Associations Between Dietary Patterns and Kidney Health Assessed in the Population-Based CHRIS Study Using Reduced Rank Regression.

OBJECTIVE: While diet plays a key role in chronic kidney disease (CKD) management, the potential for diet to impact CKD prevention in the general population is less clear. Using a priori knowledge, we derived disease-related dietary patterns (DPs) through reduced rank regression (RRR) and investigated associations with kidney function, separately focusing on generally healthy individuals and those with self-reported kidney diseases, hypertension, or diabetes mellitus. METHODS: Eight thousand six hundred eighty-six participants from the population-based Cooperative Health Research in South Tyrol study were split into a group free of kidney disease, hypertension and diabetes (n = 6,133) and a group with any of the 3 conditions (n = 2,553). Diet was assessed through the self-administered Global Allergy and Asthma Network of Excellence food frequency questionnaire and DPs were derived through RRR selecting food frequency questionnaire-derived sodium, potassium, phosphorus, and protein intake as mediators. Outcomes were creatinine-based estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, CKD and microalbuminuria. Multiple linear and logistic models were used to assess associations between RRR-based DPs and kidney outcomes separately in the 2 analytic groups. RESULTS: We identified 3 DPs, where high adherence reflected high levels of all nutrients (DP1), high potassium-phosphorus and low protein-sodium levels (DP2), and low potassium-sodium and high protein-phosphorus levels (DP3), respectively. We observed heterogeneous associations with kidney outcomes, varying by analytic group and sex. Kidney outcomes were much more strongly associated with DPs than with single nutrients. CONCLUSION: RRR is a feasible approach to estimate disease-related DPs and explore the combined effects of nutrients on kidney health. Heterogeneous associations across kidney outcomes suggest possible specificity to kidney function or damage. In individuals reporting kidney disease, hypertension or diabetes, specific dietary habits were associated with better kidney health, indicating that disease-specific dietary interventions can be effective for disease control.

Smoking and salivary microbiota: a cross-sectional analysis of an Italian alpine population.

The oral microbiota plays an important role in the exogenous nitrate reduction pathway and is associated with heart and periodontal disease and cigarette smoking. We describe smoking-related changes in oral microbiota composition and resulting potential metabolic pathway changes that may explain smoking-related changes in disease risk. We analyzed health information and salivary microbiota composition among 1601 Cooperative Health Research in South Tyrol participants collected 2017-2018. Salivary microbiota taxa were assigned from amplicon sequences of the 16S-V4 rRNA and used to describe microbiota composition and predict metabolic pathways. Aerobic taxa relative abundance decreased with daily smoking intensity and increased with years since cessation, as did inferred nitrate reduction. Former smokers tended to be more similar to Never smokers than to Current smokers, especially those who had quit for longer than 5 years. Cigarette smoking has a consistent, generalizable association on oral microbiota composition and predicted metabolic pathways, some of which associate in a dose-dependent fashion. Smokers who quit for longer than 5 years tend to have salivary microbiota profiles comparable to never smokers.

Trends and symptoms of SARS-CoV-2 infection: a longitudinal study on an Alpine population representative sample.

OBJECTIVES: The continuous monitoring of SARS-CoV-2 infection waves and the emergence of novel pathogens pose a challenge for effective public health surveillance strategies based on diagnostics. Longitudinal population representative studies on incident events and symptoms of SARS-CoV-2 infection are scarce. We aimed at describing the evolution of the COVID-19 pandemic during 2020 and 2021 through regular monitoring of self-reported symptoms in an Alpine community sample. DESIGN: To this purpose, we designed a longitudinal population representative study, the Cooperative Health Research in South Tyrol COVID-19 study. PARTICIPANTS AND OUTCOME MEASURES: A sample of 845 participants was retrospectively investigated for active and past infections with swab and blood tests, by August 2020, allowing adjusted cumulative incidence estimation. Of them, 700 participants without previous infection or vaccination were followed up monthly until July 2021 for first-time infection and symptom self-reporting: COVID-19 anamnesis, social contacts, lifestyle and sociodemographic data were assessed remotely through digital questionnaires. Temporal symptom trajectories and infection rates were modelled through longitudinal clustering and dynamic correlation analysis. Negative binomial regression and random forest analysis assessed the relative importance of symptoms. RESULTS: At baseline, the cumulative incidence of SARS-CoV-2 infection was 1.10% (95% CI 0.51%, 2.10%). Symptom trajectories mimicked both self-reported and confirmed cases of incident infections. Cluster analysis identified two groups of high-frequency and low-frequency symptoms. Symptoms like fever and loss of smell fell in the low-frequency cluster. Symptoms most discriminative of test positivity (loss of smell, fatigue and joint-muscle aches) confirmed prior evidence. CONCLUSIONS: Regular symptom tracking from population representative samples is an effective screening tool auxiliary to laboratory diagnostics for novel pathogens at critical times, as manifested in this study of COVID-19 patterns. Integrated surveillance systems might benefit from more direct involvement of citizens' active symptom tracking.

