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AbstractPurposeMaterials and MethodsResultsConclusion\nIMPLICATIONS FOR REHABILITATIONStroke research Priority Setting Partnerships identified a need for interventions that address wellbeing and communication. This paper outlines the development of a communication and wellbeing intervention for delivery in the virtual world, EVA Park, for people with aphasia called Virtual Elaborated Semantic Feature Analysis.The Medical Research Council framework for developing complex interventions was followed to combine evidence (literature review), underpinning theory (semantic processing theories, framework for situated language use and learning theories) and involvement with stakeholders (four people with aphasia and three speech and language therapists) in an intervention that addresses word finding, situated language and wellbeing.Evidence for the semantic word interventions and situated conversation interventions was synthesised. Theory underpinning the proposed intervention included Hebbian learning, the hub and spokes model of semantic processing, semantic spreading activation theory, the framework for situated language use and learning theories. Stakeholders with aphasia identified intervention content, an acceptable intervention regimen and gave feedback on a taster session. Speech therapists advised how the intervention could be implemented in clinical practice.Virtual Elaborated Semantic Feature Analysis is a user-informed, theory-based complex aphasia intervention that is expected to improve word finding, word use in situated conversation and wellbeing.When consulted on acceptable therapy regimens for an aphasia therapy in a virtual world, a lived experience advisory group preferred a distributed regimen (4 days a week over 8 weeks) over a more intense regimen (5 days a week over 6 weeks).Individual word retrieval activities and group conversation activities were equally prioritised by the lived experience advisory group.It is more challenging to retrieve a word in a conversation context, therefore word retrieval practiced in conversations was valued by the lived experienced advisory group.A simulated, supported, virtual space for communication practice, such as groups in the EVA Park virtual world, provides a social context for learning and experiencing success with limited loss of face.When consulted on acceptable therapy regimens for an aphasia therapy in a virtual world, a lived experience advisory group preferred a distributed regimen (4 days a week over 8 weeks) over a more intense regimen (5 days a week over 6 weeks).Individual word retrieval activities and group conversation activities were equally prioritised by the lived experience advisory group.It is more challenging to retrieve a word in a conversation context, therefore word retrieval practiced in conversations was valued by the lived experienced advisory group.A simulated, supported, virtual space for communication practice, such as groups in the EVA Park virtual world, provides a social context for learning and experiencing success with limited loss of face. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are widely prescribed drugs that have been associated with increased prostate cancer (PCa) cell proliferation in vitro and worse oncological outcomes in vivo. However, data on their influence on PSA levels in the general population are lacking. Methods: We extracted individual participant data from the 2001–2010 cycles of the National Health and Nutrition Examination Survey (NHANES), in which PSA levels were measured in all male participants aged 40 years or older. The association of PPI use with total PSA levels and free/total PSA ratio was evaluated through multivariable linear regression analyses, adjusted for potential confounders. Results: A total of 7366 subjects were included (median age: 53 years; median serum PSA: 0.9 ng/mL), of whom 746 were receiving PPI treatment at the time of the study. After adjustment for potential confounders, ongoing PPI use was associated with lower total PSA levels (-0.24 ng/mL, 95%CI: [-0.37,-0.11], p < 0.001), while no significant association with free/total PSA ratio was found (p = 0.881). A significant effect modification was observed according to age, with the association being limited to older participants (≥ 60 years) at stratified analyses. Conclusions: Contrary to the available data in the context of PCa, we found no evidence of increased PSA levels in PPI users with no prostate malignancy. Instead, PPI use was associated with a decrease of total PSA in older adults. This adds knowledge on how PPIs may influence PSA in population-based screening programs. [ABSTRACT FROM AUTHOR]

The minor spliceosome catalyzes excision of U12-dependent introns from precursors of eukaryotic messenger RNAs (pre-mRNAs). This process is critical for many cellular functions, but the underlying molecular mechanisms remain elusive. Here, we report a cryoelectron microscopy (cryo-EM) reconstruction of the 13-subunit human U11 small nuclear ribonucleoprotein particle (snRNP) complex in apo and substrate-bound forms, revealing the architecture of the U11 small nuclear RNA (snRNA), five minor spliceosome-specific factors, and the mechanism of the U12-type 5′ splice site (5′SS) recognition. SNRNP25 and SNRNP35 specifically recognize U11 snRNA, while PDCD7 bridges SNRNP25 and SNRNP48, located at the distal ends of the particle. SNRNP48 and ZMAT5 are positioned near the 5′ end of U11 snRNA and stabilize binding of the incoming 5′SS. Recognition of the U12-type 5′SS is achieved through base-pairing to the 5′ end of the U11 snRNA and unexpected, non-canonical base-triple interactions with the U11 snRNA stem-loop 3. Our structures provide mechanistic insights into U12-dependent intron recognition and the evolution of the splicing machinery. [Display omitted] • Cryo-EM reveals the architecture of the minor spliceosomal U11 snRNP • Unique U11 snRNA structure allows recruitment of minor spliceosome-specific factors • U11 snRNP is very distinct from the major spliceosomal U1 snRNP counterpart • U12-type 5′SS recognition involves base-pairing and non-canonical interactions Zhao et al. present two cryo-EM structures of apo and substrate-bound U11 snRNP complexes, elucidating their architecture and the mechanism of the U12-type 5′ splice site recognition. The unique structure of the U11 snRNA is incompatible with the binding of U1 snRNP-specific proteins, providing a structural basis for specific recognition. [ABSTRACT FROM AUTHOR]

Protein interactions are crucial for understanding biological functions and disease mechanisms, but predicting these remains a complex task in computational biology. Increasingly, Deep Learning models are having success in interface prediction. This study presents PIPENN-EMB which explores the added value of using embeddings from the ProtT5-XL protein language model. Our results show substantial improvement over the previously published PIPENN model for protein interaction interface prediction, reaching an MCC of 0.313 vs. 0.249, and AUROC 0.800 vs. 0.755 on the BIO_DL_TE test set. We furthermore show that these embeddings cover a broad range of 'hand-crafted' protein features in ablation studies. PIPENN-EMB reaches state-of-the-art performance on the ZK448 dataset for protein-protein interface prediction. We showcase predictions on 25 resistance-related proteins from Mycobacterium tuberculosis. Furthermore, whereas other state-of-the-art sequence-based methods perform worse for proteins that have little recognisable homology in their training data, PIPENN-EMB generalises to remote homologs, yielding stable AUROC across all three test sets with less than 30% sequence identity to the training dataset, and even to proteins with less than 15% sequence identity. [ABSTRACT FROM AUTHOR]

