Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

Rosmarinic acid alleviates ultraviolet-mediated skin aging via attenuation of mitochondrial and ER stress responses.

Chronic exposure to Ultraviolet B radiation (UV-B) evokes a myriad of toxic signalling events in the irradiated skin. One of such response is ER stress, which is known to exacerbate photodamage responses. Also, recent literature has highlighted the adverse impact of environmental toxicants on mitochondrial dynamics and mitophagy. Impaired mitochondrial dynamics escalates oxidative damage and causes apoptosis. There have been evidences that support crosstalk between ER stress and mitochondrial dysfunction. However, mechanistic clarification is still needed to verify the interactions between UPR responses and mitochondrial dynamics impairment in UV-B-induced photodamage models. Lastly, plant-based natural agents have garnered attention as therapeutic agents against skin photodamage. Thus, gaining mechanistic insights of plant-based natural agents is required for their application and feasibility in clinical settings. With this aim in view, this study was performed in primary human dermal fibroblasts (HDFs) and Balb/C mice. Different parameters regarding mitochondrial dynamics, ER stress, intracellular damage and histological damage were analyzed using western blot, rt-PCR and microscopy. We demonstrated that UV-B exposure leads to induction of UPR responses, upregulation of Drp-1 and inhibition of mitophagy. Further, 4-PBA treatment leads to reversal of these noxious stimuli in irradiated HDF cells, thereby, indicating an upstream role of UPR induction in mitophagy inhibition. Also, we explored the therapeutic effect of Rosmarinic acid (RA) against ER stress and impaired mitophagy in photodamage models. RA prevents intracellular damage via alleviation of ER stress and mitophagic responses in HDFs and irradiated Balb/C mice skin. The current study summarizes the mechanistic insights into UVB-mediated intracellular damage and role of natural plant-based agent (RA) in ameliorating these toxic responses.

A Survey on COVID-19 Data Analysis Using AI, IoT, and Social Media.

Coronaviruses are a well-established and deadly group of viruses that cause illness in both humans and animals. The novel type of this virus group, named COVID-19, was firstly reported in December 2019, and, with the passage of time, coronavirus has spread to almost all parts of the world. Coronavirus has been the cause of millions of deaths around the world. Furthermore, many countries are struggling with COVID-19 and have experimented with various kinds of vaccines to eliminate the deadly virus and its variants. This survey deals with COVID-19 data analysis and its impact on human social life. Data analysis and information related to coronavirus can greatly help scientists and governments in controlling the spread and symptoms of the deadly coronavirus. In this survey, we cover many areas of discussion related to COVID-19 data analysis, such as how artificial intelligence, along with machine learning, deep learning, and IoT, have worked together to fight against COVID-19. We also discuss artificial intelligence and IoT techniques used to forecast, detect, and diagnose patients of the novel coronavirus. Moreover, this survey also describes how fake news, doctored results, and conspiracy theories were spread over social media sites, such as Twitter, by applying various social network analysis and sentimental analysis techniques. A comprehensive comparative analysis of existing techniques has also been conducted. In the end, the Discussion section presents different data analysis techniques, provides future directions for research, and suggests general guidelines for handling coronavirus, as well as changing work and life conditions.

Evaluating patient safety research performance in Arab world countries: Changing trends and reflections.

Background and Objective: Patient safety is a major concern in health care. Research is an important tool to minimize preventable errors. Research performance and trends evaluation need to be identified for future guidance. Our objective was to evaluate the research performance in Arab World countries related to patient safety so that real picture is available to all stake holders for future application. Methods: This was a descriptive exploratory study carried at King Abdulaziz University Jeddah, using Bibliometric analyses on Web of Science extracted data, exploring the research publications related to Patient Safety from the Arab World in last two decades (2001-2020). Digital resources were used. Data collected was further explored to see the trends. Results: Only 2% of total worldwide publications on Patient Safety were from Arab World. A positive trend, however, has emerged since 2015. Out of 5940 documents identified, only 383 had single authorship. Egypt and Saudi Arab were the major contributors. Other countries had less or even zero publications. Researchers are coordinating with others in Western countries to enhance the research productivity. Cairo University with 734 publications had most affiliations. Publications on safety culture and medication safety were frequent. Hospital Acquired Infections and error reporting had limited research. Conclusion: Researches on patient safety in the Arab World are not sufficient. Countries other than Egypt and Saudi Arabia also need to contribute more frequently. Critical problems, like Hospital Acquired Infections, should have regular research from all countries to assist those treating patients and those making health related policies.

