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Objectives The objective of this study is to understand the role of vitamin B12 supplementation in improving skeletal muscle function among the elderly. Methods A literature review in the Medline database was conducted to understand the association between vitamin B12 and muscle function in Section A. In Section B, 28 healthy elderly participants aged ≥60 years were recruited in a cross‐sectional design for estimation of plasma vitamin B12 status and assessment of upper limb muscle strength Maximal voluntary contraction (MVC) and muscle quality (expressed as MVC/total muscle mass). Participants were grouped based on vitamin B12 status into vitamin B12‐depleted (<148 pmol/L) and replete (≥148 pmol/L) groups. In a quasi‐experimental study design, the vitamin B12‐depleted group (n = 14) received daily oral vitamin B12 supplementation of 100 μg for 3 months. All the study measures were repeated post‐supplementation. Results Vitamin B12 deficiency was identified to contribute adversely to muscle strength, quality, and physical performance among older people in the extensive literature review. The pilot intervention study showed significant improvement in MVC and muscle quality (p < 0.050) post‐vitamin B12 supplementation, comparable to the vitamin B12‐replete group. Conclusions Vitamin B12 may have a crucial role in the maintenance of muscle function. 3‐month oral vitamin B12 supplementation among subclinical vitamin B12 deficient elderly improved muscle strength and quality and reached levels similar to the vitamin B12 replete group. Vitamin B12 may have a crucial role in the maintenance of muscle strength and quality. 3‐month oral vitamin B12 supplementation among subclinical vitamin B12 deficient elderly improved both muscle strength and quality and reached levels similar to the vitamin B12 replete group.

Primary healthcare providers play a critical role in diagnosing and managing digestive disorders. Standardized clinical care guidelines have been developed, but with limited and inconsistent implementation. An evidence-based gastroenterology clinical care pathway (GUTLINK) has been proposed in one region of Canada; however, little is known in the medical literature about potential barriers to pathway implementation within primary care. We aimed to identify behavioral and environmental barriers and facilitators to implementation of evidence-based care pathways for undifferentiated lower gastrointestinal tract symptoms in primary care. One-on-one semi-structured interviews were conducted with primary healthcare providers between September 2021 and May 2022. Interview script development was guided by the COM-B framework. Interviews were transcribed and data were analyzed using an inductive thematic analysis approach. A total of 15 primary healthcare provider interviews were conducted. Several key barriers to GUTLINK implementation were identified in all three domains of the COM-B framework. Key barriers included Capability (e.g., Physician Knowledge and Access to Allied Health), Opportunity (e.g., Access to diagnostic tools), and Motivation (e.g., Comfort with managing cases and optimism). Some of these barriers have not previously been identified in medical literature. Evidence-based clinical care pathways have the potential to support access to quality gastroenterology care, yet primary healthcare providers in this study identified several barriers to implementation. Potential solutions exist at the individual and clinic levels (e.g., greater education, improved provider-specialist communication), but must be supported with systems-level changes (e.g., increased funding for gastrointestinal care and e-Health platforms) to support pathway implementation and improve quality of care.

Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models for predicting cancer of unknown primary, using three RNA-seq datasets with 10,968 samples across 57 cancer types. Our results highlight that simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation. Moreover, we designed a prototypical metric—the area between development and production curve (ADP), which evaluates the accuracy loss when deploying models from development to production. Using ADP, we demonstrate that Bayesian DL improves accuracy under data distributional shifts when utilising ‘uncertainty thresholding’. In summary, Bayesian DL is a promising approach for generalising uncertainty, improving performance, transparency, and safety of DL models for deployment in the real world.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5 , CD8A , and NKG7 . The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials. It remains critical to understand the genomic events in response to treatment of oesophageal adenocarcinoma (OAC). Here, the authors perform a multi-omics analysis of OAC patients from the DOCTOR phase II clinical trial, finding genomic features and immune clusters associated with survival.

A plateau in treatment effect can be seen for the current ‘one-size-fits-all’ approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multi-modality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8 + cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8 + cells, and low infiltration with CD163 + cells was associated with improved survival. High tumour core CD8 + T cell infiltration, and a low tumour margin infiltration of CD163 + cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8 + , or high CD163 + cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163 + cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease.

Background αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have suggested potential tumor promoter (oncogene) roles for αB-Crystallin in a wide-spectrum of cancers. Methods To determine the causal relationship between CRYAB  overexpression and cancer, we generated a  Cryab overexpression knock-in mouse model and monitor them for development of spontaneous and carcinogen (DMBA)-induced tumorigenesis. In order to investigate the mechanism of malignancies observed in this model multiple techniques were used such as immunohistochemical characterizations of tumors, bioinformatics analysis of publically available human tumor datasets, and generation of mouse embryonic fibroblasts (MEFs) for in vitro assays (clonogenic survival and migration assays and proteome analysis by mass-spectrometry). Results This model revealed that constitutive overexpression of  Cryab  results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo ,  the overexpression of  Cryab  correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed MEFs, we observed that the overexpression of  Cryab  led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3 and Annexin V staining. Conclusions Overall, through the generation and characterization of  Cryab  overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