Transcatheter aortic valve replacement (TAVR) has rapidly displaced surgical aortic valve replacement (SAVR). However, certain post-TAVR complications persist, with cardiac conduction abnormalities (CCA) being one of the major ones. The elevated pressure exerted by the TAVR stent onto the conduction fibers situated between the aortic annulus and the His bundle, in proximity to the atrioventricular (AV) node, may disrupt the cardiac conduction leading to the emergence of CCA. In this study, an in silico framework was developed to assess the CCA risk, incorporating the effect of a dynamic beating heart and preprocedural parameters such as implantation depth and preexisting cardiac asynchrony in the new onset of post-TAVR CCA. A self-expandable TAVR device deployment was simulated inside an electromechanically coupled beating heart model in five patient scenarios, including three implantation depths and two preexisting cardiac asynchronies: (i) a right bundle branch block (RBBB) and (ii) a left bundle branch block (LBBB). Subsequently, several biomechanical parameters were analyzed to assess the post-TAVR CCA risk. The results manifested a lower cumulative contact pressure on the conduction fibers following TAVR for aortic deployment (0.018 MPa) compared to nominal condition (0.29 MPa) and ventricular deployment (0.52 MPa). Notably, the preexisting RBBB demonstrated a higher cumulative contact pressure (0.34 MPa) compared to the nominal condition and preexisting LBBB (0.25 MPa). Deeper implantation and preexisting RBBB cause higher stresses and contact pressure on the conduction fibers leading to an increased risk of post-TAVR CCA. Conversely, implantation above the MS landmark and preexisting LBBB reduces the risk. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) include two types of proteins: partial disordered regions (IDRs) and wholly disordered proteins (WDPs). Extensive studies focused on the proteins with IDRs, but less is known about WDPs because of their difficult-to-form folded tertiary structure. In this study, we developed a bioinformatics method for screening more than 50 amino acids in the genome level and found a total of 27 categories, including 56 WDPs, in Arabidopsis. After comparing with 56 randomly selected structural proteins, we found that WDPs possessed a more wide range of theoretical isoelectric point (PI), a more negative of Grand Average of Hydropathicity (GRAVY), a higher value of Instability Index (II), and lower values of Aliphatic Index (AI). In addition, by calculating the FCR (fraction of charged residue) and NCPR (net charge per residue) values of each WDP, we found 20 WDPs in R1 (FCR < 0.25 and NCPR < 0.25) group, 15 in R2 (0.25 ≤ FCR ≤ 0.35 and NCPR ≤ 0.35), 19 in R3 (FCR > 0.35 and NCPR ≤ 0.35), and two in R4 (FCR > 0.35 and NCPR > 0.35). Moreover, the gene expression and protein-protein interaction (PPI) network analysis showed that WDPs perform different biological functions. We also showed that two WDPs, SIS (Salt Induced Serine rich) and RAB18 (a dehydrin family protein), undergo the in vitro liquid-liquid phase separation (LLPS). Therefore, our results provide insight into understanding the biochemical characters and biological functions of WDPs in plants. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory condition of the esophagus characterized by eosinophilic infiltration, and hallmark symptoms of esophageal dysfunction such as dysphagia and food impaction. Over the past three decades, EoE has been recognized as a distinct clinical entity, distinguished from gastroesophageal reflux disease (GERD) through advancements in diagnostic techniques, particularly endoscopy with biopsy. The rising global prevalence of EoE reflects enhanced diagnostic awareness, evolving criteria, and environmental along with lifestyle changes. The etiology of EoE is multifactorial, involving genetic predispositions, immune dysregulation, the gut microbiome, and environmental triggers, including dietary allergens and aeroallergens. Key mechanisms include a type 2 helper T-cell (Th2)-driven immune response, epithelial barrier dysfunction, and genetic variants such as CAPN14 and TSLP. Chronic inflammation leads to tissue remodeling, fibrosis, and esophageal narrowing, contributing to disease progression and complications. Management strategies have evolved to include dietary elimination, proton pump inhibitors, topical corticosteroids, biologics, and endoscopic interventions for fibrostenotic complications. Emerging therapies targeting cytokines such as interleukin (IL)-4, IL-5, and IL-13, alongside novel diagnostic tools like the esophageal string test and Cytosponge, offer promising avenues for improved disease control and non-invasive monitoring. Long-term surveillance combining endoscopic and histological evaluations with biomarkers and non-invasive tools is critical to optimizing outcomes and preventing complications. Future research should address gaps in understanding the role of the esophageal microbiome, refine therapeutic approaches, and develop personalized strategies to improve disease management and patient quality of life. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both. In the last few years, a potential link between PPI intake and the development of headaches—especially migraine–has come to increased attention. In this review, we critically examine the scientific data concerning the co-occurrence of these two entities. Findings: There seems to be a possible link between the use of PPIs and the occurrence of headache, especially migraine, suggesting a pathophysiological connection on several levels. Moreover, PPI use is only partially without side effects, even if these may not occur immediately. Whether the relation is causative or merely co-existential is currently not yet clear. The influence of genetics, environment, gut microbiome, medication intake and evolution of headache is multidirectional. Conclusion: A relation between the prevalence of migraine and the use of PPIs on a population and personal level seems likely. Although PPIs have many advantages, they should be prescribed with caution, especially in patients who suffer from headaches and migraine. In this narrative review, we aim to critically evaluate existing data and offer a potential approach to accurately identify any connections and interactions, leading to a better understanding of how these conditions may influence each other. [ABSTRACT FROM AUTHOR]

Barley leaf stripe, a disease mainly caused by Pyrenophora graminea (P. graminea) infection, severely affects barley yield and quality and is one of the most widespread diseases in barley production. However, little is known about the underlying molecular mechanisms of leaf stripe resistance. In this study, the transcript expression profiles of normal and infected leaves of resistant Tibetan hulless barley (Hordeum vulgare L. var. nudum Hook. f.) variety Kunlun 14 and susceptible variety Z1141 were analyzed by RNA sequencing (RNA-seq). The results showed a total of 7,669 and 5,943 differentially expressed genes (DEGs) were found in resistant and susceptible Kunlun 14 and Z1141, respectively, with 8,916 DEGs found between Kunlun 14 and Z1141. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the 8,916 DEGs identified many significantly enriched categories and pathways, of which a plant–pathogen interaction pathway, containing a total of 102 genes (100 known genes and two novel genes), was found, that was very important for the study of the leaf stripe resistance mechanism. Using RNA-seq, small RNA sequencing (miRNA-seq) combined with degradome sequencing (degradome-seq), four pairs associated with leaf-stripe miRNAs and target genes were obtained, namely Hvu-miR168-5p and Argonaute1 (HvAGO1), Hvu-novel-52 and growth-regulating factor 6 (HvGRF6), Hvu-miR6195 and chemocyanin-like protein (CLP), and Hvu-miR159b and gibberellin-dependent MYB (GAMYB). Transformation of the important target gene HvAGO1 into Arabidopsis verified that HvAGO1 could against Botrytis cinerea. Then RNA-seq and miRNA-seq of Arabidopsis transformed with overexpressed of HvAGO1 were performed. Based on the above research results, we constructed a Protein-Protein Interaction (PPI) network of barley leaf stripe resistance. This study lays the foundation for the study of the barley leaf stripe resistance mechanism and provides new targets for the genetic improvement of disease-resistant barley varieties. [ABSTRACT FROM AUTHOR]

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6−/−) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6−/−) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1-TRPM6−/− mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6−/− mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6−/− and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration. [ABSTRACT FROM AUTHOR]

Introduction: Co-production involves researchers, practitioners and people with lived experience working in a collaborative manner, with shared power. The potential benefits of co-production are well documented. However, there is little research describing the experience of having been involved in co-production from the perspective of Experts By Lived Experience (EBLE). The aim of the present study is to explore the experiences of EBLE of obsessive-compulsive disorder (OCD) on their involvement in co-producing a blended intervention to prevent relapse for OCD. Methods: Five EBLE took part in semi-structured interviews enquiring about their experiences of co-producing a relapse prevention intervention. Reflexive thematic analysis was used to analyse the data. Results: Four themes were developed: (1) Welcome but unexpected therapeutic benefits; (2) The parameters of a safe space; (3) Genuine co-production brings meaningful change; and (4) Navigating the challenging terrain of co-production. Conclusions: Overall, EBLE reported their involvement in the co-production process to have had positive impacts on both the development of the intervention and their own personal recovery journey. EBLE valued the safety created within the group, and the importance this had for allowing them to speak open and honestly about their experiences and the difficulties that can arise with the nature of the work. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the role of the neurodegenerative disease gene C19orf12 in the H1299 cell line and to analyze the potential impact of its pathogenic mutant (p.Ala63Pro). Methods: The expression levels of C19orf12 in various cell lines, including Hela, A549, U2OS, and H1299, were analyzed using Reverse Transcription Quantitative PCR (RT-qPCR) and West- ern Blot. An shRNA lentiviral expression vector targeting C19orf12 was constructed, and C19orf12 was knocked down in the H1299 cell line. Data-independent acquisition (DIA) proteomics was utilized to analyze the effect of C19orf12 knockdown on the cellular protein expression profile. Differentially expressed proteins were subjected to protein-protein interaction (PPI) network analysis, and the MCODE tool was used to identify key protein interaction sub-networks. Finally, immunofluorescence and coimmunoprecipitation were performed to analyze the subcellular localization and interaction changes of the C19orf12 mutant proteins. Results: C19orf12 was expressed at relatively high levels in H1299 cells and its knockdown significantly inhibited cell growth. Proteomic analysis identified 216 significantly differentially expressed proteins, with 132 upregulated and 84 downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these differentially expressed proteins were mainly involved in pathways related to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, as well as mitochondrial oxidative phosphorylation, lipid metabolism, and heart disease-related pathways. The pathogenic mutant of C19orf12 (p.Ala63Pro) lost the ability to interact with multiple key proteins. Conclusion: C19orf12 plays a key role in cell growth, mitochondrial oxidative phosphorylation, lipid metabolism, and cardiac disease, and its mutation can lead to alterations in protein interaction networks. [ABSTRACT FROM AUTHOR]