Control of Ionic Conductivity by Lithium Distribution in Cubic Oxide Argyrodites Li6+xP1-xSixO5Cl.

Argyrodite is a key structure type for ion-transporting materials. Oxide argyrodites are largely unexplored despite sulfide argyrodites being a leading family of solid-state lithium-ion conductors, in which the control of lithium distribution over a wide range of available sites strongly influences the conductivity. We present a new cubic Li-rich (>6 Li+ per formula unit) oxide argyrodite Li7SiO5Cl that crystallizes with an ordered cubic (P213) structure at room temperature, undergoing a transition at 473 K to a Li+ site disordered F4̅3m structure, consistent with the symmetry adopted by superionic sulfide argyrodites. Four different Li+ sites are occupied in Li7SiO5Cl (T5, T5a, T3, and T4), the combination of which is previously unreported for Li-containing argyrodites. The disordered F4̅3m structure is stabilized to room temperature via substitution of Si4+ with P5+ in Li6+xP1-xSixO5Cl (0.3 < x < 0.85) solid solution. The resulting delocalization of Li+ sites leads to a maximum ionic conductivity of 1.82(1) × 10-6 S cm-1 at x = 0.75, which is 3 orders of magnitude higher than the conductivities reported previously for oxide argyrodites. The variation of ionic conductivity with composition in Li6+xP1-xSixO5Cl is directly connected to structural changes occurring within the Li+ sublattice. These materials present superior atmospheric stability over analogous sulfide argyrodites and are stable against Li metal. The ability to control the ionic conductivity through structure and composition emphasizes the advances that can be made with further research in the open field of oxide argyrodites.

Agent-Based Semantic Role Mining for Intelligent Access Control in Multi-Domain Collaborative Applications of Smart Cities.

Significance and popularity of Role-Based Access Control (RBAC) is inevitable; however, its application is highly challenging in multi-domain collaborative smart city environments. The reason is its limitations in adapting the dynamically changing information of users, tasks, access policies and resources in such applications. It also does not incorporate semantically meaningful business roles, which could have a diverse impact upon access decisions in such multi-domain collaborative business environments. We propose an Intelligent Role-based Access Control (I-RBAC) model that uses intelligent software agents for achieving intelligent access control in such highly dynamic multi-domain environments. The novelty of this model lies in using a core I-RBAC ontology that is developed using real-world semantic business roles as occupational roles provided by Standard Occupational Classification (SOC), USA. It contains around 1400 business roles, from nearly all domains, along with their detailed task descriptions as well as hierarchical relationships among them. The semantic role mining process is performed through intelligent agents that use word embedding and a bidirectional LSTM deep neural network for automated population of organizational ontology from its unstructured text policy and, subsequently, matching this ontology with core I-RBAC ontology to extract unified business roles. The experimentation was performed on a large number of collaboration case scenarios of five multi-domain organizations and promising results were obtained regarding the accuracy of automatically derived RDF triples (Subject, Predicate, Object) from organizational text policies as well as the accuracy of extracted semantically meaningful roles.

Assessing reliability and validity of Revised Biggs Two-Factor study process questionnaire to measure learning approaches among undergraduate medical students in Lahore, Pakistan.

