Search

Background Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL. Methods This case–control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group. Results In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22–29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2–8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients. Discussion HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas. Trial registration information Clinicaltrials.gov, NCT03979521, submitted: June 7, 2019, first patient enrolled: May 1, 2019, https://clinicaltrials.gov/ct2/show/NCT03979521

Purpose To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI). Methods Ambispective cohort study (2011–2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression. Results The median age of the study population was 58.8 years (42.0–74.6 IQR). Older age (≥ 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2–121.3) compared to 6.6 h (4.4–47.9) in younger patients (≤ 44y). Main reasons for delayed surgery in older individuals were secondary referrals and multimorbidity. Shorter time span to surgery (≤ 12 h) was associated with higher rates of ASIA impairment scale (AIS) conversion (OR 4.22, 95%CI 1.85–9.65), as mirrored by adjusted spline curves ( 60 h Conclusion Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients.

Ziel Vor dem Hintergrund der demografischen Entwicklung werden zukunftig Versorgungsmodelle wichtig, die Hausarzte in der Versorgung von Patienten mit komplexem Bedarf unterstutzen konnen. Die vorliegende Fragebogenstudie untersucht, welche Formen der Unterstutzung sich Berliner Hausarzte wunschen. Methodik Alle niedergelassenen Hausarzte Berlins (n=2354) wurden im Zeitraum August bis September 2018 postalisch gebeten, einen fur die Fragestellung entwickelten Fragebogen auszufullen. Die Fragen adressierten den Unterstutzungsbedarf sowie verschiedene Unterstutzungsmodelle. Es wurde zwischen Unterstutzungsmoglichkeiten innerhalb (Delegation, Substitution) und auserhalb (Sozialarbeiter, Versorgungslotsen, Pflegestutzpunkt) von Hausarztpraxen differenziert. Die Auswertung erfolgte deskriptiv, sowie explorativ multivariat in Bezug auf Zusammenhange zwischen der Zustimmung zu Unterstutzungsmodellen und Praxis- bzw. Arztcharakteristika (Alter, Geschlecht der Arzte, Lage der Praxis, Praxisform, Arbeitszeit). Ergebnisse 557 Fragebogen (Response Rate 23,7%) wurden ausgewertet. Unterstutzungsbedarf wurde v. a. fur administrative, koordinative und organisatorische Tatigkeiten gesehen sowie fur soziale und sozialrechtliche Fragestellungen. Ein Grosteil der teilnehmenden hausarztlichen Praxen steht sowohl der Delegation als auch der Substitution arztlicher Leistungen positiv gegenuber. Daruber hinaus ist fur Hausarzte auch Unterstutzung auserhalb der eigenen Praxis durch Mitarbeiter eines ambulanten Pflegedienstes, eines Pflegestutzpunktes, oder durch Sozialarbeiter und Versorgungslotsen vorstellbar. Insbesondere jungere und weibliche Hausarzte sowie diejenigen, die bereits in kooperativen Praxis-Strukturen tatig sind, sind offen fur kooperative Ansatze unter Einbeziehung weiterer Gesundheitsberufe. Schlussfolgerung Es bestehen noch unzureichend genutzte Potenziale der Delegation und der Kooperation mit bestehenden Strukturen. Die hier befragten Berliner Hausarzte zeigten ein hohes Mas an Zustimmung zu Delegation und Substitution. Aber auch Gesundheitsberufe und Institutionen auserhalb der eigenen Praxis konnten die Hausarzte starker unterstutzen. Insbesondere fur administrative und koordinative Tatigkeiten sowie fur soziale und sozialrechtliche Fragestellungen wird Unterstutzungsbedarf gesehen. In weiteren Untersuchungen sollte die Akzeptanz unter der Arzteschaft und die Machbarkeit unterschiedlicher Modelle weiter untersucht werden.

Background: This randomized controlled trial investigated if uni- and bihemispheric transcranial direct current stimulation (tDCS) of the motor cortex can enhance the effects of visuo-motor grip force tracking task training and transfer to clinical assessments of upper extremity motor function.Methods: In a randomized, double-blind, sham-controlled trial, 40 chronic stroke patients underwent 5 days of visuo-motor grip force tracking task training of the paretic hand with either unilateral or bilateral (N = 15/group) or placebo tDCS (N = 10). Immediate and long-term (3 months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, and WMFT) were investigated.Results: Trained task performance significantly improved independently of tDCS in a curvilinear fashion. In the anodal stimulation group UE-FM scores were higher than in the sham group at day 5 (adjusted mean difference: 2.6, 95%CI: 0.6–4.5, p = 0.010) and at 3 months follow up (adjusted mean difference: 2.8, 95%CI: 0.8–4.7, p = 0.006). Neither training alone, nor the combination of training and tDCS improved WMFT performance.Conclusions: Visuo-motor grip force tracking task training can facilitate recovery of upper extremity function. Only minimal add-on effects of anodal but not dual tDCS were observed.Clinical Trial Registration:https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=NCT01969097&cntry=&state=&city=&dist=, identifier: NCT01969097, retrospectively registered on 25/10/2013.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

Background: genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize similar to 10,000 participants. Methods: recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing. Results: initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of similar to 14% among a PD cohort from tertiary referral centers. Conclusions: the ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials., Denali Therapeutics Inc. (South San Francisco, CA) partially funded laboratory testing services.

From 2008 to 2018 research across the social sciences has burgeoned concerning sex work and social stigma. This paper employs a scoping review methodology to map scholarship produced during this period and develop a more coherent body of knowledge concerning the relationship between social stigma and female-identified sex workers. Twenty-six pieces of research related to sex work stigma are identified and reviewed from across the disciplines of sociology (n = 8), public health (n = 6), social work (n = 4), criminology (n = 2), psychology (n = 2), communications (n = 2), nursing (n = 1), and political science (n = 1). This scoping review identifies the main sources of sex-work stigma, the ways in which sex-work stigma manifests for sex workers, and stigma resistance strategies, as discussed in this body of literature. If, as theorists and researchers suggest, social stigma is at the foundation of the pernicious violence against sex workers, understanding the sources, manifestations, and resistance strategies of sex-work stigma is critical to countering and shifting this stigma. Findings include potential areas of research, policy, and practice to address and challenge sex-work stigma, recognizing that successful social transformation occurs in a dialectic between society’s socio-structural, community, and intrapersonal levels.

ObjectivesTo evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS.MethodsComprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments.ResultsIntrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45–6.44], p = 0.003) after adjustment for age (0.96 [0.93–1.00], p = 0.059), OCB (0.92 [0.33–2.61], p = 0.879), intrathecal IgG production (0.98 [0.48–1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11–6.22], p = 0.028).ConclusionIntrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.

