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Objective: To investigate a dose-response relationship between the magnitude of decrease in pediatric respiratory tract infections (RTI) during the 2020 implementation of non-pharmaceutical interventions (NPI) and the rise thereafter during NPI lifting., Study Design: We conducted an interrupted, time-series analysis, based on a multinational surveillance system. All patients <16 years of age coming to medical attention with various symptoms and signs of RTI at 25 pediatric emergency departments from 13 European countries between January 2018 and June 2022 were included. We used generalized additive models to correlate the magnitude of decrease of each RTI during NPI (such as social distancing) implementation and its subsequent increase during NPI lifting. Urinary tract infections (UTI) served as control outcome., Results: 528,055 patients were included. We observed reductions in cases during the NPI period, from -76% (95%CI -113;-53) in pneumonia) to -65% (95%CI[-100;-39) for tonsillitis/pharyngitis), followed by strong increases during NPI lifting, from +83% (95%CI 29;150) for tonsillitis/pharyngitis) to +329% (95%CI (149;517) bronchiolitis). For each RTI, we found a significant association between the magnitude of decrease during NPI implementation and the increase during NPI lifting. UTI cases remained stable., Conclusions: The magnitude of increase in RTI observed following NPI lifting was directly correlated to the magnitude of cases' reduction during NPI implementation, suggesting a "dose-response" relationship from an "immune debt" phenomenon. The likely rebound in RTIs should be expected when implementing and lifting NPI in the future., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Condensation trail (contrail) formation in an airplane's wake requires thermodynamics supersaturation and ice nucleation to form visible ice crystals. Here, using a thermodynamic analysis, we evaluate the potential for forming contrails in a carbon-free, ammonia-powered propulsion system compared to conventional planes powered by jet fuel. The analysis calculates the moisture released by fuel into the atmosphere for each one-degree increase in air temperature due to exhaust gas. It then determines if this moisture can saturate the initially undersaturated atmosphere, maintain saturation as temperature rises, and result in supersaturation with respect to ice while leaving enough moisture for a visible cloud to form. With ammonia increases the critical temperature required for supersaturation. Although ammonia does not generate soot particles in the exhaust gas, various aerosols exist in the atmosphere through other sources that can facilitate heterogeneous ice nucleation. Hence, while ammonia's contrails might not be as dense, they can form at lower altitudes where the air is warmer and endure longer due to the increased water content, which preserves supersaturation for longer as fresh air dilutes the contrail., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Children and young people (CYP) with asthma in the UK are at higher risk of poor outcomes compared with other high-income European countries due to factors including poor access to high-quality asthma reviews, diagnostic testing and inconsistent postattack reviews. The Leicester Integrated Care Board funded the first UK pilot asthma hub for CYP, to investigate the feasibility and effectiveness of hubs, in providing postattack reviews along with providing asthma education, the opportunity to carry out diagnostic lung function tests and optimise treatment., Methods: Clinical pilot study including CYP aged 4-17 years referred to the hub with uncontrolled asthma or postattack from November 2021 to April 2022. CYP received a structured clinical assessment including National Institute for Health and Care Excellence (NICE) first-line diagnostic investigations for asthma including spirometry, bronchodilator reversibility (BDR) and fraction of exhaled nitric oxide (FeNO)., Results: Of 312 CYP referred (mean age 8.6±3.2 years; 42% women), 266 (85.3%) attended their appointment. Median time from referral to review was 2 days (IQR 1-3). Three CYP (1.1%) were severely unwell at review and required further hospital treatment. In the 231 CYP who completed first-line tests, asthma was confirmed for 73 (31.6%) based on NICE diagnostic criteria for CYP. Twenty-two per cent of children with normal baseline spirometry had ≥12% BDR., Conclusion: Paediatric asthma hubs are a feasible model of care to deliver CYP postasthma attack reviews and identify high-risk patients requiring further treatment. Spirometry, BDR and FeNO testing allowed diagnostic confirmation in a significant proportion of CYP., Competing Interests: Competing interests: EAG: none relating to this manuscript. Unrelated to this manuscript, consultancy work for Boehringer Ingelheim with money paid to the institution (University of Leicester). Investigator led research grants from Circassia Group, Gilead Sciences, Chiesi Limited and Propeller Health. Research collaboration with AstraZeneca, Helicon Health and Adherium (NZ) Limited. Speaker fees Circassia Group and Sanofi. MIA: Children’s and Young people clinical lead at Leicester, Leicestershire and Rutland Integrated Care Board. National Webinar for Proveca Limited., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Paediatric trauma elbow radiographs are difficult to interpret and there is a potential for harm if misdiagnosed. The primary goal of this study was to assess the ability of healthcare professionals internationally to interpret paediatric trauma elbow radiographs from the radiograph alone by formulating the correct diagnosis., Methods: This prospective international study was conducted online via the Free Open Access Medical Education platform, Don't Forget the Bubbles (DFTB, ISSN 2754-5407). Participants were recruited via the DFTB social media accounts between 17 August and 14 September 2021. Submissions that were incomplete or from participants who do not interpret paediatric elbow radiographs in their clinical practice were excluded. Participants completed an online survey of demographic data followed by interpreting 10 trauma-indicated elbow radiographs, by selecting multiple-choice options. The primary outcome was correct diagnosis., Results: Participant responses from 18 countries were analysed, with most responses from the UK, Australia and Ireland. Participants had backgrounds in emergency medicine (EM), paediatric emergency medicine (PEM), general practice (GP) and paediatrics, with over 70% having 6+ years of postgraduate experience. 3180 radiographs were interpreted by 318 healthcare professionals. Only nine (2.8%) participants correctly diagnosed all 10. The mean number of radiographs correctly interpreted was 5.44 (SD 2.3). The mean number for those with 6+ years of experience was 6.02 (SD 2.2). On reviewing the normal radiograph, 158 (49.7%) overcalled injuries. Participants with EM or PEM background were equally likely to have more correct answers than those from paediatric or GP backgrounds., Conclusion: Globally, healthcare professional's success in correctly diagnosing paediatric elbow injuries from radiographs was suboptimal in this non-clinical exercise, despite capturing quite an experienced cohort of clinicians. This study has provided us with detailed baseline data to accurately assess the impact of interventions aimed at improving clinicians' interpretation of paediatric elbow radiographs in future studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Globally, ex-post legislative evaluations are becoming increasingly important for understanding how laws function in practice and identifying their limitations and their effects upon stakeholders. This study delves into the impact of ex-post legislative evaluations within the Dutch healthcare system. Building upon insights from previous literature, we aim to refine existing ideas within the field through empirical data. Utilising the realist evaluation method, we examine three distinct case studies followed by a cross-case analysis. Our research underscores that the impact of these evaluations extends beyond policy and politics to the broader societal arena. Our findings also point towards opportunities for strengthening the impact of ex-post legislative evaluations within this broader societal arena. Specifically, we identify strategic phases within the evaluation process through which we aim to maximise impact. Finally, the study emphasises the importance of context awareness, the strategic utilisation of research quality as well as interactional factors for enhancing impact., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

