NETosis in Acute Thrombotic Disorders.

The release of extracellular traps by neutrophils (NETs) represents a novel active mechanism of cell death that has been recently implicated in the pathogenesis of thrombotic disorders. The aim of this study was to investigate the generation of NETs in different groups of patients with acute thrombotic events (ATEs) and to establish whether NETs markers can predict the risk of new cardiovascular events. We performed a case-control study of patients with ATE, including acute coronary syndrome (n = 60), cerebrovascular accident (n = 50), and venous thromboembolism (n = 55). Control subjects (n = 70) were identified among patients admitted for acute chest pain and in which a diagnosis of ATE was excluded. Serum levels of NET markers and neutrophil activation, such as myeloperoxidase (MPO)-DNA complexes, neutrophil gelatinase-associated lipocalin, polymorphonuclear neutrophil elastase, lactoferrin, and MPO, were measured in each patient. We found that circulating levels of MPO-DNA complexes were significantly increased in patients with ATE (p < 0.001) compared with controls and that this association remained significant even after fully adjustment for traditional risk factors (p = 0.001). A receiver operating characteristics analysis of circulating MPO-DNA complexes in discriminating between controls and patients with ATE showed a significant area under the curve of 0.76 (95% confidence interval: 0.69-0.82). After a median follow-up of 40.7 (± 13.8) months, 24 out of the 165 patients with ATE presented a new cardiovascular event and 18 patients died. None of the markers under investigation influenced survival or the incidence of new cardiovascular events. In conclusion, we found that increase of markers of NETosis can be observed in acute thrombotic conditions, occurring both on the arterial and venous site. Nevertheless, the level of neutrophil markers measured during the ATE is not predictive of future risk of mortality and cardiovascular events.

SARS-CoV-2 infection in patients with inflammatory bowel disease: comparison between the first and second pandemic waves.

BACKGROUND: In Italy, the incidence of SARS-CoV-2 infection peaked in April and November 2020, defining two pandemic waves of coronavirus disease 2019 (COVID-19). This study compared the characteristics and outcomes of patients with inflammatory bowel disease (IBD) and SARS-CoV-2 infections between pandemic waves. METHODS: Observational longitudinal study of IBD patients with SARS-CoV-2 infection. Patients with established diagnoses of IBD and of SARS-CoV-2 infection were consecutively enrolled in two periods: (i) first wave, from 1 March 2020 to 31 May 2020; and (ii) second wave, from 15 September to 15 December 2020. RESULTS: We enrolled 937 IBD patients (219 in the first wave, 718 in the second wave). Patients of the first wave were older (mean ± SD: 46.3 ± 16.2 vs. 44.1 ± 15.4 years, p = 0.06), more likely to have ulcerative colitis (58.0% vs. 44.4%, p < 0.001) and comorbidities (48.9% vs. 38.9%; p < 0.01), and more frequently residing in Northern Italy (73.1% vs. 46.0%, p < 0.001) than patients of the second wave. There were no significant differences between pandemic waves in sex (male: 54.3% vs. 53.3%, p = 0.82) or frequency of active IBD (44.3% vs. 39.0%, p = 0.18). The rates of negative outcomes were significantly higher in the first than second wave: pneumonia (27.8% vs. 11.7%, p < 0.001), hospital admission (27.4% vs. 9.7%, p < 0.001), ventilatory support (11.9% vs. 5.4%, p < 0.003) and death (5.5% vs. 1.8%, p < 0.007). CONCLUSION: Between the first and second SARS-CoV-2 pandemic waves, demographic, clinical and geographical features of IBD patients were different as were the symptoms and outcomes of infection. These differences are likely due to the different epidemiological situations and diagnostic possibilities between the two waves.

Cytokines in Spondyloarthritis and Inflammatory Bowel Diseases: From Pathogenesis to Therapeutic Implications.

