Miracle-dz/UniFAR-FTUs huggingface dataset:
KRAS‐G12D mutation drives immune suppression and the primary resistance of anti‐PD‐1/PD‐L1 immunotherapy in non‐small cell lung cancer

Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.
An unexpected cause of colitis

Gastrointestinal manifestations are common among patients with advanced kidney disease. Common symptoms include poor appetite, nausea, and vomiting. Prevalent lesions include esophagitis, gastritis, and duodenitis. Uremia‐associated colitis is extremely rare. In this case report we present a young patient who present with end‐stage kidney disease of unknown origin accompanied by abdominal pain and vomiting. Computed tomography showed severe bowel wall thickening of the colon. Due to extreme uremic state uremia‐associated colitis was suspected and hemodialysis was initiated immediately, resulted in clinical and radiology improvement.
A Clustering Approach to Meal-Based Analysis of Dietary Intakes Applied to Population and Individual Data

ABSTRACT Background Examination of meal intakes can elucidate the role of individual meals or meal patterns in health not evident by examining nutrient and food intakes. To date, meal-based research has been limited to focus on population rather than individual intakes, without considering portions or nutrient content when characterizing meals. Objectives We aimed to characterize meals commonly consumed, incorporating portions and nutritional content, and to determine the accuracy of nutrient intake estimates using these meals at both population and individual levels. Methods The 2008–2010 Irish National Adult Nutrition Survey (NANS) data were used. A total of 1500 participants, with a mean ± SD age of 44.5 ± 17.0 y and BMI of 27.1 ± 5.0 kg/m2, recorded their intake using a 4-d weighed food diary. Food groups were identified using k-means clustering. Partitioning around the medoids clustering was used to categorize similar meals into groups (generic meals) based on their Nutrient Rich Foods Index (NRF9.3) score and the food groups that they contained. The nutrient content for each generic meal was defined as the mean content of the grouped meals. Seven standard portion sizes were defined for each generic meal. Mean daily nutrient intakes were estimated using the original and the generic data. Results The 27,336 meals consumed were aggregated to 63 generic meals. Effect sizes from the comparisons of mean daily nutrient intakes (from the original compared with generic meals) were negligible or small, with P values ranging from <0.001 to 0.941. When participants were classified according to nutrient-based guidelines (high, adequate, or low), the proportion of individuals who were classified into the same category ranged from 55.3% to 91.5%. Conclusions A generic meal–based method can estimate nutrient intakes based on meal rather than food intake at the sample population and individual levels. Future work will focus on incorporating this concept into a meal-based dietary intake assessment tool.
Developmental changes in iron metabolism and erythropoiesis in mice with human gain‐of‐function erythropoietin receptor

Iron availability for erythropoiesis is controlled by the iron‐regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain‐of‐function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3–6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age‐related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive‐mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose‐dependent alterations of downstream EPOR stimulation.
Biotransformation novel advances – 2021 year in review

Abstract Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).
Preventing organ damage in systemic lupus erythematosus: the impact of early biological treatment

ABSTRACT Introduction One of the most important aims in the management of systemic lupus erythematosus (SLE) is to avoid or delay the accumulation of organ damage. The first five years after diagnosis are crucial for prognosis. Areas covered This manuscript reviews available data on organ damage accrual in SLE and early therapeutic intervention as a possible strategy to prevent its long-term accrual. Expert opinion Organ damage can be minimized by controlling disease activity and risk of flares, reducing the dose of glucocorticoids, and ensuring a proper therapeutic intervention with an early introduction of the right therapies. The current standard treatment cannot provide clinical remission in all patients with SLE. Therefore, there is a clinical need for introducing new therapeutic strategies able to achieve the main therapeutic objectives. The addition of biologic and other therapeutic agents to the standard of care is effective for controlling disease activity and for preventing severe flares, enabling a reduced use of glucocorticoids, and presumably reducing organ damage progression. Considering its efficacy and safety, early inclusion of biologic agents in the first lines of the treatment algorithm, at least in certain patients, could be considered as an innovative treatment approach to decrease disease burden in SLE patients.
Analysing Smart Metering Systems from a Consumer Perspective

