Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Mansonella sp. and associated Wolbachia endosymbionts in ring-tailed coatis (Nasua nasua) in periurban areas from Midwestern Brazil.

Coatis (Nasua nasua) are wild carnivorous well adapted to anthropized environments especially important because they act as reservoirs hosts for many arthropod-borne zoonotic pathogens. Information about filarioids from coatis and associated Wolbachia spp. in Brazil is scant. To investigate the diversity of filarial nematodes, blood samples (n = 100 animals) were obtained from two urban areas in midwestern Brazil and analyzed using blood smears and buffy coats and cPCR assays based on the cox1, 12S rRNA, 18S rRNA, hsp70 and myoHC genes for nematodes and 16S rRNA for Wolbachia. When analyzing coati blood smears and buffy coats, 30% and 80% of the samples presented at least one microfilaria, respectively. Twenty-five cox1 sequences were obtained showing 89% nucleotide identity with Mansonella ozzardi. Phylogenetic analyses clustered cox1 sequences herein obtained within the Mansonella spp. clade. Sequences of both myoHC and two hsp70 genes showed 99.8% nucleotide identity with Mansonella sp. and clustered into a clade within Mansonella sp., previously detected in coatis from Brazil. Two blood samples were positive for Wolbachia, with a 99% nucleotide identity with Wolbachia previously found in Mansonella perstans, Mansonella ozzardi and Mansonella atelensis and in ectoparasites of the genus Pseudolynchia, Melophagus and Cimex. The study showed a high prevalence of Mansonella sp. in the coati population examined, suggesting that this animal species play a role as reservoirs of a novel, yet to be described, species within the Onchocercidae family.

Molecular detection of Babesia spp. and Rickettsia spp. in coatis (Nasua nasua) and associated ticks from midwestern Brazil.

Procyonids are reservoirs of many zoonotic infectious diseases, including tick-borne pathogens. The role of coatis (Nasua nasua) in the epidemiology of piroplasmids and Rickettsia has not been fully addressed in Brazil. To molecularly study these agents in coatis and associated ticks, animals were sampled in two urban areas in Midwestern Brazil. Blood (n = 163) and tick (n = 248) DNA samples were screened by PCR assays targeting the 18S rRNA and gltA genes of piroplasmids and Rickettsia spp., respectively. Positive samples were further molecularly tested targeting cox-1, cox-3, ß-tubulin, cytB, and hsp70 (piroplasmid) and ompA, ompB, and htrA 17-kDa (Rickettsia spp.) genes, sequenced and phylogenetically analyzed. All coatis' blood samples were negative for piroplasmids, whereas five pools of ticks (2%) were positive for two different sequences of Babesia spp.. The first from Amblyomma sculptum nymphs was close (i.e., ≥ 99% nucleotide identity) to a Babesia sp. previously found in capybaras (Hydrochoerus hydrochaeris); the second from Amblyomma dubitatum nymphs and Amblyomma spp. larvae was identical (100% nucleotide identity) to a Babesia sp. detected in opossums (Didelphis albiventris) and associated ticks. Four samples (0.8%) were positive by PCR to two different Rickettsia spp. sequences, being the first from Amblyomma sp. larva identical to Rickettsia belli and the second from A. dubitatum nymph identical to Rickettsia species from Spotted Fever Group (SFG). The detection of piroplasmids and SFG Rickettsia sp. highlights the importance of Amblyomma spp. in the maintenance of tick-borne agents in urban parks where humans and wild and domestic animals are living in sympatry.

Artificial intelligence and high-resolution anoscopy: automatic identification of anal squamous cell carcinoma precursors using a convolutional neural network.

