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Abstract Background A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. Methods Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann–Whitney U and Wilcoxon matched-pairs signed rank tests. Results Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p

Purpose: Sustaining healthcare operations without adequate energy capacity creates significant challenges, especially during periods of constrained energy supply. This research develops a clinical and non-clinical activity-based hospital energy model for electrical load prioritization during periods of constrained energy supply. Design/methodology/approach: Discrete event modelling is adopted for development of the hospital energy model (HEM). The basis of the HEM is business process mapping of the hospitals clinical and non-clinical activities. The model prioritizes the electrical load demand as Priority 1, 2 and 3; with Priority 1 activities essential to the survival of patients, Priority 2 activities are critical activities that are required after one to four hours, and Priority 3 activities can run for several hours without electricity. Findings: The model was applied to a small, medium, and large hospital. The results demonstrate that Priority 2 activities have the highest energy demand, followed by Priority 1 and Priority 3 activities, respectively for all hospital sizes. For the medium and large hospitals, the top three contributors to energy demand are lighting, HVAC, and patient services. For the small hospital, it is patient services, lighting, and HVAC, respectively. Research limitations/implications: The model is specific to hospitals but can be modified for other healthcare facilities. Practical implications: The resolution of the electrical energy demand down to the business activity level, enables hospitals to evaluate current practices for optimization. It facilitates multiple energy supply scenarios, enabling hospital management to conduct feasibility studies based on available power supply options Social implications: Improved planning of capital expenditure and operational budgets and during constrained energy supply. This reduces risk to hospitals and ensures consistent quality of service. Originality/value: Current hospital energy models are limited, especially for operations management under constrained energy supply. A simple to use model is proposed to assist in planning of activities based on available supply.

The formation of long-lived immune memory cells specific for pathogens is critical for the establishment of long-term immune protection against future infections. BNIP3L/NIX and BNIP3, two functionally redundant BCL2 family members required for mitophagy, undergo significant upregulation after memory B cells are formed. Deletion of Bnip3l and Bnip3 leads to mitochondrial accumulation, and increases in oxidative phosphorylation and fatty acid synthesis, resulting in the loss of memory B cells. These observations suggest that after the formation of memory B cells, mitophagy is critical for clearing superfluous mitochondria to re-shape the metabolic programs, thereby protecting the metabolic quiescence and longevity of memory B cells .

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

Objective: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease‐modifying antirheumatic drugs (bDMARDs). Methods: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case‐based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. Results: Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow‐up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. Conclusion: CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry‐based prospective comparative effectiveness studies. [ABSTRACT FROM AUTHOR]

The HIV-1 reservoirs harbor the latent proviruses that are integrated into the host genome. It is a challenging task to eradicate the proviruses in order to achieve an HIV cure. We have described a strategy for the clearance of HIV-1 infection through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and promotion of apoptosis during viral re-activation. HIV-1 can infect various CD4+ T cell subsets, but it is not known whether the SECH approach is equally effective in targeting HIV-1 reservoirs in these different subsets in vivo. In a humanized mouse model, we found that treatments of HIV-1 infection by suppressive antiretroviral therapy (ART) led to the establishment of latent HIV reservoirs in naïve, central memory and effector memory T cells. Moreover, SECH treatments could clear latent HIV-1 reservoirs in these different T cell subsets of humanized mice. Co-culture studies showed that T cell subsets latently infected by HIV-1, but not uninfected bystander cells, were susceptible to cell death induced by SECH treatments. Our study suggests that the SECH strategy is effective for specific targeting of latent HIV-1 reservoirs in different T cell subsets.

Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.

Objective: Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti‐Sp4 autoantibodies co‐occurred in patients with anti–transcription intermediary factor 1 (anti‐TIF1) autoantibody‐positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti‐Sp4 autoantibodies in juvenile‐onset IIM were investigated. Methods: Serum samples from 336 patients with juvenile myositis in a cross‐sectional cohort and 91 healthy controls were screened for anti‐Sp4 autoantibodies using enzyme‐linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti‐Sp4 autoantibodies were compared. Results: Anti‐Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti‐Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti‐Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti‐TIF1 autoantibody–positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti‐Sp4 autoantibodies. None of the patients with anti‐Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti‐Sp4 autoantibodies. Conclusion: Anti‐Sp4 autoantibodies were found in patients with juvenile‐onset IIM, predominantly those with coexisting anti‐TIF1 autoantibodies. Patients with anti‐Sp4 autoantibodies represent a phenotypic subset of anti‐TIF1 autoantibody–positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti‐Sp4 autoantibodies. [ABSTRACT FROM AUTHOR]