Metallic foams have become a cutting-edge solution for many thermal management problems. These are of interest by thermal research community because of the cellular structure and have gas-filled pores inside a metal matrix. Due to the uniqueness in their structure, they exhibit good performance in boiling heat transfer because of the properties such as higher specific surface area, large number of nucleation sites, wettability characteristics, and capillary action. The boiling heat transfer over metal foam is a complex phenomenon, greatly affected by the thickness, porosity, and pores per inch (PPI) of metal foam along with the thermo-physical properties of the foam and boiling liquid. By thoroughly examining recent research investigations, the paper explains the impact of open-cell metal foams on pool boiling of different liquids such as water, refrigerants, organic liquids, and dielectric liquids. This paper reviews the complexity and various influencing factors involved in flow boiling through metal foam in tubes. It also highlights findings that show metal foam significantly enhances jet impingement boiling heat transfer. Moreover, the discussion on gradient metal foams, offering insights into their potential to enhance boiling heat transfer. The comprehensive review also encompasses numerical modeling studies, such as the lattice Boltzmann method, contributing to a deeper understanding of the intricate flow and heat transfer characteristics within channels filled with metal foam. [ABSTRACT FROM AUTHOR]

Background Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity during glioblastoma (GBM) treatment, but were recently identified as strong inducers of aldehyde dehydrogenase-1A1 (ALDH1A1). ALDH1A1 is a primary metabolic enzyme impacting the outcome of chemotherapy, including temozolomide. High expression of ALDH1A1 is associated with poor prognosis in multiple cancers, suggesting PPIs may have a negative impact on survival. Methods Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients with known IDH1/2 mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications including MGMT methylation status, age, sex, duration of corticosteroid use, extent of resection, starting standard-of-care, and PPI use. Results EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs (51%) had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 vs. 40.1 months). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI: 1.15–2.44], P  = .007). Conclusions Evidence from a nationwide cancer registry has suggested PPIs have a negative impact on OS for GBM patients, particularly those with MGMT promoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background and Aim: Helicobacter pylori infection is one of the most common bacterial infections affecting humans, causing gastroduodenal and extraintestinal diseases. Treatment of the infection remains challenging for the clinicians, and different factors are involved in the failure of the therapeutic approach. The importance of the intensity of acid secretion inhibition remains an unclear issue. The aim of this study is to assess whether 80 mg/day esomeprazole‐based 10‐day sequential therapy (esomeprazole‐ST) achieved different eradication rates when compared to 80 mg/day pantoprazole‐based analogous regimen (pantoprazole‐ST). Methods: This was a retrospective observational study where data of consecutive patients referred by their physicians to our unit to perform an upper gastrointestinal endoscopy were analyzed. Results: Overall, 1,327 patients were available for the analysis: 599 and 728 patients received pantoprazole‐ST and esomeprazole‐ST, respectively. Eradication rate was significantly higher in patients receiving esomeprazole‐ST (92.6%, 95% CI: 91–94.5) than pantoprazole‐ST (89.3%, 95% CI: 86.7–91.7; difference: 3.3%; 95% CI: 0.2–6.5; P = 0.037). Even after a multivariate analysis, the esomeprazole‐ST achieved a significantly higher eradiation (OR: 1.44; 95% CI: 1.1–2.17). Conclusions: This study showed that esomeprazole‐ST achieved significantly higher H. pylori cure rates than pantoprazole‐ST. Prospective and well‐designed trials are demander to confirm this prelaminar finding. [ABSTRACT FROM AUTHOR]

Introduction: Proton pump inhibitors (PPIs) are anti-ulcer drugs that have reportedly been used inappropriately in therapeutic settings, raising the risk of adverse effects, drug interactions, and costs. Aim: This study aimed to evto evaluate the inappropriate use of PPI medication and which category of PPIs frequently was used for patients in Bangladeshi hospitals. Material and Methods: A one month cross-sectional study was carried out in a tertiary care hospital to evaluate the kinds of PPI prescriptions, their appropriateness, and their tendency to be utilized among patients. Results: Among 298 patients interviewed,140 patients used PPIs inappropriately. The most common reasons for inappropriate use included gastric appetite (29.59%, 29 individuals) and nausea. Other reasons included (15%) no clear indication, (20%) gastric discomfort, (13.57%) asthma, and (8.57%) infections. Esomeprazole was the most prescribed PPI, used by 41% of patients, followed by omeprazole at 32%. Nearly 44% of the 140 patients exhibited a strong tendency to use PPIs. Conclusion: Important steps must be taken to ensure that PPIs are used properly, to increase knowledge, and implement educational TV programs that can reduce the risk of drug interactions, side effects, and unnecessary expenses. [ABSTRACT FROM AUTHOR]

Introduction: There are many recognised benefits of public involvement, including more relevant research. The COVID‐19 pandemic highlighted the existing health inequalities and disparities in access to care and treatment for under‐served groups, necessitating meaningful and sustainable approaches to engaging them in health research. However, there is limited guidance to suggest what groundwork and processes are necessary for initiating such projects. This paper outlines the practical approaches taken to initiate a community involvement project scheme and offers key recommendations from this work. Methods: The National Institute for Health and Care Research (NIHR) Health Protection Research Unit established a community involvement scheme in 2021, funding four community involvement projects enabling researchers to engage with under‐served communities. Reflections were captured through regular quarterly meeting group discussions, meeting notes and email correspondence. Results: The paper presents the steps taken to initiate a scheme that provided funding for a diverse range of projects working with under‐served communities. The projects demonstrated the value of allocating time to build relationships and trust, maintaining flexibility, and providing short‐term benefits such as remuneration and training to the community. Discussion: This paper has highlighted the need for research organisations to allocate funding and resources within their infrastructures for building trusting relationships with community leaders and communities. Conclusion: This paper has outlined the steps undertaken to engage with under‐served communities to bridge the gap between public health research and those communities. We present key recommendations to guide future initiatives aspiring to engage under‐served communities in health research. Patient or Public Contribution: Public contributors have been involved in all of the four community involvement projects mentioned in this paper. Two public contributors are also co‐authors and have provided input to the writing and review of this manuscript. [ABSTRACT FROM AUTHOR]

Objective: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease. The budesonide orodispersible tablet (BOT) is recommended as second-line treatment according to the Danish guideline. This study aimed to compare potential treatment disparities before BOT initiation, follow-up practices, clinico-histologic remission rates during BOT treatment, and adherence to the national guideline between the highly specialized EoE-Cph cohort and the population-based DanEoE cohort. Material and methods: This cohort study compared 65 adult patients from the EoE-Cph cohort with 65 patients from the DanEoE cohort. All patients were diagnosed between 2015-2021. The diagnosis of EoE was defined according to the AGREE consensus. Data were extracted manually from medical records and registries. Results: In the EoE-Cph cohort, 88% were prescribed proton pump inhibitors (PPIs) before started on BOT compared to 100% in the DanEoE cohort (p = 0.0035). Symptomatic follow-up occurred in 89% of EoE-Cph patients compared to 97% of DanEoE patients after BOT treatment (p = 0.0841). No difference was found between patients who underwent histologic follow-up after topical steroid treatment (83% versus 82%, p = 0.8162). Complete clinico-histologic remission was frequently observed, and no significant difference was observed between the two cohorts (67% versus 80%, p =0.1789). One out of four patients had conflicting symptomatic and histological responses. Conclusions: This study did not provide conclusive evidence favoring the treatment of EoE patients exclusively at highly specialized EoE centers. However, the authors acknowledge that further evidence is necessary before considering changes in clinical practice. Conflicting treatment responses, and discontinuation of treatment due to side effects remains a notable concern. [ABSTRACT FROM AUTHOR]

