Prevalence of common and rare ophthalmic findings in adults attending a medical survey institute.

PURPOSE: To examine the ophthalmic data from a large database of people attending a general medical survey institute, and to investigate ophthalmic findings of the eye and its adnexa, including differences in age and sex. METHODS: Retrospective analysis including medical data of all consecutive individuals whose ophthalmic data and the prevalences of ocular pathologies were extracted from a very large database of subjects examined at a single general medical survey institute. RESULTS: Data were derived from 184,589 visits of 3676 patients (mean age 52 years, 68% males). The prevalence of the following eye pathologies were extracted. Eyelids: blepharitis (n = 4885, 13.3%), dermatochalasis (n = 4666, 12.7%), ptosis (n = 677, 1.8%), ectropion (n = 73, 0.2%), and xanthelasma (n = 160, 0.4%). Anterior segment: pinguecula (n = 3368, 9.2%), pterygium (n = 852, 2.3%), and cataract or pseudophakia (n = 9381, 27.1%). Cataract type (percentage of all phakic patients): nuclear sclerosis (n = 8908, 24.2%), posterior subcapsular (n = 846, 2.3%), and capsular anterior (n = 781, 2.1%). Pseudophakia was recorded for 697 patients (4.6%), and posterior subcapsular opacification for 229 (0.6%) patients. Optic nerve head (ONH): peripapillary atrophy (n = 4947, 13.5%), tilted disc (n = 3344, 9.1%), temporal slope (n = 410, 1.1%), ONH notch (n = 61, 0.2%), myelinated nerve fiber layer (n = 94, 0.3%), ONH drusen (n = 37, 0.1%), optic pit (n = 3, 0.0%), and ON coloboma (n = 4, 0.0%). Most pathologies were more common in males except for ONH, and most pathologies demonstrated a higher prevalence with increasing age. CONCLUSIONS: Normal ophthalmic data and the prevalences of ocular pathologies were extracted from a very large database of subjects seen at a single medical survey institute.

Mild renal impairment is associated with increased cardiovascular events and all-cause mortality following cancer diagnosis.

BACKGROUND: The association between mildly decreased renal function and cardiovascular (CV) outcomes in cancer patients remains unestablished. AIMS: We sought to explore this association in asymptomatic self-referred healthy adults. METHOD: We followed 25, 274 adults, aged 40-79 years, who were screened in preventive healthcare settings. Participants were free of CV disease or cancer at baseline. The estimated glomerular filtration rate (eGFR) was calculated according to the CKD Epidemiology Collaboration equation and categorized into groups [≤59, 60-69, 70-79, 80-89, 90-99, ≥100 (ml/min/1.73 m²)]. The outcome included a composite of death, acute coronary syndrome, or stroke, examined using a Cox model with cancer as a time-dependent variable. RESULTS: Mean age at baseline was 50 ±â€…8 years and 7973 (32%) were women. During a median follow-up of 6 years (interquartile range: 3-11), 1879 (7.4%) participants were diagnosed with cancer, of them 504 (27%) develop the composite outcome and 82 (4%) presented with CV events. Multivariable time-dependent analysis showed an increased risk of 1.6, 1.4, and 1.8 for the composite outcome among individuals with eGFR of 90-99 [95% confidence interval (CI): 1.2-2.1 P = 0.01], 80-89 (95% CI: 1.1-1.9, P = 0.01) and 70-79 (95% CI: 1.4-2.3, P < 0.001), respectively. The association between eGFR and the composite outcome was modified by cancer with 2.7-2.9 greater risk among cancer patients with eGFR of 90-99 and 80-89 but not among individuals free from cancer ( Pinteraction < 0.001). CONCLUSION: Patients with mild renal impairment are at high risk for CV events and all-cause mortality following cancer diagnosis. eGFR evaluation should be considered in the CV risk assessment of cancer patients.

Glaucoma Prediction Models Based on Ocular and Systemic Findings.

