The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Non-pharmacological interventions for improving language and communication in people with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) accounts for approximately 43% of frontotemporal dementias and is mainly characterised by a progressive impairment of speech and communication abilities. Three clinical variants have been identified: (a) non-fluent/agrammatic, (b) semantic, and (c) logopenic/phonological PPA variants. There is currently no curative treatment for PPA, and the disease progresses inexorably over time, with devastating effects on speech and communication ability, functional status, and quality of life. Several non-pharmacological interventions that may improve symptoms (e.g. different forms of language training and non-invasive brain stimulation) have been investigated in people with PPA. OBJECTIVES: To assess the effects of non-pharmacological interventions for people with PPA on word retrieval (our primary outcome), global language functions, cognition, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's trial register, MEDLINE (Ovid SP), Embase (Ovid SP), four other databases and two other trial registers. The latest searches were run on 26 January 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of non-pharmacological interventions in people with PPA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: There were insufficient data available to conduct the network meta-analyses that we had originally planned (due to trial data being insufficiently reported or not reported at all, as well as the heterogeneous content of the included interventions). Therefore, we provide a descriptive summary of the included studies and results. We included 10 studies, with a total of 132 participants, evaluating non-pharmacological interventions. These were: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) as stand-alone treatments (used by two and one studies, respectively); tDCS combined with semantic and phonological word-retrieval training (five studies); tDCS combined with semantic word-retrieval training (one study); and tDCS combined with phonological word-retrieval training (one study). Results for our primary outcome of word retrieval were mixed. For the two studies that investigated the effects of tDCS as stand-alone treatment compared to placebo ("sham") tDCS, we rated the results as having very low-certainty evidence. One study found a significant beneficial effect on word retrieval after active tDCS; one study did not report any significant effects in favour of the active tDCS group. Five studies investigated tDCS administered to the dorsolateral prefrontal cortex, inferior frontal cortex, left frontotemporal region, or the temporoparietal cortex, combined with semantic and phonological word-retrieval training. The most consistent finding was enhancement of word-retrieval ability for trained items immediately after the intervention, when behavioural training was combined with active tDCS compared to behavioural training plus sham tDCS. We found mixed effects for untrained items and maintenance of treatment effects during follow-up assessments. We rated the certainty of the evidence as very low in all studies. One study investigated tDCS combined with semantic word-retrieval training. Training was provided across 15 sessions with a frequency of three to five sessions per week, depending on the personal preferences of the participants. tDCS targeted the left frontotemporal region. The study included three participants: two received 1 mA stimulation and one received 2 mA stimulation. The study showed mixed results. We rated it as very low-certainty evidence. One study investigated tDCS combined with phonological word-retrieval training. Training was again provided across 15 sessions over a period of three weeks. tDCS targeted the left inferior frontal gyrus. This study showed a significantly more pronounced improvement for trained and untrained words in favour of the group that had received active tDCS, but we rated the certainty of the evidence as very low. One study compared active rTMS applied to an individually determined target site to active rTMS applied to a control site (vertex) for effects on participants' word retrieval. This study demonstrated better word retrieval for active rTMS administered to individually determined target brain regions than in the control intervention, but we rated the results as having a very low certainty of evidence. Four studies assessed overall language ability, three studies assessed cognition, five studies assessed potential adverse effects of brain stimulation, and one study investigated quality of life. AUTHORS' CONCLUSIONS: There is currently no high-certainty evidence to inform clinical decision-making regarding non-pharmacological treatment selection for people with PPA. Preliminary evidence suggests that the combination of active tDCS with specific language therapy may improve impaired word retrieval for specifically trained items beyond the effects of behavioural treatment alone. However, more research is needed, including high-quality RCTs with detailed descriptions of participants and methods, and consideration of outcomes such as quality of life, depressive symptoms, and overall cognitive functioning. Moreover, studies assessing optimal treatments (i.e. behavioural interventions, brain stimulation interventions, and their combinations) for individual patients and PPA subtypes are needed. We were not able to conduct the planned (network) meta-analyses due to missing data that could not be obtained from most of the authors, a general lack of RCTs in the field, and heterogeneous interventions in eligible trials. Journals should implement a mandatory data-sharing requirement to assure transparency and accessibility of data from clinical trials.

