Respiratory function in adult patients with spinal muscular atrophy treated with nusinersen - a monocenter observational study.

Background/objective: Insufficiency of respiratory muscles is the most important reason for mortality in the natural history of SMA. Thus, improvement or stabilization of respiratory function by disease-modifying therapies (DMT) is a very important issue. Methods: We examined respiratory function using forced vital capacity (FVC) in 42 adult SMA patients (2 SMA type 1, 15 SMA type 2, 24 SMA type 3, 1 SMA type 4, median age 37 years, range 17-61 years) treated with nusinersen for a median of 22.1 months (range 2.1 to 46.7 months). Change in FVC was assessed using mixed effects linear regression models. Results: Baseline FVC differed significantly between SMA type 1 (4.0, 8.0%), 2 (median 22.0%, IQR 18.0-44.0), 3 (median 81.0%, IQR 67.0-90.8) and, respectively, type 4 (84.0%) patients reflecting the heterogeneity of respiratory impairment based on the SMA type in adulthood (p < 0.0001). FVC remained stable during follow-up (mean -0.047, 95% CI -0.115 to 0.020, p = 0.17); however, subgroup analysis showed an increase in FVC of type 2 patients (mean 0.144, 95% CI 0.086 to 0.202, p < 0.0001) and a decrease in FVC of type 3/4 patients (-0.142, 95% CI -0.239 to -0.044, p = 0.005). Conclusion: The observed improvement in FVC in patients with SMA type 2 can be seen as a therapeutic response differing from the progressive decline typically seen in the spontaneous course. For SMA type 3/4 patients approaching normal spirometry at baseline, FVC may only be of limited use as an outcome parameter due to ceiling effects.

Analysis of a nurse-provided on-call peritoneal dialysis support in an outpatient reference care centre.

BACKGROUND: To analyse the nature of medical or technical emergency issues of ambulatory peritoneal dialysis (PD) patients calling a nurse-provided emergency PD support service of a reference centre that is provided all year in the after-hours. METHODS: We retrospectively analysed patients' chief complaint, urgency, resolution of and association to current PD treatment and modality directed to an on-call nurse-provided PD support service from 2015-2021 based on routinely collected health data. Calls were systematically categorized being technical/procedural-, medical-, material-related or type of correspondence. Call urgency was categorized to have "immediate consequence", inquiry was eligible for "processing next working day" or whether there was "no need for further action". Call outcomes were classified according to whether patients were able to initiate, resume or finalize their treatments or whether additional interventions were required. Unexpected adverse events such as patients' acute hospitalization or need for nurses' home visits were evaluated and quantified. RESULTS: In total 753 calls were documented. Most calls were made around 7:30 a.m. (5:00-9:00; median, 25-75th CI) and 6:30 p.m. (5:00-8:15). 645 calls were assigned to continuous ambulatory- (CAPD) or automated PD (APD). Of those, 430 calls (66.7%) had an "immediate consequence". Of those 77% (N = 331) were technical/procedural-, 12.8% (N = 55) medical- and 6.3% (N = 27) material related issues. 4% (N = 17) were categorized as other correspondence. Issues disrupting the course of PD were identified in 413 cases. In 77.5% (N = 320) patients were able to initiate, resume or finalize their treatment after phone consultation. Last-bag exchange was used in 6.1% enabling continued therapy in 83.6%. In 35 cases a nurse visit at patients' home or patients' visit to the practice at the earliest possible date were required, while hospitalization was required in seven medical category cases (5.4% and 1.09% of total assessed calls, respectively). CONCLUSION: The on-call PD-nurse provides patient support for acute and imminent issues enabling them to successfully initiate, resume or finalize their prescribed treatment. Nurses triage of acute conditions facilitated rapid diagnostics and therapy. Maintaining quality PD homecare, the provision of trained personnel is indispensable. The information gathered in this study may therefore be used as a foundation to tailor educational programs for nephrology nurses and doctors to further develop their competencies in PD.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.

Medical education during the Covid-19 pandemic long-term experiences of German clinical medical students.