Many countries are deploying smart meters and Advanced Metering Infrastructure systems as part of demand management and grid modernisation efforts. Several of these projects are facing consumer resistance. The advertised benefits to the consumer appear mainly monetary but detailed analysis shows that financial benefits are hard to realise since the fixed services charges are high. Additionally, the data collected from smart meters have security and privacy implications for the consumer. These projects failed to consider end-users as an important stakeholder group during planning stages resulting in the design and roll-out of expensive systems, which do not demonstrate clear consumer benefits. The overall goal of the research reported in this thesis was to improve the smart metering system to deliver consumer benefits that increase confidence and acceptance of these projects. The smart metering system was examined from an end-user perspective for realistic insights into consumer concerns. Processes from Design Science Research methodology were utilised to conduct this research due to the utilitarian nature of the objective. Consumer segmentation was central to the proposed measures. Initially, a consumerfriendly risk analysis framework was devised, and appropriate requirement elicitation techniques were identified. Control options for smart meter data transfer and storage were explored. Various scenarios were analysed to determine consumer-friendly features in the smart metering system, including control options for smart meter data transfer and storage. Proposed functionalities (billing choices, feedback information and specific configurations to match the needs of different user segments) were studied using the Australian smart metering system. Smart meters vary in capabilities depending on the manufacturer, mode and place of deployment. The research showed that features proposed in this thesis are implementable in smart meters, by examining their applicability to those used in Victoria (Australia). This study demonstrated that intelligent systems for demand and distribution-side management can be built without the use of detailed consumption data from the consumer. Many issues related to smart meter data could be avoided by distributing intelligent metering devices across the network. A check-list was generated to guide project proponents to achieve a consumer-friendly outcome. This research establishes that by applying well-established theories during the planning process, in particular requirement elicitation and risk analysis, consumer support can be gained leading to the deployment of user-friendly and sustainable systems. The
Forecasting the elimination of active trachoma: An empirical model

Background Great progress has been made toward the elimination of trachoma as a public-health problem. Mathematical and statistical models have been used to forecast when the program will attain the goal of the elimination of active trachoma, defined as prevalence of trachomatous inflammation—follicular in 1–9 year olds (TF1–9) <5%. Here we use program data to create an empirical model predicting the year of attaining global elimination of TF1–9. Methodology/Principal findings We calculated the mean number of years (95% CI) observed for an implementation unit (IU) to move from a baseline TF1–9 prevalence ≥5% to the elimination threshold, based on the region (Ethiopia vs. non-Ethiopia) and baseline prevalence category. Ethiopia IUs had significantly different rates of reaching the TF1–9 elimination threshold after a trachoma impact survey (TIS) compared to non-Ethiopia IUs across all baseline categories. We used those estimates to predict when remaining active trachoma-endemic IUs (TF1–9 ≥5%) would have their last round of mass drug administration (MDA) based on the mean number of years required and number of MDA rounds already completed. Our model predicts that elimination of TF1–9 will be achieved in 2028 in Ethiopia (95% CI: 2026–2033) and 2029 outside of Ethiopia (95% CI: 2023–2034), with some IUs in East Africa predicted to be the last requiring MDA globally. Conclusions/Significance Our empirical estimate is similar to those resulting from previous susceptible-infectious-susceptible (SIS) and mathematical models, suggesting that the forecast achievement of TF1–9 elimination is realistic with the caveat that although disease elimination progress can be predicted for most IUs, there is an important minority of IUs that is not declining or has not yet started trachoma elimination activities. These IUs represent an important barrier to the timely global elimination of active trachoma.
Executive summary of the Korean Society of Nephrology 2021 clinical practice guideline for optimal hemodialysis treatment

The Korean Society of Nephrology (KSN) has published a clinical practice guideline (CPG) document for maintenance hemodialysis (HD). The document, 2021 Clinical Practice Guideline on Optimal HD Treatment, is based on an extensive evidence-oriented review of the benefits of preparation, initiation, and maintenance therapy for HD, with the participation of representative experts from the KSN under the methodologists’ support for guideline development. It was intended to help clinicians participating in HD treatment make safer and more effective clinical decisions by providing user-friendly guidelines. We hope that this CPG will be meaningful as a recommendation in practice, but not on a regulatory rule basis, as different approaches and treatments may be used by health care providers depending on the individual patient’s condition. This CPG consists of eight sections and 15 key questions. Each begins with statements that are graded by the strength of recommendations and quality of the evidence. Each statement is followed by a summary of the evidence supporting the recommendations. There are also a link to full-text documents and lists of the most important reports so that the readers can read further (most of this is available online).
USP8 promotes cancer progression and extracellular vesicle‐mediated CD8+ T cell exhaustion by deubiquitinating the TGF‐β receptor TβRII

TGF‐β signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin‐specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness‐promoting factor and an activator of the TGF‐β/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF‐β receptor TβRII, leading to its increased expression in the plasma membrane and in tumor‐derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF‐β/SMAD‐induced epithelial‐mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TβRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF‐β/SMAD signaling, and reduces TβRII stability and the number of TβRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti‐tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.
A Problem for Generations: Impact of E-Cigarette Type on Immune Homeostasis

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Isolating Nuclei From Frozen Human Heart Tissue for Single‐Nucleus RNA Sequencing

