Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of ...uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
INTRODUCTION: Despite research efforts, predicting Clostridioides difficile incidence and its outcomes remains challenging. The aim of this systematic review was to evaluate the performance of ...machine learning (ML) models in predicting C. difficile infection (CDI) incidence and complications using clinical data from electronic health records. METHODS: We conducted a comprehensive search of databases (OVID, Embase, MEDLINE ALL, Web of Science, and Scopus) from inception up to September 2023. Studies employing ML techniques for predicting CDI or its complications were included. The primary outcome was the type and performance of ML models assessed using the area under the receiver operating characteristic curve. RESULTS: Twelve retrospective studies that evaluated CDI incidence and/or outcomes were included. The most commonly used ML models were random forest and gradient boosting. The area under the receiver operating characteristic curve ranged from 0.60 to 0.81 for predicting CDI incidence, 0.59 to 0.80 for recurrence, and 0.64 to 0.88 for predicting complications. Advanced ML models demonstrated similar performance to traditional logistic regression. However, there was notable heterogeneity in defining CDI and the different outcomes, including incidence, recurrence, and complications, and a lack of external validation in most studies. DISCUSSION: ML models show promise in predicting CDI incidence and outcomes. However, the observed heterogeneity in CDI definitions and the lack of real-world validation highlight challenges in clinical implementation. Future research should focus on external validation and the use of standardized definitions across studies.
Most people were taught the uses of the colon inadequately, if at all. Very few were ever taught how to use the semicolon; as a result, they tend to shy away from using it at all. But the proper use ...of these two punctuation marks can help writers better control a reader's reading experience. For both the colon and the semicolon, the grammatical rule states that what precedes those punctuation marks must be able to stand by itself as a complete sentence. By giving syntactic closure to the preceding main clause, the colon and semicolon are able to create a stress position in the middle of a sentence.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite these interventions, the patient demonstrated progressive disease, and hence she received multiple courses of palliative chemo and radiotherapy. 3 weeks prior to presentation, she started to ...have progressive shortness of breath that limited her exercise tolerance significantly with cough and noisy breathing. Palliative endobronchial treatment via interventional pulmonology has now become standard of care for EMD and is associated with better quality of life.
Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice.
TRansabdominal Ultrasonography of the bowel in ...Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography.
At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001).
IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.
An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of ...novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.
To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.
We identified 13 loci that reached genome-wide significance (p<5×10
) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.
Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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