Background: In 2021 we launched the BronchStart study, which collected information on 17,899 presentations in children with serious respiratory tract infections following the release of lockdown restrictions. Our study informed the Joint Committee on Vaccination and Immunisation's decision to recommend the introduction maternal respiratory syncytial virus (RSV) vaccination, which was introduced in the United Kingdom in August/September 2024., Study Question: We modified our original protocol to conduct a United Kingdom-wide assessment of maternal vaccination against RSV., Methods and Likely Impact: We will conduct a multi-centre study, utilising the PERUKI network used in the original BronchStart study, to assess the effectiveness of maternal vaccination using a test-negative study design. We will gather detailed clinical information on children admitted with bronchiolitis in the post-RSV vaccination era, and understand possible reasons for incomplete vaccine uptake., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Williams TC et al.)

Background: Treating children with acute severe asthma (ASA) who fail to respond to first-line inhaled bronchodilators is problematic: use of intravenous agents is inconsistent and side-effects are common. High-flow humidified oxygen (HiFlo) has shown promise in other respiratory conditions and is increasingly used in ASA, but with little evidence., Methods: We conducted a feasibility randomised controlled trial with deferred consent to assess early HiFlo in children aged 2-11 years with ASA not responding to "burst" therapy (high-dose inhaled salbutamol ± ipratropium). Children with Paediatric Respiratory Assessment Measure (PRAM) score 5+ after "burst" were randomised to commence HiFlo or follow standard care. Candidate primary outcomes assessed were treatment failure requiring escalation, and time to meeting hospital discharge criteria., Results: The target was met despite coronavirus disease 2019 pandemic disruption: 56 children were randomised across four sites, with deferred consent received in 50 out of 56 (89%), and mean recruitment rate 1.1 per site per month. 28 were allocated early HiFlo and 22 standard care. Data collection was complete for both candidate primary outcomes. Treatment failure requiring escalation occurred in 18 of 28 children (64%) in the HiFlo arm and in 19 of 22 (86%) in the standard care arm. Median (interquartile range) time from randomisation to meeting discharge criteria was 29.3 h (21.8-43.7 h) in the HiFlo arm and 36.8 h (24.1-46.3 h) in the standard care arm., Conclusions: HiFlo in childhood ASA is a potentially promising intervention whose use is increasing despite lack of evidence. A definitive randomised controlled trial to assess its effectiveness is required and appears to be feasible., Competing Interests: Conflict of interest: A. Kapur has nothing to disclose. Conflict of interest: H. Rojas-Anaya has nothing to disclose. Conflict of interest: G. Roberts has nothing to disclose. Conflict of interest: D. Roland has nothing to disclose. Conflict of interest: A. Gupta has nothing to disclose. Conflict of interest: M. Lazner was an advisory board member for Aerogen Ltd for non-HiFlo study-related research and received an honorarium of £952.89 for this work. Conflict of interest: J. Bayreuther has nothing to disclose. Conflict of interest: F. Cantle has nothing to disclose. Conflict of interest: C. Jones has nothing to disclose. Conflict of interest: J. Pappachan has nothing to disclose. Conflict of interest: S. Bremner has nothing to disclose. Conflict of interest: D. James has nothing to disclose. Conflict of interest: S. Fitzgerald has nothing to disclose. Conflict of interest: K. Owens has nothing to disclose. Conflict of interest: L. Asim has nothing to disclose. Conflict of interest: E. Khaleva has nothing to disclose. Conflict of interest: P. Seddon, in March 2023, chaired an advisory board (unrelated to HiFlo) for Aerogen Ltd, which loaned nebuliser equipment for the study, and received an honorarium., (Copyright ©The authors 2024.)

Orthostatic hypotension is a highly prevalent medical condition that is an independent risk factor for falls and mortality. It reflects a condition in which autonomic reflexes are impaired or intravascular volume is depleted, causing a significant reduction in blood pressure upon standing. This disorder is frequently unrecognized until later in its clinical course. Symptoms like orthostatic dizziness do not reliably identify patients with orthostatic hypotension, who are often asymptomatic, leading further to the difficulty of this diagnosis. We summarize seven clinically important misconceptions about orthostatic hypotension., (Copyright © 2024. Published by Elsevier Inc.)

People with epilepsy are at risk of premature death, of which sudden unexpected death in epilepsy (SUDEP), sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) are the primary, partly overlapping, clinical scenarios. We discuss the epidemiologies, risk factors and pathophysiological mechanisms for these sudden death events. We reviewed the existing evidence on sudden death in epilepsy. Classification of sudden death depends on the presence of autopsy and expertise of the clinician determining aetiology. The definitions of SUDEP, SCD and SADS lead to substantial openings for overlap. Seizure-induced arrhythmias constitute a minority of SUDEP cases. Comorbid cardiovascular conditions are the primary determinants of increased SCD risk in chronic epilepsy. Genetic mutations overlap between the states, yet whether these are causative, associated or incidentally present is often unclear. Risk stratification for sudden death in people with epilepsy requires a multidisciplinary approach, including a review of clinical history, toxicological analysis and complete autopsy with histologic and, preferably, genetic examination. We recommend pursuing genetic testing of relatives of people with epilepsy who died suddenly, mainly if a post-mortem genetic test contained a Class IV/V (pathogenic/likely pathogenic) gene variant. Further research may allow more precise differentiation of SUDEP, SCD and SADS and the development of algorithms for risk stratification and preventative strategies., Competing Interests: N.A.S., D.G.B. and K.Z. report no conflicts of interest. R.D.T. has received personal compensation for serving on the Advisory Boards or Speaker’s Bureau for Xenon, Theravance, Novartis, Esai, Angelini Pharma and UCB. J.W.S. or his department has received grants from Esai, Angelini Pharma and UCB. He has received personal compensation for serving on the Advisory Boards or Speaker’s Bureau for UCB and Angelini Pharma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic-clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence., (© 2024. The Author(s).)

