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Abstract Background Clinical decision support systems (CDSSs) enable the automated, real-time detection of situations associated with a risk of adverse drug events (ADEs). However, the effectiveness of CDSS in reducing ADEs has yet to be demonstrated. We have chosen to focus on the detection of ADE such as hyperkalemia and/or acute kidney injury (AKI), which are common among hospitalized older adults. The present study’s primary objective is to use a CDSS to reduce the number of ADEs (such as AKI and/or hyperkalemia) that occur in hospitalized older adults. Methods This is a multicenter, stepped-wedge, cluster-randomized study involving five hospitals. Each hospital will start with a control period (i.e., routine care, during which each center’s CDSS is deactivated) and then switch to an intervention period (during which the CDSS is activated). The intervention will be the use of a CDSS and a strategy for managing and transmitting alerts to clinical pharmacists. The rules concerning AKI and hyperkalemia have been drafted and reviewed by a multidisciplinary group. Each rule created in the CDSS is associated with a standardized procedure, based on a review of the literature. Older patients (aged 65 or over) admitted to a participating general medicine ward, a surgical ward, or obstetrics ward will be eligible for inclusion after the provision of verbal informed consent. Discussion This study will assess the effectiveness of the CDSS in reducing the incidence of AKI and hyperkalemia. The implementation of the CDSS can assist clinical pharmacists in their daily work and is expected to prevent ADEs. Trial registration ClinicalTrials.gov Identifier: NCT05923983. Registered February 02, 2023.

Objective To determine whether adding urine culture to urinary tract infection diagnosis in pregnant women from refugee camps in Lebanon reduced unnecessary antibiotic use. Methods We conducted a prospective, cross-sectional study between April and June 2022 involving pregnant women attending a Medecins Sans Frontieres sexual reproductive health clinic in south Beirut. Women with two positive urine dipstick tests (i.e. a suspected urinary tract infection) provided urine samples for culture. Bacterial identification and antimicrobial sensitivity testing were conducted following European Committee on Antimicrobial Susceptibility Testing guidelines. We compared the characteristics of women with positive and negative urine culture findings and we calculated the proportion of antibiotics overprescribed or inappropriately used. We also estimated the cost of adding urine culture to the diagnostic algorithm. Findings The study included 449 pregnant women with suspected urinary tract infections: 18.0% (81/449) had positive urine culture findings. If antibiotics were administered following urine dipstick results alone, 368 women would have received antibiotics unnecessarily: an overprescription rate of 82% (368/449). If administration was based on urine culture findings plus urinary tract infection symptoms, 144 of 368 women with negative urine culture findings would have received antibiotics unnecessarily: an overprescription rate of 39.1% (144/368). The additional cost of urine culture was 0.48 euros per woman. Conclusion A high proportion of pregnant women with suspected urinary tract infections from refugee camps unnecessarily received antibiotics. Including urine culture in diagnosis, which is affordable in Lebanon, would greatly reduce antibiotic overprescription. Similar approaches could be adopted in other regions where microbiology laboratories are accessible. Objectif Determiner si l'ajout d'une uroculture pour diagnostiquer une infection urinaire chez les femmes enceintes dans les camps de refugies au Liban permet d'eviter de recourir inutilement aux antibiotiques. Methodes Nous avons mene une etude transversale prospective entre avril et juin 2022 sur des femmes enceintes frequentant une clinique de sante sexuelle et reproductive geree par Medecins Sans Frontieres dans le sud de Beyrouth. Les femmes presentant deux tests positifs par bandelette urinaire (c'est-a-dire souffrant potentiellement d'une infection urinaire) ont fourni des echantillons d'urine pour culture. Les tests d'identification bacterienne et de sensibilite aux antimicrobiens ont ete effectues conformement aux lignes directrices du Comite europeen des antibiogrammes. Nous avons compare les caracteristiques des femmes ayant obtenu des resultats d'uroculture positifs et negatifs puis nous avons calcule la proportion d'antibiotiques surprescrits ou utilises de fagon inappropriee. Enfin, nous avons estime combien couterait l'ajout d'une uroculture a l'algorithme de diagnostic. Resultats Letude a porte sur 449 femmes enceintes susceptibles de souffrir d'infections urinaires: 18,0% (81/449) ont obtenu des resultats positifs lors de l'uroculture. Si des antibiotiques avaient ete administres uniquement sur la base des resultats aux tests par bandelette urinaire, 368 femmes en auraient regu sans en avoir besoin, ce qui equivaut a un taux de surprescription de 82% (368/449). S'ils avaient ete administres sur la base des resultats de l'uroculture ainsi que des symptomes d'infection urinaire, 144 des 368 femmes ayant obtenu des resultats negatifs auraient regu des antibiotiques sans en avoir besoin, ce qui represente un taux de surprescription de 39,1% (144/368). La mise en place de l'uroculture a engendre un cout supplemental de 0,48 euro par femme. Conclusion Dans les camps de refugies, une proportion elevee de femmes enceintes potentiellement atteintes d'infections urinaires se sont vu prescrire des antibiotiques sans que ce ne soit necessaire. Inclure dans le diagnostic une uroculture, proposee a prix abordable au Liban, permettrait de reduire considerablement leur surprescription. Des approches similaires pourraient en outre etre adoptees dans d'autres regions ou des laboratoires de microbiologie sont accessibles. Objetivo Determinar si la adicion del urocultivo al diagnostico de infeccion urinaria en mujeres embarazadas de campos de refugiados en Libano redujo el uso innecesario de antibioticos. Metodos Entre abril y junio de 2022, se realizo un estudio prospectivo transversal en el que participaron mujeres embarazadas que acudian a una clinica de salud reproductiva sexual de Medicos Sin Fronteras en el sur de Beirut. Las mujeres con dos pruebas de tira reactiva en orina positivas (es decir, sospecha de infeccion urinaria) proporcionaron muestras de orina para cultivo. La identificacion bacteriana y las pruebas de sensibilidad antimicrobiana se realizaron siguiendo las directrices del Comite Europeo sobre Pruebas de Susceptibilidad Antimicrobiana. Se compararon las caracteristicas de las mujeres con urocultivos positivos y negativos, y se calculo el porcentaje de antibioticos prescritos en exceso o utilizados de forma inadecuada. Tambien se calculo el coste de anadir el urocultivo al algoritmo diagnostico. Resultados En el estudio participaron 449 mujeres embarazadas con sospecha de infeccion urinaria: el 18,0% (81/449) tuvieron resultados positivos en el urocultivo. Si la administracion de antibioticos se basaba unicamente en los resultados de la tira reactiva de orina, 368 mujeres habrian recibido antibioticos sin necesidad: una tasa de prescripcion excesiva del 82% (368/449). Si la administracion se basaba en los resultados del urocultivo mas los sintomas de infeccion urinaria, 144 de las 368 mujeres con resultados negativos del urocultivo habrian recibido antibioticos sin necesidad: una tasa de sobreprescripcion del 39,1% (144/368). El coste adicional del urocultivo fue de 0,48 [euro] por mujer. Conclusion Un alto porcentaje de embarazadas con sospecha de infeccion urinaria procedentes de campos de refugiados recibieron antibioticos innecesariamente. La inclusion del urocultivo en el diagnostico, asequible en Libano, reduciria en gran medida la prescripcion excesiva de antibioticos. Se podrian adoptar enfoques similares en otras regiones donde se pueda acceder a los laboratorios de microbiologia. [phrase omitted], Introduction Inappropriate antibiotic use is one of the main drivers of anti-microbial resistance. (1) The standard of care for pregnant women is to give antibiotics to prevent complications, particularly in [...]