Background Glomerulonephritis refers to renal diseases characterized by glomerular and tubulointerstitial fibrosis. Multifrequency US time-harmonic elastography enables the noninvasive quantification of tissue elasticity. Purpose To assess the diagnostic performance of US time-harmonic elastography for the early detection of glomerulonephritis. Materials and Methods From August 2016 through May 2017, study participants with biopsy-proven glomerulonephritis were prospectively examined with US time-harmonic elastography. Participants were subdivided according to chronic kidney disease (CKD) stage. All participants underwent elastography of both kidneys to generate full-field-of-view maps of renal shear wave speed (SWS). SWS was determined separately for the whole renal parenchyma, cortex, and medulla and was correlated with quantitative B-mode findings such as renal length and parenchymal thickness. Diagnostic performance of renal elastography was assessed with receiver operating characteristic curve analysis. Results Fifty-three participants with glomerulonephritis (mean age ± standard deviation, 49 years ± 14) and 30 healthy volunteers (mean age, 37 years ± 11) were evaluated. Age-adjusted renal SWS was lower in participants with glomerulonephritis than in healthy volunteers in the parenchyma, cortex, and medulla, with mean values of 1.55 m/sec (95% confidence interval [CI]: 1.51 m/sec, 1.59 m/sec) and 1.69 m/sec (95% CI: 1.64 m/sec, 1.74 m/sec; P < .001), respectively, in parenchyma, 1.80 m/sec (95% CI: 1.75 m/sec, 1.84 m/sec) and 2.08 m/sec (95% CI: 2.02 m/sec, 2.13 m/sec; P < .001) in cortex, and 1.25 m/sec (95% CI: 1.21 m/sec, 1.29 m/sec) and 1.33 (95% CI: 1.27 m/sec, 1.38 m/sec; P = .03) in medulla. Age-adjusted renal cortex SWS was lower in participants with glomerulonephritis and stage 1 CKD (preserved renal function) than in healthy volunteers (mean, 1.88 [95% CI: 1.81, 1.96] vs 2.08 [95% CI: 2.02, 2.13]; P < .001). In participants with CKD, renal cortex SWS values showed a positive association with estimated glomerular filtration rate (n = 39; r = 0.56; P < .001). Exploratory diagnostic performance of US time-harmonic elastography (area under the receiver operating characteristic curve [AUC], 0.89; 95% CI: 0.82, 0.97) outperformed that of B-mode parameters such as parenchymal thickness (AUC, 0.64; 95% CI: 0.51, 0.77; P < .001) and renal length (AUC, 0.55; 95% CI: 0.40, 0.68; P < .001) in identifying glomerulonephritis. Conclusion US time-harmonic elastography depicts abnormal renal stiffness in glomerulonephritis, particularly among patients with early disease and preserved renal function. Advanced chronic kidney disease is associated with further cortical softening. Time-harmonic elastography outperforms B-mode-based size quantification. © RSNA, 2019 Online supplemental material is available for this article.

Objectives:To investigate global and momentary effects of a tablet-based non-pharmacological intervention for nursing home residents living with dementia.Design:Cluster-randomized controlled trial.Setting:Ten nursing homes in Germany were randomly allocated to the tablet-based intervention (TBI, 5 units) or conventional activity sessions (CAS, 5 units).Participants:N = 162 residents with dementia.Intervention:Participants received regular TBI (n = 80) with stimulating activities developed to engage people with dementia or CAS (n = 82) for 8 weeks.Measurements:Apathy Evaluation Scale (AES-I, primary outcome), Quality of Life in Alzheimer’s Disease scale, QUALIDEM scale, Neuropsychiatric Inventory, Geriatric Depression Scale, and psychotropic medication (secondary outcomes). Momentary quality of life was assessed before and after each activity session. Participants and staff were blinded until the collection of baseline data was completed. Data were analyzed with linear mixed-effects models.Results:Levels of apathy decreased slightly in both groups (mean decrease in AES-I of .61 points, 95% CI −3.54, 2.33 for TBI and .36 points, 95% CI −3.27, 2.55 for CAS). Group difference in change of apathy was not statistically significant (β = .25; 95% CI 3.89, 4.38, p = .91). This corresponds to a standardized effect size (Cohen’s d) of .02. A reduction of psychotropic medication was found for TBI compared to CAS. Further analyses revealed a post-intervention improvement in QUALIDEM scores across both groups and short-term improvements of momentary quality of life in the CAS group.Conclusions:Our findings suggest that interventions involving tailored activities have a beneficial impact on global and momentary quality of life in nursing home residents with dementia. Although we found no clear advantage of TBI compared to CAS, tablet computers can support delivery of non-pharmacological interventions in nursing homes and facilitate regular assessments of fluctuating momentary states.

IntroductionCurrent analysis approaches of accelerometry data use sum score measures which do not provide insight in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we used a functional approach to analyze accelerometer data that models activity pattern and circadian rhythm. As a test case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Moreover, we assessed the impact of chronotype on distribution of activity data.MethodsData of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. In a second step, analyses were controlled for chronotype using the German version of the morningness-eveningness questionnaire (d-MEQ).ResultsInformation on 47 HOV (mean age 66 SD 6 years) and 13 patients with MCI (mean age 69, SD 8 years) were available for this analysis. MCI patients displayed slightly higher activity in the morning hours as compared to HOV (maximum relative activity at 7:35 am: 75.6%, 95% CI 2.6 to 200.4%, p = 0.031). After controlling for d-MEQ, disturbed activity patterns were found in MCI of intermediate or evening chronotype, compared to HOV, i.e., MCI presented with higher activities in the morning hours (peak at 8:40 am: 357.6%, 95% CI 92.9 to 985.1, p < 0.001) and early afternoon hours (peak at 1:40 pm: 401.8%, 95% CI 63.9 to 1436.4, p < 0.001).DiscussionUsing a novel approach of FoSR, we found timeframes with higher activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used. In addition, we found that previously described activity patterns as a function of chronotype swere altered in MCI patients, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry.Clinical TrialsEffects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, https://clinicaltrials.gov/ct2/show/NCT01782391?term=NCT01782391&rank=1,ClinicalTrial.gov identifier: NCT01782391Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment,https://clinicaltrials.gov/ct2/show/NCT01782365?term=NCT01782365&rank=1,ClinicalTrial.gov identifier: NCT01782365

Background and aim To report the six-month safety analyses among patients enrolled in the “Physical Fitness Training in Subacute Stroke—PHYS-STROKE” trial and identify underlying risk factors associated with serious adverse events. Methods We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5–45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training. Results Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81). Conclusions Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials. Data access statement The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.

