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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.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 meGFRJPN-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.

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.

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.

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.

BackgroundCommunity-based studies are essential to quantify the spread of SARS-CoV-2 infection and for unbiased characterization of its determinants and outcomes. We conducted a cross-sectional study in the Gardena valley, a major Alpine touristic destination which was struck in the expansion phase of the COVID-19 pandemic over the winter 2020.MethodsWe surveyed 2244 representative study participants who underwent swab and serum antibody tests. We made multiple comparisons among the Abbott and Diasorin bioassays and serum neutralization titers. Seroprevalence accounted for the stratified design, non-response and test accuracy. Determinants and symptoms predictive of infection were analyzed by weighted multiple logistic regression.ResultsSARS-CoV-2 seroprevalence was 26.9% (95% confidence interval: 25.2%, 28.6%) by June 2020. The serum antibody bioassays had modest agreement with each other. Receiver operating characteristic curve analysis on the serum neutralizing capacity showed better performance of the Abbott test at lower than the canonical threshold. Socio-demographic characteristics showed no clear evidence of association with seropositivity, which was instead associated with place of residence and economic activity. Loss of taste or smell, fever, difficulty in breathing, pain in the limbs, and weakness were the most predictive symptoms of positive antibody test results. Fever and weakness associations were age-dependent.ConclusionThe Gardena valley had one of the highest SARS-CoV-2 infection prevalence in Europe. The age-dependent risk associated with COVID-19 related symptoms implies targeted strategies for screening and prophylaxis planning.

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.

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.

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.

Mobilization of haematopoietic stem cells for autologous transplantation in lymphoma patients currently lacks optimal and universally accepted protocol guidelines. Available mobilization procedures use either cytokines alone, predominantly granulocyte colony-stimulating factor, or cytokines in combination with chemotherapy. Chemomobilization may increase the CD34+ cell yield, and some studies indicate that a higher number of CD34+ cells reinfused is associated with better outcome after autologous haematopoietic stem cells transplantation. We aimed to compare the peak of CD34+ cells in peripheral blood between two alternative mobilization therapies in a retrospective cohort of patients affected by lymphoma. Between 2001–2012, 125 retrospectively observed lymphoma patients were treated with either cytarabine ( $n = 36$ ) or cyclophosphamide ( $n = 89$ ), both combined with granulocyte colony-stimulating factor. The difference in the peak of circulating CD34+ cells was the study primary endpoint. The peak of circulating CD34+ cells were significantly higher in the cytarabine group compared with the cyclophosphamide group (median 129/μL vs 77/μL; $p < 0.05$ ), even when accounting for the timing at collection (169% higher in the cytarabine group, $p < 0.01$ ). Haematopoietic stem cells median time collection started 3 days later in the cytarabine group (16 vs 13 days; $p < 0.01$ ). A leukaphaeresis single session was adequate to collect an optimal number of CD34+ cells (greater than $5 \times 10^{6}/\text{kg}$ ) in 69% patients in the cytarabine group compared with 57% in the cyclophosphamide group ( $p = 0.21$ ). Cytarabine gives a higher peak of circulating CD34+ cells in comparison with cyclophosphamide in a retrospective observational cohort of lymphoma patients submitted to chemomobilization.

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). 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. 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). 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.

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 (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.

Background and purpose A higher prevalence of restless legs syndrome (RLS) in migraineurs has been reported in clinical samples and in two large-scale clinical trials performed on healthcare workers but general population-based studies on this topic are lacking. The aim of this study was to assess the association between migraine and RLS in an Italian rural adult population-based setting. Methods The presence of migraine and RLS was assessed via a computer-assisted personal interview and self-administered questionnaires according to current diagnostic criteria in 1567 participants of a preliminary phase of an adult population-based study performed in South Tyrol, Italy. Results Migraineurs had an increased risk of having RLS also after adjustment for confounding factors such as age, sex, major depression, anxiety and sleep quality (odds ratio 1.79; confidence interval 1.00–3.19; P = 0.049). This association was not modified by aura status and possible causes of secondary RLS. RLS was not significantly associated with tension-type headache. Conclusions Restless legs syndrome and migraine were associated in our rural adult population. This association could be explained by a possible shared pathogenic pathway which would implicate new management strategies of these two disorders.