Emergency clinicians must rapidly evaluate the acutely ill or injured child. In a resource-stressed environment, "spotting the sick child" is essential for appropriate stabilization, treatment, and further management. Overlooking clinical features in a child's presentation may impede timely care. Complicating factors include the volume of patients seeking care, unfettered access to emergency services, parental perceptions and expectations, and clinician biases. Notwithstanding, after an appropriate history and physical exam, some children do not fall under the standard rubric of "sick or not sick". This article explores strategies to recognise the child who may lie in the diagnostic void between those who are obviously well and those who are not., (© 2024. The Author(s).)

Importance: How epilepsy may promote cardiovascular disease remains poorly understood., Objective: To estimate the odds of new-onset cardiovascular events (CVEs) over 6 years in older people with vs without epilepsy, exploring how enzyme-inducing antiseizure medications (EIASMs) and traditional cardiovascular risk factors mediate these odds., Design, Setting, and Participants: This was a prospective cohort study using the comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA), with 6 years of follow-up (2015-2021, analysis performed in December 2023). The CLSA is an ongoing, national study of 51 338 adults aged 45 to 85 years at baseline who are recruited in Canada. The comprehensive cohort includes 30 097 individuals living near 1 of 11 data collection centers. Participation in the CLSA was voluntary; participation rate was 45%. Among those in the comprehensive cohort, individuals reporting no previous history of CVEs (ie, stroke, transient ischemic attack [TIA], or myocardial infarction [MI]) at baseline were excluded. No other exclusion criteria were applied. A total of 86% of participants completed follow-up., Exposure: Lifetime history of epilepsy., Main Outcomes and Measures: The primary outcome was new-onset CVEs over 6 years. Secondary outcomes were new-onset strokes, TIAs, and MIs. Logistic models were fitted for these outcomes as a function of epilepsy, age, sex, household income, and education level. Mediation analyses were conducted for strong EIASM use, weak EIASM use, Framingham score, Physical Activity Scale for the Elderly (PASE) score, and waist to hip ratio., Results: Among the 30 097 individuals in the comprehensive cohort, a total of 27 230 individuals (mean [SD] age, 62.3 [10.1] years; 14 268 female [52.4%]) were included, 431 with a lifetime history of epilepsy. New-onset CVEs were more likely in epilepsy, with an adjusted odds ratio of 2.20 (95% CI, 1.48-3.27). The proportion of the effect of epilepsy on new-onset CVEs was mediated as follows by each of the following variables: strong EIASM use, 24.6% (95% CI, 6.5%-54.6%), weak EIASM use, 4.0% (95% CI, 0.8%-11.0%), Framingham score, 1.4% (95% CI, -1.6% to 4.5%), PASE score, 3.3% (95% CI, 1.4%-6.8%), and waist to hip ratio, 1.6% (95% CI, 0.4%-3.7%)., Conclusions and Relevance: Results of this cohort study reveal that epilepsy was associated with new-onset CVEs. Nearly one-third of this association can be explained by EIASMs. These findings should be considered when choosing an antiseizure medication for a person at risk for cardiovascular disease.

Purpose: We studied the relative contributions of total peripheral resistance (TPR), stroke volume (SV) and heart rate (HR) to low blood pressure in classical orthostatic hypotension (cOH) on group and individual levels., Methods: We retrospectively analyzed tilt test records from cOH patients and age/sex-matched controls. We quantified relative effects of HR, SV and TPR on mean arterial pressure (MAP) with the log-ratio method. We studied relations of changes of HR, SV or TPR with the change of MAP across patients and variability of contributions of HR, SV and TPR to MAP. We also explored neurogenic vs. nonneurogenic causes., Results: MAP responded to tilt with a decrease in patients (n = 80) and an increase in controls (n = 80). A too small TPR-increase contributed most to cOH, followed by a too large SV-decrease; both effects were partially corrected by a larger increase of HR. Only TPR changes consistently affected MAP change in patients and controls. TPR decreased almost exclusively in patients, most in those with severe cOH. Contributions of HR, SV and TPR to MAP did not differ between probable neurogenic and nonneurogenic causes., Conclusion: HR, SV and TPR all contributed to cOH, with a key role for TPR; a decrease of TPR was almost unique to patients and may be due to hyperventilation. The lack of differences between neurogenic and nonneurogenic causes needs further study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: A.H.S., S.S., and M.K.B. declare no competing interest. N.M.V. serves as an associate editor of the Journal of Parkinson’s Disease and receives funding from the Michael J. Fox Foundation for Parkinson’s Research, the Netherlands Organisation for Health Sciences and Development and from Verily Life Sciences. B.R.B. currently serves as an associate editor for the Journal of Parkinson’s Disease, has received honoraria from serving on the scientific advisory board for Zambon and Kyowa Kirin, has received fees for speaking at conferences from AbbVie, Zambon, and Bial, and has received research support from the Netherlands Organization for Scientific Research (NWO), the Michael J. Fox Foundation for Parkinson’s Research, UCB, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson’s Foundation, Verily Life Sciences, Top Sector Life Sciences and Health, and the Parkinson Vereniging. R.D.T. reports consultancy and speakers’ fees from Union Chimique Belge, Angellini, GlaxoSmithKline, Theravance, Novartis, and Zogenix; and grants from the Dutch National Epilepsy Fund (EpilepsieNL), the Michael J. Fox Foundation for Parkinson’s Research (MJFF-020200), Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, Medtronic, New Life Wearables, VriendenLoterij, and the Netherlands Organisation for Health Research and Development (114025101)., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2024. The Author(s).)

