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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.

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.

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 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.

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.

To systematically summarize the evidence of head-up tilt sleeping (HUTS) on orthostatic tolerance, we conducted a systematic, predefined search in PubMed, OVID Embase, Cochrane and Web of Science. We included studies assessing the effect of HUTS on orthostatic tolerance and other cardiovascular measures and rated the quality with the American Academy of Neurology risk of bias tool. We included 10 studies (n = 185) in four groups: orthostatic hypotension (OH; 6 studies, n = 103), vasovagal syncope (1 study, n = 12), nocturnal angina pectoris (1 study, n = 10) and healthy subjects (2 studies, n = 58). HUTS duration varied (1 day–4 months) with variable inclinations (5°–15°). In two of six OH studies, HUTS significantly improved standing systolic blood pressure. Orthostatic tolerance was consistently enhanced in OH studies with higher angles (≥12°), in 2 out of 3 with smaller angles (5°) but also in one studying horizontal sleeping. In vasovagal syncope, HUTS significantly augmented resilience to extreme orthostatic stress. One study was rated as a class II risk of bias, one of Class II/III and eight of Class IV. The evidence favouring HUTS to improve orthostatic tolerance is weak due to variable interventions, populations, small samples and a high risk of bias. Despite this, we found some physiological signs suggesting a beneficial effect.

Jujube is a nutritious fruit, and is high in vitamin C, fiber, phenolics, flavonoids, nucleotides, and organic acids. It is both an important food and a source of traditional medicine. Metabolomics can reveal metabolic differences between Ziziphus jujuba fruits from different jujube cultivars and growth sites. In the fall of 2022, mature fresh fruit of eleven cultivars from replicated trials at three sites in New Mexico—Leyendecker, Los Lunas, and Alcalde—were sampled from September to October for an untargeted metabolomics study. The 11 cultivars were Alcalde 1, Dongzao, Jinsi (JS), Jinkuiwang (JKW), Jixin, Kongfucui (KFC), Lang, Li, Maya, Shanxi Li, and Zaocuiwang (ZCW). Based on the LC–MS/MS analysis, there were 1315 compounds detected with amino acids and derivatives (20.15%) and flavonoids (15.44%) as dominant categories. The results reveal that the cultivar was the dominant factor in metabolite profiles, while the location was secondary. A pairwise comparison of cultivar metabolomes revealed that two pairs had fewer differential metabolites (i.e., Li/Shanxi Li and JS/JKW) than all the other pairs, highlighting that pairwise metabolic comparison can be applied for cultivar fingerprinting. Differential metabolite analysis also showed that half of drying cultivars have up-regulated lipid metabolites compared to fresh or multi-purpose fruit cultivars and that specialized metabolites vary significantly between cultivars from 35.3% (Dongzao/ZCW) to 56.7% (Jixin/KFC). An exemplary analyte matching sedative cyclopeptide alkaloid sanjoinine A was only detected in the Jinsi and Jinkuiwang cultivars. Overall, our metabolic analysis of the jujube cultivar’s mature fruits provides the largest resource of jujube fruit metabolomes to date and will inform cultivar selection for nutritional and medicinal research and for fruit metabolic breeding.

Abstract Objective To define and evaluate hemodynamic criteria to distinguish between classical orthostatic hypotension (cOH) and vasovagal syncope (VVS) in tilt table testing (TTT). Methods Inclusion criteria for VVS were a history of VVS and tilt‐induced syncope defined as a blood pressure (BP) decrease and electroencephalographic changes during syncope with complaint recognition. Criteria for cOH were a history of cOH and a BP decrease meeting published criteria. Clinical diagnoses were established prior to TTT. We assessed (1) whether the decrease of systolic BP accelerated, “convex,” or decelerated, “concave”; (2) the time from head‐up tilt to when BP reached one‐half its maximal decrease; (3) the difference between baseline heart rate (HR) and HR at BP nadir. We calculated the diagnostic yield of optimized thresholds of these features and their combinations. Results We included 82 VVS cases (40% men, median age 44 years) and 65 cOH cases (66% men, median age 70 years). BP decrease was concave in cOH in 79% and convex in VVS in 94% (p

