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Background: Despite the effectiveness of colonoscopy for reducing colorectal cancer (CRC) mortality, poor screening compliance ranks CRC as the second most deadly malignancy. There is a need to develop a preventative, non-invasive diagnostic test, such as a fecal microbiota test, for early detection of both pre-cancerous adenomas and carcinomas to effectively reduce mortality. Results: We conducted a clinical meta-analysis of published deep metagenomic stool sequence datasets including 1,670 subjects from 9 countries, including 703 healthy controls, 161 precancerous colorectal adenoma (CRA), 48 advanced precancerous colorectal adenoma (CRAA) and 758 CRC cases diagnosed by colonoscopy. We analyzed these data through a novel automated machine learning workflow using a two-stage feature importance ranking and ensemble modeling method to identify and select highly predictive taxonomic and functional biomarkers. Machine learning modeling of selected features differentiated the metagenomic profiles of healthy patients from CRA, CRAA and CRC cases with an average area under the curve (AUC) for external holdout testing of 0.84 (sensitivity=0.82; specificity=0.71, accuracy=0.77) for CRC; an AUC of 0.97 (sensitivity=0.78; specificity=0.98, accuracy=0.97) for CRAA; and an AUC of 0.90 (sensitivity=0.74, specificity=0.89, accuracy=0.86) for CRA. These performance outcomes represented a 2%, 3% and 8% increase in AUC, compared to baseline ML performance, respectively. The predictive features identified for each disease class were largely distinct and represented differing proportions of taxonomic and functional features. Conclusions: The predictive taxonomic features identified for each disease class were largely distinct, whereas many functional gene features were shared across disease classes but displayed differing direction of change. Application of our ensemble approach for feature selection increased the predictive power of each disease class and moreover may generate discriminatory models with greater generalizability.

The educational value of formative assessment (FA) has been widely acknowledged within higher education. At the same time, there is little consensus on what FA entails, or how it should be defined and understood when looking at the Western education system; this is even more problematic when adapted by TNE institutions. This chapter looks at the definition issues together with key characteristics of quality formative feedback, including the role of the student in co-creating feedback, something that is particularly challenging within the context of this chapter, TNE in China. It looks at the most apparent challenges that are associated with FA implementation within a Chinese higher education context, such as educational heritage and a deep-rooted collectivist approach to learning. It also ventures to propose an alternative conception, formative routines framework FRF), to emphasise the importance of student and teacher training when engaging in formative tasks and using these to support the ongoing development of curricula.

Background Crohn’s disease (CD) is associated with a high risk of intestinal complications such as stricture, fistula and abscess formation, as well as perianal disease, frequently requiring surgical procedures and intestinal stoma formation. The aim of the present study was to evaluate the prevalence as well as predictors for surgical stoma formation in CD patients. Methods This is a retrospective single tertiary center cohort study of 1157 patients with CD with a median follow-up of 15 years whose characteristics (Table 1) are recorded via a validated data software (IBDIS, Inflammatory Bowel Disease Information System). The primary objective was the assessment of risk factors for intestinal stoma formation during follow-up. The probability of stoma-free survival was calculated for the entire patient population and for subgroups defined by their time of diagnosis (-1999, 2000–2009, 2010-), location and behavior of disease, presence of perianal disease (ever), gender, and smoking habits by means of Kaplan-Meier estimates. Results 135 (11.7%) patients with intestinal stomas [78 (57.8%) ileostomies and 57 (42.2%) colostomies] were registered. The probability of stoma-free survival after 5, 10, and 20 years was 95.9%, 91.8%, and 85.5%, respectively. Stoma formation surgery was elective in 51 (37.8%) cases, emergency in 49 (36.3%) and unknown in the others (25.9%). The most common indications were perianal disease [(n=34; 25.2%), internal fistula/abscess [n=25 (18.5%)], postoperative complications [n=21 (15.6%)], stricture [n=11 (8.1%)], and refractory to treatment [n=10 (7.4%)]. The probability of stoma-free survival was significantly lower in patients with perianal disease (p Conclusion We found a high prevalence of intestinal stoma formation in CD patients of a tertiary center. Patients with perianal disease, penetrating behavior and colonic location, have a lower probability of stoma-free survival.

We report for the first time on the parahydrophobicity and stick-slip wetting dynamics of vertically aligned carbon-nanotube (CNT) forests and compare it with previously observed droplet infiltration characteristics. CNT surfaces have generally been reported to be superhydrophobic, but unstable, as the water rapidly infiltrates the forest. In this paper, we demonstrate the first observation of parahydrophobicity of CNT forests, where the surface exhibits an apparent static water contact angle close to 150° but may be turned upside down without the droplet rolling off. Evaporation plays a critical role in the dynamic wetting behavior of these high-density samples as water droplets are stable in moisture-saturated environments. The wetting dynamics in the ambient is driven by evaporation as opposed to infiltration and characterized by contact line pinning from the strong adhesive forces in the CNTs. The pinning force at the contact line gradually increases as the droplet evaporates until a critical force is reached, where the contact line suddenly jumps radially inward with a concomitant deflection of CNTs inward. We observe that taller CNT forests have a higher critical force for deflection and coalesce into cellular patterns with larger cell size, which both suggest that taller CNTs have stronger mechanical interactions with each other.