Background: The efficacy of injections of mesenchymal stem cells (MSC) for anal fistula treatment may be impaired by the persistence of stools passing into the fistula, causing bacterial contamination and a local inflammatory reaction. We aimed to compare remission rates between patients treated by MSC injection with simple sutures and those treated with a rectal advancement flap., Methods: This single-center prospective study compared the first patients who underwent internal opening closure with sutures with the subsequent patients treated with a flap. Complete clinical remission was defined as complete closure of the external opening(s) without pain or discharge, and complete radiological remission was defined as a Magnifi-CD score of 0., Results: We compared the first 42 patients who had sutures with the 20 subsequent patients who had an advancement flap. The median follow-up was 15.5 [8.8-24.9] months. The cumulative incidence of complete clinical response at M12 was 53.8% [38.1-69.6%] in the suture group versus 93.3% [77.4-100.0] in the flap group (p < 0.001). The Magnifi-CD score was 0 for 41.7% [25.5-59.2%]) of patients treated with sutures versus 72.7% [39.0-63.9%]) of patients treated with a flap (p = 0.093). Anal incontinence score did not differ between the two groups. Practicing an advancement flap was the only significant factor associated with complete clinical remission over time (adjusted HR [95% CI] of 2.6 [1.4-4.9], p = 0.003)., Conclusions: Complete clinical remission rates following MSC injection are significantly higher after closure of the internal opening with a rectal flap than after closure with sutures, without consequences on anal continence., (© 2024. Springer Nature Switzerland AG.)

Objective: This study was undertaken to develop a model and perform a preliminary internal validation study of the Scale for Objective Diagnostic Components of Paroxysmal Events (STAMP)., Methods: We developed STAMP, which builds on the International League Against Epilepsy task force scale for functional seizures with additional categories for epileptic seizures and syncope. We included 200 consecutive referrals to a Dutch tertiary epilepsy center to evaluate seizurelike events. We recorded demographic and clinical data and collected the clinical evaluation at referral and after 3, 6, 9, and 12 months of follow-up. We ascertained the STAMP at each time point and evaluated factors predicting an improvement in STAMP grade during follow-up., Results: Of the 200 referrals at baseline, 131 were classified as having epileptic seizures, 17 as functional seizures, and three as syncope, and 49 were unclassifiable. STAMP grade at baseline was 4 (absent) in 56 individuals, 3 (circumstantial) in 78, 2 (clinically established) in six, and 1 (documented) in 11. Over time, 62 cases STAMP grades improved, and 23 remained unclassifiable. A refinement of STAMP grade during follow-up was due to successful event recordings in 34 people (30 video-electroencephalographic [EEG] recordings, four tilt table testing), home videos or clinician-witnessed events in 13, and identification of interictal EEG or magnetic resonance imaging abnormalities in seven. An improved STAMP grade after 12 months of follow-up was significantly more likely in those with higher event frequency, unclassifiable events, longer event duration, and a shorter time since the first event and less likely in those with a history suggestive of seizures., Significance: This epilepsy service evaluation underscores the crucial role of event recording in improving diagnostic certainty. STAMP may be used to monitor diagnostic performance over time but requires further validation., (© 2024 International League Against Epilepsy.)

Background: The involvement of patients or next of kin (P/N) after a serious adverse event (SAE) is evolving. Beyond providing mandatory information, there is growing recognition of the need to incorporate their interests. This study explores practical manifestations of P/N involvement and identifies significant considerations for hospitals., Methods: The data collection involved various qualitative research methods: 7 focus groups with 56 professionals from 37 hospitals, an interview with 2 representatives from the Dutch Association of Hospitals, and an interactive reflection seminar with over 60 participants from 34 hospitals. Before the focus groups, a brief questionnaire was sent out to survey participants' practices regarding into SAE investigations. After the study, another questionnaire was distributed to gather suggestions for future improvements and to identify their lessons learned. Thematic analysis was applied to the gathered data to identify key themes., Results: Hospitals are increasingly acknowledging the interests and perspectives of P/N, recognizing their potential contributions to organizational learning and improvement. P/N involvement following SAEs includes active participation in different stages of the investigation process, not just passive information dissemination. Important factors influencing involvement are the provision of (emotional) support, identification of needs, and transparency of the SAE investigation., Conclusions: This study enhances understanding of evolving practices surrounding P/N involvement in the context of SAEs in Dutch hospitals. The findings highlight the importance of promoting meaningful involvement, recognizing the significance of P/N experiences, and fostering a culture of transparency and collaboration. By examining the dynamics of involvement, this research aims to inform policy development and facilitate the implementation of patient-centered approaches to post-SAE care., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Neurobehavioural comorbidities have a detrimental effect on the quality of life of people with epilepsy, yet tracking their impact is challenging as behaviour may vary with seizures and anti-seizure medication (ASM) side effects. Smartphones have the potential to monitor day-to-day neurobehavioural patterns objectively. We present the case of a man in his late twenties with drug-resistant focal epilepsy in whom we ascertained the effects of ASM withdrawal and a convulsive seizure on his touchscreen interactions., Methods: Using a dedicated app, we recorded over 185 days the timestamps of 718,357 interactions. We divided the various smartphone behaviours according to the next-interval dynamics of the interactions by using a joint interval distribution (JID). During two ASM load transitions, namely before versus during tapering and tapering versus restarting medication, we used cluster-based permutation tests to compare the JIDs. We also compared the JID of the seizure day to the average of the previous 3 days., Results: The cluster-based permutation tests revealed significant differences, with accelerated next-interval dynamics during tapering and a reversal upon medication restart. The day of the convulsion exhibited a marked slowing of next-interval dynamics compared to the preceding 3 days., Conclusion: Our findings suggest that the temporal dynamics of smartphone touchscreen interactions may help monitor neurobehavioural comorbidities in neurological care., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To systematically review the literature describing children and young people (CYP) admissions to paediatric general wards because of primary mental health (MH) reasons, particularly in MH crisis., Design: PubMed, Embase, PsycINFO, Web of Science and Google Scholar were searched, with no restriction on country or language. We addressed five search questions to inform: trends and/or the number of admissions, the risk factors for adverse care, the experiences of CYP, families/carers and healthcare professionals (HCPs) and the evidence of interventions aimed at improving the care during admissions.Two reviewers independently assessed the relevance of abstracts identified, extracted data and undertook quality assessment. This review was registered with PROSPERO (CRD42022350655)., Results: Thirty-two studies met the inclusion criteria. Eighteen addressed trends and/or numbers/proportions of admissions, 12 provided data about the views/experiences of HCPs, two provided data about CYP's experiences and four explored improving care. We were unable to identify studies examining risk factors for harm during admissions, but studies did report the length of stay in general paediatric/adult settings while waiting for specialised care, which could be considered a risk factor while caring for this group., Conclusions: MH admissions to children's wards are a long-standing issue and are increasing. CYP will continue to need to be admitted in crisis, with paediatric wards a common location while waiting for assessment. For services to be delivered effectively and for CYP and their families/carers to feel supported and HCPs to feel confident, we need to facilitate more integrated physical and MH pathways of care., Prospero Registration Number: CRD42022350655., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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., (© 2024 The Authors.)

