Missing data in patient-reported outcome measures (PROMs) can affect estimation accuracy and inferential validity, particularly under missing-at-random (MAR) mechanisms. Multiple imputation (MI) is commonly recommended, but the relative performance of item-level and score-level imputation for longitudinal PROM composite scores remains insufficiently understood. We conducted a simulation study based on longitudinal clinical trial PROM data. Predictive mean matching (PMM) and random forest (RF) imputation were evaluated at both the item and score level under empirically calibrated MAR mechanisms. Simulation scenarios varied sample size, overall missingness, and the proportion of unit nonresponse. Performance was assessed using root mean squared error (RMSE), bias magnitude, relative efficiency compared with complete case analysis (CCA), conditional confidence interval coverage, and variance ratio estimates. RMSE decreased with increasing sample size and increased with higher proportions of missingness across all methods. Both PMM and RF generally outperformed CCA in terms of RMSE and relative efficiency, particularly under higher missingness. Differences between item-level and score-level imputation were generally modest, although score-level imputation tended to yield slightly lower RMSE and bias magnitudes under more severe missingness conditions. Conditional coverage remained close to nominal levels across most MI settings. Variance tended to be overestimated in some scenarios, although sensitivity analyses with larger numbers of imputations substantially reduced this effect. PMM showed comparatively stable performance across simulation settings. Multiple imputation methods generally outperformed complete case analysis for handling longitudinal PROM data under MAR. While score-level imputation sometimes showed slightly more favorable performance than item-level imputation when targeting composite score means, the magnitude of these differences was frequently small in practical terms. PMM provided stable performance across a wide range of settings and represents a reasonable default approach for many applied PROM analyses.

BACKGROUND:Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years. METHODS:We included 246 TIA patients from the INSPiRE-TMS study (ClinicalTrials.gov: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0-4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years. RESULTS:At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD-score was independently associated with greater cognitive decline over 3 years (β = -0.52, 95% CI -0.95- -0.08, p = 0.020), along with older age (β = -0.08, 95% CI -0.13 to -0.03, p = 0.001). CMB burden was the strongest predictive component of the CSVD-score (β = 0.42, 95% CI -0.63 to -0.22, p < 0.001). CSVD-score was particularly associated with decline in the memory domain (adjusted β of -0.18, 95% CI -0.32 to -0.04, p = 0.015). CONCLUSION:CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on memory. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Falls are a frequent and serious complication after stroke, affecting more than 30% of survivors within the first year. While age and comorbidities are established risk factors for falls, stroke-specific contributors—particularly lesion-related impairments in mobility and gait—are less well understood and may inform targeted secondary prevention. We analyzed data from 94 patients with disabling subacute ischemic stroke enrolled in the prospective BAPTISe cohort, a predefined imaging and biomarker sub-cohort of the multicenter PHYS-STROKE trial. Detailed gait and mobility assessments were performed at baseline. Principal component (PC) analysis reduced seven mobility-related and four gait-related variables into two composite scores: PC1-Mobility and PC1-Gait, explaining 56% and 82% of variance, respectively. PC1-Mobility reflected global disability and functional mobility in daily life, whereas PC1-Gait captured spatiotemporal walking capacity and efficiency. Lesion network mapping (LNM) using a normative connectome identified functional networks associated with each domain. Patient-reported falls up to six months post-enrollment were the primary endpoint. LNM of PC1-Mobility revealed a predominantly cortical network involving pre- and postcentral gyri, superior and middle frontal gyri, and sensorimotor integration areas. In contrast, PC1-Gait was associated with subcortical and infratentorial connectivity, including bilateral thalamus, brainstem, and cerebellum. In multivariable regression, network similarity scores were not independently associated with falls; only older age was significant (adjusted OR1.08, 95%CI1.02–1.15,p=0.013). LNM of fall occurrence showed a cortical network with significant spatial overlap with the PC1-Mobility network(p<0.001). This exploratory, hypothesis-generating study identified distinct lesion-derived functional networks associated with post-stroke mobility and gait impairment. Our findings suggest that falls may be more closely linked to disruptions in cortical networks involved in voluntary motor control and whole-body coordination, rather than subcortical structures primarily modulating gait. These results provide a foundation for future research aimed at improving fall risk stratification and targeted prevention strategies in stroke survivors.

