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BackgroundThis study aimed to describe available evidence of cochlear implantation delivery arrangements in adults and the outcomes by which these service models are measured.MethodsScoping review of English language, primary studies conducted on adults (≥18 years) with ten or more subjects, published between January 2000 and June 2022, which assessed the effects of delivery arrangements of cochlear implantation were included. MEDLINE, EMBASE, CINAHL Plus, AMED, PsycINFO, LILACS, KoreaMed, IndMed, Cochrane CRCT, ISRCTN registry, WHO ICTRP and Web of Science were systematically searched. Included studies had to have a method section explicitly measure at least one of the Cochrane Effective Practice and Organization of Care (EPOC) outcome category. Criteria for systematic reviews and delivery arrangement category based on EPOC taxonomy was included in data extraction. Data was narratively synthesized based on EPOC categories.ResultsA total of 8135 abstracts were screened after exclusion of duplicates, of these 357 studies fulfilled the inclusion criteria. Around 40% of the studies investigated how care is delivered, focusing on quality and safety systems. New care pathways to coordinate care and the use of information and communication technology were emerging areas. There was little evidence on continuity, coordination and integration of care, how the workforce is managed, where care is provided and changes in the healthcare environment. The main outcome measure for various delivery arrangements were the health status and performance in a test.ConclusionA substantial body of evidence exists about safety and efficacy of cochlear implantation in adults, predominantly focused on surgical aspects and this area is rapidly growing. There is a lack of evidence on aspects of care delivery that may have more impact on patients' experience such as continuity, coordination and integration of care and should be a focus of future research. This would lead to a better understanding of how patient's view CI experience, associated costs and the value of different care models.

Aiming at streamlining GPCR production from E. coli inclusion bodies for structural analysis, we present a generic approach to assess and optimize refolding yield through thermostability analysis. Since commonly used hydrophobic dyes cannot be applied as probes for membrane protein unfolding, we adapted a technique based on reacting cysteins exposed upon thermal denaturation with fluorescent 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM). Successful expression, purification and refolding is shown for two G protein-coupled receptors (GPCR), the sphingosine-1-phosphate receptor S1P1, and the orphan receptor GPR3. Refolded receptors were subjected to lipidic cubic phase crystallization screening.

IntroductionSeasonal influenza is a major global health problem causing substantial morbidity and health care costs. Yet, in many countries, the rates of influenza vaccination remain low. Chronic kidney or liver diseases (CKLD) predispose patients to severe influenza infections, but data on vaccination acceptance and status is limited in this risk population. We investigated the influenza vaccination awareness considering sociodemographic factors in CKLD patients.Patients and methodsThis cross-sectional, questionnaire-based study recruited CKLD patients managed at three Viennese tertiary care centers between July and October 2020. CKLD was defined as chronic kidney- (all stages) or compensated/decompensated liver disease, including kidney/liver transplant recipients. Questionnaires assessed sociodemographic and transplant- associated parameters, patients vaccination status and the individuals self-perceived risks of infection and associated complications.ResultsIn total 516 patients (38.1% female, mean age 56.4 years) were included. 43.9% of patients declared their willingness to be vaccinated in the winter season 2020/2021, compared to 25.4% in 2019/2020 and 27.3% in 2016-2018. Vaccination uptake was associated with the self-perceived risks of infection (OR: 2.8 (95%CI: 1.8-4.5), pConclusionWhile influenza vaccination willingness in patients with CKLD is increasing in the 2020/2021 season, vaccination rates may still remain

