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Contains fulltext : 283519.pdf (Publisher’s version ) (Open Access) BACKGROUND: The assessment of symptom-rhythm correlation (SRC) in patients with persistent atrial fibrillation (AF) is challenging. Therefore, we performed a novel mobile app-based approach to assess SRC in persistent AF. METHODS: Consecutive persistent AF patients planned for electrical cardioversion (ECV) used a mobile app to record a 60-s photoplethysmogram (PPG) and report symptoms once daily and in case of symptoms for four weeks prior and three weeks after ECV. Within each patient, SRC was quantified by the SRC-index defined as the sum of symptomatic AF recordings and asymptomatic non-AF recordings divided by the sum of all recordings. RESULTS: Of 88 patients (33% women, age 68 ± 9 years) included, 78% reported any symptoms during recordings. The overall SRC-index was 0.61 (0.44-0.79). The study population was divided into SRC-index tertiles: low (

BACKGROUND AND AIMS: Hepatitis C is poorly documented in migrants. The published studies mainly concern the screening in this population and are limited to some countries in Europe and North America. This study aimed to evaluate the characteristics and care of chronic hepatitis C in this population compared to the nonmigrant population, in the era of direct-acting antivirals (DAAs). METHOD: We performed a retrospective analysis based on data presented at the multidisciplinary team meetings of our tertiary care center between 2015 and 2019. RESULTS: We included 277 migrant- and 1390 nonmigrant patients mono-infected with hepatitis C virus (HCV) and treated with DAAs. The majority of the migrants were from Eastern European countries. In multivariable analysis, BMI classes associated with more obesity (OR = 1.84; 95% CI, 1.37-2.49; P < 0.001) and therapeutic patient education (OR = 3.91; 95% CI, 2.38-6.49; P < 0.001) were positively associated with migrant status, whereas age (OR = 0.92; 95% CI, 0.90-0.94; P < 0.001), female gender (OR = 0.46; 95% CI, 0.28-0.74; P = 0.002), modes of contamination with less drug use, transfusion history or nosocomial risk, as well more unknown mode (OR = 0.70; 95% CI, 0.50-0.96; P = 0.031), alcohol consumption (OR = 0.48; 95% CI, 0.29-0.73; P = 0.001), types of structures with less care in a general hospital or health network of general practitioners and more care in a university hospital or primary addictology center (OR = 0.78; 95% CI, 0.60-0.99; P = 0.046) and opioid substitution therapy (OR = 0.25; 95% CI, 0.08-0.68; P = 0.008) were negatively associated with migrant status. The substained virologic response 12 was close to 97% in both groups. CONCLUSION: Despite multiple differences in characteristics and therapeutic care between the two populations, the chances of healing hepatitis C were the same among migrant- compared with nonmigrant patients.

Highlights • First longitudinal data analyses on sports activity patterns and health. • Long-standing sports activity engagement improves cardio-metabolic health. • Starting regular sports activity reduces cardio-metabolic risk factor occurrence. • Relapse from regular sports activity increases cardio-metabolic disease incidence., Background Physical activity is favorable for health, and vigorous sports activity is particularly beneficial. This study investigates the association between changes in sports participation patterns over time and cardio-metabolic and self-perceived health outcomes. Methods Data from 3752 adults (18–79 years of age) who participated in 2 national health interview and examination surveys in 1997–1999 and 2008–2011 were included, with a mean follow-up time of about 12 years. A change in self-reported sports activity was analyzed with respect to the incidence of type 2 diabetes, coronary heart disease (CHD), hypertension, obesity, dyslipidemia, metabolic syndrome, and poor self-perceived health. Participants with pre-existing disease or risk factor of interest at baseline were excluded from the analysis. Being sufficiently active in sports was specified as doing sports for at least 1–2 h per week, and 4 activity categories were defined: 1) inactive at both time points (inactive–inactive), 2) inactive at baseline and active at follow-up (inactive–active), 3) active at baseline and inactive at follow-up (active–inactive), and 4) active at both time points (active–active). Associations between sports activity engagement and health outcomes were estimated by logistic regression models with different stages of adjustments. Results Not engaging in any regular sports activity at both time points (inactive–inactive) was associated with higher rates of type 2 diabetes (odds ratio (OR) = 1.82, 95% confidence interval (95%CI): 1.08–3.08), CHD (OR = 1.82, 95%CI: 1.16–2.84), hypertension (OR = 1.36, 95%CI: 1.03–1.81), metabolic syndrome (OR = 1.58, 95%CI: 1.08–2.32), and poor self-perceived health (OR = 2.54, 95%CI: 1.83–3.53) compared to doing regular sports for a minimum of 1–2 h per week over time (active–active). In case of change from inactivity to any regular sports activity (inactive–active), the rate of risk factor occurrence was not statistically different from the active–active reference group except for poor self-perceived health, but it was higher for type 2 diabetes (OR = 2.15, 95%CI: 1.12–4.14) and CHD (OR = 1.77, 95%CI: 1.03–3.03). Being active at baseline but inactive at follow-up (active–inactive) was not associated with higher disease incidence of type 2 diabetes (OR = 0.70, 95%CI: 0.25–1.97) or CHD (OR = 1.20, 95%CI: 0.49–2.99), but was associated with higher rates of hypertension (OR = 1.61, 95%CI: 1.11–2.34), obesity (OR = 2.34, 95%CI: 1.53–3.57), metabolic syndrome (OR = 1.70, 95%CI: 1.11–2.63), and poor self-perceived health (OR = 2.16, 95%CI: 1.53–3.07) at follow-up. Conclusion Even a low weekly quantity (1–2 h) of regular sports activity is partly associated with health benefits. Being formerly but not currently active was not associated with an increased disease incidence, but was associated with a higher risk-factor development compared to the reference group (active–active). Becoming active was preventive for risk-factor development but was not preventive for disease incidence, which probably means that the health benefits from sports activity are not sustainable and disease incidence is only shifted to a later period in life. For this reason, the promotion of and commitment to regular sports activity should be addressed as early as possible over the lifespan to achieve the best health benefits., Graphical Abstract Image, graphical abstract

