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Neuroprotection and brain repair in patients after acute brain damage are still major unfulfilled medical needs. Pharmacological treatments are either ineffective or confounded by adverse effects. Consequently, endogenous mechanisms by which the brain protects itself against noxious stimuli and recovers from damage are being studied. Research on preconditioning, also known as induced tolerance, over the past decade has resulted in various promising strategies for the treatment of patients with acute brain injury. Several of these strategies are being tested in randomised clinical trials. Additionally, research into preconditioning has led to the idea of prophylactically inducing protection in patients such as those undergoing brain surgery and those with transient ischaemic attack or subarachnoid haemorrhage who are at high risk of brain injury in the near future. In this Review, we focus on the clinical issues relating to preconditioning and tolerance in the brain; specifically, we discuss the clinical situations that might benefit from such procedures. We also discuss whether preconditioning and tolerance occur naturally in the brain and assess the most promising candidate strategies that are being investigated.

BackgroundMyasthenia 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.MethodsThis 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.ResultsIn 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.DiscussionHRQoL 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 informationClinicaltrials.gov, NCT03979521, submitted: June 7, 2019, first patient enrolled: May 1, 2019, https://clinicaltrials.gov/ct2/show/NCT03979521

Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

Psychiatric comorbidities are relevant in patients with Myasthenia gravis (MG). Also, MG patients experience a reduced health-related quality of life (HRQoL). We aimed to quantify the impact of depression as well as self-perceived MG severity on HRQoL and caregivers' burden. In this cross-sectional study, we used a survey encompassing demographic, disease-related information, and standardized questionnaires to assess symptoms of depression, anxiety, HRQoL (MG Quality of Life scale; MG-QoL15), and caregiver burden (Burden Scale for Family Caregivers; BSFC). Data from 1399 participating patients (96%) and 1042 caregivers (65%) were eligible for further analysis. Symptoms of depression and anxiety disorder were indicated by 31% and 36% of patients. Self-reported MG severity (MG severity) and MG-QoL15 scores were strongly associated (estimated marginal means for severe versus mild MG severity = 18 95% CI [16; 21]; p  ≤ 0.001). Adjusting for symptoms of depression decreased the estimated strength of this association (estimated marginal means for severe versus mild MG severity = 15 [13; 17]; p  ≤ 0.001). Caregiver burden was associated to MG disease severity (estimated marginal means for severe vs. mild MG severity = 0.16 [0.13; 0,19); p  ≤ 0.001) and also negatively influenced by symptoms of depression (estimated marginal means = 0.12 [0.09; 0.15]). Symptoms of depression and anxiety disorder in MG are frequent. Beyond MG severity, symptoms of depression have negative effects on HRQoL as well as on caregivers’ burden. Diagnosis and treatment of psychiatric comorbidities should be considered an important element in MG care. Screening tools for mental health conditions should be implemented at least in specialized MG centers.

Background Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. Methods We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. Results 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. Conclusions MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients. Graphical Abstract

Impairments to comprehension and production of speech (aphasia, dysarthria) and swallowing disorders (dysphagia) are common sequelae of stroke, reducing patients' quality of life and social participation. Treatment oriented on evidence-based guidelines seems likely to improve outcomes. Currently, little is known about guideline adherence in stroke aftercare for the above-mentioned sequelae. This study aims to analyse guideline adherence in the treatment of aphasia, dysarthria and dysphagia after stroke, based on suitable test parameters, and to determine factors that influence the implementation of recommended therapies. Six test parameters were defined, based on systematic study of guidelines for the treatment of speech impairments and swallowing disorders (e.g. comprehensive diagnostics, early initiation and continuity). Guideline adherence in treatment was tested using claims data from four statutory health insurance companies. Multivariate logistic and linear regression analyses were performed in order to test the outcomes. 4,486 stroke patients who were diagnosed with specific disorders or received speech therapy were included in the study. The median age was 78 years; the proportion of women was 55.9%. Within the first year after the stroke, 90.3% of patients were diagnosed with speech impairments and swallowing disorders. Overall, 44.1% of patients received outpatient speech and language therapy aftercare. Women were less frequently diagnosed with specific disorders (OR 0.70 [95%CI:0.55/0.88], p = 0.003) and less frequently received longer therapy sessions (OR 0.64 [95%CI:0.43/0.94], p = 0.022). Older age and longer hospitalization duration increased the likelihood of guideline recommendations being implemented and of earlier initiation of stroke aftercare measures. Our observations indicate deficits in the implementation of guideline recommendations in stroke aftercare. At the same time, they underscore the need for regular monitoring of implementation measures in stroke aftercare to address group-based disparities in care.