Objectives: Team or group cohesion is a multifaceted construct with a variety of definitions and measurement instruments. However, most of these measures are context and group-specific and/or time-consuming. There is no adaptable and economic measure of group cohesion in Germany. Therefore, the aim of this study was to validate the German version of the 6-item Perceived Cohesion Scale (PCS) in a sample of adult nurses in a German University Hospital., Material and Methods: The German version of the PCS was generated according to existing guidelines. Confirmatory factor analysis was conducted to assess factor structure. Reliability was tested via internal consistency. To assess convergent and divergent validity, the authors applied the Copenhagen Psychosocial Questionnaire (COPSOQ), the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Inventory (ESSI), the Effort-Reward Imbalance (ERI) scale and the Patient Health Questionnaire (PHQ-4)., Results: The confirmatory factor analysis confirmed a 2-factor structure. Psychometric properties of the German PCS prove satisfactory. Internal consistency was excellent for the whole scale (α = 0.95), as well as for both subscales: sense of belonging (SOB) (α = 0.94) and morale (MOR) (α = 0.93). Moderate to strong correlations with the subscales of COPSOQ (Kendall's Tau (τ) = 0.239 - 0.471) indicated very good convergent validity. Regarding divergent validity, the correlations of the PCS subscales and the PHQ-4 were low (τ = -0.109-[-0.143]), as were the correlations with ESSI (τ = 0.045-0.136). Correlations with ERI were low to moderate (τ = -0.181-0.283)., Conclusions: The German version of the PCS showed good psychometric properties. Due to its economic and universal deployment, group cohesion can be measured in a variety of contexts and settings. Int J Occup Med Environ Health. 2024;37(4):421-32., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Description: Endoscopic scoring systems evaluate the severity of inflammation and provide objectivity, uniformity, and standardization of reporting of mucosal appearances in patients with inflammatory bowel disease; thus, they have been advised for assessing the efficacy of medical treatment and prognosis. This American Gastroenterological Association (AGA) Clinical Practice Update Expert Commentary aims to review the utilized endoscopic scoring systems and their role in assessing mucosal healing in inflammatory bowel disease and the practical challenges in their applications, as well as to discuss the future of endoscopic scoring systems., Methods: This expert commentary was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology., Results/conclusion: This expert commentary incorporates essential studies in this field and reflects the authors' expertise in the endoscopic evaluation of inflammatory bowel disease., (Copyright © 2024. Published by Elsevier Inc.)

The impact of stroke on global health is profound, with both high mortality and morbidity rates. This condition can result from cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). The pathophysiology of stroke involves secondary damage and irreversible loss of neuronal function. Post-translational modifications (PTMs) have been recognized as crucial regulatory mechanisms in ischemic and hemorrhagic stroke-induced brain injury. These PTMs include phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and succinylation. This comprehensive review delves into recent research on the PTMs landscape associated with neuroinflammation and neuronal death specific to cerebral ischemia, ICH, and SAH. This review aims to explain the role of PTMs in regulating pathologic mechanisms and present critical techniques and proteomic strategies for identifying PTMs. This knowledge helps us comprehend the underlying mechanisms of stroke injury and repair processes, leading to the development of innovative treatment strategies. Importantly, this review underscores the significance of exploring PTMs to understand the pathophysiology of stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: We applied a previously established common T-score metric for patient-reported and performance-based physical function (PF), offering the unique opportunity to directly compare measurement type-specific patterns of associations with potential laboratory-based, psychosocial, sociodemographic, and health-related determinants in hemodialysis patients., Methods: We analyzed baseline data from the CONVINCE trial (N = 1,360), a multinational randomized controlled trial comparing high-flux hemodialysis with high-dose hemodiafiltration. To explore the associations of potential determinants with performance-based versus patient-reported PF, we conducted multiple linear regression (backward elimination with cross-validation and Lasso regression). We used standardized T-scores as estimated from the PROMIS PF short-form 4a (patient-reported PF) and the Physical Performance Test (performance-based PF) as dependent variables., Results: Performance-based and patient-reported PF were both significantly associated with a laboratory marker-based indicator of muscle mass (simplified creatinine index), although the effects were relatively small (partial f 2  = 0.04). Age was negatively associated with PF; the effect size was larger for performance-based (partial f 2  = 0.12) than for patient-reported PF (partial f 2  = 0.08). Compared to performance-based PF, patient-reported PF showed a stronger association with self-reported health domains, particularly pain interference and fatigue. When using the individual difference between patient-reported and performance-based T-scores as outcome, we found that younger age and more fatigue were associated with lower patient-reported PF compared to performance-based PF (small effect size)., Conclusion: Patient-reported and performance-based assessments were similarly associated with an objective marker of physical impairment in hemodialysis patients. Age and fatigue may result in discrepancies when comparing performance-based and patient-reported scores on the common PF scale. Trial Registration CONVINCE is registered in the Dutch Trial Register (Register ID: NL64750.041.18). The registration can be accessed at: https://onderzoekmetmensen.nl/en/trial/52958 ., (© 2024. The Author(s).)