NEW FINDINGS What is the central question of this study? Would ovariectomy cause prolonged changes in ventilation and sustained loss of acute, intermittent hypoxia-induced neuroplasticity or would these outcomes be restored with time? What is the main finding and its importance? Our main findings demonstrate that ovariectomy elicits minimal alteration in overall breathing function but impairs acute, intermittent hypoxia-induced plasticity for ≤ 12 weeks. ABSTRACT Sex hormones are necessary to enable respiratory neuroplasticity, including phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity elicited by acute, intermittent hypoxia (AIH). Female rats exhibit a progressive increase in phrenic nerve amplitude after AIH characteristic of pLTF only during pro-oestrus, the stage of the oestrous cycle notable for elevated circulating oestradiol levels. Removal of the ovaries [ovariectomy (OVX)], the primary source of circulating oestradiol, also eliminates AIH-induced pLTF after 1 week. Ovariectomy is used routinely as a model to examine the impact of sex hormones on CNS structure and function, but the long-term impact of OVX is rarely examined. Extra-ovarian sites of oestradiol synthesis, including multiple CNS sites, have been identified and might possess the capacity to restore oestradiol levels, in part, over time, impacting respiratory function and the expression of respiratory neuroplasticity. We examined both ventilation in awake, freely behaving female rats, using barometric plethysmography, and the expression of AIH-induced pLTF in anaesthetized, ventilated female rats 2 and 12 weeks after OVX and compared them with age-matched ovarian-intact female rats. Our findings indicate that chronic OVX had little impact on baseline breathing or in the response to respiratory challenge (10% O2 , 5% CO2 , balance N2 ) during plethysmography. However, OVX rats at both 2 and 12 weeks demonstrated a persistent loss of AIH-induced pLTF relative to control animals (P

Background: Transcranial direct current stimulation (tDCS) may improve motor recovery after stroke. This study investigated if uni- and bihemispheric tDCS of the motor cortex can enhances fine motor training outcome and transfer to clinical assessments of upper motor function. Methods: In a randomized, double-blinded, sham-controlled trial, forty chronic stroke patients underwent five days of fine motor skill training of the paretic hand with either unilateral or bilateral (N=15/group) or placebo tDCS (N=10). Immediate and long-term (three months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, WMFT) were investigated. Results: Trained task performance significantly improved independently of tDCS in a curvilinear fashion. Anodal, but not dual tDCS resulted in a steeper learning curve on the UE-FM. Neither training nor combined training-tDCS improved WMFT performance.Conclusions: Fine motor skill training can facilitate recovery of upper extremity function. Minimal add-on effects of tDCS were observed.Clinical Trial Registration-URL: NCT01969097 retrospectively registered on 25/10/2013.

Importance Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.This cohort study compares global disability at 3 months among Berlin patients with out-of-hospital ischemic stroke brought to care via a mobile stroke unit ambulance (with prehospital CT scanning with or without angiography, point-of-care laboratory testing, prehospital thrombolysis) vs conventional ambulance alone.Question Is the dispatch of mobile stroke units in the out-of-hospital setting before arriving at the hospital associated with better functional outcomes among patients with acute ischemic stroke eligible for thrombolysis or thrombectomy? Findings In this prospective nonrandomized controlled intervention study involving 1543 patients in Berlin, Germany, the dispatch of mobile stroke units in addition to conventional ambulances vs conventional ambulances alone was significantly associated with lower levels of global disability at 3 months (common odds ratio for higher modified Rankin Scale scores [ie, worse outcome], 0.71). Meaning Among patients with acute ischemic stroke in Berlin, Germany, dispatch of a mobile stroke unit was associated with lower global disability at 3 months; further research in diverse settings is needed.

OBJECTIVE The authors sought to validate the navigated transcranial magnetic stimulation (nTMS)–based risk stratification model. The postoperative motor outcome in glioma surgery may be preoperatively predicted based on data derived by nTMS. The tumor-to-tract distance (TTD) and the interhemispheric resting motor threshold (RMT) ratio (as a surrogate parameter for cortical excitability) emerged as major factors related to a new postoperative deficit. METHODS In this bicentric study, a consecutive prospectively collected cohort underwent nTMS mapping with diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract prior to surgery of motor eloquent gliomas. The authors analyzed whether the following items were associated with the patient’s outcome: patient characteristics, TTD, RMT value, and diffusivity parameters (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]). The authors assessed the validity of the published risk stratification model and derived a new model. RESULTS A new postoperative motor deficit occurred in 36 of 165 patients (22%), of whom 20 patients still had a deficit after 3 months (13%; n3 months = 152). nTMS-verified infiltration of the motor cortex as well as a TTD ≤ 8 mm were confirmed as risk factors. No new postoperative motor deficit occurred in patients with TTD > 8 mm. In contrast to the previous risk stratification, the RMT ratio was not substantially correlated with the motor outcome, but high RMT values of both the tumorous and healthy hemisphere were associated with worse motor outcome. The FA value was negatively associated with worsening of motor outcome. Accuracy analysis of the final model showed a high negative predictive value (NPV), so the preoperative application may accurately predict the preservation of motor function in particular (day of discharge: sensitivity 47.2%, specificity 90.7%, positive predictive value [PPV] 58.6%, NPV 86.0%; 3 months: sensitivity 85.0%, specificity 78.8%, PPV 37.8%, NPV 97.2%). CONCLUSIONS This bicentric validation analysis further improved the model by adding the FA value of the corticospinal tract, demonstrating the relevance of nTMS/nTMS-based DTI fiber tracking for clinical decision making.

Background Previous studies suggest that genetic polymorphisms and aging modulate inter-individual variability in brain stimulation-induced plasticity. However, the relationship between genetic polymorphisms and behavioral modulation through transcranial direct current stimulation (tDCS) in older adults remains poorly understood. Objective Link individual tDCS responsiveness, operationalized as performance difference between tDCS and sham condition, to common genetic polymorphisms in healthy older adults. Methods 106 healthy older participants from five tDCS-studies were re-invited to donate blood for genotyping of apoliproprotein E (APOE: e4 carriers and e4 non-carriers), catechol-O-methyltransferase (COMT: val/val, val/met, met/met), brain-derived neurotrophic factor (BDNF: val/val, val/met, met/met) and KIdney/BRAin encoding gene (KIBRA: C/C, C/T, T/T). Studies had assessed cognitive performance during tDCS and sham in cross-over designs. We now asked whether the tDCS responsiveness was related to the four genotypes using a linear regression models. Results We found that tDCS responsiveness was significantly associated with COMT polymorphism; i.e., COMT val carriers (compared to met/met) showed higher tDCS responsiveness. No other significant associations emerged. Conclusion Using data from five brain stimulation studies conducted in our group, we showed that only individual variation of COMT genotypes modulated behavioral response to tDCS. These findings contribute to the understanding of inherent factors that explain inter-individual variability in functional tDCS effects in older adults, and might help to better stratify participants for future clinical trials.

