Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes.

Chemotherapeutics used in cancer therapy are often linked to muscle wasting or cachexia. Insights into the molecular basis of chemotherapy-induced cachexia is essential to improve treatment strategies. Here, we demonstrated that Sorafenib-tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents-induced cachexia. System-wide analyses revealed that Sorafenib alters the global transcriptional program and proteostasis in muscle cells. Mechanistically, Sorafenib treatment reduced active epigenetic mark H3K4 methylation on distinct muscle-specific genes by impeding chromatin association of SET1A-catalytic component of the SET1/MLL histone methyltransferase complex. This mechanism favored transcriptional disorientation that led to disrupted sarcomere assembly, calcium homeostasis and mitochondrial respiration. Consequently, the contractile ability of muscle cells was severely compromised. Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.

Clinical Neuroscience Research in Saudi Arabia: A Comparative Evaluation of Performance at Country and Worldwide Levels Based on the Relative Specialization Index.

This review is an appraisal of the performance of clinical neuroscience research in Saudi Arabia based on the measurement of the Relative Specialization Index (RSI). The latter is an established quantitative performance indicator that determines whether a country has a relatively higher or lower share in world publications in a specialty than its overall part in the world total publications. The study aimed to assess the trends in the specialty's RSI, comparing it to other medical specialties in Saudi Arabia and to that of the top 50 countries worldwide in clinical neuroscience. SCImago Journal and Country Rank were used to determine the total articles and total citations for 46 medical specialties in Saudi Arabia and clinical neuroscience in the worldwide top 50 countries during 1996­ 2023. The RSI was calculated for each medical specialty and each country. A positive or negative RSI implied that the specialty's share in the country's total documents or total citations was higher or lower than the average for the specialty worldwide. A steady increase in Saudi Arabia's total articles and total citations in clinical neuroscience was observed over the last 28 years. The RSI values, however, remained negative throughout except for limited periods (2003-2006 for total articles) and (1996 and 1998 for total citations). Compared to other medical specialties in Saudi Arabia, the specialization performance for clinical neuroscience was within the mid-range in total articles (ranking 30th out of 46 specialties) and the low range in total citations (ranking 39th out of 46 specialties). Saudi Arabia's worldwide ranking in clinical neuroscience based on total citations was 39; however, the country's ranking dropped to 45 when the RSI values were applied. Furthermore, clinical neuroscience was considered to have had a strong relative contribution (RSI ≥ 0.1) to the total articles in five countries (Italy, Austria, Germany, Japan, and Canada) and total citations in six countries (Luxembourg, Austria, Germany, Canada, Italy, and Finland). In conclusion, despite an increase in Saudi Arabia's total articles and total citations in clinical neuroscience over the years, the specialty's relative share of the total productivity in the country remains lower than the overall for the specialty worldwide. The performance of the specialty was within the mid-to-low range compared to the other 45 medical specialties in Saudi Arabia. In addition, the country's worldwide ranking based on total citations in the specialty dropped when the RSI was used. Clinical neuroscience researchers in Saudi Arabia are encouraged to improve the quality and quantity of their research productivity to be one of the leading medical specialties in Saudi Arabia.

Leukocyte mitochondrial DNA copy number and cardiovascular disease: A systematic review and meta-analysis of cohort studies.

Increasing cohort studies have examined the link between mitochondrial DNA copy number (mtDNA-CN) and cardiovascular disease (CVD), with inconsistent findings. We searched PubMed, EMBASE, and Web of Science up to July 11, 2023 and used a random-effects model to calculate summary hazard ratios (HRs) and 95% confidence intervals (CIs). This systematic review and meta-analysis included 8 articles encompassing 29 studies with 646,398 participants. Individuals with the lowest mtDNA-CN had a summary HR of 1.27 (95% CI 1.02-1.59) for CVD, 1.18 (95% CI 0.92-1.50) for coronary heart disease (CHD), 1.10 (95% CI 0.89-1.37) for stroke, and 1.30 (95% CI 1.07-1.56) for heart failure (HF). Decreased mtDNA-CN is linked to an increased risk of CVD and HF but not CHD and stroke. These findings suggest mtDNA-CN from leukocytes may be a potential early biomarker for CVD. However, more prospective studies with long follow-up are needed.

Real time monitoring of respiratory viral infections in cohort studies using a smartphone app.

