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Abstract: Background: The ideal objective assessment method for laparoscopic technical skills is difficult to achieve in the operating room. Recent “VR2OR” studies have used a blinded, 2-reviewer error-based video tape analysis for intraoperative performance assessment. This study examines the validity of this methodology applied to laparoscopic intracorporeal suturing and knot tying. Methods: Four groups of subjects—experts (EX), surgery residents trained to expert criterion levels using simulation (TR), surgery residents receiving no supplemental training (NR), and medical students receiving simulation-based training (MS)—performed the fundal suturing portion of a laparoscopic Nissen fundoplication and were video-recorded for analysis. Two separate groups of surgeon reviewers (K.V.S. + M.B.; I.-P.H. + A.G.) were trained to evaluate laparoscopic suturing and knot tying performance using specific metrics. Subjects'' operative performance was assessed by reviewers blinded to their training status and scored using an error-based, step specific scoring system to an inter-rater agreement of 80% or greater. Three primary performance measures were assessed: time, errors, and needle manipulations and comparisons between groups were made using a 1-way analysis of variance (ANOVA) with post-test. Results: A total of 40 fundal sutures (10 in each group) were scored by 2 separate rater groups with inter-rater agreement consistently greater than 80%. Inter-rater agreement was highest with the EX group (91%, range 76%–100%) and lowest with the NR group (85%, range 81%–98%). On average, the EX group significantly outperformed the other groups with regards to time (P <.0001), errors (P <.002), and needle manipulations (P <.01). Performance of the TR group was comparable to the EX group with regards to errors and manipulations (P = not significant [NS]), and outperformed the NR and MS groups with regards to time (P <.05 and P <.001). Performance between the NR and MS groups were similar for all 3 measures. Conclusions: This assessment method demonstrates discriminative validity. Time appears to be the most sensitive indicator of skill level, as significant differences between EX, TR, and NR/MS groups were seen. The methodology is transferable across different reviewers and is acceptable for high-stakes assessment. [Copyright &y& Elsevier]

Background: Radiolabeling is critical in complex chemical reactions involving positron emission tomography (PET) radiotracer production. The process is now automated within a synthesis module to enhance efficiency and reduce radiation exposure. The key to this automation is the use of radiation detectors to monitor radioactivity transfer and ensure the progression of reactions. However, the high cost of these detectors has motivated the need for a more affordable alternative., Purpose: This study aimed to develop a compact and cost-efficient detector using scintillating fibers and silicon photomultipliers (SiPMs) to track radioactivity throughout PET radiotracer production., Methods: Monte Carlo simulations were performed with the Geant4-based M-TAG software for four detector geometries (single fiber, single fiber with bolus, 16-fiber bundle, and spiral) to optimize the detector construction for better detection efficiency. The simulations scored the energy deposited into the scintillating fibers per simulated particle, which was used to estimate the expected voltage pulse height from the SiPM considering the total light collection efficiency. Based on the simulation results, two detector configurations (16-fiber bundle and spiral fiber) were constructed using plastic scintillating fibers, optical fibers, a 6 mm × $\times$ 6 mm SiPM, and commonly available electronic components. The detectors were calibrated using a Fluorine-18 ( 18 F $^{18}{\rm F}$ ) source with typical activity levels used in radiotracer production. Detector performances were subsequently evaluated through linearity tests and measurement uncertainty assessments. Errors up to ± 5 % $\pm 5\%$ were considered acceptable for troubleshooting purposes., Results: The calibration curves showed a linear response with changing activity for both detectors. The calibrated detectors offered real-time activity measurements ranging from 0.10 to 49.41 GBq, with a 3-s refresh rate. In the activity range above 0.145 GBq, the uncertainties were less than 5 % $5\%$ for both the 16-fiber and spiral configurations. The spiral detector recorded a signal with a half-life of 105.88 ± 0.40 $105.88 \pm 0.40$ min, closely aligning with the reference half-life of 18 F $^{18}{\rm F}$ ., Conclusions: Cost-efficient plastic scintillation fiber detectors were developed to facilitate the troubleshooting of automated synthesis of PET radiotracers., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Introduction: Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction of unknown origin. The aim of this study was to evaluate the global prevalence of this disorder and its associated factors., Methods: Data were collected from nationwide Internet surveys in 26 countries, with subjects evenly distributed by age, sex, and country. The survey included the Rome IV questionnaire and an extensive supplemental questionnaire to evaluate additional factors., Results: A total of 54,127 participants completed the questionnaire (51% male, mean age 44.3 years). The pooled prevalence of CVS was 0.3% (95% confidence interval [CI] 0.3%-0.4%; n = 187), highest in Brazil (1%, 95% CI 0.6-1.5), and lowest in Japan and Germany (with no subject who fulfilled the criteria for CVS). The mean age of participants with CVS was 36.7 years (SD 13.5), and it was more common in women (56.7% vs 43.5%). Factors independently associated with this syndrome were female sex (odds ratio [OR] 1.52, 95% CI 1.13-2.03), young age (OR 2.57, 95% CI 1.34-4.94, for people between the ages of 18 and 39 years, compared with those older than 65 years), depression (OR 3.14, 95% CI 2.05-4.82, P < 0.001), and anxiety (OR 1.79, 95% CI 1.15-2.78, P < 0.001). Individuals with CVS had impaired quality of life (QoL) (Patient-Reported Outcomes Measurement and Information System 10-item score: physical QoL mean, 12.9 vs 15.5, P < 0.001; mental QoL mean 12.3 vs 14.4, P < 0.001) compared with others., Discussion: CVS is a relatively common disorder that has a negative impact on QoL. It is important to raise awareness on this syndrome to avoid underdiagnosis and improve clinical practice., (Copyright © 2024 by The American College of Gastroenterology.)

The outbreak of COVID-19 pandemic has raised urgent vaccine development to prevent viral transmission. Cutaneous adverse events such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been observed following COVID-19 vaccination. In this systematic review, we aimed to investigate the clinical features and outcomes of EM/SJS/TEN following COVID-19 vaccination. A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to July 3, 2022. We included studies reporting patients who developed EM, SJS, or TEN following COVID-19 vaccination. A total of 47 studies involving 90 patients with EM and 16 patients with SJS/TEN were reviewed and outlined. EM predominantly occurred after the messenger ribonucleic acid vaccines (70.4%), mostly after the first (47.5%) and second doses (42.4%), with delayed onsets ranging from 1 day to 30 days. SJS/TEN were observed following either the first (55.6%)- or second-dose (33.3%) vaccination, with onset times ranging from 6 hours to 14 weeks. Three EM cases and 1 SJS case showed recurrence upon reexposure to the same vaccines. No mortality was reported. Most patients exhibited improvement or resolution after treatment, with resolution times ranging from 6 days to 8 weeks. In conclusion, EM and epidermal necrolysis, including SJS and TEN, have emerged as potential cutaneous adverse events following COVID-19 vaccine administration. Further research is warranted to elucidate the pathogenesis and casual relationship between COVID-19 vaccines and EM/SJS/TEN.