Spondyloarthritis and inflammatory bowel diseases are chronic immune disorders of the joints and the gut that often coexist in the same patient, increasing the burden of each disorder, worsening patients' quality of life, and influencing therapeutic strategies. Genetic predisposition, environmental triggers, microbiome features, immune cell trafficking, and soluble factors such as cytokines contribute to the pathogenesis of both articular and intestinal inflammation. Most of the molecular targeted biological therapies developed over the last two decades were based on evidence that specific cytokines may be involved in these immune diseases. Despite pro-inflammatory cytokine pathways sharing the pathogenesis of both articular and gut diseases (i.e., tumor necrosis factor and interleukin-23), several other cytokines (i.e., interleukin-17) may be differently involved in the tissue damage process, depending on the specific disease and the organ involved in inflammation, making difficult the identification of a therapeutic plan that is efficacious for both inflammatory manifestations. In this narrative review, we comprehensively summarize the current knowledge on cytokine involvement in spondyloarthritis and inflammatory bowel diseases, underlining similarities and differences among their pathogenetic pathways; finally, we provide an overview of current and potential future treatment strategies to simultaneously target both articular and gut immune disorders.

Anoplasty for anatomical anal stenosis: systematic review of complications and recurrences.

AIM: The optimal surgical treatment for anatomical anal stenosis (AS) remains to be determined. The aim of this study was to determine the rates of complications and recurrence after anoplasty for anatomical AS and, wherever feasible, compare the outcomes for the various techniques. METHOD: A PROSPERO-registered systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Medline, PubMed, Embase, Cochrane Library of Systematic Review, Scopus and Web of Science were searched for articles published up to May 2021. Studies that assessed the outcomes of anoplasty in adult patients with anatomical AS were selected. The primary outcomes were complications and recurrence. The methodological quality of studies was appraised using the Joanna Briggs Institute critical appraisal tools. RESULTS: From the total of 2705 unique screened records, 151 were assessed for eligibility. Only 29 studies (two prospective) met the inclusion criteria, reporting data on 556 patients [mean age 53 (18-83) years, 46% female]. Previous history of surgery for haemorrhoidal disease accounted for three quarters of cases. A total of 14 types of anoplasty were found, with the Y-V flap being the most performed technique [27% of cases (n = 149)]. Complications frequently occurred, with a pooled prevalence of 10.2% (95% CI 3.9%-24.1%) after Y-V flap and 11.5% (5.3%-23.0%) after rhomboid/diamond flap. Patients undergoing house flap achieved better results in terms of clinical improvement, satisfaction and quality of life compared with Y-V flap and rhomboid/diamond flap. When considering only studies with at least 12 months of follow-up, the pooled prevalence of recurrence was 4.7% (2.2%-9.8%), with significantly higher rates observed in the prospective versus retrospective series [pooled prevalence 18.9% (11.5%-29.5%) vs. 3.6% (1.7-7.8%), respectively; p < 0.001]. CONCLUSION: Both complications and recurrence were significantly lower after house flap compared with rhomboid/diamond and Y-V flap. Better designed multicentre studies with longer follow-up are needed to confirm these findings. PROSPERO REGISTRATION NUMBER: CRD42021239493.

Chest radiography findings of COVID-19 pneumonia: a specific pattern for a confident differential diagnosis.

BACKGROUND: Chest radiography (CR) patterns for the diagnosis of COVID-19 have been established. However, they were not ideated comparing CR features with those of other pulmonary diseases. PURPOSE: To create the most accurate COVID-19 pneumonia pattern comparing CR findings of COVID-19 and non-COVID-19 pulmonary diseases and to test the model against the British Society of Thoracic Imaging (BSTI) criteria. MATERIAL AND METHODS: CR of COVID-19 and non-COVID-19 pulmonary diseases, admitted to the emergency department, were evaluated. Assessed features were interstitial opacities, ground glass opacities, and/or consolidations and the predominant lung alteration. We also assessed uni-/bilaterality, location (upper/middle/lower), and distribution (peripheral/perihilar), as well as pleural effusion and perihilar vessels blurring. A binary logistic regression was adopted to obtain the most accurate CR COVID-19 pattern, and sensitivity and specificity were computed. The newly defined pattern was compared to BSTI criteria. RESULTS: CR of 274 patients were evaluated (146 COVID-19, 128 non-COVID-19). The most accurate COVID-19 pneumonia pattern consisted of four features: bilateral alterations (Expß=2.8, P=0.002), peripheral distribution of the predominant (Expß=2.3, P=0.013), no pleural effusion (Expß=0.4, P=0.009), and perihilar vessels' contour not blurred (Expß=0.3, P=0.002). The pattern showed 49% sensitivity, 81% specificity, and 64% accuracy, while BSTI criteria showed 51%, 77%, and 63%, respectively. CONCLUSION: Bilaterality, peripheral distribution of the predominant lung alteration, no pleural effusion, and perihilar vessels contour not blurred determine the most accurate COVID-19 pneumonia pattern. Lower field involvement, proposed by BSTI criteria, was not a distinctive finding. The BSTI criteria has lower specificity.

