Evaluation of the current guidelines for the management of haemorrhoidal disease using the Appraisal of Guidelines Research and Evaluation II instrument.

Background: Haemorrhoids are a very common disease and many professional societies have produced guidelines for their treatment. The aim of this study is to appraise the quality of the existing guidelines in the management of haemorrhoids. Methods: A systematic search of the literature was conducted in the EMBASE, Google Scholar, Cochrane library, and PubMed databases. The quality of guidelines was independently appraised using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument by five of the authors. Results: Six guidelines of varying quality were identified and included in this study. The highest scoring guidelines were the SICCR (Società Italiana di Chirurgia Colorectale, which is Italian Society of Colorectal Surgery), ESCP (European Society of Coloproctology) and ASCRS (American Society of Colon and Rectal Surgeons) guidelines, scoring 86% each overall. There was considerable variability across not just the studies but across the different domains. The highest scoring domains were domain VI: editorial independence (median =95% across all studies) and domain I: Scope & Purpose (85%). The lowest scores were observed in domain V: Applicability (48%) and domain II: Stakeholder Involvement (41%). Only three of the six gained unanimous support for their use, whilst two of the guidelines were unanimously declared not suitable for clinical use. Conclusions: With the notable exception of three guidelines (SICCR, ESCP and ASCRS), the general quality of haemorrhoid guidelines is poor. Stakeholder (especially patient) involvement and instructions on how to implement recommendations is lacking from the majority of guidelines. This is an area that requires urgent attention if we are to improve guidelines in haemorrhoid management.

Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling.

Kruppel-like factor 2 (KLF2) has been linked with fibrosis and neutrophil-associated thromboinflammation; however, its role in COVID-19 remains elusive. We investigated the effect of disease microenvironment on the fibrotic potential of human lung fibroblasts (LFs) and its association with KLF2 expression. LFs stimulated with plasma from severe COVID-19 patients down-regulated KLF2 expression at mRNA/protein and functional level acquiring a pre-fibrotic phenotype, as indicated by increased CCN2/collagen levels. Pre-incubation with the COMBI-treatment-agents (DNase I and JAKs/IL-6 inhibitors baricitinib/tocilizumab) restored KLF2 levels of LFs to normal abolishing their fibrotic activity. LFs stimulated with plasma from COMBI-treated patients at day-7 expressed lower CCN2 and higher KLF2 levels, compared to plasma prior-to-treatment, an effect not observed in standard-of-care treatment. In line with this, COMBI-treated patients had better outcome than standard-of-care group. These data link fibroblast KLF2 with NETosis and JAK/IL-6 signaling, suggesting the potential of combined therapeutic strategies in immunofibrotic diseases, such as COVID-19.

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure.

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.

Appraisal of the Current Guidelines for Management of Malignant Left-Sided Colonic Obstruction Using the Appraisal of Guidelines Research and Evaluation II Instrument.

INTRODUCTION: Colorectal cancer (CRC) is the fourth leading cause of death with 1.4 million new cases occurring annually worldwide. High-quality clinical practice guidelines are needed to tailor high-quality individualized treatment. The aim of the present study was to evaluate the methodological quality of the current guidelines for the management of acute malignant left-sided colonic bowel obstruction. METHODS: A systematic search of the literature was carried out using electronic databases. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument was used to assess the quality of each guideline. RESULTS: Search results returned a total of 14 guidelines appropriate for assessment. Both domain I (scope and purpose) and domain VI (editorial independence) were assessed with the same median score of 83%. The lowest scoring domain was domain V (applicability), scoring only 43%. The 2 guidelines that had the highest score were the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN), each scoring 100%. However, there were significant variations in terms of quality. The NICE and New Zealand guidelines were voted unanimously for use unchanged, whilst 8 other guidelines were voted for use with modifications. CONCLUSION: Variation in guideline quality in CRC is a concern despite some clearly excellent published guidelines. All guidelines score poorly when it comes to describing how the guidelines could be applied. Lack of patient participation in guideline development is also a shortcoming that requires urgent redress.

The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality.

BACKGROUND: Activins are members of the transforming growth factor-ß superfamily implicated in the pathogenesis of several immunoinflammatory disorders. Based on our previous studies demonstrating that overexpression of activin-A in murine lung causes pathology sharing key features of coronavirus disease 2019 (COVID-19), we hypothesized that activins and their natural inhibitor follistatin might be particularly relevant to COVID-19 pathophysiology. METHODS: Activin-A, activin-B, and follistatin were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers, and compared with demographic, clinical, and laboratory parameters. Optimal scaling with ridge regression was used to screen variables and establish a prediction model. RESULT: The activin/follistatin axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a scoring system incorporating follistatin, activin-A, activin-B, C-reactive protein, lactate dehydrogenase, intensive care unit admission, neutrophil/lymphocyte ratio, age, comorbidities, and D-dimers, efficiently predicted fatal outcome (area under the curve [AUC], 0.951; 95% confidence interval, .919-.983; P <10-6). Two validation cohorts indicated similar AUC values. CONCLUSIONS: This study demonstrates a link between activin/follistatin axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.