Background: Gastric sensorimotor disorders are prevalent. While gastric emptying measurements are commonly used, they may not fully capture the underlying pathophysiology. Body surface gastric mapping (BSGM) recently emerged to assess gastric sensorimotor dysfunction. This study assessed varying meal size on BSGM responses to inform test use in a wider variety of contexts., Methods: Data from multiple healthy cohorts receiving BSGM were pooled, using four different test meals. A standard BSGM protocol was employed: 30-min fasting, 4-h post-prandial, using Gastric Alimetry® (Alimetry, New Zealand). Meals comprised: (i) nutrient drink + oatmeal bar (482 kcal; 'standard meal'); (ii) oatmeal bar alone; egg and toast meal, and pancake (all ~250 kcal). Gastric Alimetry metrics included BMI-adjusted Amplitude, Principal Gastric Frequency, Gastric Alimetry Rhythm Index (GA-RI) and Fed:Fasted Amplitude Ratio (ff-AR)., Key Results: 238 participants (59.2% female) were included. All meals significantly increased amplitude and frequency during the first postprandial hour (p < 0.05). There were no differences in postprandial frequency across meals (p > 0.05). The amplitude and GA-RI of the standard meal (n = 110) were significantly higher than the energy bar alone (n = 45) and egg meal (n = 65) (all p < 0.05). All BSGM metrics were comparable across the three smaller meals (p > 0.05). A higher symptom burden was found in the oatmeal bar group versus the standard meal and pancake meal (p = 0.01, 0.003, respectively)., Conclusions & Inferences: The consumption of lower calorie meals elicited different postprandial responses, when compared to the standard Gastric Alimetry meal. These data will guide interpretations of BSGM when applied with lower calorie meals., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Objective: There is currently a lack of validated questionnaires designed specifically to assess mental health within patients with chronic gastroduodenal symptoms. This research describes the multi-phase process used to develop and validate a novel mental health scale for patients with chronic gastroduodenal symptoms, the Alimetry® Gut-Brain Wellbeing (AGBW) Survey., Methods: A patient-centered multi-phase process was implemented. In Phase 1, the most relevant concepts for this patient population were selected from existing mental health scales, using data from 79 patients. In Phase 2, an interdisciplinary panel of experts generated scale items. In Phase 3, the scale underwent pre-testing with gastroenterologists ( n = 9), health psychologists ( n = 3), and patients ( n = 12), with feedback incorporated over multiple rounds. Lastly, the psychometric properties of the scale were assessed in a sample of 311 patients via an online survey., Results: The AGBW Survey comprises a patient preface, 10 close-ended questions, and an optional open-ended question. This multidimensional scale assesses general mental health, alongside specific subscales relating to depression, stress, and anxiety. The subscale and total scores demonstrated high internal consistency ( α = 0.91 for the total scale; α = 0.72-0.86 for subscales) and good convergent, divergent, concurrent validity, and known groups validity, with large effect sizes., Conclusion: The AGBW Survey is a brief, valid, and reliable scale for assessing mental health in patients with chronic gastroduodenal symptoms. It can be used as a tool to complement physiological tests and has the potential to guide psychological referrals, inform multidisciplinary management, and evaluate treatment outcomes., Competing Interests: GO’G and AG hold grants and intellectual property in the field of gastrointestinal electrophysiology and are Directors in Alimetry Ltd. GO’G is also a Director in The Insides Company. ML, IP, GSe, GSc, PD, CD, CA, and SC are members of Alimetry Ltd. GH holds options in Alimetry. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Law, Pickering, Humphrey, Sebaratnam, Schamberg, Simpson, Varghese, Du, Daker, Huang, Khalsa, Gharibans, O'Grady, Andrews and Calder.)

Background: Gastrointestinal dysmotility is frequently suspected in patients with gastroparesis, functional dyspepsia, and ileus, and in the intensive care unit. Monitoring of gastric motility in clinical practice remains challenging. A novel technology was developed to meet the medical need for a widely available bedside tool to monitor gastric motility continuously. The VIPUN™ Gastric Monitoring System (GMS) comprises a nasogastric feeding tube with intragastric balloon to allow for measuring gastric contractions., Aims: To compare the performance of the VIPUN GMS versus a reference technique (manometry)., Methods: In this validation study in healthy subjects, the investigational catheter and a solid-state manometry catheter were placed in the stomach concomitantly. Motility was recorded for 2.5 h: 2 h in a fasting state, followed by a 400-kcal liquid meal, and monitoring of the fed state for the remaining half hour. The performance of both systems was compared by automated recognition and manual identification of the contractile activity. Data are presented as mean (standard deviation)., Key Results: The analysis set comprised 13 healthy subjects (6 women, age: 27.5 (8.1) years, BMI: 22.2 (2.46) kg/m 2 ). Automatically-recognized contractility was strongly correlated between the two techniques (endpoint: contraction duration; Spearman ρ = 0.96, p < 0.001). A correlation was also observed between the number of individual contractions identified by expert gastroenterologists on both technologies independently (ρ = 0.71, p = .007) and between the contractions identified by the experts and by the GMS software (ρ = 0.87, p = 0.001). No serious or unanticipated adverse events occurred., Conclusions & Inferences: The observed strong correlations with the gold standard, manometry, validate the performance of the VIPUN GMS as a gastric monitoring system., (© 2024 John Wiley & Sons Ltd.)

Bacterial pore-forming toxins (PFTs) that disrupt host plasma membrane integrity (PMI) significantly contribute to the virulence of various pathogens. However, how host cells protect PMI in response to PFT perforation in vivo remains obscure. Previously, we demonstrated that the HLH-30/TFEB-dependent intrinsic cellular defense (INCED) is elicited by PFT to maintain PMI in Caenorhabditis elegans intestinal epithelium. Yet, the molecular mechanism for the full activation of HLH-30/TFEB by PFT remains elusive. Here, we reveal that PRMT-7 (protein arginine methyltransferase-7) is indispensable to the nuclear transactivation of HLH-30 elicited by PFTs. We demonstrate that PRMT-7 participates in the methylation of HLH-30 on its RAG complex binding domain to facilitate its nuclear localization and activation. Moreover, we showed that PRMT7 is evolutionarily conserved to regulate TFEB cellular localization and repair plasma damage caused by PFTs in human intestinal cells. Together, our observations not only unveil a novel PRMT-7/PRMT7-dependent post-translational regulation of HLH-30/TFEB but also shed insight on the evolutionarily conserved mechanism of the INCED against PFT in metazoans.

Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m 2 ] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, P = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, P < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo. NEW & NOTEWORTHY In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.