Understanding and modulating memory functions in older adults continues to be a fundamental challenge for neuroscientific research. Given age-associated declines in long-range connectivity, network approaches targeting these connections are of particular interest. We investigated whether dual-site transcranial alternating current stimulation can modulate episodic (sequential) memory in cognitively healthy older adults (N = 44, aged 60-80 years). In a sham-controlled crossover design, participants received in-phase (0°) and anti-phase (180°) transcranial alternating current stimulation during a temporal order memory task, with a counterbalanced order of conditions. We computed source analysis-based weighted phase lag indices and corrected amplitude envelope correlation between left hemispheric fronto-parietal stimulation targets from resting-state electroencephalography to quantify modulation of functional connectivity, and conducted analyses of phase angles between these targets. No overall memory effects were observed in either active stimulation conditions, compared with sham. However, the results showed an interaction between memory modulation and age, indicating that the older the participants the higher the memory improvement in the anti-phase condition. Functional coupling increase was observed in both anti- and in-phase conditions as an elevated weighted phase lag indices theta change, compared with sham. No differences were observed for weighted phase lag indices in other frequency bands (alpha, beta) or for the corrected amplitude envelope correlation (theta, alpha, beta). Theta phase angle shifts were increased in the anti-phase compared with the sham condition. Further, in the anti-phase condition, the increase in theta connectivity was linked to age and memory improvement, indicating a potential mechanistic link between neurophysiological and cognitive outcomes. In sum, our findings suggest that dual-site anti-phase stimulation may increase functional connectivity in older adults with large interindividual variability in memory effects, warranting further investigation to optimize stimulation strategies.

Importance Postoperative delirium (POD) occurs as a significant complication after elective surgery. Objective To investigate the modulation of delirium incidence by transcranial electric stimulation (tES). Design, Setting, and Participants A double-blind, sham-controlled randomized clinical trial (Modulating Delirium Through Stimulation [MODEST]) was conducted at University Medicine Greifswald, Germany, from February 8, 2024, to January 15, 2025. Patients were aged 65 years or older who were scheduled to undergo elective surgery. Exclusion criteria were any history of neurological or psychiatric disease, or intake of central nervous system–active medication. Data were analyzed from June 10, 2025, to June 5, 2026. Intervention α-Transcranial alternating current stimulation (tACS) of the salience network, transcranial direct current stimulation (tDCS) of the frontoparietal network (dosing: 20 minutes, 2 mA), or sham, in the postanesthesia care unit (PACU) after major elective surgery. Main Outcomes and Measures The primary outcome was POD incidence in the ward during 1 of up to 5 postoperative days for the comparison of tACS vs the sham group. The secondary outcomes included POD in the ward for the comparison of tDCS vs sham group, POD in PACU, POD severity and motor type, and postoperative pain. Prespecified subgroup analyses opted to test the dependence of POD incidence on age, sex, duration, and type of surgery, baseline cognitive function, and preoperative pain levels. Results A total of 225 patients (mean [SD] age, 73.0 [6.0] years; 59.6% [134] male) were randomly assigned to tACS (n = 68), tDCS (n = 83), or sham stimulation (n = 74). No substantial between group differences were observed for POD incidence in ward (tACS, 11.5% [6 of 52]; tDCS, 14.3% [9 of 63]; sham, 9.2% [6 of 65]; tACS vs sham: odds ratio [OR], 1.60 [95% CI, 0.47-5.46]; P = .45; tDCS vs sham: OR, 1.51 [95% CI, 0.49-4.68]; P = .47) or in PACU (tACS, 14.6% [7 of 48]; tDCS, 21.4% [12 of 56]; sham, 21.7% [13 of 60]; tACS vs sham: OR, 0.95 [95% CI, 0.38-2.36]; P = .91; tDCS vs sham: OR, 0.91 [95% CI, 0.36-2.30]; P = .83). Further secondary analyses of POD severity and motor type, and modulation of pain levels, did not show any substantial difference between stimulation groups. Prespecified subgroup analyses revealed different modulation of POD incidence in PACU depending on duration of surgery (OR, 0.15 [95% CI, 0.02-0.97]; P = .046), indicating that tACS may reduce POD incidence for patients with longer surgery (absolute risk difference for POD in the tACS compared with the sham group, for a surgical duration of 3 to 5 hours of −26.6% to −46.5%). Ratings of adverse events did not differ between groups (incidence rate ratio, 2.3 [95% CI, 0.8-6.5]), and no serious adverse events were reported. Conclusions and Relevance In this randomized clinical trial of tES for POD, there was no evidence for a uniform effect of postoperative tES on the incidence of POD, but it suggested a benefit of parietal α oscillatory enhancement for patients with longer surgery. Future research has to test the specific effect on vulnerable groups, examine the optimal timing for tES application to modulate POD, and investigate the value of personalizing tES parameters. Trial Registration German Clinical Trials Register: DRKS00033703