Cluster analysis of angiotensin biomarkers to identify antihypertensive drug treatment in population studies.

BACKGROUND: The recent progress in molecular biology generates an increasing interest in investigating molecular biomarkers as markers of response to treatments. The present work is motivated by a study, where the objective was to explore the potential of the molecular biomarkers of renin-angiotensin-aldosterone system (RAAS) to identify the undertaken antihypertensive treatments in the general population. Population-based studies offer an opportunity to assess the effectiveness of treatments in real-world scenarios. However, lack of quality documentation, especially when electronic health record linkage is unavailable, leads to inaccurate reporting and classification bias. METHOD: We present a machine learning clustering technique to determine the potential of measured RAAS biomarkers for the identification of undertaken treatments in the general population. The biomarkers were simultaneously determined through a novel mass-spectrometry analysis in 800 participants of the Cooperative Health Research In South Tyrol (CHRIS) study with documented antihypertensive treatments. We assessed the agreement, sensitivity and specificity of the resulting clusters against known treatment types. Through the lasso penalized regression, we identified clinical characteristics associated with the biomarkers, accounting for the effects of cluster and treatment classifications. RESULTS: We identified three well-separated clusters: cluster 1 (n = 444) preferentially including individuals not receiving RAAS-targeting drugs; cluster 2 (n = 235) identifying angiotensin type 1 receptor blockers (ARB) users (weighted kappa κw = 74%; sensitivity = 73%; specificity = 83%); and cluster 3 (n = 121) well discriminating angiotensin-converting enzyme inhibitors (ACEi) users (κw = 81%; sensitivity = 55%; specificity = 90%). Individuals in clusters 2 and 3 had higher frequency of diabetes as well as higher fasting glucose and BMI levels. Age, sex and kidney function were strong predictors of the RAAS biomarkers independently of the cluster structure. CONCLUSIONS: Unsupervised clustering of angiotensin-based biomarkers is a viable technique to identify individuals on specific antihypertensive treatments, pointing to a potential application of the biomarkers as useful clinical diagnostic tools even outside of a controlled clinical setting.

Structural equation modeling (SEM) of kidney function markers and longitudinal CVD risk assessment.

Lower kidney function is known to enhance cardiovascular disease (CVD) risk. It is unclear which estimated glomerular filtration rate (eGFR) equation best predict an increased CVD risk and if prediction can be improved by integration of multiple kidney function markers. We performed structural equation modeling (SEM) of kidney markers and compared the performance of the resulting pooled indexes with established eGFR equations to predict CVD risk in a 10-year longitudinal population-based design. We split the study sample into a set of participants with only baseline data (n = 647; model-building set) and a set with longitudinal data (n = 670; longitudinal set). In the model-building set, we fitted five SEM models based on serum creatinine or creatinine-based eGFR (eGFRcre), cystatin C or cystatin-based eGFR (eGFRcys), uric acid (UA), and blood urea nitrogen (BUN). In the longitudinal set, 10-year incident CVD risk was defined as a Framingham risk score (FRS)>5% and a pooled cohort equation (PCE)>5%. Predictive performances of the different kidney function indexes were compared using the C-statistic and the DeLong test. In the longitudinal set, a SEM-based estimate of latent kidney function based on eGFRcre, eGFRcys, UA, and BUN showed better prediction performance for both FRS>5% (C-statistic: 0.70; 95% CI: 0.65-0.74) and PCE>5% (C-statistic: 0.75; 95%CI: 0.71-0.79) than other SEM models and different eGFR formulas (DeLong test p-values<3.21×10-6 for FRS>5% and <1.49×10-9 for PCE>5%, respectively). However, the new derived marker could not outperform eGFRcys (DeLong test p-values = 0.88 for FRS>5% and 0.20 for PCE>5%, respectively). SEM is a promising approach to identify latent kidney function signatures. However, for incident CVD risk prediction, eGFRcys could still be preferrable given its simpler derivation.