Background: The comparative efficacy of biologics and small-molecule inhibitors in treating palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP) remains uncertain., Objective: The aim was to perform a systematic review and network meta-analysis (NMA) to compare the efficacy of biologics and small-molecule inhibitors for the treatment of PP and PPP., Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched for eligible studies from inception to May 13, 2023. This NMA was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension Statement for Network Meta-Analyses guidelines. Frequentist random-effects models NMA was performed with the surface under the cumulative ranking curve calculated for ranking. Our primary outcome was the proportion of patients achieving a clear/minimal Palmoplantar Psoriasis/Pustulosis Physician Global Assessment score (PPPGA 0/1 or PPPPGA 0/1) response at 12-16 weeks. Secondary outcomes consisted of the percentage of overall improvement in palmoplantar score and of improvement ≥ 75%, at 12-16 weeks., Results: The study comprised a total of 29 randomized controlled trials (RCTs), involving 4798 psoriasis patients with palmoplantar diseases. For PP, 16 RCTs with nine different treatments, including adalimumab, apremilast, bimekizumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab, and ustekinumab were included for the analysis. In the NMA of PP, secukinumab 300 mg ranked highest (odds ratio [OR] 33.50, 95% confidence interval [CI] 4.37-256.86) in achieving PPPGA 0/1, followed by guselkumab 100 mg (OR 18.68, 95% CI 10.07-34.65). In the case of PPP, seven RCTs with six treatments, including apremilast, etanercept, guselkumab, imsidolimab, spesolimab, and ustekinumab, were included for the analysis. In the NMA of PPP, although no treatment demonstrated a significant difference compared to placebo in achieving PPPPGA 0/1, guselkumab 100 mg showed the greatest statistically significant improvement in the palmoplantar score (weighted mean difference 31.73, 95% CI 19.89-43.57) as a secondary outcome., Conclusion: Among all available biologics and small-molecule inhibitors, secukinumab 300 mg and guselkumab 100 mg had the most favorable efficacy in treating PP and PPP, respectively., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Dyspepsia is a prevalent condition in the general population. Besides organic causes, the differential diagnosis of dyspepsia includes functional dyspepsia (FD) and gastroparesis (GP) which share similar pathophysiological mechanisms and clinical presentation. So far, no study investigated the prevalence of FD and GP in a primary care in Belgium., Methods: Data were obtained from Intego, a Flemish-Belgian general practice-based morbidity registration network. From 586,164 patients between 2000 and 2021, we selected patients with ICD-10 code for FD and GP. Patients with organic gastrointestinal diseases were excluded. We determined demographics and comorbidities of FD/GP. For prevalence and incidence calculation, we included those who consulted their general practitioners at least once in the given year. Pair-wise comparison was conducted to access the impact of comorbidities on risk of FD/GP., Key Results: Between 2011 and 2021, the prevalence of FD/GP ranged from 1.03% to 1.21%. The incidence of FD/GP ranged from 109 to 142 per 100,000 adults. In total 5242 cases of FD/GP were identified. These cases shared commonly coexisting diagnoses of gastroesophageal reflux disease (18.8%), irritable bowel syndrome (17.1%), and chronic constipation (18.7%). Patients with somatization/anxiety/depression had significantly higher risk of FD/GP, compared to the control (OR 1.38, 95% CI 1.19-1.61, p < 0.01)., Conclusions and Inferences: The prevalence (1.03%-1.21%) and incidence (109-142/100,000) of FD/GP in primary care over last decade appear to conflict with epidemiological research in the general population. The discrepancies suggest a potential lack of awareness of FD and GP among physicians and/or patients in Flemish-Belgium., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Importance: Sulfamethoxazole (SMX) and cotrimoxazole (CTX), a fixed-dose combination of SMX and trimethoprim in a 5:1 ratio, are antibacterial sulfonamides commonly used for treating various diseases. A substantial prevalence of severe cutaneous adverse reactions (SCARs) following the administration of these drugs has been reported. However, the association between human leukocyte antigen (HLA) genotypes and SMX/CTX-induced SCARs has remained unclear., Objective: To investigate the association between HLA genotypes and SMX/CTX-induced SCARs., Data Sources: A comprehensive search was conducted in CENTRAL (Cochrane Library), MEDLINE, and Embase from inception to January 17, 2023., Study Selection: Case-control studies that recruited patients who had experienced SCARs following SMX or CTX were included, and HLA alleles were analyzed., Data Extraction and Synthesis: Two independent authors extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. The Newcastle-Ottawa Scale for case-control studies was used to assess study quality. Odds ratios (ORs) were calculated using a random-effects model for meta-analysis., Main Outcomes and Measures: The prespecified outcome was the OR comparing SMX/CTX-induced SCARs with healthy or SMX/CTX-tolerant controls based on different HLA alleles., Results: Six studies involving 322 patients with SCAR were included, including 236 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 86 with drug reaction with eosinophilia and systemic symptoms, 8448 healthy controls, and 229 tolerant controls. Significant associations were found in HLA-A*11:01 (OR, 2.10; 95% CI, 1.11-4.00), HLA-B*13:01 (OR, 5.96; 95% CI, 1.58-22.56), HLA-B*15:02 (OR, 2.23; 95% CI, 1.20-4.14), HLA-B*38:02 (OR, 3.47; 95% CI, 1.42-8.48), and HLA-C*08:01 (OR, 2.63; 95% CI, 1.07-6.44) compared with tolerant controls. In the Stevens-Johnson syndrome/toxic epidermal necrolysis subgroup, significant associations were found in HLA-B*15:02 (OR, 3.01; 95% CI, 1.56-5.80) and HLA-B*38:02 (OR, 5.13; 95% CI, 1.96-13.47). In the drug reaction with eosinophilia and systemic symptoms subgroup, significant associations were found in HLA-A*68:01 (OR, 12.86; 95% CI, 1.09-151.34), HLA-B*13:01 (OR, 23.09; 95% CI, 3.31-161.00), HLA-B*39:01 (OR, 4.56; 95% CI, 1.31-15.82)., Conclusions and Relevance: The results of this systematic review and meta-analysis suggest that multiple HLA alleles (HLA-A*11:01, HLA-B*13:01, HLA-B*15:02, HLA-B*38:02, and HLA-C*0801) are associated with SMX/CTX-induced SCARs.