Bioelectrochemical sensor (BES) technologies have been developed to measure soluble carbon concentrations in wastewater. However, architectures and analytical methods developed in controlled laboratory environments fail to predict BES behavior during field deployments at water resource recovery facilities (WRRFs). Here, we examine the possibilities and obstacles associated with integrating BESs into environmental sensing networks and machine learning algorithms to monitor the biodegradable carbon dynamics and microbial metabolism at WRRFs. This approach highlights the potential of BESs to provide real-time insights into full-scale biodegradable carbon consumption across WRRFs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to the manuscript submission., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Long-term ambulatory EEG recordings can improve the monitoring of absence epilepsy in children, but signal quality and increased review workload are a concern. We evaluated the feasibility of around-the-ears EEG arrays (cEEGrids) to capture 3-Hz short-lasting and ictal spike-and-wave discharges and assessed the performance of automated detection software in cEEGrids data. We compared patterns of bilateral synchronisation between short-lasting and ictal spike-and-wave discharges., Methods: We recruited children with suspected generalised epilepsy undergoing routine video-EEG monitoring and performed simultaneous cEEGrids recordings. We used ASSYST software to detect short-lasting 3-Hz spike-and-wave discharges (1-3 s) and ictal spike-and-wave discharges in the cEEGrids data. We assessed data quality and sensitivity of cEEGrids for spike-and-wave discharges in routine EEG. We determined the sensitivity and false detection rate for automated spike-and-wave discharge detection in cEEGrids data. We compared bihemispheric synchrony across the onset of short-lasting and ictal spike-and-wave discharges using the mean phase coherence in the 2-4 Hz frequency band., Results: We included nine children with absence epilepsy (median age = 11 y, range 8-15 y, nine females) and recorded 4 h and 27 min of cEEGrids data. The recordings from seven participants were suitable for quantitative analysis, containing 82 spike-and-wave discharges. The cEEGrids captured 58 % of all spike-and-wave discharges (median individual sensitivity: 100 %, range: 47-100 %). ASSYST detected 82 % of all spike-and-wave discharges (median: 100 %, range: 41-100 %) with a false detection rate of 48/h (median: 6/h, range: 0-154/h). The mean phase coherence significantly increased during short-lasting and ictal spike-and-wave discharges in the 500-ms pre-onset to 1-s post-onset interval., Conclusions: cEEGrids are of variable quality for monitoring spike-and-wave discharges in children with absence epilepsy. ASSYST could facilitate the detection of short-lasting and ictal spike-and-wave discharges with clear periodic structures but with low specificity. A similar course of bihemispheric synchrony between short-lasting and ictal spike-and-wave discharges indicates that cortico-thalamic driving may be relevant for both types of spike-and-wave discharges., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emergency department (ED) crowding causes increased mortality. Professionals working in crowded departments feel unable to provide high-quality care and are predisposed to burnout. Awareness of the impact on patients, however, is limited to metrics and surveys rather than understanding perspectives. This project investigated patients' experiences and identified mitigating interventions., Methods: A qualitative service evaluation was undertaken in a large UK ED. Adults were recruited during periods of high occupancy or delayed transfers. Semi-structured interviews explored experience during these attendances. Participants shared potential mitigating interventions. Analysis was based on the interpretative phenomenological approach. Verbatim transcripts were read, checked for accuracy, re-read and discussed during interviewer debriefing. Reflections about positionality informed the interpretative process., Results: Seven patients and three accompanying partners participated. They were aged 24-87 with characteristics representing the catchment population. Participants' experiences were characterised by 'loss of autonomy', 'unmet expectations' and 'vulnerability'. Potential mitigating interventions centred around information provision and better identification of existing ED facilities for personal needs., Conclusion: Participants attending a crowded ED experienced uncertainty, helplessness and discomfort. Recommendations included process and environmental orientation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interventions introduced to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a widespread reduction in childhood infections. However, from spring 2021 onwards the United Kingdom and Ireland experienced an unusual out-of-season epidemic of respiratory disease., Methods: We conducted a prospective observational study (BronchStart), enrolling children 0-23 months of age presenting with bronchiolitis, lower respiratory tract infection, or first episode of wheeze to 59 emergency departments across England, Scotland, and Ireland from May 2021 to April 2022. We combined testing data with national admissions datasets to infer the impact of respiratory syncytial virus (RSV) disease., Results: The BronchStart study collected data on 17 899 presentations for 17 164 children. Risk factors for admission and escalation of care included prematurity and congenital heart disease, but most admissions were for previously healthy term-born children. Of those aged 0-11 months who were admitted and tested for RSV, 1907 of 3912 (48.7%) tested positive. We estimate that every year in England and Scotland 28 561 (95% confidence interval, 27 637-29 486) infants are admitted with RSV infection., Conclusions: RSV infection was the main cause of hospitalizations in this cohort, but 51.3% of admissions in infants were not associated with the virus. The majority of admissions were in previously healthy term-born infants., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: In pre-hospital settings, identifying a deteriorating child can be challenging, especially considering that the proportion of paediatric patients with acute illnesses is lower compared with adults. This challenge is exacerbated in pre-hospital settings, where information might be scarce. Physiological alterations indicating changes in a patient's condition can be detected hours preceding a cardiac arrest. Therefore, maintaining continuous monitoring of the patient's clinical condition is crucial to detecting any physiological changes promptly, facilitating early identification of critical illness. This scoping review aims to assess the extent, range and nature of published research related to recognising paediatric out-of-hospital clinical deterioration by pre-hospital staff., Methods and Analysis: This scoping review is registered with the Open Science Framework. The review will follow the Joanna Briggs Institute's (JBI) methodology for scoping reviews. A systematic search of relevant databases (MEDLINE, EMBASE, Web of Science, CINAHL and Scopus) will be conducted. In this scoping review, all types of study designs including quantitative and qualitative studies will be considered. The inclusion is limited to English-language studies published between January 1990 and March 2024. Two independent reviewers (AG and SS) will conduct a thorough screening of titles and abstracts against the pre-defined inclusion criteria for the review. For the selected citations, the full texts will undergo detailed assessment by the two reviewers, ensuring alignment with the inclusion criteria. A quality assessment of the included studies will be done using the Mixed Methods Appraisal Tool. The findings will be presented using diagrams or tables, supplemented by narrative summaries following the JBI guidelines., Ethics and Dissemination: Ethical approval is not required. The findings will be disseminated through publication in a peer-reviewed journal and presentation at conferences and/or seminars., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Covering 1965 to February 2024Plants are prolific peptide chemists and are known to make thousands of different peptidic molecules. These peptides vary dramatically in their size, chemistry, and bioactivity. Despite their differences, all plant peptides to date are biosynthesized as ribosomally synthesized and post-translationally modified peptides (RiPPs). Decades of research in plant RiPP biosynthesis have extended the definition and scope of RiPPs from microbial sources, establishing paradigms and discovering new families of biosynthetic enzymes. The discovery and elucidation of plant peptide pathways is challenging due to repurposing and evolution of housekeeping genes as both precursor peptides and biosynthetic enzymes and due to the low rates of gene clustering in plants. In this review, we highlight the chemistry, biosynthesis, and function of the known RiPP classes from plants and recommend a nomenclature for the recent addition of BURP-domain-derived RiPPs termed burpitides. Burpitides are an emerging family of cyclic plant RiPPs characterized by macrocyclic crosslinks between tyrosine or tryptophan side chains and other amino acid side chains or their peptide backbone that are formed by copper-dependent BURP-domain-containing proteins termed burpitide cyclases. Finally, we review the discovery of plant RiPPs through bioactivity-guided, structure-guided, and gene-guided approaches.

