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Protein-protein interactions (PPIs) are fundamental to understanding biological systems as protein complexes are the active molecular modules critical for carrying out cellular functions. Dysfunctional PPIs have been associated with various diseases including cancer. Systems-wide PPI analysis not only sheds light on pathological mechanisms, but also represents a paradigm in identifying potential therapeutic targets. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for defining endogenous PPIs of cellular networks. While proteome-wide studies have been performed in cell lysates, intact cells and tissues, applications of XL-MS in clinical samples have not been reported. In this study, we adopted a DSBSO-based in vivo XL-MS platform to map interaction landscapes from two breast cancer patient-derived xenograft (PDX) models. As a result, we have generated a PDX interaction network comprising 2,557 human proteins and identified interactions unique to breast cancer subtypes. Interestingly, most of the observed differences in PPIs correlated well with protein abundance changes determined by TMT-based proteome quantitation. Collectively, this work has demonstrated the feasibility of XL-MS analysis in clinical samples, and established an analytical workflow for tissue cross-linking that can be generalized for mapping PPIs from patient samples in the future to dissect disease-relevant cellular networks.

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.

The recent assembly and annotation of the 26 maize nested association mapping (NAM) population founder inbreds have enabled large-scale pan-genomic comparative studies. These studies have expanded our understanding of agronomically important traits by integrating pan-transcriptomic data with trait-specific gene candidates from previous association mapping results. In contrast to the availability of pan-transcriptomic data, obtaining reliable protein-protein interaction (PPI) data has remained a challenge due to its high cost and complexity. We generated predicted PPI networks for each of the 26 genomes using the established STRING database. The individual genome-interactomes were then integrated to generate core- and pan-interactomes. We deployed the PPI clustering algorithm ClusterONE to identify numerous PPI clusters that were functionally annotated using gene ontology (GO) functional enrichment, demonstrating a diverse range of enriched GO terms across different clusters. Additional cluster annotations were generated by integrating gene co-expression data and gene description annotations, providing additional useful information. We show that the functionally annotated PPI clusters establish a useful framework for protein function prediction and prioritization of candidate genes of interest. Our study not only provides a comprehensive resource of predicted PPI networks for 26 maize genomes, but also offers annotated interactome clusters for predicting protein functions and prioritizing gene candidates. The source code for the Python implementation of the analysis workflow and a standalone web application for accessing the analysis results are available at https://github.com/eporetsky/PanPPI.

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]

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]

AbstractObjectiveMaterial and methodsResultsConclusionsEosinophilic 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.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.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.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: Incorporating patient and public involvement (PPI) in research is crucial for ensuring the relevance and success of studies, yet it remains significantly underutilised in surgical research. Main body: This commentary presents insights from our neurosurgical research team's experience with establishing and working with a PPI group called "Science for Tomorrow's Neurosurgery" on research regarding novel intra-operative optical imaging techniques. Through collaboration with patient-focused charities, we have successfully incorporated patient perspectives into our work at each stage of the research pipeline, whilst adhering to core PPI principles, such as reciprocal relationships, co-learning, partnerships, and transparency. Conclusion: We highlight the specific value added to our work in terms of participant recruitment, research ethics and results dissemination. Plain English summary: Including patients and members of the public in medical research is really important. It helps make sure the research is useful and successful. Surprisingly, it's not used enough in surgical research. This article talks about how our team of brain surgeons and scientists worked with a group called "Science for Tomorrow's Neurosurgery" to include brain surgery patients in our research about new ways to look at the brain during surgery. We worked closely with charities that focus on helping patients with brain conditions, and we made sure to listen to what patients had to say every step of the way, from planning our research to sharing our results. We followed some important rules, like making sure everyone involved felt like they were being treated fairly, learning together, working together with different groups, and being honest and open. We found that having patients involved in the design and development really helped us find the right people to take part in our research, make sure we were doing things the right way, and share our findings in a way that made sense to everyone. [ABSTRACT FROM AUTHOR]