Abstract Background Primary health care data have shown that most patients who were treated for overweight or obesity by a dietitian did not accomplish the recommended treatment period. It is hypothesised that a slow rate of weight loss might discourage patients from continuing dietetic treatment. This study evaluated intermediate weight changes during regular dietetic treatment in Dutch primary health care, and examined whether weight losses at previous consultations were associated with attendance at follow-up consultations. Methods This observational study was based on real life practice data of overweight and obese patients during the period 2013–2017, derived from Dutch dietetic practices that participated in the Nivel Primary Care Database. Multilevel regression analyses were conducted to estimate the mean changes in body mass index (BMI) during six consecutive consultations and to calculate odds ratios for the association of weight change at previous consultations with attendance at follow-up consultations. Results The total study population consisted of 25,588 overweight or obese patients, with a mean initial BMI of 32.7 kg/m2. The BMI decreased between consecutive consultations, with the highest weight losses between the first and second consultation. After six consultations, a mean weight loss of − 1.5 kg/m2 was estimated. Patients who lost weight between the two previous consultations were more likely to attend the next consultation than patients who did not lose weight or gained weight. Conclusions Body mass index decreased during consecutive consultations, and intermediate weight losses were associated with a higher attendance at follow-up consultations during dietetic treatment in overweight patients. Dietitians should therefore focus on discussing intermediate weight loss expectations with their patients.

Abstract Objectives We ascertained the prevalence of ictal arrhythmias to explain the high rate of sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome (DS). Methods We selected cases with clinical DS, ≥6 years, SCN1A mutation, and ≥1 seizure/week. Home‐based ECG recordings were performed for 20 days continuously. Cases were matched for age and sex to two epilepsy controls with no DS and ≥1 major motor seizure during video‐EEG. We determined the prevalence of peri‐ictal asystole, bradycardia, QTc changes, and effects of convulsive seizures (CS) on heart rate, heart rate variability (HRV), and PR/QRS. Generalized estimating equations were used to account for multiple seizures within subjects, seizure type, and sleep/wakefulness. Results We included 59 cases. Ictal recordings were obtained in 45 cases and compared to 90 controls. We analyzed 547 seizures in DS (300 CS) and 169 in controls (120 CS). No asystole occurred. Postictal bradycardia was more common in controls (n = 11, 6.5%) than cases (n = 4, 0.7%; P = 0.002). Peri‐ictal QTc‐lengthening (≥60ms) occurred more frequently in DS (n = 64, 12%) than controls (n = 8, 4.7%, P = 0.048); pathologically prolonged QTc was rare (once in each group). In DS, interictal HRV was lower compared to controls (RMSSD P = 0.029); peri‐ictal values did not differ between the groups. Prolonged QRS/PR was rare and more common in controls (QRS: one vs. none; PR: three vs. one). Interpretation We did not identify major arrhythmias in DS which can directly explain high SUDEP rates. Peri‐ictal QTc‐lengthening was, however, more common in DS. This may reflect unstable repolarization and an increased propensity for arrhythmias.

Copper is an important transition metal cofactor in plant metabolism, which enables diverse biocatalysis in aerobic environments. Multiple classes of plant metalloenzymes evolved and underwent genetic expansions during the evolution of terrestrial plants and, to date, several representatives of these copper enzyme classes have characterized mechanisms. In this review, we give an updated overview of chemistry, structure, mechanism, function and phylogenetic distribution of plant copper metalloenzymes with an emphasis on biosynthesis of aromatic compounds such as phenylpropanoids (lignin, lignan, flavonoids) and cyclic peptides with macrocyclizations via aromatic amino acids. We also review a recent addition to plant copper enzymology in a copper-dependent peptide cyclase called the BURP domain. Given growing plant genetic resources, a large pool of copper biocatalysts remains to be characterized from plants as plant genomes contain on average more than 70 copper enzyme genes. A major challenge in characterization of copper biocatalysts from plant genomes is the identification of endogenous substrates and catalyzed reactions. We highlight some recent and future trends in filling these knowledge gaps in plant metabolism and the potential for genomic discovery of copper-based enzymology from plants.

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson’s disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA–miRNA–mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets.

Syncope usually lasts less than a minute, in which short time arterial blood pressure temporarily falls enough to decrease brain perfusion so much that loss of consciousness ensues. Blood pressure decreases quickest when the heart suddenly stops pumping, which happens in arrhythmia and in severe cardioinhibitory reflex syncope. Loss of consciousness starts about 8 s after the last heart beat and circulatory standstill occurs after 10–15 s. A much slower blood pressure decrease can occur in syncope due to orthostatic hypotension Standing blood pressure can then stabilize at low values often causing more subtle signs (i.e., inability to act) but often not low enough to cause loss of consciousness. Cerebral autoregulation attempts to keep cerebral blood flow constant when blood pressure decreases. In reflex syncope both the quick blood pressure decrease and its low absolute value mean that cerebral autoregulation cannot prevent syncope. It has more protective value in orthostatic hypotension. Neurological signs are related to the severity and timing of cerebral hypoperfusion. Several unanswered pathophysiological questions with possible clinical implications are identified.

