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Gastric atrophy (GA) and gastric intestinal metaplasia (GIM) are precursor conditions to gastric adenocarcinoma (GAC) and should be monitored endoscopically in selected individuals. However, little is known about adherence to recommendations in clinical practice in low-risk countries. The aim of this study was to evaluate endoscopic recognition and adequacy of surveillance for GA and GIM in countries with low GAC prevalence. We retrospectively analysed patients diagnosed with GIM or GA in three centers in The Netherlands and UK between 2012 and 2019. Cases with GIM and/or GA diagnosis at index endoscopy were retrieved through systematic search of pathology databases using 'gastric' and 'intestinal metaplasia' or 'atrophy' keywords. Endoscopy reports were analysed to ascertain accuracy of endoscopic diagnoses. Adequacy of surveillance was assessed following histological diagnosis at the index endoscopy based on ESGE guidelines published in 2012. We included 396 patients with a median follow-up of 57.2 months. Mean age was 66 years and the rates of antrum-predominant versus extensive GIM were comparable (37% vs 38%). Endoscopic recognition rates were 48.5% for GA and 16.3% for GIM. Surveillance was adequately carried out in 215 of 396 patients (54.3%). In countries with a low incidence of GAC, the rate of endoscopic recognition of gastric pre-cancerous lesions and adherence to surveillance recommendation are low. Substantial improvement is required in endoscopic training and awareness of guidelines recommendation in order to optimise detection and management of pre-malignant gastric conditions.

Alzheimer’s Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials. Alzheimer’s disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, the authors show an AI-guided model enhances patient stratification, improving outcomes and increasing efficiency in the AMARANTH trial.

Endoscopic surveillance is recommended for patients with Barrett's oesophagus because, although the progression risk is low, endoscopic intervention is highly effective for high-grade dysplasia and cancer. However, repeated endoscopy has associated harms and access has been limited during the COVID-19 pandemic. We aimed to evaluate the role of a non-endoscopic device (Cytosponge) coupled with laboratory biomarkers and clinical factors to prioritise endoscopy for Barrett's oesophagus. We first conducted a retrospective, multicentre, cross-sectional study in patients older than 18 years who were having endoscopic surveillance for Barrett's oesophagus (with intestinal metaplasia confirmed by TFF3 and a minimum Barrett's segment length of 1 cm [circumferential or tongues by the Prague C and M criteria]). All patients had received the Cytosponge and confirmatory endoscopy during the BEST2 (ISRCTN12730505) and BEST3 (ISRCTN68382401) clinical trials, from July 7, 2011, to April 1, 2019 (UK Clinical Research Network Study Portfolio 9461). Participants were divided into training (n=557) and validation (n=334) cohorts to identify optimal risk groups. The biomarkers evaluated were overexpression of p53, cellular atypia, and 17 clinical demographic variables. Endoscopic biopsy diagnosis of high-grade dysplasia or cancer was the primary endpoint. Clinical feasibility of a decision tree for Cytosponge triage was evaluated in a real-world prospective cohort from Aug 27, 2020 (DELTA; ISRCTN91655550; n=223), in response to COVID-19 and the need to provide an alternative to endoscopic surveillance. The prevalence of high-grade dysplasia or cancer determined by the current gold standard of endoscopic biopsy was 17% (92 of 557 patients) in the training cohort and 10% (35 of 344) in the validation cohort. From the new biomarker analysis, three risk groups were identified: high risk, defined as atypia or p53 overexpression or both on Cytosponge; moderate risk, defined by the presence of a clinical risk factor (age, sex, and segment length); and low risk, defined as Cytosponge-negative and no clinical risk factors. The risk of high-grade dysplasia or intramucosal cancer in the high-risk group was 52% (68 of 132 patients) in the training cohort and 41% (31 of 75) in the validation cohort, compared with 2% (five of 210) and 1% (two of 185) in the low-risk group, respectively. In the real-world setting, Cytosponge results prospectively identified 39 (17%) of 223 patients as high risk (atypia or p53 overexpression, or both) requiring endoscopy, among whom the positive predictive value was 31% (12 of 39 patients) for high-grade dysplasia or intramucosal cancer and 44% (17 of 39) for any grade of dysplasia. Cytosponge atypia, p53 overexpression, and clinical risk factors (age, sex, and segment length) could be used to prioritise patients for endoscopy. Further investigation could validate their use in clinical practice and lead to a substantial reduction in endoscopy procedures compared with current surveillance pathways. Medical Research Council, Cancer Research UK, Innovate UK.