OBJECTIVE: To assess reliability and validity of Revised Biggs Two-Factor Study Process Questionnaire to measure Learning approaches among medical students. METHODS: The cross-sectional study was conducted at Shaikh Zayed Medical College, Lahore, Pakistan, from November 15, 2014, to January 15, 2015. The 20-item Revised Biggs Two-Factor Study Process Questionnaire was used to assess medical students enrolled from the first to the final year of their studies. Data was analysed using SPSS 20. The reliability of the questionnaire was assessed by Cronbach's alpha, and confirmatory factor analysis was done to confirm the factor model. RESULTS: Of the 480 students approached, 284(59.2%) completed the questionnaire. Cronbach's alpha value was found acceptable at 0.79 and 0.72 for the deep approach and surface approach scales respectively. Comparative Fit Index value (0.858) confirmed a good fit for the model. CONCLUSIONS: Revised Biggs Two-Factor Study Process Questionnaire was found to be a reliable and valid instrument to measure learning approaches among medical students.

Haemoglobinuria And Portal Venous Thrombosis In A Young Male.

Paroxysmal nocturnal haemoglobinuria is a non-malignant stem cell disorder due to acquired somatic mutations in cell surface anchored proteins CD55 and CD59. Both have a compliment inhibitory role and their deficiency leads to intravascular haemolysis. This paper reports a challenging case of a 25 years old male who presented with generalized weakness, exertional dyspnoea and episodic early morning haematuria. Recently, he started developing progressive abdominal distention and dull generalized abdominal pain. Investigations revealed haemoglobin 3.5 g/dl with 10% reticulocytes, total bilirubin 54.5 mg/dl, LDH 3155 U/L, negative Coomb's test and erythroid hyperplasia on bone marrow biopsy. Urine complete exam was significant for haemoglobinuria without red blood cells. Doppler scan of abdomen showed portal vein thrombosis. Loss of expression of CD14, CD16, CD55 and CD59 on leukocytes and erythrocytes was seen on PNH analysis, confirming paroxysmal nocturnal haemoglobinuria. He was managed with blood transfusions and was advised folic acid and bone marrow transplant.

Hypertension Research in Pakistan: A Scientometric Analysis of Two Decades (2003-2022).

Hypertension is a highly prevalent chronic disease that leads to a significant number of deaths and disabilities as a consequence of cardiovascular complications. However, there is insufficient information regarding research trends and performance assessments from South Asian countries, including Pakistan. In this review, we analyzed research data related to hypertension from Pakistan over the last 20 years (2003-2022). We used the Web of Science (WoS) database to retrieve research data related to hypertension from Pakistan, and then applied scientometric analysis using the "R-Bibliometrix" package. An extensive range of indicators was studied to determine the quality and quantity of these hypertension-related publications. A total of 4,008 research articles from 891 sources were extracted through WoS over the last 20 years (2003-2022). There was a continuous growth in the number of research articles, with relatively more increase observed from 2012, and maximum output in 2021. Among 16,855 authors contributing from 67 countries, three authors had >50 publications and five had >1,500 citations. The country's leading affiliation was the Aga Khan University which showed networking trends with international institutes while the other national universities restricted their institutional partnerships to the provincial or city level. The Higher Education Commission was the only local sponsoring institute among the top funding sources. Pakistan Journal of Medical Sciences was the leading and most consistent source, whereas hypertension, diabetes mellitus, and obesity were the most frequently used keywords. This review provides a comprehensive account of hypertension-related research productivity from Pakistan. Some characteristic trends were detected for top authors' contributions, impact, productivity, international collaborations, funding sources, and institutional affiliations. Particularly, the funding sources and collaboration patterns of corresponding authors along with their affiliated institutes showed striking results. These findings can be very helpful for the relevant stakeholders in the accurate interpretation of trends and performance of hypertension-related research work from the region.

A Cotton Rope in the Colon: A Rare Cause of Chronic Abdominal Pain.

Retained surgical sponge is a relatively rare medical condition with potential serious medicolegal implications. The term "gossypiboma" is frequently used to describe this condition. We present a case of a 40-cm-long retained surgical sponge in a 43-year-old woman who presented with unexplained chronic abdominal pain for several years. She had a history of open cholecystectomy, hepaticojejunostomy, and enteroenterostomy. Computed tomography scan revealed a large cotton sponge anchored within the large bowel. Surgical exploration is usually required for the retrieval of gossypiboma. However, it was successfully removed endoscopically using a diathermic needle knife with no immediate complications. The patient was discharged after 48 hours with marked improvement in her abdominal pain. This case emphasizes the emerging role of novel endoscopic interventions, resulting in excellent clinical outcomes, avoiding major surgical interventions, and providing cost-effective benefits.