INTRODUCTION: Our aim was to explore the impact of various systemic and ocular findings on predicting the development of glaucoma. METHODS: Medical records of 37,692 consecutive patients examined at a single medical center between 2001 and 2020 were analyzed using machine learning algorithms. Systemic and ocular features were included. Univariate and multivariate analyses followed by CatBoost and Light gradient-boosting machine prediction models were performed. Main outcome measures were systemic and ocular features associated with progression to glaucoma. RESULTS: A total of 7,880 patients (mean age 54.7 ± 12.6 years, 5,520 males [70.1%]) were included in a 3-year prediction model, and 314 patients (3.98%) had a final diagnosis of glaucoma. The combined model included 185 systemic and 42 ocular findings, and reached an ROC AUC of 0.84. The associated features were intraocular pressure (48.6%), cup-to-disk ratio (22.7%), age (8.6%), mean corpuscular volume (MCV) of red blood cell trend (5.2%), urinary system disease (3.3%), MCV (2.6%), creatinine level trend (2.1%), monocyte count trend (1.7%), ergometry metabolic equivalent task score (1.7%), dyslipidemia duration (1.6%), prostate-specific antigen level (1.2%), and musculoskeletal disease duration (0.5%). The ocular prediction model reached an ROC AUC of 0.86. Additional features included were age-related macular degeneration (10.0%), anterior capsular cataract (3.3%), visual acuity (2.0%), and peripapillary atrophy (1.3%). CONCLUSIONS: Ocular and combined systemic-ocular models can strongly predict the development of glaucoma in the forthcoming 3 years. Novel progression indicators may include anterior subcapsular cataracts, urinary disorders, and complete blood test results (mainly increased MCV and monocyte count).

Big Data Analysis of Glaucoma Prevalence in Israel.

PRCIS: The prevalence of glaucoma in the adult population included in this study was 2.3%. Normal values of routine eye examinations are provided including age and sex variations. PURPOSE: The purpose of this study was to analyze the prevalence of glaucoma in a very large database. METHODS: Retrospective analysis of medical records of patients examined at the Medical Survey Institute of a tertiary care university referral center between 2001 and 2020. A natural language process (NLP) algorithm identified patients with a diagnosis of glaucoma. The main outcome measures included the prevalence and age distribution of glaucoma. The secondary outcome measures included the prevalence and distribution of visual acuity (VA), intraocular pressure (IOP), and cup-to-disc ratio (CDR). RESULTS: Data were derived from 184,589 visits of 36,762 patients (mean age: 52 y, 68% males). The NLP model was highly sensitive in identifying glaucoma, achieving an accuracy of 94.98% (area under the curve=93.85%), and 633 of 27,517 patients (2.3%) were diagnosed as having glaucoma with increasing prevalence in older age. The mean VA was 20/21, IOP 14.4±2.84 mm Hg, and CDR 0.28±0.16, higher in males. The VA decreased with age, while the IOP and CDR increased with age. CONCLUSIONS: The prevalence of glaucoma in the adult population included in this study was 2.3%. Normal values of routine eye examinations are provided including age and sex variations. We proved the validity and accuracy of the NLP model in identifying glaucoma.

Baseline renal function and the risk of cancer among apparently healthy middle-aged adults.

BACKGROUND: The association between mildly impaired renal function with all-site and site-specific cancer risk is not established. We aim to explore this association among apparently healthy adults. METHODS: We followed 25,073 men and women, aged 40-79 years, free of cancer or cardiovascular disease at baseline who were screened annually in preventive healthcare settings. The estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation (CKD-EPI) and classified into four mutually exclusive groups: <60, 60-74, 75-89, ≥90 (mL/min/1.73 m²). The primary outcome was all-site cancer while the secondary outcome was site-specific cancer. Cancer data was available from a national registry. RESULTS: Mean age at baseline was 50 ± 8 years and 7973 (32 %) were women. During a median follow-up of 9 years (IQR 3-16) and 256,279 person years, 2045 (8.2 %) participants were diagnosed with cancer. Multivariable Cox model showed a 1.2 (95 %CI: 1.0-1.4 p = 0.05), 1.2 (95 %CI: 1.0-1.4 p = 0.02), and 1.4 (95 %CI: 1.1-1.7 p = 0.003) higher risk for cancer with eGFR of 75-89, 60-74, and < 60, respectively. Site-specific analysis demonstrated a 1.8 (95 %CI: 1.2-2.6 p = 0.004), 1.7 (95 %CI: 1.2-2.6 p = 0.004) and 2.2 (95 %CI: 1.3-3.6 p = 0.002) increased risk for prostate cancer with eGFR of 75-89, 60-74, and < 60, respectively. eGFR< 60 was associated with a 2.0 (95 %CI: 1.1-3.7 p = 0.03) and 3.7 (95 %CI: 1.1-13.1 p = 0.04) greater risk for melanoma and gynecological caner respectively. CONCLUSIONS: CKD stage 2 and worse is independently associated with higher risk for cancer incidence, primarily prostate cancer. Early intervention and screening are warranted among these individuals in order to reduce cancer burden.