Background & aims Increasing numbers of autochthonous hepatitis E virus infections have been reported in Europe. Chronic infections have been shown in immune-compromised patients after solid organ transplantation. Hepatitis E virus might be a possible trigger for autoimmune hepatitis and might cause disease flares or relapses in the further course of disease. Aim of this study was to investigate the presence of hepatitis E virus antibodies and hepatitis E virus RNA, and to analyse their impact on immunosuppressive treatment in patients with autoimmune hepatitis. Methods Sera from 92 autoimmune hepatitis patients (73/79.3% female, age: 42.2 ± 16.3 years [mean ± SD]) were tested. Patients were scored according to the simplified and revised scoring systems of the International Autoimmune Hepatitis Group. The prevalence of anti- hepatitis E virus antibodies (Beijing Wantai Biological Pharmacy Enterprises Co., Ltd, Beijing, China) and hepatitis E virus RNA was determined. Results 19/20.7% autoimmune hepatitis patients tested positive for hepatitis E virus-IgG, which was higher than in previous reports of healthy Austrian individuals (12.4%, P = 0.031); hepatitis E virus RNA was not detectable in any patient. Anti-hepatitis E virus positive patients were older (49.5 ± 9.5 vs 40.4 ± 17.2 years [mean ± SD], P = 0.033) but did not differ in laboratory findings at diagnosis (AST: 14.6 [1.3-70.6] vs 9.5 [0.7-62.7] × ULN [median/range]; P = 0.387, alanine aminotransferase: 18.3 [1.6-62.7] vs. 12.9 [0.8-62.6] × ULN; P = 0.511; IgG: 1.4 [1.0-2.5] vs 1.3 [0.6-3.8] g/dL × ULN; P = 0.278) nor in alanine aminotransferase levels after six months (0.7 [0.5-2.4] vs 1.0 U/L × ULN [0.1-22.4]; P = 0.077). Conclusions No chronic hepatitis E virus infection was observed in our cohort of autoimmune hepatitis patients. Anti- hepatitis E virus-IgG positive patients were older and the seroprevalence was nearly twice as high as reported previously in healthy Austrian individuals, suggesting that hepatitis E virus-infection might act as trigger for the development of autoimmune hepatitis.

Genetic variants including PNPLA3-rs738409 C&gt, G, TM6SF2-rs58542926 C&gt, T, MBOAT7-rs641738 C&gt, T, and HSD17B13-rs72613567 T&gt, TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.

Background and Aims Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal hypertension (liver stiffness measurement [LSM] by vibration‐controlled transient elastography and von Willebrand factor/platelet count ratio [VITRO]) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure. Approach and Results A total of 276 patients with pretreatment ACLD and information on pretreatment and posttreatment follow‐up (FU)‐LSM and FU‐VITRO were followed for a median of 36.6 months after the end of interferon‐free therapy. FU‐LSM (area under the receiver operating characteristic curve [AUROC]: 0.875 [95% confidence interval [CI]: 0.796‐0.954]) and FU‐VITRO (AUROC: 0.925 [95% CI: 0.874‐0.977]) showed an excellent predictive performance for hepatic decompensation. Both parameters provided incremental information and were significantly associated with hepatic decompensation in adjusted models. A previously proposed combined approach (FU‐LSM 25.3 kPa and/or FU‐VITRO > 3.3; 25.0% of patients), the risk of hepatic decompensation at 3 years following treatment was high (17.4%). Patients within the diagnostic gray‐zone for FU‐CSPH (17.8% of patients) had a very low risk of hepatic decompensation during FU (2.6%). The prognostic value of this algorithm was validated in an internal (n = 86) and external (n = 162) cohort. Conclusion FU‐LSM/FU‐VITRO are strongly and independently predictive of posttreatment hepatic decompensation in HCV‐induced ACLD. An algorithm combining these noninvasive markers not only rules in or rules out FU‐CSPH, but also identifies populations at negligible versus high risk for hepatic decompensation. FU‐LSM/FU‐VITRO are readily accessible and enable risk stratification after sustained virological response, and thus facilitate personalized management.

MEF2C has been shown to be a critical transcription factor for neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Here, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found an aberrant micro-RNA-mediated gliogenesis pathway that contributes to decreased neurogenesis. We also demonstrate network-level hyperexcitability in neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the extrasynaptic NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks suggesting that our approach may lead to personalized therapy for multiple forms of ASD.One sentence summaryAutism-like MEF2C+/- patient hiPSC models show miRNA-mediated overproduction of astrocytes and hyperactivity of neurons.

Dendritic cells (DCs) are increasingly important for research and clinical use but obtaining sufficient numbers of dendritic cells is a growing challenge. We systemically investigated the effect of monocyte (MO) seeding density on the generation of monocyte-derived immature DCs (iDCs) in MicroDEN, a perfusion-based culture system, as well as 6-well plates. Cell surface markers and the ability of the iDCs to induce proliferation of allogeneic T cells were examined. The data shows a strong relationship between iDC phenotype, specifically CD80/83/86 expression, and T cell proliferation. MicroDEN generated iDCs proved better than well plate generated iDCs at inducing T cell proliferation within the 200k-600k MO/cm(2) seeding density range studied. We attribute this to perfusion in MicroDEN which supplies fresh differentiation medium continuously to the differentiating MOs while concurrently removing depleted medium and toxic byproducts of cellular respiration. MicroDEN generated fewer iDCs on a normalized basis than the well plates at lower MO seeding densities but generated equivalent numbers of iDCs at 600k MO seeding density. These results demonstrate that MicroDEN is capable of generating greater numbers of iDCs with less manual work than standard well plate culture and the MicroDEN generated iDCs have greater ability to induce T cell proliferation.

Dendritic cells (DCs) are an indispensable part of studying human responses that are important for protective immunity against cancer and infectious diseases as well as prevention of autoimmunity and transplant rejection. These cells are also key elements of personalized vaccines for cancer and infectious diseases. Despite the vital role of DCs in both clinical and basic research contexts, methods for obtaining these cells from individuals remains a comparatively under-developed and inefficient process. DCs are present in very low concentrations (