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.

BackgroundHeart 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.MethodsWe 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.ResultsPast 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.ConclusionsSmoking 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.

Objective To test the prognostic value of multicolor fluorescence in situ hybridization analyses of tumor cells in urine for prediction of the recurrence and progression of tumor in patients with intermediate risk non-muscle invasive bladder cancer. Methods A total of 168 patients with non-muscle invasive bladder cancer were included in the study. Fluorescence in situ hybridization was carried out on the bladder wash urine collected before resection. Tumors were classified as low molecular grading if they had a diploid chromosomal pattern or only a loss of p16 or ch3 aneuploidy, and as high molecular grading if they showed aneuploidy of ch7 or 17. Cox regression models assessed the added prognostic value of fluorescence in situ hybridization for primary tumor recurrence or progression, respectively. Results Median follow up was 67 months. A total of 57% of tumors were classified as low molecular grading. The 2- and 5-year recurrence-free survival was 68% and 49% for low molecular grading, and 47% and 30% for high molecular grading, respectively. The 2- and 5-year progression-free survival was 95% and 84% for low molecular grading, and 79% and 58% for high molecular grading tumor patients, respectively. Molecular grading (hazard ratio 1.60; P = 0.03) was associated with recurrence, when also accounting for histopathology and a patient's characteristics. Both cancer severity score (hazard ratio 1.51; P

The aim of the study was to investigate the influence of alcohol exposure during pregnancy on a mother's responsiveness towards her infant after birth. Using longitudinal data from a subsample of 687 mother-infant dyads from a UK cohort study (Avon Longitudinal Study of Parents and Children), we investigated the influence of alcohol use during mid- and late pregnancy on observed mother-infant interactions after birth. We found that women who drank one or more glasses of alcohol a week during their mid-trimester of pregnancy were 19 % (95 % CI, 1 to 40 %; p = 0.033) more likely to show non-responsive behaviour towards their infant 12 months after birth. In contrast, we found that alcohol use during late pregnancy was not associated with later maternal responsiveness. This study adds to the growing evidence for the importance of factors during pregnancy on later maternal responsiveness. Further research is needed to replicate these findings and to examine potential mechanisms linking maternal responsiveness to alcohol use during pregnancy.

Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.

Background: Maternal depression is known to be associated with impairments in child cognitive development, although the effect of timing of exposure tomaternal depression isunclear. Methods: Data collected for the Avon Longitudinal Study of Parents and Children, a longitudinal study beginning in pregnancy, included self-report measures of maternal depression the Edinburgh Postnatal Depression Scale, completed on 6 occasions up to 3 years of age, and IQ of the index child (WISC) measured at aged 8 years. We used these data to assign women to 8 groups according to whether depression occurred in the antenatal, postnatal, preschool period, any combination of these times, or not at all. We compared a model comprising all patterns of depression (saturated model) with models nested within this to test whether there is a relationship between depression and child cognitive development and, if so, whether there is a sensitive period. We then investigated the relationship with child IQ for each model, following adjustment for confounders. Results: Six thousand seven hundred and thirty-five of 13,615 children from singleton births (49.5%, of eligible core sample) attended a research clinic at 8 years and completed a WISC with a score ‡ 70. A total of 5,029 mothers of these children had completed mood assessments over the 3 time periods. In unadjusted analyses, all three sensitive period models were as good as the saturated model, as was an accumulation model. Of the sensitive period models, only that for antenatal exposure was a consistently better fit than the accumulation model. After multiple imputation for missing data (to n = 6,735), there was no effect of postnatal depression on child IQ independent of depression at other times [)0.19 IQ points, 95% confidence interval (CI) )1.5 to 1.1 points]. There was an effect of antenatal depression ()3.19 IQ points, 95% CI: )4.33 to )2.06) which attenuated following adjustment ()0.64 IQ points, 95% CI: )1.68 to 0.40). Conclusions: The postnatal period is not a sensitive one for the effect of maternal depression on child cognitive development. Keywords: Perinatal, maternal depression, child development, depression, intelligence.