Background: Patient and Public Involvement (PPI) is increasingly recognized as an essential aspect of clinical research, particularly for ensuring relevancy and impact of research to those most affected. This study addresses the gap in involving older patients, particularly nursing home residents, in the research process by exploring motivations, expectations, and experiences of nursing home residents in Bremen, Germany, involved in PPI for developing a clinical trial on polypharmacy. Methods: Two Patient Advisory Boards (PABs) were established in nursing homes as part of the INVOLVE-Clin project. A Patient Advocate (PA) facilitated communication between nursing home residents and researchers. A qualitative case study approach was employed, involving semi-structured interviews and group discussions with nursing home residents and researchers. Data was analyzed using structured qualitative content analysis. Results: The study found varied motivations and expectations between nursing home residents and researchers. Nursing home residents valued the social interaction and the opportunity to voice their health concerns, while researchers aimed to incorporate patients' perspectives into study design. The PA was considered crucial in facilitating communication between nursing home residents and researchers. Challenges included the complexity of the study topic and the need for methodological adjustments to suit nursing home residents´ cognitive abilities. Generally, PAB participation was experienced to provide mental stimulation and increased confidence among nursing home residents in discussing their medication management. The PAB's influence led to the decision not to conduct a polypharmacy study. Discussion: The findings underscore the importance of flexible approaches to PPI, particularly when involving older nursing home residents. Methodological adjustments, such as tailoring content and structure of PABs, and the inclusion of additional boards for diverse perspectives, are vital for effective involvement. The study also highlights the need for ongoing innovation in PPI methods to ensure meaningful engagement of older patients in clinical research. Conclusion: This study contributes essential insights into the practical implementation of PPI with nursing home residents, highlighting the need for patient-centric approaches that recognize their unique challenges and contributions. These findings are critical for shaping scientifically robust but also socially relevant and impactful research, especially in an aging society. Plain English Summary: This study looked at how nursing home residents in two nursing homes in Bremen, Germany, feel about being part of health research. It focused on their reasons for joining, what they hoped to get out of it, and their experiences. The study used two groups, called Patient Advisory Boards (PABs), in these nursing homes. An important part of making this work was having someone called a Patient Advocate, who talked to the nursing home residents and communicated their perspectives to the research team. Researchers talked to the residents and other researchers through interviews and group discussions. The study found that nursing home residents and researchers had different reasons for being involved. The nursing home residents enjoyed the chance to talk with others and share their health worries, while the researchers wanted to make sure the study considered the views of older patients. There were some challenges for both, researchers and nursing home residents. The topic of the study, which was about using many different medicines (polypharmacy), was complex. Nursing home residents would need easier methods to take part. Nonetheless, being part of the PABs was experienced to be good by the nursing home residents. It helped them think more about their health and feel more confident talking about their medicines. The study shows that when including nursing home residents in health research, it's important to think about their specific needs to ensure meaningful engagement. [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: We conducted an NIHR-funded evidence synthesis project, reviewing evidence relating to interventions for perceptual disorders following stroke. This related paper describes how people with lived experience of stroke-related perceptual disorders contributed to and influenced the project, and identifies lessons for future review projects. Methods: We planned our patient and public involvement and engagement (PPIE) activities within a study protocol, described according to the domains of the ACTIVE framework; these were founded on principles for good practice in PPIE. Activities occurred across the lifespan of the project, consisting primarily of group discussions and voting to determine if there was consensus. To assess impact and individual experiences, we sought feedback using an evaluation form after each discussion, and conducted an online meeting at the end of the project to allow further reflection. Results: We recruited five people to a Lived Experience Group, including two stroke survivors and three carers. Members attended one face-to-face meeting during the development of the review. Subsequent activities were all held online due to the COVID-19 pandemic; with six online meetings, plus email interactions. Positive impacts of the Lived Experience Group on the reviews included clear definitions of key terms, selection of outcome measures, agreement on implications of review findings, and identification of research recommendations. Key challenges identified related to the complexity of the topic and challenges in the use of new online technology as a consequence of the COVID-pandemic. Conclusions: A number of lessons were learned during this project. Specific recommendations for future PPIE are to ensure that those involved have an opportunity to get to know one another, and to provide optional sessions to increase familiarity with online meeting software, clear explanations of the purpose of involvement and specific feedback after each activity. These lessons should be considered when planning the PPIE within future reviews. Plain English summary: We reviewed research into treatments for disorders of perception after stroke. These disorders reduce a person's ability to recognise and understand information from their senses. We involved people affected, to ensure that (i) their experiences were reflected and (ii) this complex topic was treated in a clear and understandable way. This paper discusses their involvement, the impact it had, and the lessons learnt. We involved five people affected, within a dedicated 'Lived Experience Group'. Two members were stroke survivors, while three were carers. Their activities spanned the whole duration of the project. An initial face-to-face meeting with the entire research team was followed by six online activities (because of COVID-19 related restrictions) and email communication. The Lived Experience Group had a clear impact on the review. This included creating clear definitions of key terms, selecting which tests of treatment effectiveness were most important, determining the real-world meaning of the review findings, and agreeing the recommendations for stroke survivors, clinicians and researchers based on these findings. Key challenges were the complexity of the topic and terminology, the difficulty of using new technology, and the loss of personal connections arising from this mode of working. This study demonstrates how online involvement can successfully engage stroke survivors in research. It also suggests strategies to improve future work, such as providing time and support to both practice new technologies, and for social engagement. [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]