Stroke is one of the leading causes of death worldwide and the biggest reason for long-term disability. Basic research has formed the modern understanding of stroke pathophysiology, and has revealed important molecular, cellular and systemic mechanisms. However, despite decades of research, most translational stroke trials that aim to introduce basic research findings into clinical treatment strategies – most notably in the field of neuroprotection – have failed. Among other obstacles, poor methodological and statistical standards, negative publication bias, and incomplete preclinical testing have been proposed as ‘translational roadblocks’. In this article, we introduce the models commonly used in preclinical stroke research, discuss some of the causes of failed translational success and review potential remedies. We further introduce the concept of modeling ‘care’ of stroke patients, because current preclinical research models the disorder but does not model care or state-of-the-art clinical testing. Stringent statistical methods and controlled preclinical trials have been suggested to counteract weaknesses in preclinical research. We conclude that preclinical stroke research requires (1) appropriate modeling of the disorder, (2) appropriate modeling of the care of stroke patients and (3) an approach to preclinical testing that is similar to clinical testing, including Phase 3 randomized controlled preclinical trials as necessary additional steps before new therapies enter clinical testing.

Myasthenia gravis (MG) is a neuromuscular disorder resulting in exertion-dependent muscle fatigability. Affecting all age groups MG is a chronic disease with unpredictable fluctuations and a range of symptom expression which can require costly immunosuppressive therapy and intensive care critically influencing economic burden. Here we aim to elucidate both the personal and societal economic burden of MG. Data were used from two sources: (1) a cross sectional study of MG patients registered in the German Myasthenia Society (DMG) collected by a survey in 2019 (n = 1660), and (2) from a dataset provided by a German health insurance company covering the period from 01/01/2014 to 31/12/2019 (n = 750) and categorized to similar subgroups for comparison. Individual and societal economic burden was highest in patients with intensified medical treatment. Absence days from work per patient year in the first year after index in claims data were 67.1 days (95% CI 66.1–68.2) (referring to n = 260 non-retired patients). Of 686 patients with early onset (< 50 years) MG 260 (41.2%) reported loss of income due to MG in DMG data. Average inpatient costs from claims data in patients with intensified treatment (38,669€; 95% CI 38,627–38,712€) were particularly high compared with standard treatment (2980€; 95% CI 2975–2986€) and to no MG-related treatment (887€; 95% CI 877–886€). MG represents a major economic burden for the individual and the health care system. The costs are positively associated with the severity of disease. The economic burden is particularly high for working patients. UCB Pharma provided financial support for the subanalysis, but was not involved in the design of the study. Trial registration : clinicaltrials.gov, NCT03979521, submitted: June 7, 2019, first patient enrolled: May 1, 2019, https://clinicaltrials.gov/ct2/show/NCT03979521 .

Stroke remains a leading cause of premature death, impairment and reduced quality of life. Its aftercare is performed by numerous different health care service providers, resulting in a high need for coordination. Personally delivered patient navigation (PN) is a promising approach for managing pathways through health care systems and for improving patient outcomes. Although PN in stroke care is evolving, no summarized information on its cost-effectiveness in stroke survivors is available. Hence, the aim of this systematic review is to analyze the level of evidence on the cost-effectiveness of PN for stroke survivors. A systematic literature search without time limitations was carried out in PubMed, EMBASE, CENTRAL, CINAHL as well as PsycINFO and supplemented by a manual search. Randomized controlled trials published prior to April 2020 in English or German were considered eligible if any results regarding the cost-effectiveness of PN for stroke survivors were reported. The review was conducted according to PRISMA guidelines. Quality of included studies was assessed with the RoB2 tool. Main study characteristics and cost-effectiveness results were summarized and discussed. The search identified 1442 records, and two studies met the inclusion criteria. Quality of included studies was rated moderate and high. Programs, settings and cost-effectiveness results were heterogeneous, with one study showing a 90% probability of being cost-effective at a willingness to pay of $25600 per QALY (health/social care perspective) and the other showing similar QALYs and higher costs. Since only two studies were eligible, this review reveals a large gap in knowledge regarding the cost-effectiveness of PN for stroke survivors. Furthermore, no conclusive statement about the cost-effectiveness can be made. Future attempts to evaluate PN for stroke survivors are necessary and should also involve cost-effectiveness issues.