Determinants of SARS-CoV-2 nasopharyngeal testing in a rural community sample susceptible of first infection: the CHRIS COVID-19 study.

To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four-week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandemic intensity and public health interventions, COVID-19-related symptoms (odds ratio, OR:8.26; 95% confidence interval, CI:6.04-11.31), contacts with infected individuals within home (OR:7.47, 95%CI:3.81-14.62) or outside home (OR:9.87, 95%CI:5.78-16.85), and being retired (OR:0.50, 95%CI:0.34-0.73). Symptoms and next within- and outside-home contacts were the leading determinants of swab testing predisposition in the most acute phase of the pandemics. Testing was not associated with age, sex, education, comorbidities, or lifestyle factors. In the study area, contextual determinants reflecting the course of the pandemic were predominant compared to individual sociodemographic characteristics in explaining the SARS-CoV-2 probability of testing. Decision makers should evaluate whether the intended target groups were correctly prioritized by the testing campaign.

Comparison of glomerular filtration rate estimating formulas among Japanese adults without kidney disease.

BACKGROUND: Previous studies have proposed different formulas of estimating glomerular filtration rate (eGFR) among clinical patients. The comprehensive comparison of eGFR formulas is not well established in a Japanese population. We compared eGFR values and chronic kidney disease (CKD) classification of nine different eGFR in a Japanese general population sample. METHODS: We analyzed 469 Japanese community-dwelling adults (184 men) without any self-reported kidney disease. GFR estimated using the 4- and 6-parameter Modification of Diet in Renal Disease (MDRD) formulas (MDRD4 and MDRD6); the CKD-EPI formulas based on creatinine with (CKD-EPI-2009) and without race coefficient (CKD-EPI-2021), on cystatin C (CKD-EPI-Cys), on both (CKD-EPI-CreCys); the Japanese creatinine-based formula (JPN-Cre), cystatin C-based formula (JPN-Cys), and modified CKD-EPI formula (JPN-CKD-EPI). CKD stages were defined by KDIGO guidelines (eGFR < 60 ml/min/1.73 m2). RESULTS: eGFRJPN-Cre (mean = 71.2; SD = 14.3) were much lower than eGFRCKD-EPI-2021 (mean = 94.2; SD = 12.7), while eGFRJPN-Cys (mean = 102.8; SD = 24.2) was comparable to the MDRD and CKD-EPI formulas. The difference between eGFRCKD-EPI-2021 and eGFRJPN-Cre showed a V-shaped distribution across eGFR levels, indicating complex errors between these formulas. We observed very low agreement in CKD classification between eGFRJPN-Cre and the eGFRCKD-EPI-2021 (kappa = 0.13; 95% confidence interval: 0.06, 0.23). CONCLUSIONS: JPN-Cre was substantially different from the CKD-EPI formula without race term (CKD-EPI-2021), which means that it is impossible to recalibrate those with a simple coefficient. Although a comparison with measured GFR should be necessary, choice of the estimation method needs caution in clinical decision-making and academic research.

Ten years of dynamic consent in the CHRIS study: informed consent as a dynamic process.