INTRODUCTION: Due to the Covid-19 pandemic and the accompanying hygiene regulations, medical students in Germany faced multiple educational and personal challenges. The challenges included the cancellation and digitalisation of courses, the closing of university institutions such as libraries, a decrease in social contacts, and the risk of a Covid-19 infection. The aim of this study was to understand medical students' pandemic experiences as well as the consequences of these experiences for the students' future work as physicians. MATERIALS AND METHODS: We performed 15 guided, one-on-one interviews with clinical medical students (third to fifth year) at the Otto-von-Guericke-University Magdeburg. Interviews were recorded, transcribed, and anonymised. We performed a qualitative content analysis in accordance with Mayring and thereby formed an inductive category system. The Consolidated Criteria for Reporting Qualitative Research (COREQ) were applied. RESULTS: Five categories were inductively formed: "Changes in the teaching experience", "negative effects on the learning experience", "decrease in personal social contacts", "contact with covid-19", and "pandemic-associated stress increase". The participating students reported higher levels of stress due to isolation and uncertainty regarding their educational future. Furthermore, students welcomed the digitalisation of lectures, developed individual coping strategies, and voluntarily took part in the care of Covid-19 patients. Limitations to social interactions were perceived as the major restrictive factor to their educational structure, their perceived learning success and personal development. CONCLUSION: This study identified social restrictions as well as didactic and academic structural challenges as relevant factors contributing to perceived stress and fear for medical students during the Covid-19 pandemic, especially as regards their learning experience. Students' acceptance of digitalised learning may enable regular interaction with university peers and may facilitate a structured educational life. However, the implementation of digital resources could not provide a sufficient substitute for in-person courses.

Neutrophil Gelatinase-Associated Lipocalin Cutoff Value Selection and Acute Kidney Injury Classification System Determine Phenotype Allocation and Associated Outcomes.

Background: We explored the extent to which neutrophil gelatinase-associated lipocalin (NGAL) cutoff value selection and the acute kidney injury (AKI) classification system determine clinical AKI-phenotype allocation and associated outcomes. Methods: Cutoff values from ROC curves of data from two independent prospective cardiac surgery study cohorts (Magdeburg and Berlin, Germany) were used to predict Kidney Disease: Improving Global Outcome (KDIGO)- or Risk, Injury, Failure, Loss of kidney function, End-stage (RIFLE)-defined AKI. Statistical methodologies (maximum Youden index, lowest distance to [0, 1] in ROC space, sensitivity≍specificity) and cutoff values from two NGAL meta-analyses were evaluated. Associated risks of adverse outcomes (acute dialysis initiation and in-hospital mortality) were compared. Results: NGAL cutoff concentrations calculated from ROC curves to predict AKI varied according to the statistical methodology and AKI classification system (10.6-159.1 and 16.85-149.3 ng/mL in the Magdeburg and Berlin cohorts, respectively). Proportions of attributed subclinical AKI ranged 2%-33.0% and 10.1%-33.1% in the Magdeburg and Berlin cohorts, respectively. The difference in calculated risk for adverse outcomes (fraction of odds ratios for AKI-phenotype group differences) varied considerably when changing the cutoff concentration within the RIFLE or KDIGO classification (up to 18.33- and 16.11-times risk difference, respectively) and was even greater when comparing cutoff methodologies between RIFLE and KDIGO classifications (up to 25.7-times risk difference). Conclusions: NGAL positivity adds prognostic information regardless of RIFLE or KDIGO classification or cutoff selection methodology. The risk of adverse events depends on the methodology of cutoff selection and AKI classification system.

Mapping and assessing ecosystem services for sustainable policy and decision-making in Eritrea.

The mapping and assessment of ecosystems and their services (MAES) is key to inform sustainable policy and decision-making at national and sub-national levels. Responding to the paucity of research in sub-Saharan Africa, we conduct a pilot study for Eritrea that aims to map and assess the temporal dynamics of key ecosystems and their services. We reviewed policy and legal documents, analyzed land cover changes and estimated the potential for ecosystem services supply through an expert-based matrix approach. Our results showed that from 2015 to 2019, the potential supply of the ecosystem services analyzed (e.g., crop provisioning, water supply and recreation) increased, with the exception of wood supply. Overall, our study presents policy-relevant insights as to where to conserve, develop, or restore ecosystem services supply in Eritrea. Our approach is transferable to similar data scarce contexts and can thereby support policies toward more sustainable land development for people and nature.

Altered Gaze Control During Emotional Face Exploration in Patients With Amyotrophic Lateral Sclerosis.

OBJECTIVES: Up to 50% of patients with amyotrophic lateral sclerosis (ALS) present with cognitive problems and behavioral dysfunctions including recognition of human faces presenting different emotions. We investigated whether impaired processing of emotional faces is associated with abnormal scan paths during visual exploration. METHODS: Cognitively unimpaired patients with ALS (n = 45) and matched healthy controls (n = 37) underwent neuropsychological assessment and video-based eye tracking. Eye movements were recorded while participants visually explored faces expressing different emotions (neutral, disgusted, happy, fearful, and sad) and houses mimicking faces. RESULTS: Compared with controls, patients with ALS fixated significantly longer to regions which are not relevant for emotional information when faces expressed fear (p = 0.007) and disgust (p = 0.006), whereas the eyes received less attention in faces expressing disgust (p = 0.041). Fixation duration in any area of interest was not significantly associated with the cognitive state or clinical symptoms of disease severity. DISCUSSION: In cognitively unimpaired patients with ALS, altered gaze patterns while visually exploring faces expressing different emotions might derive from impaired top-down attentional control with possible involvement of subliminal frontotemporal areas. This may account for indistinctness in emotion recognition reported in previous studies because nonsalient features retrieve more attention compared with salient areas. Current findings may indicate distinct emotion processing dysfunction of ALS pathology, which may be different from, for example, executive dysfunction.