OBJECTIVE: To examine the association between use of alcohol and cigarettes among adolescents and their early socioeconomic background. METHODS: Members of a longitudinal birth cohort (Avon Longitudinal Study of Parents and Children [ALSPAC], United Kingdom) were invited to attend a personal interview. A total of 5837 children aged 13 years were asked about previous consumption of alcohol and tobacco. Information on parental socioeconomic position, collected from questionnaires from the mother, included both social class and education of the expectant mother and her partner and average household disposable income in early preschool childhood. The impact of missing data was assessed by multiple imputation. RESULTS: Consuming a drink of alcohol in the previous 6 months was linearly associated with higher income levels even when adjusting for other socioeconomic indicators. In contrast, both the risk of binge drinking and recent drinking was lower for children whose mothers had a higher educational level. Smoking tobacco was associated with lower socioeconomic position irrespective of the indicator used. Analyses after imputation of missing data confirmed these associations. CONCLUSIONS: Alcohol drinking was more common in young people from higher-income households but less common with higher levels of maternal education. A consistent inverse socioeconomic gradient with tobacco smoking was apparent. These results may reflect how different aspects of socioeconomic position can influence health behavior in opposing directions. Higher income may increase the availability of alcohol in the family, whereas mothers with higher educational attainment might encourage more healthy behaviors in their children, including reduced alcohol use.

A study conducted to establish the most accurate combination of questionnaire and physical signs for the diagnosis of carpal tunnel syndrome. Nerve conduction studies confirmed 70 patients with having carpal tunnel syndrome who were enrolled along with 70 age- and sex-matched controls. Patients were assessed using a symptom questionnaire, Phalen’s test, Hoffmann–Tinel’s sign, hand elevation test, carpal compression test, tourniquet test, pressure aesthesiometry and two-point discrimination. Through multivariate analysis, the best combination of tests was tourniquet, carpal compression and Phalen’s tests but the difference between these and hand elevation test alone was negligible. The hand elevation test may be used in isolation and is superior to questionnaires and other physical signs in the clinical diagnosis of carpal tunnel syndrome.

Background Only one population-based study in one country has reported effects of smoking cessation and weight change on lung function, and none has reported the net effect. We estimated the net benefit of smoking cessation, and the independent effects of smoking and weight change on change in ventilatory lung function in the international European Community Respiratory Health Survey.Methods 6654 participants in 27 centres had lung function measured in 1991-93, when aged 20-44 years, and in 1998-2002. Smoking information was obtained from detailed questionnaires. Changes in lung function were analysed by change in smoking and weight, adjusted for age and height, in men and women separately and together with interaction terms.Findings Compared with those who had never smoked, decline in FEV1 was lower in male sustained quitters (mean difference 5.4 mL per year, 95% CI 1.7 to 9.1) and those who quit between surveys (2.5 mL, -1.9 to 7.0), and greater in smokers (-4.8 mL, -7.9 to -1.6). In women, estimates were 1.3 mL per year (-1.5 to 4.1), 2.8 mL (-0.8 to 6.3) and -5.1 mL (-7.5 to -2.8), respectively.. These sex differences were not significant. FEV1 changed by -11.5 mL (-13.3 to -9.6) per kg weight gained in men, and by -3.7 mL per kg (-5.0 to -2.5) in women, which diminished the benefit of quitting by 38% in men, and by 17% in women.Interpretation Smoking cessation is beneficial for lung function, but maximum benefit needs control of weight gain, especially in men.

