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Long term improvement of body weight and metabolism is highly requested in obesity. The specific impact of weight loss associated temporary negative energy balance or modified body composition on metabolism and weight regain is unclear. We randomly assigned 80 post-menopausal women (BMI 33.9 (32.2–36.8)kg/m2) to an intervention (IG) or control group (CG). IG underwent a dietary three month-weight loss intervention followed by a four week-weight maintenance period without negative energy balance. The CG was instructed to keep their weight stable. Phenotyping was performed at baseline (M0), after weight loss (M3), the maintenance period (M4) and 24-month follow-up (M24). Co-primary outcomes were changes of insulin sensitivity (ISI Clamp) and lean body mass (LBM). Energy metabolism and adipose gene expression were secondary endpoints. Between March 2012 and July 2015, 479 subjects were screened for eligibility. 80 subjects were randomly assigned to IG (n = 40) or CG (n = 40). The total number of dropouts was 18 (IG: n = 13, CG: n = 5). LBM and ISI Clamp were stable in the CG between M0 and M3, but were changed in the IG at M3 (LBM: −1.4 (95%CI -2.2-(-0.6)) kg and ISI Clamp : +0.020 (95%CI 0.012–0.028) mg·kg−1·min−1/(mU·l−1)) (p < 0.01 and p < 0.05 for IG vs. CG, respectively). Effects on LBM, ISI Clamp , FM and BMI were preserved until M4. Lower resting energy expenditure per LBM (REE LBM) at M3 and stronger difference of REE LBM between M3 and M4 (ΔREE LBM-M3M4), which indicates a thrifty phenotype, were positively associated with FM regain at M24 (p = 0.022 and p = 0.044, respectively). Gene set enrichment analysis revealed a relationship of this phenotype to weight loss-induced adaption of adipose FGFR1 signaling. Negative energy balance had no additional effect on insulin sensitivity. FGFR1 signaling might be involved in the adaption of energy expenditure to temporary negative energy balance, which indicates a thrifty phenotype susceptible to weight regain. ClinicalTrials.gov number: NCT01105143, https://clinicaltrials.gov/ct2/show/NCT01105143 , date of registration: April 16th, 2010 [ABSTRACT FROM AUTHOR]

Sustained weight loss is highly desirable in obesity. Although the role of incretins in the regulation of body weight is well known, macronutrient specific incretin response and the effects of weight loss on this response have not been investigated before. We aimed to examine GLP-1, GIP, ghrelin, insulin, and satiety response to meals with different macronutrient composition in overweight and obese subjects before and after weight loss. 32 overweight and obese participants underwent meal tests before and after weight loss intervention. Test meals were designed to be either carbohydrate (CHO), fat (FAT), or protein (PRO) enriched to test macronutrient specific response. Macronutrient specific response of GLP-1, GIP, and ghrelin before and after weight loss were the primary outcome measures. Response of insulin and satiety were predefined secondary endpoints. There were macronutrient specific response patterns of GLP-1 (PRO>FAT=CHO), GIP (CHO=FAT>PRO), and insulin (CHO>PRO=FAT). Postprandial decline of ghrelin did not differ between the test meals. Hunger, desire to eat, and prospective food consumption were highest after CHO intake (CHO>PRO=FAT) at baseline. After weight loss, fasting and postprandial GLP-1 and insulin were reduced while concomitant ghrelin levels were increased. However, the macronutrient specific hormonal response pattern did not change after weight loss. While weight loss increased hunger and desire to eat, the macronutrient specific differences were lost after weight reduction. Higher weight loss was associated with a stronger decline of PRO induced GLP-1 response (ρ = 0.45, p = 0.024, n = 27). Both hormones and satiety showed a macronutrient specific response in overweight/obese participants with a possibly favorable role of protein. However, weight loss may cause a partial disruption of this hormone-satiety-connection as macronutrient specific response pattern of satiety scores representing impulse control in particular but not incretins disappeared. NCT02649907. https://clinicaltrials.gov/ct2/show/NCT02649907 [ABSTRACT FROM AUTHOR]

Head and brain anatomy have been related to e-field strength induced by transcranial electrical stimulation (tES). Individualization based on anatomic factors require high-quality structural magnetic resonance images, which are not always available. Head circumference (HC) can serve as an alternative means, but its linkage to electric field strength has not yet been established. We simulated electric fields induced by tES based on individual T1w- and T2w-images of 47 healthy adults, for four conventional ("standard") and four corresponding focal ("4x1") electrode montages. Associations of electric field strength with individual HC were calculated using linear mixed models. Larger HC was associated with lower electric field strength across montages. We provide mathematical equations to estimate individual electric field strength based on the HC. HC can be used as an alternative to estimate interindividual differences of the tES-induced electric field strength and to prospectively individualize stimulation dose, e.g., in the clinical context. [ABSTRACT FROM AUTHOR]