A Novel Artificial Intelligence Based Denoising Method for Ultra-Low Dose CT Used for Lung Cancer Screening.

RATIONALE AND OBJECTIVES: To assess ultra-low-dose (ULD) computed tomography as well as a novel artificial intelligence-based reconstruction denoising method for ULD (dULD) in screening for lung cancer. MATERIALS AND METHODS: This prospective study included 123 patients, 84 (70.6%) men, mean age 62.6 ± 5.35 (55-75), who had a low dose and an ULD scan. A fully convolutional-network, trained using a unique perceptual loss was used for denoising. The network used for the extraction of the perceptual features was trained in an unsupervised manner on the data itself by denoising stacked auto-encoders. The perceptual features were a combination of feature maps taken from different layers of the network, instead of using a single layer for training. Two readers independently reviewed all sets of images. RESULTS: ULD decreased average radiation-dose by 76% (48%-85%). When comparing negative and actionable Lung-RADS categories, there was no difference between dULD and LD (p = 0.22 RE, p > 0.999 RR) nor between ULD and LD scans (p = 0.75 RE, p > 0.999 RR). ULD negative likelihood ratio (LR) for the readers was 0.033-0.097. dULD performed better with a negative LR of 0.021-0.051. Coronary artery calcifications (CAC) were documented on the dULD scan in 88(74%) and 81(68%) patients, and on the ULD in 74(62.2%) and 77(64.7%) patients. The dULD demonstrated high sensitivity, 93.9%-97.6%, with an accuracy of 91.7%. An almost perfect agreement between readers was noted for CAC scores: for LD (ICC = 0.924), dULD (ICC = 0.903), and for ULD (ICC = 0.817) scans. CONCLUSION: A novel AI-based denoising method allows a substantial decrease in radiation dose, without misinterpretation of actionable pulmonary nodules or life-threatening findings such as aortic aneurysms.

Cardiovascular Risk Factors and Physical Fitness Among Subjects with Asymptomatic Colonic Diverticulosis.

BACKGROUND: The association between diverticular disease and atherosclerotic cardiovascular disease (ASCVD) has been demonstrated previously, mainly in symptomatic subjects. AIMS: To evaluate 10 years cardiovascular risk, exercise performance and association to ASCVD among subjects with asymptomatic diverticulosis. METHODS: 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. RESULTS: 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]. CONCLUSIONS: 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.

Serum uric acid significantly improves the accuracy of cardiovascular risk score models.

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.

The Multi-Ethnic Study of Atherosclerosis-Calcium Score Improves Statin Treatment Allocation in Asymptomatic Adults.

Background: The current categorization of cardiovascular (CV) risk broadens the indications for statin therapy. Coronary artery calcium (CAC) identifies those who are most likely to benefit from primary prevention with statin therapy. The multi-ethnic study of atherosclerosis-calcium (MESA-C) includes CAC for CV risk stratification. Objective: We aimed to establish whether the MESA-C score improves allocation to statin treatment in a cohort of asymptomatic adults. We also analyzed patient survival according to their risk score calculation. Design: A retrospective analysis of asymptomatic adults. Participants: A total of 632 consecutive subjects free of coronary artery disease (CAD) and/or stroke, mean age 56 ± 7 years, 84% male, underwent clinical evaluations and CAC measurements. Main Measures: PCE and MESA-C risk scores were calculated for each subject. According to the 10-year risk for CV events, subjects were classified into moderate and high CV risk (≥7.5%) for whom a statin is clearly indicated, or borderline and low CV risk (<7.5%). Key Results: During mean follow-up of 6.5 ± 3.3 years, 52 subjects experienced their first CV event. Those with a MESA-C risk score < 7.5% had favorable outcomes even when the PCE indicated a risk of ≥ 7.5%. The MESA-C score improved the discrimination of CV risk with the ROC curves C-statistics increasing from 0.653 for the PCE to 0.770 for the MESA-C. Of those, 84% (99/118) with borderline CV risk (5-7.5%) according to the PCE score, were reallocated by the MESA-C score into a higher (≥7.5%) or lower (<5%) CV risk category. Furthermore, subjects with low MESA-C scores had the highest survival rate regardless of the PCE risk, while those with high MESA-C risks had the lowest survival rate regardless of the PCE risk. Conclusion: In asymptomatic subjects, the MESA-C score improves allocation to statin treatment and CV risk discrimination, while both scores are essential for more precise survival estimations.