Treating hyperglycemia in previously non-diabetic individuals with exogenous insulin immediately after kidney transplantation reduced the odds of developing Posttransplantation Diabetes Mellitus (PTDM) in our previous proof-of-concept clinical trial. We hypothesized that insulin-pump therapy with maximal insulin dosage during the afternoon would improve glycemic control compared to basal insulin and standard-of-care. In a multi-center, randomized, controlled trial testing insulin isophane for PTDM prevention, we added a third study arm applying continuous subcutaneous insulin lispro infusion (CSII) treatment. CSII was initiated in 24 patients aged 55±12 years, without diabetes history, receiving tacrolimus. The mean daily insulin lispro dose was 9.2±5.2 IU. 2.3±1.1% of the total insulin dose were administered between 00:00 and 6:00, 19.5±11.6% between 6:00 and 12:00, 62.3±15.6% between 12:00 and 18:00 and 15.9±9.1% between 18:00 and 24:00. Additional bolus injections were necessary in five patients. Mild hypoglycemia (52-60 mg/dL) occurred in two patients. During the first post-operative week glucose control in CSII patients was overall superior compared to standard-of-care as well as once-daily insulin isophane for fasting and post-supper glucose. We present an algorithm for CSII treatment in kidney transplant recipients, demonstrating similar safety and superior short-term efficacy compared to standard-of-care and once-daily insulin isophane.

Transfusion therapy is associated with increased morbidity, mortality and costs. Conventional coagulation tests (CCT) are weak bleeding predictors, poorly reflecting coagulation in vivo. Thromboelastometry (ROTEM) provides early identification of coagulation disorders and can guide transfusion therapy by goals, reducing blood components transfusion.The aim of this study is to describe coagulation profile of critically ill patients using ROTEM and evaluate the association between CCT and thromboelastometry.This is a retrospective, observational study conducted in medical-surgical intensive care unit (ICU). Adult patients (≥18 years) admitted to ICU between November 2012 and December 2014, in whom ROTEM analyses were performed for bleeding management were included in this study. The first ROTEM and CCT after ICU admission were recorded simultaneously. Additionally, we collected data on blood components transfusion and hemostatic agents immediately after laboratory tests results.The study included 531 patients. Most ROTEM tests showed normal coagulation profile [INTEM (54.8%), EXTEM (54.1%) and FIBTEM (53.3%)] with divergent results in relation to CCT: low platelet count (51.8% in INTEM and 55.9% in EXTEM); prolonged aPTT (69.9% in INTEM and 63.7% in EXTEM) and higher INR (23.8% in INTEM and 27.4% in EXTEM). However 16,7% of patients with normocoagulability in ROTEM received platelet concentrates and 10% fresh frozen plasma.The predominant ROTEM profile observed in this sample of critically ill patients was normal. In contrast, CCT suggested coagulopathy leading to a possibly unnecessary allogenic blood component transfusion. ROTEM test may avoid inappropriate allogeneic blood products transfusion in these patients.

[This corrects the article DOI: 10.1371/journal.pone.0189973.].

In the United States, women accounted for 19% of new HIV diagnoses in 2015 and were less likely to reach virologic suppression when compared to men. We assessed trends and disparities in virologic suppression among HIV-positive women to inform HIV treatment strategies. Data were from a prospective cohort of the HIV Outpatient Study and collected at nine United States HIV clinics. We included women aged ≥18 years, with ≥1 visit, who were prescribed antiretroviral therapy, and had ≥1 viral load test performed between 2010 and 2015. We defined virologic suppression as viral load

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

Protease-mediated degradation of proteins is critical in a plethora of physiological processes. Neutrophils secrete serine proteases including cathepsin G (CatG), neutrophile elastase (NE), and proteinase 3 (PR3) together with lactoferrin (LF) as a first cellular immune response against pathogens. Here, we demonstrate that LF increases the catalytic activity of CatG at physiological concentration, with its highest enhancing capacity under acidic (pH 5.0) conditions, and broadens the substrate selectivity of CatG. On a functional level, the enzymatic activity of CatG was increased in the presence of LF in granulocyte-derived supernatant. Furthermore, LF enhanced CatG-induced activation of platelets as determined by cell surface expression of CD62P. Consequently, LF-mediated enhancement of CatG activity might promote innate immunity during acute inflammation.