Recent research on neural and behavioral consequences of transcranial direct current stimulation (tDCS) has highlighted the impact of individual factors, such as brain anatomy which determines current field distribution and may thus significantly impact stimulation effects. Computational modeling approaches may significantly advance our understanding of such factors, but the association of simulation-based tDCS-induced fields and neurophysiological outcomes has not been investigated. To provide empirical evidence for the relationship between tDCS-induced neurophysiological outcomes and individually induced electric fields. We applied tDCS during eyes-closed resting-state functional resonance imaging (rsfMRI) and assessed pre-post magnetic resonance spectroscopy (MRS) in 24 participants. We aimed to quantify effects of 15-min tDCS using the "classical" left SM1-right supraorbital area montage on sensorimotor network (SMN) strength and gamma-aminobutyric acid (GABA) and glutamate concentrations, implementing a cross-over counterbalanced design with three stimulation conditions. Additional structural anatomical MRI sequences and recordings of individual electrode configurations allowed individual electric field simulations based on realistic head models of all participants for both conditions. On a neurophysiological level, we observed the expected reduction of GABA concentrations and increase in SMN strength, both during anodal and cathodal compared to sham tDCS, replicating previous results. The magnitudes of neurophysiological modulations induced by tDCS were significantly associated with simulation-based electric field strengths within the targeted left precentral gyrus. Our findings corroborate previous reports on tDCS-induced neurophysiological modulations and further advance the understanding of underlying mechanisms by providing first empirical evidence for the association of the injected electric field and neuromodulatory effects. • GABA concentrations were reduced after anodal and cathodal compared to sham tDCS. • Functional coupling in the sensorimotor network was increased. • Neurophysiological modulations were associated with electric field strengths. [ABSTRACT FROM AUTHOR]

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Background Previous studies have demonstrated an enhancement of hippocampal-dependent declarative memory consolidation, associated slow wave sleep (SWS) and slow wave activity (SWA) after weak slow oscillatory stimulation (so-tDCS) during early non-rapid eye movement sleep (NREM) in young adults. Recent studies in older individuals could not confirm these findings. However, it remained unclear if this difference was due to variations in study protocol or to the age group under study. Objective/Hypothesis Here, we asked if so-tDCS promotes neurophysiological events and associated sleep-dependent memory in the visuo-spatial domain in older adults, using a stimulation protocol that closely resembled the one employed in young adults. Methods In a randomized, placebo-controlled single-blind (participant) crossover study so-tDCS (0.75 Hz; max. current density 0.522 mA/cm 2 ) vs. sham stimulation was applied over the frontal cortex of 21 healthy older subjects. Impact of stimulation on frequency band activity (linear mixed models), two declarative and one procedural memory tasks (repeated measures ANOVA) and percentage of sleep stages (comparison of means) was assessed. Results so-tDCS, as compared to sham, increased SWA and spindle activity immediately following stimulation, accompanied by significantly impaired visuo-spatial memory consolidation. Furthermore, verbal and procedural memory remained unchanged, while percentage of NREM sleep stage 4 was decreased over the entire night (uncorrected). Conclusion so-tDCS increased SWA and spindle activity in older adults, events previously associated with stimulation-induced improved consolidation of declarative memories in young subjects. However, consolidation of visuo-spatial (primary outcome) and verbal memories was not beneficially modulated, possibly due to decline in SWS over the entire night that may have prevented and even reversed immediate beneficial effects of so-tDCS on SWA. [ABSTRACT FROM AUTHOR]

Background: Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previous evidence has been mixed, and the underlying mechanisms remain unclear. Objective: We determined whether serum VitB12 concentrations within the normal range were linked to memory functions and related neuronal structures in patients with mild cognitive impairment (MCI). Design: In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high-normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n = 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure. Results: MCI patients with low-normal VitB12 showed a significantly poorer learning ability (P = 0.014) and recognition performance (P = 0.008) than did patients with high-normal VitB12. Also, the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and dentate gyrus region (P = 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects. Conclusions: Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural integrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency. [ABSTRACT FROM AUTHOR]