Background: Self‐harm and suicide related behaviours are increasing in young people, and clinical support is not adequately meeting needs. Improved approaches to assessment and the clinical management of self‐harm will result from codesign processes and include greater shared decision‐making between young people and practitioners. The CaTS‐App (an adapted digital version of the existing Card‐Sort Task for Self‐harm research tool) aims to facilitate a collaborative understanding of adolescent self‐harm and support decision‐making within clinical settings. The codevelopment of a digital, clinical tool which meets the needs of multiple stakeholders requires careful consideration. Methods: We present a case‐study describing the participatory aspects of the development of the CaTS‐App, which included comprehensive patient involvement, research activities and coproduction with diverse young people aged 17–24 with lived experience of self‐harm. We share our processes and activities to deliver safe, engaging, sustainable, ethical and responsible participatory practice and co‐created knowledge, in the codevelopment of the CaTS‐App. Results: Activities spanned a 48‐month period in both face‐to‐face and online settings. Example processes and activities are provided in narrative, tabular and diagrammatic form, alongside discussion of the rationale for choices made. A summary methodology is also shared to stimulate continued discussion and development of participatory approaches in digital mental health. Conclusions: The paper contributes important insight and practical detail for the delivery of genuine participatory processes in digital mental health development when working with a population who may be considered vulnerable. [ABSTRACT FROM AUTHOR]

Involving young people with lived experience in youth mental health research is important. In recognition of the value of collaborating with experts by experience, international funders are increasingly mandating that mental health research is developed by teams that include individuals from the population of study. Yet, research into how Patient Public Involvement, specifically co‐production and co‐design, is implemented in youth mental health research is limited to date. The current review examined this question and identified common practices for collaborating with experts by experience in young people's mental health research. Academic databases were systematically searched for studies that had involved young people in mental health research, had described these activities, and had reported some demographic information about the experts by experience. From a total of 2130 studies that were screened, 37 studies were eligible for inclusion. The use of co‐production and co‐design spanned a wide range of topics, including interventions, digital support tools and psychometric studies. Interactive workshops were the primary method of engaging experts by experience, although some studies utilised interviews or focus groups. From the reviewed studies we identified common methodological practices including: Scene setting, utilising a cyclical process, ensuring appropriate engagement and recognition of the cultural context. We draw on these findings to suggest common methods for conducting co‐production and co‐design activities, and emphasise the importance of ensuring experts by experience are respected and safeguarded throughout their collaboration in research. We also outline areas that deserve future attention and development, and include a response from two young people aged 16–18 and their suggestions for improving and extending co‐production methods. [ABSTRACT FROM AUTHOR]

Background: Participant and Public Involvement in youth mental health research aims at making research more responsive to the needs of youth struggling with mental health issues, their parents, and mental health professionals and other stakeholders. Do characteristics of Patient and Public Involvement (PPI) in youth mental health research align with transparency and replication prerequisites as necessary conditions for translation? Relatedly, the question is addressed whether co‐authorship should be assigned to youth involved in the study. Methods: Here we address these questions re‐visiting 50 PPI studies included in two recent systematic reviews of PPI on characteristics that are pertinent to questions about transparency, replicability, translatability, and co‐authorship in PPI research. Results: Almost two‐third of the studies on youth mental health incorporating PPI translate their results to policy or practice, mostly as recommendations but sometimes also by dissemination of (online) interventions. At the same time the authors of a substantial majority of the studies (70%) also suggest the need for further work on their results, for example, in randomized controlled trials to validate the outcome of their exploratory inquiry. Only a quarter of the studies using PPI met the conditions for replicability, thus a majority of the PPI studies suggest premature translation of results. Authorship to involved participants was assigned in 24% of the studies. Conclusions: "Anything goes" for PPI in an exploratory stage to generate fruitful hypotheses. Translation of the findings of PPI studies however require a firm evidence base of replicated results. Radical merging of research and action in participatory action research seems incompatible with replicable and therefore translatable inquiry. Assigning co‐authorship to PPI representatives is often at odds with current guidelines for authorship. More evidence from randomized trials on the translational impact of PPI is needed before grant foundations should require PPI in grant proposals. [ABSTRACT FROM AUTHOR]

Gastroparesis (Gp) patients often have gastroesophageal reflux disease (GERD). Management of GERD in Gp patients is a challenge. Many studies have shown that gastric peroral endoscopic pyloromyotomy (G-POEM or POP) is moderately effective in reducing nausea and vomiting in patients with Gp. This study aims to determine whether G-POEM can improve GERD in Gp Patients. Patients who underwent G-POEM from July 2021 to October 2022 were enrolled in the study. GERD Health-Related Quality of Life (GERD HRQL) and Reflux Symptom Index (RSI) were used to assess patients' GERD before and after G-POEM. The use of proton pump inhibitors (PPIs) before and after G-POEM were also documented. The Gastroparesis Cardinal Symptom Index (GCSI) was used to assess the severity of Gp before and after G-POEM. A 'Welch two-sample t -test' was used to find differences in GERD HRQL (health-related quality of life) and RSI scores before and after the procedure. Pearson's chi-square test was used to find differences for use of PPI before and after G-POEM. Twenty-three consecutive refractory Gp patients with 30% male (average age 63.2) and 70% female patients (average age 53.9) were enrolled. Of these, 14 had diabetes, 3 had a history of surgery, and 6 had idiopathic Gp. The mean follow-up was 41 days (range 7–61 days). There was a significant decrease in the mean GERD HRQL score from 16.5 to 6.5 after G POEM with a P -value <0.0001 (95% level of significance) and a significant decrease in mean RSI score from 15.3 to 5.2 after G-POEM with P -value <0.0001 (95% level of significance). The proportion of use of PPI before GPOEM was 0.91, and the proportion of PPI use after GPOEM was 0.43 (P  = 0.0008). The mean GCSI pre- and post-GPOEM were 3.53 and 1.59, respectively. Eighteen had clinical success in Gp as defined by decreased mean GCSI score greater than 1. In this short-term outcome study, 87% of patients' GERD HRQL scores and RSI scores decreased after G-POEM. These findings indicate that GPOEM not only effectively reduces Gp symptoms but also improves GERD symptoms leading to decreased or more effective use of PPI in these patients. To our knowledge, this is the first study to comprehensively show G-POEM significantly improves GERD. Further studies with a larger patient population and long-term outcomes are needed. [ABSTRACT FROM AUTHOR]

Deficits in positive emotion regulation skills may be an important factor in the development and maintenance of anxiety and mood disorders. A treatment, which includes strategies to build and strengthen positive emotion regulation skills has been provided to patients primarily diagnosed with an anxiety and or mood disorder in an adult mental health outpatient service setting. To study the effects on positive and negative emotion, emotion regulation skills, emotional disorder symptoms, quality of life, and wellbeing during a new developed treatment. An exploratory clinical trial was used to conduct a preliminary assessment of a novel intervention. The intervention was provided in a group format over a 6-week period and independent practice over an 8-week period. Outcome variables were assessed pre- and post-treatment and at a 2-month follow up. Life quality, subjective wellbeing ratings, depressive and anxiety symptoms improved at follow up. The data suggests that the intervention may have the potential to produce desired change in positive emotion regulation. Preliminary findings suggest the intervention can have beneficial effects. These findings are promising and support the possibility that disturbances in positive emotion regulation may be a generative target for treatment research. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) disorders range from intermittent heartburn to life-threatening GI hemorrhage. One of the most common GI disorders is gastroesophageal reflux disease (GERD), which affects an estimated 19% of adults in North America. This article discusses the advantages and disadvantages of acidsuppressive therapy for patients with GERD as well as relevant nursing considerations. [ABSTRACT FROM AUTHOR]