The Cooperative Health Research in South Tyrol (CHRIS) is a longitudinal study in Northern Italy, using dynamic consent since its inception in 2011. The CHRIS study collects health data and biosamples for research, and foresees regular follow-ups over time. We describe the experience with the CHRIS study dynamic consent, providing an overview of its conceptualization and implementation, and of the participant-centered strategies used to assess and improve the process, directly linked to participation and communication. In order to comply with high ethical standards and to allow broadness in the areas of research, CHRIS dynamic consent was conceived as an interactive process: based on a strong governance and an ongoing tailored communication with participants, it aims to promote autonomy and to develop a trust-based engaged relationship with participants, also relevant for retention. Built within an online platform, the consent allows granular choices, which can be changed over time. In a process of co-production, participants views have been investigated and kept into account in policy development. Participants showed a high degree of participation, thus enabling the consolidation of the CHRIS resources. Even though a low change rate was reported in the baseline, participants valued the possibility of changing their informed consent choices. Communication (language-tailored, ongoing, multimedia) was important for participants, and for participation and retention. In our experience, dynamic consent was proven to be a flexible consent model, which allowed to meet ethical and legal standards for participation in research, and to accommodate participants' and researchers' needs.

Pain sensitivity is modulated by affective temperament: Results from the population-based CHRIS Affective Disorder (CHRIS-AD) study.

BACKGROUND: Nociceptive pain modulation is related to psychological and psychiatric conditions. Evidence from clinical studies backs innate temperaments as potential precursors of mood symptoms and disorders, and pain sensitivity. Our study examines the modulation effect of affective temperaments on pain sensitivity in a general population adult sample, accounting for possible intervening mood symptoms, lifetime anxiety and depression, and pain treatments. METHODS: The sample is part of the CHRIS-AD study, Italy. Primary outcomes were the pain sensitivity questionnaire PSQ-total intensity score and the experimental pressure pain threshold (PPT). Affective temperaments were evaluated with the TEMPS-M. Lifetime depression, anxiety, current mood disorders, and treatments were self-reported via rating-scales. Directed acyclic graphs theory guided linear and mixed linear regression model analyses. RESULTS: Among 3804 participants (aged 18-65; response rate 78.4 %, females 53.3 %, mean age 38.4 years) for any given temperament, both the PSQ-total and the PPT were associated with temperament. The TEMPS-M four cyclothymic-related temperaments aligned on the pain-sensitive pole and the hyperthymic on the pain-resilient pole. The inclusion of current or lifetime mood symptoms, or pain drug use, as possible intervening pathways only partly diluted these associations, with stronger evidence for an effect of trait anxiety. LIMITATIONS: The main limitations were the lack of experimental measures of suprathreshold pain intensity perception, and detailed information on affective disorders in the study population. CONCLUSIONS: These findings support the hypothesis of a biological dichotomous diathesis of affective temperaments towards pain sensitivity; hyperthymic suggesting protection, whereas cyclothymic suggesting predisposition.

Prospective epidemiological, molecular, and genetic characterization of a novel coronavirus disease in the Val Venosta/Vinschgau: the CHRIS COVID-19 study protocol.

The COVID-19 pandemic has been threatening the healthcare and socioeconomic systems of entire nations. While population-based surveys to assess the distribution of SARS-CoV-2 infection have become a priority, pre-existing longitudinal studies are ideally suited to assess the determinants of COVID-19 onset and severity.The Cooperative Health Research In South Tyrol (CHRIS) study completed the baseline recruitment of 13,393 adults from the Venosta/Vinschgau rural district in 2018, collecting extensive phenotypic and biomarker data, metabolomic data, densely imputed genotype and whole-exome sequencing data.Based on CHRIS, we designed a prospective study, called CHRIS COVID-19, aimed at: 1) estimating the incidence of SARS-CoV-2 infections; 2) screening for and investigating the determinants of incident infection among CHRIS participants and their household members; 3) monitoring the immune response of infected participants prospectively.An online screening questionnaire was sent to all CHRIS participants and their household members. A random sample of 1450 participants representative of the district population was invited to assess active (nasopharyngeal swab) or past (serum antibody test) infections. We prospectively invited for complete SARS-CoV-2 testing all questionnaire completers gauged as possible cases of past infection and their household members. In positive tested individuals, antibody response is monitored quarterly for one year. Untested and negative participants receive the screening questionnaire every four weeks until gauged as possible incident cases or till the study end.Originated from a collaboration between researchers and community stakeholders, the CHRIS COVID-19 study aims at generating knowledge about the epidemiological, molecular, and genetic characterization of COVID-19 and its long-term sequelae.

