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Multiple sclerosis (MS) is characterized as an autoimmune disease affecting the central nervous system. It is one of the most common neurological disorders in young adults. Over the past decades, increasing evidence suggested that hypovitaminosis D is a contributing factor to the risk of developing MS. From different risk factors contributing to the development of MS, vitamin D status is of particular interest since it is not only a modifiable risk factor but is also associated with MS disease activity. MS patients with lower serum vitamin D concentrations were shown to have higher disease activity. However, this finding does not demonstrate causality. In this regard, prospective vitamin D supplementation studies missed statistical significance in its primary endpoints but showed promising results in secondary outcome measures or analyses. An explanation for missed primary endpoints may be underpowered trials. Besides vitamin D supplementation as a potential add-on to long-term immunotherapeutic treatment, a recent laboratory study of our group pointed toward a beneficial effect of vitamin D to improve the efficacy of glucocorticoids in relapse therapy. In the following article, we will briefly review the effects of vitamin D on MS by outlining its effects on the immune and nervous system and by reviewing the association between vitamin D and MS risk as well as MS disease activity. We will also review the effects of vitamin D supplementation on MS risk and MS disease activity.

Background Semaglutide, a GLP-1 receptor agonist widely prescribed for type 2 diabetes and obesity, has recently raised concerns about its ocular safety. This study aimed to investigate the association between semaglutide use and vision impairment using data from the FDA Adverse Event Reporting System (FAERS). Methods We conducted an analysis of FAERS data, comparing reports of vision impairment associated with semaglutide to those associated with other antidiabetic and weight loss medications. The main outcome measure was the reporting odds ratio (rOR) for vision impairment linked to semaglutide use compared to other medications. Results Semaglutide showed significantly higher reporting of vision impairment compared to other GLP-1 receptor agonists (rOR 1.95, 95% CI 1.75–2.17, p  < 0.0001), DPP-4 inhibitors (rOR 2.46, 95% CI 2.12–2.86, p  < 0.0001), SGLT2 inhibitors (rOR 3.89, 95% CI 3.35–4.51, p  < 0.0001), and metformin (rOR 2.23, 95% CI 1.90–2.62, p  < 0.0001). Similar findings were observed when compared to phentermine (rOR 1.57, 95% CI 1.07–2.31, p  = 0.026) and orlistat (rOR 3.77, 95% CI 2.96–4.81, p  < 0.0001). Topiramate was the sole exception, showing higher vision impairment reporting than semaglutide (rOR 0.30, 95% CI 0.20–0.45, p  < 0.0001). Conclusions These findings suggest a potentially elevated risk of vision impairment with semaglutide use compared to other diabetes and weight loss medications, warranting further investigation and vigilant post-marketing surveillance. Future studies should assess the clinical impact of this potential increased risk on an absolute scale to better inform treatment decisions.

Introduction: Patients under immunotherapies were excluded from the pivotal trials of vaccinations against the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), and no population-level data on disease outcomes such as case fatality rates in relation to vaccination coverage exist. Our study aims to fill this gap by investigating whether CFRs in patients with immunotherapies decrease with increasing vaccination coverage in the total population. Methods: We combined aggregated open source data on COVID-19 vaccination coverage from “Our World in Data” with publicly available anonymized COVID-19 case reports from the FDA Adverse Event Reporting System to compute COVID-19 CFRs for patients under immunotherapy at different vaccination coverage levels in the total population. CFRs at different vaccination coverage levels were then compared to CFRs before vaccination campaign start. Results: While we found an overall decrease in CFRs on population level with increasing vaccination coverage, we found no decrease in people using anti-CD20 or glucocorticoids. Discussion: Risk-mitigation strategies on an individual- and population-level are thus still needed to lower the probability of fatal SARS-CoV2 infection for these vulnerable populations.

Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1-phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-β-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer's disease, and other neurodegenerative disorders.