The promotion of healthy aging has become a priority in most parts of the world and should be promoted at all ages. However, the baseline training of health and social professionals is currently not adequately tailored to these challenges. This paper reports the results of a Delphi study conducted to reach expert agreement about health and social professionals' competencies to promote healthy aging throughout the lifespan within the SIENHA project. Materials and methods: This study was developed following the CREDES standards. The initial version of the competence framework was based on the results of a scoping review and following the CanMEDS model. The expert panel consisted of a purposive sample of twenty-two experts in healthy aging with diverse academic and clinical backgrounds, fields and years of expertise from seven European countries. Agreement was reached after three rounds. The final framework consisted of a set of 18 key competencies and 80 enabling competencies distributed across six domains. The SIENHA competence framework for healthy aging may help students and educators enrich their learning and the academic content of their subjects and/or programs and incentivize innovation., (© 2024. The Author(s).)

In the CONVINCE trial, the primary analysis demonstrated a survival benefit for patients receiving high-dose hemodiafiltration (HDF) as compared with high-flux hemodialysis (HD). A secondary objective was to evaluate effects on health-related quality of life (HRQoL); assessed in eight domains (physical function, cognitive function, fatigue, sleep disturbance, anxiety, depression, pain interference, social participation) applying instruments from the Patient-Reported Outcome Measurement Information System (PROMIS) before randomization and every three months thereafter. In total 1360 adults with dialysis-dependent chronic kidney disease, eligible to receive high-flux HDF (23 liters or more), were randomized (1:1); 84% response rate to all questionnaires. Both groups reported a continuous deterioration in all HRQoL domains. Overall, raw score changes from baseline were more favorable in the HDF group, resulting in a significant omnibus test after a median observation period of 30 months. Most relevant single raw score differences were reported for cognitive function. Patients receiving HDF reported a decline of -0.95 units (95% confidence interval - 2.23 to +0.34) whereas HD treated patients declined by -3.90 units (-5.28 to - 2.52). A joint model, adjusted for mortality differences, utilizing all quarterly assessments, identified a significantly slower HRQoL decline in physical function, cognitive function, pain interference, and social participation for the HDF group. Their physical health summary score declined -0.46 units/year slower compared to the HD group. Thus, the CONVINCE trial showed a beneficial effect of high-dose hemodiafiltration for survival as well as a moderate positive effect on patients' quality of life, most pronounced with respect to their cognitive function. REGISTRATION: NTR7138 on the International Clinical Trials Registry Platform., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: SARS-CoV-2 pandemic resulted in lifestyle change of world's population because of the measures adopted by governments to contain the virus spread., Design and Methods: This study examined whether lockdown impacted anthropometric indices, Mediterranean Diet (MD) adherence, Physical Activity Level (PAL), and Quality of Life (SF-12) in a cohort of 116 patients (96 F, aged 57.2 ± 13.1 years) affected by thyroid disorders. Before lockdown, data were collected during the endocrinological examination; after lockdown they were collected through a tele-phone interview (via video call)., Results: Data revealed an overweight condition in 59% of patients, with no significant differences between the two observations (BMI values: 26.5 ± 4.9 vs 26.6 ± 4.9 kg/m 2 ), whereas waist circumference values significantly increased over time (93.3 ± 12.6 vs 94.4 ± 12.5 cm; p  = 0.003). Moreover, a lower adherence to the MD (PREDIMED score: 7.3 ± 1.8 vs 7.0 ± 1.8; p  = 0.003) and a significant increase of sitting time (6.4 ± 3.2 h/die vs 9.0 ± 4.2; p  < 0.001) were observed. A not significant decrease in PAL, which revealed a sedentary condition in pre- and post-lockdown (648 and 562 METs/week respectively), was found. The SF-12 score did not show relevant changes between the two observations., Conclusion: Our study highlights that patients with thyroid diseases are often sedentary and exhibit a high prevalence of over-weight, underscoring the need for a systematic anthropometric evaluation and, at times, lifestyle interventions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

The gap between endoscopy and histology is getting closer with the introduction of sophisticated endoscopic technologies. Furthermore, unprecedented advances in artificial intelligence (AI) have enabled objective assessment of endoscopy and digital pathology, providing accurate, consistent, and reproducible evaluations of endoscopic appearance and histologic activity. These advancements result in improved disease management by predicting treatment response and long-term outcomes. AI will also support endoscopy in raising the standard of clinical trial study design by facilitating patient recruitment and improving the validity of endoscopic readings and endoscopy quality, thus overcoming the subjective variability in scoring. Accordingly, AI will be an ideal adjunct tool for enhancing, complementing, and improving our understanding of ulcerative colitis course. This review explores promising AI applications enabled by endoscopy and histology techniques. We further discuss future directions, envisioning a bright future where AI technology extends the frontiers beyond human limits and boundaries., (© The Author(s), 2024.)