Background: Cases of autoimmune bullous dermatosis (AIBD) have been reported following COVID-19 vaccination., Objective: We aimed to provide an overview of clinical characteristics, treatments, and outcomes of AIBDs following COVID-19 vaccination., Methods: We conducted a systematic review and searched the Embase, Cochrane Library, and Medline databases from their inception to 27 March 2024. We included all studies reporting ≥ 1 patient who developed new-onset AIBD or experienced flare of AIBD following at least one dose of any COVID-19 vaccine., Results: We included 98 studies with 229 patients in the new-onset group and 216 in the flare group. Among the new-onset cases, bullous pemphigoid (BP) was the most frequently reported subtype. Notably, mRNA vaccines were commonly associated with the development of AIBD. Regarding the flare group, pemphigus was the most frequently reported subtype, with the mRNA vaccines being the predominant vaccine type. The onset of AIBD ranged from 1 to 123 days post-vaccination, with most patients displaying favorable outcomes and showing improvement or resolution from 1 week to 8 months after treatment initiation., Conclusions: Both new-onset AIBD and exacerbation of pre-existing AIBD may occur following COVID-19 vaccination. Healthcare practitioners should be alert, and post-vaccination monitoring may be essential.

Facing a 40% mortality rate in candidemia patients, drug-resistant Candida and their petite mutants remain a major treatment challenge. Antimicrobial photodynamic therapy (aPDT) targets multiple fungal structures, unlike antibiotics/antifungals, potentially thwarting resistance. Traditional methods for inducing petite colonies rely on ethidium bromide or fluconazole, which can influence drug susceptibility and stress responses. This study investigated the application of green light (peak 520 nm) and rose bengal (RB) photosensitizer to combat a drug-resistant Candida glabrata isolate. The findings revealed that aPDT treatment significantly inhibited cell growth (≥99.9% reduction) and effectively induced petite colony formation, as evidenced by reduced size and loss of mitochondrial redox indicator staining. This study provides initial evidence that aPDT can induce petite colonies in a multidrug-resistant C. glabrata strain in vitro, offering a potentially transformative approach for combating resistant fungal infections.

Clostridioides difficile is a Gram-positive, anaerobic, and spore-forming bacterial member of the human gut microbiome. The primary virulence factors of C. difficile are toxin A and toxin B. These toxins damage the cell cytoskeleton and cause various diseases, from diarrhea to severe pseudomembranous colitis. Evidence suggests that bacteriophages can regulate the expression of the pathogenicity locus (PaLoc) genes of C. difficile. We previously demonstrated that the genome of the C. difficile RT027 strain NCKUH-21 contains a prophage-like DNA sequence, which was found to be markedly similar to that of the φCD38-2 phage. In the present study, we investigated the mechanisms underlying the φNCKUH-21-mediated regulation of the pathogenicity and the PaLoc genes expression in the lysogenized C. difficile strain R20291. The carriage of φNCKUH-21 in R20291 cells substantially enhanced toxin production, bacterial motility, biofilm formation, and spore germination in vitro. Subsequent mouse studies revealed that the lysogenized R20291 strain caused a more severe infection than the wild-type strain. We screened three φNCKUH-21 genes encoding DNA-binding proteins to check their effects on PaLoc genes expression. The overexpression of NCKUH-21&#95;03890, annotated as a transcriptional regulator (phage transcriptional regulator X, PtrX), considerably enhanced toxin production, biofilm formation, and bacterial motility of R20291. Transcriptome analysis further confirmed that the overexpression of ptrX led to the upregulation of the expression of toxin genes, flagellar genes, and csrA. In the ptrX-overexpressing R20291 strain, PtrX influenced the expression of flagellar genes and the sigma factor gene sigD, possibly through an increased flagellar phase ON configuration ratio., Competing Interests: Declaration of Interest Statement The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Introduction: Gastric emptying testing (GET) assesses gastric motility, however, is nonspecific and insensitive for neuromuscular disorders. Gastric Alimetry (GA) is a new medical device combining noninvasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared with GET., Methods: Patients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline, 99m TC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: (i) sensorimotor, (ii) continuous, and (iii) other., Results: Seventy-five patients were assessed, 77% female. Motility abnormality detection rates were as follows: GET 22.7% (14 delayed, 3 rapid), GA spectral analysis 33.3% (14 low rhythm stability/low amplitude, 5 high amplitude, and 6 abnormal frequency), and combined yield 42.7%. In patients with normal spectral analysis, GA symptom phenotypes included sensorimotor 17% (where symptoms strongly paired with gastric amplitude, median r = 0.61), continuous 30%, and other 53%. GA phenotypes showed superior correlations with Gastroparesis Cardinal Symptom Index, Patient Assessment of Upper Gastrointestinal Symptom Severity Index, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores ( P > 0.05). Delayed emptying was not predictive of specific GA phenotypes., Discussion: GA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with increased correlation with symptoms and psychometrics compared with gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders., (Copyright © 2023 by The American College of Gastroenterology.)

Background: In Asian countries, such as Taiwan, social taboos regarding organ and tissue donation decreases the prevalence of organ and tissue transplants. This also applies to cornea recovery, which is a skill that requires precision and practice to perform well. In Taiwan, to ensure the maintenance of high-quality corneas, a comprehensive training program and certified examination has been implemented. This study aims to investigate the impact of these programs and examinations on cornea recovery., Methods: Researchers evaluated the efficiency of the training and certified examination process by comparing the corneoscleral rim width, Descemet's membrane folds, endothelial layer stress lines, and endothelial cell density performed by ophthalmology residents in 2018 and 2019., Results: After training and certification, the Descemet's membrane folds rate decreased from 14.3 % to 2.0 % and endothelial layer stress lines rate decreased from 22.5 % to 5.0 %. The endothelial cell density of donor grafts significantly improved from 2681.9 cells/mm 2 to 2869.7 cells/mm 2 ( p  < 0.001)., Conclusions: This study used objective data to evaluate cornea recovery quality after training and certification. The training and certified examination significantly improved the surgical skills of ophthalmology residents and could be applied in other tissue or organ recovery procedures to maintain and improve quality., Competing Interests: 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., (© 2023 The Authors.)

