Functional and Promiscuity Studies of Three-Residue Cyclophane Forming Enzymes Show Nonnative C-C Cross-Linked Products and Leader-Dependent Cyclization.

Enzymes catalyzing peptide macrocyclization are important biochemical tools in drug discovery. The three-residue cyclophane-forming enzymes (3-CyFEs) are an emerging family of post-translational modifying enzymes that catalyze the formation of three-residue peptide cyclophanes. In this report, we introduce three additional 3-CyFEs, including ChlB, WnsB, and FnnB, that catalyze cyclophane formation on Tyr, Trp, and Phe, respectively. To understand the promiscuity of these enzymes and those previously reported (MscB, HaaB, and YxdB), we tested single amino acid substitutions at the three-residue motif of modification (Ω1X2X3, Ω1 = aromatic). Collectively, we observe that substrate promiscuity is observed at the Ω1 and X2 positions, but a greater specificity is observed for the X3 residue. Two nonnative cyclophane products were characterized showing a Phe-C3 to Arg-Cß and His-C2 to Pro-Cß cross-links, respectively. We also tested the leader dependence of selected 3-CyFEs and show that a predicted helix region is important for cyclophane formation. These results demonstrate the biocatalytic potential of these maturases and allow rational design of substrates to obtain a diverse array of genetically encoded 3-residue cyclophanes.

Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs. APPROACH AND RESULTS: Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97). CONCLUSIONS: This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.

A meta-analysis of clinical manifestations in asian systemic lupus erythematous: The effects of ancestry, ethnicity and gender.

OBJECTIVES: Systemic lupus erythematosus (SLE) in Asians is a unique patient group that has been thought to present with more severe organ involvement in comparison to their non-Asian counterparts. We set out to perform a meta-analysis to compare clinical manifestations between ancestries, with a focus on Southeast Asian ethnicities and gender. MATERIALS AND METHODS: A cross-sectional study was performed in conjunction with a meta-analysis to identify differences in prevalences of SLE clinical manifestations. Searches were conducted on Medline for articles comparing between: (i) Asian and non-Asian ancestry; (ii) Southeast Asian ethnicities (Chinese, Malay and Indian); and (iii) male and female Asians. Using random effects model, effect sizes as odd ratios were pooled with DerSimonian and Laird's model. RESULTS: A total of 13 articles were identified and pooled together with our study for this meta-analysis. Comparing among patients of Asian with Non-Asian/European ancestries, no significance difference was found in severe organ manifestations such as renal and neurological involvement [odds ratio (OR): 1.398, p= 0.320 and OR: 1.224, p= 0.526 respectively]. There was significantly greater proportion of Asian SLE patients with thrombocytopenia compared to non-Asian SLE. Chinese SLE patients were less likely to have oral ulcers compared to Indian SLE patients. Lastly, Asian male SLE patients had greater incidence of renal involvement and thrombocytopenia compared to Asian female SLE patients. CONCLUSIONS: Severe SLE manifestations such as renal and neurological involvement were not significantly more frequent in Asian SLE compared to non-Asian/European SLE in this analysis.

Systematic review with meta-analysis: The prevalence, risk factors and outcomes of upper gastrointestinal tract Crohn's disease.

AIMS: Upper gastrointestinal Crohn's disease (UGI-CD) is an important subclassification of Crohn's Disease (CD). We performed a systematic review and meta-analysis to evaluate the prevalence, risk factors, and clinical outcomes associated with UGI-CD. METHODS: We searched Embase and Medline for articles reporting the clinical information of UGI-CD in CD patients, through 27 October 2020. Disease location and phenotype were coded according to the Montreal classification, and results were pooled with random effects by DerSimonian and Laird model. RESULTS: 26 articles were included. The prevalence of UGI-CD was 13%. UGI-CD was most commonly found in the stomach (56%) and was associated with concurrent ileocolonic involvement (54%). Non-stricturing, non-penetrating UGI-CD was the most common behavioral phenotype (61%). L4-jejunal disease was associated with the highest rates of surgery. Region of origin did not significantly influence the location and phenotype of UGI-CD. Young, male patients presenting with erythema nodosum, aphthous ulcers and stricturing-phenotype are more likely to have UGI-CD, which in turn is linked to increased risk of hospitalization and surgery. CONCLUSION: UGI-CD is present in 13% of patients with CD, and patients with L4-jejunal disease are more likely to require surgery. Further studies examining the effect of ethnicity and region on UGI-CD are needed.

Kono-S anastomosis for Crohn's disease: a systemic review, meta-analysis, and meta-regression.

The Kono-S anastomosis was introduced in 2011 as an alternative anastomosis in Crohn's disease (CD) surgery. Since then, prevailing evidence of the favorable results of the Kono-S anastomosis has been published from around the world. We conducted this study to analyze the effectiveness of the Kono-S anastomosis, by searching Medline, Embase, CNKI, and google scholar. Binominal data were analyzed after Freeman-Tukey double-arcsine transformation. Comparative data were analyzed using the Mantel-Haenszel model for dichotomous outcomes and the mean difference for continuous outcomes. We identified 676 patients who underwent surgery with a Kono-S anastomosis. Surgical recurrence was pooled at an average of 0% (CI: 0.00-0.01) and a reduced mean Rutgeerts score of 1.375 (CI: 0.727-2.023) after Kono-S anastomosis. Endoscopic recurrence after sensitivity analysis was 5% (CI: 0.00-0.15). Complications were rare, with a 3% incidence of ileus (CI: 0.01-0.05), a 4% incidence of small bowel obstruction (CI: 0.01-0.10), a 1% incidence of an anastomotic leak incidence (CI: 0.00-0.03), and a 10% incidence of postoperative infection (CI: 0.03-0.20). Evidence from this meta-analysis favors the Kono-S anastomosis for CD patients, especially for ileocolic anastomosis. Thus, clinicians should consider the applicability of Kono-S anastomosis in respective institutions.