Traditional handicrafts have lost their role in daily life, and industrialization has transformed production modes, reshaping place-based identities and prompting residents to reevaluate their connection to traditional handicrafts within this transformation.This research focuses on the case of Wangjiang Tiaohua and employs the Means-End Chain theory to explore residents' attributes and values and how these lead to consequences through a soft-laddering interview method. A novel approach was used to determine the cut-off levels by differentiating them into positive and negative dimensions and then constructing a hierarchical value map (HVM). Analysis of the HVM's three main pathways revealed the following: 1. Changes in appearance can transform the identity of utilitarian objects into works of art. 2. Innovative products foster cultural identity and a sense of belonging. 3. Learning constructs new identities. 4. Identity is distorted after the commercialization and factorization of traditional handicraft. This study reveals the changes in residents' identity following heritagization and industrialization, emphasizing that the preservation of intangible cultural heritage should focus on the protection and development of the cultural ecosystem.

Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases. Several neurodegenerative diseases are characterized by the aggregation of cytoplasmic proteins. Here, the authors demonstrate that the small molecule SMER28 activates VCP, which enhances both autophagic and proteasomal clearance of aggregate-prone proteins.

Individual variation in pain sensation makes pain clinical trials quite challenging to interpret. Now, Michael Salter and colleagues report that genetic variation in the P2RX7 gene affects pore formation of the protein and pain sensation in humans. Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary 1 . Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da 2 , 3 . Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7 . Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.

Introduction Treatment‐resistant depression (TRD) is a condition in which patients suffering from depression no longer respond to common methods of treatment, such as anti‐depressant medication. Neurosurgical procedures such as ablative surgery, deep brain stimulation, and vagus nerve stimulation have been used in efforts to overcome TRD. Objectives This review aims to provide an overview of the side effects of neurosurgery performed in clinical studies related to depression. Methods A literature search was conducted through PubMed, MEDLINE, EMBASE, Ovid, and ClinicalTrials.gov databases. Results This review selected 10 studies for ablative surgery, 12 for deep brain stimulation, and 10 for vagus nerve stimulation, analyzing their side effect profiles of neurosurgery for TRD. The major side effects of each type of neurosurgery were identified, such as incontinence and confusion for ablative surgery, headaches and increased suicide ideation for deep brain stimulation, and voice hoarseness and dyspnea for vagus nerve stimulation. Conclusion The review discusses the merits and demerits of neurosurgery as a treatment option for TRD. It also suggests new insights into decreasing the burden of these neurosurgical side effects so that they can be a viable, high‐efficacy treatment method for TRD. Neurosurgical treatments are used in the treatment of treatment‐resistant depression. The major side‐effects arising from each neurosurgical procedure differ depending on the region of the brain targeted by the treatment, with very little overlap between side‐effects. Increasing awareness of these potential side‐effects will assist clinicians in reducing the burden of treatment and provide patients with better quality of life.

Purpose Data on colorectal cancer in Malaysia, particularly from southern regions such as Johor Bahru is underreported. To address this gap, we conducted a retrospective review of colorectal cancer patients treated in Johor Bahru 5 years ago. Methods The study included patients with colorectal cancer in year 2017 or 2018. We included only 63 patients with complete data. Patient’s sociodemographic features and clinical characteristics including site of tumour, staging, symptoms at presentation, and management/types of surgery was recorded and analysed in this study. Results There were 43 male and 20 female patients. The median age were 63 years, IQR = 55 -71. Chinese patients were disproportionately higher (60.3%), followed by Malay (36.5%). The tumor site is more often found in sigmoid (27.0%) and mid-rectum (22.2%). Anterior resection (74.6%) is the most frequently performed surgery. The 5-year survival rate of colorectal cancer patients was 63.5%. The 5-year survival rate of patients with stage I, stage II, stage III and stage IV disease were 66%, 81.8%, 68.6% and 0% respectively. Conclusion The clinical features of colorectal cancer in Johor Bahru closely resemble those in other regions of Malaysia. The survival rates among colorectal cancer patients in Johor Bahru, particularly in stages 1 and 4, are unexpectedly lower. This discrepancy in oncologic outcomes could be attributed to a small sample size. Therefore, the establishment of a unified surgical registry for all colorectal surgeries across Malaysia is recommended.

Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link the nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation and establish that perturbations in this pathway result in anemia. To multiply and grow, cells need to create more of the molecules—such as proteins—that make up their structure. This only happens if the cell has a good supply of the nutrients used to build the proteins. Red blood cells are particularly sensitive to the supply of nutrients, especially iron, which is a key component of the hemoglobin molecules that enable the cells to transport oxygen around the body. A lack of iron can lead to a shortage of red blood cells and a condition called anemia. People with mild forms of anemia may feel tired or weak, but more severe forms of anemia can cause heart problems and even death. A protein called mTOR forms part of a protein complex that helps alert the cells of many different organisms to the presence of nutrients. mTOR can add phosphate groups to ribosomes—the molecular machines that translate molecules of mRNA to build proteins. In 2012, researchers developed a technique called Phospho-Trap that can isolate these phosphorylated ribosomes from cells. Cells with an activated mTOR complex express more mTOR protein and in turn have more ribosomes that are modified. Examining the mRNA molecules associated with these ribosomes can reveal which proteins are produced in greater amounts in these cells. Previous experiments using Phospho-Trap found the proteins that make up hemoglobin in unexpectedly high amounts in the mouse brain. Now, Knight et al.—and other researchers involved in the 2012 work—have established that the hemoglobin was not coming from the brain cells but from immature red blood cells circulating within the brain. These immature blood cells were found to have a highly active mTOR complex that promotes the production of hemoglobin and new blood cells. Using genetic techniques in mice, Knight et al. found that the mTOR complex can cause anemia if it is underactive or overactive. Underactive mTOR complexes cause a type of anemia that produces small red blood cells and is usually triggered by a lack of iron. This made sense because mTOR is known to regulate both protein production and cell size. Boosting the activity of the mTOR complex leads to a type of anemia in which the cells are much larger than normal, and which is normally associated with inadequate amounts of folate and B12 vitamins. When Knight et al. gave mice a drug that inhibits the mTOR protein, the mice developed anemia that resolved when the treatment stopped. However, mice that were given the mTOR inhibitor at the same time as a drug that destroys red blood cells, all died within days. Clinical trials are currently testing mTOR inhibitors as a possible cancer treatment; however, a common side effect of chemotherapy is that it stops new red blood cells being produced. Knight et al. suggest that the red blood cells of patients in these clinical trials must be closely monitored before deciding whether to continue the treatment further.

IntroductionScreening for Barrett’s oesophagus (BO) is a consideration due to the high mortality from oesophageal adenocarcinoma (OAC). The aim of this study was to utilise data from the randomised controlled Barrett’s oEsophagus Screening Trial 3 (BEST3) to estimate: 1) the optimal age for screening of BO/OAC; and 2) the number of missed cases under current primary care reflux referral pathway.MethodsIndividuals in the BEST3 who swallowed the Cytosponge (n=1654) were included. For aim 1, we used the positive-predictive value (PPV) of the Cytosponge for a diagnosis of BO/OAC as a proxy for the disease prevalence in the community and modelled the probability of a diagnosis of BO/OAC. Both analyses were stratified by age and sex. For aim 2, we used the BEST3 intervention (n=6834) and control arm (n=6388) data to estimate the number of missed BO/OAC under current reflux referral pathway.ResultsUsing a 5% risk cut-off for undiagnosed BO/OAC, the ideal age for screening males and females with reflux is 55–79, and 65–79 years, respectively (Figure 1). The overall PPV for a diagnosis of BO/OAC were 65% (95% CI 57–73%) for males and 50% (95% CI 39–61%) for females. The number of missed BO/OAC was estimated using BEST3 data. There were 16/6388 (0.3%) and 131/6834 (1.9%) cases of BO/OAC diagnosed among those randomised to usual care or who had the Cytosponge, respectively. If we correct for those who were: randomised to the Cytosponge group but did not accept the offer (5180/6834, 78.8%); unable to swallow the Cytosponge (96/1750, 5.5%); declined confirmatory endoscopy (10/231, 4.3%); and those with a false negative diagnosis - based on the random sample who were invited for endoscopy at end of the study among the TFF3 negative group (2/64, 3.1%); we estimate that 680 cases of BO/OAC among the 6388 individuals in the controls, and 500 of these could have been screen-detected if all had attempted to swallow a Cytosponge. Compared to 16 cases of BO/OAC identified through usual care, 97.6% of BO/OAC are likely to be missed using the current referral pathway and 73.5% of undiagnosed disease could be detected by screening.Abstract O6 Figure 1Probability of a diagnosis of BO or OAC by age, stratified by gender. Dashed lines represent 3% and 5% risk cut-off for BO or OACConclusionA Cytosponge-based screening strategy for BO/OAC could include males aged 55–79 and females aged 65–79; depending on uptake rates, it would allow us to discover a greater proportion of the 97.6% estimated missed BO/OAC in the community.