Cereblon, a primary target of thalidomide and its derivatives, has been characterized structurally from both bacteria and animals. Especially well studied is the thalidomide binding domain, CULT, which shows an invariable structure across different organisms and in complex with different ligands. Here, based on a series of crystal structures of a bacterial representative, we reveal the conformational flexibility and structural dynamics of this domain. In particular, we follow the unfolding of large fractions of the domain upon release of thalidomide in the crystalline state. Our results imply that a third of the domain, including the thalidomide binding pocket, only folds upon ligand binding. We further characterize the structural effect of the C-terminal truncation resulting from the mental-retardation linked R419X nonsense mutation in vitro and offer a mechanistic hypothesis for its irresponsiveness to thalidomide. At 1.2Å resolution, our data provide a view of thalidomide binding at atomic resolution.

Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic glomerulonephritis with poor renal prognosis. Current therapy favours plasma exchange (PE) for removal of pathogenic antibodies. Immunoadsorption (IAS) is superior to PE regarding efficiency of antibody-removal and safety. Apart from anecdotal data, there is no systemic analysis of the long-term effects of IAS on anti-GBM-disease and antibody kinetics.To examine the long-term effect of high-frequency IAS combined with standard immunosuppression on patient and renal survival in patients with anti-GBM-disease and to quantify antibody removal and kinetics through IAS.Retrospective review of patients treated with IAS for anti-GBM-antibody disease confirmed by biopsy and/or anti-GBM-antibodies.University Hospital of Vienna, Austria.10 patients with anti-GBM-disease treated with IAS.Patient and renal survival, renal histology, anti-GBM-antibodies.Anti-GBM-antibodies were reduced by the first 9 IAS treatments (mean number of 23) to negative levels in all patients. Renal survival was 40% at diagnosis, 70% after the end of IAS, 63% after one year and 50% at the end of observation (mean 84 months, range 9 to 186). Dialysis dependency was successfully reversed in three of six patients. Patient survival was 90% at the end of observation.IAS efficiently eliminates anti-GBM-antibodies suggesting non-inferiority to PE with regard to renal and patient survival. Hence IAS should be considered as a valuable treatment option for anti-GBM-disease, especially in patients presenting with a high percentage of crescents and dialysis dependency due to an unusual high proportion of responders.

Ubiquitylation is a highly diverse and complex post-translational modification for the regulation of protein function and stability. Studies of ubiquitylation have, however, been hampered by its rapid reversal in cell extracts, for example through the action of de-ubiquitylating enzymes (DUBs). Here we describe a novel ubiquitin-binding protein reagent, MultiDsk, composed of an array of five UBA domains from the yeast ubiquitin-binding protein Dsk2, fused to GST. MultiDsk binds ubiquitylated substrates with unprecedented avidity, and can be used as both an affinity resin to study protein ubiquitylation, and to effectively protect ubiquitylated proteins from the action of DUBs and the proteasome in crude cell extracts. We use the resin to show that the Def1 protein becomes ubiquitylated in response to DNA damage, and to isolate ubiquitylated forms of RNA polymerase II.

The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop.

Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment.We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size.Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force.

Estrogens are used extensively to treat hot flashes in menopausal women. Some of the beneficial effects of estrogens in hormone therapy on the brain might be due to nongenomic effects in neurons such as the rapid stimulation of calcium oscillations. Most studies have examined the nongenomic effects of estrogen receptors (ER) in primary neurons or brain slices from the rodent brain. However, these cells can not be maintained continuously in culture because neurons are post-mitotic. Neurons derived from embryonic stem cells could be a potential continuous, cell-based model to study nongenomic actions of estrogens in neurons if they are responsive to estrogens after differentiation. In this study ER-subtype specific estrogens were used to examine the role of ERalpha and ERbeta on calcium oscillations in neurons derived from human (hES) and mouse embryonic stem cells. Unlike the undifferentiated hES cells the differentiated cells expressed neuronal markers, ERbeta, but not ERalpha. The non-selective ER agonist 17beta-estradiol (E(2)) rapidly increased [Ca2+]i oscillations and synchronizations within a few minutes. No change in calcium oscillations was observed with the selective ERalpha agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT). In contrast, the selective ERbeta agonists, 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN), MF101, and 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3 benzoxazol-5-ol (ERB-041; WAY-202041) stimulated calcium oscillations similar to E(2). The ERbeta agonists also increased calcium oscillations and phosphorylated PKC, AKT and ERK1/2 in neurons derived from mouse ES cells, which was inhibited by nifedipine demonstrating that ERbeta activates L-type voltage gated calcium channels to regulate neuronal activity. Our results demonstrate that ERbeta signaling regulates nongenomic pathways in neurons derived from ES cells, and suggest that these cells might be useful to study the nongenomic mechanisms of estrogenic compounds.