Heart disease is the leading cause of global morbidity and mortality. This is in part because, despite an abundance of animal and in vitro models, it has been a challenge to date to study human heart tissue with sufficient depth and resolution to develop disease‐modifying therapies for common cardiac conditions. Single‐nucleus RNA sequencing (snRNA‐seq) has emerged as a powerful tool capable of analyzing cellular function and signaling in health and disease, and has already contributed to significant advances in areas such as oncology and hematology. Employing snRNA‐seq technology on flash‐frozen human tissue has the potential to unlock novel disease mechanisms and pathways in any organ. Studying the human heart using snRNA‐seq is a key priority for the field of cardiovascular sciences; however, progress to date has been slowed by numerous barriers. One key challenge is the fact that the human heart is very resistant to shearing and stress, making tissue dissociation and nuclear isolation difficult. Here, we describe a tissue dissociation method allowing the efficient and cost‐effective isolation of high‐quality nuclei from flash‐frozen human heart tissue collected in surgical operating rooms. Our protocol addresses the challenge of nuclear isolation from human hearts, enables snRNA‐seq of the human heart, and paves the way for an improved understanding of the human heart in health and disease. Ultimately, this will be key to uncovering signaling pathways and networks amenable to therapeutic intervention and the development of novel biomarkers and disease‐modifying therapies. © 2022 Wiley Periodicals LLC.
Assessing the Impact of Interorganizational Linkages on Medical Home Model Adoption by U.S. Acute Care Hospitals

The medical home model aims to increase care coordination and health care quality. While the adoption of the model has been increasing, the role of U.S. acute care hospitals’ interorganizational linkages on adoption is yet to be explored. Using a national sample of hospitals throughout the United States, we examined what interorganizational linkage features are associated with medical home adoption of hospital-owned physician practices and assess the pattern of adoption by acute care hospitals between 2011 and 2019. A generalized estimating equation with binomial distribution was utilized to assess the association between interorganizational linkages and medical home adoption. Hospitals with structural linkages and institutional linkages were more likely to have adopted the medical home. Moreover, the likelihood of medical home adoption increased relative to an increasing number of interorganizational linkages. Medical home adoption and dissemination efforts may be more effective when focused on hospitals possessing interorganizational linkages, specifically those with structural linkages.
The effect of vitamin D supplementation on depressive symptoms in adults: A systematic review and meta‐analysis of randomized controlled trials

Abstract Neurosteroid and immunological actions of vitamin D may regulate depression-linked physiology. Meta‐analyses investigating the effect of vitamin D on depression have been inconsistent. This meta-analysis investigated the efficacy of vitamin D in reducing depressive symptoms among adults in randomized placebo-controlled trials (RCT). General and clinical populations, and studies of ill individuals with systemic diseases were included. Light therapy, co-supplementation (except calcium) and bipolar disorder were exclusionary. Databases Medline, PsycINFO, CINAHL and The Cochrane Library were searched to identify relevant articles in English published before April 2022. Cochrane risk-of-bias tool (RoB 2) and GRADE were used to appraise studies. Forty-one RCTs (n = 53,235) were included. Analyses based on random-effects models were performed with the Comprehensive Meta-analysis Software. Results for main outcome (n = 53,235) revealed a positive effect of vitamin D on depressive symptoms (Hedges’ g = −0.317, 95% CI [−0.405, −0.230], p < 0.001, I2 = 88.16%; GRADE: very low certainty). RoB assessment was concerning in most studies. Notwithstanding high heterogeneity, vitamin D supplementation ≥ 2,000 IU/day appears to reduce depressive symptoms. Future research should investigate possible benefits of augmenting standard treatments with vitamin D in clinical depression. PROSPERO registration number: CRD42020149760. Funding: Finnish Medical Foundation, grant 4120 and Juho Vainio Foundation, grant 202100353.
Fear of Failure: Psychological Actions for Control in Santiagueros School Pessimist

This paper summarizes the results of an investigation carried out with weightlifters of the 15-16 years category of the EIDE "Captain Orestes Acosta" of Santiago de Cuba. From the application of methods and techniques such as observations to training and competitions, semi-structured interviews to athletes and coaches, Inventory of Evaluation of the Error in performance, Attitude Test for Competition, the Inventory of Psychological Performance, as well as the review of documents and statistical records of coaches, among others; it was found that these athletes did not achieve the successful realization of the lifts, manifesting in them a high level of tension, generating insecurity, nervousness, among other negative psychological manifestations that affected the athlete's performance, associated with irrational or maladaptive beliefs and thoughts. To help solve this problem, an action plan was implemented that involved the psychologist, coaches, athletes, and family members. It was an open, flexible, participatory, group, practical and experiential. Its effectiveness was proven from the cognitive restructuring of dysfunctional ideas and thoughts that hinder the achievement of adequate sports performance.