Cold ecosystems are experiencing a warming rate that is twice as fast as the global average and are particularly vulnerable to the consequences of climate change. In mountain ecosystems, it is particularly important to monitor vegetation to understand ecosystem dynamics, biodiversity conservation, and the resilience of these fragile ecosystems to global change. Hence, we used satellite data acquired by Sentinel-2 to perform a comparative assessment of the Normalized Difference Vegetation Index (NDVI) and the Plant Phenology Index (PPI) in mountainous regions (canton of Valais-Switzerland in the European Alps) for monitoring vegetation dynamics of four types: deciduous trees, coniferous trees, grasslands, and shrublands. Results indicate that the NDVI is particularly noisy in the seasonal cycle at the beginning/end of the snow season and for coniferous trees, which is consistent with its known snow sensitivity issue and difficulties in retrieving signal variation in dense and evergreen vegetation. The PPI seems to deal with these problems but tends to overestimate peak values, which could be attributed to its logarithmic formula and derived high sensitivity to variations in near-infrared (NIR) and red reflectance during the peak growing season. Concerning seasonal parameters retrieval, we find close concordance in the results for the start of season (SOS) and end of season (EOS) between indices, except for coniferous trees. Peak of season (POS) results exhibit important differences between the indices. Our findings suggest that PPI is a robust remote sensed index for vegetation monitoring in seasonal snow-covered and complex mountain environments. [ABSTRACT FROM AUTHOR]

Background: Concerns have been raised regarding proton pump inhibitor (PPI) use and risk of severe coronavirus disease 2019 (COVID‐19). Observational studies have yielded heterogeneous results and were subject to important methodological limitations. Aims: To examine the association between the receipt of PPIs and risk of COVID‐19 hospitalizations and severe in‐hospital outcomes or death. Methods: Case–control study among Medicare fee‐for‐service beneficiaries 66+ years old with gastroesophageal reflux disorder (GERD). Within this population, we identified cases by an incident hospital discharge diagnosis of COVID‐19 from April 1 to December 11, 2020, using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) U07.1, and randomly selected up to 10 controls per case, matched on date and neighborhood. We defined PPI use as a prescription providing ≥15 days of supply in the 30 days before admission, with H2‐receptor antagonist (H2RA) use as the reference to account for indication. We analyzed uncomplicated hospitalizations and hospitalizations with severe outcomes (intensive/coronary care unit admission, invasive mechanical ventilation, or death), estimating odds ratios (ORs), and 95% confidence intervals (CIs) with multinomial conditional logistic regression adjusted for demographics, comorbidities, chronic medications, and health care utilization. Results: We matched 25,867 uncomplicated and 12,954 severe hospitalized COVID‐19 cases to 146,972 and 73,104 controls, respectively. Cases tended to be older and have more comorbidities. Relative to H2RA use, we found no association of PPI use with uncomplicated COVID‐19 hospitalization (OR 0.99, 95% CI 0.93–1.06) or severe COVID‐19 hospitalization (OR 1.00, 95% CI 0.91–1.10). Conclusions: Relative to H2RA use, PPI use was not associated with uncomplicated or severe COVID‐19 hospitalizations among Medicare beneficiaries with GERD. [ABSTRACT FROM AUTHOR]

AbstractIntroductionMaterial and MethodsResults and discussionConclusion\nIMPLICATION FOR REHABILITATIONMost people with a spinal cord injury are concerned by pressure injuries (PrI). Since dynamic activities may involve distributions of forces over time that are different from static and given the significant impact of PrIs on healthcare costs, it is, important to study these sitting forces. We aim to investigate sitting forces (overall normal, shear forces and Peak Pressure Index (PPI)) assessed in both able-bodied and wheelchair users (WCU) under static and dynamic conditions. Our hypothesis is that wheelchair sitting forces encountered by able-bodied participants are significantly different from those of WCUs.An experimental seat and a pressure mapping system were used to investigate forces in two different populations, 102 able-bodied and 15 WCUs, in static conditions and during synchronised hand-cycling. The analysis includes statistical comparisons of the sitting conditions (static/dynamic) and of the populations (able-bodied/WCUs).Significant differences in normal forces and PPI were observed between able-bodied and WCUs; conversely, differences in shear forces were non-significant. This suggests that contrary to shear forces, no conclusion on normal forces drawn from trials with healthy participants can directly be applied to WCUs. Secondly, the present results indicate significant reduced averaged: normal force, PPI, and shear forces for able-bodied performing a dynamic activity compared to static sitting. WCUs experienced non-significant lower averaged normal force and PPI but significant lower averaged shear forces.While the present results seem to indicate lower forces for able-bodied performing a dynamic activity compared to static sitting, due to reduced averaged forces, this conclusion is less clear-cut for WCUs.The present observational study can help understand the specific characteristics of wheelchair users concerning the biomechanical sitting load in rest and during propulsive activity: the shear forces are reduced during activity compared to static conditions.From the data collected in the present study, it seems that no conclusion on normal sitting forces drawn from trials with healthy participants can directly be applied to wheelchair users.The present observational study can help understand the specific characteristics of wheelchair users concerning the biomechanical sitting load in rest and during propulsive activity: the shear forces are reduced during activity compared to static conditions.From the data collected in the present study, it seems that no conclusion on normal sitting forces drawn from trials with healthy participants can directly be applied to wheelchair users. [ABSTRACT FROM AUTHOR]

Background: There has been a growing push to involve patients in clinical research, shifting from conducting research on, about, or for them to conducting it with them. Two arguments advocate for this approach, known as Patient and Public Involvement (PPI): to improve research quality, appropriateness, relevance, and credibility by including patients' diverse perspectives, and to use PPI to empower patients and democratize research for more equity in research and healthcare. However, while empowerment is a core objective, it is often not clear what is meant by empowerment in the context of PPI in clinical research. This vacancy can lead to insecurities for both patients and researchers and a disconnect between the rhetoric of empowerment in PPI and the reality of its practice in clinical trials. Thus, clarifying the understanding of empowerment within PPI in clinical research is essential to ensure that involvement does not become tokenistic and depletes patients' capacity to advocate for their rights and needs. Methods: We explored the historical roots of empowerment, primarily emerging from mid-20th century social movements like feminism and civil rights and reflected the conceptual roots of empowerment from diverse fields to better understand the (potential) role of empowerment in PPI in clinical research including its possibilities and limitations. Results: Common themes of empowerment in PPI and other fields are participation, challenging power structures, valuing diverse perspectives, and promoting collaboration. On the other hand, themes such as contextual differences in the empowerment objectives, the relationship between empowerment and scientific demands, research expertise, and power asymmetries mark a clear distinction from empowerment in other fields. Conclusion: PPI offers potential for patient empowerment in clinical trials, even when its primary goal may be research quality. Elements like participation, sharing opinions, and active engagement can contribute to patient empowerment. Nonetheless, some expectations tied to empowerment might not be met within the constraints of clinical research. To empower patients, stakeholders must be explicit about what empowerment means in their research, engage in transparent communication about its realistic scope, and continuously reflect on how empowerment can be fostered and sustained within the research process. [ABSTRACT FROM AUTHOR]

