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Abstract Background Over the last decade attention has grown to give patients and next of kin (P/N) more substantial roles in adverse event investigations. Adverse event investigations occur after adverse events that resulted in death or severe injury. Few studies have focused on patient perspectives on their involvement in such investigations. The present study sets out to investigate how P/N and patient representatives (client councils and the Patient Federation Netherlands) view the involvement of P/N in adverse event investigations, particularly whether and why they want to involved, and how they want to shape their involvement. Methods The study features qualitative data on three levels: interviews with P/N (personal), focus groups with representatives of client councils (institutional), and an interview with the Patient Federation Netherlands (national). Researchers used inductive, thematic analysis and validated the results through data source triangulation. Results The initiative taken by the hospitals in this study provided P/N with the space to feel heard and a position as legitimate stakeholder. P/N appreciated the opportunity to choose whether and how they wanted to be involved in the investigation as stakeholders. P/N emphasized the need for hospitals to learn from the investigations, but for them the investigation was also part of a more encompassing relationship. P/N’s views showed the inextricable link between the first conversation with the health care professional and the investigation, and the ongoing care after the investigation was finalized. Hence, an adverse event investigation is part of a broader experience when understood from a patient perspective. Conclusions An adverse event investigation should be considered as part of an existing relationship between P/N and hospital that starts before the investigation and continues during follow up care. It is crucial for hospitals to take the initiative in the investigation and in the involvement of P/N. P/N motivations for involvement can be understood as driven by agency or communion. Agentic motivations include being an active participant by choice, while communion motivations include the need to be heard.

Addressing the quality of circulating medicines in low- and middle-Income countries is challenging due to limited access to affordable and rapid laboratory analyses. Moreover, traditional analytical methods generate hazardous waste, posing further environmental and health risks, conflicting with several United Nations Sustainable Development Goals, such as reducing pollution and conserving ecosystems.In response to these environmental challenges, the concept of green analytical chemistry emerged promoting environmentally friendly practices through principles such as reducing chemical use, minimizing energy consumption, and managing waste. Various green metric tools have been developed to assess the environmental impact of analytical methods, but these often neglect the reliability and applicability of the methods. To address this gap, approaches like White Analytical Chemistry (WAC) have been proposed, integrating criteria for environmental safety, reliability, and cost-effectiveness. WAC's principles are categorized into red (fitness for purpose), green (environmental safety), and blue (cost-efficiency) criteria.This study aims to use the WAC approach to provide a holistic comparison of different medicines' quality screening devices, helping developing countries with high SF medicine prevalence make informed choices. Three different situations are investigated: ex-ante evaluation, ex-post evaluation of the qualitative performances and ex-post evaluation of the quantitative performances of the most used medicines’ quality screening devices in low- and middle-income countries field settings.

Abstract Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown. Characterizing polyketides relies on bioactivity-guided purification, which is expensive and time-consuming. To address this, we present Seq2PKS, a machine learning algorithm that predicts chemical structures derived from Type 1 polyketide synthases. Seq2PKS predicts numerous putative structures for each gene cluster to enhance accuracy. The correct structure is identified using a variable mass spectral database search. Benchmarks show that Seq2PKS outperforms existing methods. Applying Seq2PKS to Actinobacteria datasets, we discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamide-actiphenol.

Abstract Objective Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure‐free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low‐ versus high‐risk patients. Methods We pooled three datasets including seizure‐free patients who did and did not discontinue ASMs. We conducted time‐to‐first‐seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2‐year risk increase as predicted by our adjusted logistic regressions. Results We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2‐year seizure risk was 43% [95% confidence interval (CI) 39%–46%] for discontinuation versus 21% (95% CI 19%–24%) for continuation. The mean 2‐year absolute seizure risk increase was 21% (95% CI 18%–26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%–24%; range 7%–37%). Results were unchanged when restricting analyses to only the two RCTs. Significance No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2‐year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two‐armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. Plain Language Summary Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk—between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