Virtual participatory mapping of nature-based solutions in the Grande de Tárcoles River basin, Costa Rica: Connecting diverse knowledge systems in a context of physical immobility.

Co-design processes are of key importance in planning and implementing Nature-based Solutions (NBS), but require boundary management between diverse holders of local, practical and scientific knowledge. Participatory and map-based planning tools, such as Geodesign workshops, can facilitate such boundary management through mobilising knowledge holders, and translating and negotiating between different perspectives. The COVID-19 pandemic hindered physical mobility, but offered an, albeit unintended, opportunity to explore new ways of virtual mobility for facilitating boundary management in NBS co-design through digital participatory tools. This short communication aims to demonstrate how a spatial planning process for NBS can be facilitated in an online context. We draw on an international case study for co-designing NBS in Costa Rica, conducted during the severe lock-down restriction of the COVID-19 pandemic. This novel approach showcases how physical presence and movement is replaced by virtual mobility enabled through an online geographic map-based environment that allowed participants to communicate their opinions and co-create local and regional NBS actions. The case study included developing and testing a co-design tool to understand and map local perceptions of social-ecological problems, and an actual co-design process for siting NBS options and jointly exploring their implications. We present two levels of the process: 1) the adaptation of the co-design tool, and 2) the use and usefulness of the co-design tool. Our evaluation shows that the tool served its purpose well and provided useful support to local stakeholders. We recommend to test further strategical combinations of in-person and virtual methods in NBS co-design processes to improve NBS planning and implementation.

Access to urban green spaces in Hannover: An exploration considering age groups, recreational nature qualities and potential demand.

City dwellers' accessibility of urban green spaces (UGS) has recently gained immense interest in research and policy. Related scientific studies thus far have focused primarily on spatial distances, largely missing considerations of UGS qualities. We analysed the entire UGS setting of Hannover considering the recreational nature quality and potential demands to identify age-appropriate green spaces by applying a geographic information system analysis of several data sets. Additionally, we assessed the accessibility of UGS for different age groups, varying recreational nature qualities, and potential demands. Results indicate that children and elderly people have poor access to UGS that offers age-related requirements to enable unrestricted nature-based recreation. Nature quality and age-related requirements play a significant role in the assessment of UGS for recreation and accessibility. We conclude that detected vulnerabilities regarding age-related recreation in cities are anchors to mainstream the issue and enhance future planning practices and research.

[Innovative facultative seminar concepts regarding clinical teaching and preparing practice-oriented phases, such as medical clerkships and the final clinical internship from a surgical perspective]. / Innovative fakultative Seminarkonzepte besonders klinisch-praktisch ausgerichteter Lehre zur Famulatur- und PJ-Vorbereitung aus spezifisch chirurgischer Sicht.

BACKGROUND: Practice-oriented phases, such as the mandatory clinical traineeships and the final clinical internship, are of great importance in the teaching curriculum and skilful learning of medical students. AIM: With respect to the practical phases, such as clinical clerkship and medical internship, the concept of two innovative courses to prepare and evaluate these crucial training sections is presented including initial experiences from teaching practice. METHOD: A narrative review is given. RESULTS: A common aim of facultatively initiated lectures is a better qualification of medical students to fulfil the requirements of clerkship and the last practical year of the study of human medicine to facilitate taking first steps towards professional work as a clinical physician, in particular, the self-confidence of the medical students is to be substantially increased. The experiences obtained during clerkship and the last practical year influence interest, motivation and final choice for a certain medical speciality. In that respect, this period is of great importance for the whole professional career. The content of the preparation courses for the first medical clerkships and the final clinical internship provide a valuable contribution to prepare for challenging clinical work as a physician with sole responsibility. In particular, they aim to introduce students to the concept of a multiprofessional and extensive patient care. Taking into account the different practical experiences obtained in previous study sections, students are taught according to the overall aim to achieve an interdisciplinary competence in clinical care. CONCLUSION: The improvement of teaching and optimized preparation for practical phases in medical studies promotes a more successful learning process during the clerkship and last practical year.

Thrombolysis in central retinal artery occlusion: a retrospective observational study.