Percutaneous Transhepatic Sphincterotome-Guided Management of Post-Living Donor Liver Transplant Biliary Anastomotic Stricture: An Innovative Approach.

Post-liver transplantation biliary complications remain a serious concern and are associated with reduced patient and graft survival. Among various biliary complications, anastomotic stricture (AS) is the most frequent and challenging one. The frequency of AS after living donor liver transplantation (LDLT) is higher as compared to deceased donor liver transplantation. The management involves endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic biliary drainage, but refractory cases necessitate surgical revision. We present a case of complex biliary AS in a 63-year-old man after LDLT. The conventional approaches including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and cholangioscope-guided interventions remained unsuccessful. An innovative approach using a wire-guided sphincterotome through percutaneous transhepatic route successfully managed the complex post-LDLT AS. This is perhaps the first reported case of novel utilization of sphincterotome through transhepatic route for the management of AS in LDLT, averting major surgical interventions with related morbidity and mortality.

Neurosurgery and Social Media: A Bibliometric Analysis of Scientific Production from 2004 to 2023.

BACKGROUND: Neurosurgery is a rapidly advancing surgical specialty. Social media has significantly impacted the landscape of advancements in the field of neurosurgery. Research on the subject of neurosurgery and social media plays a vital role in combating disability and mortality due to neurological diseases, especially in trauma-affected individuals by increasing cooperation and sharing of clinical experiences between neurosurgeons via social media. This study aimed to evaluate the global neurosurgery and social media research performance from 2004 to 2023. METHODS: All the data for neurosurgery and social media-related research publications from 2004 to 2023 were extracted from the Web of Science database and a comprehensive analysis was performed on the R-bibliometrix package. RESULTS: An increasing number of publications with an annual growth rate of 22.04% was observed, with >91% of total articles published in the last decade. The United States, the United Kingdom, Italy, France, Canada, and India made up of more than 67% of the global contribution. Out of 1449 authors, Chaurasia B was the most productive with 14 publications and the most globally cited document was JEAN WC, 2020 with 117 citations. The University of Cambridge was the leading institutional affiliation. World Neurosurgery was the most productive with >60 articles. CONCLUSIONS: Exploring neurosurgery on social media enhances global collaboration, utilizing dynamic platforms for real-time knowledge exchange and holds immense potential for the field's global advancement.

The Latest Evidence on Bempedoic Acid: Meta-Analysis of Safety and Efficacy in High Cardiovascular Risk Patients With Hypercholesterolemia⋆.

Background: Bempedoic Acid (BA) is a novel drug that has a potential to serve as an alternative to statins to decrease lipid levels and improve cardiovascular disease (CVD) outcomes, particularly for statin-intolerant individuals. However, insufficient statistical power has limited our understanding of the efficacy and safety of BA. This meta-analysis utilizes the latest data to improve our knowledge of BA's effects on lipids and CVD with increased statistical power. Methods: MEDLINE, Embase, Cochrane Central, Clinicaltrials.gov, abstracts of national and international conferences, and reference lists of studies were searched for relevant studies. Rayyan was used to screen the search results, and Revman 5.3 was used for the meta-analysis and sensitivity analysis. Results: Our final analysis included seven randomized control trials (RCTs) with 17,782 participants, 53.6 % in the BA group (n = 9535) and 46.4 % in the placebo group (n = 8247). BA significantly decreased major adverse cardiovascular events (MACE) (OR: 0.86; 95 % CI 0.78-0.95; p = 0.03), non-fatal myocardial infarction (OR 0.72; 95 % CI 0.61-0.85; p = 0.0001), and new onset/worsening diabetes (OR:0.55; 95 % CI 0.30-0.98, p = 0.04), while reducing low-density lipoprotein cholesterol (LDL-C) levels by 22.5 % (MD: -22.53 %; 95 % CI -25.54 to -19.52, p < 0.00001). Conclusion: The findings of this meta-analysis suggest that BA is a promising and effective alternative to statin therapy, particularly for statin-intolerant and high CVD-risk patients. However, further studies with diverse populations are needed to quantify the long-term efficacy and safety endpoints.

