Miracle-dz/UniFAR-FTUs huggingface dataset:
WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP

ABSTRACT The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy. Abbreviations: ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2
Expert-Identified Practices for Achieving Measurable Performance Improvements With Lean Implementation

Background and Objectives: Despite the rapid spread of Lean management in health care, few organizations have achieved measurable overall performance improvements with Lean. What differentiates these organizations from those that struggle with realizing the potential benefits of Lean management is unclear. In this qualitative study we explore measuring the impact of Lean and the recommended practices for achieving measurable performance improvements with Lean in health care organizations. Methods: Informed by preliminary quantitative results from analyses of high- and low-performing Lean hospitals, we conducted 17 semi-structured interviews with Lean health care experts on the Lean principles and practices associated with better performance. We conducted qualitative content analyses of the interview transcripts based on grounded theory and linking to core principles and practices of the Lean management system. Results: The qualitative data revealed 3 categories of metrics for measuring the impact of Lean: currently used institutional measures, measures tailored to Lean initiatives, and population-level measures. Leadership engagement/commitment and clear organizational focus/prioritization/alignment had the highest weighted averages of success factors. The lack of these 2 factors had the highest weighted averages of biggest barriers for achieving measurable performance improvements with Lean implementation. Conclusions: Leadership engagement and organizational focus can facilitate achieving the organization's performance improvement goals, whereas their absence can considerably hinder performance improvement efforts. Many different approaches have been used to quantify the impact of Lean, but currently used institutional performance measures are preferred by the majority of Lean experts.
Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer

We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). We show that tumor antigenicity sculpts myeloid cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, and overcomes macrophage-mediated suppression. The therapeutic activity of adoptive T cell therapy or programmed cell death ligand 1 blockade required cDC1s, which sustained splenic Klrg1+ cytotoxic antitumor T cells and functional intratumoral T cells. KLRG1 and cDC1 genes correlated in human tumors, and PDA patients with high intratumoral KLRG1 survived longer than patients with low intratumoral KLRG1. The immunotherapy CD40 agonist also required host cDC1s for maximal therapeutic benefit. However, CD40 agonist exhibited partial therapeutic benefit in cDC1-deficient hosts and resulted in priming of tumor-specific yet atypical CD8+ T cells with a regulatory phenotype and that failed to participate in tumor control. Monocyte/macrophage depletion using clodronate liposomes abrogated T cell priming yet enhanced the antitumor activity of CD40 agonist in cDC1-deficient hosts via engagement of innate immunity. In sum, our study supports that cDC1s are essential for sustaining effective antitumor T cells and supports differential roles for cDC1s and monocytes/macrophages in instructing T cell fate and immunotherapy response.
A Participatory Design Approach to Develop Visualization of Wearable Actigraphy Data for Health Care Professionals: Case Study in Qatar

Background Several tools have been developed for health care professionals to monitor the physical activity of their patients, but most of these tools have been considering only the needs of users in North American and European countries and applicable for only specific analytic tasks. To our knowledge, no research study has utilized the participatory design (PD) approach in the Middle East region to develop such tools, involving all the stakeholders in the product development phases, and no clear use cases have been derived from such studies that could serve future development in the field. Objective This study aims to develop an interactive visualization tool (ActiVis) to support local health care professionals in monitoring the physical activity of their patients measured through wearable sensors, with the overall objective of improving the health of the Qatari population. Methods We used PD and user-centered design methodologies to develop ActiVis, including persona development, brainwriting, and heuristic walkthrough as part of user evaluation workshops; and use cases, heuristic walkthrough, interface walkthrough, and survey as part of expert evaluation sessions. Results We derived and validated 6 data analysis use cases targeted at specific health care professionals from a collaborative design workshop and an expert user study. These use cases led to improving the design of the ActiVis tool to support the monitoring of patients’ physical activity by nurses and family doctors. The ActiVis research prototype (RP) compared favorably with the Fitbit Dashboard, showing the importance of design tools specific to end users’ needs rather than relying on repurposing existing tools designed for other types of users. The use cases we derived happen to be culturally agnostic, despite our assumption that the local Muslim and Arabic culture could impact the design of such visualization tools. At last, taking a step back, we reflect on running collaborative design sessions in a multicultural environment and oil-based economy. Conclusions Beyond the development of the ActiVis tool, this study can serve other visualization and human–computer interaction designers in the region to prepare their design projects and encourage health care professionals to engage with designers and engineers to improve the tools they use for supporting their daily routine. The development of the ActiVis tool for nurses, and other visualization tools specific to family doctors and clinician researchers, is still ongoing and we plan to integrate them into an operational platform for health care professionals in Qatar in the near future.
Brief behavioral treatment for insomnia decreases trauma-related nightmare frequency in veterans.