Lupus nephritis (LN) is a challenging condition with limited diagnostic and treatment options. In this study, we applied 12 distinct machine learning algorithms along with Non-negative Matrix Factorization (NMF) to analyze single-cell datasets from kidney biopsies, aiming to provide a comprehensive profile of LN. Through this analysis, we identified various immune cell populations and their roles in LN progression and constructed 102 machine learning-based immune-related gene (IRG) predictive models. The most effective models demonstrated high predictive accuracy, evidenced by Area Under the Curve (AUC) values, and were further validated in external cohorts. These models highlight six hub IRGs (CD14, CYBB, IFNGR1, IL1B, MSR1, and PLAUR) as key diagnostic markers for LN, showing remarkable diagnostic performance in both renal and peripheral blood cohorts, thus offering a novel approach for noninvasive LN diagnosis. Further clinical correlation analysis revealed that expressions of IFNGR1, PLAUR, and CYBB were negatively correlated with the glomerular filtration rate (GFR), while CYBB also positively correlated with proteinuria and serum creatinine levels, highlighting their roles in LN pathophysiology. Additionally, protein-protein interaction (PPI) analysis revealed significant networks involving hub IRGs, emphasizing the importance of the interleukin family and chemokines in LN pathogenesis. This study highlights the potential of integrating advanced genomic tools and machine learning algorithms to improve diagnosis and personalize management of complex autoimmune diseases like LN. [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]

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]

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]

Introduction: Patients on systemic oral anticoagulation with vitamin K antagonists (VKA) or non-vitamin K oral anticoagulants (NOAC) often require triple therapy following percutaneous coronary intervention, substantially increasing the risk of bleeding. Gastroprotective agents like proton pump inhibitors (PPI) are often employed to mitigate this risk, despite potential competitive inhibition between P2Y12-receptor inhibitors, NOACs, and VKAs. While the interactions and clinical outcomes of PPIs and DAPT have been frequently explored in literature, not many studies have evaluated the same outcomes for triple therapy. Areas covered: This comprehensive narrative review of three studies on PPIs and triple from the PubMed/MEDLINE database supplemented by 23 other relevant studies aims to use the available literature to analyze the potential interactions between PPIs and triple therapy while shedding light on their mechanisms, clinical implications, and areas for optimization. Expert opinion: If triple therapy is indicated following PCI, then patients at high-risk for bleeding may benefit from transition to apixaban and a PPI to lower the risk of gastrointestinal bleeding. More research is needed to determine the role of PPIs in triple therapies in prevention of gastrointestinal bleeding or potentiation of other adverse outcomes. [ABSTRACT FROM AUTHOR]

The ability to accurately predict antibody–antigen complex structures from their sequences could greatly advance our understanding of the immune system and would aid in the development of novel antibody therapeutics. There have been considerable recent advancements in predicting protein–protein interactions (PPIs) fueled by progress in machine learning (ML). To understand the current state of the field, we compare six representative methods for predicting antibody–antigen complexes from sequence, including two deep learning approaches trained to predict PPIs in general (AlphaFold‐Multimer and RoseTTAFold), two composite methods that initially predict antibody and antigen structures separately and dock them (using antibody‐mode ClusPro), local refinement in Rosetta (SnugDock) of globally docked poses from ClusPro, and a pipeline combining homology modeling with rigid‐body docking informed by ML‐based epitope and paratope prediction (AbAdapt). We find that AlphaFold‐Multimer outperformed other methods, although the absolute performance leaves considerable room for improvement. AlphaFold‐Multimer models of lower quality display significant structural biases at the level of tertiary motifs (TERMs) toward having fewer structural matches in non‐antibody‐containing structures from the Protein Data Bank (PDB). Specifically, better models exhibit more common PDB‐like TERMs at the antibody–antigen interface than worse ones. Importantly, the clear relationship between performance and the commonness of interfacial TERMs suggests that the scarcity of interfacial geometry data in the structural database may currently limit the application of ML to the prediction of antibody–antigen interactions. [ABSTRACT FROM AUTHOR]