BACKGROUND: There is no evidence-based therapy for non-arteritic central retinal artery occlusion (NA-CRAO). Intravenous thrombolysis (IVT) with alteplase in a time window < 4.5 h may lead to a favorable outcome. Purpose of this study was to investigate the feasibility, efficacy and safety of IVT in patients classified as functionally blind. METHODS: We conducted a retrospective observational study of NA-CRAO-patients. All patients underwent an ophthalmological and neurological examination including cerebral magnetic resonance imaging (MRI) for assessment of additional stroke lesions. Patients were treated either conservatively or with IVT within 4.5 h. Visual acuity (VA) was evaluated in logMAR and a categorical analysis was performed. RESULTS: Thirty-seven patients were included in the study, 21 patients in the conservative treatment group (CTG) and 16 patients in the IVT group. The median logMAR visual acuity at admission and discharge was similar in both groups. The medium symptom to treatment time in the IVT group was 158.0 min. 3 patients (19%) of the IVT group showed a favorable outcome, all CTG patients remained at the level of functional blindness. No serious adverse events were observed after IVT. MRI showed additional acute stroke in over one-third of the patients (n = 14). CONCLUSIONS: Early intravenous thrombolysis therapy according to the current stroke protocol n a time window up to 4.5 h after the onset of symptoms was feasible and might be a potential treatment option for NA-CRAO. Patients with NA-CRAO are at very high risk of ischemic stroke and MRI should be done in all patients for optimized treatment and secondary stroke prevention. A prospective randomized study is required.

RCVS: by clinicians for clinicians-a narrative review.

BACKGROUND/OBJECTIVE: Reversible cerebral vasoconstriction syndrome may be underdiagnosed. It can be accompanied by various complications, mainly intracerebral hemorrhage and ischemic stroke. The clinical presentation of this condition varies according to its localization. The aims of this review are to raise awareness of the disease, especially in the presence of corresponding risk factors; to connect its precipitating factors, pathophysiology, and complications; and to compare various differential diagnoses of vasoconstriction. METHODS: A review of the literature in PubMed/MEDLINE and Google Scholar was conducted from May 1997 until May 2022. RESULTS: Reversible cerebral vasoconstriction syndrome, which is a clinical-radiological syndrome, is mainly characterized by the occurrence of thunderclap headache and widespread vasoconstriction. The most common precipitating factors are the use of vasoactive substances and postpartum status. The pathophysiology is currently assumed to include two mechanisms: sympathetic overactivity and endothelial dysfunction. From these mechanisms, it is possible to derive potential complications as well as the most important differential diagnoses: posterior reversible encephalopathy syndrome, convexity subarachnoid hemorrhage, ischemic and hemorrhagic stroke, and primary angiitis of the central nervous system. CONCLUSION: In general, the outcome of reversible cerebral vasoconstriction syndrome is very good. Vasospasm as well as thunderclap headache attacks can be fully reversible, and > 90% of patients are functionally independent at discharge.

Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol.

Background: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects. Methods: The TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers. Conclusion: This trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care. Clinical trial registration: ClinicalTrials.gov, identifier: NCT03800524.

Students' perception and learning experience in the first medical clerkship.

BACKGROUND: The German clerkship ("Famulatur") is the first phase in medical education, in which students learn from a physician's perspective. According to the German Licensing Regulations for Physicians, students shall "familiarise" with providing care. However, specific learning objectives for the clerkship are not defined, although the acquisition of different competencies is implicitly demanded. Therefore, an additional understanding of the clerkship students' learning experience is needed. The goal of this study is to explore the student's learning perspective and experiences in the clerkship. METHODS: Twelve guideline-based interviews were conducted with third year medical students. All participants completed their first clerkship. A qualitative content analysis was performed. The inductively identified categories were transferred into a quantitative questionnaire using a 5-point Likert-scale to explore their relevance in a validation cohort. The questionnaire was completed by 222 clinical students of the Otto-von-Guericke-Universität Magdeburg. RESULTS: The qualitative analysis led to 26 individual items assigned to 4 main categories that describe the clerkship experience: 1) "coping with insecurities", 2) "the clerkship as a social arrangement", 3) "the clerkship as a learning opportunity" and 4) "the clerkship as a teaching opportunity". In the quantitative validation cohort, category one yielded a well-balanced result (median 3 = "neither agree nor disagree"; IQR 2-4), items addressed in categories 2-4 were generally supported by the students, predominantly selecting "strongly agree" or "agree" (Median 2; IQR 1-2 for each category). Students rated the role of the clinical team as especially important for their learning success and feared exclusion or negative reactions. CONCLUSIONS: The medical clerkship provides an institutional, professional, and social framework, in which students are learning. Insecurities arose from curricular inconsistencies, a high dependency on the clinical team as well as the absence of specific learning objectives. Therefore, a better curricular integration regarding the semester structure and the learning objectives of the German clerkship is needed.