STUDY OBJECTIVES Trauma-related nightmares are highly prevalent among veterans and are associated with higher severity insomnia and PTSD. Cognitive behavioral therapy for insomnia (CBT-I, typically 6-8 sessions) has been shown to reduce trauma-related nightmares. Brief behavioral treatment for insomnia (BBTI, 4 sessions) has been found to be comparable to CBT-I in decreasing insomnia severity; however, the effects of BBTI on nightmares have not been investigated. The current study tested the effects of BBTI on both trauma-related nightmares and non-trauma-related bad dreams using an active control group, progressive muscle relaxation therapy (PMRT). Additionally, we tested whether baseline trauma-related nightmare frequency and baseline non-trauma-related bad dream frequency moderated changes in insomnia severity. METHODS Participants were 91 military veterans with insomnia disorder randomized to BBTI or PMRT. Participants reported insomnia severity on the Insomnia Severity Index and reported trauma-related nightmare frequency and non-trauma-related bad dream frequency on the Pittsburgh Sleep Quality Index--PTSD Addendum. RESULTS We found that BBTI significantly reduced trauma-related nightmares from baseline to post-treatment while PMRT did not. However, reductions in trauma-related nightmares were not maintained at six month follow up. Neither BBTI nor PMRT reduced non-trauma-related bad dreams from baseline to post-treatment. We also found that neither baseline trauma-related nightmare frequency nor baseline non-trauma-related bad dream frequency moderated changes in insomnia symptom severity. CONCLUSIONS Findings from the current study suggest that BBTI may help to reduce trauma-related nightmares. Further research is needed to better understand potential mechanisms underlying how improved sleep may reduce trauma-related nightmares. CLINICAL TRIAL REGISTRATION Registry: ClinicalTrials.gov; Name: Brief Behavioral Insomnia Treatment Study (BBTI); Identifier: NCT02571452; URL: https://clinicaltrials.gov/ct2/show/NCT02571452.
Dermatological Conditions Inducing Acute and Chronic Pain

Pain is a common condition in dermatology. The aim of this review is to analyse the characteristics of pain in dermatology. Some skin diseases are conventionally known to cause pain; e.g. ulcers, pyoderma gangrenosum and herpes zoster. Common dermatoses, such as psoriasis or atopic dermatitis, can also cause significant pain. Some conditions are characterized by neuropathic pain and/or pruritus, without visible primary lesions: e.g. the neurocutaneous diseases, including small fibre neuropathies. Patients often fear pain in skin surgery; however, surgical procedures are rather well tolerated and any pain is mainly due to administration of local anaesthetic. Some therapies may also be uncomfortable for the patient, such as photodynamic therapy or aesthetic procedures. Thus, pain in dermatology is common, and its aetiology and characteristics are very varied. Knowledge of the different situations that cause pain will enable dermatologists to propose suitable analgesic solutions.
Postmortem diagnoses in South American camelids and factors influencing diagnostic rate in the Upper Midwest USA, 2009–2019

South American camelids (SACs) have become increasingly popular as livestock and companion animals in the Midwestern United States. With increased ownership, postmortem evaluations and samples available for diagnostic assessment are being submitted more frequently to veterinary diagnostic laboratories. We searched archived pathology records at the Wisconsin Veterinary Diagnostic Laboratory (WVDL) between 2009–2019 for SAC cases. Postmortem records from 166 alpacas and 27 llamas were included, with an average of 1.42 diagnoses per animal. The overall average diagnostic rate was 79.8%. Abortion and neonatal cases (fetus to 1-wk-old) had the lowest diagnostic rate (33.3%) and was the only group with a diagnostic rate statistically significantly lower than the average. The most common diagnoses were gastrointestinal parasitism and suboptimal nutritional status or inanition; 78% of cases diagnosed with suboptimal nutritional status were also parasitized. The gastrointestinal parasites identified most frequently were Eimeria sp. and strongyles, especially Nematodirus sp. Our findings may aid allocation of diagnostic resources to better serve regional SAC populations and provide a framework for practitioners who send samples to laboratories for analysis. Submission of whole bodies, euthanized animals, fresh tissue, and inclusion of placental tissues in abortion cases are recommended for optimal diagnostic outcome.
Abdominal versus perineal approach for external rectal prolapse: systematic review with meta-analysis