Our group has analyzed the usefulness of cytology, immunocytology (ucyt+) and multitarget-fluorescence in situ hybidization (FISH) in the context of bladder cancer (BC) disease diagnosis and progression prediction. We still strongly believe in the usefulness of cytology in clinical practice, and in its value in progression and recurrence prognostication as reported in a recent publication. 1 Nevertheless, this is especially true in high-grade tumor patients in whom cytology shows the best sensitivity and specificity. When we exclude G3 and cis BC, cytology does not have the same sensitivity and specificity. For this reason, we addressed our interest on the multitargetFISH technique, which is more sensitive even in low- and intermediate-grade tumors. Treatment and follow up for BC is already particularly expensive. The addition of new or old tumor markers should therefore have a minimum impact on the cost of disease management, and should have a great impact on controlling the disease. In the case of multitarget-FISH, we decided not to use it in the detection setting, but in the prognostication setting, so that the cost of the test could be justified by the change of the treatment strategies. Multitarget-FISH was introduced and approved by the FDA in 2001, but after this, several large-scale whole genome array analyses were carried out. 2,3 A critical evaluation of the more recent data has changed the genomic regions involved in BC evolution. Additional genomic regions that are altered preferentially in aggressive tumors include gains of 5p and 6p (associated with the oncogene, E2F3), and the losses of 17p (associated with the tumor suppressor gene, TP53) and 13q (associated with the tumor suppressor gene RB1). The loss of 8p23 was reported to also correlate to prognosis, and is not included in the FISH Urovysion test. 4

Background and purpose Restless legs syndrome (RLS) is a sleep-related movement disorder characterized by an irresistible urge to move the legs accompanied by paresthesia and/or dysesthesia that begins or worsens in the evening and night and that is partially or totally relieved by movement. Many studies have investigated the association between RLS and cardiovascular risk factors, particularly hypertension, leading to conflicting results. The aim of this study was to assess the association between RLS and hypertension considering also other cardiovascular risk factors that could act as confounders. Methods In all, 1709 participants of an on-going adult population-based study performed in South Tyrol, northern Italy, were enrolled. RLS was assessed through face-to-face interviews according to current International Restless Legs Syndrome Study Group diagnostic criteria. The presence of hypertension was self-reported and determined by questionnaires administered by trained study nurses. Results The association between RLS and hypertension was not significant after adjustment for age, sex, diabetes mellitus, history of myocardial infarction, raised blood lipids and body mass index (odds ratio 1.24, 95% CI 0.85–1.80, P = 0.271). Conclusion Despite the small sample size of this study, RLS and hypertension were not associated in our adult population after adjustment for possible confounding factors. The presence of other cardiovascular risk factors could play a role as a confounder of this association.

To test the prognostic value of multicolor fluorescence in situ hybridization analyses of tumor cells in urine for prediction of the recurrence and progression of tumor in patients with intermediate risk non-muscle invasive bladder cancer.A total of 168 patients with non-muscle invasive bladder cancer were included in the study. Fluorescence in situ hybridization was carried out on the bladder wash urine collected before resection. Tumors were classified as low molecular grading if they had a diploid chromosomal pattern or only a loss of p16 or ch3 aneuploidy, and as high molecular grading if they showed aneuploidy of ch7 or 17. Cox regression models assessed the added prognostic value of fluorescence in situ hybridization for primary tumor recurrence or progression, respectively.Median follow up was 67 months. A total of 57% of tumors were classified as low molecular grading. The 2- and 5-year recurrence-free survival was 68% and 49% for low molecular grading, and 47% and 30% for high molecular grading, respectively. The 2- and 5-year progression-free survival was 95% and 84% for low molecular grading, and 79% and 58% for high molecular grading tumor patients, respectively. Molecular grading (hazard ratio 1.60; P = 0.03) was associated with recurrence, when also accounting for histopathology and a patient's characteristics. Both cancer severity score (hazard ratio 1.51; P 0.01) and molecular grading (hazard ratio 2.53; P 0.01) independently and positively predicted progression in multivariable models. The C-index for predicting recurrence increased from 0.58 to 0.61 when molecular grading fluorescence in situ hybridization was included in the model, and from 0.68 to 0.72 when predicting progression.Fluorescence in situ hybridization-based molecular grading increases the accuracy of a prognostic model, predicting both recurrence and progression in patients with intermediate risk non-muscle invasive bladder cancer.