BACKGROUND: High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell cancer (ASCC) precursors. Although it is superior to other diagnostic methods, particularly cytology, the visual identification of areas suspected of having high-grade squamous intraepithelial lesions remains difficult. Convolutional neural networks (CNNs) have shown great potential for assessing endoscopic images. The aim of the present study was to develop a CNN-based system for automatic detection and differentiation of HSIL versus LSIL in HRA images. METHODS: A CNN was developed based on 78 HRA exams from a total of 71 patients who underwent HRA at a single high-volume center (GH Paris Saint-Joseph, Paris, France) between January 2021 and January 2022. A total of 5026 images were included, 1517 images containing HSIL and 3509 LSIL. A training dataset comprising 90% of the total pool of images was defined for the development of the network. The performance of the CNN was evaluated using an independent testing dataset comprising the remaining 10%. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve (AUC) were calculated. RESULTS: The algorithm was optimized for the automatic detection of HSIL and its differentiation from LSIL. Our model had an overall accuracy of 90.3%. The CNN had sensitivity, specificity, positive and negative predictive values of 91.4%, 89.7%, 80.9%, and 95.6%, respectively. The area under the curve was 0.97. CONCLUSIONS: The CNN architecture for application to HRA accurately detected precursors of squamous anal cancer. Further development and implementation of these tools in clinical practice may significantly modify the management of these patients.

Longitudinal dynamics and health impact of Hepatozoon procyonis (Apicomplexa: Hepatozoidae) on naturally infected ring-tailed coatis Nasua nasua (Carnivora: Procyonidae) from Midwestern Brazil.

This study aimed to morphologically and molecularly detect Hepatozoon procyonis in ring-tailed coatis' (Nasua nasua) blood and associated ticks from central-western Brazil, Campo Grande, Mato Grosso do Sul state and also evaluate the impact of the protozoa in blood parameters and coati´s health. Samplings were performed in a conservation area Parque Estadual do Prosa (PEP) and in a Brazilian Air Force Private Area namely Vila da Base Aérea (VBA), between March 2018 and April 2019. We collected 165 blood samples, 61 from recaptured coatis. Peripheral blood smears were stained with Romanovsky-type stain for H. procyonis parasitemia assessment. DNA extracted from blood samples and ticks (Amblyomma spp.) were submitted to a nested PCR (nPCR) assay based on the 18S rRNA gene for Hepatozoon spp. Out of 104 individuals sampled, 80 (77%) were positive for H. procyonis in at least one capture. Overall, 67/165 (40.6%) blood smears showed H. procyonis gametocytes (PEP: 41/63 - 65%; VBA: 26/102 - 25.5%). Parasitemia based on 500 assessed leucocytes ranged from 1 (0.2%) to 50 (10%) and 1 (0.2%) to 25 (5%), from animals sampled in PEP and VBA, respectively. Fluctuation on the parasitemia was observed during recaptures. nPCR results showed higher positivity when compared to blood smears, i.e. 112/165 (68%) positive blood samples [PEP: 41/63 (65%), VBA: 26/102 (25.5%)]. In total, 63/248 (25.4%) tick DNA samples were positive at nPCR for Hepatozoon sp., including 32/87 (37%) pools (1 to 10 larvae) of Amblyomma larvae, 21/105 (20%) pools (1 to 5 nymphs) of Amblyomma sculptum nymphs, 9/43 (21%) pools (1 to 5 nymphs) of Amblyomma dubitatumnymphs, and 1/12 (8%) A. sculptum adult female. The partial 18S rRNA sequence from one coati's blood sample and one representative of each positive tick species randomly selected from each area for sequencing (1,000 bp) showed 100% identity with sequences of H. procyonis from GenBank previously detected in coatis. Regarding H. procyonis infection, no statistical differences were obtained when comparing males vs. females (p-value 0.67), immature animals vs. adults (p-value 0.31), rainy vs. dry season (p-value 0.51) and sampling location (p-value 0.42). No noticeable alteration in blood parameters or heath status was observed in parasite animals. H. procyonis circulates in a high prevalence in coatis from central-western Brazil. Parasitemia fluctuates among different coatis' recaptures and apparently the infection has no influence in coatis' hematological and clinical parameters.

Risk factors and clinical outcomes of acute esophageal necrosis: retrospective case series of a rare disease with "black" prognosis.