Objectives: To identify and present the available evidence regarding workforce well-being in the emergency department., Design: Scoping review., Setting: The emergency department (ED)., Data Sources: CINAHL, MEDLINE, APA PsycINFO and Web of Science were searched with no publication time parameters. The reference lists of articles selected for full-text review were also screened for additional papers., Eligibility Criteria for Study Selection: All peer-reviewed, empirical papers were included if: (1) participants included staff-based full-time in the ED, (2) ED workforce well-being was a key component of the research, (3) English language was available and (4) the main focus was not burnout or other mental illness-related variables., Results: The search identified 6109 papers and 34 papers were included in the review. Most papers used a quantitative or mixed methods survey design, with very limited evidence using in-depth qualitative methods to explore ED workforce well-being. Interventions accounted for 41% of reviewed studies. Findings highlighted pressing issues with ED workforce well-being, contributed to by a range of interpersonal, organisational and individual challenges (eg, high workloads, lack of support). However, the limited evidence base, tenuous conceptualisations and links to well-being in existing literature mean that the findings were neither consistent nor conclusive., Conclusions: This scoping review highlights the need for more high-quality research to be conducted, particularly using qualitative methods and the development of a working definition of ED workforce well-being., Competing Interests: Competing interests: KK and DR are clinical academics; KK is an ED nurse and DR is a paediatric emergency medicine clinician scientist. NA is supported by the National Institute for Health and Care Research (NIHR) Greater Manchester Patient Safety Research Collaboration (GM PSRC) and by the NIHR Applied Research Collaboration East Midlands (ARC EM). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute illness accounts for the majority of episodes of illness in children under five years of age and is the age group with the highest consultation rate in general practice in the UK. The number of children presenting to emergency care is also steadily increasing, having risen beyond pre-pandemic numbers. Such high, and increasing, rates of consultation have prompted concerns about parents' level of knowledge and confidence in caring for their children when they are ill, and particularly when and how to seek help appropriately., Aim: The ASK SNIFF collaboration research programme identified parents' need for accurate and accessible information to help them know when to seek help for a sick child in 2010. This paper presents the resulting programme of research which aimed to co-develop an evidence-based safety netting intervention (mobile app) to help parents know when to seek help for an acutely ill child under the age of five years in the UK., Methods: Our programme used a collaborative six step process with 147 parent and 324 health professional participants over a period of six years including: scoping existing interventions, systematic review, qualitative research, video capture, content identification and development, consensus methodology, parent and expert clinical review., Results: Our programme has produced evidence-based content for an app supported by video clips. Our collaborative approach has supported every stage of our work, ensuring that the end result reflects the experiences, perspectives and expressed needs of parents and the clinicians they consult., Conclusion: We have not found any other resource which has used this type of approach, which may explain why there is no published evaluation data demonstrating the impact of existing UK resources. Future mobile apps should be designed and developed with the service users for whom they are intended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