Background: Obesity is a risk factor of several types of cancer, including breast cancer. In this study, we aimed to histologically characterize the adipose tissue of the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) in overweight/obese versus normal-weight patients. Methods: TNBC tissue sections from normal-weight (BMI <25 ) and overweight/obese patients (BMI ≥25 ) were stained with antibodies against CD68, CD163, CD31, CD34, and vimentin. At the invasive tumor front, positive cells were counted in tumor adjacent adipose tissue (AT) and within cancer tissue (CT). Further, the size of the tumor-adjacent and distant mammary adipocytes was determined in perilipin stained sections. Expression of ANGPTL4, CD36 and FABP4, proteins involved in fatty acid metabolism, was analyzed in marginal tumor cells using an immune reactive score. Results: Overweight/obese TNBC patients had significantly larger adipocytes, higher numbers of CD163+ macrophages (BMI <25 : 2.80 vs. BMI ≥25 : 10.45; p = 0.011) and lower numbers of CD31+ (BMI <25 : 4.20 vs. BMI ≥25 : 2.40; p = 0.018) and CD34+ (BMI <25 : 14.60 vs. BMI ≥25 : 5.20; p = 0.045) cells as markers of angiogenesis in the AT as well as a higher frequency of cancer-associated-fibroblast-like cells in the AT and CT (BMI <25 : 7.60 vs. BMI ≥25 : 25.39 in total; p = 0.001). Moreover, expression of CD36 (BMI <25 : 2.15 vs. BMI ≥25 : 2.60; p = 0.041) and ANGPTL4 (BMI <25 : 6.00 vs. BMI ≥25 : 9.80; p = 0.026) was elevated in the TNBC cells of overweight/obese patients. Conclusions: Our data suggest BMI-related changes in the TME of overweight/obese TNBC patients, including hypertrophied adipocytes, reduced vascularization, more M2-like macrophages and CAF-like cells, and an increase in the expression of fatty acid metabolizing proteins in marginal tumor cells, all contributing to a more tumor-promoting, immunosuppressive environment.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO Guidelines., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Over the past two decades, the development of nerve guide conduits (NGCs) has gained much attention due to the impellent need to find innovative strategies to take care of damaged or degenerated peripheral nerves in clinical surgery. In this view, significant effort has been spent on the development of high-performance NGCs by different materials and manufacturing approaches. Herein, a highly versatile and easy-to-handle route to process 3D porous tubes made of chitosan and gelatin to be used as a nerve guide conduit were investigated. This allowed us to fabricate highly porous substrates with a porosity that ranged from 94.07 ± 1.04% to 97.23 ± 1.15% and average pore sizes-estimated via X-ray computed tomography (XCT) reconstruction and image analysis-of hundreds of microns and an irregular shape with an aspect ratio that ranged from 0.70 ± 0.19 to 0.80 ± 0.15 as a function of the chitosan/gelatin ratio. More interestingly, the addition of gelatin allowed us to modulate the mechanical properties, which gradually reduced the stiffness-max strength from 0.634 ± 0.015 MPa to 0.367 ± 0.021 MPa-and scaffold toughness-from 46.2 kJ/m 3 to 14.0 kJ/m 3 -as the gelatin content increased. All these data fall into the typical ranges of the morphological and mechanical parameters of currently commercialized NGC products. Preliminary in vitro studies proved the ability of 3D porous tubes to support neuroblastoma cell (SH-SY5Y) adhesion and proliferation. In perspective, the proposed approach could also be easily implemented with the integration of other processing techniques (e.g., electrospinning) for the design of innovative bi-layered systems with an improved cell interface and molecular transport abilities.