Abstract Background External rectal prolapse (ERP) is a debilitating condition in which surgery plays an important role. The aim of this study was to evaluate the outcomes of abdominal approaches (AA) and perineal approaches (PA) to ERP. Methods This was a PRISMA-compliant systematic review with meta-analysis. Studies published between 1990 and 2021 were retrieved. The primary endpoint was recurrence at the last available follow-up. Secondary endpoints included factors associated with recurrence and function. All studies were assessed for bias using the Newcastle–Ottawa Scale and Cochrane tool. Results Fifteen studies involving 1611 patients (AA = 817; PA = 794) treated for ERP were included, three of which were randomized controlled trials (RCTs; 114 patients (AA = 54; PA = 60)). Duration of follow-up ranged from 12 to 82 months. Recurrence in non-randomized studies was 7.7 per cent in AA versus 20.1 per cent in PA (odds ratio (OR) 0.29, 95 per cent confidence interval (c.i.) 0.17 to 0.50; P < 0.001, I2 = 45 per cent). In RCTs, there was no significant difference (9.8 per cent versus 16.3 per cent, AA versus PA (OR 0.82, 95 per cent c.i. 0.29 to 2.37; P = 0.72, I2 = 0.0 per cent)). Age at surgery and duration of follow-up were risk factors for recurrence. Following AA, the recurrence rates were 10.1 per cent and 6.2 per cent in patients aged 65 years and older and less than 65 years of age, respectively (effect size [e.s.] 7.7, 95 per cent c.i. 4.5 to 11.5). Following PA, rates were 27 per cent and 16.3 per cent (e.s. 20.1, 95 per cent c.i. 13 to 28.2). Extending follow-up to at least 40 months increased the likelihood of recurrence. The median duration of hospital stay was 4.9 days after PA versus 7.2 days after AA. Overall, incontinence was less likely after AA (OR 0.32), but constipation occurred more frequently (OR 1.68). Most studies were retrospective, and several outcomes from RCTs were not consistent with those observed in non-RCTs. Conclusion The overall risk of recurrence of ERP appears to be higher with PA versus AA. Incontinence is less frequent after AA but at the cost of increased constipation. Age at surgery and duration of follow-up are associated with increased risk of recurrence, which warrants adequate reporting of future studies on this topic.
Intratumoral genetic and immune microenvironmental heterogeneity in T4N0M0 (diameter ≥ 7 cm) non‐small cell lung cancers

Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non‐small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs.
Bile acid–gut microbiota crosstalk in irritable bowel syndrome

Abstract Irritable bowel syndrome (IBS) is a common disorder of gut–brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid–gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.
Effect of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria with or without high disease activity: Real‐world findings from the International Paroxysmal Nocturnal Hemoglobinuria Registry

The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high‐disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major adverse vascular events (MAVEs; including thrombotic events [TEs]); anemia; and/or physician‐reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated.
Potential Reporters of Suspected Child Maltreatment are Sensitive to the Amount of Evidence and the Potential Consequences of Reporting

The context of suspected maltreatment cases is likely to influence the decision of whether or not to make a formal report. Across one pilot study (N = 368) and two experiments (Exp. 1 N = 444; Exp. 2 N =416), undergraduate students and online community participants reported their anticipated actions and beliefs when confronted with evidence of child maltreatment. Participants reviewed case dossiers built from real-world child neglect cases in which increasing levels of evidence were presented and the consequences of reporting, or not reporting, the maltreatment were made salient to the adult or child. The experiments revealed a clear difficulty in deciding whether or not to report suspected maltreatment. Highlighting the impact on either the child or the adult by describing potential consequences moved participants either closer to (child-salient) or farther from (adult-salient) a formal report. Participants were also sensitive to the amount of evidence to support a suspicion of abuse, which influenced the likelihood of a formal report. This work suggests that increasing the salience of maltreatment consequences to child victims may increase the likelihood that suspected maltreatment will be reported.
New Predictive Resting Metabolic Rate Equations for High-Level Athletes: A Cross-Validation Study