INTRODUCTION: Organophosphate (OP) insecticides, including chlorpyrifos, have been linked with numerous harmful health effects on maternal and child health. Limited data are available on the biological mechanisms and endogenous pathways underlying the toxicity of chlorpyrifos exposures on pregnancy and birth outcomes. In this study, we measured a urinary chlorpyrifos metabolite and used high-resolution metabolomics (HRM) to identify biological perturbations associated with chlorpyrifos exposure among pregnant women in Thailand, who are disparately exposed to high levels of OP insecticides. METHODS: This study included 50 participants from the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE). We used liquid chromatography-high resolution mass spectrometry to conduct metabolic profiling on first trimester serum samples collected from participants to evaluate metabolic perturbations in relation to chlorpyrifos exposures. We measured 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos and chlorpyrifos-methyl, in first trimester urine samples to assess the levels of exposures. Following an untargeted metabolome-wide association study workflow, we used generalized linear models, pathway enrichment analyses, and chemical annotation to identify significant metabolites and pathways associated with urinary TCPy levels. RESULTS: In the 50 SAWASDEE participants, the median urinary TCPy level was 4.36 μg TCPy/g creatinine. In total, 691 unique metabolic features were found significantly associated with TCPy levels (p < 0.05) after controlling for confounding factors. Pathway analysis of metabolic features associated with TCPy indicated perturbations in 24 metabolic pathways, most closely linked to the production of reactive oxygen species and cellular damage. These pathways include tryptophan metabolism, fatty acid oxidation and peroxisome metabolism, cytochromes P450 metabolism, glutathione metabolism, and vitamin B3 metabolism. We confirmed the chemical identities of 25 metabolites associated with TCPy levels, including glutathione, cystine, arachidic acid, itaconate, and nicotinamide adenine dinucleotide. DISCUSSION: The metabolic perturbations associated with TCPy levels were related to oxidative stress, cellular damage and repair, and systemic inflammation, which could ultimately contribute to health outcomes, including neurodevelopmental deficits in the child. These findings support the future development of sensitive biomarkers to investigate the metabolic underpinnings related to pesticide exposure during pregnancy and to understand its link to adverse outcomes in children.

Introduction. As the clinical manifestation of neonatal infection is nonspecific and characterised by varied clinical features, it is highly problematic to establish an early diagnosis. Recently, hopes have been raised by the new acute-phase protein—pentraxin 3 (PTX3). PTX3 belongs to the family of long pentraxins, which is synthesized in numerous cells like endothelial cells, macrophages, and monocytes infiltrating sites of inflammation. Material and Methods. In our research, we have enrolled 29 newborns with infection as the study group and 47 healthy ones as the control group, as well as their mothers. The C-reactive protein (CRP), procalcitonin (PCT), and PTX3 levels were determined in venous blood samples from all investigated neonates and their mothers. Moreover, PTX3 concentrations were assessed in the umbilical cord. Results. There were statistically significant differences in PTX3 levels between healthy and sick newborns both in the umbilical cord ( p = 0.02 ) and venous blood ( p = 0.01 ). The highest PTX3 concentrations were observed in children with infection in the presence of premature rupture of membranes (PROM). PTX3 concentrations in this group were significantly higher compared to those in healthy children without PROM. We observed elevated PCT levels in newborns with infection. No differences in CRP levels in 12 hours of life were noticed between the investigated groups. A comparison of ROC curves for PTX3 and PCT concentrations revealed similar sensitivity and specificity in the prediction of infection in neonates. Conclusions. Serum PTX3 is an important and specific biomarker of early infection. It is already elevated in the umbilical cord, so measuring PTX3 concentration might be useful in the early prediction of infection in newborns.

Aims To quantify the arousal burden (AB) across large cohort studies and determine its association with long-term cardiovascular (CV) and overall mortality in men and women. Methods and results We measured the AB on overnight polysomnograms of 2782 men in the Osteoporotic Fractures in Men Study (MrOS) Sleep study, 424 women in the Study of Osteoporotic Fractures (SOF) and 2221 men and 2574 women in the Sleep Heart Health Study (SHHS). During 11.2 ± 2.1 years of follow-up in MrOS, 665 men died, including 236 CV deaths. During 6.4 ± 1.6 years of follow-up in SOF, 105 women died, including 47 CV deaths. During 10.7 ± 3.1 years of follow-up in SHHS, 987 participants died, including 344 CV deaths. In women, multivariable Cox proportional hazard analysis adjusted for common confounders demonstrated that AB is associated with all-cause mortality [SOF: hazard ratio (HR) 1.58 (1.01–2.42), P = 0.038; SHHS-women: HR 1.21 (1.06–1.42), P = 0.012] and CV mortality [SOF: HR 2.17 (1.04–4.50), P = 0.037; SHHS-women: HR 1.60 (1.12–2.28), P = 0.009]. In men, the association between AB and all-cause mortality [MrOS: HR 1.11 (0.94–1.32), P = 0.261; SHHS-men: HR 1.31 (1.06–1.62), P = 0.011] and CV mortality [MrOS: HR 1.35 (1.02–1.79), P = 0.034; SHHS-men: HR 1.24 (0.86–1.79), P = 0.271] was less clear. Conclusions Nocturnal AB is associated with long-term CV and all-cause mortality in women and to a lesser extent in men.

Background: Cow’s milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low level CM exposure, as well as the reproducibility of reaction thresholds. Objective: To undertake an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges (DBPCFC) in CM, to determine the rate of anaphylaxis to low level exposures and the reproducibility of reaction thresholds. Methods: Systematic review and individual participant data (IPD) meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarifications as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodological checklists. Results: 34 studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95%CI 0.2-0.5) and 2.9 (95%CI 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95%CI 2.0-10.9%) and 4.8% (95%CI 0.7-27.1%) of individuals reacting to ≤5mg and ≤0.5mg of CM protein (respectively) had anaphylaxis (minimal heterogeneity, I 2 =0%). 110 individuals subsequently underwent a repeat DBPCFC: the intra-individual variation in reaction threshold was limited to a ½-log change in 80% (95%CI 65-89%) of participants. Two individuals initially tolerated 5mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: Around 5% of CM-allergic individuals reacting to an ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose respectively, in the broader CM-allergic population. The vast majority of these anaphylactic reactions would be at the more mild end of the spectrum of anaphylaxis severity, responding to single dose of epinephrine.

U.S.-based research suggests conservatism is linked with less concern about contracting coronavirus and less preventative behaviors to avoid infection. Here, we investigate whether these tendencies are partly attributable to distrust in scientific information, and evaluate whether they generalize outside the U.S., using public data and recruited representative samples across three studies (Ntotal = 34,710). In Studies 1 and 2, we examine these relationships in the U.S., yielding converging evidence for a sequential indirect effect of conservatism on compliance through scientific (dis)trust and infection concern. In Study 3, we compare these relationships across 19 distinct countries. Although the relationships between trust in scientific information about the coronavirus, concern about coronavirus infection, and compliance are consistent cross-nationally, the relationships between conservatism and trust in scientific information are not. These relationships are strongest in North America. Consequently, the indirect effects observed in Studies 1–2 only replicate in North America (the U.S. and Canada) and in Indonesia. Study 3 also found parallel direct and indirect effects on support for lockdown restrictions. These associations suggest not only that relationships between conservatism and compliance are not universal, but localized to particular countries where conservatism is more strongly related to trust in scientific information about the coronavirus pandemic.