Background: Patients with inflammatory bowel disease (IBD) in clinical and endoscopic remission may still experience disease relapse. Therefore, there is a need to identify outcome predictors. Recently, the role of neutrophils in predicting outcomes in ulcerative colitis (UC) has been highlighted. Furthermore, the impairment of intestinal barrier plays a key role in forecasting disease outcomes in IBD., Objective: This observational study aimed to assess the predictive role of neutrophils according to tissue localization and intestinal barrier protein expression in IBD., Methods: IBD patients in clinical remission who underwent colonoscopy between January 2020 and June 2022 at two tertiary referral centres were enrolled. Patients with Mayo Endoscopic Score ≤1 (UC) and Simple Endoscopic Score ≤6 (Crohn's disease) were included. Histological activity was assessed using validated scores. Experienced pathologists evaluated neutrophil localization in the epithelium and lamina propria and immunohistochemical expression of Claudin-2 and junctional adhesion molecule A (JAM-A)., Results: Of 60 UC and 76 CD patients, 59.7% had histological activity. 25.8% of patients developed an adverse outcome within 12 months. Neutrophils in the epithelium predicted adverse outcomes for UC (hazard ratio [HR] 5.198, p = 0.01) and CD (HR 4.377, p = 0.03) patients in endoscopic remission. Claudin-2 expression correlated with endoscopic and histological activity and predicted outcomes in UC. Similar results were found for JAM-A in CD despite this protein showing less specificity as a barrier predictor of outcome., Conclusion: This study highlights the potential role of epithelial neutrophil localization and Claudin-2 'leaky gut' expression as tools for predicting IBD outcomes and guiding further patient-tailored therapy., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Patients with Crohn's disease (CD) after ileocolic resection may develop an endoscopic postoperative recurrence (ePOR) that reaches 40% to 70% of incidence within 6 months. Recently, there has been growing interest in the potential effect of anastomotic configurations on ePOR. Kono-S anastomosis has been proposed for reducing the risk of clinical and ePOR. Most studies have assessed the association of ileocolonic anastomosis and ePOR individually, while there is currently limited data simultaneously comparing several types of anastomosis. Therefore, we performed a systematic review and meta-analysis to assess the impact of different ileocolonic anastomosis on ePOR in CD., Methods: We searched PubMed and Embase from inception to January 2023 for eligible studies reporting the types of anastomoses and, based on these, the rate of endoscopic recurrence at ≥6 months. Studies were grouped by conventional anastomosis, including side-to-side, end-to-end, and end-to-side vs Kono-S, and comparisons were made between these groups. Pooled incidence rates of ePOR were computed using random-effect modelling., Results: Seventeen studies, with 2087 patients who underwent ileocolic resection for CD were included. Among these patients, 369 (17,7%) Kono-S anastomoses were performed, while 1690 (81,0%) were conventional ileocolic anastomosis. Endoscopic postoperative recurrence at ≥6 months showed a pooled incidence of 37.2% (95% CI, 27.7-47.2) with significant heterogeneity among the studies (P < .0001). In detail, patients receiving a Kono-S anastomosis had a pooled incidence of ePOR of 24.7% (95% CI, 6.8%-49.4%), while patients receiving a conventional anastomosis had an ePOR of 42.6% (95% CI, 32.2%-53.4%)., Conclusions: Kono-S ileocolic anastomosis was more likely to decrease the risk of ePOR at ≥6 months compared with conventional anastomosis. Our findings highlight the need to implement the use of Kono-S anastomosis, particularly for difficult to treat patients. However, results from larger randomized controlled trials are needed to confirm these data., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Bariatric surgery poses an ever-increasing importance in the effective and long-lasting treatment of obesity, a condition strongly associated with inflammation and increased risk of other diseases and health problems. In obesity-related inflammation, maintaining a balance between pro-inflammatory and anti-inflammatory cytokines is crucial. In this study, we examined early effects of laparoscopic sleeve gastrectomy (LSG) on inflammatory and anti-inflammatory cytokines in obese patients, and assessed their effect on postoperative weight loss., Materials and Methods: This prospective cohort study was conducted from September 2022 till June 2023. Fifty obese adults were enrolled for LSG. All patients underwent assessments of body measurements, as well as levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and TNF-alpha at baseline and 3 months postsurgery. We developed a decision tree model to predict the success of weight loss., Results: At 3 months postsurgery, patients lost 18.9 ± 6.9 kg of excess body weight. A significant decrease was observed for IL-10 (p < 0.0001), simultaneously with a significant increase in IL-6 (p < 0.0001). We found that high IL-6 (> 1.169 pg/mL) levels could contribute to an effective weight loss among patients with a baseline BMI less than 47.46 kg/m 2 ., Conclusion: Study revealed that 3 months after bariatric surgery, inflammation persists, and its markers significantly influence postoperative weight loss, as indicated by BMI range. Distinct behaviors of IL-10 and IL-6 in relation to obesity underline the necessity of considering individual cytokine profiles when evaluating bariatric surgery outcomes., (© 2024. The Author(s).)