Background and Aims: Drug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by assessing a high-throughput, microfluidic liver-on-a-chip system, termed “Curio Barrier Liver Chips,” and its capacity to recapitulate the effects of chronic hepatotoxic drug treatment through metabolic and phenotypic characterization. Methods: Curio Barrier liver chips (Curiochips), fabricated in an 8 × 2 well configuration, were utilized to establish three dimensional liver organoid cultures. Human-induced pluripotent stem cells were differentiated into human liver organoids, and their viability, liver-specific functions, and pharmacological responses were assessed over 28 days. Results: The Curiochips successfully maintained liver physiology and function, showing strong albumin secretion and cytochrome (CYP) P450 activities for 28 days. Unlike traditional models requiring millimolar drug concentrations to detect hepatotoxicity, this platform showed increased sensitivity for acetaminophen and fialuridine at micromolar concentrations. In situ differentiation of foregut spheroids to liver organoids was also achieved, further simplifying the establishment of liver chips. Furthermore, the chips demonstrated viability, function, and DILI responsiveness for 28 days, making this an improved model for studying idiosyncratic DILI with prolonged drug exposure and high-throughput capabilities compared to other available systems or primary human hepatocytes. Conclusion: The Curiochips offer an advanced, miniaturized in vitro model for early-stage drug development and a sensitive, responsive, and cost-effective means to detect direct hepatotoxicity. Induced pluripotent stem cell liver organoids, in conjunction with the Curiochip, deliver a high-throughput platform with robust functionality and pharmacological responsiveness that make it a promising tool for improving the prediction and understanding of DILI risk prediction, especially with prolonged drug exposure. The model also opens new avenues for research in other chronic liver diseases.

Abstract Background In persons with Parkinson’s Disease (PD) or certain forms of atypical parkinsonism, orthostatic hypotension is common and disabling, yet often underrecognized and undertreated. About half of affected individuals also exhibit supine hypertension. This common co-occurrence of both orthostatic hypotension and supine hypertension complicates pharmacological treatments as the treatment of the one can aggravate the other. Whole-body head-up tilt sleeping (HUTS) is the only known intervention that may improve both. Evidence on its effectiveness and tolerability is, however, lacking, and little is known about the implementability. Methods In this double-blind multicenter randomized controlled trial (phase II) we will test the efficacy and tolerability of HUTS at different angles in 50 people with PD or parkinsonism who have both symptomatic orthostatic hypotension and supine hypertension. All participants start with one week of horizontal sleeping and subsequently sleep at three different angles, each maintained for two weeks. The exact intervention will vary between the randomly allocated groups. Specifically, the intervention group will consecutively sleep at 6°, 12° and 18°, while the delayed treatment group starts with a placebo angle (1°), followed by 6° and 12°. We will evaluate tolerability using questionnaires and compliance to the study protocol. The primary endpoint is the change in average overnight blood pressure measured by a 24-hour ambulatory blood pressure recording. Secondary outcomes include orthostatic blood pressure, orthostatic tolerance, supine blood pressure, nocturia and various other motor and non-motor tests and questionnaires. Discussion We hypothesize that HUTS can simultaneously alleviate orthostatic hypotension and supine hypertension, and that higher angles of HUTS are more effective but less tolerable. The Heads-Up trial will help to clarify the effectiveness, tolerability, and feasibility of this intervention at home and can guide at-home implementation. Trial registration ClinicalTrials.gov NCT05551377; Date of registration: September 22, 2022.