Background: Management of urticaria can be optimized with clinical practice guidelines (CPGs). However, the quality of recent urticaria CPGs remains unclear., Objective: To identify and appraise urticaria CPGs worldwide published in the last 5 years., Methods: A search for relevant urticaria CPGs was conducted between January 1, 2017, and May 31, 2022, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE) Evidence Search, Guidelines International Network, ECRI Guidelines Trust, Australian Clinical Practice Guidelines, Trip Medical Database, and DynaMed. The included CPGs were critically appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al's red flags, and the Institute of Medicine (IOM) criteria of trustworthiness., Results: We included 21 urticaria CPGs. Most guidelines reviewed treatment recommendations of chronic spontaneous urticaria. The majority of guidelines were from European and Asian countries with high and high-middle sociodemographic index, written in English, and openly accessible. Seventeen guidelines (81%) had at least 1 AGREE II domain rated poor quality. Applicability, rigor of development, and stakeholder involvement were the 3 AGREE II domains that scored the lowest across guidelines. Appraisal with Lenzer et al's red flags showed that 18 guidelines (86%) raised at least 1 red flag indicating potential bias. The top 3 domains raising red flags were: no inclusion of nonphysician experts/patient representative/community stakeholders, no or limited involvement of a methodologist in the evaluation of evidence, and lack of external review. Based on IOM's criteria of trustworthiness, 20 guidelines (95%) had 1 or more criteria that did not meet best practice standards. The 3 domains with the highest number of best practice standards not met were updating procedures, rating strength of recommendations, and external review. Guidelines scored highest for the AGREE II domains of defining scope and purpose and clarity of presentation, and had the most fully met IOM's best practice standard for articulation of recommendations. However, only 1 urticaria CPG by NICE was identified as rigorously developed across all 3 appraisal tools., Conclusions: The quality of urticaria CPGs in the last 5 years varied widely. Only the NICE urticaria guideline consistently demonstrated excellent quality, high trustworthiness, and low risk of bias. Use of a rigorous framework to rate certainty of evidence and grade strength of recommendation, involvement of methodologists, stakeholder engagement with external review, and clear guidance for updating can help improve the quality of future CPGs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Acne is an extremely common skin disease with an estimated global prevalence of 9.4%. We aim to provide comprehensive comparisons of the common pharmacological treatments for acne., Methods: Randomized controlled trials comparing the efficacy of pharmacological therapies for acne vulgaris in patients of any age and sex and with a treatment duration of >2 weeks were included. PubMed and Embase databases were searched from inception until February 2022. Our prespecified primary end points were mean percentage reduction in total, inflammatory, and noninflammatory lesions. Treatment ranking was determined by P values., Results: There were 210 articles describing 221 trials and 37 interventions included in the analysis. Our primary analysis of percentage reduction in total lesion count had 65,601 patients enrolled. Across all trials, the mean age was 20.4 years. The median duration of treatment was 12 weeks. The median total, inflammatory, and noninflammatory lesion counts were 72, 27, and 44, respectively. The most effective treatment was oral isotretinoin (mean difference [MD] = 48.41; P = 1.00), followed by triple therapy containing a topical antibiotic, a topical retinoid, and benzoyl peroxide (BPO) (MD = 38.15; P = .95) and by triple therapy containing an oral antibiotic, a topical retinoid, and BPO (MD = 34.83; P = .90). For monotherapies, oral or topical antibiotics or topical retinoids have comparable efficacy for inflammatory lesions, while oral or topical antibiotics have less effect on noninflammatory lesions., Conclusion: The most effective treatment for acne is oral isotretinoin, followed by triple therapies containing a topical retinoid, BPO, and an antibiotic. We present detailed comparisons of each intervention to serve as a practical database., (© 2023 Annals of Family Medicine, Inc.)

Background and Objectives: To evaluate the association between psoriasis and migraine., Patients and Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant observational studies from their respective inception to May 1, 2022. A random-effects model meta-analysis was performed to calculate the risk estimates quantifying the associations between psoriasis and migraine. We also performed a sensitivity analysis by including only studies with adjusted risk estimates and a subgroup analysis according to the severity of psoriasis., Results: We included 9 studies with 6,742,075 participants. The meta-analysis illustrated increased odds for prevalent migraine among patients with psoriasis (pooled OR: 1.69, 95% CI: 1.26-2.28) and increased odds for prevalent psoriasis among those with migraine (OR: 1.88, 95% CI: 1.32-3.67). A subgroup analysis of cohort studies demonstrated an increasingly higher risk of incident migraine in patients with mild psoriasis and severe psoriasis (IRR being 1.37 (95% CI 1.30-1.44) and 1.55 (95% CI 1.29-1.86), respectively)., Conclusions: This meta-analysis revealed significant bidirectional associations between migraine and psoriasis. Greater severity of psoriasis appears to be associated with a higher risk of developing migraine. Clinicians should evaluate symptoms of migraine in patients with psoriasis and provide proper treatments., (© 2023 Deutsche Dermatologische Gesellschaft (DDG).)

Background: The European consensus defined gastroparesis as a condition characterised by delayed gastric emptying (GE) in the absence of mechanical obstruction, with a symptom pattern of predominant nausea and/or vomiting and overlapping postprandial distress syndrome (PDS). The distinction between patients with gastroparesis and those with functional dyspepsia (FD), another gastrointestinal condition characterised by predominant PDS or epigastric pain syndrome symptoms, is ongoing., Aim: To investigate the extent that symptom patterns may differentiate gastroparesis from FD., Methods: This retrospective study included 637 patients from Leuven University Hospital in 2006-2021 who had upper gastrointestinal symptoms, underwent a GE test, and completed the Dyspepsia Symptom Severity (DSS) questionnaire. Patients were identified as with gastroparesis-like symptoms (GPLS; i.e., moderate to severe nausea with moderate to severe PDS) or FD symptoms (not fitting GPLS). We excluded patients aged <18 years, and those with diabetes, organic gastrointestinal disease or a history of abdominal surgeries. Demographic and clinical variables were compared., Results: Among 545 patients, 238 reported GPLS and 307 reported FD symptoms. Those with GPLS had a significantly higher prevalence of delayed GE (half emptying time (T1/2) ≥109 min) and lower body mass index than those with FD (33.2% vs 17.6%, p < 0.01; 19.9 vs 21.2, p < 0.01, respectively). Among GPLS patients, those with delayed GE had higher DSS than those without (13.0 vs 12.0, p < 0.01)., Conclusions: In tertiary care patients who reported gastroparesis or FD symptoms, the presence of delayed GE was associated with GPLS. In patients with GPLS, delayed GE was associated with higher symptom severity., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions., Objective: To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis., Design: Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials., Results: Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology., Conclusions: The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum , cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B are used as medical therapeutics and anti-wrinkle reagents. In this study, we investigated the efficacy of BoNT/CD, a mosaic toxin of BoNT/C and BoNT/D, to assess its potential as a therapeutic alternative for BoNT/A. In a cultured neuron assay, BoNT/CD cleaved syntaxin and SNAP-25 with higher efficacy than BoNT/C and BoNT/A. Intramuscularly administrated BoNT/CD induced dose-dependent muscle paralysis, and the paralysis lasted ~21 days in a mouse digit abduction score assay (BoNT/A-induced paralysis lasted ~30 days). BoNT/C failed to induce local paralysis without systemic toxicity. Multiple alignment analyses of the amino acid sequences of the receptor binding domain (H C ) of eight BoNT/CDs and two BoNT/Ds showed sequence clustering in five groups. Comparing BoNT/CD strain 003-9 (BoNT/CD 003-9 ) and strain 6813 (BoNT/CD 6813 ) showed that both BoNT/CDs displayed similar efficacies in cultured neurons, but BoNT/CD 003-9 displayed higher efficacy in a mouse model than BoNT/CD 6813 . These findings suggest that BoNT/CD may be a potential alternative for patients who do not respond to existing BoNT-based therapeutics.