To assess the stability of somatic symptoms in community-dwelling participants.The study included 2472 participants (1190 men, 1282 women; mean age 44.3 ± 10.9) from the prospective population-based MONICA-S3 cohort (1994/95) and the 10-year follow-up KORA-F3 cohort. Somatic symptoms were assessed by an adapted version of the Somatic Symptom Scale-8 (SSS-8a) with scores ranging from 0 to 24. Somatic symptom stability was assessed by weighted kappa values (κ). Generalized Estimating Equation models assessing symptom stability were adjusted for sociodemographic, lifestyle, clinical and psychosocial risk factors, as well as pre-existing medical conditions.The mean (±SD) SSS-8a was lower in men (S3: 6.88 ± 3.87, F3: 6.60 ± 3.86) than women (S3: 8.43 ± 4.0, F3: 8.31 ± 4.2) at both time points. However, somatic symptoms remained moderately stable in both genders over 10 years (κ =0.42 in men and κ = 0.48 in women), with the largest stability observed in trouble sleeping for men (κ =0.41) and pain in the joints for women (κ =0.41). Pre-existing somatic symptoms were significantly associated with increasing symptoms at follow-up [men: β = 0.82 (SE 0.12), women: β = 0.85 (SE 0.12)], followed by age and psychosocial factors, whereas higher education and recent health care utilization were inversely associated with increasing symptoms. Although hypertension and obesity were associated with increasing somatic symptoms in men, pre-existing medical conditions were not associated with increasing somatic symptoms in men nor women.The current findings indicate that somatic symptoms remain moderately stable in the general population during 10 years of follow-up, mainly driven by sociodemographic and psychosocial factors.

ObjectiveThe effects of food sensitivity can easily be masked by other digestive symptoms in ostomates and are unknown. We investigated food-specific-IgG presence in ostomates relative to participants affected by other digestive diseases.DesignFood-specific-IgG was evaluated for 198 participants with a panel of 109 foods. Immunocompetency status was also tested. Jejunostomates, ileostomates and colostomates were compared with individuals with digestive tract diseases with inflammatory components (periodontitis, eosinophilic esophagitis, duodenitis, ulcerative colitis, Crohn’s disease and appendicitis), as well as food malabsorption due to intolerance. A logistic regression model with covariates was used to estimate the effect of the experimental data and demographic characteristics on the likelihood of the immune response.ResultsJejunostomates and ileostomates had a significant risk of presenting circulating food-specific-IgG in contrast to colostomates (OR 12.70 (p=0.002), 6.19 (p=0.011) and 2.69 (p=0.22), respectively). Crohn’s disease, eosinophilic esophagitis and food malabsorption groups also showed significantly elevated risks (OR 4.67 (p=0.048), 8.16 (p=0.016) and 18.00 (p=0.003), respectively), but not the ulcerative colitis group (OR 2.05 (p=0.36)). Individuals with profoundly or significantly reduced, and mild to moderately reduced, levels of total IgG were protected from the formation of food-specific IgG (OR 0.09 (p=ConclusionThe strength of a subject’s immunocompetence plays a role in the intensity to which the humoral system responds via food-specific-IgG. An element of biogeography emerges in which the maintenance of a colonic space might influence the risk of having circulating food-specific-IgG in ostomates.

Bio-acoustic properties of speech show evolving value in analyzing psychiatric illnesses. Obtaining a sufficient speech sample length to quantify these properties is essential, but the impact of sample duration on the stability of bio-acoustic features has not been systematically explored. We aimed to evaluate bio-acoustic features' reproducibility against changes in speech durations and tasks. We extracted source, spectral, formant, and prosodic features in 185 English-speaking adults (98 w, 87 m) for reading-a-story and counting tasks. We compared features at 25% of the total sample duration of the reading task to those obtained from non-overlapping randomly selected sub-samples shortened to 75%, 50%, and 25% of total duration using intraclass correlation coefficients. We also compared the features extracted from entire recordings to those measured at 25% of the duration and features obtained from 50% of the duration. Further, we compared features extracted from reading-a-story to counting tasks. Our results show that the number of reproducible features (out of 125) decreased stepwise with duration reduction. Spectral shape, pitch, and formants reached excellent reproducibility. Mel-frequency cepstral coefficients (MFCCs), loudness, and zero-crossing rate achieved excellent reproducibility only at a longer duration. Reproducibility of source, MFCC derivatives, and voicing probability (VP) was poor. Significant gender differences existed in jitter, MFCC first-derivative, spectral skewness, pitch, VP, and formants. Around 97% of features in both genders were not reproducible across speech tasks, in part due to the short counting task duration. In conclusion, bio-acoustic features are less reproducible in shorter samples and are affected by gender.

Introduction: Regenerative capacity of the heart is limited, and the post-infarct left ventricle (LV) dysfunction is associated with poor prognosis. Administration of stem/progenitor cells (SPCs) is a promising approach for cardiac regeneration. Objectives: In the study, we assessed LV function and post-infarcted remodeling in patients with ST-elevated myocardial infarct (STEMI) who received autologous lineage-negative (LIN-) SPCs. Patients and methods: Patients with STEMI and one-vessel coronary artery disease treated with percutaneous revascularisation were divided into study group (LIN- group, 15 patients) that received standard therapy and autologous BM-derived LIN- SPCs and control group (standard therapy group, 19 patients). The cells were administered intracoronary 24 hours after STEMI. The follow-up was 12 months with subsequent non-invasive tests and laboratory parameter evaluation on days 1st, 3rd, and 7th as well as at 1st, 3rd, 6th and 12th month after STEMI. Results: All procedures related to SPCs administration were well tolerated by the patients. In 12-month follow-up, there were no major adverse cardiac events connected with LIN- SPCs administration. During 12-month follow-up, 9 patients from LIN- group (Responders) achieved an improvement in LV ejection fraction (>10% after 12 months) with no signs of unfavorable LV remodeling. Laboratory parameters analysis showed that Troponin T levels were significantly lower until day 7th in the Responders group, while brain natriuretic peptide (BNP) level remained significantly lower from day 3rd to 12th month respectively. Conclusions: Intracoronary infusion of autologous BM-derived LIN- stem/progenitor cells is feasible and safe for patient. Improvement in LV function and prevention of unfavorable remodeling in the 60% of study group seems relatively promising. Stem cell-based therapy for cardiac regeneration still needs more accurate and extensive investigations to estimate and improve their efficacy.

