 mg twice a day to the adult patients (mean dosage of 21( +/- 6.7) mg/kg body weight) for a mean period ( +/- S.D.) of 11( +/- 4) days. The mean cerebrospinal fluid concentration of pefloxacin was 8.8( +/- 5.0) mg/l which was 54% of the mean peak serum concentration (16.3( +/- 8.8]. The mean MIC and MBC of the causative organisms were 1.1( +/- 1.2) mg/l and 1.64( +/- 1.2) mg/l. Thirteen patients (87%) were cured or clinically improved and twelve (80%) were bacteriologically cured. One patient failed, another patient had reinfection and one was not assessable. No side effects were observed. In the present study pefloxacin offered an efficacious and safe treatment of Gram-negative meningitis following failure of other antibiotic therapy.

A cohort of 127 nursing home residents aged 60-98 years were vaccinated during the winter of 1985-86 with the A-Chile 1/83 (C), A-Philippines 2/82 (P), and B-USSR (B) commercial influenza vaccines. Before vaccination 40%, 23%, and 69% were susceptible to influenza Ac, Ap, and B, respectively [hemagglutinin inhibition (H.I.) titer less than 1:40]. One month following initial vaccination, 32 patients [25%] remained unprotected against two or all three vaccine strains. These patients were revaccinated with the same influenza vaccine and followed up. At five months 11%, 19%, and 23% of the initial cohort were still unprotected against Ac, Ap, and B strains, respectively. We conclude that two conventional influenza vaccines administered one month apart leave unprotected 30% of healthy elderly people who are initial influenza vaccine failures.

Twenty-five male patients with nongonococcal urethritis including 15 chlamydial infections, were treated with spiramycin for ten days. All but four patients had been treated previously, mostly with tetracyclines. Chlamydia trachomatis was cultured in seven patients and was detected in three additional men by immunofluorescent smear. Five other patients had antibodies to chlamydia, and one patient yielded a positive culture for Ureaplasma urealyticum and Mycoplasma hominis. A successful clinical response was observed in 64% of the patients; C. trachomatis was eradicated from six of seven patients with positive cultures and the three positive direct smears were negative after treatment. It is concluded that spiramycin can be used effectively for the therapy of acute nongonococcal urethritis, as well as in patients who have failed to respond to previous treatment with tetracyclines and erythromycin.