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The risk of conversion from a first demyelinating event to MS was lower with minocycline than with placebo over 6 months but not over 24 months. Changes of demyelination on MRI favored minocycline over placebo. Adverse events were more frequent with minocycline. After a first focal clinical demyelinating event (also called a clinically isolated syndrome), the risk of conversion to multiple sclerosis is high. Minocycline is a tetracycline antibiotic agent that has immune-modulating properties; preliminary data have shown activity of minocycline in patients with multiple sclerosis. 1 – 4 Minocycline has a good safety profile, 5 although rash, headache, dizziness, and photosensitivity are common side effects. Pseudotumor cerebri and hypersensitivity syndromes are rare but serious complications, and hyperpigmentation may occur with long-term use. Antibiotic resistance is infrequently associated with minocycline therapy. 6 In one small clinical trial involving patients with relapsing–remitting multiple sclerosis, minocycline therapy reduced . . .

A seismic swarm affected the 53.3°–54.3° Latitude North section of the Mid‐Atlantic Ridge from 26 September to 10 December 2022. We rely on regional, teleseismic and array data to relocate 61 hypocenters and derive 77 moment tensors. The 2022 swarm released a cumulative moment equivalent to Mw 6.3. Seismicity was shallow (7 ± 3 km depth). Most earthquakes are located along the ridge axis with typical, NS oriented normal faulting mechanisms, but a few among the largest and latest earthquakes have unusual thrust mechanisms and locations as far as ∼25 km from the ridge. We attribute the swarm to a shallow magmatic intrusion, with a vertical dike first propagating ∼60 km along axis, accompanied by shallow normal faulting, and then thickening and triggering thrust earthquakes off the ridge, in response to compressive stress buildup. The unrest provides a rare example of an energetic, magmatic driven swarm episode at the mid‐ocean ridge. Plain Language Summary The largest plate boundary systems on Earth are Mid‐ocean ridges (MOR), where the plates continuously drift apart and new lithosphere is constantly being formed. Although the process is well understood, we rarely detect spreading events at MOR, mainly because these regions are remote and local monitoring is rarely possible. In September–November 2022 a large, unusual seismic swarm occurred along a spreading center ridge segment of the North Mid‐Atlantic Ridge. Despite the remoteness of the region, we managed to model regional and teleseismic data to perform earthquake relocation, depth estimation and moment tensor inversion. In this way, we could reconstruct the geometry and the evolution of the seismicity. We found that in the early days of the swarm, seismicity migrated unilaterally over ∼60 km along the ridge axis, from North to South, triggering normal faulting earthquakes, which are typical at MOR. Later, large thrust mechanisms, anomalous in an extensional environment, appeared and quickly became predominant. We explain seismological observations by a magmatic intrusion, which first propagated southward, producing shallow normal faulting earthquakes above the vertical magma dike, and later thickened, increasing compressional stresses on its sides, and triggering large thrust earthquakes. Key Points Analysis of a short, intense seismic swarm at the Mid‐Atlantic Ridge Identification of unusual, thrust focal mechanisms in an extensional environment Swarm triggered by dike intrusion at the mid‐ocean ridge

Skin wound infections are a significant health problem, and antibiotic resistance is on the rise. Mast cells (MCs) have been shown to contribute to host–defense responses in certain bacterial infections, but their role in skin wound superinfection is unknown. We subjected 2 MC-deficient mouse strains to Pseudomonas aeruginosa skin wound infection and found significantly delayed wound closure in infected skin wounds. This delay was associated with impaired bacterial clearance in the absence of MCs. Engraftment of MCs restored both bacterial clearance and wound closure. Bacterial killing was dependent on IL-6 released from MCs, and engraftment with IL-6–deficient MCs failed to control wound infection. Treatment with recombinant IL-6 enhanced bacterial killing and resulted in the control of wound infection and normal wound healing in vivo. Taken together, our results demonstrate a defense mechanism for boosting host innate immune responses, namely effects of MC-derived IL-6 on antimicrobial functions of keratinocytes.

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.