Background: Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. Objective: We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. Methods: Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. Results: In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. Conclusion: With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption. © 2019 American Academy of Allergy, Asthma & Immunology

Summary Objective This study aimed to assess oral health-related quality of life (OHRQoL) in relation to associated covariates in orthodontic patients of different age groups (children, adolescents, and adults) in a cross-sectional study. Methods A total of 898 subjects (50.6% females, 49.4% males; mean age 16.89 years) undergoing orthodontic treatment anonymously completed the German version of the Oral Health Impact Profile (OHIP-G14) to assess OHRQoL in addition to completing 23 other items. Descriptive, exploratory statistical analysis and multiple linear regression modelling were performed. Results The mean score of the OHIP-G14 was 8.3 for the 6- to 11-year olds, 8.9 for the 12- to 17-year olds, and 12.6 for adults. Physical pain (Subscale 2) was the highest factor in all groups. Additionally, a relevant factor was Subscale 3 (psychological discomfort). A linear regression model showed that, in the adolescent group, aesthetics in combination with pain had a significant negative influence on OHRQoL, whereas, in the adult group, function in combination with pain showed the same significant negative influence. Second, except for the children, fixed appliances had a significant negative effect on OHRQoL compared to removable appliances. Conclusions Our study showed that the majority of the 6- to 11-year olds and 12- to 17-year olds reported a good OHRQoL. Nevertheless, adolescents and adults who reported aesthetic/pain and function/pain problems, respectively, as reasons for orthodontic treatment showed a significant occurrence for reduced OHRQoL. Fixed appliances, in comparison with removable appliances, also resulted in a significant reduction in OHRQoL for both groups.

Background Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of a rapid course. In 25% of ALS sufferers, speech disorders occur as prodromal symptoms of the disease. Impaired communication affects physical health and has a negative impact on mental and emotional condition. In this study, we assessed which domains of speech are particularly affected in ALS. Subsequently, we estimated possible correlations between the ALS patients’ subjective perception of their speech quality and an objective assessment of the speech organs carried out by an expert. Methods The study group consisted of 63 patients with sporadic ALS. The patients were examined for articulatory functions by means of Voice Handicap Index (VHI) and the Frenchay Dysarthria Assessment (FDA). Results On the basis of the VHI scores, the entire cohort was divided into 2 groups: group I (40 subjects) with mild speech impairment, and group II (23 subjects) displaying moderate and profound speech deficits. In an early phase of ALS, changes were typically reported in the tongue, lips and soft palate. The FDA and VHI-based measurements revealed a high, positive correlation between the objective and subjective evaluation of articulation quality. Conclusions Deterioration of the articulatory organs resulted in the reduction of social, physical and emotional functioning. The highly positive correlation between the VHI and FDA scales seems to indicate that the VHI questionnaire may be a reliable, self-contained tool for monitoring the course and progression of speech disorders in ALS. Trial registration NCT02193893.

Traditional frequency domain analysis of heart period (HP) variability allows the estimation of the parasympathetic modulation directed to the heart but the sympathetic one remains largely unknown. Recently, sympathetic and parasympathetic activity indexes (SAI and PAI) have been proposed to address this issue. SAI and PAI were derived from HP variability via the application of an orthonormal Laguerre expansion allowing the separation of HP variations driven by sympathetic and parasympathetic outflows. In this study, SAI and PAI were validated against tonic and variability measures of muscle sympathetic nerve activity (MSNA) and more traditional markers derived from HP variability. Indexes were calculated in 12 healthy subjects (9 females, age from 20 to 36 years, median 22.5 years) undergoing incremental head-up tilt. Results showed that traditional HP and MSNA variability markers as well as SAI and PAI were modified in proportion to the magnitude of the postural challenge. However, SAI was not correlated with any MSNA markers and PAI was not linked to respiratory sinus arrhythmia. SAI and PAI can capture modifications of cardiac control induced by the orthostatic challenge but they might be weak surrogates of vagal and sympathetic activities and/or modulations.Clinical Relevance- SAI and PAI markers are useful to characterize cardiac control but poorly linked with autonomic nervous system state.

To describe clinical outcomes of patients aged 75 years and above after partial nephrectomy (PN), and to assess independent factors of postoperative complications. We retrospectively reviewed information from our multi-institutional database. Every patient over 75 years old who underwent a PN between 2003 and 2016 was included. Peri-operative and follow up data were collected. Multivariate logistic regression was performed to determine independent predictive factors of postoperative complications. We reviewed 191 procedures including 69 (40%) open-surgery, and 122 (60%) laparoscopic procedures, of which 105 were robot-assisted. Median follow-up was 25 months. The mean age was 78 [75–88]. The American Society of Anesthesiologist’s score was 1, 2, 3 and 4 in 10.5%, 60%, 29% and 0.5% of patients respectively. The mean tumor size was 4.6 cm. Indication of PN was elective in 122 (65%) patients and imperative in 52 patients (28%). The median length of surgery was 150(± 60) minutes, and the median estimated blood loss 200 ml. The mean glomerular filtration rate was 71.5 ml/minute preoperatively, and 62 ml/min three months after surgery. The severe complications (Clavien III-V) rate was 6.2%. On multivariate analysis, the robotic-assisted procedure was an independent protective factor of medical postoperative complications (Odds Ration (OR) = 0.31 [0.12–0.80], p = 0.01). It was adjusted for age and RENAL score, robotic-assisted surgery (OR = 0.22 [0.06–0.79], p = 0.02), and tumor size (OR = 1.13 [1.02–1.26], p = 0.01), but the patients age did not forecast surgical complications. Partial nephrectomy can be performed safely in elderly patients with an acceptable morbidity, and should be considered as a viable treatment option. Robotic assistance is an independent protective factor of postoperative complications.

There is evidence for an increased type 2 diabetes (T2D) risk associated with depression, but its role for diabetes prevention remains unclear. This study aimed to add insight by investigating the impact of major depressive disorder (MDD) on prospective glycaemic changes.The study was based on a cohort of n = 1,766 adults without diabetes (776 men, 990 women; 18-65 years of age) who participated in the mental health supplement of the German National Health Interview and Examination Survey (GNHIES98-MHS, 1997-1999) and in a follow-up survey (DEGS1, 2008-2011). Glycaemic status was defined as normoglycaemia [HbA1c39 mmol/mol (5.7%)], prediabetes [39 ≤ HbA1c 48 mmol/mol (5.7-6.4%)] and diabetes [HbA1c ≥ 48 mmol/mol (≥ 6.5%), diagnosed diabetes, or antidiabetic medication], and glycaemic changes categorized as 'remission', 'stability' and 'progression'. Baseline MDD was assessed via a modified German version of the WHO Composite International Diagnostic Interview. Multivariable logistic regressions were applied to analyse the association of MDD with glycaemic changes and incident T2D, adjusting for socio-demographics, lifestyle conditions, chronic diseases, antidepressant use and mental health care.MDD prevalence was 21.4% for women and 8.9% for men. Among women, MDD was associated with a lower chance for remission (RRR 0.43; 95% CI 0.23, 0.82). Among men, MDD was not significantly related to glycaemic changes. MDD had no significant effect on incident T2D (men: OR 1.58; 0.55, 4.52; women: OR 0.76; 0.37, 1.58).Findings of the current study highlight the role of depression in T2D prevention, particularly among women.