Introduction: While there are several web-based mental health interventions, few target higher education (HE) students. Importantly, more research is needed to establish their effectiveness. Here, we provide a pragmatic evaluation of an online intervention (MePlusMe) specifically designed to improve the mental health, well-being, and study skills of HE students., Methods: In accordance with the published protocol for a feasibility study, we recruited a convenience sample of 137 HE students to participate in an eight-week intervention, with 26 participants retained at week 8. Validated measures of mood (depression and anxiety), well-being, and self-efficacy were collected at baseline, 2, 4, and 8   weeks, alongside two feedback forms assessing design and functionality (baseline) and engagement (week 4 and 8)., Results: We observed significant reductions in levels of anxiety and depression as well as increases in well-being, but no changes in self-efficacy. Participants rated the system design and functionality positively and qualitative findings indicated high levels of satisfaction with MePlusMe., Discussion: Findings support both the acceptability and the effectiveness of MePlusMe. Nonetheless, modest retention rates limit the precision and generalisability of these findings. Further investigation should ascertain optimal duration of engagement, most acceptable means of outcome assessment, and further detail about obstacles to utilisation.

The role of autophagy goes far beyond the elimination of damaged cellular components and the quality control of proteins. It also cleanses cells from inclusions, including pathogenic viruses, and provides energy-forming components. The liver, which is an organ with increased metabolism, is made up of cells that are particularly vulnerable to damage. Therefore, detoxification of liver cells in the process of autophagy has become a very important issue clinically. The aim of this study was an immunohistochemical evaluation of proteins activated in rat liver cells at different stages of hyperbaric autophagy. The rats used for the study were randomly divided into six equivalent groups-three control groups and three experimental groups. Animals from the experimental groups were subjected to hyperbaric treatment in a hyperbaric chamber, with a pressure of 1.6 ATA for 120 min. They breathed atmospheric air. Rats were decapitated within 5 or 10 days after removal from the chamber. Immunohistochemical reactions with beclin 1, LC3B, RAB7, and HSC73 proteins were carried out on preparations made from liver slices. A three-step labeled streptavidin-biotin detection method of paraffin blocks (LSAB three-step) was used for immunohistochemical research. The results were evaluated using computer programs for morphometric analysis of microscopic images by calculating the mean surface areas occupied by a positive immunohistochemical reaction in individual groups for all antibodies tested. Increased closure of substrates in the autophagosome (beclin 1) induced late endosome transport and accelerated autophagosome maturation process (RAB7). Furthermore, a larger number of autophagosomes (LC3B) was observed in liver cells immediately after the cessation of hyperbaric activity; however, this decreased after 5 days. During this time, chaperone-mediated autophagy (HSC73) was observed on a larger scale. This means that increased macroautophagy induced by hyperbaric treatment weakens with time that has elapsed since the cessation of high pressure, whereas similarly induced chaperone-mediated autophagy intensifies over time.