Multicenter neuroimaging studies face challenges from scanner-related measurement biases that can obscure biological effects. Traveling-subject (TS) designs allow direct quantification of such biases by scanning the same participants across multiple sites. While reliability of structural, functional, and diffusion MRI has been established, the reliability of electric field simulations for transcranial brain stimulation has not been examined. We assessed inter-scanner and scan-rescan reliability of simulated electric field magnitudes in 10 participants scanned twice on each of five 3T Siemens scanners, using SimNIBS v4.1 to simulate focal tDCS across seven cortical and cerebellar targets. ICC values indicated good to excellent inter-scanner (0.86-0.97) and scan-rescan (0.94-0.98) reliability, with between-scanner variance not exceeding measurement error. Intra-individual segmentation variability substantially explained within-person differences in field magnitudes, whereas image quality did not predict segmentation variability. These results demonstrate that individualized electric field simulations are robust to scanner-related variation, supporting their use in multicenter brain stimulation research.

Hearing loss has been reported as a major, potentially modifiable risk factor for dementia and often co-occurs with tinnitus. Both conditions are prevalent and have been linked to brain health and cognitive decline. However, evidence from studies containing the whole age span of adults remains limited. Therefore, this study investigated associations of hearing loss and tinnitus with brain structure and cognitive performance in a large population-based cohort from northeastern Germany. Data from the baseline investigation of 4,420 participants (age 20–84 years) for the SHIP-TREND cohort was analysed. Thereof, 4,400 completed a self-assessment for hearing and 3,937 for tinnitus. Cognitive performance was assessed by tests on verbal memory and executive function. T1-weighted magnetic resonance imaging yielded data on global and regional volumes and cortical thickness for 2,144 participants. Multiple linear regression and mediation analyses were conducted, adjusted for age, sex, and further risk factors for dementia. A total of 1,455 participants reported hearing loss, 679 thereof a clinically relevant degree while 874 participants reported tinnitus. Hearing loss was associated with worse memory performance and unfavourable brain measures, particularly along the central auditory pathway and in regions implicated in cognitive function and Alzheimer’s Disease. Notably, white matter hypointensity volume partially mediated (8.8

Abstract Background Myasthenia gravis has a variable disease course. Early identification of patients with a highly active disease is crucial to prevent myasthenic exacerbations and crisis, necessitating more aggressive immunotherapy. However, no biomarkers currently exist to identify patients at risk for highly active disease course. Objective The PROGNO-MG study aims to identify blood-based biomarker signatures associated with a highly active disease course in immunotherapy-naïve patients with acetylcholine-receptor-antibody positive (AChR+) generalized Myasthenia gravis (gMG). Methods This is an investigator-initiated prospective, multicentric, observational study. Seventy newly diagnosed immunotherapy-naïve AChR+ gMG patients will be enrolled and followed up for 24 months. Blood samples and clinical data will be collected biannually. Biomarkers (calprotectin, neurofilament light chain, ITIH3, complement activation, kappa free light chains, and exploratory proteome-analyses and immune cell phenotyping) will be measured and their association with clinical outcomes will be evaluated. Perspective The results will provide evidence for prognostic biomarkers, supporting risk stratification and early individualized treatment for AChR+ gMG patients. Trial registration The study is registered in the German clinical trial register (DRKS00035457).