Using LASSO Regression to Estimate the Population-Level Impact of Pneumococcal Conjugate Vaccines.

Pneumococcal conjugate vaccines (PCVs) protect against diseases caused by Streptococcus pneumoniae, such as meningitis, bacteremia, and pneumonia. It is challenging to estimate their population-level impact due to the lack of a perfect control population and the subtleness of signals when the endpoint-such as all-cause pneumonia-is nonspecific. Here we present a new approach for estimating the impact of PCVs: using least absolute shrinkage and selection operator (LASSO) regression to select variables in a synthetic control model to predict the counterfactual outcome for vaccine impact inference. We first used a simulation study based on hospitalization data from Mexico (2000-2013) to test the performance of LASSO and established methods, including the synthetic control model with Bayesian variable selection (SC). We found that LASSO achieved accurate and precise estimation, even in complex simulation scenarios where the association between the outcome and all control variables was noncausal. We then applied LASSO to real-world hospitalization data from Chile (2001-2012), Ecuador (2001-2012), Mexico (2000-2013), and the United States (1996-2005), and found that it yielded estimates of vaccine impact similar to SC. The LASSO method is accurate and easily implementable and can be applied to study the impact of PCVs and other vaccines.

Reproducibility of cerebral perfusion measurements using BOLD delay.

BOLD delay is an emerging, noninvasive method for assessing cerebral perfusion that does not require the use of intravenous contrast agents and is thus particularly suited for longitudinal monitoring. In this study, we assess the reproducibility of BOLD delay using data from 136 subjects with normal cerebral perfusion scanned on two separate occasions with scanners, sequence parameters, and intervals between scans varying between subjects. The effects of various factors on the reproducibility of BOLD delay, defined here as the differences in BOLD delay values between the scanning sessions, were investigated using a linear mixed model. Reproducibility was additionally assessed using the intraclass correlation coefficient of BOLD delay between sessions. Reproducibility was highest in the posterior cerebral artery territory. The mean BOLD delay test-retest difference after accounting for the aforementioned factors was 1.2 s (95% CI = 1.0 to 1.4 s). Overall, BOLD delay shows good reproducibility, but care should be taken when interpreting longitudinal BOLD delay changes that are either very small or are located in certain brain regions.

Interrelations and functional roles of key oscillatory activities during daytime sleep in older adults.

Certain neurophysiological characteristics of sleep, in particular slow oscillations (SOs), sleep spindles, and their temporal coupling, have been well characterised and associated with human memory abilities. Delta waves, which are somewhat higher in frequency and lower in amplitude compared to SOs, and their interaction with spindles have only recently been found to play a critical role in memory processing of rodents, through a competitive interaction between SO-spindle and delta-spindle coupling. However, human studies that comprehensively address delta wave interactions with spindles and SOs, as well as their functional role for memory are still lacking. Electroencephalographic data were acquired across three naps of 33 healthy older human participants (17 female) to investigate delta-spindle coupling and the interplay between delta- and SO-related activity. Additionally, we determined intra-individual stability of coupling measures and their potential link to the ability to form novel memories in a verbal memory task. Our results revealed weaker delta-spindle compared to SO-spindle coupling. Contrary to our initial hypothesis, we found no evidence for an opposing dependency between SO- and delta-related activities during non-rapid eye movement sleep. Moreover, the ratio between SO- and delta-nested spindles rather than SO-spindle and delta-spindle coupling measures by themselves predicted the ability to form novel memories best. In conclusion, our results do not confirm previous findings in rodents on competitive interactions between delta activity and SO-spindle coupling in older adults. However, they support the hypothesis that SO, delta wave, and spindle activity should be jointly considered when aiming to link sleep physiology and memory formation.

Identifying and handling unbalanced baseline characteristics in a non-randomized, controlled, multicenter social care nurse intervention study for patients in advanced stages of cancer.