15th Anniversary this year: the ECN workshop is set up in Paris, down town. Every year ECN workshop offers a unique opportunity for clinicians and researchers interested in crystals, inflammation, crystal-induced diseases including gout, to present their latest results and discuss novel concepts. Twenty nine out of 52 accepted abstracts are reported here. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are produced during cellular metabolism and in response to environmental stress. While low levels of ROS play essential physiological roles, excess ROS can damage cellular components, leading to cell death or transformation. ROS can also regulate protein interactions in cancer cells, thereby affecting processes such as cell growth, migration, and angiogenesis. Dysregulated interactions occur via various mechanisms, including amino acid modifications, conformational changes, and alterations in complex stability. Understanding ROS-mediated changes in protein interactions is crucial for targeted cancer therapies. In this review, we examine the role that ROS mechanisms in regulating pathways through protein–protein interactions. [ABSTRACT FROM AUTHOR]

The Ebola virus poses a severe public health threat, yet understanding factors influencing disease outcomes remains incomplete. Our study aimed to identify critical pathways and hub genes associated with fatal and survivor Ebola disease outcomes. We analyzed differentially expressed hub genes (DEGs) between groups with fatal and survival outcomes, as well as a healthy control group. We conducted additional analysis to determine the functions and pathways associated with these DEGs. We found 13,198 DEGs in the fatal and 12,039 DEGs in the survival group compared to healthy controls, and 1873 DEGs in the acute fatal and survivor groups comparison. Upregulated DEGs in the comparison between the acute fatal and survivor groups were linked to ECM receptor interaction, complement and coagulation cascades, and PI3K‐Akt signaling. Upregulated hub genes identified from the acute fatal and survivor comparison (FGB, C1QA, SERPINF2, PLAT, C9, SERPINE1, F3, VWF) were enriched in complement and coagulation cascades; the downregulated hub genes (IL1B, 1L17RE, XCL1, CXCL6, CCL4, CD8A, CD8B, CD3D) were associated with immune cell processes. Hub genes CCL2 and F2 were unique to fatal outcomes, while CXCL1, HIST1H4F, and IL1A were upregulated hub genes unique to survival outcomes compared to healthy controls. Our results demonstrate for the first time the association of EVD outcomes to specific hub genes and their associated pathways and biological processes. The identified hub genes and pathways could help better elucidate Ebola disease pathogenesis and contribute to the development of targeted interventions and personalized treatment for distinct EVD outcomes. [ABSTRACT FROM AUTHOR]

Background: Precise implantation could play a crucial role in the technical success of transcatheter aortic valve replacement (TAVR) for some prostheses. The impact of an accidental implantation depth (ID) outside the recommended range has not been assessed for the ACURATE neo2 (NEO2). Methods: Data from 1839 patients with severe native aortic stenosis treated with the NEO2 prosthesis were evaluated. We compared the results of prostheses implanted in an ID both inside and outside the recommendations. The outcome assessment followed the Valve Academic Research Consortium-3 criteria. Results: Patients were retrospectively divided into high (<3 mm; n = 412), optimal (3–7 mm; n = 1236), and low (>7 mm; n = 169) implantations. Technical success (94.7% vs. 94.7% vs. 91.7%, p = 0.296) and device success were high (90.1% vs. 89.3% vs. 84.6%, p = 0.112) without differences between groups. Rates of relevant paravalvular regurgitation (PVL; >mild or VinV due to PVL) were comparable (1.2% vs. 1.8% vs. 1.2%, p = 0.759). Even when hemodynamics were superior in the high-implantation group, with greater iEOA (1.01 cm2/m2 vs. 0.95 cm2/m2 vs. 0.92 cm2/m2, p < 0.001), spontaneous embolization or after post-dilatation was more common. Low implantation was associated with a higher rate of associated pacemaker implantation (PPI) (6.1% vs. 8.8% vs. 14.8%, p = 0.001). Conclusions: Implantation with the ACURATE neo2 showed excellent hemodynamic results, including low gradients and a small number of relevant PVL, in line with a high technical success rate that was irrespective of the ID. A favorable outcome can also be achieved in accidental low or high positions. Low implantation was associated with a higher rate of associated pacemaker implantation. Deliberately high implantation should be avoided due to the risk of embolization. [ABSTRACT FROM AUTHOR]

There is a lack of effective treatment options for diabetic refractory wounds, which presents a critical clinical issue that needs to be addressed urgently. Our research has demonstrated that human placenta‐derived mesenchymal stem cells (plaMSCs) facilitate the migration and proliferation of HaCat cells, thereby enhancing diabetic wound healing primarily via the exosomes derived from plaMSCs (plaMSCs‐Ex). Using label‐free proteomics, plaMSCs and their exosomes were analysed for proteome taxonomic content in order to explore the underlying effective components mechanism of plaMSCs‐Ex in diabetic wound healing. Differentially expressed proteins enriched in plaMSCs‐Ex were identified and underwent bioinformatics analysis including GO annotation, KEGG pathway enrichment, gene set enrichment analysis (GSEA) and protein–protein interaction analysis (PPI). Results showed that the proteins enriched in plaMSCs‐Ex are significantly involved in extracellular matrix organisation, epithelium morphogenesis, cell growth, adhesion, proliferation and angiogenesis. PPI analysis filtered 2 wound healing‐related clusters characterised by hub proteins such as POSTN, FN1, SPARC, TIMP1, SERPINE1, LRP1 and multiple collagens. In brief, the exosomal proteins derived from plaMSCs reveal diverse functions of regeneration and tissue remodelling based on proteomics analysis and potentially play a role in diabetic wound healing. [ABSTRACT FROM AUTHOR]

Proline is a unique amino acid in that its side-chain is cyclised to the backbone, thus giving proline an exceptional rigidity and a considerably restricted conformational space. Polyproline forms two well-characterized helical structures: a left-handed polyproline helix (PPII) and a right-handed polyproline helix (PPI). Usually, sequences made only of prolyl residues are in PPII conformation, but even sequences not rich in proline but which are rich in glycine, lysine, glutamate, or aspartate have also a tendency to form PPII helices. Currently, the only way to study unambiguously PPII structure in solution is to use spectroscopies based on optical activity such as circular dichroism, vibrational circular dichroism and Raman optical activity. The importance of the PPII structure is emphasized by its ubiquitous presence in different organisms from yeast to human beings where proline-rich motifs and their binding domains are believed to be involved in vital biological processes. Some of the domains that are bound by proline-rich motifs include SH3 domains, WW domains, GYF domains and UEV domains, etc. The PPII structure has been demonstrated to be essential to biological activities such as signal transduction, transcription, cell motility, and immune response. [ABSTRACT FROM AUTHOR]

Introduction: Over the past few decades, proton pump inhibitors (PPIs) have been used more often; nonetheless, there are concern regarding misuse and the severe adverse effects that have been described. Methods: This paper will present information from relevant professional/scientific sources including Scopus, EBSCO, PubMed regarding unwanted adverse events of PPIs. Topic: The causality of correlations between PPI usage and possible adverse effects is unknown. Increased risk of kidney, liver, and cardiovascular disease; dementia; gastrointestinal tract enteroendocrine tumors; susceptibility to respiratory and gastrointestinal infections; and reduced nutritional absorption are just a few of the long-term adverse effects of widespread use of PPI that have come to light. Thus, given growing concerns regarding PPI overuse in the general population, the purpose of this investigation is to review the relationship between PPI usage and the risk of major side consequences. Conclusion: Due to the numerous known side effects of PPIs on the system, further study is necessary, including changing the drug’s molecular structure and creating a new medication from its parent. By administering these drugs effectively for the relevant diagnosis, reevaluating patients’ symptoms on a regular basis to determine the least amount and duration of therapy, and closely monitoring any potential side effects, it is feasible to minimize expenditures with health risk and maximize beneficial outcomes. [ABSTRACT FROM AUTHOR]