Risk factors and prediction algorithm for advanced neoplasia on screening colonoscopy for average-risk individuals.

Background: Screening with colonoscopy for all average-risk population is probably not cost-effective due to the limited sources and over-generalization of the risk, and risk stratification can be used to optimize colorectal cancer screening. Objectives: We aimed to assess risk factors for advanced neoplasia (AN) and a classification tree algorithm to predict the risk. Design: This is a retrospective cross-sectional study. Methods: This study was composed of consecutive asymptomatic average-risk individuals undergoing first screening colonoscopy between 2008 and 2019. Detailed characteristics including background diseases, habits, and medications were collected. We used multivariable logistic regression to investigate the associations between clinical variables and the presence of AN and built a classification algorithm to predict AN. Results: A total of 3856 patients were included (73.2% male, median age 55). Adenoma and AN detection rate were 15.8% and 3.4%, respectively. On multivariable analysis, predictors of AN [odds ratio (OR), 95% confidence interval (CI)] were age (1.04, 1.01-1.06, p = 0.003), male sex (2.69, 1.56-4.64, p < 0.001), and smoking (1.97, 1.38-2.81, p < 0.001). A classification tree algorithm showed that smoking was the most important risk factor for prediction of AN (4.9% versus 2.4%, p < 0.001), followed by age with a cutoff value of 60 in the smokers (8.4% versus 3.8%, p = 0.001) and 50 in the non-smokers (2.9% versus 0.9%, p = 0.004). Conclusion: Smoking habits, old age, and male gender are highly associated with an increased risk for AN and should be incorporated in the individualized risk-assessment to adapt a screening program.

Cardiorespiratory fitness and survival following cancer diagnosis.

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 < 0.001). The association of cancer with survival was fitness dependent such that in the lower fitness group cancer was associated with a higher risk of death, whereas among the high fitness group the risk of death was lower (hazard ratio 20 vs. 15; Pfor interaction = 0.047). The effect modification persisted after applying a 4-year blanking period between fitness assessment and cancer diagnosis (Pfor interaction = 0.003). CONCLUSION: Higher midlife cardiorespiratory fitness is associated with better survival among cancer patients. Our findings support fitness assessment in preventive healthcare settings.

An impact of lipid profile and lipid lowering drugs on ≥70 year olds of an upper socioeconomic class: a retrospective cohort study.

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.

Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population.

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.

Cardiorespiratory Fitness Is an Independent Predictor of Cardiovascular Morbidity and Mortality and Improves Accuracy of Prediction Models.

BACKGROUND: Although cardiorespiratory fitness (CRF) is a strong independent predictor of adverse cardiovascular outcomes, it is not considered as a risk enhancer by current guidelines. METHODS: 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 equivalents < 8) 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. RESULTS: 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 (P < 0.001 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 value < 0.001) in the accuracy of classification when fitness was added to the ASCVD model. CONCLUSIONS: 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.

Physical fitness mediates the association between age and cognition in healthy adults.

BACKGROUND: Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline. AIMS: 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. METHODS: 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). RESULTS: 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: ß = 0.10, p = 0.008; Direct effect: ß = 0.16, p = 0.20). CONCLUSIONS AND DISCUSSION: 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.

High fitness might be associated with the development of new-onset atrial fibrillation in obese non-athletic adults.

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 < .01). Subgroup interaction analysis showed that AF risk is obesity-dependent, such that in the obese group (≥30 kg/m2 ) high fitness was independently associated with a significant 79% increased AF risk (95% CI 1.15-2.78; P = .01), whereas among non-obese subjects the rate of events was similar between both fitness groups (P for interaction = (.02)). CONCLUSIONS: Our findings suggest that high fitness might be associated with increased AF risk among obese subjects.

Alterations in the Gut Microbiome in the Progression of Cirrhosis to Hepatocellular Carcinoma.

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.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

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.

Correction: Population screening for BRCA1/BRCA2 founder mutations in Ashkenazi Jews: proactive recruitment compared with self-referral.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Relation of Neutrophil to Lymphocyte Ratio to Risk of Incident Atrial Fibrillation.

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, p < 0.001) 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.