Exome-wide association study of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.

Prevalence and determinants of serum antibodies to SARS-CoV-2 in the general population of the Gardena valley.

Estimating the spread of SARS-CoV-2 infection in communities is critical. We surveyed 2244 stratified random sample community members of the Gardena valley, a winter touristic area, amidst the first expansion phase of the COVID-19 pandemic in Europe. We measured agreement between Diasorin and Abbott serum bioassay outputs and the Abbott optimal discriminant threshold of serum neutralisation titres with recursive receiver operating characteristic curve. We analytically adjusted serum antibody tests for unbiased seroprevalence estimate and analysed the determinants of infection with non-response weighted multiple logistic regression. SARS-CoV-2 seroprevalence was 26.9% (95% CI 25.2-28.6) by June 2020. The bioassays had a modest agreement with each other. At a lower threshold than the manufacturer's recommended level, the Abbott assay reflected greater discrimination of serum neutralisation capacity. Seropositivity was associated with place and economic activity, not with sex or age. Symptoms like fever and weakness were age-dependent. SARS-CoV-2 mitigation strategies should account for context in high prevalence areas.

Central Venous Pressure Estimation by Ultrasound Measurement of Inferior Vena Cava and Aorta Diameters in Pediatric Critical Patients: An Observational Study.

OBJECTIVES: To evaluate the ability to predict central venous pressure by ultrasound measured inferior vena cava and aortic diameters in a PICU population and to assess interoperator concordance. DESIGN: Noninterventional observational study. SETTING: PICU of a tertiary-care academic center. PATIENTS: Eighty-eight pediatric patients (0-16 yr old) with a central venous catheter in place were studied. Sixty-nine percent of the patients received positive-pressure ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An experienced and a nonexperienced operator used ultrasound to measure the maximal diameter of inferior vena cava and minimal diameter of the inferior vena cava and the maximum diameter of the abdominal aorta from the subxiphoid window. The inferior vena cava collapsibility index and the ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta were then derived. The central venous pressure was measured using a central venous catheter and recorded. Twenty-three patients had low central venous pressure values (≤ 4 mm Hg), 35 patients a value in the range of 5-9 mm Hg, and 30 patients high values (≥ 10 mm Hg). Both inferior vena cava collapsibility index and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta were predictive of high (≥ 10 mm Hg) or low (≤ 4 mm Hg) central venous pressure. The test accuracy showed the best results in predicting low central venous pressure with an inferior vena cava collapsibility index greater than or equal to 35% and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta less than or equal to 0.8, and in predicting high central venous pressure with an inferior vena cava collapsibility index less than or equal to 20% and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta greater than or equal to 1.3. Inferior vena cava collapsibility index returned generally higher accuracy values than ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta. Lin's coefficient of concordance between the operators was 0.78 for inferior vena cava collapsibility index and 0.86 for ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta. CONCLUSIONS: Inferior vena cava collapsibility index and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta correlate well with central venous pressure measurements in this PICU population, and specific inferior vena cava collapsibility index or ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta thresholds appear to be able to differentiate children with high or low central venous pressure. However, the actual clinical application of these statistically significant results remains limited, especially by the intrinsic flaws of the procedure.

Radiological assessment of Peritoneal Cancer Index on preoperative CT in ovarian cancer is related to surgical outcome and survival.