Introduction: There have been some concerns about the impact of temporary doctors, otherwise known as locums, on patient safety and the quality of care. Despite these concerns, research has paid little attention to the implications of locum working on patient experience. Methods: A qualitative semi‐structured interview study was conducted with 130 participants including locums, people working with locums and patients with experience of being seen or treated by locums. Analysis was conducted using a reflexive thematic approach and abductive analysis to position themes against wider knowledge. Results: Three main themes were constructed through analysis: (1) Awareness and disclosure; patients were not always aware if their doctor was a locum, and there was some debate about whether patients had a right to know, particularly if locum working presented quality and safety risks. (2) Continuity and accessibility of care; access was regarded as priority for acute conditions, but for long‐term or serious conditions, patients preferred to see a permanent doctor who knew their history, although it was acknowledged that locums could provide fresh perspectives. (3) Communication and practice; locums and patients described how consultations were approached differently when doctors worked as locums. Patients evaluated their interactions based on how safe they felt with practitioners. Conclusion: Patients reported that they were unlikely to have continuity of care with any doctors delivering care, regardless of their contractual status. Locums sometimes provided new perspectives on care which could be beneficial for patient outcomes, but for patients with long‐term, complex or serious conditions continuity of care was important, and these patients may avoid or delay seeking care when locums are the only available option. Patient or Public Contribution: Patients and carers were involved in our study from inception to dissemination. Our Patient and Public Involvement (PPI) forum was involved throughout project design and planning and gave us feedback and guidance on research materials and outputs (e.g., study protocol, participant information sheets, survey tools, interview schedules, emerging findings). Our PPI forum co‐produced our patient interview schedule, two members of our PPI forum led the patient focus groups and all were involved in analysis of patient interviews. Our PPI Chair was involved in the preparation of this manuscript. [ABSTRACT FROM AUTHOR]

Background: Working together and co‐production with public advisors have become popular among health researchers. This practice extends to doctoral researchers who involve public advisors at different stages of their research or throughout their doctoral journey. Objective: A doctoral researcher and two public advisors jointly evaluated public involvement in doctoral research. Methods: Using the established public involvement evaluation framework by Gibson and colleagues, public advisors and a doctoral researcher mapped and evaluated their experiences of public involvement in doctoral research. The four‐dimensional framework allowed the authors to reflect on (1) the strength of the public voice, (2) the number of ways in which public advisors had an opportunity to get involved, (3) whether the discussion was about the public or organisation's (doctoral researcher, university or funder) concerns and (4) if the organisation changed or resisted feedback. Results are presented in a diagrammatic and narrative way. Results: Public advisors saw themselves as having a stronger voice in doctoral research than the doctoral researcher perceived. All agreed that there existed multiple ways for public advisors to be involved. Public advisors' feedback was taken on board, but it was also limited due to restrictions of what the doctoral programme allowed. Conclusion: Public advisors ensured that the doctoral research was more relevant to the public. The ongoing involvement also shaped the doctoral researcher's thinking and views. Patient and Public Involvement: Two public advisors were involved throughout the 3 years of this doctoral research. They co‐evaluated this involvement and are co‐authors of this paper. [ABSTRACT FROM AUTHOR]

• Wakefulness fluctuations and centro-temporal spikes (CTS) density are anticorrelated if drowsiness is followed by proper sleep. • Wakefulness oscillations influence the fMRI-based connectivity between CTS generators and the left frontal operculum. • Wakefulness fluctuations modulate the neuronal activity of key regions of the language circuitry in SeLECTS patients. Drowsiness has been implicated in the modulation of centro-temporal spikes (CTS) in Self-limited epilepsy with Centro-Temporal Spikes (SeLECTS). Here, we explore this relationship and whether fluctuations in wakefulness influence the brain networks involved in CTS generation. Functional MRI (fMRI) and electroencephalography (EEG) was simultaneously acquired in 25 SeLECTS. A multispectral EEG index quantified drowsiness ('EWI': EEG Wakefulness Index). EEG (Pearson Correlation, Cross Correlation, Trend Estimation, Granger Causality) and fMRI (PPI: psychophysiological interactions) analytic approaches were adopted to explore respectively: (a) the relationship between EWI and changes in CTS frequency and (b) the functional connectivity of the networks involved in CTS generation and wakefulness oscillations. EEG analyses were repeated on a sample of routine EEG from the same patient's cohort. No correlation was found between EWI fluctuations and CTS density during the EEG-fMRI recordings, while they showed an anticorrelated trend when drowsiness was followed by proper sleep in routine EEG traces. According to PPI findings, EWI fluctuations modulate the connectivity between the brain networks engaged by CTS and the left frontal operculum. While CTS frequency per se seems unrelated to drowsiness, wakefulness oscillations modulate the connectivity between CTS generators and key regions of the language circuitry, a cognitive function often impaired in SeLECTS. This work advances our understanding of (a) interaction between CTS occurrence and vigilance fluctuations and (b) possible mechanisms responsible for language disruption in SeLECTS. [ABSTRACT FROM AUTHOR]

Background: In the absence of Helicobacter pylori (HP) infection, a characteristic gastric mucus adhesion may appear during the use of vonoprazan. We named this novel characteristic mucus "web-like mucus" (WLM). This study aimed to determine the incidence and risk factors for WLM. Methods: Between January 2017 and January 2022, 5665 patients were enrolled in this study. The patients were divided into a proton-pump inhibitor (PPI)-prescribed group (n = 2000), a vonoprazan-prescribed group (n = 268), and a no-PPI/vonoprazan-prescribed (n = 3397) group, and the presence of WLM was examined. After excluding four patients with autoimmune gastritis, the remaining 264 patients in the vonoprazan group were divided into WLM and non-WLM groups, and their clinical features were analyzed. Results: A total of 55 (21%) patients had WLM, all in the vonoprazan-prescribed group. There were no significant differences in factors such as, sex, age, chronic kidney disease, diabetes mellitus, HP eradication history, smoking, or alcohol consumption between the WLM and non-WLM groups. The median duration from the start of vonoprazan administration to the endoscopic detection of WLM was 2 (1–24) months. Conclusions: WLM appears to be a characteristic feature in patients treated with vonoprazan. [ABSTRACT FROM AUTHOR]

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger–Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency. [ABSTRACT FROM AUTHOR]

One of the most significant diseases in the swine business, porcine reproductive and respiratory syndrome virus (PRRSV) causes respiratory problems in piglets and reproductive failure in sows. The PRRSV nucleocapsid (N) protein is essential for the virus' assembly, replication, and immune evasion. Stages in the viral replication cycle can be impacted by interactions between the PRRSV nucleocapsid protein and the host protein components. Therefore, it is of great significance to explore the interaction between the PRRSV nucleocapsid protein and the host. Nevertheless, no information has been published on the network of interactions between the nucleocapsid protein and the host proteins in primary porcine alveolar macrophages (PAMs). In this study, 349 host proteins interacting with nucleocapsid protein were screened in the PRRSV-infected PAMs through a liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based proteomics approach. Bioinformatics analysis, which included gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes database enrichment, and a protein–protein interaction (PPI) network, revealed that the host proteins interacting with PRRSV-N may be involved in protein binding, DNA transcription, metabolism, and innate immune responses. This study confirmed the interaction between the nucleocapsid protein and the natural immune-related proteins. Ultimately, our findings suggest that the nucleocapsid protein plays a pivotal role in facilitating immune evasion during a PRRSV infection. This study contributes to enhancing our understanding of the role played by the nucleocapsid protein in viral pathogenesis and virus–host interaction, thereby offering novel insights for the prevention and control of PRRS as well as the development of vaccines. [ABSTRACT FROM AUTHOR]