Abstract Background Routine weight recording in electronic health records (EHRs) could assist general practitioners (GPs) in the identification, prevention, and management of overweight patients. However, the extent to which weight management is embedded in general practice in the Netherlands has not been investigated. The purpose of this study was to evaluate the frequency of weight recording in general practice in the Netherlands for patients who self-reported as being overweight. The specific objectives of this study were to assess whether weight recording varied according to patient characteristics, and to determine the frequency of weight recording over time for patients with and without a chronic condition related to being overweight. Methods Baseline data from the Occupational and Environmental Health Cohort Study (2012) were combined with data from EHRs of general practices (2012–2015). Data concerned 3446 self-reported overweight patients who visited their GP in 2012, and 1516 patients who visited their GP every year between 2012 and 2015. Logistic multilevel regression analyses were performed to identify associations between patient characteristics and weight recording. Results In 2012, weight was recorded in the EHRs of a quarter of patients who self-reported as being overweight. Greater age, lower education level, higher self-reported body mass index, and the presence of diabetes mellitus, chronic obstructive pulmonary disease, and/or cardiovascular disorders were associated with higher rates of weight recording. The strongest association was found for diabetes mellitus (adjusted OR = 10.3; 95% CI [7.3, 14.5]). Between 2012 and 2015, 90% of patients with diabetes mellitus had at least one weight measurement recorded in their EHR. In the group of patients without a chronic condition related to being overweight, this percentage was 33%. Conclusions Weight was frequently recorded for overweight patients with a chronic condition, for whom regular weight measurement is recommended in clinical guidelines, and for which weight recording is a performance indicator as part of the payment system. For younger patients and those without a chronic condition related to being overweight, weight was less frequently recorded. For these patients, routine recording of weight in EHRs deserves more attention, with the aim to support early recognition and treatment of overweight.

Biologics are substances synthetized from biological sources used in the prevention and treatment of several diseases. Rheumatologists have many years of experience with biologics for the treatment of immune-mediated diseases and osteoporosis. Randomized clinical trials and postmarketing studies have demonstrated that treatment with biologics can result, albeit infrequently, in serious adverse events. To date, several risk mitigation strategies have been identified and implemented. The objective of the present perspective review is to examine the risk mitigation strategies of biologic treatments, with special focus on anti-tumor necrosis factors and denosumab.

Capacitive deionization (CDI) with electric double layers is an electrochemical desalination technology in which porous carbon electrodes are polarized to reversibly store ions. Planar composite CDI electrodes exhibit poor energetic performance due the resistance associated with salt depletion and tortuous diffusion in the macroporous structure. In this work, we investigate the impact of bi-tortuosity on desalination performance by etching macroporous patterns along the length of activated carbon porous electrodes in a flow-by CDI architecture. Capacitive electrodes were also coated with thin asymmetrically charged polyelectrolytes to improve ion-selectivity while maintaining the bitortuous macroporous channels. Under constant current operation, the equivalent circuit resistance in CDI cells operating with bi-tortuous electrodes was approximately 2.2 times less than a control cell with unpatterned electrodes, leading to significant increases in working capacitance (20–22 to 26.7–27.8 F g−1), round-trip efficiency (52–71 to 71–80%), and charge efficiency (33–59 to 35–67%). Improvements in these key performance indicators also translated to enhanced salt adsorption capacity, rate, and most importantly, the thermodynamic efficiency of salt separation (1.0–2.0 to 2.2–4.1%). These findings demonstrate that the use of bi-tortuous electrodes is a novel approach of reducing impedance to ionic flux in CDI. Keywords: Capacitive deionization, Polyelectrolyte coating, Bi-tortuous electrodes