Background Type 2 diabetes (T2D) causes substantial disease burden and is projected to affect an increasing number of people in coming decades. This study provides projected estimates of life years free of type 2 diabetes (T2D) and years of life lost ($${\mathrm{YLL}}$$ YLL ) associated with T2D for Germany in the years 2015 and 2040. Methods Based on an illness-death model and the associated mathematical relation between prevalence, incidence and mortality, we projected the prevalence of diagnosed T2D using currently available data on the incidence rate of diagnosed T2D and mortality rates of people with and without diagnosed T2D. Projection of prevalence was achieved by integration of a partial differential equation, which governs the illness-death model. These projected parameters were used as input values to calculate life years free of T2D and $${\mathrm{YLL}}$$ YLL associated with T2D for the German population aged 40 to 100 years in the years 2015 and 2040, while accounting for different assumptions on future trends in T2D incidence and mortality. Results Assuming a constant incidence rate, women and men at age 40 years in 2015 will live approximately 38 years and 33 years free of T2D, respectively. Up to the year 2040, these numbers are projected to increase by 1.0 years and 1.3 years. Assuming a decrease in T2D-associated excess mortality of 2% per year, women and men aged 40 years with T2D in 2015 will be expected to lose 1.6 and 2.7 years of life, respectively, compared to a same aged person without T2D. In 2040, these numbers would reduce by approximately 0.9 years and 1.6 years. This translates to 10.8 million and 6.4 million $${\mathrm{YLL}}$$ YLL in the German population aged 40–100 years with prevalent T2D in 2015 and 2040, respectively. Conclusions Given expected trends in mortality and no increase in T2D incidence, the burden due to premature mortality associated with T2D will decrease on the individual as well as on the population level. In addition, the expected lifetime without T2D is likely to increase. However, these trends strongly depend on future improvements of excess mortality associated with T2D and future incidence of T2D, which should motivate increased efforts of primary and tertiary prevention.

Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow's milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. Objective: We examined associations between PFAS exposure and glucose metabolism in youth. Methods: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n=310) participated in annual visits for an average of 3.3±2.9y. Generalizability of findings were tested in young adults from the Southern California Children’s Health Study (CHS; n=135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and β-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography–high-resolution mass spectrometry; high levels were defined as concentrations >66th percentile. Results: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels (≥2.0 ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12, 39mg/dL; p

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice with humanized livers. METHODS: We performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection. RESULTS: We found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n = 216), a subset of which (n = 21) achieved viral clearance. CONCLUSIONS: In an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection., Graphical Abstract

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS), PUGNAc, an inhibitor of O-GlcNAcase, or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

Single-cell RNA-Seq unravels heterogeneity and compartmentalization of both hepatitis B virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis., Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) world-wide. The molecular mechanisms of viral hepatocarcinogenesis are still partially understood. Here, we applied two complementary single-cell RNA-sequencing protocols to investigate HBV–HCC host cell interactions at the single cell level of patient-derived HCC. Computational analyses revealed a marked HCC heterogeneity with a robust and significant correlation between HBV reads and cancer cell differentiation. Viral reads significantly correlated with the expression of HBV-dependency factors such as HLF in different tumor compartments. Analyses of virus-induced host responses identified previously undiscovered pathways mediating viral carcinogenesis, such as E2F- and MYC targets as well as adipogenesis. Mapping of fused HBV–host cell transcripts allowed the characterization of integration sites in individual cancer cells. Collectively, single-cell RNA-Seq unravels heterogeneity and compartmentalization of both, virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis. The perturbation of pro-carcinogenic gene expression even at low HBV levels highlights the need of HBV cure to eliminate HCC risk.

Background Measurements of urinary dialkyl phosphate (DAP) metabolites are often used to characterize exposures to organophosphate (OP) insecticides; however, some challenges to using urinary DAP metabolites as an exposure measure exist. OP insecticides have short biological half-lives with measurement in a single urine sample typically only reflecting recent exposure within the last few days. Because of the field staff and participant burden of longitudinal sample collection and the high cost of multiple measurements, typically only one or two urine samples have been used to evaluate OP insecticide exposure during pregnancy, which is unlikely to capture an accurate picture of prenatal exposure. Methods We recruited pregnant farmworker women in Chom Thong and Fang, two districts of Chiang Mai province in northern Thailand (N = 330) into the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) from 2017 to 2019. We collected up to 6 serial urine samples per participant during gestation and composited the samples to represent early, mid, and late pregnancy. We measured concentrations of urinary DAP metabolites in the composited urine samples and evaluated the within- and between-participant variability of these levels. We also investigated predictors of OP insecticide exposure. Results DAP metabolite concentrations in serial composite samples were weakly to moderately correlated. Spearman correlations indicated that composite urine samples were more highly correlated in Fang participants than in Chom Thong participants. The within-person variances (0.064–0.65) exceeded the between-person variances for DETP, DEP, ∑DEAP, DMP, DMTP, ∑DMAP, ∑DAP. The intraclass correlations (ICCs) for the volume-based individual metabolite levels (ng/mL) ranged from 0.10 to 0.66. For ∑DEAP, ∑DMAP, and ∑DAP the ICCs were, 0.47, 0.17, 0.45 respectively. We observed significant differences between participants from Fang compared to those from Chom Thong both in demographic and exposure characteristics. Spearman correlations of composite samples from Fang participants ranged from 0.55 to 0.66 for the ∑DEAP metabolite concentrations in Fang indicating moderate correlation between pregnancy periods. The ICCs were higher for samples from Fang participants, which drove the overall ICCs. Conclusions Collecting multiple (∼6) urine samples during pregnancy rather than just 1 or 2 improved our ability to accurately assess exposure during the prenatal period. By compositing the samples, we were able to still obtain trimester-specific information on exposure while keeping the analytic costs and laboratory burden low. This analysis also helped to inform how to best conduct future analyses within the SAWASDEE study. We observed two different exposure profiles in participants in which the concentrations and variability in data were highly linked to the residential location of the participants.

The identification of recurrent, transient perturbations in brain activity during sleep, so called cyclic alternating patterns (CAP), is of significant interest as they have been linked to neurological pathologies. CAP sequences comprise multiple, consecutive cycles of phasic activation (A-phases). Here, we propose a novel, automated system exploiting the dynamical, temporal information in electroencephalography (EEG) recordings for the classification of A-phases and their subtypes. Using recurrent neural networks (RNN), crucial information in the temporal behavior of the EEG is extracted. The automatic classification system is equipped to deal with the biasing issue of imbalanced data sets and uses state-of-the-art signal processing methods to reduce inter-subject variation. To evaluate our system, we applied recordings from the publicly available CAP Sleep Database on Physionet. Our results show that the RNN improved the detection accuracy by 3–5% and the F1-score by approximately 7% on two data sets compared to a normal feed-forward neural network. Our system achieves a sensitivity of approximately 76–78% and F1-score between 63–68%, significantly outperforming existing technologies. Moreover, its sensitivity for subtype classification of 60–63% (A1), 42–45% (A2), and 71–74% (A3) indicates superior multi-class classification performance for CAP detection. In conclusion, we have developed a fully automated high performance CAP scoring system that includes A-phase subtype classification. RNN classifiers yield a significant improvement in accuracy and sensitivity compared to previously proposed systems.