BackgroundObesity is a global health concern and risk factor for cardiovascular disease. The assessment of central blood pressure (cBP) has been shown to improve prediction of cardiovascular events. However, few studies have investigated the impact of obesity on cBP in adults, and invasive data on this issue are lacking. This study aimed to evaluate cBP differences between patients with and without obesity, identify cBP determinants, and evaluate the accuracy of the algorithm Antares for non-invasive cBP estimation.MethodsA total of 190 patients (25% female; 39% with BMI ≥30kg/m2; age: 67±12 years) undergoing elective cardiac catheterization were included. cBP was measured invasively and simultaneously estimated non-invasively using the custo screen 400 device with integrated Antares algorithm.ResultsNo significant cBP differences were found between obese and non-obese patients. However, females, especially those with obesity, had higher systolic cBP compared to males (PConclusionsThis study discovered no significant difference in cBP between obese and non-obese patients. However, it revealed higher cBP values in women, especially those with obesity, which requires further investigation. Additionally, the study highlights Antares' effectiveness in non-invasively determining cBP in obese individuals. This could improve the diagnosis and treatment of hypertension in this special patient population.

Modeling time series has been a particularly challenging aspect due to the need for constant adjustments in a rapidly changing environment, data uncertainty, dependencies between variables, volatile fluctuations, and the need to identify ideal hyperparameters. The present study presents a Framework capable of making projections from time series related to cases and deaths by COVID-19 in the Amazonian state of Pará, in Brazil. For the first time, deep learning models such as TCN, TRANSFORMER, TFT, N-BEATS, and N-HiTS were assessed for this purpose. The ARIMA statistical model was also used in post-processing for residual adjustment and short-term smoothing of the generated forecasts. The Framework generates probabilistic forecasts, with multivariate support, considering the following variables: daily cases per day of the first symptom, cases published daily, the occurrence of deaths, deaths published daily, and percentage of daily vaccination. The generated predictions are statistically evaluated by determining the best model for 7-day moving average projections using evaluating metrics such as MSE, RMSE, MAPE, sMAPE, r2, Coefficient of Variation, and residual analysis. As a result, the generated projections showed an average error of 5.4% for Cases Publication, 8.0% for Cases Symptoms, 11.12% for Deaths Publication, and 4.6% for Deaths Occurrence, with the N-HiTS and N-BEATS models obtaining better results. In general terms, the use of deep learning models to predict cases and deaths from COVID-19 has proven to be a valuable practice for analyzing the spread of the virus, which allows health managers to better understand and respond to this kind of pandemic outbreak.

Microglial cells are brain-specific macrophages that swiftly react to disruptive events in the brain. Microglial activation leads to specific modifications, including proliferation, morphological changes, migration to the site of insult, and changes in gene expression profiles. A change in inflammatory status has been linked to many neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. For this reason, the investigation and quantification of microglial cells is essential for better understanding their role in disease progression as well as for evaluating the cytocompatibility of novel therapeutic approaches for such conditions. In the following study we implemented a machine learning-based approach for the fast and automatized quantification of microglial cells; this tool was compared with manual quantification (ground truth), and with alternative free-ware such as the threshold-based ImageJ and the machine learning-based Ilastik. We first trained the algorithms on brain tissue obtained from rats and non-human primate immunohistochemically labelled for microglia. Subsequently we validated the accuracy of the trained algorithms in a preclinical rodent model of Parkinson's disease and demonstrated the robustness of the algorithms on tissue obtained from mice, as well as from images provided by three collaborating laboratories. Our results indicate that machine learning algorithms can detect and quantify microglial cells in all the three mammalian species in a precise manner, equipotent to the one observed following manual counting. Using this tool, we were able to detect and quantify small changes between the hemispheres, suggesting the power and reliability of the algorithm. Such a tool will be very useful for investigation of microglial response in disease development, as well as in the investigation of compatible novel therapeutics targeting the brain. As all network weights and labelled training data are made available, together with our step-by-step user guide, we anticipate that many laboratories will implement machine learning-based quantification of microglial cells in their research.