PurposeImaging glioma biology holds great promise to unravel the complex nature of these tumors. Besides well-established imaging techniques such O-(2-[18F]fluoroethyl)-l-tyrosine (FET)-PET and dynamic susceptibility contrast (DSC) perfusion imaging, amide proton transfer–weighted (APTw) imaging has emerged as a promising novel MR technique. In this study, we aimed to better understand the relation between these imaging biomarkers and how well they capture cellularity and vascularity in newly diagnosed gliomas.MethodsPreoperative MRI and FET-PET data of 46 patients (31 glioblastoma and 15 lower-grade glioma) were segmented into contrast-enhancing and FLAIR-hyperintense areas. Using established cutoffs, we calculated hot-spot volumes (HSV) and their spatial overlap. We further investigated APTw and CBV values in FET-HSV. In a subset of 10 glioblastoma patients, we compared cellularity and vascularization in 34 stereotactically targeted biopsies with imaging.ResultsIn glioblastomas, the largest HSV was found for APTw, followed by PET and CBV (p < 0.05). In lower-grade gliomas, APTw–HSV was clearly lower than in glioblastomas. The spatial overlap of HSV was highest between APTw and FET in both tumor entities and regions. APTw correlated significantly with cellularity, similar to FET, while the association with vascularity was more pronounced in CBV and FET.ConclusionsWe found a relevant spatial overlap in glioblastomas between hotspots of APTw and FET both in contrast-enhancing and FLAIR-hyperintense tumor. As suggested by earlier studies, APTw was lower in lower-grade gliomas compared with glioblastomas. APTw meaningfully contributes to biological imaging of gliomas.

Chromogranin A (CgA) belongs to the granin family of uniquely acidic secretory proteins co-stored and co-secreted with other hormones and peptides in elements of the diffuse neuroendocrine system. The granins arise from different genes and are characterized by numerous sites for post-translational cleavage into shorter peptides with postulated regulatory properties. This review is directed towards endocrine aspects of CgA and its biologically active peptides. There is ample evidence from in vitro studies of distinct effects and targets for three CgA-derived peptides, vasostatin-I, pancreastatin and catestatin. Endocrine regulations are indicated from in vivo studies, consistent with the postulated prohormone function of CgA for peptides with regulatory properties. Most of the effects fit into patterns of direct or indirect, inhibitory modulations of major functions, implicating CgA peptides in regulation of calcium and glucose metabolism, cardiovascular functions, gastrointestinal motility and nociception, tissue repair, inflammatory responses and as host defense peptides in the first phase of microbial invasions.

The availability of both global and regional elevation datasets acquired by modern remote sensing technologies provides an opportunity to significantly improve the accuracy of stream mapping, especially in remote, hard to reach regions. Stream extraction from digital elevation models (DEMs) is based on computation of flow accumulation, a summary parameter that poses performance and accuracy challenges when applied to large, noisy DEMs generated by remote sensing technologies. Robust handling of DEM depressions is essential for reliable extraction of connected drainage networks from this type of data. The least-cost flow routing method implemented in GRASS GIS as the module r.watershed was redesigned to significantly improve its speed, functionality, and memory requirements and make it an efficient tool for stream mapping and watershed analysis from large DEMs. To evaluate its handling of large depressions, typical for remote sensing derived DEMs, three different methods were compared: traditional sink filling, impact reduction approach, and least-cost path search. The comparison was performed using the Shuttle Radar Topographic Mission (SRTM) and Interferometric Synthetic Aperture Radar for Elevation (IFSARE) datasets covering central Panama at 90 m and 10 m resolutions, respectively. The accuracy assessment was based on ground control points acquired by GPS and reference points digitized from Landsat imagery along segments of selected Panamanian rivers. The results demonstrate that the new implementation of the least-cost path method is significantly faster than the original version, can cope with massive datasets, and provides the most accurate results in terms of stream locations validated against reference points.