In a prospective birth cohort study of 5295 girls from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), we examined the association between biological father absence in childhood and age at menarche whilst adjusting for antenatal indicators of socioeconomic disadvantage and maternal characteristics. We also examined whether exposure to maternal depression and financial problems during middle childhood mediate the association between father absence and age at menarche. There was stronger evidence for an association between father absence during the first 5 years of life and early timing of menarche compared with father absence between 5 and 10 years. There was evidence that maternal depression and major financial problems explained some of the association between early childhood father absence and age at menarche. Although father absence cannot be a direct target of prevention, family-based programs to address family processes influenced by maternal depression and socioeconomic disadvantage may be effective.

Background Cephalalgiaphobia is the fear of having a headache attack during a pain-free period that may induce patients to use analgesic in the absence of pain to prevent headache and to improve their performances. This study aims at assessing if cephalalgiaphobia is related to migraine frequency or medication overuse, and if it is per se a predictor of increase in migraine frequency. Methods This is a pilot prospective cohort study on 126 consecutive migraineurs referred to a tertiary Headache Centre. A headache specialist collected data regarding migraine features, frequency and medications at baseline (T0) and 2 years later (T1). Cephalalgiaphobia was investigated at T0 and T1 through a score determined by a 4 items questionnaire. Results Moderate-high migraine frequency was associated with higher risk of cephalalgiaphobia (p Conclusions Cephalalgiaphobia may represent a high-frequency migraine feature and may play a role in chronicization. Therefore, it should be better investigated by clinicians and treated or prevented in order to reduce the risk of disability and the increase in migraine frequency.

Fly and bottom ashes are the main by-products arising from the combustion of solid biomass. Since the production of energy from this source is increasing, the processing and disposal of the resulting ashes has become an environmental and economic issue. Such ashes are of interest as a construction material because they are composed of very fine particles similar to fillers normally employed in bituminous and cementitious mixtures. This research investigates the potential use of ash from biomass as filler in bituminous mixtures. The morphological, physical and chemical characteristics of 21 different ashes and two traditional fillers (calcium carbonate and “recovered” plant filler) were evaluated and discussed. Leaching tests, performed in order to quantify the release of pollutants, revealed that five ashes do not comply with the Italian environmental re-use limits. Experimental results show a wide range of values for almost all the investigated properties and a low correlation with biomass type in terms of origin and chemical composition. Furthermore, sieving and milling processes were found to improve the properties of the raw material in terms of grading and sample porosity. The effectiveness of these treatments and the low content of organic matter and harmful fines suggest that most of the biomass ashes investigated may be regarded as potential replacements for natural filler in bituminous mixtures.

Both prenatal and postnatal maternal depression are independently associated with an increased risk of adverse infant development. The impact of postnatal depression on infants may be mediated through the effect of depression in reducing maternal responsiveness. However, the mechanisms underlying the effect of prenatal depression are unclear. Using longitudinal data from over 900 mother–infant pairs in a UK birth cohort (ALSPAC), we found that women with high depressive symptom scores during mid pregnancy, but NOT when their infants were 8 months, had a 30% increased risk of low maternal responsiveness when the infant was 12 months compared to women with consistently low depression. This may provide a mechanism to explain the independent association between prenatal depression and poorer infant development.

Adolescent risk behaviours such as smoking, alcohol use and antisocial behaviour are associated with increased risk of morbidity and mortality. Patterns of risk behaviour may vary between genders during adolescence.Analysis of data from a longitudinal birth cohort to assess the prevalence and distribution of multiple risk behaviours by gender at age 15-16 years with a focus on alcohol use at age 10, 13 and 15 years.By age 15 years, over half of boys and girls had consumed alcohol and one-fifth had engaged in binge drinking with no clear difference by gender. At age 15-16 years, the most prevalent risk behaviours were physical inactivity (74%), antisocial and criminal behaviour (42%) and hazardous drinking (34%). Boys and girls engaged in a similar number of behaviours but antisocial and criminal behaviours, cannabis use and vehicle-related risk behaviours were more prevalent among boys, whilst tobacco smoking, self-harm and physical inactivity were more prevalent among girls.Multiple risk behaviour is prevalent in both genders during adolescence but the pattern of individual risk behaviour varies between boys and girls. Effective interventions at the individual, family, school, community or population level are needed to address gender-specific patterns of risk behaviour during adolescence.