In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer.

Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-ß and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma.

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Health coping strategies of the people vulnerable to climate change in a resource-poor rural setting in Bangladesh.

BACKGROUND: Among the many challenges faced by the people of Bangladesh, the effects of climate change are discernibly threatening, impacting on human settlement, agricultural production, economic development, and human health. Bangladesh is a low-income country with limited resources; its vulnerability to climate change has influenced individuals to seek out health coping strategies. The objectives of the study were to explore the different strategies/measures people employ to cope with climate sensitive diseases and sickness. METHODS: A cross-sectional study was conducted among 450 households from Rajshahi and Khulna districts of Bangladesh selected through multi-stage sampling techniques, using a semi-structured questionnaire supplemented by 12 focus group discussions and 15 key informant interviews. RESULTS: Respondents applied 22 types of primary health coping strategies to prevent climate related diseases and sickness. To cope with health problems, 80.8% used personal treatment experiences and 99.3% sought any treatments available at village level. The percentage of respondents that visited unqualified health providers to cope with climate induced health problems was quite high, namely 92.7% visited village doctors, 75.9% drug stores, and 67.3% self-medicated. Ninety per cent of the respondents took treatment from unqualified providers as their first choice. Public health facilities were the first choice of treatment for only 11.0% of respondents. On average, every household spent Bangladesh Currency Taka 9,323 per year for the treatment of climate sensitive diseases and sickness. Only 46% of health expenditure was managed from their savings. The rest, 54% expenditure, was supported by using 24 different sources, such as social capital and the selling of family assets. The rate of out-of-pocket payment was almost 100%. CONCLUSION: People are concerned about climate induced diseases and sickness and sought preventive as well as curative measures to cope with health problems. The most common and widely used climate health coping strategies among the respondents included self-medicating and seeking the health service of unqualified private health care providers. Per family spending to cope with such health problems is expensive and completely based on out of pocket payment. There is no fund pooling, community funding or health insurance program in rural areas to support the health coping of the people. Policies are needed to reduce out-of-pocket payment, to improve the quality of the unqualified providers and to extend public health services at rural areas and support climate related health coping. Collection of such knowledge on climate related health coping strategies can allow researchers to study any specific issue on health coping, and policy makers to initiate effective climate related health coping strategies for climate vulnerable people.

Progressive kidney failure as the sole manifestation of extrapulmonary sarcoidosis.

Sarcoidosis is a chronic multisystem disorder characterized by an accumulation of T lymphocytes and mononuclear phagocytes, non-caseating epitheliod granulomas and derangement of normal tissue architecture in affected organs. Sarcoidosis can affect any organ system, however approximately 90% of patients with sarcoidosis have pulmonary, lymph node, cutaneous or ocular manifestations. Renal involvement in sarcoidosis is rare and clinically significant renal dysfunction even less common. We present a case of isolated renal sarcoidosis which manifested with progressively worsening renal function and hypercalcemia. A systematic diagnostic approach with pertinent laboratory studies, imaging and renal biopsy elucidated the diagnosis of renal sarcoidosis without any evidence of systemic involvement.

Cholangioscope-Guided Electrohydraulic Lithotripsy as a Rescue Technique for an Impacted Dormia Basket With Large Common Bile Duct Stone.

Impaction of Dormia basket while extracting common bile duct (CBD) stones during endoscopic retrograde cholangiopancreatography is a well-known but relatively rare complication. Its management could be very challenging and may require percutaneous, endoscopic, or major surgical intervention. In this study, we present a case of a 65-year-old man with a history of obstructive jaundice secondary to a large CBD stone. For stone extraction, mechanical lithotripsy with a Dormia basket was attempted resulting in its entrapment within CBD. Subsequently, the entrapped basket and large stone were retrieved using a novel technique of cholangioscope-guided electrohydraulic lithotripsy with excellent clinical outcomes.