Abstract: Treatment with direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is effective and safe. However, bleeding complications still occur. Whether DOAC level measurement may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" study, venous blood was collected 15-30 days after DOAC initiation in patients with AF who were then followed up for 1 year to record the occurrence of major and clinically relevant nonmajor bleeding. DOAC plasma levels were measured in 1 laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients (957 [57.7%] and 700 patients treated with standard and low-dose, respectively). Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (>0.50), whereas 35 events (2.69% pt/yrs) occurred in those with values in the 2 lower classes (≤0.50, P = .0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first 3 months of treatment. Overall, 19% of patients receiving low doses had standardized values in the highest class. More bleeding occurred in patients on low (4.3% pt/yrs) vs standard (2.2% pt/yrs; P = .0160) dose DOAC. Early measurement of DOAC levels in patients with AF identified many individuals with high levels despite the low doses use and had more bleeding risk during the first 3 months of treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03803579., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chikungunya virus (CHIKV) is a re-emerging, pathogenic alphavirus that is transmitted to humans by Aedesspp. mosquitoes-causing fever and debilitating joint pain, with frequent long-term health implications and high morbidity. The CHIKV replication cycle is poorly understood and specific antiviral therapeutics are lacking. In the current study, we identify host cell Musashi RNA binding protein-2 (MSI-2) as a proviral factor. MSI-2 depletion and small molecule inhibition assays demonstrated that MSI-2 is required for efficient CHIKV genome replication. Depletion of both MSI-2 and MSI-1 homologues was found to synergistically inhibit CHIKV replication, suggesting redundancy in their proviral function. Electromobility shift assay (EMSA) competition studies demonstrated that MSI-2 interacts specifically with an RNA binding motif within the 5' untranslated region (5'UTR) of CHIKV and reverse genetic analysis showed that mutation of the binding motif inhibited genome replication and blocked rescue of mutant virus. For the first time, this study identifies the proviral role of MSI RNA binding proteins in the replication of the CHIKV genome, providing important new insight into mechanisms controlling replication of this significant human pathogen and the potential of a novel therapeutic target., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: A significant proportion of inflammatory bowel disease (IBD) patients fail to respond to advanced therapies. Combining advanced therapies may improve treatment outcome. This study aimed to assess the effectiveness, adverse events, and costs associated with combining advanced therapies in IBD patients., Methods: Combination advanced therapy was defined as the concurrent use of two biological agents or one biological agent with a small molecule therapy. Clinical data, including disease characteristics, treatment regimens, and adverse events, were collected from electronic patient records. Clinical response rates, biochemical markers, and treatment costs were evaluated., Results: The study included 109 IBD patients receiving combination advanced therapies from 9 academic centers in Ireland. Corticosteroid-free clinical response rates at 12 weeks and 52 weeks were 39 % and 38 %, respectively. Adverse events occurred in 26 % of therapeutic trials, with disease-related events being the most common. Notably, there were 3 cases of non-melanomatous skin cancer and 10 infectious complications. The annual cost of maintenance therapy for combination advanced therapies ranged from €17,560 to €30,724 per patient., Conclusion: Combination advanced therapies demonstrated effectiveness and acceptable safety profiles in a cohort of treatment-refractory IBD patients. Further large, prospective trials are required to definitively evaluate the role of combination advanced therapies in IBD., Competing Interests: Conflicts of interest There are no conflicts of interest pertaining to this paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: Non-surgical endodontic treatment aims to prevent apical periodontitis, achieved with the disinfection of the root canal system. Additionally, there are pathologies where the toxic content of the canal goes to the periradicular tissues, causing osteolysis or lesions of the bone tissue that are radiographically observed as radiolucent images. When the endodontic treatment is successful, the repair of these lesions occurs over time., Aim: To analyze the periradicular repair process of non-surgical endodontic treatment and the factors that affect it., Materials and Methods: An electronic search was carried out using the search engines PUBMED, Scopus, Google Academic, and Scielo with the words "Non-Surgical Endodontic Treatment," "Periapical Tissues," "Biological Repair," "Apical Repair." Factors such as incomplete texts, PDF texts, and publication date of the article were considered, including data from the last five (05) years., Results: The information reviewed comprised 236 articles analyzed with the inclusion and exclusion criteria, and only 42 articles met these criteria., Conclusion: The success of endodontic treatment lies in the absence of clinical and radiographic signs and symptoms of infection; this is achieved with a good application of clinical protocols and procedures focused on the disinfection of the root canal system, from diagnosis, biomechanical preparation, and disinfection of the root canal system with irrigating substances and filling, including coronal rehabilitation from an aesthetic and/or prosthetic point of view.