Objective: Recovery from acute wheeze and asthma attacks should be supported with safety netting, including treatment advice. We evaluated emergency department (ED) discharge practices for acute childhood wheeze/asthma attacks to describe variation in safety netting and recovery bronchodilator dosing., Design: Two-phase study between June 2020 and September 2021, comprising (1) Departmental discharge practice survey, and (2) Analysis of written discharge instructions for caregivers., Setting: Secondary and tertiary EDs in rural and urban settings, from Paediatric Emergency Research in the UK and Ireland (PERUKI)., Main Outcome Measures: Describe practice and variation in discharge advice, treatment recommendations and safety netting provision., Results: Of 66/71 (93%) participating sites, 62/66 (93.9%) reported providing written safety netting information. 52/66 (78.8%) 'nearly always' assessed inhaler/spacer technique; routine medication review (21/66; 31.8%) and adherence (16/66; 21.4%) were less frequent. In phase II, 61/66 (92.4%) submitted their discharge documents; 50/66 (81.9%) included bronchodilator plans. 11/66 (18.0%) provided Personalised Asthma Action Plans as sole discharge information. 45/50 (90%) provided 'fixed' bronchodilator dosing regimes; dose tapering was common (38/50; 76.0%). Median starting dose was 10 puffs 4 hourly (27/50, 54.0%); median duration was 4 days (29/50, 58.0%). 13/61 (21.3%) did not provide bronchodilator advice for acute deterioration; where provided, 42/48 (87.5%) recommended 10 puffs immediately. Subsequent dosages varied considerably. Common red flags included inability to speak (52/61, 85.2%), inhalers not lasting 4 hours (51/61, 83.6%) and respiratory distress (49/61, 80.3%)., Conclusions: There is variation in bronchodilator dosing and safety netting content for recovery following acute wheeze and asthma attacks. This reflects a lack of evidence, affirming need for further multicentre studies regarding bronchodilator recovery strategies and optimal safety netting advice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflict of interest: R.D.T. has received personal compensation for serving on the Advisory Boards or Speaker’s Bureau for Xenon, Theravance, Novartis, Esai, Angelini Pharma and UCB. J.W.S. or his department has received grants from Esai, Angelini Pharma and UCB. He has received personal compensation for serving on the Advisory Boards or Speaker’s Bureau for UCB and Angelini Pharma. N.A.S. has no conflicts of interest.

We aimed to describe differences in the epidemiology, management, and outcomes existing between centers located in countries which differ by geographical location and economic status during to post-pandemic bronchiolitis seasons.  This was a prospective observational cohort study performed in two academic centers in Latin America (LA) and three in Italy. All consecutive children with a clinical diagnosis of bronchiolitis were included, following the same data collection form.  Nine hundred forty-three patients have been enrolled: 275 from the two Latin American Centers (San Jose, 215; Buenos Aires, 60), and 668 from Italy (Rome, 178; Milano, 163; Bologna, 251; Catania, 76). Children in LA had more frequently comorbidities, and only rarely received palivizumab. A higher number of patients in LA had been hospitalized in a ward (64% versus 23.9%, p < 0.001) or in a PICU (16% versus 6.2%, p < 0.001), and children in LA required overall more often respiratory support, from low flow oxygen to invasive mechanical ventilation, except for CPAP which was more used in Italy. There was no significant difference in prescription rates for antibiotics, but a significantly higher number of patients treated with systemic steroids in Italy., Conclusions: We found significant differences in the care for children with bronchiolitis in Italy and LA. Reasons behind such differences are unclear and would require further investigations to optimize and homogenize practice all over the world., What Is Known: • Bronchiolitis is among the commest cause of morbidity and mortality in infants all over the world., What Is New: • There are significant differences on how clinicians care for bronchiolitis in different centers and continents. Differences in care can be principally due to different local practices than differences in patients severity/presentations. • Understanding these differences should be a priority to optime and standardize bronchiolitis care globally., (© 2024. The Author(s).)

Aims: The aim of this trial was to assess the cost-effectiveness of a soft bandage and immediate discharge, compared with rigid immobilization, in children aged four to 15 years with a torus fracture of the distal radius., Methods: A within-trial economic evaluation was conducted from the UK NHS and personal social services (PSS) perspective, as well as a broader societal point of view. Health resources and quality of life (the youth version of the EuroQol five-dimension questionnaire (EQ-5D-Y)) data were collected, as part of the Forearm Recovery in Children Evaluation (FORCE) multicentre randomized controlled trial over a six-week period, using trial case report forms and patient-completed questionnaires. Costs and health gains (quality-adjusted life years (QALYs)) were estimated for the two trial treatment groups. Regression was used to estimate the probability of the new treatment being cost-effective at a range of 'willingness-to-pay' thresholds, which reflect a range of costs per QALY at which governments are typically prepared to reimburse for treatment., Results: The offer of a soft bandage significantly reduced cost per patient (saving £12.55 (95% confidence interval (CI) -£5.30 to £19.80)) while QALYs were similar (QALY difference between groups: 0.0013 (95% CI -0.0004 to 0.003)). The high probability (95%) that offering a bandage is a cost-effective option was consistent when examining the data in a range of sensitivity analyses., Conclusion: In addition to the known clinical equivalence, this study found that the offer of a bandage reduced cost compared with rigid immobilization among children with a torus fracture of the distal radius. While the cost saving was small for each patient, the high frequency of these injuries indicates a significant saving across the healthcare system., Competing Interests: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (17/23/02). D. C. Perry was funded through an NIHR Clinician Scientist Fellowship (CS-2014–14–012) and latterly an NIHR Research Professorship. The trial was supported by the NIHR Oxford Biomedical Research Centre. The University of Oxford acted as the study Sponsor. J. Achten and M. L. Costa's employer, The University of Oxford, receives research funding from the NIHR and Wellcome Trust for research into musculoskeletal trauma. S. Messahel holds a voluntary position as Secretary of the Executive Committee of Paediatric Emergency Research UK and Ireland Network., (© 2024 Perry et al.)

Competing Interests: None declared.

Mixed community microalgal wastewater treatment technologies have the potential to advance the limits of technology for biological nutrient recovery while producing a renewable carbon feedstock, but a deeper understanding of their performance is required for system optimization and control. In this study, we characterized the performance of a 568 m 3 ·day -1 Clearas EcoRecover system for tertiary phosphorus removal (and recovery as biomass) at an operating water resource recovery facility (WRRF). The process consists of a (dark) mix tank, photobioreactors (PBRs), and a membrane tank with ultrafiltration membranes for the separation of hydraulic and solids residence times. Through continuous online monitoring, long-term on-site monitoring, and on-site batch experiments, we demonstrate (i) the importance of carbohydrate storage in PBRs to support phosphorus uptake under dark conditions in the mix tank and (ii) the potential for polyphosphate accumulation in the mixed algal communities. Over a 3-month winter period with limited outside influences (e.g., no major upstream process changes), the effluent total phosphorus (TP) concentration was 0.03 ± 0.03 mg-P·L -1 (0.01 ± 0.02 mg-P·L -1 orthophosphate). Core microbial community taxa included Chlorella spp. , Scenedesmus spp. , and Monoraphidium spp. , and key indicators of stable performance included near-neutral pH, sufficient alkalinity, and a diel rhythm in dissolved oxygen.