Introduction: Oral anticoagulation (OAC) substantially reduces stroke risk in patients with atrial fibrillation (AF) at risk for stroke. Whether non-vitamin K-dependent oral anticoagulants (NOACs) improve OAC use in stroke prevention requires investigation.Methods: To investigate temporal trends of OAC use in patients with known AF pre-stroke, we retrospectively analyzed records of 6,803 stroke patients admitted in 2003-2004 (n=1,496), 2008-2010 (n=1,638) or 2013-2015 (n=3,669) to the Charité-Universitätsmedizin Berlin, Germany. Adjusted regression models were used to identify factors associated with OAC use.Results: Of 1,209 AF patients (mean age 79 years, 55.9% female) with given indication for OAC according to the CHADS2/CHA2DS2-VASc score, 484 (40.0%) were anticoagulated prior to the index stroke, 458 (37.9%) received antiplatelets and 236 (19.5%) had no antithrombotic medication. Compared to 2003-2004 and 2008-2010, there was a higher rate of pre-admission OAC in 2013-2015 (28.2% vs. 49.6%, p<0.001). After adjustment for possible confounders, factors associated with OAC pre-admission were young age (OR 0.74 per decade [95%CI 0.64-0.85]), previous stroke/TIA (OR 1.29 [95%CI 1.00-1.67]), absence of heart failure (OR 0.63 [95%CI 0.47-0.85]) and admission in 2013-2015 (OR 2.45 [95%CI 1.91-3.15]). Prescription of OAC at hospital discharge increased from 2003-2010 compared to 2013-2015 (45.2% vs. 69.5%, p < 0.001).Conclusions: Irrespective of temporal trends and despite given indication, more than half of all patients with known AF were not anticoagulated prior to the index stroke. In the NOAC era, there was an increase in OAC intake pre-stroke and a higher rate of OAC prescription at hospital discharge in stroke survivors with known AF. [ABSTRACT FROM AUTHOR]

Background Common carotid artery intima-media thickness (CCA-IMT) is an established marker for atherosclerosis. The role of triglycerides in CCA-IMT remains controversial. We sought to determine if elevated fasting and post-challenge triglycerides are associated with CCA-IMT. Methods All acute ischemic stroke patients who participated in the Berlin “Cream & Sugar” study in the Charité Virchow and Charité Mitte Campuses between January 2009 and January 2014 and underwent carotid artery ultrasound studies were eligible for inclusion. A combined oral glucose and triglyceride tolerance test was performed 3–7 days after first ever ischemic stroke. Patients were classified according to triglyceride metabolism—namely, (1) patients reaching a maximum triglyceride levels 3 h post-challenge (“fast metabolizers,” n = 37), (2) patients with increasing triglycerides 4 (medium metabolizers, n = 64), and (3) 5 h post-challenge (“slow metabolizers,” n = 44; 13 missing). Results We included 158 patients (34% female; mean age 63 years, SD 14). Absolute non-fasting triglyceride levels were positively associated with CCA-IMT. A final multiple regression model revealed that older age, more severe strokes, and higher levels of fasting triglycerides were significantly and independently associated with higher mean CCA-IMT. Older age, higher waist-to-hip ratio, and higher levels of thyroid-stimulating hormone were independently associated with higher maximum CCA-IMT. Conclusion Fasting triglycerides but not post-challenge triglycerides associate with CCA-IMT. An oral fat challenge may not add information on atherosclerotic status in ischemic stroke patients. Clinical Trial Registration Information: The Berlin “Cream & Sugar” study is registered with EudraCT (2009-010356-97) and clinicaltrials.gov (NCT 01378468). [ABSTRACT FROM AUTHOR]

Background Higher heart rate (HR) is associated with worse outcomes - in particular death - in long term follow-up of patients with vascular diseases. We investigated the association between HR measured on admission and early in-hospital mortality in acute ischemic stroke patients. Methods Over a period of 30 months all patients admitted to our hospital with acute ischemic stroke but without atrial fibrillation were prospectively enrolled. Univariate and multiple logistic regression analyses were conducted to estimate the impact of HR on in-hospital mortality. HR was analyzed as continuous and categorical variable (tertiles). Results A total of 1335 patients (median age 73 (IQR 65-81), median National Institutes of Health Stroke Scale score 4 (IQR 2-8), median length of stay 5 days (IQR 4-7), female sex 46%) were studied. In-hospital mortality was 2.6%. When analyzed as categorical variable, HR ≥ 83 bpm was independently associated with in-hospital mortality after adjustment for predictors of poor outcome compared to the reference tertile (HR ≤ 69 bpm) (adjusted odds ratio 4.42, 95% CI 1.36-14.42, p = 0.01). When HR was modeled as continuous variable, relative risk for in-hospital death was elevated by 40% for every additional 10-bpm (p = 0.003). These results were not changed by including beta-blockers as covariate into the multiple regression model. Conclusions HR on admission is independently associated with in-hospital mortality in acute ischemic stroke patients suggesting early negative effects of autonomic imbalance. HR may represent a therapeutic target to improve outcome after ischemic stroke. [ABSTRACT FROM AUTHOR]