ObjectiveNeglect after stroke is a disabling disorder and its rehabilitation is a major challenge. Transcranial direct current stimulation (tDCS) seems to be a promising adjuvant technique to improve standard care neglect therapy. Since electric fields are influenced by age-related factors, higher current densities are probably needed for effective treatment in aged stroke patients. Validation of treatment efficacy requires sham-controlled experiments, but increased current densities might comprise blinding. Therefore, a pilot study was conducted to test sham adequacy when using current density of 0.8 A/m2. Whether especially neglect patients who mainly suffer from perceptual and attentional deficits are able to differentiate beyond chance active from sham tDCS was investigated in a randomized cross-over design (active/sham stimulation) in 12 early subacute patients with left-sided hemineglect. Stimulation (0.8 A/m2) was performed simultaneous to standard care neglect therapy.ResultsOdds ratio of correct guessing an atDCS condition compared to wrongly judge an atDCS condition as sham was 10.00 (95%CI 0.65–154.40, p = 0.099). However, given the small sample size and high OR, although likely somewhat overestimated, results require careful interpretation and blinding success in neglect studies with current densities of 0.8 A/m2should be further confirmed.

Variations in head and brain anatomy determine the strength and distribution of electrical fields in humans and may account for inconsistent behavioral and neurophysiological results in transcranial electrical stimulation (tES) studies. However, it is insufficiently understood which anatomical features contribute to the variability of the modelled electric fields, and if their impact varies across age groups. In the present study, we tested the associations of global head anatomy, indexed by extra- and intra-cranial volumes, with electric field measures, comparing young and older adults. We modelled six “conventional” electrode montages typically used in tES studies using SimNIBS software in 40 individuals (20 young, 20 older adults; 20-35, 64-79 years). We extracted individual electric field strengths and focality values for each montage to identify tissue volumes that account for variability of the induced electric fields in both groups. Linear mixed models explained most of the inter-individual variability of the overall induced field strength in the brain, but not of field focality. Higher absolute head volume and relative volume of skin, skull and cerebrospinal fluid (CSF) were associated with lower overall electric field strengths. Additionally, we found interactions of age group with head volume and CSF, indicating that this relationship was mitigated in the older group. Our results demonstrate the importance to adjust brain stimulation not only according to brain atrophy, but also to additional parameters of head anatomy. Future studies need to elucidate the mechanisms underlying individual variability of tES effects in young and older adults, and verify the usefulness of the proposed models in terms of neurophysiology and behavior in empirical studies.

BackgroundPatient-reported outcome measures (PROMs) are commonly used and are surrogates for clinical outcomes in cancer research. In the research setting of very severe diseases such as cancer, it is difficult to avoid the problem of incomplete questionnaires from drop-out or missing data due to patients who deceased during observation period. We aimed to explore patient characteristics and patient-reported outcomes associated with the time-to-dropout. MethodsIn the Oncological Social Care Project (OSCAR) study the condition of participants was assessed four times within 12 months (t0: baseline, t1: 3 months, t2: 6 months, and t3: 12 months) by validated PROMs. We performed competing-risks regression based on Fine and Gray’s proportional sub-distribution hazards model for exploring factors associated with time-to-dropout. Death was considered as competing risk. ResultsThree hundred sixty-two participants were analyzed in the study. 193 (53.3%) completed follow-up at 12 months, 67 (18.5%) patients dropped out, and 102 patients (28.2%) died during the study period. Poor subjective social support was related to higher risk for drop-out (SHR=2.10; 95%CI: 1.01 – 4.35). Lower values in health-related quality of life were related to drop-out and death. The subscales global health status/QoL, role functioning, physical functioning, and fatigue symptom in the EORTC QLQ-C30 were key characteristics associated with early drop-out.ConclusionSeverely affected cancer patients with poor social support and poor quality of life seem more likely to drop out of studies compared to patients with higher levels of social support and quality of life. This should be considered when planning studies assessing cancer patients. Methods to monitor drop-outs timely and handle missing outcomes might be used. Results of such studies have to be interpreted with caution in light of the particular drop-out mechanisms.

Summary Background Pulmonary dysfunction and cardiovascular disease are major causes of impaired health status in later life, and co-development of these diseases has been reported. Aim To better understand the pathobiology involved in the co-development of these diseases. Methods We investigated the impact of pulmonary dysfunction on the development of cardiovascular disease among people aged ≥ 50 years in the English longitudinal study of ageing (ELSA). Hazard ratios were estimated by Cox proportional hazards regression models, with and without a time-dependent update of exposure and confounders. Pulmonary function was divided into three categories, with the least affected category as the reference. Results People with pulmonary dysfunction were at higher risk of developing cardiovascular disease than those with normal pulmonary function: the hazard ratio for pulmonary dysfunction versus healthy in the time-dependent crude analysis of model 1, adjusted for age, body mass index, sex, angina pectoris and heart arrhythmia, was 1.49 (95% confidence interval 1.2–1.9). The effect varied with the precise definition of pulmonary dysfunction and the subtype of the cardiovascular disease, and decreased after correction for some additional confounders but not after correction for inflammatory biomarkers. Conclusions A history of pulmonary disease increased the risk of developing cardiovascular disease, but inflammation did not seem to alter the effect of pulmonary dysfunction on cardiovascular disease development. This insight may lead to better understanding and treatment of cardiovascular comorbidities in pulmonary disease; it also indicates that the potentially beneficial effect of targeted anti-inflammatory drugs for pulmonary disease, in terms of reducing cardiovascular risk in these patients, may be limited.

Background and Purpose— Data on effects of intravenous thrombolysis on outcome of patients with ischemic stroke who are dependent on assistance in activities of daily living prestroke are scarce. Recent registry based analyses in activities of daily –independent patients suggest that earlier start of intravenous thrombolysis in the prehospital setting leads to better outcomes when compared with the treatment start in hospital. We evaluated whether these observations can be corroborated in patients with prestroke dependency. Methods— This observational, retrospective analysis included all patients with acute ischemic stroke depending on assistance before stroke who received intravenous thrombolysis either on the Stroke Emergency Mobile (STEMO) or through conventional in-hospital care (CC) in a tertiary stroke center (Charité, Campus Benjamin Franklin, Berlin) during routine care. Prespecified outcomes were modified Rankin Scale scores of 0 to 3 and survival at 3 months, as well as symptomatic intracranial hemorrhage. Outcomes were adjusted in multivariable logistic regression. Results— Between February 2011 and March 2015, 122 of 427 patients (28%) treated on STEMO and 142 of 505 patients (28%) treated via CC needed assistance before stroke. Median onset-to-treatment times were 97 (interquartile range, 69–159; STEMO) and 135 (interquartile range, 98–184; CC; P P =0.01) and 86 (70%, STEMO) versus 85 (60%, CC) patients were alive ( P =0.07). After adjustment, STEMO care was favorable with respect to modified Rankin Scale scores of 0 to 3 (odds ratio, 1.99; 95% confidence interval, 1.02–3.87; P =0.042) with a nonsignificant result for survival (odds ratio, 1.73; 95% confidence interval, 0.95–3.16; P =0.07). Symptomatic intracranial hemorrhage occurred in 5 STEMO versus 12 CC patients (4.2% versus 8.5%; P =0.167). Conclusions— The results of this study suggest that earlier, prehospital (as compared with in-hospital) start of intravenous thrombolysis in acute ischemic stroke may translate into better clinical outcome in patients with prestroke dependency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02358772.