Cholesterol-dependent cytolysin (CDC) is a bacterial toxin that binds to eukaryotic cholesterol-containing membranes, forms oligomeric complexes, and is inserted into the bilayer to create large aqueous pores. Recently, we reported a species-specific duplication of the hemolysin gene in group III Clostridium botulinum. The duplicated genes (bly1 and bly2) encoded two separate CDC proteins (botulinolysins; BLY1 and BLY2). Here, we aimed to investigate whether BLY1 and BLY2 exert differential cytotoxicity. We isolated two bly genes from C. botulinum and evaluated the cytotoxicity of two recombinant BLY proteins (rBLY1 and rBLY2) in HeLa, IEC-6, and NRK cells. rBLYs were cytotoxic to equine erythrocytes. rBLY1 showed higher hemolytic activity than rBLY2. rBLY2 showed no or very weak cytotoxicity to the HeLa, IEC-6, and NRK cells, whereas rBLY1 showed high cytotoxicity to these cells. The comparison of the amino acid sequence of BLYs with those of other CDCs revealed that the already-known amino acid residues involved in cholesterol-containing membrane recognition, oligomerization, and insertion into membranes are well conserved in both BLYs. However, several amino acid substitutions were observed in the conserved regions, particularly in L2 and L3 regions involved in cell binding. These findings suggest that gene duplication in group III C. botulinum evolved distinct functional specializations, and differential cytotoxicity of BLY1 and BLY2 could be due to the amino acid substitution in the conserved regions. However, the structural and functional comparisons of the two BLYs are essential to gain insights into the function of the CDCs., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although past research has shown an association between obesity and herpes simplex virus infection, the relationship between body mass index (BMI) and herpetic stromal keratitis (HSK) recurrence has never been investigated. In this study, we included HSK patients who received oral valacyclovir as prophylactic treatment between January 2016 and January 2021. Recurrence, possible risk factors, and the time to recurrence were recorded during follow-ups. Among the 56 patients included in this study, recurrence was reported in 21 (37.5%) patients. The age at disease onset and mean follow-up time were not significantly different in the recurrence and non-recurrence groups. However, in the Cox regression analysis, BMI ≥ 24 kg/m 2 was noted as the variable having significant correlation with recurrence ( p = 0.01 in univariate analysis and p = 0.001 in multivariate analysis). In conclusion, overweight and obesity were revealed as risk factors for HSK recurrence in patients receiving long-term antiviral prophylaxis. Further studies are needed to determine the appropriate acyclovir concentrations in the blood or aqueous humour in order to achieve desirable prophylactic effects, especially in the overweight and obese patients.

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK-STAT signal transduction. Furthermore, JAK-STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK-STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK-STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Chung, Wu and Chen.)

Clostridium botulinum produces seven botulinum neurotoxin (BoNT) serotypes. In nature, BoNT exists as a part of the progenitor toxin complex (PTC) through associations with neurotoxin associated proteins (NAPs), including nontoxic nonhemagglutinin and hemagglutinin (HA) complex, consists of HA-70, HA-17 and HA-33. Because PTC displays higher oral toxicity than pure BoNTs, NAPs play a critical role in food poisoning. In a previous study, we demonstrated that the NAP complex in mature large-sized PTC (L-PTC) from serotypes C and D concomitantly induced cell death and cytoplasmic vacuolation in the rat intestinal epithelial cell line IEC-6. Here, we found that the serotype D NAP complex induces only cytoplasmic vacuolation in the normal rat kidney cell line NRK-52E without reducing cell viability. NAP complexes from serotype A and B L-PTCs did not affect cell viability or cytoplasmic vacuolation in IEC-6 and NRK-52E cells. Furthermore, we assessed the effect of immature L-PTCs with fewer HA-33/HA-17 trimers (two HA-33 and one HA-17) than mature L-PTCs on cell viability and cytoplasmic vacuolation in IEC-6 and NRK-52E cells. As a result, mature L-PTCs with the maximum number of HA-33/HA-17 trimers displayed the greatest potency. Consequently, the reduction in cell viability and vacuolation induction are related to the number of HA-33/HA-17 trimers in PTC. The discovery of an epithelial cell model where botulinum PTC specifically induces vacuolization may help clarify the unknown cytotoxicity of PTC, which plays an important role in the trans-epithelial transport of the toxin., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hintergrund Und Ziele: Trotz des wohlbekannten Zusammenhangs zwischen bullösem Pemphigoid (BP) und neurologischen Erkrankungen ist der Zusammenhang zwischen BP und psychiatrischen Erkrankungen nach wie vor ungeklärt. In dieser Studie war es unser Ziel, den Zusammenhang zwischen BP und verschiedenen psychischen Störungen zu untersuchen., Patienten Und Methoden: Die Datenbanken PubMed, Embase und Cochrane Library wurden bis zum 30. Mai 2021 hinsichtlich der Identifizierung geeigneter Kohorten- und Fall-Kontroll-Studien durchsucht. Anschließend wurden Metaanalysen der rohen Schätzwerte sowie der bereinigten Schätzwerte der Odds-Ratio (OR) für Fall-Kontroll-Studien und der Hazard-Ratio (HR) für Kohortenstudien durchgeführt., Ergebnisse: Es wurden 16 Studien mit 637 285 Patienten in die qualitative Synthese eingeschlossen. In der Metaanalyse der bereinigten Schätzwerte für Fall-Kontroll-Studien zeigten Patienten mit BP eine signifikant höhere Prävalenz psychischer Störungen (OR 1,77, 95 %-Konfidenzintervall (KI) 1,07-2,92) und Schizophrenie (OR 2,63, 95 %-KI 2,03-3,39). Hinsichtlich der Analyse der bereinigten Schätzwerte für Kohortenstudien stellte BP kein signifikant höheres Risiko für Depression (HR 1,09, 95 %-KI 0,94-1,26) und Schizophrenie (HR 1,35, 95 %-KI 0,76-2,39) dar., Schlussfolgerungen: Bei psychiatrischen Erkrankungen, insbesondere Schizophrenie, besteht ein signifikant höheres Risiko, dass sie einem BP vorausgehen., (© 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

This is the first report to discover Clostridiodes difficile (C. difficile) ribotype RT126 and RT598 (both ribotypes belong to RT078-lineage) in a river water system in southern Taiwan. Fluoroquinolone resistance was also found. The connection between clinical isolates and those from the environment needs further investigation., (Copyright © 2022. Published by Elsevier B.V.)