BACKGROUND:Falls affect over 30% of stroke survivors within the first year, yet lesion-related mobility and gait impairments underlying fall risk remain poorly understood. This study aimed to identify lesion-derived functional networks associated with impaired mobility, gait, and fall risk in subacute stroke, and to determine whether disruption to these networks is associated with falls during the six-month follow-up. METHODS:We analyzed data from 94 patients with disabling subacute ischemic stroke from the prospective Baptize cohort, an imaging sub-cohort of the multicenter PHYS-STROKE trial. Principal component (PC) analysis reduced seven mobility-related and four gait-related baseline variables into two composites: PC1-Mobility and PC1-Gait, explaining 56% and 82% of variance, respectively. PC1-Mobility indexed global disability, whereas PC1-Gait reflected spatiotemporal walking capacity. Lesion network mapping (LNM) identified functional networks associated with each domain. Patient-reported falls up to six months post-enrollment were the primary endpoint. RESULTS:LNM revealed that the mobility-related network predominantly involved cortical regions, whereas the gait-related network was linked to subcortical and infratentorial connectivity. In binary multivariable logistic regression, network similarity scores were not associated with falls; only older age was significant (adjusted OR 1.08, 95% CI 1.02-1.16, p = 0.01). LNM of fall occurrence identified a cortical network with significant spatial overlap with the mobility-related network (p < 0.001). CONCLUSION:This exploratory, hypothesis-generating study identified distinct functional networks for post-stroke mobility and gait impairment. Falls may be more closely linked to disruptions in cortical networks supporting voluntary motor control and whole-body coordination than to subcortical gait-modulating structures, potentially informing fall risk stratification and targeted prevention. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: BAPTISe: NCT01954797, PHYS-STROKE: NCT01363856.

Introduction Following a cerebrovascular event, the associated risks for further major adverse cerebro- and cardiovascular events and death (MACE) and important aspects of cognitive, mental and patient-reported outcomes are currently not understood, particularly long-term. Here, we present the study design of the ongoing Berlin Long-term Observation of Vascular Events (BeLOVE) stroke stratum and report data of the first study phase.Methods and analysis BeLOVE is a prospective, longitudinal, observational, hospital-based cohort study. Its stroke stratum enrols adult patients with acute ischaemic stroke, transient ischaemic attack (TIA) or non-traumatic intracerebral haemorrhage. Patients undergo deep phenotyping including cerebral and cardiac MRI, ECG, echocardiography and bio-sampling including multi-omics analyses. Regular, standardised follow-ups take place annually over a period of up to 10 years and record the frequency of MACE as the primary outcome.Secondary outcomes include the frequency, progression and interactions of functional impairments, namely post-stroke cognition, pain, depression, seizures and their relationship to quality of life.The first study phase included 758 patients (median 69 years, 37% female). At 2-year follow-up, the cumulative incidence (95% CI) of the composite primary endpoint MACE was 0.107 (0.085 to 0.132) and that of first ischaemic stroke, first myocardial infarction and death were 0.066 (0.049 to 0.086), 0.015 (0.008 to 0.026) and 0.040 (0.027 to 0.056), respectively.Ethics and dissemination Each participant will provide informed written consent during the acute in-hospital phase. Data will be available for research purposes via a written request to the data use and access committee.Trial registration number German Clinical Trials Register: http://www.drks.de/DRKS00023323 on 4 November 2020.

Joint models offer an unbiased statistical approach for analyzing the effects of longitudinal biomarkers on time-to-event outcomes, providing an alternative to time-varying Cox proportional-hazards regression and the two-stage approach. However, whether available implementations of these methods perform reliably across different practically relevant scenarios remains insufficiently studied. We conducted a simulation study based on the Berlin Initiative Study examining kidney function and survival in older adults. In a manner comparable to phase IV studies in clinical research, our evaluation aims to provide insights into the practical performance of commonly used R package implementations of these methods, mostly under their default settings. By varying data generating scenarios, we assessed how different numbers of events and longitudinal measurements affect performance of Bayesian (JMbayes2) and frequentist joint model implementations (JM and joineRML), time-varying Cox PH regression (survival), and the two-stage approach (nlme and survival), focusing on bias in parameter estimates. Results revealed substantial variability across implementations. The JM package exhibited considerable bias and frequent convergence issues. In contrast, joineRML performed robustly with approximately unbiased estimates for association parameters and high convergence frequencies comparable to the implementations of the simpler methods across diverse scenarios. However, both frequentist packages systematically underestimated the effects of baseline covariates in the survival model. The Bayesian JMbayes2 was largely unbiased, but performance deteriorated under two conditions: with few events (< 70), convergence was low and bias persisted even in converged models; and with observation-to-event ratios below 2, convergence declined, although estimates from converged models remained approximately unbiased. Time-varying Cox PH regression and the two-stage approach showed more bias than JMbayes2 in certain settings but tended to achieve more robust performance and convergence across most scenarios.