Rationale: There is significant practice variation in acute paediatric asthma, particularly severe exacerbations. It is unknown whether this is due to differences in clinical guidelines., Objectives: To describe and compare the content and quality of clinical guidelines for the management of acute exacerbations of asthma in children between geographic regions., Methods: Observational study of guidelines for the management of acute paediatric asthma from institutions across a global collaboration of six regional paediatric emergency research networks., Measurements and Main Results: 158 guidelines were identified. Half provided recommendations for at least two age groups, and most guidelines provided treatment recommendations according to asthma severity.There were consistent recommendations for the use of inhaled short-acting beta-agonists and systemic corticosteroids. Inhaled anticholinergic therapy was recommended in most guidelines for severe and critical asthma, but there were inconsistent recommendations for its use in mild and moderate exacerbations. Other inhaled therapies such as helium-oxygen mixture (Heliox) and nebulised magnesium were inconsistently recommended for severe and critical illness.Parenteral bronchodilator therapy and epinephrine were mostly reserved for severe and critical asthma, with intravenous magnesium most recommended. There were regional differences in the use of other parenteral bronchodilators, particularly aminophylline.Guideline quality assessment identified high ratings for clarity of presentation, scope and purpose, but low ratings for stakeholder involvement, rigour of development, applicability and editorial independence., Conclusions: Current guidelines for the management of acute paediatric asthma exacerbations have substantial deficits in important quality domains and provide limited and inconsistent guidance for severe exacerbations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Understanding the distribution of hundreds of thousands of plant metabolites across the plant kingdom presents a challenge. To address this, we curated publicly available LC-MS/MS data from 19,075 plant extracts and developed the plantMASST reference database encompassing 246 botanical families, 1,469 genera, and 2,793 species. This taxonomically focused database facilitates the exploration of plant-derived molecules using tandem mass spectrometry (MS/MS) spectra. This tool will aid in drug discovery, biosynthesis, (chemo)taxonomy, and the evolutionary ecology of herbivore interactions.

The biosynthetic dogma of ribosomally synthesized and posttranslationally modified peptides (RiPP) involves enzymatic intermolecular modification of core peptide motifs in precursor peptides. The plant-specific BURP-domain protein family, named after their four founding members, includes autocatalytic peptide cyclases involved in the biosynthesis of side-chain-macrocyclic plant RiPPs. Here we show that AhyBURP, a representative of the founding Unknown Seed Protein-type BURP-domain subfamily, catalyzes intramolecular macrocyclizations of its core peptide during the sequential biosynthesis of monocyclic lyciumin I via glycine-tryptophan crosslinking and bicyclic legumenin via glutamine-tyrosine crosslinking. X-ray crystallography of AhyBURP reveals the BURP-domain fold with two type II copper centers derived from a conserved stapled-disulfide and His motif. We show the macrocyclization of lyciumin-C(sp 3 )-N-bond formation followed by legumenin-C(sp 3 )-O-bond formation requires dioxygen and radical involvement based on enzyme assays in anoxic conditions and isotopic labeling. Our study expands enzymatic intramolecular modifications beyond catalytic moiety and chromophore biogenesis to RiPP biosynthesis., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Acute severe asthma (ASA) is a leading cause of hospital attendance in children. Standard first-line therapy consists of high-dose inhaled bronchodilators plus oral corticosteroids. Treatment for children who fail to respond to first-line therapy is problematic: the use of intravenous agents is inconsistent, and side effects are frequent. High-flow humidified oxygen (HiFlo) is widely used in respiratory conditions and is increasingly being used in ASA, but with little evidence for its effectiveness. A well-designed, adequately powered randomized controlled trial (RCT) of HiFlo therapy in ASA is urgently needed, and feasibility data are required to plan such an RCT. In this study, we describe the protocol for a feasibility study designed to fill this knowledge gap., Objective: This study aims to establish whether a full RCT of early HiFlo therapy in children with ASA can be conducted successfully and safely, to establish whether recruitment using deferred consent is practicable, and to define appropriate outcome measures and sample sizes for a definitive RCT. The underlying hypothesis is that early HiFlo therapy in ASA will reduce the need for more invasive treatments, allow faster recovery and discharge from hospital, and in both these ways reduce distress to children and their families., Methods: We conducted a feasibility RCT with deferred consent to assess the use of early HiFlo therapy in children aged 2 to 11 years with acute severe wheeze not responding to burst therapy (ie, high-dose inhaled salbutamol with or without ipratropium). Children with a Preschool Respiratory Assessment Measure score ≥5 after burst therapy were randomized to commence HiFlo therapy or follow standard care. The candidate primary outcomes assessed were treatment failure requiring escalation and time to meet hospital discharge criteria. Patient and parent experiences were also assessed using questionnaires and telephone interviews., Results: The trial was opened to recruitment in February 2020 but was paused for 15 months owing to the COVID-19 pandemic. The trial was reopened at the lead site in July 2021 and opened at the other 3 sites from August to December 2022. Recruitment was completed in June 2023., Conclusions: This feasibility RCT of early HiFlo therapy in children with ASA recruited to the target despite major disturbances owing to the COVID-19 pandemic. The data are currently being analyzed and will be published separately., Trial Registration: International Standard Randomised Controlled Trial Number Registry ISRCTN78297040; https://www.isrctn.com/ISRCTN78297040., International Registered Report Identifier (irrid): DERR1-10.2196/54081., (©Hector Rojas-Anaya, Akshat Kapur, Graham Roberts, Damian Roland, Atul Gupta, Michaela Lazner, Jane Bayreuther, John Pappachan, Christina Jones, Stephen Bremner, Fleur Cantle, Paul Seddon. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.03.2024.)