PURPOSE: To evaluate whether Peritoneal Cancer Index (PCI) assessed on preoperative CT (CT-PCI) can be used as non-invasive preoperative tool to predict surgical outcome, disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: This is a retrospective, observational cohort study performed in a single institution. We considered all patients with diagnosis of ovarian cancer and preoperative CT, who had undergone upfront cytoreductive surgery between 2008 and 2010 and had post-operative clinical follow-up to December 2015. Two radiologists reviewed CT scans and assessed CT-PCI using Sugarbaker's diagram. We assessed the discriminatory capacity of the CT-PCI score on the surgical outcome by ROC curve analysis. DFS and OS were assessed by Kaplan-Meier nonparametric curves and by multivariable Cox-regression analysis. RESULTS: A total of 297 patients were included in the present analysis. CT-PCI was positively correlated with post-operative residual disease [odds ratio (OR) 1.04, 95% CI 1.01-1.07, p = 0.003]. ROC curve analysis returned AUC = 0.64 for the prediction of total macroscopic tumour clearance. In multivariable analysis, patients with no peritoneal disease seen on CT had a significantly longer DFS [Hazard ratio (HR) 2.28, p = 0.007]. Radiological serosal small bowel involvement was an independent predictor for shorter OS (HR 3.01, p = 0.002). CONCLUSION: Radiological PCI assessed on preoperative CT is associated with the probability of residual disease after cytoreductive surgery; however, it has low performance as a triage test to reliably identify patients who are likely to have complete cytoreductive surgery. CT-PCI is positively correlated with both DFS and OS and may be used as an independent prognostic factor, for example in patients with high FIGO stages.

Microbiota, type 2 diabetes and non-alcoholic fatty liver disease: protocol of an observational study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation in the hepatocytes in the absence of alcohol overconsumption, commonly associated with insulin resistance and obesity. Both NAFLD and type 2 diabetes (T2D) are characterized by an altered microbiota composition, however the role of the microbiota in NAFLD and T2D is not well understood. To assess the relationship between alteration in the microbiota and NAFLD while dissecting the role of T2D, we established a nested study on T2D and non-T2D individuals within the Cooperative Health Research In South Tyrol (CHRIS) study, called the CHRIS-NAFLD study. Here, we present the study protocol along with baseline and follow-up characteristics of study participants. METHODS: Among the first 4979 CHRIS study participants, 227 individuals with T2D were identified and recalled, along with 227 age- and sex-matched non-T2D individuals. Participants underwent ultrasound and transient elastography examination to evaluate the presence of hepatic steatosis and liver stiffness. Additionally, sampling of saliva and faeces, biochemical measurements and clinical interviews were carried out. RESULTS: We recruited 173 T2D and 183 non-T2D participants (78% overall response rate). Hepatic steatosis was more common in T2D (63.7%) than non-T2D (36.3%) participants. T2D participants also had higher levels of liver stiffness (median 4.8 kPa, interquartile range (IQR) 3.7, 5.9) than non-T2D participants (median 3.9 kPa, IQR 3.3, 5.1). The non-invasive scoring systems like the NAFLD fibrosis score (NFS) suggests an increased liver fibrosis in T2D (mean - 0.55, standard deviation, SD, 1.30) than non-T2D participants (mean - 1.30, SD, 1.17). DISCUSSION: Given the comprehensive biochemical and clinical characterization of study participants, once the bioinformatics classification of the microbiota will be completed, the CHRIS-NAFLD study will become a useful resource to further our understanding of the relationship between microbiota, T2D and NAFLD.

Lipidomics, Atrial Conduction, and Body Mass Index.

BACKGROUND: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. METHODS: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). RESULTS: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3-3.9; P=1.1×10-4) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P=8.3×10-5) and %PC 38:3 ( P=0.014). CONCLUSIONS: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI's involvement into atrial electrical activity.

Effects of smoking status, history and intensity on heart rate variability in the general population: The CHRIS study.

BACKGROUND: Heart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results. METHODS: We assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials. RESULTS: Past smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity. CONCLUSIONS: Smoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect.

Structural Consistency of the Pain Sensitivity Questionnaire in the Cooperative Health Research In South Tyrol (CHRIS) Population-Based Study.