ABSTRACT Purpose The present study aims a) to assess the agreement between the measured resting metabolic rate (RMR) using indirect calorimetry and different predictive equations (predicted RMR), and b) to propose and cross-validate two new predictive equations for estimating the RMR in high-level athletes. Methods The RMR of 102 athletes (44 women) was assessed using indirect calorimetry, whereas the body composition was assessed using skinfolds. Comparisons between measured and predicted RMR values were performed using one-way ANOVA. Mean difference, root mean square error (RMSE), simple linear regression, and Bland–Altman plots were used to evaluate the agreement between measured and predicted RMR. The accuracy of predictive equations was analyzed using narrower and wider accuracy limits (±5% and ±10%, respectively) of measured RMR. Multiple linear regression models were employed to develop the new predictive equations based on traditional predictors (equation 1) and the stepwise method (equation 2). Results The new equations 1 and 2 presented good agreement based on the mean difference (3 and −15 kcal·d−1), RMSE (200 and 192 kcal·d−1), and R2 (0.71 and 0.74), respectively, and accuracy (61% of subjects between the limit of ±10% of measured RMR). Cunningham’s equation provided the best performance for males and females among the existing equations, whereas Jagim’s equation showed the worst performance for males (mean difference = −335 kcal·d−1; RMSE = 386 kcal·d−1). Compared with measured RMR, most predictive equations showed heteroscedastic distribution (linear regression’s intercept and slope significantly different from zero; P ≤ 0.05), mainly in males. Conclusions The new proposed equations can estimate the RMR in high-level athletes accurately. Cunningham’s equation is a good option from existing equations, and Jagim’s equation should not be used in high-level male athletes.
Nicotine instigates podocyte injury via NLRP3 inflammasomes activation

Background/Aims: Recent studies have shown that nicotine induces podocyte damage. However, it remains unknown how nicotine induces podocyte injury. The present study tested whether nicotine induces NLRP3 inflammasomes activation and thereby contributes to podocyte injury. Results: Nicotine treatment significantly increased the colocalization of NLRP3 with Asc, caspase-1 activity, IL-β production, cell permeability in podocytes compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD significantly abolished the nicotine-induced colocalization of NLRP3 with Asc, caspase-1 activity, IL-1β production and cell permeability in podocytes. Immunofluorescence analysis showed that nicotine treatment significantly decreased the podocin and nephrin expression compared to control cells. However, prior treatment with WEHD attenuated the nicotine-induced podocin and nephrin reduction. In addition, we found that nicotine treatment significantly increased the O2. - production compared to control cells. However, prior treatment with WEHD did not alter the nicotine-induced O2. - production. Furthermore, prior treatment with ROS scavenger, NAC significantly attenuated the nicotine-induced caspase-1 activity, IL-1β production, podocin and nephrin reduction in podocytes. Conclusions: Nicotine-induced the NLRP3 inflammasome activation in podocytes and thereby results in podocyte injury. Methods: Inflammasome formation and immunofluorescence expressions were quantified by confocal microscopy. Caspase-1 activity, IL-1β production and O2. - production were measured by ELISA and ESR.
Basal cell carcinoma: An updated review of pathogenesis and treatment options

Basal cell carcinoma (BCC) remains the most common malignancy worldwide. BCC pathogenesis is a result of the interplay between one's environment, genetics, and phenotypic factors. BCC has a low mortality but given its increasing incidence and potential to cause local destruction thus resulting in significant morbidity, it is vital for dermatologists to remain up to date with recent updates in this malignancy's pathogenesis and treatment. This article provides a comprehensive review of the pathogenesis of BCC as well as the current treatments available and clinical trials underway. We also touch upon the updated National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology in respect to BCC's recommended treatment modalities.