Abstract Background Incorporating patient and public involvement (PPI) in research is crucial for ensuring the relevance and success of studies, yet it remains significantly underutilised in surgical research. Main body This commentary presents insights from our neurosurgical research team’s experience with establishing and working with a PPI group called “Science for Tomorrow’s Neurosurgery” on research regarding novel intra-operative optical imaging techniques. Through collaboration with patient-focused charities, we have successfully incorporated patient perspectives into our work at each stage of the research pipeline, whilst adhering to core PPI principles, such as reciprocal relationships, co-learning, partnerships, and transparency. Conclusion We highlight the specific value added to our work in terms of participant recruitment, research ethics and results dissemination.

Das Verschreibungsvolumen von Protonenpumpeninhibitoren (PPI) ist nach wie vor hoch, obwohl in der Literatur zunehmend darauf hingewiesen wird, dass in Relation zu den Leitlinienempfehlungen eine übermäßige Verschreibung erfolgt. Über die Situation in Deutschland liegen keine sehr aktuellen Daten vor. Ziel dieser Studie war es, die tatsächliche Menge an verschriebenen und rezeptfreien PPIs in Deutschland zu ermitteln. Basierend auf mehreren großen IQVIA-Datenbanken zeigen wir, dass zwischen November 2020 und Oktober 2021 insgesamt 2,87 Milliarden PPI-Tabletten verkauft wurden, wobei die meisten Wirkstoffe in den größten Packungen und Stärken verordnet wurden. Darüber hinaus nahm der rezeptfreie PPI-Markt in einem Zeitraum von drei Jahren durchschnittlich um 14% pro Jahr zu. Die Ergebnisse dieser Studie lassen auf die beträchtliche Größe des PPI-Marktes in Deutschland aufgrund von Verschreibungen schließen sowie auf eine konsistente Zunahme der rezeptfreien PPI-Käufe und einen Anstieg der Verschreibungen in der jüngsten Zeit.

Abstract Background We conducted an NIHR-funded evidence synthesis project, reviewing evidence relating to interventions for perceptual disorders following stroke. This related paper describes how people with lived experience of stroke-related perceptual disorders contributed to and influenced the project, and identifies lessons for future review projects. Methods We planned our patient and public involvement and engagement (PPIE) activities within a study protocol, described according to the domains of the ACTIVE framework; these were founded on principles for good practice in PPIE. Activities occurred across the lifespan of the project, consisting primarily of group discussions and voting to determine if there was consensus. To assess impact and individual experiences, we sought feedback using an evaluation form after each discussion, and conducted an online meeting at the end of the project to allow further reflection. Results We recruited five people to a Lived Experience Group, including two stroke survivors and three carers. Members attended one face-to-face meeting during the development of the review. Subsequent activities were all held online due to the COVID-19 pandemic; with six online meetings, plus email interactions. Positive impacts of the Lived Experience Group on the reviews included clear definitions of key terms, selection of outcome measures, agreement on implications of review findings, and identification of research recommendations. Key challenges identified related to the complexity of the topic and challenges in the use of new online technology as a consequence of the COVID-pandemic. Conclusions A number of lessons were learned during this project. Specific recommendations for future PPIE are to ensure that those involved have an opportunity to get to know one another, and to provide optional sessions to increase familiarity with online meeting software, clear explanations of the purpose of involvement and specific feedback after each activity. These lessons should be considered when planning the PPIE within future reviews.