Background and Purpose— We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. Methods— We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young ( Results— Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09–1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59–2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13–1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P =0.065; 29.1% versus 16.5% for old lesions, P P P =0.001). Microbleeds (16.3% versus 4.7%, P =0.001), higher grades of white matter hyperintensities ( P P for differences in TOAST ( P =0.018) were more often present in patients with dolichoectasia. Conclusions— Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00414583.

Introduction Limited data exist on the outcome of pregnancies and deliveries in women with ischaemic stroke. We investigated the incidence of pregnancy- and delivery-related complications in women with ischaemic stroke before and after pregnancy compared with stroke-free matched controls. Patients and methods Of our 1008 consecutive patients aged 15–49 years with first-ever ischaemic stroke, 1994–2007, we included women with pregnancy data before or after stroke recorded in the Medical Birth Register (MBR) ( n = 152), and for them searched stroke-free controls matched by age, parity, year of birth, residential area and multiplicity ( n = 608). Data on hospital admissions and deaths (1987–2014) came from national health registries. Poisson regression mixed models allowed comparison of the incidence of complications. Results A total of 124 stroke mothers had 207 singleton pregnancies before and 45 mothers 68 pregnancies after stroke. The incidence rate ratio (IRR) for the composite outcome of pregnancy and delivery complications adjusted for socioeconomic status and maternal smoking was 1.43 (95% confidence interval [CI] 1.00–2.03, p = 0.05) for pre-stroke mothers, and 1.09 (95% CI 0.66–1.78) for post-stroke mothers, compared with matched controls. Similarly, the adjusted IRR for post-stroke hospital admission during pregnancy was 1.85 (95% CI 1.03–3.31). The IRR for perinatal death of the child was 3.43 (95% CI 0.57–20.53) before and 8.88 (95% CI 0.81–97.95) after stroke. Discussion and conclusions Compared with stroke-free mothers, we found a higher incidence of pregnancy- and delivery-related complications in mothers with ischaemic stroke. Larger studies are needed to verify our results.

Background and Purpose— As stroke in young adults is assumed to have different etiologies and risk factors than in older populations, the aim of this study was to examine the contribution of established potentially modifiable cardiovascular risk factors to the burden of stroke in young adults. Methods— A German nationwide case–control study based on patients enrolled in the SIFAP1 study (Stroke In Young Fabry Patients) 2007 to 2010 and controls from the population-based GEDA study (German Health Update) 2009 to 2010 was performed. Cases were 2125 consecutive patients aged 18 to 55 years with acute first-ever stroke from 26 clinical stroke centers; controls (age- and sex-matched, n=8500, without previous stroke) were from a nationwide community sample. Adjusted population-attributable risks of 8 risk factors (hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, smoking, heavy episodic alcohol consumption, low physical activity, and obesity) and their combinations for all stroke, ischemic stroke, and primary intracerebral hemorrhage were calculated. Results— Low physical activity and hypertension were the most important risk factors, accounting for 59.7% (95% confidence interval, 56.3–63.2) and 27.1% (95% confidence interval, 23.6–30.6) of all strokes, respectively. All 8 risk factors combined explained 78.9% (95% confidence interval, 76.3–81.4) of all strokes. Population-attributable risks of all risk factors were similar for all ischemic stroke subtypes. Population-attributable risks of most risk factors were higher in older age groups and in men. Conclusions— Modifiable risk factors previously established in older populations also account for a large part of stroke in younger adults, with 4 risk factors explaining almost 80% of stroke risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00414583.

Aims Several studies showed reduced stroke severity in patients with atrial fibrillation (AF) if the international normalized ratio (INR) was ≥ 2 at stroke onset. There are no respective data for non-vitamin K-dependent oral anticoagulants (NOACs). The aim of this study was to compare the impact of NOAC or phenprocoumon intake on stroke severity. Methods and results In this single-centre observational study, 3669 patients with acute ischaemic stroke were retrospectively analysed regarding AF status and medication immediately before admission. Using multivariable regression, we analysed the association of pre-admission anticoagulation with severe stroke (National Institutes of Health Stroke Scale score ≥ 11) on admission and poor outcome at discharge (modified Rankin scale score > 2). Before the index stroke, 655 patients had known AF and a CHA2DS2-VASc score ≥ 2. While 325 (49.6%) patients were anticoagulated, 159 (24.3%) were prescribed a NOAC and 75 (11.5%) phenprocoumon patients had an INR ≥ 2 on admission. Compared with AF patients without medical stroke prevention, an INR ≥ 2 [OR 0.23 (95% CI 0.10–0.53)] or NOAC intake [OR 0.48 (95% CI 0.27–0.86)] were associated with a lower probability of severe stroke after adjustment for confounders, while an INR

OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) is a noninvasive method for preoperatively localizing functional areas in patients with tumors in presumed motor eloquent areas. The aim of this study was to establish an nTMS-based risk stratification model by examining whether the results of nTMS mapping and its neurophysiological data predict postoperative motor outcome in glioma surgery. METHODS Included in this study were prospectively collected data for 113 patients undergoing bihemispheric nTMS examination prior to surgery for gliomas in presumed motor eloquent locations. Multiple ordinal logistic regression analysis was performed to test for any association between preoperative nTMS-related variables and postoperative motor outcome. RESULTS A new motor deficit or deterioration due to a preexisting deficit was observed in 20% of cases after 7 days and in 22% after 3 months. In terms of tumor location, no new permanent deficit was observed when the distance between tumor and corticospinal tract was greater than 8 mm and the precentral gyrus was not infiltrated (p = 0.014). New postoperative deficits on Day 7 were associated with a pathological excitability of the motor cortices (interhemispheric resting motor threshold [RMT] ratio < 90% or > 110%, p = 0.031). Interestingly, motor function never improved when the RMT was significantly higher in the tumorous hemisphere than in the healthy hemisphere (RMT ratio > 110%). CONCLUSIONS The proposed risk stratification model, based on objective functional-anatomical and neurophysiological measures, enables one to counsel patients about the risk of functional deterioration or the potential for recovery.