Impact of COVID-19 Outbreak on Healthcare Workers in Italy: Results from a National E-Survey.

Italy has been the first-hit European country to face the outbreak of coronavirus disease 2019 (COVID-19). Aim of this survey was to assess in depth the impact of the outbreak on healthcare workers (HCW). A 40-item online survey was disseminated via social media inviting Italian HCW, with questions exploring demographics, health status and work environment of respondents. A total of 527 were invited to take part in March 2020, of whom 74% (n = 388) responded to the survey. Of these, 235 (61%) were women. HCW were mostly physicians (74%), from high-prevalence regions (52%). 25% experienced typical symptoms during the last 14 days prior to survey completion, with only 45% of them being tested for COVID-19. Among the tested population, 18 (18%) resulted positive for COVID-19, with 33% being asymptomatic. Only 22% of HCW considered personal protective equipment adequate for quality and quantity. Females and respondents working in high-risk sectors were more likely to rate psychological support as useful (OR, 1.78 [CI 95% 1.14-2.78] P = 0.012, and 2.02 [1.12-3.65] P = 0.020, respectively) and workload as increased (mean increase, 0.38 [0.06-0.69] P = 0.018; and 0.54 [0.16-0.92] P = 0.005, respectively). The insights from this survey may help authorities in countries where COVID-19 epidemic has not yet broken out. Management strategies should be promptly undertaken in order to enhance safety and optimise resource allocation.

Discontinuation of Infliximab in Patients With Ulcerative Colitis Is Associated With Increased Risk of Relapse: A Multinational Retrospective Cohort Study.

BACKGROUND & AIMS: Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. METHODS: We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods. RESULTS: In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88-6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02-6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events. CONCLUSIONS: In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe.

Biomarkers of Neutrophil Activation in Patients with Symptomatic Chronic Peripheral Artery Disease Predict Worse Cardiovascular Outcome.

Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, to assess their association with PAD severity, and to evaluate their prognostic value in patients with PAD. The following circulating markers of neutrophil degranulation were tested: polymorphonuclear neutrophil (PMN) elastase, neutrophil gelatinase-associated lipocalin (NGAL), and myeloperoxidase (MPO). Neutrophil extracellular traps (NETs) were quantified by measuring circulating MPO-DNA complexes. Patients with PAD underwent a comprehensive series of vascular tests. The occurrence of 6-month major adverse CV (MACE) and limb events (MALE) was assessed. Overall, 110 participants were included, 66 of which had PAD. After adjustment for conventional CV risk factors, PMN-elastase (adjusted odds ratio [OR]: 1.008; 95% confidence interval [CI]: 1.002-1.015; p = 0.006), NGAL (adjusted OR: 1.045; 95%CI: 1.024-1.066; p < 0.001), and MPO (adjusted OR: 1.013; 95%CI: 1.001-1.024; p = 0.028) were significantly associated with PAD presence. PMN-elastase (adjusted hazard ratio [HR]: 1.010; 95%CI: 1.000-1.020; p = 0.040) and MPO (adjusted HR: 1.027; 95%CI: 1.004-1.051; p = 0.019) were predictive of 6-month MACE and/or MALE. MPO displayed fair prognostic performance on receiver operating characteristic (ROC) curve analyses, with an area under the curve (AUC) of 0.74 (95%CI: 0.56-0.91) and a sensitivity and specificity of 0.80 and 0.65, respectively, for a cut-off of 108.37 ng/mL. MPO-DNA showed a weak inverse correlation with transcutaneous oximetry (TcPO2) on proximal foot (adjusted ρ -0.287; p = 0.032). In conclusion, in patients with symptomatic chronic PAD, enhanced neutrophil activity may be associated with an increased risk of acute CV events, rather than correlate with disease severity. Further research is needed to clarify the role of neutrophils in PAD natural history.