Cailing E,1,&ast; Rongying Wang,1,&ast; Zudong Meng,1 Yulin Zou1,2 1Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany&ast;These authors contributed equally to this workCorrespondence: Yulin Zou, Email zouyl1007@qq.comBackground: Psoriasis, a chronic and recurrent inflammatory skin disease, current treatments can only alleviate its symptoms. There is still no complete cure. Although increasing research supports the therapeutics to be better, the common mechanism of its occurrence is still not fully elucidated. Our study is about further explore the molecular mechanism of the occurrence of this disease.Methods: The gene expression profiles of psoriasis (GSE151177, GSE41664, GSE30999) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis using R software, three kinds of analyses were performed, namely WGCNA, GWAS Analysis, Drug Target Prediction.Results: A total of 14 common DEGs was selected for subsequent analyses. Our Drug Target Prediction analysis revealed that the expression profiles influenced by certain drugs, including methotrexate, budesonide, amino purvalanol-a, and selumetinib, exhibited negative correlations with the disease-perturbed expression profiles. Finally, It was found that S100A4, JAML, TRAF3IP3, MIAT, IL7R, and KLRB1 were prominently expressed in the immune pathway related to allograft rejection. In the metabolic pathway, oxidative phosphorylation showed high expression levels, while the reactive oxygen species pathway was notably expressed in the signaling pathways domain.Conclusion: Our study reveals the potential drugs and pathogenesis of psoriasis. These potential pathway and hub genes may provide new ideas for further mechanism research.Keywords: psoriasis, hub genes, bioinformatics, PPI, inflammation

Abstract 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 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 Background A larger percentage of social housing tenants have poorer physical and mental health outcomes compared to private renters and homeowners. They are also at a greater risk of respiratory conditions, cardiovascular disease, communicable disease transmission and mortality. One approach that aims to reduce health inequalities is to create research partnerships with underserved local communities. Our primary aim was to develop a research partnership with social housing tenants in Nottingham and our secondary aim was to explore the health priorities of these social housing tenants to inform future research applications. We also hope to provide a descriptive process of PPI within a social housing context for other researchers to learn from. Methods We used Public and Patient Involvement (PPI) as the foundation of this work, as we believed that people with lived experience of social housing, also end-users of the research, were best placed to inform us of the areas with the greatest research need. Through online and in-person focus groups, we discussed with tenants, collectively named a Social Advisory Group (SAG), their health concerns and priorities. Together they raised 26 health issues, which were combined with 22 funding opportunity themes being offered by the NIHR (National Institute for Health and Care Research). This was with the purpose of investigating whether there was alignment between the health needs of Nottingham’s social housing tenants and the NIHR’s research priorities. A prioritisation technique (Diamond Nine) was used to sort in total, 48 areas of health and wellbeing, into three top priorities. Tenants were provided the opportunity to be involved in public health research in other ways too, such as reviewing this paper and also an NIHR Programme Development Grant application to expand and continue this work. One was also offered the opportunity to be a public co-applicant. Results The group prioritised improvements in the quality of social housing, mental health and healthcare services. There was only some alignment between these and the NIHR funding themes. Other factors, such as age and race, also determined individual health priorities. . The diversity and reach of the current project were limited, however this is something we hope to improve in the future with more funding. We learned that tenants have varying degrees of mobility and technological abilities, requiring both online and in-person meetings.

Linh Tran Pham,1 Si Dung Chu,1– 3 Duy Xuan Nguyen4 1Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam; 2Training and Director of Healthcare Activities Center, Bach Mai Hospital, Hanoi, Vietnam; 3Hospital of Vietnam National University, Vietnam National University, Hanoi, Vietnam; 4Department of Cardiovascular Medicine, Military Hospital 105, Hanoi, VietnamCorrespondence: Si Dung Chu, Hospital of Vietnam National University, Vietnam National University, Hanoi, Vietnam, Tel +84 906086168, Email sichu.bvbachmai@gmail.comObjective: Study on the role of electrocardiographic (ECG) exercise testing for the possibility of permanent pacemaker implantation (PPI) in patients with sinus bradycardia (SB).Methods: Cross-sectional descriptive, prospective study. The study on 60 patients with SB below 50 beats/minute on 12-lead electrocardiogram at rest, with or without symptoms of SB, conducted at the Vietnam National Heart Institute and Hanoi Heart Hospital from January 2020 to September 2021.Results: Sixty patients with SB were studied, 36 male (60%) and 24 female patients (40%), p > 0.05. The average age was 55.12 ± 13.89 years old. Maximum exercise capacity (MEC) is low and only reaches 7.78 ± 3.59 metabolic equivalents (METs); Not reaching 85% of predicted MEC accounts for 53.5%; Maximum exercise time is 10.53 ± 0.46 minutes; Impaired heart rate (HR) variability in patients with SB is high: Chronotropic Index < 0.8 accounts for 53.5%, not reaching 85% of predicted HR max accounts for 45%. The average HR max was 129.90 ± 29.22 beats per minute (BPM). The average maximum workload systolic blood pressure was 155.23 ± 20.59 mmHg. The average value of maximum exercise diastolic blood pressure was 88.10 ± 9.11 mmHg. The HR decreased by 27.87 ± 16.82 BPM in the first minute. Not achieving 85% of predicted MEC (p = 0.062), so it is not an independent factor predicting the ability for PPI. Only the HR variability index < 0.8 is an independent predictor for PPI in bradycardic patients, which has OR = 21.521 (95% CI: 2.27– 04.34, p < 0.05).Conclusion: Results can be seen that Chronotropic Index < 0.8 is an important marker for physicians to decide on PPI in ECG during exercise testing in SB patients and is a potential prognostic factor for the need for PPI.Keywords: role, exercise ECG testing, PPI, possibility of PPI