Acute esophageal necrosis is a rare syndrome classically characterized by black distal esophagus with a complex pathophysiology that usually involves a combination of esophageal ischemia, gastroesophageal reflux and impaired mucosal reparative mechanisms. We retrospectively analyzed the main risk factors, clinical characteristics and outcome in all patients diagnosed with acute esophageal necrosis between January 2015 and December 2020 at our center. Ten patients were identified in a total of 26854 upper digestive endoscopies (0.04%). Most patients were male (8/10) and the mean age of presentation was 71.1 years. The most common presenting symptoms were melena and hematemesis and half the patients required red blood cell transfusion. The most common risk factors were hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, peripheral artery disease, coronary artery disease, cerebrovascular disease, heart failure and malignancy. Compromised hemodynamic state was the most common precipitating event in four patients. Other recognized precipitating events included surgical interventions, decompensated heart failure, gastrointestinal bleeding from gastric malignancy and methotrexate. Endoscopic findings revealed diffuse and circumferential black distal esophagus with abrupt transition at gastroesophageal junction and variable proximal extension at presentation. The 1-month mortality rate was 30%, mostly from severe underlying illness. In conclusion, acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding that should be suspected in older patients with multiple comorbidities. Although associated with a high mortality rate, appropriate treatment may result in favorable outcome in most patients.

High-grade anal intraepithelial neoplasia treated with endoscopic submucosal dissection: a case report.

Anal intraepithelial neoplasia is a premalignant lesion for anal squamous cell carcinoma. Current treatment options, consisting of topical therapy and local ablative procedures with electrocautery or radiofrequency ablation, are effective although recurrence rates are high. Experience with endoscopic submucosal dissection for anal lesions is limited, with only a few cases of anal intraepithelial neoplasia and early anal squamous cell carcinoma. We present a 65-year-old woman with high-grade anal intraepithelial neoplasia successfully removed by endoscopic submucosal dissection with no complications or signs of recurrence after 5 months, suggesting that this technique could be a safe and effective approach for management of anal premalignant lesions.

An unexpected cause of proximal small intestinal obstruction.

A 63-year-old caucasian male with history of tonsil cancer, under induction chemotherapy, reported food intolerance and vomiting with duration of one month. Symptoms had increased over the last days and were associated with a weight loss of 10 Kg during the past three months. The patient lived all of is life in an urban environment. General physical examination revealed cachexia and dehydration. Gastrointestinal symptoms persisted despite intravenous pantoprazole, prokinetic drugs and nasogastric tube insertion. On investigation, patient presented normocytic and normochromic anemia (9.2 g/dL), lymphocytosis (11.78 x109/L) with neutrophilia (70.7%) and eosinophilia (7.7%), hypoalbuminemia (2.8 g/dL) and elevated C-reactive protein (25.5 mg/dL). Upper endoscopy revealed deformation of bulb and second part of the duodenum with mucosal edema, superficial ulceration and friability (Figure 1a). Biopsies were taken from the bulb and second portion of the duodenum. Computer tomography demonstrated gastric distention, duodenal wall thickening and lumen narrowing in the second and third portion of the duodenum (Figure 2). These findings were indicative of a functionally relevant duodenum stenosis. Histopathologic evaluation of biopsy specimens from the duodenum revealed moderate accumulation of eosinophilic granulocytes and nematode larvae within mucosal crypts (Figure 1b). What is the diagnosis?

Exosomal glypican-1 discriminates pancreatic ductal adenocarcinoma from chronic pancreatitis.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) diagnosis can be difficult in a chronic pancreatitis (CP) background, especially in its mass forming presentation. We aimed to assess the accuracy of glypican-1-positive circulating exosomes (GPC1+crExos) to distinguish PDAC from CP versus the state-of-the-art CA 19-9 biomarker. METHODS: This was a unicentric prospective cohort. Endoscopic ultrasound with fine-needle aspiration or biopsy and blood tests (GPC1+crExos and serum CA 19-9) were performed. RESULTS: The cohort comprised 60 PDAC and 29 CP (7 of which mass forming - MF) patients. Median levels of GPC1+crExos were significantly higher in PDAC (99.7%) versus CP (28.4%; p<0.0001) with an AUROC of 0.96 with 98.3% sensitivity and 86.2% specificity for a cut-off of 45.0% (p<0.0001); this outperforms CA 19-9 AUROC of 0.82 with 78.3% sensitivity and 65.5% specificity at a cut-off of 37 U/mL (p<0.0001). The superiority of% GPC1+crExos over CA 19-99 in differentiating PDAC from CP was observed in both early (stage I) and advanced tumors (stages II-IV). CONCLUSION: Levels of GPC1+crExos coupled to beads enable differential diagnosis between PDAC and CP including its mass-forming presentation.