Background The coronavirus disease 2019 (COVID‐19) pandemic and related restrictions globally impacted mental health, particularly for those with pre‐existing severe mental illness (SMI). This qualitative study examined how adults with SMI perceived the effects of the COVID‐19 pandemic and related restrictions in the Netherlands, focusing on their personal recovery, well‐being and daily life, including an exploration of factors influencing these effects. Methods Semi‐structured interviews were conducted, audio‐recorded and transcribed verbatim. Reflexive thematic analysis was applied. Purposive sampling was used to ensure diversity of individuals with SMI (i.e., age, gender, diagnosis, cultural background and mental healthcare institution). Results Twenty participants (median age: 45 years [SD: 12, 8]; 11 females) were interviewed between May and July 2023. Findings revealed a wide range of experiences: while some individuals reported a negative impact on their existing psychiatric symptoms, others described adaptability, resilience and even positive effects of COVID‐19 restrictions on their mental health and well‐being. Factors influencing the heterogeneic perceptions of the COVID‐19 pandemic and related restrictions include the availability of trusted social relationships and enduring interactions with health professionals. Conclusion Personalised support, both socially and professionally, is crucial for addressing fears, building resilience, reducing isolation and encouraging positive coping strategies for individuals with SMI during external crises. In this project, a participatory research approach that integrated the lived experience perspective helped uncover the unique perceptions of people with SMI with regard to the pandemic and related restrictions. Patient or Public Contribution The study used a participatory action research approach, with experts‐by‐experience involved in every stage of the project as part of the research team. This included engagement with the funding application process, recruitment strategies for interviews, developing the interview guide, piloting the interview, interpreting findings, and knowledge dissemination activities.

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001–2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.

IntroductionWorldwide, annually more than 800,000 suicides occur. In the Netherlands, suicide rates rose from 8.6 per 100,000 in 2007 to 11.4 per 100,000 in 2016. Rates in the province of Noord-Brabant were consistently higher than the national average. Noord-Brabant is a province in the south of the Netherlands covering an area of over 4700 km2 with 2.5 million inhabitants. Although Noord-Brabant has five specialised mental healthcare institutions (SMHIs), and 90% of suicides are deemed related to mental disorders, 60% of those who died by suicide did not receive mental health treatment. However, with good access to treatment, suicide could be preventable.ObjectivesTo evaluate whether the systems intervention compared to the regular care approach led to a reduction in suicides in Noord-Brabant. We aimed to attain a reduction in suicides of at least 20%.MethodsCo-design and development of a digital monitoring system and decision aid. Stepwise implementation per subregion of the systems intervention by the five specialized mental healthcare institutions (SMHIs) and their chain partners. Pre-post analysis for the whole province (Exact Rate Ratio Test, Poisson count).ResultsThe SUPREMOCOL systems intervention consisted of four pillars, which were all supported by a digital decision aid and monitoring system. This was provided via a desktop computer with a secured login. The data were kept on a secured encrypted server. The number of professionals accessing the system was limited to two per SMHI or other chain partner. They could only see patients in their subregion, not in the whole of the province. The pillars of our systems intervention for suicide prevention are:1. Swift identication of people at risk for suicide by triage on the spot after a non-fatal suicide attempt.2. Provision of swift access to specialised mental health care for those at risk3. Accommodating transitions in care following a collaborative care approach4. Prevention of suicidal attempts after discharge or treatment dropout by 12 months telephone follow-up.Suicide rates dropped 17.8% (p=.013) from baseline (2017) to implementation in 2018 and 2019. This is a significant reduction (p=0.043) compared to the non-significant drop in the rest of the Netherlands. Suicide rates dropped further by 21.5% (p = 0.002) in 2021.Noord-Brabant also dropped in the relative rank of the number of suicides, from second place in 2015 to third in 2018.ConclusionsDuring the SUPREMOCOL systems intervention, over a period of 4 years, there was a sustained and significant reduction of suicides in Noord-Brabant. We attained a reduction of 21,5% in total. Noord-Brabant dropped in the relative rank of the number of suicides, from second place in 2015 to third in 2018. This is a result that warrants further research and implementation into system interventions for suicide prevention with digital support such as SUPREMOCOL.Disclosure of InterestC. Van Der Feltz-Cornelis Grant / Research support from: The Netherlands Organisation for Health Research and Development, I. Elfeddali: None Declared, M. Metz: None Declared, S. de Jong: None Declared, M. Bakker: None Declared, C. van Nieuwenhuizen: None Declared