The Importance of Endoscopy with Biopsy: Real-World Evidence of Gastrointestinal Involvement in Primary Immunodeficiency in Two Main Northern Italian Centres.

INTRODUCTION: Inborn errors of immunity (IEI) represent a heterogeneous group of diseases in which the true prevalence of GI involvement is not well-known. This study evaluates the prevalence of lower GI manifestations in patients with common variable immunodeficiency (CVID), analysing the histologic findings in colonic samples and assessing any correlations with biochemical abnormalities. MATERIALS AND METHODS: A retrospective study was performed by collecting the data of IEI adult patients followed up at two main Northern Italian centres. Demographic and clinical data, and blood tests were collected. A colonoscopy with multiple biopsies in standard sites, in addition to a biopsy for any macroscopic lesion, was performed. The gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) were used to assess GI symptoms. RESULTS: 141 patients were included: 121 (86.5%) with CVID, 17 (12.1%) with IgG subclass deficiency, and 2 (1.4%) with X-linked agammaglobulinemia. Of the patients, 72 (51%) complained of GI symptoms. No differences were seen between patients receiving or not IgRT. GI infections were found in 9 patients (6.4%). No significant correlations were found between gut infections and symptoms or leukocyte infiltrates. Colonoscopy alterations were present in 79 patients (56%), and the most common were colon polyps (42%). Microscopical abnormalities were seen in 60 histologic samples (42.5%) and the most frequent was nodular lymphoid hyperplasia (40%). A leukocyte infiltrate was present in 67 samples (47.5%), and the most common was a lymphocyte infiltrate (33%). No correlation was found between GI symptoms and macroscopic alterations, whereas a positive correlation between symptoms and microscopic alterations was detected. CONCLUSIONS: GI symptoms and microscopic alterations in colon samples are closely related; hence, it is important to carry out serial colonic biopsies in every CVID patient, even in the absence of macroscopic lesions.

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022.

Introduction: In patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer. Methods: We conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies. Results: In the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori. Discussion: While gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs.

Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study.

BACKGROUND: Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. AIMS: To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) METHODS: Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). RESULTS: 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0-4.1]; p<0.001). CONCLUSIONS: Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258).

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFß and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFß-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFß and VPA. Treatment with VPA revealed TGFß-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFß-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis.

Ileal Crohn's disease: CEUS determination of activity.

Transabdominal ultrasound is currently accepted as a clinical first-line tool in the assessment of Crohn's disease activity. During recent years, great improvements have been achieved in ultrasound examination with the introduction of high-frequency transducers, ultrasonographic microbubble contrast agents, and dedicated contrast-specific ultrasound software. Therefore, contrast-enhanced ultrasonography (CEUS) is emerging as one of the most important imaging techniques in the diagnosis and follow-up of patients with ileal Crohn's disease. It is non-invasive and non-ionizing, easily repeatable, well-tolerated by patients and has significant diagnostic accuracy. Moreover, the possibility to monitor response to therapies, describing, and quantifying contrast enhancement behavior by specific software, represents an interesting aspect of its utilization, considering the still open questions about the correct use of immunosuppressive and biological agents. The aim of our review is to provide an updated overview of the role of CEUS in the patients who have an ileal localization of Crohn's disease, defining its qualitative and quantitative features.

Anal Fistula Human Amniotic Membrane Endosealing (F-HAME): A Proof of Concept Study.