Abstract Background Antimicrobial resistance is of great global public health concern. In order to address the paucity of antibiotic consumption data and antimicrobial resistance surveillance systems in hospitals in humanitarian settings, we estimated antibiotic consumption in six hospitals with the aim of developing recommendations for improvements in antimicrobial stewardship programs. Methods Six hospitals supported by Médecins sans Frontières were included in the study: Boost-Afghanistan, Kutupalong-Bangladesh, Baraka and Mweso-Democratic Republic of Congo, Kule-Ethiopia, and Bentiu-South Sudan. Data for 36,984 inpatients and antibiotic consumption data were collected from 2018 to 2020. Antibiotics were categorized per World Health Organization Access Watch Reserve classification. Total antibiotic consumption was measured by Defined Daily Doses (DDDs)/1000 bed-days. Results Average antibiotic consumption in all hospitals was 2745 DDDs/1000 bed-days. Boost hospital had the highest antibiotic consumption (4157 DDDs/1000 bed-days) and Bentiu the lowest (1598 DDDs/1000 bed-days). In all hospitals, Access antibiotics were mostly used (69.7%), followed by Watch antibiotics (30.1%). The most consumed antibiotics were amoxicillin (23.5%), amoxicillin and clavulanic acid (14%), and metronidazole (13.2%). Across all projects, mean annual antibiotic consumption reduced by 22.3% during the study period, mainly driven by the reduction in Boost hospital in Afghanistan. Conclusions This was the first study to assess antibiotic consumption by DDD metric in hospitals in humanitarian settings. Antibiotic consumption in project hospitals was higher than those reported from non-humanitarian settings. Routine systematic antibiotic consumption monitoring systems should be implemented in hospitals, accompanied by prescribing audits and point-prevalence surveys, to inform about the volume and appropriateness of antibiotic use and to support antimicrobial stewardship efforts in humanitarian settings.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation.SignificanceEarly management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2023;93:686-701.