Background Tuberosity repair in shoulder fracture prosthesis implantation still remains a challenge often leading to poor functional outcomes, despite a variety of materials and suggested suture patterns. We aimed to evaluate, which forces currently used suture and cerclage materials withstand and to assess whether they are useful with regard to stability of reconstruction of tuberosities and which failure modes they display. Material and methods Using sheep infraspinatus tendons with attached tuberosities three different suture materials (suture 1: Ethibond size 2; suture 2: Orthocord size 2; suture 3: Fiberwire size 5) and a 0.8 mm titanium cerclage wire were investigated. For each suture material as well as the cerclage wire 6 tests were carried out. A material testing machine was used to perform cyclic loading tests (20 mm/min, Fmin = 50 N, Fmax = 100 N, respectively after 50 cycles: Fmax + 50 N until failure). Outcome measures and thus comparison criteria were the maximum holding force, number of cycles reached, total elongation of the system (tendon and suture) and qualitative appraisal and documentation of the mechanism of failure. Results Overall average maximum forces between the fixation materials differed significantly (P = 0.003), especially suture 3 (braided polyethylene coating, non-resorbable polyfile UHMW core) displayed superior results in comparison to the cerclage wire (P = 0.016). Although, primary elongation of the cerclage technique was significantly lower compared to the suture materials (P = 0.002). All tests showed a high initial lengthening and caused incision-like defects in the bone or tendon and led to failure and huge displacement of the tuberosities. Discussion Currently used suture and cerclage materials have a limited usefulness for refixation of tuberosities due to an increased risk of obstruction for bony consolidation. Level of evidence Basic science, Biomechanics.

Background Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer’s disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted. Methods The AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention. Significance With this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with SCD and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD. Trial registration ClinicalTrials.gov, NCT04265378. Registered on 07 February 2020. Retrospectively registered. Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019). Sponsor: University Medicine Greifswald.

Background: Associative object-location memory (OLM) is known to decline even in normal aging, and this process is accelerated in patients with mild cognitive impairment (MCI). Given the lack of curative treatment for Alzheimer's disease, activating cognitive resources during its preclinical phase might prevent progression to dementia. Objective: To evaluate the effects of anodal transcranial direct current stimulation (atDCS) combined with an associative episodic memory training on OLM in MCI patients and in healthy elderly (HE). Methods: In a single-blind cross-over design, 16 MCI patients and 32 HE underwent a 3-day visuospatial OLM training paired with either 20:min or 30:s (sham) atDCS (1:mA, right temporoparietal cortex). Effects on immediate (training success) and long-term memory (1-month) were investigated by conducting Mixed Model analyses. In addition, the impact of combined intervention on within-session (online) and on between-session (offline) performance were explored. Results: OLM training+atDCS enhanced training success only in MCI patients, but not HE (difference n.s.). Relative performance gain was similar in MCI patients compared to HE under atDCS. No beneficial effect was found after 1-month. Exploratory analyses suggested a positive impact on online, but a negative effect on offline performance in MCI patients. In both groups, exploratory post-hoc analyses indicated an association between initially low-performers and greater benefit from atDCS. Conclusion: Cognitive training in MCI may be enhanced by atDCS, but further delineation of the impact of current brain state, as well as temporal characteristics of multi-session atDCS-training application, may be needed to induce longer-lasting effects. © 2020 - IOS Press and the authors. All rights reserved.

Study design Survey study. Objectives Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. Setting All departments for SCI-care in Germany. Methods The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of ‘clinically defined pneumonia’ were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). Results The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38–81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7–41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems. Conclusions This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP.

To analyse trends in quality of life (QoL) development among older stroke patients within the first year after rehabilitation discharge, and to investigate the impact of including proxy interviews in research and practice.A prospective cohort study with follow-up at 3, 6, and 12 months with 411 patients and proxy respondents was conducted. The EUROHIS-QOL 8-item index was used to assess QoL. By performing descriptive analyses, QoL development over time was compared among subgroups. Linear mixed models were calculated to estimate mean changes from baseline to 12-month follow-up. The effects of patient characteristics and time on QoL were investigated using comprehensive mixed models.One year after rehabilitation discharge, the majority of patients had neither maintained nor regained their initial QoL. Proxy respondents reported significantly lower QoL (22.6-29.5 points,Quality of life scores reported at the time of rehabilitation discharge are often not lasting. Including severely impaired patients via proxies reduces the risk of overestimating QoL outcomes. Outpatient's characteristics should be taken into account when planning therapy strategies to maintain previously achieved health goals. Regular re-assessments are required.Implications for rehabilitationThere should be an awareness that improvements in quality of life (QoL) achieved during rehabilitation are not sustainable.Regularly re-assessing pain status, psychological burden, and social network size could help clinicians to determine treatment strategies for maintaining and improving rehabilitation achievements.Conducting proxy interviews is required to assess disease burden of patients with severe stroke (e.g., non-linguistic patients).

ObjectiveTo determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke.DesignMulticentre, randomised controlled, endpoint blinded trial.SettingSeven inpatient rehabilitation sites in Germany (2013-17).Participants200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care.InterventionParticipants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment.Main outcome measuresThe primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values.ResultsCompared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (−5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36).ConclusionsAmong moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines.Trial registrationClinicalTrials.gov NCT01953549.

Studies investigating the Mobile Stroke Unit (MSU) concept have shown increased thrombolysis rates, reduced alarm-to-treatment times and improved prehospital triage. Yet, so far, there is no definite scientific proof of better functional outcome after MSU deployment compared to regular ambulances. We provide a revised protocol for the second part of the B_PROUD trial as organization of the MSU dispatch did not meet the anticipated standards in the first part. B_PROUD is a pragmatic, prospective study comparing functional outcomes of treatment candidates with or without MSU care. Treatment candidates are defined as patients with a final diagnosis of ischemic stroke or transient ischemic attack, onset-to-dispatch-times ≤4 h, disabling symptoms not resolved at time of ambulance arrival, and the ability to ambulate prior to the qualifying event. These patients are included if their emergency call prompted a stroke alarm at the dispatch center during MSU operation hours (7 am–11 pm, Monday-Sunday) and if the emergency is located within the MSU operation area in Berlin, Germany. The intervention group consists of patients who are cared for by the MSU. When the MSU is already in operation for another emergency, MSU dispatches are handled by regular ambulances (about 45%). These dispatches create the control group. Blinded stroke physicians assess the modified Rankin Scale (mRS) score in recorded structured interviews 3 months after stroke. The primary outcome is the degree of disability and death over the full range of the mRS. As a change to the previously published protocol and only pertinent in case of more than 9% lost-to-follow-up, a co-primary outcome was introduced consisting of the proportions of death, new institutional care or severe disability in patients with additional use of information from registration offices. The results will inform parties involved in acute stroke care organization on the effectiveness of the MSU concept. The protocol is registered in ( NCT03931616 ) and has been approved by the ethical review committee of the Charite – University Medicine Berlin (EA4/109/15) on September 2, 2015. The study protocol of B_PROUD part 1 had been published in the International Journal of Stroke as “Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) – study protocol” (doi: https://doi.org/10.1177/1747493017700152 ) on March 22, 2017 [1] previous to first patient’s registration.