Background: The emergence of new SARS-CoV-2 variants calls for more data on SARS-CoV-2 mRNA vaccine response. Aims: We aimed to assess the response to a third mRNA vaccine dose against SARS-CoV-2 in inflammatory bowel disease (IBD) patients. Methods: This was a single-center, observational prospective study of IBD patients who received a third mRNA vaccine dose against SARS-CoV-2. Antibody titers were taken post-third-dose at one and three months using the Roche Elecsys anti-SARS-CoV-2-S enzyme immunoassay. Titers less than 0.8 units/mL were considered negative according to the manufactures. Titers between 0.8 units/mL and 250 units/mL were considered non-neutralizing. Titers greater than 250 units/mL were considered neutralizing. Results: Eighty-three patients were included, all of whom had detectable antibodies at 3 months post-third dose. A total of 89% showed neutralizing and 11% non-neutralizing titers. Participants with non-neutralizing titers were more likely to be on systemic corticosteroids (p = 0.04). Two participants seroconverted from negative to positive, whereas 86% with non-neutralizing titers boosted to neutralizing levels. Only one participant with neutralizing titers after a third dose had a decrease to a non-neutralizing level within 3 months. Conclusions: Our findings support the ongoing recommendations for additional doses in immunocompromised individuals. However, longitudinal studies with a greater-sized patient population are needed.

Background. One third of Indian population is said to be suffering from chronic energy deficiency (CED), with increased risk of developing chronic diseases. A new anthropometric measure called A Body Shape Index (ABSI) is said to be a better index in predicting risks for premature mortality. ABSI is also in part said to be a surrogate of visceral fat. Objective. The present study aimed to explore the association between indices of HRV (heart rate variability), BMI, WC, and ABSI in healthy Indian males with low BMI (BMI < 18.5 kg/m2) and to compare with normal BMI group (BMI 18.5 to 24.9 kg/m2). Methodology. ABSI and BMI were derived from anthropometric parameters, namely, height, weight, and waist circumference in 178 males aged 18 to 78 years. Subjects were categorized into two groups based on their BMI. Results and Conclusions. Power spectral analysis of HRV demonstrated a significant negative correlation between Log HF (high frequency) and ABSI in both low BMI [−24.2 (9.4), P<0.05] and normal BMI group [−23.41 (10.1), P<0.05] even after controlling for age. Thus even with slight increase in BMI among low BMI individuals, there could be a greater risk of cardiovascular morbidity and mortality.

Abstract BACKGROUND The COVID-19 pandemic drastically impacted workflows in gastroenterology practice. Physicians managing immune-mediated diseases (IMDs) must complete special authorization (SA) and prescription renewal (Rx) forms for patients on biologic therapy. This adds significant administrative burden potentially leading to delays in therapy initiation and care continuity. Historically, document completion has largely been paper-based, with forms faxed between patient support programs (PSPs) and physician offices. Disruption of normal office processes during the pandemic necessitated the movement of existing paper-based workflows online. The use of secure electronic document signing (SEDS) platforms has allowed physicians to receive and complete documents digitally. AIMS To evaluate the impact of SEDS-based biologic documentation on clinical practice. Objectives were 1) to determine if the use of SEDS platforms increased timeliness of document returns compared to traditional workflows 2) assess whether SEDS usage is acceptable and sustainable and 3) assess MD satisfaction with SEDS platforms. METHODS This was a retrospective audit of SEDS and paper-based biologic document workflows from a single PSP (Abbvie Care). Outcomes of interest were the number of documents completed monthly using SEDS, new monthly users, and the number of active monthly users between April 1, 2020-March 31, 2021. Time (days) to SEDS completion (vs. paper process) was determined by reviewing timepoint data for SA and Rx documents from May 2019-January 2020 (‘pre- SEDS’) and for SEDS documents from May 2020-January 2021(‘SEDS’). The return time (RT) was defined as the time between date sent to a physician’s office by the PSP to the date returned to the PSP. Documents in the pre-SEDS cohort with a RT exceeding 30 days were excluded RESULTS In totally, 5573 SA and Rx documents were completed by 383 physicians using the SEDS platform from April 2020-March 2021. A mean of 14.6 (sd 21.8) documents were signed per physician. The number of monthly electronic documents processed increased from 104 in April 2020 to 800 in March 2021. Active monthly users increased from 24 in April 2020 to 213 in March 2021 (31 new users monthly). A total of 19,387 paper documents were processed during the ‘pre-SEDS’ period and 3,317 electronic documents processed in the ‘SEDS’ period. The mean RT in the ‘pre-SEDS’ period was 8.03 days (Sd 8.2) and the ‘SEDS’ period was 1.11 days (sd 2.6). CONCLUSION This data demonstrates acceptability, appropriateness, and improved processing efficiency of an SEDS platform improving timeliness of patient care. Next steps in this research include surveying physicians to understand the work-flow impact of SEDS, functionality, long-term sustainability, satisfaction and impacts on disease related outcomes.