The treatment of cryptoglandular anal fistula (AF) is often a challenge for surgeons. Several sphincter-saving procedures have been described as an alternative to fistulotomy, with the common goal of promoting healing and preserve anal continence. The aim of this proof of concept study was to assess the outcomes of human amniotic membrane (HAM) implantation in cryptoglandular transphincteric AF. Two consecutive female were recruited. The primary outcome was clinical healing at 6 months. Secondary outcomes were ultrasonographic healing, complications and reinterventions, AF symptoms, fecal incontinence, psychological impact of treatment, recurrence, development of additional AF, patient satisfaction, and quality of life, as measured using validated questionnaires. Both patients (40 and 54-year-old) previously underwent incision and drainage of anal abscess with concomitant seton placement. HAM implantation was performed as a day case under local anesthesia. No intra- or post-procedural complications occurred. Clinical and radiological healing were not achieved at 6 months. However, the external outlet discharge diminished through time, with sustained improvements in quality of life. Clinical healing occurred at 7 months in both patients. Psychological impact of treatment and patient satisfaction were overall good, with improvements in the PHQ-9, GAD-7, and Short Assessment of Patients Satisfaction. HAM implantation is safe and improves patients' quality of life, progressively leading to clinical healing. Future studies are needed to assess its safety in other etiology of AF.

Surgical Management of Hemorrhoidal Disease in Inflammatory Bowel Disease: A Systematic Review with Proportional Meta-Analysis.

Surgical treatment of hemorrhoidal disease (HD) in inflammatory bowel disease (IBD) has been considered to be potentially harmful, but the evidence for this is poor. Therefore, a systematic review of the literature was undertaken to reappraise the safety and effectiveness of surgical treatments in this special circumstance. A MEDLINE, Web of Science, Scopus, and Cochrane Library search was performed to retrieve studies reporting the outcomes of surgical treatment of HD in patients with Crohn's disease (CD) and ulcerative colitis (UC). From a total of 2072 citations, 10 retrospective studies including 222 (range, 2-70) patients were identified. Of these, 119 (54%) had CD and 103 (46%) UC. Mean age was between 41 and 49 years (range 14-77). Most studies lacked information on the interval between surgery and the onset of complications. Operative treatments included open or closed hemorrhoidectomy (n = 156 patients (70%)), rubber band ligation (n = 39 (18%)), excision or incision of thrombosed hemorrhoid (n = 14 (6%)), and doppler-guided hemorrhoidal artery ligation (DG-HAL, n = 13 (6%)). In total, 23 patients developed a complication (pooled prevalence, 9%; (95%CI, 3-16%)), with a more than two-fold higher rate in patients with CD compared to UC (11% (5-16%) vs. 5% (0-13%), respectively). Despite the low quality evidence, surgical management of HD in IBD and particularly in CD patients who have failed nonoperative therapy should still be performed with caution and limited to inactive disease. Further studies should determine whether advantages in terms of safety and effectiveness with the use of non-excisional techniques (e.g., DG-HAL) can be obtained in this patient population.

Impact of Hypogammaglobulinemia on the Course of COVID-19 in a Non-Intensive Care Setting: A Single-Center Retrospective Cohort Study.