Introduction: Orthostatic hypotension is common in people with Parkinson’s disease (PD) due to autonomic dysfunction and medication use and can have a significant negative impact on quality of life. Pharmacological treatment is often complicated due to complex blood pressure regulation problems. This case report presents a patient whose symptoms of orthostatic intolerance were successfully treated with the non-pharmacological method of head-up tilt sleeping (HUTS). Case Presentation: A 69-year-old man with PD and prominent autonomic failure received recommendation from the neurologist to use HUTS to battle orthostatic intolerance, of which complaints were worst in the early morning. The patient noted a marked improvement of the orthostatic intolerance after a period in which he slowly step-by-step inclined the bed to an angle just over 10°. When ceasing HUTS for a brief period, complaints of orthostatic intolerance immediately returned and the patient returned to tilted sleeping right away. After a follow-up of 3 months, the patient did not report orthostatic intolerance during a standing test. Conclusion: This case illuminates that, despite difficulties intrinsic to this method, whole-body HUTS can ameliorate orthostatic intolerance and improve the daily life of people with advanced movement disorders.

Abstract Recent analyses of public microbial genomes have found over a million biosynthetic gene clusters, the natural products of the majority of which remain unknown. Additionally, GNPS harbors billions of mass spectra of natural products without known structures and biosynthetic genes. We bridge the gap between large-scale genome mining and mass spectral datasets for natural product discovery by developing HypoRiPPAtlas, an Atlas of hypothetical natural product structures, which is ready-to-use for in silico database search of tandem mass spectra. HypoRiPPAtlas is constructed by mining genomes using seq2ripp, a machine-learning tool for the prediction of ribosomally synthesized and post-translationally modified peptides (RiPPs). In HypoRiPPAtlas, we identify RiPPs in microbes and plants. HypoRiPPAtlas could be extended to other natural product classes in the future by implementing corresponding biosynthetic logic. This study paves the way for large-scale explorations of biosynthetic pathways and chemical structures of microbial and plant RiPP classes.

Abstract Objective Guidelines suggest considering antiseizure medication (ASM) discontinuation in patients with epilepsy who become seizure‐free. Little is known about how discontinuation decisions are being made in practice. We measured the frequency of, and factors associated with, discussions and decisions surrounding ASM discontinuation. Methods We performed a multicenter retrospective cohort study at the University of Michigan (UM) and two Dutch centers: Wilhelmina Children's Hospital (WCH) and Stichting Epilepsie Instellingen Nederland (SEIN). We screened all children and adults with outpatient epilepsy visits in January 2015 and included those with at least one visit during the subsequent 2 years where they were seizure‐free for at least one year. We recorded whether charts documented (1) a discussion with the patient about possible ASM discontinuation and (2) any planned attempt to discontinue at least one ASM. We conducted multilevel logistic regressions to determine factors associated with each outcome. Results We included 1058 visits from 463 patients. Of all patients who were seizure‐free at least one year, 248/463 (53%) had documentation of any discussion and 98/463 (21%) planned to discontinue at least one ASM. Corresponding frequencies for patients who were seizure‐free at least 2 years were 184/285 (65%) and 74/285 (26%). The probability of discussing or discontinuing increased with longer duration of seizure freedom. Still, even for patients who were 10 years seizure‐free, our models predicated that in only 49% of visits was a discontinuation discussion documented, and in only 16% of visits was it decided to discontinue all ASMs. Provider‐to‐provider variation explained 18% of variation in whether patients discontinued any ASM. Significance Only approximately half of patients with prolonged seizure freedom had a documented discussion about ASM discontinuation. Discontinuation was fairly rare even among low‐risk patients. Future work should further explore barriers to and facilitators of counseling and discontinuation attempts.

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.