Post-stroke pain (PSP) affects nearly half of stroke survivors, severely compromising quality of life. The causes of PSP remain underexplored, although there is likely a complex interplay of lesion effects, psychological factors, and mobility that play a role in its development. The aim of the study was to investigate clinical characteristics associated with PSP, as well as structural and functional correlates of PSP using lesion symptom (LSM) and network mapping (LNM). We analyzed data from the INSPiRE-TMS cohort, encompassing 1022 minor ischemic stroke patients. Pain severity and psychological factors (EQUATION 5D-3L questionnaire) were assessed annually for up to 3 years. In a sub-group of 391 patients with available imaging data, LSM and LNM analyses were conducted to identify neural correlates of PSP. Overall, 47% of patients reported pain 1-year post-stroke. Multivariable regression analyses identified baseline anxiety as associated with PSP assessed at 1-year post-stroke (OR 2.90, 95% CI 1.17-7.17, p = 0.021). LSM did not identify any voxels associated with new severe pain. LNM identified a network involving the anterior cingulate cortex, thalamus, and insular cortex. Adjusting for anxiety highlighted distinct network contributions, suggesting interactive effects of psychological states on pain perception. Automated comparison to large metanalytical findings using Neurosynth associated the terms 'pain' and 'nociception' most strongly to the identified network. PSP is closely associated with psychological factors such as anxiety. LNM of PSP revealed disruptions in a pain-related neural network consistent with prior pain research. These results warrant external validation and could guide future network-targeted neuromodulation therapies. Trial Registration: ClinicalTrials.gov identifier: NCT01586702.

Importance:Electronic patient-reported outcome (PRO) monitoring has shown benefits in advanced cancer, but data specific to metastatic breast cancer (mBC) remain limited. Fatigue is a common, clinically important, and functionally impairing symptom in mBC, making it a patient-centered target for electronic PRO monitoring. Objective:To determine whether digital PRO monitoring with alert-based responses reduces fatigue in patients with mBC. Design, Setting, and Participants:This multicenter randomized clinical trial was conducted from May 2021 to February 2024, with 12 months of follow-up, at 52 breast cancer centers in Germany and included women aged 18 years or older with mBC who were receiving systemic therapy at any point in the metastatic disease course, had a life expectancy of longer than 3 months, were able to read German, and had smartphone access. Data analysis started in February 2024 and lasted 6 months. Interventions:The intervention group completed weekly PRO questionnaires via a smartphone using validated short forms from the European Organization for Research and Treatment of Cancer computerized adaptive testing core item bank. Automated alerts based on predefined PRO deterioration were emailed to trained local nurses or physicians, who contacted patients by telephone within 48 hours. The control group received usual care with quarterly PRO questionnaires and no alerts. Main Outcomes and Measures:The primary outcome was fatigue at 6 months. Secondary outcomes included fatigue, physical functioning, and quality of life over 12 months. PROs were reported as standardized T scores. Results:Of 2008 patients screened, 924 (46.0%) were randomized, and 909 (45.3%) were included in the primary analysis (median age, 50 years [range, 19-83 years]). Baseline mean (SD) fatigue T scores were 57.6 (9.5) in the intervention group and 60.2 (9.0) in the control group (P < .001), with baseline PROs assessed after randomization but before group-specific follow-up began. At 6 months, adjusted mean fatigue was 54.5 (95% CI, 53.7- 55.4) vs 59.9 (95% CI, 59.0-60.8), yielding a mean difference of -5.4 points (95% CI, -6.6 to -4.1; P < .001), exceeding the minimal clinically important difference (MCID) of 3.3 points. At 6 months, physical functioning was higher in the intervention group (mean difference, 4.0; 95% CI, 2.6-5.4), exceeding its MCID (3.2), whereas the between-group difference in quality of life was 0.8 points (95% CI, 0.02-1.5), which was less than the MCID of 2.9. Conclusions and Relevance:This randomized clinical trial found that digital PRO monitoring was associated with clinically meaningful reductions in fatigue and improved physical functioning. These findings support further evaluation of alert-based PRO monitoring in routine oncology care. Trial Registration:German Clinical Trials Register: DRKS00024015.