We present fully abstract encodings of the call-by-name and call-by-value $\lambda$-calculus into HOcore, a minimal higher-order process calculus with no name restriction. We consider several equivalences on the $\lambda$-calculus side -- normal-form bisimilarity, applicative bisimilarity, and contextual equivalence -- that we internalize into abstract machines in order to prove full abstraction of the encodings. We also demonstrate that this technique scales to the $\lambda\mu$-calculus, i.e., a standard extension of the $\lambda$-calculus with control operators.

[This corrects the article DOI: 10.1371/journal.pone.0269385.].

[This corrects the article DOI: 10.1371/journal.pone.0262073.].

Abstract Background Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord. Methods We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section. Results We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics. Conclusions Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.

Abstract Background Seasonal flu epidemics in the European region cause high numbers of cases and deaths. Flu-associated mortality has been estimated but morbidity studies are necessary to understand the burden of disease in the population. Our objective was to estimate the excess hospital admissions in Spain of diseases associated with influenza during four epidemic influenza periods (2000 – 2004). Methods Hospital discharge registers containing pneumonia, chronic bronchitis, heart failure and flu from all public hospitals in Spain were reviewed for the years 2000 to 2004. Epidemic periods were defined by data from the Sentinel Surveillance System. Excess hospitalisations were calculated as the difference between the average number of weekly hospitalisations/100,000 in epidemic and non-epidemic periods. Flu epidemics were defined for seasons 2001/2002, 2002/2003, 2003/2004. Results A(H3N2) was the dominant circulating serotype in 2001/2002 and 2003/2004. Negligible excess hospitalisations were observed during the 2002/2003 epidemic where A(H1N1) was circulating. During 2000/2001, flu activity remained below threshold levels and therefore no epidemic period was defined. In two epidemic periods studied a delay between the peak of the influenza epidemic and the peak of hospitalisations was observed. During flu epidemics with A(H3N2), excess hospitalisations were higher in men and in persons 64 years higher than 10 per 100,000. Pneumonia accounted for 70% of all flu associated hospitalisations followed by chronic bronchitis. No excess flu-specific hospitalisations were recorded during all seasons. Conclusion Flu epidemics have an impact on hospital morbidity in Spain. Further studies that include other variables, such as temperature and humidity, are necessary and will deepen our understanding of the role of each factor during flu epidemics and their relation with morbidity.

IntroductionNoma is a rapidly spreading infection of the oral cavity which mainly affects young children. Without early treatment, it can have a high mortality rate. Simple gingivitis is a warning sign for noma, and acute necrotizing gingivitis is the first stage of noma. The epidemiology of noma is not well understood. We aimed to understand the prevalence of all stages of noma in hospitalised children.MethodsWe conducted a prospective observational study from 1st June to 24th October 2021, enrolling patients aged 0 to 12 years who were admitted to the Anka General Hospital, Zamfara, northwest Nigeria. Consenting parents/ guardians of participants were interviewed at admission. Participants had anthropometric and oral examinations at admission and discharge.FindingsOf the 2346 patients, 58 (2.5%) were diagnosed with simple gingivitis and six (n = 0.3%) with acute necrotizing gingivitis upon admission. Of those admitted to the Inpatient Therapeutic Feeding Centre (ITFC), 3.4% (n = 37, CI 2.5-4.7%) were diagnosed with simple gingivitis upon admission compared to 1.7% of those not admitted to the ITFC (n = 21, CI 1.1-2.6%) (p = 0.008). Risk factors identified for having simple gingivitis included being aged over two years (2 to 6 yrs old, odds ratio (OR) 3.4, CI 1.77-6.5; 7 to 12 yrs OR 5.0, CI 1.7-14.6; p = ConclusionOur study showed a small proportion of children admitted to the Anka General Hospital had simple or acute necrotizing gingivitis. Hospital admission with malnutrition was a risk factor for both simple and acute necrotizing gingivitis. The lack of access to and uptake of oral health care indicates a strong need for oral examinations to be included in routine health services. This provision could improve the oral status of the population and decrease the chance of patients developing noma.

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.

Although brain functionality is often remarkably robust to lesions and other insults, it may be fragile when these take place in specific locations. Previous attempts to quantify robustness and fragility sought to understand how the functional connectivity of brain networks is affected by structural changes, using either model-based predictions or empirical studies of the effects of lesions. We advance a geometric viewpoint relying on a notion of network curvature, the so-called Ollivier-Ricci curvature. This approach has been proposed to assess financial market robustness and to differentiate biological networks of cancer cells from healthy ones. Here, we apply curvature-based measures to brain structural networks to identify robust and fragile brain regions in healthy subjects. We show that curvature can also be used to track changes in brain connectivity related to age and autism spectrum disorder (ASD), and we obtain results that are in agreement with previous MRI studies.