Introduction : Les rayons ultraviolet (UVR) peuvent-être nocifs pour la peau, par l’action des radicaux libres générés par les espèces réactives de l’oxygène (ROS), comme l’oxygène singulet (1O2). Le beurre de karité (BK) revendique des propriétés de photoprotection contre les rayons UVA et UVB, par l’action de ses insaponifiables. Notre étude consiste à déterminer la capacité antioxydante du BK extrait au Burkina Faso, et à évaluer in vitro son pouvoir de photoprotection indirecte. Matériel et Méthodes : Les composés phénoliques totaux du BK brut, ont été obtenus par extraction liquide-liquide et dosés par technique colorimétrique avec le réactif de Folin-Ciocalteu. Leur capacité antioxydante a été évaluée par les tests colorimétriques ABTS et DPPH. Un modèle expérimental UVR- like a été mis au point afin d’évaluer in vitro le pouvoir photo-protecteur indirecte du beurre brut et de ses extraits phénoliques par photosensibilisation du Rose Bengal (RB) en présence de l’anthracène. Résultats : La teneur en phénols totaux des échantillons de BK du Burkina Faso était comprise entre 14,16 ± 2,33 et 82,99 ± 8,70 ppm d'équivalent pyrogallol. Ces composés phénoliques ont montré une activité antiradicalaire dose-dépendante. Sur modèle acellulaire expérimental UVR-like, le beurre brut et sa fraction phénolique ont montré une capacité quenching dose-dépendante de l’1O2 par photosensibilisation du RB, en présence d’anthracène, ce qui met en évidence une photoprotection indirecte du beurre brut et de ses composés phénoliques. Conclusion : Le BK brut peut être utilisé pour ses propriétés antioxydantes dû à sa fraction phénolique. Outre ses propriétés antioxydantes, le BK a un pouvoir de photoprotection indirecte, par effet quenching de l’O2, qui est plus prononcé que celui de sa fraction phénolique. L'effet photoprotecteur sur modèle UVR-like pourrait donc être attribuable à un effet antioxydant indirecte, et à l’action des insaponifiables.

Abstract Objective To assess the performance of a multimodal seizure detection device, first tested in adults (sensitivity 86%, PPV 49%), in a pediatric cohort living at home or residential care. Methods In this multicenter, prospective, video‐controlled cohort‐study, nocturnal seizures were detected by heartrate and movement changes in children with epilepsy and intellectual disability. Participants with a history of >1 monthly major motor seizure wore Nightwatch bracelet at night for 3 months. Major seizures were defined as tonic–clonic, generalized tonic >30 s, hyperkinetic, or clusters (>30 min) of short myoclonic or tonic seizures. The video of all events (alarms and nurse diaries) and about 10% of whole nights were reviewed to classify major seizures, and minor or no seizures. Results Twenty‐three participants with focal or generalized epilepsy and nightly motor seizures were evaluated during 1511 nights, with 1710 major seizures. First 1014 nights, 4189 alarms occurred with average of 1.44/h, showing average sensitivity of 79.9% (median 75.4%) with mean PPV of 26.7% (median 11.1%) and false alarm rate of 0.2/hour. Over 90% of false alarms in children was due to heart rate (HR) part of the detection algorithm. To improve this rate, an adaptation was made such that the alarm was only triggered when the wearer was in horizontal position. For the remaining 497 nights, this was tested prospectively, 384 major seizures occurred. This resulted in mean PPV of 55.5% (median 58.1%) and a false alarm rate 0.08/h while maintaining a comparable mean sensitivity of 79.4% (median 93.2%). Significance Seizure detection devices that are used in bed which depend on heartrate and movement show similar sensitivity in children and adults. However, children do show general higher false alarm rate, mostly triggered while awake. By correcting for body position, the false alarms can be limited to a level that comes close to that in adults.

Background: Recent studies on the impact of ex-post legislative evaluations show that there are different types of impact and different factors that can influence it. These include the context of a legislative evaluation, research quality, and interactions between researchers and other actors within the evaluation process. However, thorough empirical research in this area is lacking. This warrants empirical research into the factors that influence the impact of ex-post legislative evaluations, so these insights can be used to increase the likelihood of ex-post legislative evaluations having an impact. Methods and analysis: In this protocol, we report on the realist evaluation methodology that will be used to evaluate the impact of three ex-post legislative evaluations in the Dutch healthcare sector. The mixed methods realist evaluation approach will facilitate this theory-driven, qualitative research. The study will consist of the following three steps: (1) Initial programme theory development, (2) theory validation, and (3) theory refinement. Knowledge from two scoping reviews conducted previously, and two subsequent expert meetings will form the basis for developing the initial programme theory. During this study, three case studies will be conducted, in which three individual ex-post legislative evaluations will be examined. Specific methods for data collection will include: documentary review, observation, structured questionnaires and focus group discussions with purposefully identified key stakeholders. Using the framework approach, the data will be analysed thematically in a within-case analysis followed by a cross-case analysis. Discussion: This protocol provides insight into how the study will be conducted. As this study uses multiple qualitative research methods to answer one question, this protocol supports refining data collection procedures. Careful consideration of the approach beforehand can minimise pitfalls, reduce publication bias and improve reproducibility. The protocol therefore specifies how the research question will be answered in detail, and this provides solid guidance for the research process.