In the United States, women accounted for 19% of new HIV diagnoses in 2015 and were less likely to reach virologic suppression when compared to men. We assessed trends and disparities in virologic suppression among HIV-positive women to inform HIV treatment strategies. Data were from a prospective cohort of the HIV Outpatient Study and collected at nine United States HIV clinics. We included women aged ≥18 years, with ≥1 visit, who were prescribed antiretroviral therapy, and had ≥1 viral load test performed between 2010 and 2015. We defined virologic suppression as viral load <50 copies/mL and calculated adjusted prevalence ratios (aPR) with 95% confidence intervals (CI) for virologic suppression by race/ethnicity and year of measure. Generalized estimating equations were used for multivariable analyses to assess factors associated with virologic suppression. Among 809 women (median age = 44 years), 482 (60%) were black, 177 (22%) white, 150 (19%) Hispanic/Latina. Virologic suppression was less prevalent among black women (73%) compared with Hispanic/Latina women (83%) and white women (91%). In multivariable analyses, not achieving virologic suppression was more likely among black women (aPR = 2.13; CI = 1.50–3.02) or Hispanic/Latina women (aPR = 1.66; CI = 1.08–2.56) compared with white women, and among women who attended public clinics (aPR = 1.42; CI = 1.07–1.87) compared with those who attended a private clinic. Between 2010 and 2015, virologic suppression among HIV-positive women increased from 68% to 83%, but racial/ethnic disparities persisted. Black and Hispanic/Latina women had significantly lower rates of virologic suppression than white women. Interventions targeting virologic suppression improvement among HIV-positive women of color, especially those who attend public clinics, are warranted. [ABSTRACT FROM AUTHOR]

To achieve herd immunity against COVID-19, it is crucial to know the drivers of vaccination intention and, thereby, vaccination. As the determinants of vaccination differ across vaccines, target groups and contexts, we investigate COVID-19 vaccination intention using data from university students from three countries, the Netherlands, Belgium and Portugal. We investigate the psychological drivers of vaccination intention using the 5C model as mediator. This model includes five antecedents of vaccination: Confidence, Complacency, Constraints, Calculation and Collective Responsibility. First, we show that the majority of students have a positive propensity toward getting vaccinated against COVID-19, though only 41% of students are completely acceptant. Second, using the 5C model, we show that ‘Confidence’ (β = 0.33, SE = 03, p < .001) and ‘Collective Responsibility’ (β = 0.35, SE = 04, p < .001) are most strongly related to students’ COVID-19 vaccination intention. Using mediation analyses, we show that the perceived risk and effectiveness of the vaccine as well as trust in the government and health authorities indirectly relate to vaccination intention through ‘Confidence’. The perceived risk of COVID-19 for one’s social circle and altruism, the need to belong and psychopathy traits indirectly relate to vaccination intention through ‘Collective Responsibility’. Hence, targeting the psychological characteristics associated with ‘Confidence’ and ‘Collective Responsibility’ can improve the effectiveness of vaccination campaigns among students.

The first case of the novel coronavirus in Brazil was notified on February 26, 2020. After 21 days, the first case was reported in the second largest State of the Brazilian Amazon. The State of Pará presented difficulties in combating the pandemic, ranging from underreporting and a low number of tests to a large territorial distance between cities with installed hospital capacity. Due to these factors, mathematical data-driven short-term forecasting models can be a promising initiative to assist government officials in more agile and reliable actions. This study presents an approach based on artificial neural networks for the daily and cumulative forecasts of cases and deaths caused by COVID-19, and the forecast of demand for hospital beds. Six scenarios with different periods were used to identify the quality of the generated forecasting and the period in which they start to deteriorate. Results indicated that the computational model adapted capably to the training period and was able to make consistent short-term forecasts, especially for the cumulative variables and for demand hospital beds.