Maternal depression is known to be associated with impairments in child cognitive development, although the effect of timing of exposure to maternal depression is unclear. Data collected for the Avon Longitudinal Study of Parents and Children, a longitudinal study beginning in pregnancy, included self-report measures of maternal depression the Edinburgh Postnatal Depression Scale, completed on 6 occasions up to 3 years of age, and IQ of the index child (WISC) measured at aged 8 years. We used these data to assign women to 8 groups according to whether depression occurred in the antenatal, postnatal, preschool period, any combination of these times, or not at all. We compared a model comprising all patterns of depression (saturated model) with models nested within this to test whether there is a relationship between depression and child cognitive development and, if so, whether there is a sensitive period. We then investigated the relationship with child IQ for each model, following adjustment for confounders. Six thousand seven hundred and thirty-five of 13,615 children from singleton births (49.5%, of eligible core sample) attended a research clinic at 8 years and completed a WISC with a score ≥ 70. A total of 5,029 mothers of these children had completed mood assessments over the 3 time periods. In unadjusted analyses, all three sensitive period models were as good as the saturated model, as was an accumulation model. Of the sensitive period models, only that for antenatal exposure was a consistently better fit than the accumulation model. After multiple imputation for missing data (to n = 6,735), there was no effect of postnatal depression on child IQ independent of depression at other times [-0.19 IQ points, 95% confidence interval (CI) -1.5 to 1.1 points]. There was an effect of antenatal depression (-3.19 IQ points, 95% CI: -4.33 to -2.06) which attenuated following adjustment (-0.64 IQ points, 95% CI: -1.68 to 0.40). The postnatal period is not a sensitive one for the effect of maternal depression on child cognitive development.

Background An infant's early environment has an important influence on their development. For example, the sensitivity and warmth of a mother's responses towards her infant is associated with the infant's later socio-emotional development. However, it is less clear whether maternal responses are associated with the infant's later cognitive development. Method We used data from a large UK cohort study to investigate the association between non-verbal maternal responses and later infant development and IQ. Maternal responses were rated at 12 months during an observed mother–infant interaction. Infant development was assessed using the Griffiths scales at 18 months and IQ at 4 years was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). Data on the infant's developmental level at 6 months (prior to the maternal response ratings) was also available. The complete case sample comprised 732 mother–infant pairs. Results There was evidence for an association between positive maternal responses and infant development at 18 months. After adjusting for infant developmental level at 6 months and other confounders, we found a difference of 0.25 standard deviations (coef 2.0, 95% CI (0.8–3.2), p = 0.002) on the Griffiths scales between infant's whose mothers showed positive compared to neutral non-verbal responses at 12 months. However, an association between positive maternal responses and IQ at 4 years diminished following adjustment for maternal educational attainment. Conclusion The results provide evidence that positive maternal responses are associated with improved development in infants at 18 months. However, the association between maternal response and IQ at 4 years may be explained by higher educational attainment in mothers who show positive responses. Future studies are needed to explore the influence of maternal responses on different aspects of infant development as well as the role of maternal factors such as education.

Ureteral stents result in significant morbidity in many patients. Manufacturers have altered stent design and composition to minimize symptoms. The Polaris™ stent is made of a Percuflex® combination, providing a firm proximal aspect with a softer distal aspect to minimize symptoms. In this prospective, randomized study we compared symptoms and quality of life after stent insertion to determine whether this stent is better tolerated than the InLay® stent.Between September 2002 and September 2006 we randomized 159 patients requiring stent insertion for stone disease to receive the InLay or the Polaris ureteral stent. Patients were asked to complete the validated Ureteral Stent Symptom Questionnaire 2 weeks after stent insertion and 1 week after removal.A total of 98 patients completed and returned each questionnaire, including 45 with the InLay and 53 with the Polaris. There were no significant differences between the groups on any health domain assessed. In the InLay and Polaris groups 91% and 94% of patients experienced pain with the stent in situ, which decreased to 40% and 43%, respectively, after stent removal. The urinary symptom score with the stent in situ was equal in the 2 groups (32, maximum 55). Of the InLay and Polaris groups 60% and 66% of patients, respectively, would be against receiving a further stent due to symptoms (p = 0.79).The Polaris stent, designed with the specific aim of improving urinary symptoms and pain associated with ureteral stents, continues to have a significant detrimental effect on patient quality of life.