Objective Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. Patients and methods Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3–6 monthly intervals. Results The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50–70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. Conclusions Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Background: Evidence on mortality risks associated with MS-immunotherapies during the SARS-CoV2 pandemic derived thus far mainly from single country experiences. Objective: In this analysis, we aim to determine the frequency of COVID-19 associated fatality reports of patients receiving an MS-immunotherapy as reported to the international Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from February 2020 to March 2021. Methods: In all, 1071 cases for this cross-sectional analysis were retrieved from FAERS and a multivariable logistic regression was performed. We adjusted for sex, age, region, month of report to FDA, immunotherapy-class and additionally for healthcare-system and pandemic-related metrics. Result: Anti-CD20 therapies (60%) followed by sphingosine-1 phosphate modulators (12%) and dimethylfumarat (10%) were reported most frequently. In 50% of the cases, MS-phenotype is not reported, relapsing MS in 35% and progressive MS in 15%. Besides older age (odds ratio [OR]: 1.1; 95% confidence interval [CI]: 1.07–1.13; p < 0.01), anti-CD20 therapies were significantly associated with a higher risk of death (OR: 4.1; 95% CI: 1.17–14.46; p = 0.03), whereas female sex was associated with a reduced mortality risk (OR: 0.4, 95% CI: 0.22–0.72; p < 0.01). Conclusion: Using international open access data and a multidisciplinary approach for risk prediction, we identified an increased mortality risk associated with anti-CD20 therapies, which is in line with national and multi-national cohort studies.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2–3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

Psychiatric disorders share an excess of seasonal birth in winter and spring, suggesting an increase of neurodevelopmental risks. Evidence suggests season of birth can serve as a proxy of harmful environmental factors. Given that prenatal exposure of these factors may trigger pathologic processes in the neurodevelopment, they may consequently lead to brain volume alterations. Here we tested the effects of season of birth on gray matter volume in a transdiagnostic sample of patients with schizophrenia and depression compared to healthy controls (n = 192). We found a significant effect of season of birth on gray matter volume with reduced right hippocampal volume in summer-born compared to winter-born patients with depression. In addition, the volume of the right hippocampus was reduced independent from season of birth in schizophrenia. Our results support the potential impact of season of birth on hippocampal volume in depression.

Pneumococcal meningitis, caused by Streptococcus pneumoniae, is exacerbated by factors released during bacterial lysis, triggering inflammation and damage to host cells. Bacteriolytic antibiotics increase inflammation meaning that there is a high unmet medical need for non-bacteriolytic antimicrobials as alternative therapeutic options. Previously, an 11-amino acid peptide was discovered in the secretome of Klebsiella pneumoniae, named V11A, and was found to inhibit growth of S. pneumoniae in a bacteriostatic and species-specific manner in vitro. Here it is shown that peptide V11A reduced the growth of not only S. pneumoniae spiked into human cerebrospinal fluid (hCSF) of non-meningitis donors but also S. pneumoniae present naturally in hCSF of a patient with pneumococcal meningitis (hmCSF). In an infant rat model of pneumococcal meningitis, V11A not only reduced the number of S. pneumoniae bacteria in CSF and blood but also reduced the concentration of cytokines GRO/KC/CINC-1 (an interleukin-8 (IL-8)-like cytokine in rats) and IL-10 in CSF. Our results support the potential of therapeutic peptide to reduce the bacterial burden and mitigate the inflammatory response in pneumococcal meningitis.

Objective Clinical trials on drug safety and efficacy are understood to be valid for all humans, but are not equally distributed worldwide. We aimed to analyze the global distribution of clinical drug trials (phase I–IV) in epilepsy and its correlation with key demographical and epidemiological factors. Methods We combined data on industry‐funded interventional drug trials in epilepsy from clinicaltrials.gov with epidemiological, geographical, socioeconomic, and human development data. This allowed us to analyze the distribution of trials and trial sites in relation to population, epilepsy incidence, and prevalence. Results Among 459 trials conducted in 69 countries, a vast majority of sites were situated in high‐income regions and countries with very high Human Development Index (HDI). There was a striking underrepresentation of low‐income countries and those with low HDI. Specifically, we found a 40‐ to 145‐fold underrepresentation of trial sites in the WHO regions of Africa and the Eastern Mediterranean when comparing the actual number of sites to the expected number, assuming an even distribution by population, incidence, or prevalence. Significance Our findings highlight inequalities in the distribution of epilepsy trial sites based on population size and disease burden. They underscore the need for more equitable trial placement strategies that consider both disease epidemiology and demographic diversity to ensure adequate representation of all affected populations. Plain Language Summary This study looked at where clinical trials for epilepsy medications are being done around the world. We found that most trials take place in high‐income countries, while many areas with a high number of people living with epilepsy—especially in Africa and the Eastern Mediterranean—are left out. This shows a big gap between where the disease is most common and where research happens. Highlighting this mismatch can help guide future efforts to make clinical research more inclusive and globally relevant.