Background and Aim Methods Results Conclusions 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).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.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).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]

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]

Background: A larger percentage of social housing tenants have poorer physical and mental health outcomes compared to private renters and homeowners. They are also at a greater risk of respiratory conditions, cardiovascular disease, communicable disease transmission and mortality. One approach that aims to reduce health inequalities is to create research partnerships with underserved local communities. Our primary aim was to develop a research partnership with social housing tenants in Nottingham and our secondary aim was to explore the health priorities of these social housing tenants to inform future research applications. We also hope to provide a descriptive process of PPI within a social housing context for other researchers to learn from. Methods: We used Public and Patient Involvement (PPI) as the foundation of this work, as we believed that people with lived experience of social housing, also end-users of the research, were best placed to inform us of the areas with the greatest research need. Through online and in-person focus groups, we discussed with tenants, collectively named a Social Advisory Group (SAG), their health concerns and priorities. Together they raised 26 health issues, which were combined with 22 funding opportunity themes being offered by the NIHR (National Institute for Health and Care Research). This was with the purpose of investigating whether there was alignment between the health needs of Nottingham's social housing tenants and the NIHR's research priorities. A prioritisation technique (Diamond Nine) was used to sort in total, 48 areas of health and wellbeing, into three top priorities. Tenants were provided the opportunity to be involved in public health research in other ways too, such as reviewing this paper and also an NIHR Programme Development Grant application to expand and continue this work. One was also offered the opportunity to be a public co-applicant. Results: The group prioritised improvements in the quality of social housing, mental health and healthcare services. There was only some alignment between these and the NIHR funding themes. Other factors, such as age and race, also determined individual health priorities.. The diversity and reach of the current project were limited, however this is something we hope to improve in the future with more funding. We learned that tenants have varying degrees of mobility and technological abilities, requiring both online and in-person meetings. Plain English summary: Social housing is offered to people who cannot afford to buy or rent in the open market, and a larger percentage of social housing tenants have poorer physical and mental health outcomes compared to the general population. One approach that aims to reduce health inequalities is to create sustainable research partnerships with underserved local communities. Our primary aim was to involve social housing tenants in public health research, as they are best placed to tell us the type of research they would benefit from. The secondary aim was to explore the health priorities of social housing tenants to inform future research applications. We also hope to describe the process of PPI within a social housing context for other researchers to learn from. To achieve these aims, we established a research partnership with a group of social housing tenants in Nottingham and spoke to them about the areas of their health they wanted to improve (i.e., their priorities). The topics that were discussed the most were the need for improved mental health, quality of social housing and healthcare services, however this varied between individuals according to race and age. We learned several things throughout this process. Firstly, the combination of mobility and technological abilities amongst tenants meant that meetings must be held both in-person and online. This ensured they remained accessible and convenient. Secondly, we learnt that in-person meetings should be held in a neutral space to encourage different members of the group to attend. Finally, in general, people were very enthusiastic about this partnership and were committed to seeing improvements in public health. We therefore provided more opportunities for the group to be involved in research. For example, they were offered the opportunity to write and edit a lay summary for a future research application, which was based on the priorities identified in this paper. One member of the group was nominated to be the public co-applicant , which would allow us to increase the reach of this housing work across the East Midlands. It would also allow us to increase the diversity of the group, as currently it is made up of mostly retired females of British origin. Involving the public in health research has been central to this process and continues to be important in the production of accessible and relevant research. [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]

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]

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]

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]

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]