The self-reported Pain Sensitivity Questionnaire (PSQ) is a valid supplement to experimental pain testing. However, the latent constructs determining the originally proposed 1 general score (PSQ-total) and 2 subscores (PSQ-moderate and PSQ-minor) have not been consistently investigated in population-based studies or between genders. Based on a single construct hypothesized by expert knowledge or alternative constructs upon empirical evidence, PSQ structures were explored and confirmed among 4,820 participants aged 18 to 93 years of the Cooperative Health Research In South Tyrol (CHRIS) study. By exploratory factor analysis, we identified 3 alternative sets of PSQ imagined painful situations comprising 14, 10, and 9 items, which displayed simple structures of the rotated factor loadings of direct interpretation. In confirmatory analysis (CFA) of 1 latent factor, the 10-item set yielded acceptable goodness-of-fit overall, better fit than the alternative sets and consistent structural properties between genders. Separate analyses based on 14- and 9-item sets returned considerable correlations between 2 latent constructs. In higher-order CFA with each set, 1 first-order general factor explained a large part of the variances of 2 second-order factors. One dominant construct consistently describes the factorial structure of the PSQ. Averaging across the 10-item set, the PSQ-short score represents a structurally robust, gender-consistent, and practical measure of general pain sensitivity. PERSPECTIVE: One dominant latent construct of general pain sensitivity consistently determines responses to the self-reported PSQ. The PSQ-short score maintains similar psychometric properties to the PSQ-total and between genders. This measure is attractive for large-scale research and clinical screening of pain sensitivity.

Validity and reliability of serologic immunophenotyping of multiple blood group systems by ORTHO Sera with fully automated procedure.

CONCLUSIONS: The increase of immunization against blood group antigens has reinforced the need for automated extensive blood typing. The aim of this study was to assess both the validity and reliability of red blood cell (RBC) automated agglutination technology in testing for antigens of Kidd (Jk), Duffy (Fy), and MNS (Ss) blood systems. ORTHO Sera (Ortho Clinical Diagnostics, Raritan, NJ) anti-Jka, anti-Jkb, Anti-Fya, anti-Fyb, anti-S, and anti-s reagents were each tested on RBC samples previously typed. Replicates were performed on three separate testing sessions with three consecutive repetitions within each session, thus obtaining 486 test results. Accuracy was assessed by aggregate analysis of sensitivity, specificity, and area under the receiver operating characteristics curve (AUC). Reliability was estimated by a cross-classified mixed-effect logistic model. All reagents tested yielded optimal accuracy (100% for sensitivity and specificity, and 1.00 for AUC), except for anti-S, for which performance was slightly lower (98%, 100%, and 0.99, respectively), owing to misclassification of one sample in a single replicate. Anomalous automated measurements were recorded in 38 of 486 tests (7.8%), which then needed additional manual interpretation. Different sessions and samples were the major contributors to measurement failures (38% and 18%, separately). Order of repetitions and antigen specificity across replicates did not contribute to the risk of failures, although weak evidence of enhanced risk was observed with Jk testing. Automated RBC typing with ORTHO Sera reagents against antigens in the Kidd, Duffy, and MNS blood group systems displayed nearly 100 percent accuracy. However, a sizable number of replicates needed additional ad hoc interpretation, thus suggesting that the reliability could still be improved. Automated agglutination technology represents a viable option for phenotyping large volumes of samples.

90-Day Mortality after Radical Cystectomy for Bladder Cancer: Prognostic Factors in a Multicenter Case Series.

OBJECTIVES: To identify preoperative risk factors for 90-day mortality and to validate existing nomograms in a multicenter series of patients undergoing radical cystectomy (RC). MATERIALS AND METHODS: We evaluated 90-day mortality in 475 patients following RC and urinary diversion at 2 Italian institutions and validated Aziz and Isbarn nomogram. Univariable logistic models assessed the predictive ability of operative volume, age at intervention, gender, body mass index, carcinoma in situ at transurethral resection of the bladder, American Society of Anesthesiologist (ASA) score, Charlson Comorbidity Index, clinical stage and pathological stage (TNM). RESULTS: Of the total number of patients, 387 of them (81%) were male. The median age at RC was 71.8. The most frequent ASA score was 2 (53%). Twenty-five deaths occurred within 90 days (5.3%), all among patients who had undergone RC and incontinent urinary diversion. Risk was higher in patients with advanced disease (OR 2.4); moreover, 90-day mortality odd in 70-79-year-old patients was 13 times higher than those of younger patients (<70). Predictive accuracy using Isbarn's and Aziz's nomogram were 67 and 71%, respectively. CONCLUSIONS: Our multicenter study confirmed the moderate predictive value of the Aziz nomogram. Larger studies are needed to improve on existing nomograms with the aim of enhancing preoperative counseling.