The objective of the present study was to quantify repolarization lability and its association with sex, sleep stage, and cardiovascular mortality. We analyzed polysomnographic recordings of 2,263 participants enrolled in the Sleep Heart Health Study (SHHS-2). Beat-to-beat QT interval variability (QTV) was quantified for consecutive epochs of 5 min according to the dominant sleep stage [wakefulness, nonrapid eye movement stage 2 (NREM2), nonrapid eye movement stage 3 (NREM3), and rapid eye movement (REM)]. To explore the effect of sleep stage and apnea-hypopnea index (AHI) on QT interval parameters, we used a general linear mixed model and mixed ANOVA. The Cox proportional hazards model was used for cardiovascular disease (CVD) death prediction. Sex-related differences in T wave amplitude ( P < 0.001) resulted in artificial QTV differences. Hence, we corrected QTV parameters by T wave amplitude for further analysis. Sleep stages showed a significant effect ( P < 0.001) on QTV. QTV was decreased in deep sleep compared with wakefulness, was higher in REM than in NREM, and showed a distinct relation to AHI in all sleep stages. The T wave amplitude-corrected QTV index (cQTVi) in REM sleep was predictive of CVD death (hazard ratio: 2.067, 95% confidence interval: 1.105–3.867, P < 0.05) in a proportional hazards model. We demonstrated a significant impact of sleep stages on ventricular repolarization variability. Sex differences in QTV are due to differences in T wave amplitude, which should be corrected for. Independent characteristics of QTV measures to sleep stages and AHI showed different behaviors of heart rate variability and QTV expressed as cQTVi. cQTVi during REM sleep predicts CVD death. NEW & NOTEWORTHY We demonstrate here, for the first time, a significant impact of sleep stages on ventricular repolarization variability, quantified as QT interval variability (QTV). We showed that QTV is increased in rapid eye movement sleep, reflective of high sympathetic drive, and predicts death from cardiovascular disease. Sex-related differences in QTV are shown to be owing to differences in T wave amplitude, which should be corrected for.

Aims To project the number of people with Type 2 diabetes in Germany between 2015 and 2040. Methods Based on data from 65 million insurees of the German statutory health insurance, we projected the age-specific prevalence of diabetes using mathematical relations between prevalence, incidence rate and mortality. We compared several scenarios regarding temporal trends in the incidence and mortality rate. The projected age-specific prevalence was applied to the projected age structure of the German population between 2015 and 2040 to calculate the number of people with Type 2 diabetes. Results Application of current age-specific prevalence estimates to the projected age structure in 2040, although ignoring temporal trends in incidence and mortality, yielded an increase in the number of Type 2 diabetes cases from 6.9 million in 2015 to 8.3 million (+21%) in 2040. More realistic scenarios that account for decreasing mortality rates and different trends in the incidence rates project between 10.7 million (+54%) and 12.3 million (+77%) Type 2 diabetes cases in 2040. Conclusions For the first time, we projected the number of future Type 2 diabetes cases for the whole adult population in Germany. The results indicate a relative increase in the number of Type 2 diabetes cases of between 54% and 77% from 2015 to 2040. Temporal trends in the incidence rate are the main drivers of this increase. Simply applying current age-specific prevalence to the future age structure probably underestimates the future number of Type 2 diabetes cases.

Background Sleep-disordered breathing (SDB) is highly prevalent in patients with atrial fibrillation (AF) and its treatment can improve rhythm control. Polysomnography (PSG) is the gold standard for the diagnosis of SDB but its high cost and limited availability constrain its role as a standard SDB screening tool. We sought to assess the diagnostic utility of overnight oximetry in predicting SDB in AF patients. Methods We analyzed prospectively collected data on 439 patients with documented AF (62% paroxysmal AF) who underwent PSG. Overnight oximetry was used to determine the oxygen desaturation index (ODI, number of desaturation/h) by a novel automated computer algorithm. ODI was validated against PSG derived apnea-hypopnea index (AHI). Results The sample consisted of 69% men with a mean age of 59.9 ± 11.3 years and body mass index of 30 ± 5 kg/m2. The median AHI was 9.5 [3.6–21.0]/h and the prevalence of moderate (AHI 15–29/h) and severe SDB (AHI ≥ 30/h) was 17.3% and 16.6% respectively. The ODI was able to detect moderate-to-severe SDB (AHI ≥ 15/h; area under the receiver-operating-characteristic curve (AUC): 0.951, 95% CI: 0.929–0.972) and severe SDB (AHI ≥ 30/h; 0.932, 95% CI: 0.895–0.968) with high diagnostic accuracy. An ODI cut-off of 4.1/h resulted in a 91% sensitivity and 83% specificity in discriminating between patients with and without AHI ≥ 15/h. An ODI of 7.6/h yielded a sensitivity and specificity for AHI ≥ 30/h of 89% and 83%, respectively. Conclusions ODI derived from a simple and low-cost overnight oximetry can be used as an accessible and reliable screening tool, particularly to rule out SDB.

ObjectiveFew studies on diabetes self-management considered the patterns and relationships of different self-management behaviours (SMB). The aims of the present study are 1) to identify patterns of SMB among persons with diabetes, 2) to identify sociodemographic and disease-related predictors of SMB among persons with diabetes.Research design and methodsThe present analysis includes data of 1,466 persons (age 18 to 99 years; 44.0% female; 56.0% male) with diabetes (type I and II) from the population-based study German Health Update 2014/2015 (GEDA 2014/2015-EHIS). We used latent class analysis in order to distinguish different patterns of self-management behaviours among persons with diabetes. The assessment of SMB was based on seven self-reported activities by respondents (dietary plan, diabetes-diary, diabetes health pass, self-assessment of blood glucose, self-examination of feet, retinopathy-screenings and assessment of HbA1c). Subsequent multinomial latent variable regressions identified factors that were associated with self-management behaviour.ResultsLatent class analysis suggested a distinction between three patterns of SMB. Based on modal posterior probabilities 42.8% of respondents showed an adherent pattern of diabetes self-management with above-average frequency in all seven indicators of SMB. 32.1% showed a nonadherent pattern with a below-average commitment in all seven forms of SMB. Another 25.1% were assigned to an ambivalent type, which showed to be adherent with regard to retinopathy screenings, foot examinations, and the assessment of HbA1c, yet nonadherent with regard to all other forms of SMB. In multivariable regression analyses, participation in Diabetes Self-Management Education programs (DSME) was the most important predictor of good self-management behaviour (marginal effect = 51.7 percentage points), followed by attentiveness towards one's personal health (31.0 percentage points). Respondents with a duration of illness of less than 10 years (19.5 percentage points), employed respondents (7.5 percentage points), as well as respondents with a high socioeconomic status (24.7 percentage points) were more likely to show suboptimal forms of diabetes self-management.DiscussionIn the present nationwide population-based study, a large proportion of persons with diabetes showed suboptimal self-management behaviour. Participation in a DSME program was the strongest predictor of good self-management. Results underline the need for continual and consistent health education for patients with diabetes.