Background/objectives: The global epidemiology of gastroparesis is unknown. The European UEG and European Society for Neurogastroenterology and motility consensus defines Gastroparesis as a condition characterized by delayed gastric emptying in the absence of mechanical obstruction, with a symptom pattern of nausea and/or vomiting and overlapping postprandial distress syndrome (PDS). Real-world evidence of this gastroparesis-like symptom pattern is a crucial step in understanding the epidemiology of gastroparesis., Methods: In the Rome Foundation Global Epidemiology Study, 54,127 respondents from 26 countries completed the Rome IV Diagnostic Questionnaire and variables associated with disorders of gut-brain interaction via Internet. We selected subjects with gastroparesis-like symptoms (GPLS) (nausea and/or vomiting ≥1 day/week and simultaneous PDS). Patients reporting organic gastrointestinal disease, or fulfilling criteria for self-induced vomiting, cyclic vomiting or cannabinoid hyperemesis syndrome were excluded. We determined prevalence, associated comorbidities, quality of life (QoL) (PROMIS Global-10), symptoms of anxiety and depression (PHQ-4), somatic symptoms (PHQ-12), and healthcare utilization., Results: The global prevalence of GPLS was 0.9% overall and 1.3% among diabetic individuals. Subjects with GPLS showed frequent overlapping of epigastric pain syndrome and irritable bowel syndrome. Subjects with GPLS had significantly lower body mass index, QoL, more non-gastrointestinal somatic complaints, symptoms of anxiety and depression, higher medication usage and doctor visits in the overall and diabetic population, compared to subjects without these symptoms., Conclusions: GPLS are common worldwide and more common in diabetic patients. The symptom complex is associated with multiple aspects of illness and an increased healthcare consumption., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background and Objectives: Despite the well-established association between bullous pemphigoid (BP) and neurological diseases, the association between BP and psychiatric disorders remains unclear. In this study, we aimed to investigate the association between BP and various psychiatric disorders., Patients and Methods: PubMed, Embase, and Cochrane Library databases were searched for the identification of eligible cohort and case-control studies until May 30, 2021. Meta-analyses of crude estimates and adjusted estimates of odds ratio (OR) for case-control studies and hazard ratio (HR) cohort studies were then conducted., Results: Sixteen studies involving 637,285 patients were included for the qualitative synthesis. In the meta-analysis of adjusted estimates for case-control studies, patients with BP exhibited a significantly higher prevalence of psychiatric disorders (OR 1.77, 95 % confidence interval (CI) 1.07-2.92) and schizophrenia (OR 2.63, 95 % CI 2.03-3.39). Regarding the analysis of adjusted estimates of cohort studies, BP presented no significantly higher risk of depression (HR 1.09, 95 % CI 0.94-1.26) and schizophrenia (HR 1.35, 95 % CI 0.76-2.39)., Conclusions: Psychiatric disorders, especially schizophrenia, have a significantly higher risk of preceding BP., (© 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Elevated thymidine phosphorylase (TP) levels, a key enzyme in the pyrimidine nucleoside salvage pathway, in cancer cells, are related to a poor prognosis in a variety of cancers. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is involved in the stabilization and maturation of many oncogenic proteins. The aim of this study is to elucidate whether Hsp90 inhibitor 17-AAG could enhance tamoxifen- and erlotinib-induced cytotoxicity in nonsmall cell lung cancer (NSCLC) cells via modulating TP expression in two squamous NSCLC cell lines, H520 and H1703. We found that 17-AAG reduced TP expression via inactivating the MKK1/2-ERK1/2-mitogen-activated protein kinase (MAPK) pathway. TP knockdown with siRNA or ERK1/2 MAPK inactivation with the pharmacological inhibitor U0126 could enhance the cytotoxic and growth inhibitory effects of 17-AAG. In contrast, MKK1-CA or MKK2-CA (a constitutively active form of MKK1/2) vector-enforced expression could reduce the cytotoxic and cell growth inhibitory effects of 17-AAG. Furthermore, 17-AAG enhanced the cytotoxic and cell growth inhibitory effects of tamoxifen and erlotinib in NSCLC cells, which were associated with TP expression downregulation and MKK1/2-ERK1/2 signal inactivation. Taken together, Hsp90 inhibition downregulates TP, enhancing the tamoxifen- and erlotinib-induced cytotoxicity in H520 and H1703 cells., 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 © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: To compare the efficacy and safety of biologic treatments for moderate-to-severe pediatric psoriasis approved by the US Food and Drug Administration and European Medicines Agency., Patients and Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials (RCTs) were searched for the identification of eligible RCTs until May 7, 2021. Fixed-effect frequentist network meta-analysis (NMA) was performed with the surface under the cumulative ranking curve (SUCRA) calculated for ranking. Our primary outcomes included ≥ 90 % improvement of Psoriasis Area and Severity Index score (PASI 90) at 12-16 weeks and discontinuation owing to adverse events (DAE) through the first 12-16 weeks., Results: Five RCTs involving 798 pediatric psoriasis patients were included. Compared to placebo, all biologic regimens exhibited a significantly higher PASI 90 response but did not differ in the risk for DAE. Based on the SUCRA, secukinumab-low dose (SEC-L) ranked first in the achieved PASI 90 response (84.7 %), followed by ixekizumab (70.8 %)., Conclusions: Among all biologic treatments, SEC-L showed the best PASI 90 response without increasing the risk for DAE. More long-term studies are warranted., (© 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported "frequent dysmenorrhea" in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P < 5 × 10 -8 , which clustered in 2 regions. The first SNP cluster was on chromosome 1, and included 24 high LD (R 2  > 0.88) variants around the NGF gene (lowest P value of 3.83 × 10 -13 for rs2982742). Most SNPs occurred within NGF introns, and were predicted to alter regulatory binding motifs. The second SNP cluster was on chromosome 2, including 7 high LD (R 2  > 0.94) variants around the IL1A and IL1B loci (lowest P value of 7.43 × 10 -10 for rs11676014) and 22 SNPs that did not reach significance after conditional analysis. Most of these SNPs resided within IL1A and IL1B introns, while 2 SNPs may be in the promoter histone marks or promoter flanking regions of IL1B. To conclude, data from this study suggest that NGF, IL1A, and IL1B may be involved in the pathogenesis of primary dysmenorrhea in the Han Chinese in Taiwan., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Clinical practice guidelines (CPGs) developed with rigorous methods can help optimize clinical care for patients with psoriasis., Objectives: To conduct an updated systematic review and comprehensive critical appraisal of global psoriasis CPGs., Methods: A search of MEDLINE and Embase for psoriasis CPGs published between 1 January 2015 and 31 March 2021 was performed. Other guideline repositories were also searched for relevant CPGs. Descriptive analysis was conducted to summarize included guidelines. Three critical appraisal tools were used to assess the quality of included CPGs: the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al.'s red flags, and the US Institute of Medicine's (IOM) criteria of trustworthiness., Results: We included 33 psoriasis CPGs, with 25 openly accessible. Most CPGs were from high sociodemographic index countries in North America and Europe. Five CPGs received 'excellent quality' appraisals across all six AGREE II domains. Stakeholder involvement, rigour of development and applicability were the three domains with the lowest appraisal scores for AGREE II. Twenty-two CPGs raised at least one red flag indicative of potential bias. By the IOM's standards, external review of the guideline draft prior to publication and clear updating procedures were most often not addressed by guidelines, and only three CPGs were assessed as having higher overall trustworthiness., Conclusions: Most psoriasis guidelines were unable to consistently demonstrate high quality across multiple appraisal tools. The EuroGuiDerm guideline on the systemic treatment of psoriasis vulgaris was the only CPG to receive 'excellent quality' across all six AGREE II domains, to raise no Lenzer's red flags, and to have higher trustworthiness by IOM criteria., (© 2022 British Association of Dermatologists.)