Background: With increasing aging populations worldwide, developing interventions against age-associated cognitive decline is particularly important. Evidence suggests that combination of brain stimulation with cognitive training intervention may enhance training effects in terms of performance gain or transfer to untrained domains. This protocol describes a Phase IIb clinical trial that investigates the intervention effects of training combined with brain stimulation in older adults. Methods: The TrainStim study is a monocentric, randomized, single-blind, placebo-controlled intervention. The study will investigate cognitive training with concurrent anodal tDCS (transcranial direct current stimulation) over the left dorsolateral prefrontal cortex (target intervention) compared to cognitive training with sham stimulation (control intervention) over nine sessions in three weeks, consisting of a letter updating task and a three-stage Markov decision-making task. Fifty-six older adults will be recruited from the general population. Baseline assessment will be performed including neuropsychological screening and performance on training tasks. Participants will be allocated to one of the two study arms using block-wise randomization stratified by age and baseline performance with a 1:1 allocation ratio. Primary outcome is performance in the letter updating task after training under anodal tDCS compared to sham stimulation. Secondary outcomes include performance changes in the decision-making task and transfer tasks, as well as brain structure and functional networks assessed by structural and functional magnetic resonance imaging that are acquired pre- and post-intervention. Significance: The main aim of the TrainStim study is to provide evidence for behavioral and neuronal effects of tDCS-accompanied cognitive training and to elucidate the underlying mechanisms in older adults. Our findings will contribute towards developing efficient interventions for age-associated cognitive decline. Trial registration: This trial was retrospectively registered at ClinicalTrials.gov with the Identifier: NCT03838211 at February 12, 2019. https://clinicaltrials.gov/ct2/show/NCT03838211 Protocol version: Based on BB 004/18 version 1.2 (May, 17, 2019).

Background Time to reperfusion treatment is closely related to outcome in ischemic stroke. Prehospital stroke work-up in CT-equipped mobile stroke units is effective in reducing time to thrombolytic treatment. Current evidence predominantly comes from mobile stroke units staffed with neurologists but telemedicine-guided management may be acceptable for providing neurological expertise in ambulances. With unsatisfactory experiences in third-generation (3G)-based approaches, fourth-generation (4G) networks may provide adequate audio-visual quality but systematic comparisons of technological parameters and decision-making are lacking. Methods Trained actors presented stroke symptoms and paramedics assisted the remotely guided extended National Institutes of Health Stroke Scale (eNIHSS) assessment on the mobile stroke unit in Berlin, Germany. We compared technical parameters of 4G and 3G connections, assessed audio-visual quality of examination, and analyzed reliability of neurological assessment and treatment decisions made by the remote neurologist versus the mobile stroke unit neurologist. Results 4G and 3G connections were evaluated in 40 scenarios each. Connectivity was not available in 17% of 4G- and 15% of 3G-attempts with 6% simultaneous unavailability of both networks. The remote examiners graded audio and video quality in 4G better than in 3G with slightly shorter assessment duration in 4G (mean: 9 (SD:5) vs. mean 11 (SD:3) min, p = 0.10). Reliability of the eNIHSS sum scores was high with intraclass correlation coefficients of 0.99 (95% CI: 0.987–1.00) for 4G and 0.98 (95% CI: 0.96–0.99) for 3G. None of the remote treatment decisions differed from onsite decisions. Conclusions 4G mobile communications provided higher quality of video-examination and allowed reliable remote assessment of stroke symptoms but coverage was still incomplete in both networks.

Background: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing. Methods: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI. Results: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups. Conclusions: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583.

Alteration of cerebral perfusion can be considered as a possible therapeutic target in mild cognitive impairment. This randomized, placebo-controlled, double-blind proof-of-concept study assessed effects of omega-3 fatty acids on cerebral perfusion in patients with mild cognitive impairment. In thirteen patients (omega:n=5; placebo:n=8) cerebral perfusion was measured before and after 26-weeks intervention within posterior cortical regions using magnetic resonance imaging. There was a medium effect of intervention on cerebral blood flow (η2=0.122) and blood volume (η2=0.098). The omega group showed an increase in blood flow (mean difference: 0.02 [corresponds to 26.1%], 95% confidence interval:0.00-0.05) and blood volume (mean difference: 0.08 [corresponds to 18.5%], 95% confidence interval:0.01-0.15), which was not observed in the placebo group. These preliminary findings suggest that omega-3 fatty acids supplementation may improve perfusion in cerebral regions typically affected in mild cognitive impairment.Regulation of perfusion may help to maintain brain structure and function and potentially delay conversion to dementia.

Background and Purpose— The association of elevated lipoprotein(a) (Lp(a)) levels and the incidence of cardiovascular disease, especially coronary heart disease and ischemic stroke, is well established. However, evidence on the association between Lp(a) levels and residual vascular risk in stroke survivors is lacking. We aimed to elucidate the risk for recurrent cardiovascular and cerebrovascular events in the patients with first-ever ischemic stroke with elevated Lp(a). Methods— All patients with acute ischemic stroke who participated in the prospective Berlin C&S study (Cream & Sugar) between January 2009 and August 2014 with available 12-month follow-up data and stored blood samples were eligible for inclusion. Lp(a) levels were determined in serum samples using an isoform-insensitive nephelometry assay. We assessed the risk for the composite vascular end point of ischemic stroke, transient ischemic attack, myocardial infarction, nonelective coronary revascularization, and cardiovascular death with elevated Lp(a) defined as >30 mg/dL using Cox regression analyses. Results— Of 465 C&S study participants, 250 patients were included into this substudy with a median National Institutes of Health Stroke Scale score of 2 (1–4). Twenty-six patients (10%) experienced a recurrent vascular event during follow-up. Among patients with normal Lp(a) levels, 11 of 157 subjects (7%) experienced an event at a median time of 161 days (interquartile range, 19–196 days), whereas in patients with elevated Lp(a) levels, 15 of 93 subjects (16%) experienced an event at a median time of 48 days (interquartile range, 9–194 days; P =0.026). The risk for a recurrent event was significantly higher in patients with elevated Lp(a) levels after adjustment for potential confounders (hazard ratio, 2.60; 95% confidence interval, 1.19–5.67; P =0.016). Conclusions— Elevated Lp(a) levels are associated with a higher risk for combined vascular event recurrence in patients with acute, first-ever ischemic stroke. This finding should be validated in larger, multicenter trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01378468.