BackgroundLack of physical activity (PA) and a high level of physical inactivity (PI) are associated with a higher risk for mortality and responsible for several non-communicable diseases including cardiovascular disease. Higher age is associated with a decrease of PA and an increasing level of PI. Studies have shown that interventions in the elderly have the potential to increase the amount of PA and to decrease the level of PI. However, most interventions are complex, elaborated, time- and resource-consuming. Here, we examined the effect of individual feedback-letters reporting the measured PA and PI in a sample of elderly people in Germany. Primary outcomes of the study were overall PA and PI after 6 months in the intervention group compared to a control group.MethodsWe examined data from the MOVING intervention study (RCT) for people aged ≥ 65 years living in the northeast of Germany. At baseline, 3 and 6-months follow-up, all study participants wore a 3-axis accelerometer over a period of seven consecutive days. After the baseline measurement, the participants were randomized into intervention and control group. Participants in the intervention group received automatically generated, individualized feedback letters reporting their PA and PI by mail after the baseline measurement and after the 3-months follow-up. A Two-Way Mixed ANOVA with repeated measures was calculated with light, moderate and overall PA as well as PI as dependent variables, and group (between subject) and time (inner subject) as factors. The analysis based on retrospective data from the MOVING study (2016-2018).ResultsN = 258 patients were recruited. N = 166 participants could be included in the analysis, thereof N = 97 women (58.4%). The mean age was 70.8 years (SD 4.8). At baseline, the participants had a mean wearing time of 5,934.5 minutes (SD = 789.5) per week, which corresponds to about 14 hours daily on average. The overall PA in the intervention group at the 6-months follow up was 2488.8 (95% CI 2358.9-2618.2) minutes and 2408.2 (95% CI 2263.0-2553.4) minutes in the control group. There was no statistically significant interaction effect (time*group) between the intervention and control group for the depending variables. Sensitivity analyses showed significant small positive effects of the interaction time*partnership, F(2, 300) = 3.020, p = 0.05, partial η2 = 0.020.DiscussionOn average, study participants had high levels of PA at baseline and showed a good adherence in wearing the accelerometer. Both is likely due to selection in the convenience study sample. Thus, some ceiling effect reduced the overall intervention effect somewhat. At baseline, the weekly average of PI was 3436.7 minutes, which correspondents to about 8.2 hours per day and about 57% of participants' daily waking time. The average level of PI could be slightly decreased in both study groups.Trial registration numberDRKS00010410, 17 May 2017.

BACKGROUND:Low levels of physical activity (PA) and high levels of physical inactivity (PI) are associated with higher mortality and cardiovascular diseases. Higher age is associated with a decrease of PA, only 2.4-29% of ≥60 year-olds achieve the PA times recommended by WHO. The aim of this study was to identify levels of and determinants for moderate PA, overall PA and PI in a sample of individuals aged ≥65 years. METHODS:We analyzed baseline data from an intervention-study aiming to increase PA and decrease PI by automatically generated feedback letters to objectively measured PA and PI. Recruitment was multimodal including re-contacting participants of previous studies and advertisements in regional public buses and newspapers. At baseline, participants wore an accelerometer over a period of 7 consecutive days. PA was categorized using cut-points suggested by Freedsoon 1998 in light, moderate and vigorous physical intensity as well as physical inactivity. Potential determinants (self-efficacy, education) were measured by questionnaires or in a physical examination (BMI). Multiple linear regression models were fitted to identify determinants for PA and PI. RESULTS:N = 199 persons (mean age 71.0 years (SD 4.9), 59.3% female) participated in the study. The weekly amount of overall PA for men was on average 1,821 minutes (SD 479.1), for women on average 1,929 minutes (SD 448.8). 79.7% of the women and 72.8% of the men achieved the WHO recommendation of 30 minutes moderate PA/day at baseline. The time of PI during the observation time period of 7 days was on average 4,057 minutes in men and 3,973 minutes in women. In males, age was found to be a significant negative determinant for overall PA (p = 0.002) and for moderate PA (p

BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.Methods and resultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.ConclusionThis study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.