Nucleation pH is the pH at which Ca and Mg come out of urine to form crystals. If the safety margin between voiding pH and nucleation pH could be increased, it would increase the possibility of an alternative to controlling the activity of urease producing bacteria as a strategy to control catheter encrustation.We performed a 6-week randomized crossover study in 24 patients with catheter blockage who were randomly allocated to a specific sequence of 3 consecutive available treatments, including increased fluid intake, lemon juice and potassium citrate. Each patient received all available regimens. At the end of each week 24-hour urine samples were analyzed for voiding and nucleation pH, citrate, Ca and Mg.Mean +/- SD nucleation pH increased from 7.45 +/- 0.60 at baseline to 7.93 +/- 0.50, 7.68 +/- 0.64 and 7.96 +/- 0.37 in the lemon juice, increased fluid intake and potassium citrate groups, respectively (p0.0001). Mean urinary citrate increased significantly (p0.0001), in particular due to lemon juice and potassium citrate effects. The association between treatment and Ca was weak (p = 0.12) while that of Mg was negative due to lemon (p0.001). Average increase in the safety margin (nucleation pH minus voiding pH) beyond baseline was 0.84 (95% CI 0.63-1.04), 0.57 (95% CI 0.37-0.78) and 0.41 (95% CI 0.20-0.61) for lemon juice, increased fluid intake and potassium citrate, respectively. A strong treatment effect on the safety margin was apparent even when controlling for study design (p0.001).Increased fluid intake with lemon juice may be a simple, inexpensive, effective strategy to control catheter encrustation.

Determination of the time since death in the early postmortem period is one of the most critical issues to be faced by criminal investigators. One of the techniques is the evaluation of the pupil pharmacological reactivity. In the present work, we aim at identifying whether an objective and single method, based on pharmacological pupil reaction, is feasible or not. Between 2002 and 2003 calendar years, we observed 309 bodies, whose eyes have been each instilled apart, within 26 hours since death, with either a myotic substance or a mydriatic solution. Our results show that the real effectiveness of pupil pharmacological reactivity as method for assessing the time since death in early postmortem period is not only questionable but even highly misleading if not replaced by alternative objective physiological tests and appropriate professional judgments by the investigators.

Summary Background In most developed countries the prevalence of smoking habits is decreasing in men, while in women the prevalence seems to decline in Northern Europe but to increase in the Mediterranean area. The present research aims at assessing time trends in smoking habits in Italy. Methods In the frame of the Italian Study on Asthma in Young Adults (ISAYA) a random sample of the Italian population aged 20–45 years was administered a mailed questionnaire in 9 Italian centers between 1998 and 2000. Cumulative response was 72.7% (18873/25969). Kaplan–Meier survival curves and log-rank test were used to compare probability of remaining a life-time non-smoker across birth cohorts (1953–58, 1959–63, 1964–68, 1969–73, 1974–78). Probability to quit smoking was also evaluated among ever-smokers. Results Probability to persist as a non-smoker significantly increased across subsequent generations in both sexes. At the age of 20 years this probability amounted to 41.7% (95% CI 39.4–44.0%) in men and 52.7% (50.4–54.9%) in women born between 1953 and 1958, and it increased to 57% (54.8–59.1%) in men and 68.7% (66.6–70.7%) in women born in 1969-73, but no further decline in smoking habits was observed in the next birth cohort (1974–78). Also the probability to quit smoking significantly increased from the 1953–58 birth cohort to the 1969–73 one. Conclusions Smoking has declined among Italian young adults of both genders. Further efforts are necessary to promote active anti-smoking campaign, especially among adolescents, which are at higher risk of starting to smoke.