IntroductionWe investigated whether the presence of depressive symptoms among adults with diagnosed diabetes is associated with adverse quality of diabetes care.Research design and methodsThe study population was drawn from the German national health survey ‘German Health Update’ 2014/2015-European Health Interview Survey and included 1712 participants aged ≥18 years with self-reported diabetes during the past 12 months. Depressive symptoms in the past 2 weeks were assessed by the eight-item depression module of the Patient Health Questionnaire (PHQ-8), with PHQ-8 sum score values ≥10 indicating current depressive symptoms. We selected 12 care indicators in diabetes based on self-reported information on care processes and outcomes. Associations of depressive symptoms with those indicators were examined in multivariable logistic regression models with stepwise adjustments.ResultsOverall, 15.6% of adults with diagnosed diabetes reported depressive symptoms, which were higher in women than in men (18.7% vs 12.9%). Adjusted for age, sex, education, social support, health-related behaviors, and diabetes duration, adults with depressive symptoms were more likely to report acute hypoglycemia (OR 1.81, 95% CI 1.13 to 2.88) or hyperglycemia (OR 2.10, 95% CI 1.30 to 3.37) in the past 12 months, long-term diabetes complications (OR 2.30, 95% CI 1.55 to 3.39) as well as currently having a diet plan (OR 2.14, 95% CI 1.39 to 3.29) than adults without depressive symptoms. Significant associations between depressive symptoms and other care indicators were not observed.ConclusionsThe present population-based study of adults with diagnosed diabetes indicates an association between depressive symptoms and adverse diabetes-specific care with respect to outcome but largely not to process indicators. Our findings underline the need for intensified care for persons with diabetes and depressive symptoms. Future research needs to identify underlying mechanisms with a focus on the inter-relationship between diabetes, depression and diabetes-related distress.

BACKGROUND: There is increasing interest in the use of eliciting doses (EDs) to inform allergen risk management. The ED can be estimated from the distribution of threshold doses for allergic subjects undergoing food challenges within a specified population. Estimated ED05 values for cow's milk (the dose expected to cause objective allergic symptoms in 5% of the milk-allergic population) range from 0.5 mg to 13.9 mg cow's milk protein. We undertook a single-dose challenge study to validate a predicted ED05 for cow's milk of 0.5 mg protein.METHODS: Participants were recruited from 4 clinical centres. Predetermined criteria were used to identify patients reacting to 0.5 mg cow's milk protein (approximately 0.015 mL of fresh cow's milk). Children over 1 year underwent formal challenge to cow's milk to confirm clinical reactivity.RESULTS: 172 children (median age 6.0 (IQR 0.7-11) years, 57% male) were included in this analysis. Twelve (7.0%, 95% CI 3.7%-11.9%) children experienced objective symptoms that met the predetermined criteria. One participant had mild anaphylaxis that responded to a single dose of adrenaline, the remainder experienced only mild symptoms with no treatment required. We did not identify any baseline predictors of sensitization that were associated with objective reactivity to the single-dose challenge using 0.5 mg cow's milk protein.CONCLUSIONS: These data support an estimated ED05 for cow's milk of 0.5 mg protein. Values for ED05 above 0.5 mg for cow's milk protein proposed for allergen risk management need to be reviewed.

ObjectivesLittle is known about the age-specific excess mortality pattern of people with diagnosed diabetes in Germany. Thus, our goal was to determine the excess mortality in diagnosed diabetes overall and stratified by age and sex based on claims data.DesignRoutine data analysis using a claims dataset from all statutory health-insured persons in Germany in 2013, which accounts for about 90% of the population.ParticipantsWe included persons who lived in Germany, were insured at least 360 days, were not self-paying any health services and were aged 30 years or older leading to a total number of 47.3 million insured persons for analyses.ExposureDiabetes was determined by the International Classification of Diseases-10 codes E10–E14, which were documented in 2013 in at least two-quarters on an outpatient setting or at least once on an inpatient setting.Outcome measuresThe vital status in the study population was drawn from the claims dataset for the year 2014. We derived the excess mortality estimated as an age-adjusted mortality rate ratio (MRR) by sex and for age groups using a Poisson model.Main resultsWe found age-adjusted MRRs (95% CI) for diabetes of 1.52 (1.51 to 1.52) for women and 1.56 (1.56 to 1.56) for men. These figures declined with increasing age and were highest for ages 30–34 years with 6.76 (4.99 to 9.15) for women and 6.87 (5.46 to 8.64) for men, and lowest for age 95 years and older with 1.13 (1.10 to 1.15) for women and 1.11 (1.05 to 1.17) for men.ConclusionsWe derived deeply age-stratified figures on excess mortality in diabetes for Germany. Establishing a sustainable analysis of excess mortality is aimed at within the framework of diabetes surveillance.

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0–77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7–82·3] with concurrent temozolomide vs 60·4 months [45·7–71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73–1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2–116·6] vs 46·9 months [37·9–56·9]; HR 0·64 [95% CI 0·52–0·79], pInterpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.Funding: Merck Sharpe & Dohme.