Electric field simulations based on individualized Magnetic Resonance Imaging (MRI)-derived head models are increasingly used to optimize non-invasive brain stimulation (NIBS) protocols, enabling individualized dose adjustments to achieve a desired current flow at cortical targets. However, the quality of structural MRI data—affected by motion artefacts, tissue contrast, and scanner-related noise—may influence the accuracy of these simulations, an issue possibly exacerbated in older adults who often exhibit lower image quality. If reduced image quality compromises electric field estimation, it could limit the feasibility of individualized dosing in aging populations. In this study, we examined whether standardized image quality metrics—entropy focus criterion (EFC), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), spatial resolution (FWHM), and intensity non-uniformity (INU)—systematically relate to the magnitude of simulated electric fields in young and older adults. We analysed MRI and simulation data of a focal C3 montage from 106 healthy adults, 47 young adults (mean age: 24.8, age range: 20–35 years) and 59 older adults (mean age: 69.5 years, age range: 60–79) using SimNIBS for computational modelling of the electric fields and MRIQC for image quality assessment. Structural equation modelling was used to quantify direct and indirect effects of age group on electric field magnitude, with image quality as a mediating factor. Head volume was included in extended models to control for anatomical variation. Our findings demonstrate that MR image quality is associated with simulated electric field magnitude, with higher EFC, lower SNR, lower CNR, and higher INU associated with reduced field estimates, and older adults showing generally lower simulated electric fields compared to younger adults. While image quality accounted for some of the age-related differences in electric field strength, group differences remained even after controlling for EFC, SNR and head volume. Critically, electric field simulations remained sufficiently reliable despite lower image quality in older adults, supporting their use for individualized dose adjustment across the lifespan.

Importance:Postoperative delirium (POD) occurs as a significant complication after elective surgery. Objective:To investigate the modulation of delirium incidence by transcranial electric stimulation (tES). Design, Setting, and Participants:A double-blind, sham-controlled randomized clinical trial (Modulating Delirium Through Stimulation [MODEST]) was conducted at University Medicine Greifswald, Germany, from February 8, 2024, to January 15, 2025. Patients were aged 65 years or older who were scheduled to undergo elective surgery. Exclusion criteria were any history of neurological or psychiatric disease, or intake of central nervous system-active medication. Data were analyzed from June 10, 2025, to June 5, 2026. Intervention:α-Transcranial alternating current stimulation (tACS) of the salience network, transcranial direct current stimulation (tDCS) of the frontoparietal network (dosing: 20 minutes, 2 mA), or sham, in the postanesthesia care unit (PACU) after major elective surgery. Main Outcomes and Measures:The primary outcome was POD incidence in the ward during 1 of up to 5 postoperative days for the comparison of tACS vs the sham group. The secondary outcomes included POD in the ward for the comparison of tDCS vs sham group, POD in PACU, POD severity and motor type, and postoperative pain. Prespecified subgroup analyses opted to test the dependence of POD incidence on age, sex, duration, and type of surgery, baseline cognitive function, and preoperative pain levels. Results:A total of 225 patients (mean [SD] age, 73.0 [6.0] years; 59.6% [134] male) were randomly assigned to tACS (n = 68), tDCS (n = 83), or sham stimulation (n = 74). No substantial between group differences were observed for POD incidence in ward (tACS, 11.5% [6 of 52]; tDCS, 14.3% [9 of 63]; sham, 9.2% [6 of 65]; tACS vs sham: odds ratio [OR], 1.60 [95% CI, 0.47-5.46]; P = .45; tDCS vs sham: OR, 1.51 [95% CI, 0.49-4.68]; P = .47) or in PACU (tACS, 14.6% [7 of 48]; tDCS, 21.4% [12 of 56]; sham, 21.7% [13 of 60]; tACS vs sham: OR, 0.95 [95% CI, 0.38-2.36]; P = .91; tDCS vs sham: OR, 0.91 [95% CI, 0.36-2.30]; P = .83). Further secondary analyses of POD severity and motor type, and modulation of pain levels, did not show any substantial difference between stimulation groups. Prespecified subgroup analyses revealed different modulation of POD incidence in PACU depending on duration of surgery (OR, 0.15 [95% CI, 0.02-0.97]; P = .046), indicating that tACS may reduce POD incidence for patients with longer surgery (absolute risk difference for POD in the tACS compared with the sham group, for a surgical duration of 3 to 5 hours of -26.6% to -46.5%). Ratings of adverse events did not differ between groups (incidence rate ratio, 2.3 [95% CI, 0.8-6.5]), and no serious adverse events were reported. Conclusions and Relevance:In this randomized clinical trial of tES for POD, there was no evidence for a uniform effect of postoperative tES on the incidence of POD, but it suggested a benefit of parietal α oscillatory enhancement for patients with longer surgery. Future research has to test the specific effect on vulnerable groups, examine the optimal timing for tES application to modulate POD, and investigate the value of personalizing tES parameters. Trial Registration:German Clinical Trials Register: DRKS00033703.