Background: Severity and mortality of COVID-19 largely depends on the ability of the immune system to clear the virus. Among various comorbidities potentially impacting on this process, the weight and the consequences of an antibody deficiency have not yet been clarified. Methods: We used serum protein electrophoresis to screen for hypogammaglobulinemia in a cohort of consecutive adult patients with COVID-19 pneumonia, hospitalized in non-intensive care setting between December 2020 and January 2021. The disease severity, measured by a validated score and by the need for semi intensive (sICU) or intensive care unit (ICU) admission, and the 30-day mortality was compared between patients presenting hypogammaglobulinemia (HYPO) and without hypogammaglobulinemia (no-HYPO). Demographics, comorbidities, COVID-19 specific treatment during the hospital stay, disease duration, complications and laboratory parameters were also evaluated in both groups. Results: We enrolled 374 patients, of which 39 represented the HYPO cohort (10.4%). In 10/39 the condition was previously neglected, while in the other 29/39 hematologic malignancies were common (61.5%); 2/39 were on regular immunoglobulin replacement therapy (IgRT). Patients belonging to the HYPO group more frequently developed a severe COVID-19 and more often required sICU/ICU admission than no-HYPO patients. IgRT were administered in 8/39 during hospitalization; none of them died or needed sICU/ICU. Among HYPO cohort, we observed a significantly higher prevalence of neoplastic affections, of active oncologic treatment and bronchiectasis, together with higher prevalence of viral and bacterial superinfections, mechanical ventilation, convalescent plasma and SARS-CoV-2 monoclonal antibodies administration during hospital stay, and longer disease duration. Multivariate logistic regression analysis and Cox proportional hazard regression confirmed the impact of hypogammaglobulinemia on the COVID-19 severity and the probability of sICU/ICU admission. The analysis of the mortality rate in the whole cohort showed no significant difference between HYPO and no-HYPO. Conclusions: Hypogammaglobulinemia, regardless of its cause, in COVID-19 patients hospitalized in a non-intensive care setting was associated to a more severe disease course and more frequent admission to s-ICU/ICU, particularly in absence of IgRT. Our findings emphasize the add-value of routine serum protein electrophoresis evaluation in patients admitted with COVID-19 to support clinicians in patient care and to consider IgRT initiation during hospitalization.

Changes in hospital admissions and complications of acute appendicitis during the COVID-19 pandemic: A systematic review and meta-analysis.

Background: Acute appendicitis (AA) is one of the most common emergencies in general surgery worldwide. During the pandemic, a significant decrease in the number of accesses to the emergency department for AA has been recorded in different countries. A systematic review of the current literature sought to determine the impact of Coronavirus Disease 2019 (COVID-19) on hospital admissions and complications of AA. Method: A systematic search was undertaken to identify repeated cross-sectional studies reporting the management of AA during the COVID-19 pandemic (index period) as compared to the previous year, or at the turn of lockdown (reference period). Data were abstracted on article (country of origin) and patients characteristics (adults, children [i.e. non adults, <18-year-old]), or mixed population) within the two given timeframes, including demographics, number of admissions for AA, number of appendectomies, and complicated appendectomies. Results: Of 201 full-text articles assessed for eligibility, 54 studies from 22 world countries were included. In total, 27 (50%) were conducted on adults, 12 (22%) on children, and 15 (28%) on a mixed patients population. The overall rate ratio of admissions for AA between the two periods was 0.94 (95%CI, 0.75-1.17), with significant differences between studies on adults (0.90 [0.74-1.09]), mixed population (0.50 [0.27-0.90]), and children (1.50 [1.01-2.22]). The overall risk ratio of complicated AA was 1.65 (1.32-2.07), ranging from 1.32 in studies on children, to 2.45 in mixed population. Conclusion: The pandemic has altered the rate of admissions for AA and appendectomy, with parallel increased incidence of complicated cases in all age groups.

The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies.

Cardiovascular calcification is the ectopic deposition of calcium-phosphate crystals within the arterial wall and the aortic valve leaflets. This pathological process leads to increased vascular stiffness, reduced arterial elasticity, and aortic valve stenosis, increasing the risk of cardiovascular diseases. Although cardiovascular calcification is an increasing health care burden, to date no medical therapies have been approved for treating or preventing it. Considering the current lack of therapeutic strategies and the increasing prevalence of cardiovascular calcification, the investigation of some nutraceuticals to prevent this pathological condition has become prevalent in recent years. Recent preclinical and clinical studies evaluated the potential anti-calcific role of nutraceuticals (including magnesium, zinc, iron, vitamin K, and phytate) in the progression of vascular calcification, providing evidence for their dietary supplementation, especially in high-risk populations. The present review summarizes the current knowledge and latest advances for nutraceuticals with the most relevant preclinical and clinical data, including magnesium, zinc, iron, vitamin K, and phytate. Their supplementation might be recommended as a cost-effective strategy to avoid nutritional deficiency and to prevent or treat cardiovascular calcification. However, the optimal dose of nutraceuticals has not been identified and large interventional trials are warranted to support their protective effects on cardiovascular disease.

GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine-threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFß following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy.