Search

Noninfective drug-related pneumonitis (DRP) is a well-known adverse effect of several drugs: clinical manifestations have mostly an acute/subacute onset and vary from mild to life-threatening. Several DRP cases have been described in patients receiving anti-tumor necrosis factor α, rituximab, and tocilizumab.1,2 To date, only 4 reports of vedolizumab-related pneumonitis have been presented.3-5.

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P

Background The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies. Results Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10. Conclusions Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites.

Introduction The aim of this study was to provide an external validation of bowel ultrasound (US) predictors of activity in ulcerative colitis (UC) and quantitative Milan Ultrasound Criteria (MUC). Methods Forty‐three consecutive patients with UC (16 in endoscopic remission and 27 with endoscopic activity) underwent bowel US and colonoscopy in a tertiary referral inflammatory bowel disease unit. Results An MUC score >6.2 discriminated patients with active versus non‐active UC with a sensitivity of 0.85 (95% confidence interval (CI) 0.66–0.96), specificity of 0.94 (95% CI 0.70–0.99) and an area under the curve of 0.902 (95% CI 0.772–0.971) in complete agreement with the derivation study. Conclusion The external validation of MUC confirms that it is an accurate tool for assessing disease activity in patients with UC.

Dendrobium officinale polysaccharide (DOP) attenuates inflammatory bowel disease (IBD), but its role in regulating cross-talk between intestinal epithelial cells (IEC) and macrophages against IBD is unclear. This study aimed to investigate DOP protective effects on the intestinal inflammatory response through regulation by miRNA in small extracellular vesicles (sEVs). Our results show that DOP interfered with the secretion of small extracellular vesicles (DIEs) by IEC, which reduced the levels of inflammatory mediators. Increased miR-433-3p expression in DIEs was identified as an important protector against intestinal inflammation. DOP regulated the loading of miR-433-3p by hnRNPA2B1 into the intestinal sEV to increase the abundance of miR-433-3p. DIEs delivered miR-433-3p to lipopolysaccharide-induced macrophages and targeted the MAPK8 gene, leading to inhibition of the MAPK signaling pathway and reduced production of inflammatory cytokines. One protective mechanism of DOP is mediated by intestinal sEV containing miR-433-3p, which is a potential therapeutic agent for the prevention of inflammatory factor accumulation from excessive intestinal macrophage activity and for restoring homeostasis in the intestinal microenvironment.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Background The definitive diagnosis of melanocytic neoplasia using solely histopathologic evaluation can be challenging. Novel techniques that objectively confirm diagnoses are needed. This study details the development and validation of a melanoma prediction model from spatially resolved multivariate protein expression profiles generated by Imaging Mass Spectrometry (IMS). Methods Three board-certified dermatopathologists blindly evaluated 333 samples. Samples with triply concordant diagnoses were included in this study, divided into a training set (n = 241) and a test set (n = 92). Both the training and test sets included various representative subclasses of unambiguous nevi and melanomas. A prediction model was developed from the training set using a linear support vector machine (SVM) classification model. Results We validated the prediction model on the independent test set of 92 specimens (75 classified correctly, two misclassified, and 15 indeterminate). IMS detects melanoma with a sensitivity of 97.6% and a specificity of 96.4% when evaluating each unique spot. IMS predicts melanoma at the sample level with a sensitivity of 97.3% and a specificity of 97.5%. Indeterminate results were excluded from sensitivity and specificity calculations. Conclusion This study provides evidence that IMS-based proteomics results are highly concordant to diagnostic results obtained by careful histopathologic evaluation from a panel of expert dermatopathologists. This article is protected by copyright. All rights reserved.

Objectives Anti-TNFα agents have been a staple of Crohn's disease treatment for 20 years, but they have weaknesses. New treatments have more recently become available. The aim of this paper is to examine the Crohn's disease patient population for whom anti-TNF treatments are not preferred and where new mechanisms of action should be considered. Methods A representative sample of 100 Italian physicians with documented expertise with biological treatment of moderate-to-severe Crohn's disease were interviewed. A literature review on Crohn's disease treatment was also conducted to identify patient populations for whom anti-TNFs are unsuitable. Results On the basis of the interviewed physicians, about 9% of moderate-to-severe Crohn's disease patients were noneligible to anti-TNFα due to contraindication or possible risk of intolerance, while 11% had discontinued anti-TNFα treatment due to complications or intolerance/hypersensitivity. Patients with severe heart disease and at high risk of infections were more frequently considered unsuitable. The proportion of patients considered unsuitable among elderly patients and in those with recurrent infections, cancer, and other comorbidities ranged between 40 and 60%. Conclusions We provided additional quantitative and qualitative information to help identify patients who are less suitable to anti-TNF agents, who could benefit from newer biologic agents with different mechanisms of action.

Background The present study provides a snapshot of Italian patients with peritoneal metastasis from gastric cancer treated by surgery in Italian centers belonging to the Italian Research Group on Gastric Cancer. Prognostic factors affecting survival in such cohort of patients were evaluated with the final aim to identify patients who may benefit from radical intent surgery. Methods It is a multicentric retrospective study based on a prospectively collected database including demographics, clinical, surgical, pathological, and follow-up data of patients with gastric cancer and synchronous macroscopic peritoneal metastases. Patients were surgically treated from January 2005 to January 2017. We focused on patients with macroscopic peritoneal carcinomatosis (PC) treated with upfront surgery in order to provide homogeneous evidences. Results Our results show that patients with peritoneal carcinomatosis cannot be considered all lost. Strictly selected cases (R0/R1 and P1 patients) could benefit from an aggressive surgical approach performing an extended lymphadenectomy and HIPEC treatment. Conclusion The main result of the study is that GC patients with limited peritoneal involvement can have a survival benefit from a surgery with “radical oncological intent”, that means extended lymphadenectomy and R0 resection. The retrospective nature of this study is an important bias, and for this reason, we have started a prospective multicentric study including Italian stage IV patients that hopefully will give us more answers.

Purpose Most reports of strabismus after glaucoma drainage device implantation study larger devices and rarely note the incidence of strabismus after Ahmed glaucoma valve (AGV) implantation. It is unknown if the pattern of strabismus is similar with smaller devices. We investigated characteristics of strabismus after AGV implantation. Design Retrospective review. Methods Institutional study of 732 patients at our institution undergoing AGV implantation between 2013 and 2018. Rate and characteristics of strabismus were the primary outcome; age, gender, and location of AGVs were also analyzed. Results We identified 29 patients who developed new-onset strabismus postoperatively after initial AGV implantation, for 4% incidence of strabismus. Twenty-one (72%) of these had diplopia. AGVs were implanted superotemporally in 21, superonasally in 5, inferotemporally in 1, and inferonasally in 2. Three patients were esotropic, 11 were exotropic, 4 had hypertropia, 2 had hypotropia, and 9 patients had combined horizontal/vertical strabismus (esotropia/hypotropia [n = 1] or exotropia/hypertropias [n = 8]). Exotropia was the most common type of strabismus in both the superotemporal and superonasal (60%) AGV groups. Superotemporal AGVs were more commonly associated with ipsilateral hypertropia (43%) than superonasal AGVs. Treatments included strabismus surgery (n = 14), prisms (n = 6), or an occlusive lens (n = 1). Discussion. In the largest single-center series of patients undergoing initial AGV implantation, the overall incidence of postoperative strabismus was 4%. This is comparable to strabismus incidence following implantation of other types of glaucoma drainage devices, even larger devices. The possibility of this complication should be discussed with patients prior to surgery.

Background Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. Patients and Methods In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. Results We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. Conclusions Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy. Graphic Abstract

Major surgical societies advised using non-operative management of appendicitis and suggested against laparoscopy during the COVID-19 pandemic. The hypothesis is that a significant reduction in the number of emergent appendectomies was observed during the pandemic, restricted to complex cases. The study aimed to analyse emergent surgical appendectomies during pandemic on a national basis and compare it to the same period of the previous year. This is a multicentre, retrospective, observational study investigating the outcomes of patients undergoing emergent appendectomy in March–April 2019 vs March–April 2020. The primary outcome was the number of appendectomies performed, classified according to the American Association for the Surgery of Trauma (AAST) score. Secondary outcomes were the type of surgical technique employed (laparoscopic vs open) and the complication rates. One thousand five hundred forty one patients with acute appendicitis underwent surgery during the two study periods. 1337 (86.8%) patients met the inclusion criteria: 546 (40.8%) patients underwent surgery for acute appendicitis in 2020 and 791 (59.2%) in 2019. According to AAST, patients with complicated appendicitis operated in 2019 were 30.3% vs 39.9% in 2020 (p = 0.001). We observed an increase in the number of post-operative complications in 2020 (15.9%) compared to 2019 (9.6%) (p 24 h after admission (+ 58%), open surgery (+ 112%) and conversion to open surgery (+ 166%). In Italian hospitals, in March and April 2020, the number of appendectomies has drastically dropped. During the first pandemic wave, patients undergoing surgery were more frequently affected by more severe appendicitis than the previous year's timeframe and experienced a higher number of complications. Trial registration number and date: Research Registry ID 5789, May 7th, 2020

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p &lt, 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p &lt, 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Background and Aims Crohn’s disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn’s disease-associated small bowel carcinoma prognosis. Methods As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn’s disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. Results Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn’s disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. Conclusions The improved distinction of lower- from higher-grade Crohn’s disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.

Background Little is known about the unmet needs of physicians caring for patients with inflammatory bowel disease (IBD). Aims This study explored the practical difficulties and needs for professional updating of Italian IBD physicians. Methods A questionnaire was distributed to 600 physicians attending IG-IBD meetings. Results 280 physicians completed the questionnaire (46.7%). On a 5-point Likert scale (from 1, strongly disagree to 5, strongly agree), they identified the most problematic issues in managing IBD patients as increasing bureaucracy (3.9), lack of extra-gastroenterological IBD expertise (3.4), lack of diagnostic techniques (3.1) and budget limitations (2.9). The most lacking techniques, ranked from 1 (greatest need) to 9 (lowest need), were: anti-drug antibody and trough level assays (2.7), device-assisted enteroscopy (3.1), exploration under anaesthesia (3.2), MR enterography (3.2), and bowel ultrasonography (3.3). About professional updating, respondents indicated (on a 5-point Likert scale) that helpful topics were practical medicine (4.3), managing difficult patients (4.1), and guidelines (4.0). The most desired modality for updating was residential courses on clinical practice (4.3). Conclusion Several factors potentially limit the best management of IBD patients in Italy. Satisfying these unmet needs could improve care for IBD patients.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, patients with defective immunity after chemo-immunotherapy due to hematological disorders showed prolonged symptoms and worse prognosis of coronavirus disease-2019 (COVID-19) pneumonia, probably due to inadequate adaptive immune response and noneffective viral clearance. We describe a single-center series of hematological immunocompromised patients undergoing passive immunization with hyperimmune plasma for persistent COVID-19 symptoms. In all cases, such treatment was well tolerated and contributed to clinical and radiological improvement and recovery; viral clearance was also achieved in a patients’ subset. Although requiring further investigation, these results suggest a specific role for hyperimmune plasma administration in hematological patients.

Purpose To present a method that allows visualization of functional and structural change in 2-dimensional space. Design Retrospective, longitudinal, observational study. Participants Patients from the Stein Eye Institute, UCLA from 1993 through 2017. Methods Patients were arranged into 2 cohorts. Cohort 1 was used to create a structural score for the horizontal axis of the structural–functional (S-F) 2-dimensional space. The visual field (VF) index was used for the vertical axis as the functional score. Cohort 2 was used to apply those scores for analysis of S-F progression with a combined vector. The first cohort included eyes with mild glaucoma (abnormal glaucoma hemifield test results, pattern standard deviation –5 dB) and normal control participants. The second cohort included all stages of open-angle glaucoma with ≥5 OCT retinal nerve fiber layer scans, ≥5 reliable visual field (VF) results, and follow-up of ≥4 years. Main Outcome Measures Vectors were created for each eye to represent the trajectory of glaucoma progression over time. Each vector was defined by structural (x-axis) and functional (y-axis) components. The structural component was calculated with a linear model of Heidelberg Retina Tomograph (Heidelberg Engineering, Heidelberg, Germany) scores over time. The functional component was calculated with a linear model of VF measurements over time. The resultant vector and its confidence interval were plotted in 2-dimensional S-F space. Eyes were divided into severity stages based on baseline MD. A mean vector was calculated for each severity stage. Results We obtained 290 vectors from 290 eyes of 196 patients. The mean ± standard deviation follow-up period was 14.6±3.1 years. Average age was 58.6±8.8 years. Preperimetric, mild, moderate, and severe categories included 41, 89, 97, and 63 eyes, respectively. Mean baseline MDs were 0.8 dB, –0.95 dB, –3.57 dB, and –11.51 dB, respectively, and mean vector slopes for each severity categories were 0.79, 0.95, 1.95, and 2.08, respectively. Cook’s distance removed 131 (7.1%) and 137 (7.4%) outliers from the structure and function regressions, respectively. Conclusions We report a method to visualize the trajectory of a patient’s glaucoma progression in a 2-dimensional S-F space. The slope of the trajectory of glaucoma progression is a function of the severity of the disease.

PURPOSE: To investigate the relationship between longitudinal changes in macular thickness measurements from optical coherence tomography (OCT) and changes in central visual field (VF) in glaucoma patients with central or advanced damage at baseline. DESIGN: Longitudinal cohort study. SUBJECTS: 116 eyes with ≥3 years of follow-up and ≥5 macular OCT images and central 10° VF tests were selected. METHODS: OCT superpixels and VF locations were matched correcting for retinal ganglion cell displacement. Superpixel thickness and visual field (VF) total deviation (TD) values, in both logarithmic and linear scales, were averaged within 3 eccentricities (3.4°, 5.6°, and 6.8°) and superior and inferior he miretinas and hemifields. We estimated pointwise TD rates of change and rates of change at superpixels for full macular thickness (FMT), ganglion cell complex (GCC), ganglion cell-inner plexiform layer (GCIPL) and ganglion cell layer (GCL). Correlation of structural and functional (SF) rates of change were investigated with parametric tests. We compared the proportion of worsening and positive slopes for superpixels and VF test locations (negative vs. positive rates of change with p

To identify predictive factors for visual field (VF) fluctuation in glaucoma patients.Retrospective cohort study.A total of 1392 eyes (816 patients) with 6 or more VFs and 3 years or more of follow-up.For each eye, the VF mean deviation (MD) and the pointwise sensitivities were regressed against time to model the series trend, and the root mean square error (RMSE) was estimated as a measure of variability. Potential predictors were selected with least absolute shrinkage and selection operator regression and included eye laterality, ethnicity, glaucoma type, intraocular pressure (IOP) fluctuation, baseline best corrected-visual acuity, intervening cataract or glaucoma surgery, length of follow-up, frequency of testing, baseline MD, rates of VF progression, and median false positive (FP) and false negative (FN) responses.Predictors of global and pointwise VF long-term fluctuation.In the global model, left eye (0.063 dB; P = 0.022), Asian descent (0.265 dB; P = 0.006), larger IOP fluctuation (0.051 dB; P0.001), intervening cataract surgery (0.090 dB; P = 0.023), longer follow-up (0.130 dB; P0.001), worse baseline MD (-0.145 dB; P0.001), faster VF decay rate (-0.090 dB; P0.001), and higher FP rate (0.145 dB; P0.001) and FN rate (0.220 dB; P0.001) were predictors of VF fluctuation. In the pointwise model, larger IOP fluctuation (0.039 dB; P = 0.022), longer follow-up (0.340 dB; P0.001), higher VF frequency (0.238 dB; P = 0.002), intervening glaucoma surgery (0.190 dB; P = 0.01), worse baseline MD (-0.535 dB; P0.001), faster VF decay rate (-0.340 dB; P0.001), and higher FP rate (0.255 dB; P0.001) and FN rate (0.395 dB; P0.001) were associated with increased fluctuation. The multivariable model explained 57% and 28% of the pointwise and global variances, respectively.This study identified novel predictors of VF fluctuation, and explains nearly 60% of the pointwise variance. In the presence of factors predictive of high fluctuation, increased frequency of testing and better analytics will help to identify VF progression more accurately.

PURPOSE The purpose of this study was to evaluate the efficacy of intraocular pressure (IOP) control after combined CyPass Micro-Stent implantation and cataract surgery (combined surgery). METHODS All cases of combined surgery performed from February 2017 to July 2018 at Stein and Doheny Eye Institutes were reviewed. The primary outcome was a qualified success with stratified IOP targets based on criteria: final IOP (A) ≤18 mm Hg and reduction of 20%, (B) ≤15 mm Hg and reduction of 25%, (C) ≤12 mm Hg and reduction of 30%. Secondary outcome measures included postoperative IOP and number of medications, complications, additional glaucoma surgery, and postoperative refractive error. Predictive factors for failure were investigated. IOP spike was defined as a postoperative IOP ≥30 or >10 mm Hg increase from preoperative IOP. RESULTS One hundred forty-one eyes (107 patients) were included. Mean (±SD) preoperative IOP was 15.4±3.4 mm Hg on an average of 2.2±1.1 medications. A statistically significant reduction in IOP and number of medications was seen at 12 months (13.8±4.2 mm Hg, 1.3±1.3 medications, P

BackgroundTo evaluate the relationship between the presence of an acquired pit of the optic nerve (APON) and the rate of visual field (VF) decay in primary open-angle glaucoma (POAG).MethodsConsecutive patients with POAG were screened for APON by three glaucoma specialists. A control group of POAG eyes without APON were matched with the APON group for factors such as age, gender, baseline intraocular pressure and baseline mean deviation (MD). The pointwise rate of change (PRC) was used for pointwise comparisons between the two groups. MD rate, Visual Field Index (VFI) rate and Glaucoma Rate Index (GRI) were used for global rate comparisons. We compared the proportions of eyes progressing in the groups with event-based guided progression analysis (GPA), MD, VFI and GRI criteria.ResultsMean (SD) PRC was faster in the APON group −1.00 (±2.57) %/year compared with the control group −0.25 (±2.19) %/year; p0.1).ConclusionsThe presence of APON in patients with POAG is associated with focal, fast rates of VF decay. Identification of patients with APON should alert clinicians to the possibility of a fast rate of functional progression and to consider appropriately aggressive treatment of their glaucoma.

Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis in vivo. Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. Implications: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

ObjectivesCOVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear.DesignThis Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death).ResultsBetween 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death.ConclusionsActive IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn’s disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

Summary Background Older age and comorbidities are the main risk factors for adverse COVID‐19 outcomes in patients with inflammatory bowel disease (IBD). The impact of IBD medications is still under investigation. Aims To assess risk factors for adverse outcomes of COVID‐19 in IBD patients and use the identified risk factors to build risk indices. Methods Observational cohort study. Univariable and multivariable logistic regression was used to identify risk factors associated with pneumonia, hospitalisation, need for ventilatory support, and death. Results Of the 937 patients (446 with ulcerative colitis [UC]) evaluated, 128 (13.7%) had asymptomatic SARS‐CoV‐2 infection, 664 (70.8%) had a favourable course, and 135 (15.5%) had moderate or severe COVID‐19. In UC patients, obesity, active disease and comorbidities were significantly associated with adverse outcomes. In patients with Crohn's disease (CD), age, obesity, comorbidities and an additional immune‐mediated inflammatory disease were identified as risk factors. These risk factors were incorporated into two indices to identify patients with UC or CD with a higher risk of adverse COVID‐19 outcomes. In multivariable analyses, no single IBD medication was associated with poor COVID‐19 outcomes, but anti‐TNF agents were associated with a lower risk of pneumonia in UC, and lower risks of hospitalisation and severe COVID‐19 in CD. Conclusion The course of COVID‐19 in patients with IBD is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID‐19 outcomes. IBD medications do not pose additional risks. The risk indices may help to identify patients who should be prioritised for COVID‐19 re‐vaccination or for therapies for SARS‐CoV‐2 infection., The course of COVID‐19 in patients with IBD patients is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID‐19 outcomes. IBD medications do not pose additional risks.

Pathologists are often called upon to diagnose colitides that differ from the two main forms of inflammatory bowel disease (IBD). These non-IBD colitides include infectious colitis, microscopic colitis, ischemic colitis, eosinophilic colitis, autoimmune enterocolitis, segmental colitis associated with diverticulosis, drug-induced colitis, radiation colitis and diversion colitis. The diagnosis of these different disease entities relies on the histopathological examination of endoscopic biopsies of the gastrointestinal tract. This paper reviews the main histomorphological characteristics of the various Non-IBD colitides.

Background and AimsA similar course of COVID-19 in patients with inflammatory bowel diseases [IBD] and in the general population has been reported. However, disease prevalence in IBD patients is presently unknown. In this prospective observational study, we aimed at determining SARS-CoV2 infection prevalence in IBD patients treated with biologic therapy.MethodsFrom IBD patients under biologic therapy and recruited from three different locations in Italy and Germany, 354 sera were evaluated for antibody presence by RBD ELISA. Control groups were: i] age-matched healthy subjects tested in the same time period in Milan, Italy; ii] healthy subjects collected in the pre-COVID era; iii] IBD patients under biologic therapy collected in the pre-COVID era.ResultsEight out of 354 patients tested positive for the anti-RBD-SARS-CoV2 IgG antibody [prevalence 2.3%]. The percentage of IgG-positive patients among those recruited from Milan was significantly higher than among those recruited from other locations [prevalence 5.4% vs 0.4%, p ConclusionsSeroprevalence of SARS-CoV2 in IBD patients treated with biologic therapy reflects values measured in the local general population. Specific symptoms and contact history with SARS-CoV2-infected individuals strongly increase the likelihood of SARS-CoV2 seropositivity.

Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/-recipients to test their pathogenicity. Human IL-17, IFN gamma/IL-17, and IFN gamma actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFN gamma secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFN gamma(-/-) mice. Moreover, IFN gamma production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFN gamma secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. Conclusions: Intestinal Th17 cell pathogenicity is associated with IFN gamma production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1-/- mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.

To investigate the retinal proteins associated with primary and secondary retinal ganglion cell (RGC) degeneration and explore their molecular pathways, SWATH label-free and target-based mass spectrometry was employed to identify the proteomes in various retinal locations in response to localized optic nerve injury. Unilateral partial optic nerve transection (pONT) was performed on adult Wistar rats and their retinas were harvested 2 weeks later. To confirm the separation of primary and secondary RGC degeneration, immunohistochemistry of RNA binding protein with multiple splicing (RBPMS) and glial fibrillary acidic protein (GFAP) was performed on retinal whole-mounts. Retinal proteomes in the temporal and nasal quadrants were evaluated with high resolution hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS), and SWATH-based acquisition, and their expression was compared to the corresponding retinal quadrant in contralateral control eyes and further validated by multiple reaction monitoring mass spectrometry (MRM-MS). A total of 3641 proteins (FDR &lt, 1%) were identified using QTOF-MS. The raw data are available via ProteomeXchange with the identifier PXD026783. Bioinformatics data analysis showed that there were 37 upregulated and 25 downregulated proteins in the temporal quadrant, whereas 20 and five proteins were upregulated and downregulated, respectively, in the nasal quadrant, respectively (n = 4, p &lt, 0.05, fold change ≥ 1.4-fold or ≤0.7). Six proteins were regulated in both the temporal and the nasal quadrants, including CLU, GFAP, GNG5, IRF2BPL, L1CAM, and CPLX1. Linear regression analysis indicated a strong association between the data obtained by means of SWATH-MS and MRM-MS (temporal, R2 = 0.97, nasal, R2 = 0.96). Gene ontology analysis revealed statistically significant changes in the biological processes and cellular components of primary RGC degeneration. The majority of the significant changes in structural, signaling, and cell death proteins were associated with the loss of RGCs in the area of primary RGC degeneration. The combined use of SWATH-MS and MRM-MS methods detects and quantifies regional changes of retinal protein expressions after localized injury. Future investigation with this integrated approach will significantly increase the understanding of diverse processes of progressive RGC degeneration from a proteomic prospective.

Purpose To test the hypothesis that baseline optical coherence tomography (OCT) measures predict visual field (VF) progression in a cohort of patients with suspected or established glaucoma and to compare their performance to semiquantitative optic disc measures. Design This was an observational cohort study. Methods The setting of this study was an academic institution. The study population included 171 eyes of 95 patients with good-quality baseline retinal nerve fiber layer (RNFL) and macular OCT images and disc photographs with >2 years of follow-up and ≥5 VFs. The observation procedures were baseline macular and RNFL OCT measures and cup-to-disc ratio and disc damage likelihood score. The main outcome measure was prediction of glaucomatous VF deterioration according to trend and event analyses. Results Median (interquartile range) baseline mean deviation and follow-up were -2.9 (-6.4 to -1.1) dB and 54 (44–65) months, respectively. Seventeen and 25 eyes progressed by final visit based on pointwise event analysis and trend analysis of visual field index (VFI), respectively. Thinner central corneal thickness (P = .005), female gender (P = .015), and thinner average peripapillary RNFL (P = .001) predicted VF progression on proportional hazard models. Thinner RNFL at baseline (P = .006) or thinner average ganglion cell-inner plexiform layer (P = .028) along with higher baseline VFI (P = .018 and .048, respectively) predicted VFI progression. Neither optic disc measures predicted VF progression in any of the explored models. Conclusions Baseline structural OCT measures predicted subsequent VF progression in contrast to semi-quantitative optic disc measures. OCT-based structural measures should be included in prognostic models of glaucomatous VF deterioration.

PurposeTo review central structure-function (SF) relationships in glaucoma; to compare contributions of within-session and between-session variability to total variability of macular optical coherence tomography (OCT) thickness measurements; and to test the hypothesis that longitudinal within-eye variability of central SF relationships is smaller than between-individual variability.MethodsWe reviewed the pertinent literature on central SF relationships in glaucoma. Thirty-eight eyes (20 normal or glaucoma subjects) had×3 macular images per session over 3 sessions, and superpixels thickness measurements for ganglion cell layer (GCL), ganglion cell/inner plexiform layer (GCIPL), ganglion cell complex (GCC), and full macular thickness (FMT) were exported. Linear mixed models were used for estimating contributions of between- and within-session variability to total thickness variability. One hundred twenty eyes with ≥3 10° visual fields (VFs)/OCT images were enrolled for the longitudinal study. We investigated within-eye longitudinal SF relationships (GCIPL thickness vs VF total deviations) with a change-point regression model and compared within-eye to between-individual variabilities with components-of-variance models.ResultsIn the cross-sectional study, the between-session component contributed 8%, 11%, 11%, and 36% of total variability for GCL, GCIPL, GCC, and FMT, respectively. In the longitudinal study, between-individual variability explained 78%, 77%, and 67% of total SF variability at 3.4°, 5.6°, and 6.8° eccentricities, respectively (P < .05). SF relationships remained stable over time within individual eyes.ConclusionsWithin-session variability accounts formost of macular thickness variability over time. Longitudinal within-eye SF variability is smaller than between-individual variability. Study of within-eye SF relationships could help clinicians better understand SF linking in glaucoma and help refine progression algorithms. NOTE: Publication of this article is sponsored bythe American Ophthalmological Society.

Purpose To compare the outcomes of Descemet membrane endothelial keratoplasty (DMEK) with those of Descemet's stripping endothelial keratoplasty (DSEK) in eyes with prior glaucoma surgery. Design Case-matched retrospective comparative case series. Methods Setting/study population: 46 DMEK procedures were matched with 46 DSEK procedures at a single institution. Observation procedures: cases were matched based on preoperative visual acuity, lens status, and surgical indication. Main outcome measurements: the outcome measurements included visual acuity improvement, primary and secondary graft failure, endothelial rejection, intraocular pressure (IOP) elevation, and the need for additional glaucoma intervention. Results Best-corrected visual acuity (BCVA) improved by −0.89 logMAR in the DMEK group and −0.62 logMAR in the DSEK group (P = 0.005) at 1 year follow-up. Visual acuity was significantly better in the DMEK group at postoperative months 1, 3, and 12 and at last follow-up. The percentage of patients achieving 20/40 or better best-corrected visual acuity was higher in the DMEK group at all time points, notably 47% in the DMEK group versus 15% in the DSEK group at 1 year (P = 0.002). Secondary graft failure was lower in the DMEK group (DMEK 0% vs. DSEK 17%; P = 0.006). Primary graft failure rates and rebubling rates were similar. There were no differences in the rates of postoperative IOP elevation or in the need for additional glaucoma intervention. Conclusions In complex eyes with prior glaucoma surgery, DMEK offers faster visual recovery, better final visual acuity, and a lower rate of secondary graft failure compared to DSEK during the first postoperative year and beyond.

To test the hypothesis that cataract surgery slows the apparent rate of visual field (VF) decay in primary open-angle glaucoma patients compared with rates measured during cataract progression.Retrospective cohort study.Consecutive open-angle glaucoma patients who underwent cataract surgery and who had ≥4 VFs and ≥3 years of follow-up before and after surgery were retrospectively reviewed. Mean deviation (MD) rate, visual field index (VFI) rate, pointwise linear regression (PLR), pointwise rate of change (PRC), and the Glaucoma Rate Index (GRI) were compared before and after cataract surgery.A total of 134 eyes of 99 patients were included. Median (interquartile range) follow-up was 6.5 (4.7-8.1) and 5.3 (4.0-7.3) years before and after cataract surgery, respectively. All intraocular pressure (IOP) parameters (mean IOP, standard deviation of IOP, and peak IOP) significantly improved (P.001) after cataract surgery. All VF indices indicated an accelerated VF decay rate after cataract surgery: MD rate (-0.18 ± 0.40 dB/year vs -0.40 ± 0.62 dB/year, P.001), VFI rate (-0.44% ± 1.09%/year vs -1.19% ± 1.85%/year, P.001), GRI (-5.5 ± 10.8 vs -13.5 ± 21.5; P.001), and PRC (-0.62% ± 2.47%/year before and -1.35% ± 3.71%/year after surgery; P.001) and PLR (-0.20 ± 0.82 dB/year before and -0.42 ± 1.16 dB/year after surgery; P.001) for all VF locations. Worse baseline MD and postoperative peak IOP were significantly associated with the postoperative VF decay rate and the change in the decay rate after cataract surgery.Although all IOP parameters improved after cataract surgery, VFs continued to progress. Cataract surgery does not slow the apparent rate of glaucomatous VF decay as compared to rates measured during the progression of the cataract.

Background Despite the improvement of medical therapies, nearly half of patients with Crohn’s disease require surgery within 10 years after diagnosis. However, intestinal resection is not curative and recurrence may occur. Aims To evaluate post-surgical outcomes for patients with Crohn’s disease in a large monocentric cohort, and to identify variables associated with clinical and surgical relapse. Methods Patients with Crohn’s disease who had surgery for ileal and colonic Crohn’s disease between 2004 and 2016 and on at least one-year follow-up following surgery were included. Results One hundred ninety-three patients were included in the study. Crohn’s disease recurrence concerned 53% of patients after a median 56-month (6–158) follow-up and 29% of patients required a second surgical intervention. At logistic regression analysis, active smoking and young age at diagnosis were identified as independent risk factor for post-surgical relapse (p = 0.01), while colonic or ileocolonic resection was recognized as a risk factor for surgical Crohn’s disease relapse (p = 0.003). Conclusions Post-surgery recurrence is frequent for patients with Crohn’s disease. Active smoking and young age at diagnosis are risk factors for Crohn’s disease recurrence. As compared with patients undergoing small-bowel surgery, patients with colonic resection are proner to relapse requiring a second surgical intervention.

ObjectiveWe aimed to investigate the relation of blood bacterial DNA load and profiling with intestinal adenoma (IA) and colorectal cancer (CRC) patients.DesignWe performed 16S rRNA gene analysis of blood from 100 incident histologically confirmed CRC cases, 100 IA and 100 healthy subjects, matched to cases by centre, sex and age. Bacterial load was analysed using multiple conditional logistic regression. Differences in terms of abundance of bacteria between groups were estimated through analysis based on negative binomial distribution normalization. Random Forest was applied to predict the group assignment.ResultsWe found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls (IA and healthy subjects). The odds ratio of colon cancer for the highest versus the lowest three quintiles of gene copies was 2.62. (95% confidence interval=1.22-5.65). No difference was found for rectal cancer and IA. For high 16S rRNA, community diversity was higher in colon cancers than controls. CRC cases had an enrichment of Peptostreptococcaceae and Acetobacteriaceae and a reduced abundance of Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae. Identified variables predicted CRC from control and IA patients with an accuracy of 0.70.ConclusionColon cancer patients had a higher DNA bacterial load and a different bacterial profiling as compared to healthy subjects, IA and rectal cancers, indicating a higher passage of bacteria from gastrointestinal tract to bloodstream. Further studies are needed to confirm this result and exploit it to conceive new non-invasive techniques for an early diagnosis of CRC.

Background/aimsTo identify clinical characteristics and factors associated with microcystic macular edema (MME) in patients with primary open-angle glaucoma (POAG).MethodsWe included 315 POAG eyes between 2010 and 2019 with good-quality macular volume scans that had reliable visual fields (VF) available within 6 months in this observational retrospective cohort study. Eyes with retinal pathologies except for epiretinal membrane (ERM) were excluded. The inner nuclear layer was qualitatively assessed for the presence of MME. Global mean deviation (MD) and Visual Field Index (VFI) decay rates, superior and inferior MD rates and pointwise total deviation rates of change were estimated with linear regression. Logistic regression was performed to identify baseline factors associated with the presence of MME and to determine whether MME is associated with progressive VF loss.Results25 out of 315 eyes (7.9%) demonstrated MME. The average (±SD) age and MD in eyes with and without MME was 57.2 (±8.7) versus 62.0 (±9.9) years (p=0.02) and −9.8 (±5.7) versus −4.9 (±5.3) dB (p0.49).ConclusionsMore severe glaucoma and younger age were associated with MME. MME was not associated with faster global VF decay in this cohort. MME may confound monitoring of glaucoma with full macular thickness.

Background COVID-19 pandemic has rapidly required a high demand of hospitalization and an increased number of intensive care units (ICUs) admission. Therefore, it became mandatory to develop prognostic models to evaluate critical COVID-19 patients. Materials and methods We retrospectively evaluate a cohort of consecutive COVID-19 critically ill patients admitted to ICU with a confirmed diagnosis of SARS-CoV-2 pneumonia. A multivariable Cox regression model including demographic, clinical and laboratory findings was developed to assess the predictive value of these variables. Internal validation was performed using the bootstrap resampling technique. The model’s discriminatory ability was assessed with Harrell’s C-statistic and the goodness-of-fit was evaluated with calibration plot. Results 242 patients were included [median age, 64 years (56–71 IQR), 196 (81%) males]. Hypertension was the most common comorbidity (46.7%), followed by diabetes (15.3%) and heart disease (14.5%). Eighty-five patients (35.1%) died within 28 days after ICU admission and the median time from ICU admission to death was 11 days (IQR 6–18). In multivariable model after internal validation, age, obesity, procaltitonin, SOFA score and PaO2/FiO2 resulted as independent predictors of 28-day mortality. The C-statistic of the model showed a very good discriminatory capacity (0.82). Conclusions We present the results of a multivariable prediction model for mortality of critically ill COVID-19 patients admitted to ICU. After adjustment for other factors, age, obesity, procalcitonin, SOFA and PaO2/FiO2 were independently associated with 28-day mortality in critically ill COVID-19 patients. The calibration plot revealed good agreements between the observed and expected probability of death.

Background Surgery is the primary treatment that can offer potential cure for gastric cancer, but is associated with significant risks. Identifying optimal surgical approaches should be based on comparing outcomes from well designed trials. Currently, trials report different outcomes, making synthesis of evidence difficult. To address this, the aim of this study was to develop a core outcome set (COS)—a standardized group of outcomes important to key international stakeholders—that should be reported by future trials in this field. Methods Stage 1 of the study involved identifying potentially important outcomes from previous trials and a series of patient interviews. Stage 2 involved patients and healthcare professionals prioritizing outcomes using a multilanguage international Delphi survey that informed an international consensus meeting at which the COS was finalized. Results Some 498 outcomes were identified from previously reported trials and patient interviews, and rationalized into 56 items presented in the Delphi survey. A total of 952 patients, surgeons, and nurses enrolled in round 1 of the survey, and 662 (70 per cent) completed round 2. Following the consensus meeting, eight outcomes were included in the COS: disease-free survival, disease-specific survival, surgery-related death, recurrence, completeness of tumour removal, overall quality of life, nutritional effects, and ‘serious’ adverse events. Conclusion A COS for surgical trials in gastric cancer has been developed with international patients and healthcare professionals. This is a minimum set of outcomes that is recommended to be used in all future trials in this field to improve trial design and synthesis of evidence.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

PurposeWe compared rates of change of macular ganglion cell/inner plexiform (GCIPL) thickness and proportion of worsening and improving rates from 2 optical coherence tomography (OCT) devices in a cohort of eyes with glaucoma.DesignLongitudinal cohort study.MethodsIn a tertiary glaucoma clinic we evaluated 68 glaucoma eyes with ≥2 years of follow-up and ≥4 OCT images. Macular volume scans from 2 OCT devices were exported, coregistered, and segmented. Global and sectoral GCIPL data from the central 4.8×4.0-mm region were extracted. GCIPL rates of change were estimated with linear regression. Permutation analyses were used to control specificity with the 2.5 percentile cutoff point used to define "true" worsening. Main outcome measures included differences in global/sectoral GCIPL rates of change between 2 OCT devices and the proportion of negative vs positive rates of change (P < .05).ResultsAverage (standard deviation) 24-2 visual field mean deviation, median (interquartile range) follow-up time, and number of OCT images were -9.4 (6.1) dB, 3.8 (3.3-4.2) years, and 6 (5-8), respectively. GCIPL rates of thinning from Spectralis OCT were faster (more negative) compared with Cirrus OCT; differences were significant in superonasal (P=.03) and superotemporal (P=.04) sectors. A higher proportion of significant negative rates was observed with Spectralis OCT both globally and in inferotemporal/superotemporal sectors (P < .04). Permutation analyses confirmed the higher proportion of global and sectoral negative rates of change with Spectralis OCT (P < .001).ConclusionsChanges in macular GCIPL were detected more frequently on Spectralis' longitudinal volume scans than those of Cirrus OCT. OCT devices are not interchangeable with regard to detection of macular structural progression.

ObjectiveTo identify the existence of a correlation among the various organs affected, focusing primarily on immuno-dermatological aspects, and to create a risk prediction model of organ-specific complications.Material and MethodsFifty-two patients with stable scleroderma, followed between 2015 and 2019, were investigated through an extensive multidisciplinary evaluation in the last year.ResultsPatients with lung involvement presented a worse degree of skin fibrosis than patients without it (p ConclusionsOut of all the organs studied, the skin is the one that correlates with the lung. Patients with a diffuse form of disease presented more frequently the anti Scl-70 antibody and had a worse lung and esophageal involvement (scleroderma pattern) than the negative group. Conversely, patients with limited disease presented all positive for the anti-centromere antibody with a better lung involvement than the negative group, without any difference among the esophageal manometric pattern. Anti PM-Scl 100/75 antibody patients were associated with pulmonary fibrosis and presented cardiac involvement. The model created has demonstrated excellent values of sensitivity, specificity, and accuracy, but further studies are needed for validation.

Avian malaria is a worldwide distributed, vector-born disease of birds caused by parasites of the order Haemosporida. There is a lack of knowledge about the presence and pathogenetic role of Haemosporida in Psittacidae. Here we report a case of avian malaria infection in lovebirds (Agapornis roseicollis), with the genetic characterization of the Plasmodium species involved. The birds were hosted in a zoo located in Italy, where avian malaria cases in African penguins (Spheniscus demersus) were already reported. Animals (n = 11) were submitted for necropsy after sudden death and were subjected to further analyses including histopathology, bacteriology, and PCR for the research of haemosporidians. Clinical history, gross lesions and histopathological observation of schizonts, together with positive PCR results for Plasmodium spp., demonstrated that avian malaria was the cause of death for one animal and the possible cause of death for the other nine. The sequences obtained were compared using BLAST and analyzed for similarity to sequences available at the MalAvi database. Genetic analyses demonstrated a 100% nucleotide identity to Plasmodium matutinum LINN1 for all the obtained sequences. To our knowledge, this is the first report describing avian malaria in lovebirds.

Porcine encephalomyelitis can be associated with many etiologies, including viral agents, such as Porcine teschovirus (PTV), Porcine sapelovirus (PSV), and Porcine astrovirus (PoAstV). In this study, we investigated the presence of these viruses in a neurological disease outbreak in a swine farm in Southern Brazil. The piglet production farm unity had 1200 weaning piglets, and 40 piglets with neurological signs such as motor incoordination, paresis, and paralysis of hind limbs, with an evolution time of approximately 4 days. Among these, 10 piglets were submitted to postmortem examination. Gross lesions were restricted to a mild enlargement of the nerve roots and ganglia of spinal cord segments. The microscopic lesions were characterized by nonsuppurative encephalomyelitis and ganglioneuritis with evident neuronal degeneration and necrosis. Samples of the central nervous system (CNS), cerebrospinal fluid, and feces were collected and submitted to molecular analysis. PTV was identified in all samples of the CNS, while eight of the piglets were also positive for PSV, and seven were positive for Porcine enterovirus (EV-G). PoAstV was identified in a pool of feces of healthy animals used as controls. This study demonstrates the occurrence of encephalomyelitis associated with PTV on a swine farm in Southern Brazil, as well as the presence of other viruses such as PSV, EV-G, and PoAstV in the swineherd. Sequences of the fragments that were previously amplified by PCR showed a high similarity to PTV 6. Herein, we describe the first case report of severe swine polioencephalomyelitis associated with PTV in South America.

Background and Aim Since the outbreak of COVID‐19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID‐19 in a large cohort of IBD patients on biologic therapy. Methods This observational retrospective multicenter study collected data about COVID‐19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end‐points were (i) to assess both the cumulative incidence and clinical outcome of COVID‐19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non‐biologic therapies. Results Among 1816 IBD patients, the cumulative incidence of COVID‐19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case‐fatality rate. The class of biologic agents was the only risk factor of developing COVID‐19 (P = 0.01). Non‐gut selective agents were associated with a lower incidence of COVID‐19 cases, related symptoms, and hospitalization (P