Patients with traumatic spinal cord injury (SCI) frequently develop urinary tract infections (UTI) which may compromise neurological rehabilitation. We explored risk factors for UTI, including immunological biomarkers, in patients with acute traumatic SCI during the transition from acute to subacute phase. Two observational studies were analysed separately: a retrospective study (COaT-SCI, n = 296, follow-up 13 weeks), and a prospective immunological study (SCIentinel, n = 70, follow-up 10 weeks). Cox regression models were used to examine associations of first UTI with patient characteristics and longitudinal immunological parameters. Cumulative incidence of first UTI was approximately 50% at six weeks. Results indicated higher UTI risk in older patients and time-varying associations for SCI severity (ASIA impairment scale) and presence of accompanying injuries. Higher cellular immune competence, particularly CD8 + T-cell counts and higher IFN-γ/IL-4 ratio in functional T-cell assays, were associated with a lower UTI risk (HR [95% CI] per log-transformed unit: CD8 + T-cells 0.34 [0.18—0.65], IFN-γ/IL-4 ratio 0.53 [0.33–0.83]). Adding cellular immune markers improved models’ discriminative ability (weighted C-index at 21 days from 0.68 to 0.76 with CD8 + T-cells). These findings indicate UTI is facilitated by systemic immune alterations, with T-cell parameters representing promising predictive biomarkers requiring further validation before clinical implementation.

Focal transcranial direct current stimulation (tDCS) using center-surround electrode montages enables region-specific cortical targeting, and holds promise for both cognitive neuroscience and clinical interventions. However, systematic examinations of dose-response relationships and their regional differences are lacking, hampering informed selections of suited stimulation parameters.In this preparatory methodological study, we present a modeling-based framework to support harmonized empirical dose-response studies of focal tDCS across different target areas. It covers three steps: Determining the approximate electric field strength that had led to behavioral and physiological effects in related prior tDCS studies. In our case, this led to a field strength of 0.2 V/m on average across magnetic resonance images (MRIs) from 43 participants and eight target areas related to different cognitive and motor functions. Second, optimizing the radii of center-surround montages for each target area to - on average across participants - achieve the intended field strength while maximizing focality. An additional test of cross-sample generalization in an independent sample confirms that the intended target field strength is achieved on average for new participants. Third, the pre-determined montage radii and a method for the individualized positioning of the center-surround electrode montages are provided for prospective planning in empirical dose-response studies.By harmonizing the electric field strength between different target regions at the group level, but preserving inter-individual variability, our framework will enable systematic analyses to relate the field strength to behavioral and neuroimaging outcomes, and to assess differences of these relations across regions. The described computational tools are open-source, allowing other researchers to tailor our framework to their specific research questions; and are currently used in a multi-center study involving approximately 1,000 datasets.