PURPOSE: Given the psychosocial burdens patients in advanced stages of cancer face, innovative care concepts are needed. At the same time, such vulnerable patient groups are difficult to reach for participation in intervention studies and randomized patient inclusion may not be feasible. This article aims to identify systematic biases respectively selection effects occurring during the recruitment phase and to discuss their potential causes based on a non-randomized, multicenter intervention study with patients in advanced stages of cancer. METHODS: Patients diagnosed with at least one of 16 predefined cancers were recruited at four hospitals in three German cities. The effect of social care nurses' continuous involvement in acute oncology wards was measured by health-related quality of life (EORTC QLQ-C30), information and participation preferences, decisional conflicts, doctor-patient communication, health literacy and symptom perception. Absolute standardized mean difference was calculated as a standardized effect size to test baseline characteristics balance between the intervention and control groups. RESULTS: The study enrolled 362 patients, 150 in the intervention and 212 in the control group. Except for gender, both groups differed in relevant socio-demographic characteristics, e.g. regarding age and educational background. With respect to the distribution of diagnoses, the intervention group showed a higher symptom burden than the control group. Moreover, the control group reported better quality of life at baseline compared to the intervention group (52.6 points (SD 21.7); 47.8 points (SD 22.0), ASMD = 0.218, p = 0.044). CONCLUSION: Overall, the intervention group showed more social and health vulnerability than the control group. Among other factors, the wide range of diagnoses included and structural variation between the recruiting clinics increased the risk for bias. We recommend a close, continuous monitoring of relevant social and health-related characteristics during the recruitment phase as well as the use of appropriate statistical analysis strategies for adjustment, such as propensity score methods. TRIAL REGISTRATION: German Clinical Trials Register (DRKS-ID: DRKS00013640 ); registered on 29th December 2017.

Exact replication: Foundation of science or game of chance?

The need for replication of initial results has been rediscovered only recently in many fields of research. In preclinical biomedical research, it is common practice to conduct exact replications with the same sample sizes as those used in the initial experiments. Such replication attempts, however, have lower probability of replication than is generally appreciated. Indeed, in the common scenario of an effect just reaching statistical significance, the statistical power of the replication experiment assuming the same effect size is approximately 50%-in essence, a coin toss. Accordingly, we use the provocative analogy of "replicating" a neuroprotective drug animal study with a coin flip to highlight the need for larger sample sizes in replication experiments. Additionally, we provide detailed background for the probability of obtaining a significant p value in a replication experiment and discuss the variability of p values as well as pitfalls of simple binary significance testing in both initial preclinical experiments and replication studies with small sample sizes. We conclude that power analysis for determining the sample size for a replication study is obligatory within the currently dominant hypothesis testing framework. Moreover, publications should include effect size point estimates and corresponding measures of precision, e.g., confidence intervals, to allow readers to assess the magnitude and direction of reported effects and to potentially combine the results of initial and replication study later through Bayesian or meta-analytic approaches.

Fear of prognosis? How anxiety, coping, and expected burden impact the decision to have cytogenetic assessment in uveal melanoma patients.

BACKGROUND: Cytogenetic testing (CGT) in uveal melanoma patients reveals prognostic information about the individual risk of developing distant metastasis with dismal prognosis. There is currently no medical intervention strategy with proven effect on the prognosis, rendering the result of the cytogenetic testing purely informative. We explored patients' socio-demographic backgrounds, psychological preconditions, coping strategies, external influences, and concerns about "knowing their fate" to study their possible interactions with decision-making for CGT. METHODS: Uveal melanoma patients were asked to complete questionnaires on their interest in undergoing CGT for prognostication and the factors influencing their decision. Data were collected on socio-demographics, baseline anxiety (GAD-7), depression (PHQ-9), coping strategies (Brief COPE), and assumed future concerns regarding the CGT result. Data were analyzed by using multiple ordinal logistic regression and exploring estimated marginal effects. RESULTS: Questionnaires were returned by 121 of 131 (92.4%) patients. Fifty-two patients (43%) had no interest in CGT, 34 (28.1%) were undecided, and 35 (28.9%) were interested. We observed no significant differences regarding age, sex, partnership, education, occupation, baseline anxiety, or depression. Decision-making favoring CGT was influenced by the treating physicians, internet resources, and level of baseline anxiety. Patients were likely to reject CGT when they worried that "knowing the result will have an unintended influence" on their life. CONCLUSION: Decision-making about CGT for prognostication in uveal melanoma is burdensome to many patients and in general not guided by medical advice regarding further treatment and screening procedures. The psychological impact of the decision is therefore unique and requires careful support by psycho-oncologists considering the patient's fears and expectations.