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: Patient and public involvement (PPI) is increasingly recognised as crucial for enhancing healthcare and research relevance. This case study aimed to describe the development of a PPI group within the context of liver disease management and research, highlighting opportunities and challenges encountered. Methods: Patients with liver disease were recruited from a gastroenterology department through an online survey. An initial group discussion meeting was held using a nominal group technique, focusing on establishing the group's purpose, identifying areas of interest for involvement and determining practical organisational aspects. Ongoing collaboration occurred through regular meetings and communication. Results: A total of 18 patients actively participated in the group. Their motivations included utilising lived experiences to support others, gain knowledge about liver disease and raise public awareness. The group contributed to developing patient information, nurse-led consultations and a patient application. Additionally, they identified a need for research on improving healthcare system pathways for liver disease patients. Conclusions: This case study demonstrates a sustainable model for PPI in liver disease. Opportunities included empowering patients as consultants, collaborators and potential patient-led researchers. Challenges included addressing diversity within the group and ensuring adequate resources for PPI activities. This study provides valuable insights for healthcare professionals and researchers seeking to implement PPI in their own settings. [ABSTRACT FROM AUTHOR]

Introduction: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications. Recently, PPI use has been linked to the development of chronic kidney disease (CKD) and cardiovascular events. Our study aimed to investigate the relationship between PPI use and the incidence of chronic kidney disease using a systematic review and meta-analysis. Methods: We performed a comprehensive literature search in PubMed, Embase, and Cochrane databases from their inception until March 2024 for relevant studies. We compared outcomes between patients using PPIs, those not using PPIs, and those using histamine-2 receptor antagonists (H2RAs). Endpoints were pooled using the DerSimonian-and-Laird random-effects model as the hazard ratio (HR) with 95% confidence intervals (CIs). Results: Our analysis included twelve studies with a total of 700,125 participants (286,488 on PPIs, 373,848 not on PPIs, and 39,789 on H2RAs), with follow-up periods ranging from three months to 14 years. The current meta-analysis revealed that PPI use is associated with a statistically significant increased risk of incident CKD (HR: 1.26, 95% CI: 1.16–1.38, p < 0.001) compared with non-users. Moreover, the risk of incident CKD is significantly higher in patients with PPI use compared to H2RA use (HR: 1.34, 95% CI: 1.13–1.59, p < 0.001). The results remained unchanged in terms of magnitude and direction after a leave-one-out analysis for both outcomes. Conclusions: Our multifaceted analysis showed that PPI use was associated with a higher incidence of CKD when compared to non-PPI use and H2RA use, respectively. These findings advocate for heightened vigilance and judicious use of long-term PPIs. Further large prospective longitudinal studies are warranted to validate these observations. [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]

Gastric heterotopia can occur in any part of the gastrointestinal tract but is rare in the rectum. This case of rectal gastric heterotopia is novel as the heterotopic mucosa contained fundic gland polyps, and there were histological changes in the gastric glands characteristic of proton pump inhibitor-related changes. These changes included apocrine-like luminal cytoplasmic protrusions in cystically dilated oxyntic gland parietal cells. These are well described in the native stomachs of PPI treated patients, but this is the first report of these changes in heterotopic gastric mucosa to our knowledge. The lesion was removed via transanal endoscopic operation (TEO) without prior biopsy due to its unusual irregular nodular appearance mimicking a high-risk rectal neoplasm. [ABSTRACT FROM AUTHOR]

Prior studies in Social Neuroeconomics have consistently reported activation in social cognition regions during interactive economic games, suggesting mentalizing during economic choice. Such mentalizing occurs during active participation in the game, as well as during passive observation of others' interactions. We designed a novel version of the classic false-belief task (FBT) in which participants read vignettes about interactions between agents in the ultimatum and trust games and were subsequently asked to infer the agents' beliefs. We compared activation patterns during the economic games FBT to those during the classic FBT using conjunction analyses. We find significant overlap in the left temporoparietal junction (TPJ) and dorsal medial prefrontal cortex, as well as the temporal pole (TP) during two task phases: belief formation and belief inference. Moreover, generalized Psychophysiological Interaction (gPPI) analyses show that during belief formation, the right TPJ is a target of both the left TPJ and the right TP seed regions, whereas during belief inferences all seed regions show interconnectivity with each other. These results indicate that across different task types and phases, mentalizing is associated with activation and connectivity across central nodes of the social cognition network. Importantly, this is the case for both the novel economic games and the classic FBTs.