Aims: To estimate the prevalence of parental substance use disorder (PSUD) in the general population based on young adults' reports adjusted for non-participation using register-based indicators of PSUD.Design: A national sample survey study combined with a retrospective register-based study. Setting Denmark. Participants 10,414 young people (aged 15-25 years) invited to two national sample surveys in 2014 and 2015 (5,755 participants and 4,659 non-participants).Measurements: A crude prevalence of PSUD was calculated based on participants' reports. Parental data from medical, mortality, prescription, and treatment registers (from the young adults' birth until the time of the surveys) were used to estimate a register-based prevalence of PSUD for both participants and non-participants. Differences between participants and non-participants were analysed using bivariate comparisons. Inverse probability weighting was used to adjust for bias due to non-participation. The crude prevalence of PSUD based on survey data was adjusted using the ratio of incidence proportion of the register-based PSUD compared with the survey-based PSUD.Findings: A total of 731 (12.7%) of the 5,755 survey participants reported PSUD. Register-based PSUD was more common among non-participants (856/4,659; 18.4%) compared with participants (738/5,755; 12.8%, OR = 1.53, 95% CI 1.38-1.70). The adjusted estimate of the survey-based PSUD increased by 2.5 percentage points, from 12.7% to 15.2%.Conclusions: In the absence of register data, youth-reported PSUD is likely to underestimate the number of young people experiencing PSUD. [ABSTRACT FROM AUTHOR]

Strategies for memory enhancement, especially for the older population, are of great scientific and public interest. Here, we aimed at investigating neuronal and behavioral effects of transcranial direct current stimulation (tDCS) paired with memory training. Young and older adults were trained on an object-location-memory task on 3 consecutive days with either anodal or sham tDCS. Recall performance was assessed immediately after training, 1 day and 1 month later, as well as performance on trained function and transfer task. Resting-state functional magnetic resonance imaging was conducted at baseline and at 1-day follow-up to analyze functional coupling in the default mode network. Anodal tDCS led to superior recall performance after training, an associated increase in default mode network strength and enhanced trained function and transfer after 1 month. Our findings suggest that tDCS-accompanied multi-day training improves performance on trained material, is associated with beneficial memory network alterations, and transfers to other memory tasks. Our study provides insight into tDCS-induced behavioral and neuronal alterations and will help to develop interventions against age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Specialised CT-equipped mobile stroke treatment units shorten time to intravenous thrombolysis in acute ischaemic stroke by starting treatment before hospital admission; however, direct effects of pre-hospital thrombolysis on clinical outcomes have not been shown. We aimed to compare 3-month functional outcomes after intravenous thrombolysis in patients with acute ischaemic who had received emergency mobile care or and conventional care.Methods: In this observational registry study, patients with ischaemic stroke received intravenous thrombolysis (alteplase) either within a stroke emergency mobile (STEMO) vehicle (pre-hospital care covering 1·3 million inhabitants of Berlin) or within conventional care (normal ambulances and in-hospital care at the Charité Campus Benjamin Franklin in Berlin). Patient data on treatment, outcome, and demographics were documented in STEMO (pre-hospital) or conventional care (in-hospital) registries. The primary outcome was the proportion of patients who had lived at home without assistance before stroke and had a 3-month modified Rankin Scale (mRS) score of 1 or lower. Our multivariable logistic regression was adjusted for demographics, comorbidities, and stroke severity. This study is registered with ClinicalTrials.gov, number NCT02358772.Findings: Between Feb 5, 2011, and March 5, 2015, 427 patients were treated within the STEMO vehicle and their data were entered into a pre-hospital registry. 505 patients received conventional care and their data were entered into an in-hospital thrombolysis registry. Of these, 305 patients in the STEMO group and 353 in the conventional care group met inclusion criteria and were included in the analysis. 161 (53%) patients in the STEMO group versus 166 (47%) in the conventional care group had an mRS score of 1 or lower (p=0·14). Compared with conventional care, adjusted odds ratios (ORs) for STEMO care for the primary outcome (OR 1·40, 95% CI 1·00-1·97; p=0·052) were not significant. Intracranial haemorrhage (p=0·27) and 7-day mortality (p=0·23) did not differ significantly between treatment groups.Interpretation: We found no significant difference between the proportion of patients with a mRS score of 1 or lower receiving STEMO care compared with conventional care. However, our results suggest that pre-hospital start of intravenous thrombolysis might lead to improved functional outcome in patients. This evidence requires substantiation in future large-scale trials.Funding: Zukunftsfonds Berlin, the Technology Foundation Berlin with EU co-financing by the European Regional Development Fund via Investitionsbank Berlin, and the German Federal Ministry for Education and Research via the Center for Stroke Research Berlin. [ABSTRACT FROM AUTHOR]