Abstract Background Health care incidents, such as medical errors, cause tragedies all over the world. Recent legislation in the Netherlands has established medical dispute committees to provide for an appeals procedure offering an alternative to civil litigation and to meet the needs of clients. Dispute committees incorporate a hybrid procedure where one can file a complaint and a claim for damages resulting in a verdict without going to court. The procedure is at the crossroads of complaints law and civil litigation. This study seeks to analyze to what extent patients and family members’ expectations and experiences with dispute committees match the goals of the new legislation. Methods This qualitative, retrospective research includes in-depth, semi-structured, face-to-face interviews with patients or family members who filed a complaint with a dispute committee in the Netherlands. The researchers conducted an inductive, thematic analysis of the qualitative data. Results A total of 26 interviews were held with 30 patients and family members. The results showed that participants particularly felt the need to be heard and to make a positive impact on health care. Some wished to be financially compensated, for others money was the last thing on their mind. The results demonstrated the existence of unequal power relationships between participants and both the defendant and dispute committee members. Participants reported the added value of (legal) support and expressed the need for dialogue at the hearing. Participants sometimes experienced closure after the proceedings, but often did not feel heard or felt a lack of a practical outcome and a tangible improvement. Conclusions This study shows that participants’ expectations and experiences were not always met by the current set up of the dispute committee proceedings. Participants did not feel heard, while they did value the potential for monetary compensation. In addition, some participants did not experience an empowered position but rather a feeling of a power misbalance. The feeling of a power misbalance and not being heard might be explained by existing epistemic injustice, which is a concept that should be carefully considered in processes after health care incidents.

Abstract Introduction The lack of reliable biomarkers constrain epilepsy management. We assessed the potential of repeated transcranial magnetic stimulation with electromyography (TMS‐EMG) to track dynamical changes in cortical excitability on a within‐subject basis. Methods We recruited people with refractory focal epilepsy who underwent video‐EEG monitoring and drug tapering as part of the presurgical evaluation. We performed daily TMS‐EMG measurements with additional postictal assessments 1–6 h following seizures to assess resting motor threshold (rMT), and motor evoked potentials (MEPs) with single‐ and paired‐pulse protocols. Anti‐seizure medication (ASM) regimens were recorded for the day before each measurement and expressed in proportion to the dosage before tapering. Additional measurements were performed in healthy controls to evaluate day‐to‐day rMT variability. Results We performed 77 (58 baseline, 19 postictal) measurements in 16 people with focal epilepsy and 35 in seven healthy controls. Controls showed minimal day‐to‐day rMT variation. Withdrawal of ASMs was associated with a lower rMT without affecting MEPs of single‐ and paired‐pulse TMS‐EMG paradigms. Postictal measurements following focal to bilateral tonic–clonic seizures demonstrated unaltered rMT and increased short interval intracortical inhibition, while measurements following focal seizures with impaired awareness showed decreased rMT's and reduced short and long interval intracortical inhibition. Conclusion Serial within‐subject rMT measurements yielded reproducible, stable results in healthy controls. ASM tapering and seizures had distinct effects on TMS‐EMG excitability indices in people with epilepsy. Drug tapering decreased rMT, indicating increased overall corticospinal excitability, whereas seizures affected intracortical inhibition with contrasting effects between seizure types.