While individual determinants of students’ well-being are well established, less is known about the association with the institutional context. This study evaluates institutional-level factors associated with students’ mental health while controlling for individual characteristics. The cross-sectional analysis used data from 12 German institutions (n = 13,715) collected in the StudiBiFra survey on study conditions and student mental health. Individual-level variables included gender, age, study subject group, and four mental health variables (general well-being, depressiveness, cognitive stress, and exhaustion). Institution-level variables comprised institution type, excellence status, multi-campus structure, size, and satisfaction with the quality of health promotion services. Multilevel binary logistic regression models were applied to examine associations between institutional characteristics and mental health outcomes, adjusting for individual factors. Students enrolled at universities of applied sciences showed a lower likelihood of reporting depressiveness and exhaustion. Higher levels of depressiveness and cognitive stress were observed among students at medium-sized institutions compared to small ones. Students not enrolled at institutions with excellence status had lower risks of depressiveness, stress, and exhaustion. Additionally, higher satisfaction with institutional health promotion services was associated with reduced odds of depressiveness. Institutional factors are related to students’ mental health beyond individual characteristics, highlighting the need for a holistic, setting-based approach.

Abstract BackgroundAtopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, associated with itching, sleep disturbance, and impaired quality of life. Structured patient education can improve disease outcomes, but in-person programs are often unavailable in rural or underserved areas. Digital interventions may help overcome these barriers; however, their efficacy compared with routine care has not been evaluated. ObjectiveThis study aims to assess whether a digitally delivered, interdisciplinary care concept (ADCompanion) is noninferior to routine, real-world care, as available in well-served areas, in reducing disease severity among patients with AD. Secondary objectives include effects on quality of life, pruritus, psychosocial burden, family well-being, and health care costs. MethodsThis is a prospective, multicenter, 2-arm, 1:1 randomized noninferiority trial. Participants are stratified by age and disease severity. The intervention group receives standard therapy plus access to a digital platform with training modules and optional video consultations on skin care, nutrition, and psychosocial support. The control group receives routine care, optionally including face-to-face group training where available, and a basic app version for symptom tracking. The primary endpoint is physician-assessed disease severity (Scoring Atopic Dermatitis Index [SCORAD]) at 6 months; secondary endpoints include patient-reported outcomes, itch, quality of life, and disease-related costs. ResultsRecruitment of 603 participants across 7 centers in Germany was completed. Data collection was finalized in June 2025. At the time of protocol submission (February 2026), data cleaning had been completed, and the statistical analysis plan was finalized; final results are expected to be published in 2026. ConclusionsThis protocol describes a randomized trial designed to evaluate whether digitally delivered interdisciplinary care is noninferior to routine care for patients with AD. The findings of this study will inform the role of digital patient education as a complementary component within established care structures.

BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling condition with limited treatment options and inadequate healthcare structures worldwide. We assessed the effectiveness of an integrated care model specifically adapted for ME/CFS.MethodsIn this prospective, open-label, non-randomized controlled intervention study conducted at Charité Fatigue Center we enrolled patients with ME/CFS between 2022 and 2023. Participants in the intervention group received multidisciplinary specialist assessment, comprehensive clinical management, and tailored inpatient rehabilitation, while the control group received a single outpatient consultation and a medical report for their primary physician. Primary outcome was change in physical functioning, measured using the SF-36 physical functioning subscale, at 12 months. Secondary outcomes included disability, symptom severity, quality of life, handgrip strength, and steps per day.Results89 intervention and 93 control participants were included in the per-protocol analysis. At 12 months, no statistically significant difference in SF-36 physical functioning scores was observed between groups. Secondary outcomes also showed no substantial between-group differences. Inpatient rehabilitation was completed by all participants who initiated it. Most participants reported that rehabilitation was helpful for learning disease management strategies, and for coping better with daily life. Post-rehabilitation Bell Disability Scale scores decreased in 42/94 (45%) and increased in only 13/94 (14%) patients.ConclusionsThe integrated multidisciplinary care model was feasible and associated with high retention but did not improve physical functioning or key secondary outcomes at 12 months. Current rehabilitative and management strategies may be insufficient to alter disease trajectory, underscoring the need for more effective, disease-modifying therapeutic interventions.