Interprofessional communication (IPC) for medical students: a scoping review.

BACKGROUND: Effective Interprofessional Communication (IPC) between healthcare professionals enhances teamwork and improves patient care. Yet IPC training remains poorly structured in medical schools. To address this gap, a scoping review is proposed to study current IPC training approaches in medical schools. METHODS: Krishna's Systematic Evidence Based Approach (SEBA) was used to guide a scoping review of IPC training for medical students published between 1 January 2000 to 31 December 2018 in PubMed, ScienceDirect, JSTOR, Google Scholar, ERIC, Embase, Scopus and PsycINFO. The data accrued was independently analysed using thematic and content analysis to enhance the reproducibility and transparency of this SEBA guided review. RESULTS: 17,809 titles and abstracts were found, 250 full-text articles were reviewed and 73 full text articles were included. Directed Content analysis revealed 4 categories corresponding to the levels of the Miller's Pyramid whilst thematic analysis revealed 5 themes including the indications, stages of trainings and evaluations, content, challenges and outcomes of IPC training. Many longitudinal programs were designed around the levels of Miller's Pyramid. CONCLUSION: IPC training is a stage-wise, competency-based learning process that pivots on a learner-centric spiralled curriculum. Progress from one stage to the next requires attainment of the particular competencies within each stage of the training process. Whilst further studies into the dynamics of IPC interactions, assessment methods and structuring of these programs are required, we forward an evidenced based framework to guide design of future IPC programs.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials.

OBJECTIVE: The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. METHODS: A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. RESULTS: Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88-7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. CONCLUSION: This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

Prevalence of thyroid eye disease in Graves' disease: A meta-analysis and systematic review.

OBJECTIVE: Thyroid eye disease (TED) is a debilitating condition that frequently manifests in patients suffering from Graves' disease (GD). This study aims to analyse the prevalence of TED among GD patients, with a focus on geographical region-specific rates. METHODS: Medline and Embase were searched for articles examining TED prevalence on April 2020, and articles were retrieved and sieved. Statistical analysis was performed after Freeman-Tukey double arcsine transformation. Thereafter, results were pooled with random effects by DerSimonian and Laird model. RESULTS: Fifty-seven articles involving 26,804 patients were included in the review. The overall pooled prevalence of TED was 40% (CI: 0.32 to 0.48) and by continent was 38% (CI: 0.31 to 0.46) for Europe, 44% (CI: 0.32 to 0.56) for Asia, 27% (CI: 0.06 to 0.56) for North America and 58% (CI: 0.55 to 0.61) for Oceania. The prevalence of TED in Southeast Asia was 35% (CI: 0.24 to 0.47) and Middle East 48% (CI: 0.19 to 0.78). Subgroup analysis showed regions with predominantly Caucasians (37%; CI: 0.28 to 0.46) had a lower prevalence of TED compared to Asians (45%; CI: 0.33 to 0.58). The pooled prevalence of lid retraction was 57% (CI: 0.39 to 0.74), proptosis 57% (CI: 0.48 to 0.65), diplopia 36% (CI: 0.24 to 0.48) and ocular hypertension 13% (CI: 0.06 to 0.19). CONCLUSION: A substantial proportion of patients with GD have TED and often manifest as lid retraction, proptosis and diplopia. Early detection through active screening might help to mitigate the progression of TED and its associated complications.

Enhancing Interprofessional Communications Training in Internal Medicine. Lessons Drawn From a Systematic Scoping Review From 2000 to 2018.

INTRODUCTION: Interprofessional communication (IPC) enhances patient experiences and outcomes and improves well-being and satisfaction among health care professionals. This scoping review seeks to guide design of IPC training in internal medicine. METHODS: The framework of Arksey and O'Malley (2005) guided this systematic scoping review in internal medicine across PubMed, Embase, CINAHL, Scopus, PsycINFO, ERIC, JSTOR, and Google Scholar databases for publications from the years 2000 to 2018. RESULTS: Twenty-two thousand eight hundred seventy-four abstracts were retrieved, 326 full-text articles were reviewed, and 32 articles were included. The themes identified using directed content analysis were indications for an IPC program, training stages, and obstacles. The rationale for IPC programs was to improve interprofessional teamwork and enhance patient care. IPC training occurs in five stages beginning with instilling the role, value, and skills behind IPC and gradually practicing these skills within the clinical setting. The challenges to IPC highlight the need to confront workplace hierarchies and the lack of resources. DISCUSSION: The findings of this systematic scoping review also serve to underscore the importance of understanding, evaluating, and influencing the clinical environment and the work environment and the need for new assessment tools that will guide the individualized, longitudinal, competency-based learning process that underpins IPC training.