Background The physiology underlying "brain fog" in the absence of orthostatic stress in postural tachycardia syndrome (POTS) remains poorly understood. Methods and Results We evaluated cognitive and hemodynamic responses (cardiovascular and cerebral: heart rate, blood pressure, end‐tidal carbon dioxide, and cerebral blood flow velocity (CBFv) in the middle cerebral artery at baseline, after initial cognitive testing, and after (30‐minutes duration) prolonged cognitive stress test (PCST) whilst seated; as well as after 5‐minute standing in consecutively enrolled participants with POTS (n=22) and healthy controls (n=18). Symptom severity was quantified with orthostatic hypotensive questionnaire at baseline and end of study. Subjects in POTS and control groups were frequency age‐ and sex‐matched (29±11 versus 28±13 years; 86 versus 72% women, respectively; both P ≥0.4). The CBFv decreased in both groups (condition, P =0.04) following PCST, but a greater reduction in CBFv was observed in the POTS versus control group (−7.8% versus −1.8%; interaction, P =0.038). Notably, the reduced CBFv following PCST in the POTS group was similar to that seen during orthostatic stress (60.0±14.9 versus 60.4±14.8 cm/s). Further, PCST resulted in greater slowing in psychomotor speed (6.1% versus 1.4%, interaction, P =0.027) and a greater increase in symptom scores at study completion (interaction, P P >0.05). Conclusions Reduced CBFv and cognitive dysfunction were evident in patients with POTS following prolonged cognitive stress even in the absence of orthostatic stress.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6–8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment.Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale.We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men.Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Background and objectives: Speech disorders are observed in 30% of newly diagnosed sporadic amyotrophic lateral sclerosis (ALS) patients. Characterized by a dynamic course, dysfunction of articulation has not so far been well understood. The aim of this study was to analyze the influence of demographic factors (sex, age, duration of the disease) and concomitant diseases (degenerative spine disease, depression, hypertension, hypothyroidism, hyperthyroidism, and allergy) on the functioning of speech organs in ALS patients. Materials and Methods: The study group consisted of 65 patients with sporadic ALS. Patients were examined for articulatory functions by means of the Frenchay Dysarthria Assessment (FDA). Results: 68% of the study sample had spinal disorders. Logistic regression analysis showed that a decline in the functioning of lips, soft palate, length of phonation, and voice loudness was more common among men. Patients diagnosed with degenerative spine disease more often suffered from respiratory disorders, while younger patients (&lt, 60 years of age) significantly more often had the impairment of the sentence and spontaneous speech functions. Conclusions: The male gender in patients with ALS is associated with an increased risk of deterioration of the phonation length function. Patients under 60 years of age are associated with more often pronouncing sentences disorders and spontaneous speech disorders.

IntroductionTo identify characteristics of people with undiagnosed type 2 diabetes (T2D) among adults in Germany.Research design and methodsThe study population comprised participants aged 40–79 years of the German Health Interview and Examination Survey for Adults 2008–2011. Glycemic status was categorized as undiagnosed T2D (glycated hemoglobin A1c (HbA1c) ≥48 mmol/mol (6.5%), n=135), diagnosed T2D (n=518) and normoglycemia (HbA1cResultsThe prevalence of undiagnosed T2D was 2.9% (95% CI 2.2% to 3.9%) at an overall prevalence of 12.3% (11.0% to 13.6%) of persons with undiagnosed or diagnosed T2D. In multivariable analyses, factors associated with undiagnosed as well as diagnosed T2D in comparison to normoglycemia were older age (OR 1.04, 95% CI 1.01 to 1.06, per year, for undiagnosed T2D; OR 1.08, 1.07 to 1.10 for diagnosed T2D), male sex (3.33, 2.18 to 5.07; 1.91, 1.43 to 2.56), obesity (3.47, 2.17 to 5.56; 2.68, 2.04 to 3.52), hypertension (1.66, 1.09 to 2.53; 2.04, 1.42 to 2.95) and parental history of diabetes (2.04, 1.24 to 3.35; 3.16, 2.30 to 4.34). Variables independently associated with undiagnosed T2D but not diagnosed T2D included living alone (2.20; 1.36 to 3.56) and not seeing a doctor within the past year (2.57; 1.34 to 4.93). People with undiagnosed T2D were further younger and more likely to be male sex and reside in the western part of Germany than people with diagnosed T2D.ConclusionApart from major known risk factors of diabetes, characteristics specific to undiagnosed diabetes among adults in Germany will serve to inform the national education and communication strategy on diabetes mellitus in Germany.

Therapeutic interventions in amyotrophic lateral sclerosis (ALS) are still far from satisfying. Immune modulating procedures raise hopes for slowing the disease progression. Stem cell therapies are believed to possess the ability to regulate innate and adaptive immune response and inflammation processes. Hence, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin&ndash, ) cells were performed every six weeks in 40 sporadic ALS patients. The concentrations of inflammatory-related proteins and expression profiles of selected miRNA in the cerebrospinal fluid (CSF) and plasma at different timepoints post-transplantation were quantified by multiplex Luminex and qRT-PCR. The global gene expression in nucleated blood cells was assessed using the gene microarray technique. According to the ALS Functional Rating Scale (FRSr), the study population was divided into responders (group I, n = 17) and non-responders (group II, n = 23). A thorough analysis of the pro-inflammatory expression profiles, regulated miRNA pathways, and global gene expression profiles at the RNA level revealed the local and systemic effects of Lin&ndash, cell therapy on the immune system of patients with ALS. The autologous application of Lin&ndash, cells in CSF modulates immune processes and might prevent the progression of neurodegeneration. However, further in-depth studies are necessary to confirm the findings, and prolonged intervention is needed to maintain therapeutic effects.

Background: Amyotrophic lateral sclerosis (ALS) is one of the most frequently occurring neurodegenerative diseases affecting speech and swallowing. This preliminary study aimed to investigate whether an autologous lineage-negative stem/progenitor cell therapy applied to ALS patients affects the level of selected trophic and proinflammatory factors, and subsequently improves the articulation. Methods: We enrolled 12 patients with sporadic ALS, who underwent autologous bone marrow-derived lineage negative (LIN-) cells administration into cerebrospinal fluid (CSF). We evaluated patients' articulation using the Frenchay Dysarthria Assessment on days 0 and 28 following the LIN- cells administration. Concentrations of various factors (BDNF, NGF, ANGP-2, VEGF, PDGF-AA, PEDF, COMP-FH, CRP, C3, C4) in CSF were quantified by multiplex fluorescent bead-based immunoassays in the samples collected on the day of LIN- cells administration and 28 days later. On top of this, we assessed levels of BDNF and NGF in the patients' plasma on the day of the injection, three, seven days and three months after the treatment. Results: Of the 12 patients who received the LIN- cell therapy 8 showed short-termed improvement in articulatory functions (group I), which was particularly noticeable in better phonation time, lips and soft palate performance, swallowing reflex and voice loudness. Four patients (group II) did not show substantial improvement. CSF concentrations of BDNF, ANGP-2 and PDGF-AA in group I decreased significantly 28 days after LIN- cells administration. The highest concentration levels of BDNF in group II and NGF in both groups in blood plasma were observed on day 3 following the injection. Conclusions: The outcomes of the LIN- cell application in ALS treatment of articulatory organs are promising. The procedure proved to be safe and feasible. A short-lasting trophic effect of autologous LIN- administration could encourage repeated cell's application in order to sustain their beneficial effects, however this approach needs further investigation.

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin&minus, ) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin&minus, cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS. journal article 2020 Feb 03 imported This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project 272983813) TRR179-TP04 (to TB), TRR179-TP01 (to MH and RT), TRR179-TP02 (to CNH), and TRR179-flexible funds (to BB) and BO 3361/4-1 (to TB). TB was supported by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg. NIAID grant U19-AI123862 (to TFB), ARC-IHU (to TFB), European Union grants ERC-AdG-2014-671231-HEPCIR and H2020-2015-667273-HEP-CAR (to TFB and RT), and ANRS grant ECTZ87384 (to TFB) also supported this work