INTRODUCTION:Dietitians are the preferred primary health care professionals for nutritional care in overweight patients. Guidelines for dietitians recommend a weight reduction of ≥ 5% of initial body weight after one year of treatment. The purpose of this study was to evaluate weight change in patients with overweight who were treated by dietitians in Dutch primary health care, and to identify patient characteristics that were associated with it. MATERIALS AND METHODS:This observational study data was based on real life practice data of patients with overweight during the period 2013-2017, derived from dietetic practices that participated in the Nivel Primary Care Database. Multilevel linear regression analyses were performed to investigate weight change after dietetic treatment and to explore associations with patient characteristics. RESULTS:In total, data were evaluated from 56 dietetic practices and 4722 patients with a body mass index (BMI) ≥ 25 kg/m2. The mean treatment time was 3 hours within an average timeframe of 5 months. Overall, patients had a mean weight change of -3.5% (95% CI: -3.8; -3.1) of their initial body weight, and a quarter of the patients reached a weight loss of 5% or more, despite the fact that most patients did not meet the recommended treatment duration of at least one year. The mean BMI change was -1.1 kg/m2 (95% CI: -1.2; -1.0). Higher weight reductions were shown for patients with a higher initial BMI and for patients with a longer treatment time. Sex and age were not associated with weight change, and patients with other dietetic diagnoses, such as diabetes, hypertension, and hypercholesterolemia, had lower weight reductions. CONCLUSIONS:This study showed that dietetic treatment in primary health care coincided with modest weight reduction in patients with overweight. The weight loss goals were not reached for most patients, which was possibly due to a low treatment adherence.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in patients with refractory epilepsy. Convergent lines of evidence suggest that SUDEP occurs due to seizure induced perturbation of respiratory, cardiac, and electrocerebral function as well as potential predisposing factors. It is consistently observed that SUDEP happens more during the night and the early hours of the morning. The aim of this review is to discuss evidence from patient cases, clinical studies, and animal research which is pertinent to the nocturnality of SUDEP. There are a number of factors which might contribute to the nighttime predilection of SUDEP. These factors fall into four categories: influences of (1) being unwitnessed, (2) lying prone in bed, (3) sleep-wake state, and (4) circadian rhythms. During the night, seizures are more likely to be unwitnessed; therefore, it is less likely that another person would be able to administer a lifesaving intervention. Patients are more likely to be prone on a bed following a nocturnal seizure. Being prone in the accouterments of a bed during the postictal period might impair breathing and increase SUDEP risk. Sleep typically happens at night and seizures which emerge from sleep might be more dangerous. Lastly, there are circadian changes to physiology during the night which might facilitate SUDEP. These possible explanations for the nocturnality of SUDEP are not mutually exclusive. The increased rate of SUDEP during the night is likely multifactorial involving both situational factors, such as being without a witness and prone, and physiological changes due to the influence of sleep and circadian rhythms. Understanding the causal elements in the nocturnality of SUDEP may be critical to the development of effective preventive countermeasures.

To investigate the efficacy of adding supplemental fusion or arthroplasty after cervical anterior discectomy for symptomatic mono-level cervical degenerative disease (radiculopathy), which has not been substantiated in controlled trials until now.A randomized controlled trial is reported with 9 years follow up comparing anterior cervical anterior discectomy without fusion, with fusion by cage standalone, or with disc prosthesis. Patients suffering from symptomatic cervical disk degeneration at one level referred to spinal sections of department of neurosurgery or orthopedic surgery of a large general hospital with educational facilities were eligible. Neck Disability Index (NDI), McGill Pain Questionnaire Dutch language version (MPQ-DLV), physical-component summary (PCS), and mental-component summary (MCS) of the 36-item Short-Form Health Survey (SF-36), and re operation rate were evaluated.142 patients between 18 and 55 years were allocated. The median follow-up was 8.9±1.9 years (5.6 to 12.2 years). The response rate at last follow-up was 98.5%. NDI at the last follow-up did not differ between the three treatment groups, nor did the secondary outcomes as MPQ-DLV and PCS or MCS from SF-36. The major improvement occurred within the first 6 weeks after surgery. Afterward, it remained stable. Eleven patients underwent surgery for recurrent symptoms and signs due to nerve root compression at the index or adjacent level.This randomized trial could not detect a difference between three surgical modalities for treating a single-level degenerative disk disease. Anterior cervical discectomy without implant seems to be similar to anterior cervical discectomy with fusion by cage stand-alone or with disk prosthesis. Due to the small study sample size, this statement should be considered as inconclusive so far.ISRCTN41681847.

We report data from two patients who developed reversible downbeat nystagmus (DBN) while using AEDs within the therapeutic range. All previous reported cases of epilepsy with drug-induced DBN related to toxic levels of AEDs were summarized, and DBN was found mostly occurring in those using a sodium channel blocking AED. We propose that in our cases, the DBN with therapeutic AED levels may be explained by additive effects of sodium channel blockers. Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs.

OBJECTIVE:To examine when, where and how fractures occur in postmenopausal women. METHODS:We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3. RESULTS:Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68-86% of NHNV and 68-83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling. CONCLUSION:In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year.

People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study.This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1-8.0.], p=0.034). The risk for SCA in epilepsy was particularly increased in young and females.Epilepsy in the general population seems to be associated with an increased risk for SCA.

Chromatin immunoprecipitation combined with genome tile path microarrays or deep sequencing can be used to study genome-wide epigenetic profiles and the transcription factor binding repertoire. Although well studied in a variety of cell lines, these genome-wide profiles have so far been little explored in vertebrate embryos.Here we report on two genome tile path ChIP-chip designs for interrogating the Xenopus tropicalis genome. In particular, a whole-genome microarray design was used to identify active promoters by close proximity to histone H3 lysine 4 trimethylation. A second microarray design features these experimentally derived promoter regions in addition to currently annotated 5' ends of genes. These regions truly represent promoters as shown by binding of TBP, a key transcription initiation factor.A whole-genome and a promoter tile path microarray design was developed. Both designs can be used to study epigenetic phenomena and transcription factor binding in developing Xenopus embryos.