Introduction: Vaccinations are important for informal caregivers and their care recipients. Mental health problems are common among care givers. The aim of this study was to investigate vaccination readiness in informal caregivers and associations with mental health issues. Associations between vaccination readiness in informal caregivers and the vaccination status of their aged care recipients were examined., Methods: Within the multicenter prospective registry study 'Bavarian ambulatory Covid-19 Monitor (BaCoM) ', informal caregivers were asked for symptoms of depression (PHQ-9), burden of caretaking (BSFC-s), psychological antecedents of vaccination readiness (5C model) and previous Covid-19 infections of their care recipients. The vaccination status against Covid-19, seasonal influenza and pneumococcal disease was determined via vaccination certificates. Data analysis was performed using ordinal regressions and Mann-Whitney-U tests., Results: Data of n = 91 informal caregivers, associated with n = 84 care recipients were collected. Symptoms of depression were associated with reduced vaccination readiness (Calculation: p = 0.026, OR = 1.18), as well as the perceived burden of caretaking (Confidence: p = 0.006, OR = 0.88). A previous Covid-19 infection of the care recipients was associated with decreased vaccination readiness of informal caregivers (Median (Q1-Q3) Confidence: 5.0 (4.5-6.0) vs. 4.0 (3.0-5.0); Calculation: 5.0 (3.0-6.0) vs. 4.0 (1.0-5.0)). The vaccination status of the care recipients interrelated significantly with vaccination readiness of their informal caregivers (Confidence: p < 0.001; Complacency: p < 0.01; Constraints p < 0.05). No significant interrelations between vaccination readiness and the vaccination status against seasonal influenza or pneumococcal disease occurred., Conclusion: Mental health issues of informal caregivers seem to be associated with the actual vaccination status against Covid-19 in their care recipients. Target group specific counselling as well as an active involvement of informal caregivers in shared decision-making processes can be of relevance, but even more attention should be paid to the protection of mental health for informal caregivers., Trial Registration Number: German Register of Clinical Studies DRKS 26039., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In addition to physical symptoms such as dyspnea, fatigue, post-exertional malaise, and pain, a subgroup of patients with Post-COVID-19 syndrome (Post-Acute Sequelae of COVID-19, PASC) suffers from mental illnesses such as anxiety, depression, and neurocognitive impairments. To date, there are no causal treatments available for PASC. While initial studies show that psychotherapy improves psychological symptoms, PASC-related fatigue, and psychosocial functioning, further research is needed to evaluate the effectiveness of psychotherapeutic treatment for PASC., Methods and Analysis: This study presents a non-randomized controlled trial aimed at evaluating the effectiveness of a five-week multimodal inpatient psychosomatic treatment program for individuals experiencing PASC symptoms and comorbid mental illness. A total of 118 patients presented at the Post-COVID Center at the Universitätsklinikum Erlangen will be assigned to the intervention group receiving inpatient psychosomatic treatment or the control group receiving treatment as usual. The inclusion criteria for the intervention group are a diagnosis of PASC and at least one condition of mental distress and problems with coping with illness. The primary objective of the intervention is to reduce mental ailments, including depression and anxiety, as well as neurocognitive deficits, and to address PASC symptoms such as fatigue and pain. The core elements of the treatment are psychotherapy in individual and group settings, medical treatment, neurocognitive training, and physical therapy, adapted to the individual's capacity and oriented towards the concept of pacing. After enrollment, participants will undergo a 6-month follow-up to assess long-term results and the sustainability of the intervention effects., Discussion: This study examines the effectiveness of inpatient psychotherapeutic treatment in PASC patients with comorbid mental illness in comparison with a control group based on treatment as usual. The results of the study can contribute to the development of evidence-based interventions to address the complex needs of patients with PASC and comorbid mental illness., Trial Registration: German Clinical Trial Register (DRKS), retrospectively registered 15.02.2024 DRKSID DRKS00033562., (© 2024. The Author(s).)

Background: Antidepressants have a pivotal role in the treatment of many psychiatric disorders, but there are concerns about long-term use and adverse effects. The objectives of this study were (1) to examine time trends in antidepressant use, (2) to estimate the prevalence of long-term and potential high-risk antidepressant use, and (3) to examine patient characteristics associated with potential deprescribing indications (PDIs) (i.e., simultaneous long-term and potential high-risk antidepressant use)., Methods: Repeated population-based cross-sectional study for all 609,299 people aged ≥ 18 years resident in the Tayside or Fife regions of Scotland. The prevalence of antidepressant use was examined on June 30th (index date) of each year from 2012 to 2019, while the prevalence of long-term and potential high-risk use as well as PDIs was assessed and compared on the same dates in 2012 and 2019. Binary logistic regression modeling was used to examine patient characteristics associated with PDIs., Results: Antidepressant use increased by 27% from 12.0 to 15.3% among adult residents between 2012 and 2019. While the proportion of antidepressants users dispensed ≥ 1 antidepressant for > 2 years increased from 54.3 to 61.9% between 2012 and 2019, the proportion of antidepressant users triggering ≥ 1 indicator of potential high-risk use decreased slightly from 37.9 to 34.7%. In 2019, potential high-risk use most commonly related to indicators targeting fall risk (16.0%), cardiovascular risks (14.1%), insomnia (10.6%), and risk of orthostatic hypotension (8.6%). More than 1 in 4 (25.8%) antidepressant users had PDIs. The main risk factors associated with PDIs included increasing age (65-79, adjusted OR 14.12; 95% CI, 13.15-15.17), increasing number of drugs taken concomitantly (≥ 15 drugs, adjusted OR 7.37; 95% CI, 6.71-8.10), use of tricyclic antidepressants (≥ 50 mg) (adjusted OR 5.49; 95% CI, 5.02-6.01), and concomitant use of ≥ 2 antidepressants (adjusted OR 5.52; 95% CI, 5.20-5.85)., Conclusions: Long-term and potential high-risk use of antidepressants is widespread, and potential deprescribing indications (PDIs) are increasing, suggesting the need for a critical review of their ongoing use by clinicians. If deemed necessary, future deprescribing interventions may use the criteria applied here for identification of patients with PDIs and for evaluating intervention effectiveness., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.