Background: Most patients undergoing anti-reflux surgery (ARS) have a history of preoperative proton pump inhibitor (PPI) use. It is well-established that ARS is effective in restoring the anti-reflux barrier, eliminating the ongoing need for costly PPIs. Current literature lacks objective evidence supporting an optimal postoperative PPI cessation or weaning strategy, leading to wide practice variations. We sought to objectively gauge current practice and opinion surrounding the postoperative management of PPIs among expert foregut surgeons and gastroenterologists in the United States. Methods: We created a survey of postoperative PPI management protocols, with an emphasis on discontinuation and timing of PPI cessation, and aimed to determine what factors played a role in the decision-making. An electronic survey tool (Qualtrics XM, Qualtrics, Provo, UT) was used to distribute the survey and to record the responses anonymously for a period of three months. Results: The survey was viewed 2658 times by 373 institutions and shared with 644 members. In total, 121 respondents participated in the survey and 111 were surgeons (92%). Fifty respondents (42%) always discontinue PPIs immediately after ARS. Of the remaining 70 respondents (58%), 46% always wean or taper PPIs postoperatively and 47% wean or taper them selectively. The majority (92%) of practitioners taper within a 3-month period postoperatively. Five respondents never discontinue PPIs after ARS. Overall, only 23 respondents (19%) stated their protocol is based on medical literature or evidence-based medicine. Instead, decision-making is primarily based on anecdotal evidence/personal preference (42%, n = 50) or prior training/mentors (39%, n = 47). Conclusions: There are two major protocols used for PPI discontinuation after ARS: Nearly half of providers abruptly stop PPIs, while just over half gradually tapers them, most often in the early postoperative period. These decisions are primarily driven by institutional practices and personal preferences, underscoring the need for evidence-based recommendations. [ABSTRACT FROM AUTHOR]

The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014–2023) focusing on molecular glues (MGs)—monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action. [Display omitted] Konstantinidou and Arkin review a decade of the evolution of molecular glues—molecules that modulate protein-protein interactions by inducing proximity. The authors emphasize key features of molecular recognition and cooperative binding, providing insights toward systematic discovery and optimization. Detailed examples highlight the diverse opportunities for molecular glues in drug discovery. [ABSTRACT FROM AUTHOR]

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein–protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE. [ABSTRACT FROM AUTHOR]

Background: Despite several decades of treatment research for anorexia nervosa (AN), many of the same questions remain: how to boost enrollment, engage participants, prevent attrition, and meet the needs of a diverse patient population within the rigorous framework of a randomized controlled trial (RCT). Methods: In this research forum, we highlight some of the challenges and opportunities observed over the course of TRIANGLE, the largest RCT for severe AN treatment in the UK to date. We discuss strategies for addressing common challenges and avoiding common pitfalls and propose solutions to future researchers seeking to conduct treatment research in AN. Results: Our experience underscores the value of involving people with lived experience at every stage of intervention research. We offer additional recommendations for treatment researchers, including, (1) early qualitative research to identify patient barriers and obstacles, (2) clear, systematic collaboration with clinical sites for patient recruitment and passive data collection, (3) careful consideration of assessment metrics, including repeated measurement of quality of life, (4) adopting a flexible, patient‐centered approach to clinical trial research, and (5) considering the unique needs and obstacles that might impact carer participation in research and their ability to provide support to their loved ones. Discussion: We hope that these lessons learned will prove fruitful for the next generation of researchers embarking on treatment research for AN. Public Significance: Using the TRIANGLE trial as an illustrative case study, we highlight the value of lived experience and codesign for developing and testing interventions for AN. We offer several lessons learned over the course of the trial, pertaining to trial enrollment, retention and engagement, measurement of outcomes, and research adaptations for real‐world settings, and hope that these recommendations facilitate future treatment research for AN. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of potassium-competitive acid blockers (P-CABs) in the eradication of Helicobacter pylori (Hp) remains controversial when compared with proton pump inhibitors (PPIs). Objectives: The current study set out to compare the differences in the eradication rate and adverse reactions between eradication regimens based on P-CAB or PPI drugs and the differences between the vonoprazan-based and the tegoprazan-based regimens to explore the efficacy and safety of different Hp eradication regimens. Data sources and methods: Databases including PubMed, EMBASE, Cochrane Library, and WOS were searched from the inception of these databases up to July 2023, and eligible randomized controlled trials (RCTs) were included. The outcome measures were the eradication rate and the incidence of adverse reactions of different regimens in treating Hp. The results were estimated as relative risk (RR) and its 95% confidence interval (CI), and R 4.2.1 software was used to perform the network meta-analysis (NMA). Results: A total of 20 studies were included in the analysis, involving 5815 patients with Hp. In terms of eradication rate, the 2-week vonoprazan-based triple regimen (V-Tri-2w) was the best, which was superior to the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 0.9, 95% CI: (0.85–0.95)] and the 1-week tegoprazan-based triple regimen [T-Tri-1w, RR = 0.79, 95% CI: (0.64–0.97)]; the 2-week tegoprazan-based quadruple regimen (T-Qua-2w) was superior to the 1-week PPI-based triple regimen [P-Tri-1w, RR = 0.82, 95% CI: (0.67–0.99)], and there was no difference between the remaining tegoprazan-based regimens and the PPI-based or vonoprazan-based regimens. In terms of the incidence of adverse reactions, the 2-week vonoprazan-based binary regimen (V-Bi-2w) was lower than that of the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 1.98, 95% CI: (1.57–2.52)]; there was no significant difference between 1 and 2 weeks for each regimen, such as the vonoprazan-based triple regimen [RR = 1.11, 95% CI: (0.82–1.52)]. Conclusion: In the eradication treatment of Hp, the efficacy and safety of vonoprazan-based regimens are generally better than those of PPI-based regimens. Among them, the V-Tri-2w regimen has the highest eradication rate and may be the preferred choice for Hp eradication. [ABSTRACT FROM AUTHOR]

Background: Globus pharyngeus is a clinical condition, wherein, a patient senses a lump or a foreign body in the throat with a tightening or choking feeling. A strong association between globus pharyngeus and gastroesophageal reflux disease (GERD) was reported. Therefore, we sought to investigate the predictive factors of globus pharyngeus in patients with established GERD and fit a predictive scoring model for globus pharyngeus. Methods: In this case-control study, 143 patients having globus pharyngeus along with GERD (case) and 109 patients having globus pharyngeus without GERD (control) were enrolled. Data comprising demographics, comorbidities, and psychosocial stress levels were recorded. The predictive factors of globus pharyngeus in patients with GERD were unraveled, and a predictive scoring model was fit for globus pharyngeus. Results: Proton pump inhibitor usage in the case group was significantly higher compared to controls (63.63% vs 24.78%, P < 0.001), and differences in Hiatus Hernia and Stress levels were highly significant between the two groups (P < 0.001). Multivariate logistic regression revealed that variates, Hiatus Hernia, psychosocial stress, and age were highly significant (P < 0.001) independent predictors of globus pharyngeus. Using the regression coefficients of all the independent predictor variables, a predictive scoring model was fitted, which yielded an area under receiver operating characteristic (AUROC) curve of 78.9. Conclusion: Hiatus hernia, psychosocial stress, and age are significant independent predictors of globus pharyngeus in GERD, and our predictive scoring model may help in identifying patients at higher odds of experiencing globus pharyngeus and modulate treatment accordingly. [ABSTRACT FROM AUTHOR]

Family farming is characterized by using the intensive force of collective work within the family. In Mazagão, a municipality in Amapá state, the basis of agricultural production is family farming, represented by settlers and extractivists, among other things. This research aims to analyze how public policies can foster better conditions for productive activities development, income, and better working conditions, but also how such investments can alter the communities' ways of life. To carry out this analysis, we methodologically used a theoretical review of family farming, public policy, and rural development, as well as institutional technic reports from the rural sector in Amapá, referring to the Integrated Food Production Program (PPI) in 2022, in which the information shows the number of operations, the volume of financing, the number of representative entities and the profiles of economic activities developed. Among the results, it is worth noting that the investments obtained amounted to R$20,254,166.38, distributed among 19 associations/cooperatives representing rural communities in Mazagão, serving 865 families working in family farming, açaí management, manioc farming, free-range chicken and shrimp breeding. It has made it possible to change the way of life of local people, contributing to an increase in productive activities. [ABSTRACT FROM AUTHOR]