Objective:To quantitatively evaluate blood–brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI.Methods:We examined 54 stroke patients (clinicaltrials.govNCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow-up examination on day 5–7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes.Results:Median stroke Ktrans values (0.7 × 10−3 min−1 [interquartile range (IQR) 0.4–1.8] × 10−3 min−1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 × 10−3 min−1, IQR 0.1–0.7 × 10−3 min−1, p < 0.001) and further increased at follow-up (n = 28, 2.3 × 10−3 min−1, IQR 0.8–4.6 × 10−3 min−1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 × 10−3 min−1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker.Conclusion:BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow-up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct.

Background and purpose Several studies have described an association between insular infarction and mortality. Large infarcts often include the insula and lesion size is associated with mortality. We hypothesized that there is an association between insular infarction and mortality independent of lesion volume. Methods We included consecutive stroke patients between 1 September 2008 and 11 November 2012 from the 1000Plus database with an acute ischaemic lesion on diffusion-weighted imaging on day 1 and a completed 90-day follow-up. Insular infarct location was determined using the in-house software Stroke Lesion Atlas. In multiple Cox regression analysis (dependent variable: mortality), we adjusted for insular infarcts, age, lesion volume, history of atrial fibrillation, National Institutes of Health Stroke Scale and previous stroke. Results We included 736 patients, of whom 168 had an insular infarction. Within a medium follow-up time of 107 days, cumulative survival was 90% in patients with insular infarction and 99% in patients without insular infarction (P < 0.001). Right insular infarction was independently associated with mortality (hazard ratio, 2.60; confidence interval, 1.3–5.4; P = 0.010). Conclusions In our study, right insular involvement was a prognostic marker for mortality after ischaemic stroke. A selection bias towards patients able to give informed consent warrants further studies.

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.

BACKGROUND AND PURPOSE: Acute lesions in patients with transient ischaemic attack (TIA) are important as they are associated with increased risk for recurrence. Characteristics associated with acute lesions in young TIA patients were therefore investigated.METHODS: The sifap1 study prospectively recruited a multinational European cohort (n = 5023) of patients aged 18-55 years with acute cerebrovascular event. The detection of acute ischaemic lesions was based on diffusion-weighted imaging (DWI). The frequency of DWI lesions was assessed in 829 TIA patients who met the criteria of symptom duration

As the process of Alzheimer's disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.

Highlights • Injury to major white matter pathways during language-area associated glioma surgery often results in permanent aphasia. • DTI-based tractography of language pathways allows to correlate individual tract injury profiles with functional outcome. • Infiltration of the AF is particularly associated with functional deterioration. • The temporo-parieto-occipital junction and the temporal stem were confirmed as pivotal functional nodes. • Standardized DTI-based tractography can help to determine the individual aphasia risk profile before surgery., Objectives Injury to major white matter pathways during language-area associated glioma surgery often leads to permanent loss of neurological function. The aim was to establish standardized tractography of language pathways as a predictor of language outcome in clinical neurosurgery. Methods We prospectively analyzed 50 surgical cases of patients with left perisylvian, diffuse gliomas. Standardized preoperative Diffusion-Tensor-Imaging (DTI)-based tractography of the 5 main language tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) and spatial analysis of tumor and tracts was performed. Postoperative imaging and the resulting resection map were analyzed for potential surgical injury of tracts. The language status was assessed preoperatively, postoperatively and after 3 months using the Aachen Aphasia Test and Berlin Aphasia Score. Correlation analyses, two-step cluster analysis and binary logistic regression were used to analyze associations of tractography results with language outcome after surgery. Results In 14 out of 50 patients (28%), new aphasic symptoms were detected 3 months after surgery. The preoperative infiltration of the AF was associated with functional worsening (cc = 0.314; p = 0.019). Cluster analysis of tract injury profiles revealed two areas particularly related to aphasia: the temporo-parieto-occipital junction (TPO; temporo-parietal AF, middle IFOF, middle ILF) and the temporal stem/peri-insular white matter (middle IFOF, anterior ILF, temporal UF, temporal AF). Injury to these areas (TPO: OR: 23.04; CI: 4.11 – 129.06; temporal stem: OR: 21.96; CI: 2.93 – 164.41) was associated with a higher-risk of persisting aphasia. Conclusions Tractography of language pathways can help to determine the individual aphasia risk profile pre-surgically. The TPO and temporal stem/peri-insular white matter were confirmed as functional nodes particularly sensitive to surgical injuries.

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.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.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

Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay&rsquo, s longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the &ldquo, under treatment&rdquo, versus &ldquo, not under treatment&rdquo, conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.

Introduction Nutritional intervention with the natural polyamine spermidine, an autophagy-enhancing agent, can prevent memory loss in aging model organisms. This is the first human study to evaluate the impact of spermidine supplementation on memory performance in older adults at risk for the development of Alzheimer's disease. Methods Cognitively intact participants with subjective cognitive decline (n = 30, 60–80 years of age) were included in this three-months, randomized, placebo-controlled, double-blind Phase IIa pilot trial with a spermidine-rich plant extract supplement. Effects of intervention were assessed using the behavioral mnemonic similarity task, measured at baseline and post-intervention visits. Data analysis was focused on reporting and interpreting effectiveness based on effect sizes. Results Memory performance was moderately enhanced in the spermidine group compared with placebo at the end of intervention [contrast mean = .17, 95% confidence interval (CI): −.01, .35, Cohen's d = .77, 95% CI: 0, 1.53]. Mnemonic discrimination ability improved in the spermidine-treated group with a medium effect size (mean difference = −.11, 95% CI: −.19, −.03, Cohen's d = .79, 95% CI: .01, 1.55). A similar effect was not found in the placebo-treated group (mean difference = .07, 95% CI: −.13, .27, Cohen's d = −.20, 95% CI: −.94, .54). Discussion In this pilot trial, nutritional spermidine was associated with a positive impact on memory performance in older adults with subject cognitive decline. The beneficial effect might be mediated by stimulation of neuromodulatory actions in the memory system. A follow-up Phase IIb randomized controlled trial will help validate the therapeutic potential of spermidine supplementation and delineate possible neurophysiological mechanisms of action. Trial registration Registered in ClinicalTrials.gov with the Identifier NCT02755246 .