A tablet-based intervention for activating nursing home residents with dementia: results from a cluster-randomized controlled trial.

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 (ß = .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.

Changes in Alcohol Use in Denmark during the Initial Months of the COVID-19 Pandemic: Further Evidence of Polarization of Drinking Responses.

INTRODUCTION: The year 2020 was marked by the COVID-19 pandemic. Policy responses to COVID-19 affected social and economic life and the availability of alcohol. Previous research has shown an overall small decrease in alcohol use in Denmark in the first months of the pandemic. The present paper focused on identifying which subgroups of individuals had decreased or increased their consumption. MATERIALS AND METHODS: Data were collected between May and July 2020 (n = 2,566 respondents, convenience sample). Weights were applied to reflect the actual Danish general population. Variables included the pre-pandemic alcohol consumption, change in alcohol consumption in the past month, socio-demographics, and reported economic consequences. Responses to a single item assessing changes in alcohol consumption in the past month were classified as no change, increase, or decrease in consumption. Regression models investigated how changes in consumption were linked to pre-pandemic drinking levels, socio-demographics (gender, age groups, education), and reported economic consequences. RESULTS: While 39% of participants reported decreased consumption levels and 34% had stable levels, 27% increased consumption. Characteristics associated with changes in consumption were associated with both increases and decreases in consumption: younger people, those with higher consumption levels before the pandemic, and those with lower education more often both reported increases as well as decreases in consumption. DISCUSSION/CONCLUSIONS: We confirmed that more people decreased rather than increased their alcohol consumption in the first few months of the pandemic in Denmark. Characteristics associated with changes in consumption such as younger age, higher consumption levels, and lower education demonstrated a polarization of drinking since these were associated with both increases and decreases in consumption. Public health authorities should monitor alcohol use and other health behaviours for increased risks during the pandemic.

Association of age with the timing of acute spine surgery-effects on neurological outcome after traumatic spinal cord injury.

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 (< 20 h 20-25%, 20-60 h 10-20%, > 60 h < 10% probability of AIS conversion). In incomplete SCI, the probability of AIS conversion was lower in older patients [e.g., OR 0.09 (0.02-0.44) for'45-59y' vs.' ≤ 44y'], as confirmed by spline curves (< 40y 20-80%, ≥ 40y 5-20% probability). 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.

A gender-focused multilevel analysis of how country, regional and individual level factors relate to harm from others' drinking.

BACKGROUND: The aim of this study was to examine how gender, age and education, regional prevalence of male and female risky drinking and country-level economic gender equality are associated with harms from other people's drinking. METHODS: 24,823 adults in ten countries were surveyed about harms from drinking by people they know and strangers. Country-level economic gender equality and regional prevalence of risky drinking along with age and gender were entered as independent variables into three-level random intercept models predicting alcohol-related harm. FINDINGS: At the individual level, younger respondents were consistently more likely to report harms from others' drinking, while, for women, higher education was associated with lower risk of harms from known drinkers but higher risk of harms from strangers. Regional rate of men's risky drinking was associated with known and stranger harm, while regional-level women's risky drinking was associated with harm from strangers. Gender equality was only associated with harms in models in models that did not include risky drinking. CONCLUSIONS: Youth and regional levels of men's drinking was consistently associated with harm from others attributable to alcohol. Policies that decrease the risky drinking of men would be likely to reduce harms attributable to the drinking of others.