Summary: While the consolidation of declarative memory is supported by slow wave sleep (SWS) in healthy subjects, it has been shown to be associated with rapid eye movement (REM) sleep in patients with insomnia. Sleep during a subject''s first night in an unfamiliar environment is often disturbed, and this so-called first-night effect (FNE) has often been used as a model of transient insomnia. Additionally, sleeping for the first time in an unfamiliar environment can lead to increased cortisol secretion, and declarative memory consolidation likely depends on low cortisol levels, especially during the early part of the night. Accounting for intersubject variability in the FNE, we examined the relationship between sleep stages, cortisol secretion and declarative memory performance in 27 healthy young men. Declarative memory performance improved significantly after sleep. Whereas memory performance during the learning session and retrieval testing was strongly associated with cortisol secretion, the overnight gain was not. Post hoc analyses indicated that the overnight gain appears to be modulated by the extent of the FNE: a significant overnight improvement in memory performance was found only in subjects with a weak FNE (n =12). In these subjects, no association was found between any sleep stage and the improvement observed in their memory performance. In subjects with a strong FNE (n =12), however, the overnight change in memory performance was associated with the proportion of REM sleep and the total number of REMs. Disturbed sleep in an unfamiliar environment therefore appears to affect the memory consolidation process. [Copyright &y& Elsevier]

Abstract: There has been increasing interest in investigating whether inhabitants in socially or physically deprived neighborhoods have higher mortality when individual socioeconomic status is adjusted for. Results so far appear ambiguous and the objective of this study was to conduct a systematic literature review of previous studies and to quantify the association between area-level socioeconomic status (ALSES) and all-cause mortality in a meta-analysis. Current guidelines for systematic reviews and meta-analyses were followed. Articles were retrieved from Medline, Embase, Social Sciences Citation Index and PsycInfo and individually evaluated by two researchers. Only peer-reviewed multilevel studies from high-income countries, which analyzed the influence of at least one area-level indicator and which controlled for individual SES, were included. The ALSES estimates in each study were first combined into a single estimate using weighted linear regression. In the meta-analysis we calculated combined estimates with random effects to account for heterogeneity between studies. Out of the 40 studies found eligible for the systematic review 18 studies were included in the meta-analysis. The systematic review suggests that there is an association between social cohesion and mortality but found no evidence for a clear association for area-level income inequality or for social capital. Studies including more than one area level suggest that characteristics on different area levels contribute to individual mortality. In the meta-analysis we found significantly higher mortality among inhabitants living in areas with low ALSES. Associations were stronger for men and younger age groups and in studies analyzing geographical units with fewer inhabitants. [Copyright &y& Elsevier]

Abstract: For seventeen 1,4-benzothiazine potassium channel openers, we performed binding studies in rat aortic smooth muscle cells and cardiomyocytes, compared their binding affinities with published relaxation data, and derived 3D-QSAR models using GRIND/ALMOND descriptors. Binding affinities in smooth muscle cells range from a pK D of 4.76 for compound 3e to 9.10 for compound 4c. Comparison of data for smooth muscle relaxation and binding shows preferentially higher pEC50s for the former. In cardiomyocytes, pK D values range from 4.21 for 3e to 8.16 for 4c. 3D-QSAR analysis resulted in PLS models of two latent variables for all three activities with determination coefficients of 0.97 (smooth muscle relaxation) and 0.94 (smooth muscle cells- and cardiomyocytes-binding). Internal validation yielded q 2 values of 0.69, 0.66, and 0.64. The carbonyl on the N-4 substituent, the hydrogen bond acceptor at C-6, the five-membered ring at N-4, and the gem-dimethyls mainly guide strong binding and strong smooth muscle relaxation. [Copyright &y& Elsevier]