Purpose: This study aimed to evaluate the therapeutic efficacy and long-term outcomes of treatment with topical 2% ganciclovir solution in immunocompetent patients with aqueous humor polymerase chain reaction (PCR)-proven cytomegalovirus (CMV) anterior uveitis and corneal endotheliitis., Methods: We retrospectively reviewed the findings for immunocompetent patients diagnosed with CMV uveitis or endotheliitis based on clinical manifestations and polymerase chain reaction (PCR) examination results and treated with topical 2% ganciclovir solution at National Cheng Kung University Hospital. Clinical outcome measurements included evaluations of the response rate, relapses, resolution of anterior chamber inflammation, visual acuity, and intraocular pressure., Results: The study included 38 eyes of 32 patients. Long-term administration of topical 2% ganciclovir significantly decreased keratic precipitates (p = 0.001), anterior chamber cells (p = 0.001), and reduced intraocular pressure (p < 0.001). Only one eye was unresponsive to topical ganciclovir treatment, and the recurrence decreased to 0.13 relapses per year. The presence of keratic precipitates and higher intraocular pressure at the initial presentation were significantly associated with recurrence ( p = 0.036 and p = 0.001, respectively)., Conclusions: Long-term use of topical 2% ganciclovir solution is effective, safe, and applicable when commercialized ganciclovir gel is not available., Competing Interests: The authors declare no conflicts of interest in this work., (© 2022 Chen et al.)

Background: The treatment guidelines for hidradenitis suppurativa (HS) vary among different countries, and several biologics and small molecule inhibitors have been tested for treating moderate-to-severe HS over the past few years. However, treatment guidelines for HS vary among different countries., Methods: A systematic review and meta-analysis was performed to exam the efficacy and serious adverse events (SAEs) of biologics and small-molecule inhibitors in treating moderate-to-severe HS. Binary outcomes were presented as risk ratio (RR) with 95% confidence interval (CI)., Results: We included 16 RCTs with a total of 2076 participants on nine biologics and three small-molecule inhibitors for treating moderate-to-severe HS, including adalimumab, anakinra, apremilast, avacopan, bimekizumab, CJM112, etanercept, guselkumab, IFX-1, INCB054707, infliximab, and MABp1. The meta-analysis revealed only adalimumab (RR 1.77, 95% CI, 1.44-2.17) and bimekizumab (RR 2.25, 95% CI, 1.03-4.92) achieved significant improvement on hidradenitis suppurativa clinical response (HiSCR), and adalimumab was superior to placebo in achieving dermatology life quality index (DLQI) 0/1 (RR 3.97; 95% CI, 1.70-9.28). No increase in SAEs was found for all included active treatments when compared with placebo., Conclusions: Adalimumab and bimekizumab are the only two biologics effective in achieving HiSCR with acceptable safety profile, whereas adalimumab is the only biologic effective in achieving DLQI 0/1.

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [ 11 C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [ 11 C]martinostat using [ 11 C]methyl triflate in ethanol, as opposed to the originally described synthesis using [ 11 C]methyl iodide and DMSO. [ 11 C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [ 11 C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [ 11 C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [ 11 C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing., (© 2022 John Wiley & Sons, Ltd.)

Rationale and Objective: Gut microbiota have been targeted by alternative therapies for non-communicable diseases. We examined the gut microbiota of a healthy Taiwanese population, identified various bacterial drivers in different demographics, and compared them with dialysis patients to associate kidney disease progression with changes in gut microbiota., Study Design: This was a cross-sectional cohort study., Settings and Participants: Fecal samples were obtained from 119 healthy Taiwanese volunteers, and 16S rRNA sequencing was done on the V3-V4 regions to identify the bacterial enterotypes. Twenty-six samples from the above cohort were compared with fecal samples from 22 peritoneal dialysis and 16 hemodialysis patients to identify species-level bacterial biomarkers in the dysbiotic gut of chronic kidney disease (CKD) patients., Results: Specific bacterial species were identified pertaining to different demographics such as gender, age, BMI, physical activity, and sleeping habits. Dialysis patients had a significant difference in gut microbiome composition compared to healthy controls. The most abundant genus identified in CKD patients was Bacteroides , and at the species level hemodialysis patients showed significant abundance in B. ovatus , B. caccae, B. uniformis , and peritoneal dialysis patients showed higher abundance in Blautia producta (p ≤ 0.05) than the control group. Pathways pertaining to the production of uremic toxins were enriched in CKD patients. The abundance of the bacterial species depended on the type of dialysis treatment., Conclusion: This study characterizes the healthy gut microbiome of a Taiwanese population in terms of various demographics. In a case-control examination, the results showed the alteration in gut microbiota in CKD patients corresponding to different dialysis treatments. Also, this study identified the bacterial species abundant in CKD patients and their possible role in complicating the patients' condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shivani, Kao, Chattopadhyay, Chen, Lai, Lin, Lu, Huang, Tsai, Teng, Wu, Hsieh, Wang and Chuang.)

Background: Aerosol spread is key to interpret the risk of viral contamination during clinical procedures such as esophageal high-resolution manometry (HRM). Installing an air purifier seems a legitimate strategy, but this has recently been questioned., Methods: Patients undergoing an HRM procedure at the Leuven University Hospital were included in this clinical study. All subjects had to wear a surgical mask which was only lowered beneath the nose during the placement and removal of the nasogastric catheter. The number of aerosol particles was measured by a Lasair ® II Particle Counter to obtain data about different particles sizes: 0.3; 0.5; 1.0; 3.0; 5.0; and 10.0 µm. Measurements were done immediately before the placement and the removal of the HRM catheter, and one and 5 min after. A portable air purifier with high-efficiency particle air filters was installed in the hospital room., Key Results: Thirteen patients underwent a manometry examination. The amount of 0.3 µm-sized particles was unaffected during the whole procedure. The larger particle sizes (1.0; 3.0; 5.0; and 10.0 µm) decreased when the catheter was positioned, but not 0.5 µm. During the HRM measurements itself, these numbers decreased further. Yet, 1 min after catheter removal a significant elevation of particles was seen, which did not recover within 5 min., Conclusions & Interferences: Based on this study, there is no evidence that filtration systems reduce aerosol particles properly during a clinical investigation., (© 2021 John Wiley & Sons Ltd.)