Inter-individual and age-dependent variability in simulated electric fields induced by conventional transcranial electrical stimulation.

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.

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD. METHODS: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years. RESULTS: In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD. CONCLUSION: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

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 ~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 ~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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characteristics and patient-reported outcomes associated with dropout in severely affected oncological patients: an exploratory study.

BACKGROUND: Patient-reported outcome measures (PROMs) are commonly-used surrogates for clinical outcomes in cancer research. When researching severe diseases such as cancer, it is difficult to avoid the problem of incomplete questionnaires from drop-outs or missing data from patients who pass away during the observation period. The aim of this exploratory study was to explore patient characteristics and the patient-reported outcomes associated with the time-to-dropout. METHODS: In an Oncological Social Care Project (OSCAR) study, the condition of the 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-risk regressions based on Fine and Gray's proportional sub-distribution hazards model for exploring factors associated with time-to-dropout. Death was considered a competing risk. RESULTS: Three hundred sixty-two participants were analyzed in the study. 193 (53.3%) completed a follow-up after 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 a higher risk of 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 sub-scales global health status/QoL, role functioning, physical functioning, and fatigue symptom in the EORTC QLQ-C30 were key characteristics of early drop-out. CONCLUSION: Severely affected cancer patients with poor social support and poor quality of life seem more likely to drop out of studies than patients with higher levels of social support and a better quality of life. This should be considered when planning studies to assess advanced cancer patients. Methods of close continued monitoring should be actively used when patient experiences a substantial deterioration in their health-related quality of life and symptoms during the study. Results for such studies have to be interpreted with caution in light of specific drop-out mechanisms. TRIAL REGISTRATION: OSCAR study was registered to the German Clinical Trials Register (DRKS-ID: DRKS00013640 ). Registered 29 December 2017.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

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.

[Support for General Practitioners in the Care of Patients with Complex Needs: A Questionnaire Survey of General Practitioners in Berlin]. / Unterstützungsbedarf und -möglichkeiten für Hausärzte in der Versorgung von Patienten mit komplexem Bedarf: Eine Fragebogenerhebung Berliner Hausärzte.

OBJECTIVES: Because of demographic changes, new models of care are important for supporting general practitioners in the care of patients with complex needs. This study addresses the question of the type of support that is requested by general practitioners working in Berlin. METHODS: All general practitioners working in Berlin (n=2354) were asked between August and September 2018 to return a questionnaire by post which has been developed for this study. Questions addressed support needs as well as support models within the practice (delegation, substitution) and outside the practice (social worker, navigator, community care points). Data were analysed descriptively and by exploratory multivariate analysis to show the influence of practice and doctor characteristics on the preference of support models (age, gender, location of the practice, type of practice, working hours). RESULTS: A total of 557 questionnaires (response rate 23.7%) were included in the analysis. Need for support was seen particularly for administrative, coordinative and organisational tasks and for advice on social issues. The majority of the study participants approved delegation and substitution. In their view, it was conceivable to get support from professionals or institutions outside their practice, such as mobile care services, community care points, social workers or navigators. Particularly younger and female doctors working in group practices were open for cooperative care models integrating other health professions. CONCLUSIONS: There is unused potential for delegation and cooperation within existing structures. Further research should investigate the acceptance and feasibility of different support models.

Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations.

For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions.

Spermidine intake is associated with cortical thickness and hippocampal volume in older adults.

BACKGROUND: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer's disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC). METHODS: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures. RESULTS: Higher spermidine intake was associated with larger hippocampal volume (standardized ߠ​= â€‹0.262, p â€‹= â€‹0.002), greater mean cortical thickness (standardized ߠ​= â€‹0.187, p â€‹= â€‹0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized ߠ​= â€‹0.176, p â€‹= â€‹0.042), the parietal (standardized ߠ​= â€‹0.202, p â€‹= â€‹0.020), and temporal lobes (standardized ߠ​= â€‹0.217, p â€‹= â€‹0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed. CONCLUSION: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.