Role of enteroscopy in the diagnosis of whipple's disease.

Whipple's disease is a rare chronic systemic infection caused by Tropheryma whipplei. The widespread infection by this rod is responsible for the protean clinical manifestations of the disease, although its classical form is notable for the prevalence of abdominal symptoms such as chronic diarrhea and abdominal pain. Whitish-yellow patches, suggestive of lymphangiectasia, are typically observed in the duodenum during upper endoscopy. The diagnosis of this condition is supported by the identification in duodenal biopsies of Periodic acid-Schiff staining within lamina propria macrophages. Nevertheless, a significant portion of patients do not have lesions within the range of conventional upper endoscopy. Therefore, other endoscopic procedures such as video capsule endoscopy and enteroscopy may be useful to detect more distal lesions. The authors describe a case where the combined used of both techniques allowed the unmasking of this disease.

Artificial intelligence and colon capsule endoscopy: development of an automated diagnostic system of protruding lesions in colon capsule endoscopy.

BACKGROUND: Colon capsule endoscopy (CCE) is a minimally invasive alternative for patients unwilling to undergo conventional colonoscopy, or for whom the latter exam is contraindicated. This is particularly important in the setting of colorectal cancer screening. Nevertheless, these exams produce large numbers of images, and reading them is a monotonous and time-consuming task, with the risk of overlooking important lesions. The development of automated tools based on artificial intelligence (AI) technology may improve some of the drawbacks of this diagnostic instrument. METHODS: A database of CCE images was used for development of a Convolutional Neural Network (CNN) model. This database included anonymized images of patients with protruding lesions in the colon or patients with normal colonic mucosa or with other pathologic findings. A total of 3,387,259 frames from 24 CCE exams were retrospectively reviewed. For CNN development, 3640 images (860 protruding lesions and 2780 with normal mucosa or other findings) were ultimately extracted. Training and validation datasets were constructed for the development and testing of the CNN. RESULTS: The CNN detected protruding lesions with a sensitivity, specificity, positive and negative predictive values of 90.7, 92.6, 79.2 and 96.9%, respectively. The area under the receiver operating characteristic curve for detection of protruding lesions was 0.97. CONCLUSIONS: The deep learning algorithm we developed is capable of accurately detecting protruding lesions. The application of AI technology to CCE may increase its diagnostic accuracy and acceptance for screening of colorectal neoplasia.

Perianal warts as a risk marker for anal high-risk-human papillomavirus (HPV) detection and HPV-associated diseases.

BACKGROUND: Genital warts are the most common sexually transmitted infection (STI) and are caused by human papillomavirus (HPV). Persistent anal infection by oncogenic genotypes of HPV is a determinant for anal cancer. Currently, anal cancer screening is not widely implemented. OBJECTIVES: Our aim is to evaluate the role of perianal warts as a risk marker for anal high-risk (HR) HPV detection and anal dysplasia. METHODS: In this observational, retrospective, cohort study of attendees of a STI outpatient clinic between January 2010 and June 2018, all human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) who performed anal cytology, anal HPV DNA detection and anoscopy were included. A comparison was made between patients with and without perianal warts. Primary endpoint: proportion of patients with an abnormal anal cytology. Secondary endpoints: proportion of patients with (i) anal HR-HPV detection; (ii) anal HPV 16 detection; (iii) abnormal anal biopsy; and (iv) anal high-grade squamous intraepithelial lesion (HSIL). RESULTS: Seventy-eight individuals were included: 39 with perianal warts and 39 without perianal warts. Subjects with perianal warts more frequently had an abnormal anal cytology (71.8% vs. 38.5%; P = 0.003). This group also had a higher rate of anal HPV 16 detection (38.5% vs. 12.8%; P = 0.01). No differences were detected in the proportion of patients with anal HR-HPV detection, with an abnormal anal biopsy or with anal HSIL. Perianal warts was an independent risk factor for an abnormal anal cytology (OR: 7.2) and for anal HPV 16 detection (OR: 6.7). CONCLUSION: Given the high risk of anal cancer in HIV-positive MSM, effective screening strategies are greatly needed. This study suggests that the presence of perianal warts is a suitable risk marker for anal HPV 16 detection and anal dysplasia.