Cohort studies investigating respiratory disease pathogenesis aim to pair mechanistic investigations with longitudinal virus detection but are limited by the burden of methods tracking illness over time. In this study, we explored the utility of a purpose-built AERIAL TempTracker smartphone app to assess real-time data collection and adherence monitoring and overall burden to participants, while identifying symptomatic respiratory illnesses in two birth cohort studies. We observed strong adherence with daily app usage over the six-month study period, with positive feedback from participant families. A total of 648 symptomatic respiratory illness events were identified with significant variability between individuals in the frequency, duration, and virus detected. Collectively, our data show that a smartphone app provides a reliable method to capture the longitudinal virus data in cohort studies which facilitates the understanding of early life infections in chronic respiratory disease development.

Effect of intrapartum azithromycin on gut microbiota development in early childhood: A post hoc analysis of a double-blind randomized trial.

Intrapartum azithromycin prophylaxis has shown the potential to reduce maternal infections but showed no effect on neonatal sepsis and mortality. Antibiotic exposure early in life may affect gut microbiota development, leading to undesired consequences. Therefore, we here assessed the impact of 2 g oral intrapartum azithromycin on gut microbiota development from birth to the age of 3 years, by 16S-rRNA gene profiling of rectal samples from 127 healthy Gambian infants selected from a double-blind randomized placebo-controlled clinical trial (PregnAnZI-2). Microbiota trajectories showed, over the first month of life, a slower community transition and increase of Enterobacteriaceae (p = 0.001) and Enterococcaceae (p = 0.064) and a decrease of Bifidobacterium (p < 0.001) in the azithromycin compared to the placebo arm. Intrapartum azithromycin alters gut microbiota development and increases proinflammatory bacteria in the first month of life, which may have undesirable effects on the child.

Plasma endocannabinoidome and fecal microbiota interplay in people with HIV and subclinical coronary artery disease: Results from the Canadian HIV and Aging Cohort Study.

Chronic HIV infection is associated with accelerated coronary artery disease (CAD) due to chronic inflammation. The expanded endocannabinoid system (eCBome) and gut microbiota modulate each other and are key regulators of cardiovascular functions and inflammation. We herein investigated the interplay between plasma eCBome mediators and gut microbiota in people with HIV (PWH) and/or subclinical CAD versus HIV-uninfected individuals. CAD was determined by coronary computed tomography (CT) angiography performed on all participants. Plasma eCBome mediator and fecal microbiota composition were assessed by tandem mass spectrometry and 16S rDNA sequencing, respectively. HIV infection was associated with perturbed plasma eCBome mediators characterized by an inverse relationship between anandamide and N-acyl-ethanolamines (NAEs) versus 2-AG and 2-monoacylglycerols (MAGs). Plasma triglyceride levels were positively associated with MAGs. Several fecal bacterial taxa were altered in HIV-CAD+ versus controls and correlated with plasma eCBome mediators. CAD-associated taxonomic alterations in fecal bacterial taxa were not found in PWH.

A radiogenomic clinical decision support system to inform individualized treatment in advanced nasopharyngeal carcinoma.

Both concurrent chemoradiotherapy (CCRT) and induction chemotherapy (ICT) followed by CCRT are standard care of advanced nasopharyngeal carcinoma (NPC). However, tailoring personalized treatment is lacking. Herein, we established a radiogenomic clinical decision support system to classify patients into three subgroups according to their predicted disease-free survival (DFS) with CCRT and ICT response. The CCRT-preferred group was suitable for CCRT since they achieved good survival with CCRT, which could not be improved by ICT. The ICT-preferred group was suitable for ICT plus CCRT since they had poor survival with CCRT; additional ICT could afford an improved DFS. The clinical trial-preferred group was suitable for clinical trials since they exhibited poor survival regardless of receiving CCRT or ICT plus CCRT. These findings suggest that our radiogenomic clinical decision support system could identify optimal candidates for CCRT, ICT plus CCRT, and clinical trials, and may thus aid in personalized management of advanced NPC.

Characteristics of calcified nodule attributable to culprit lesion in acute coronary syndrome: A systematic review and meta-analysis.

The presence of calcified nodule (CN) is a significant characteristic of atherothrombosis in acute coronary syndrome (ACS). However, its characteristics continue to be understudied. This review aimed to further investigate these characteristics. This study found that CN was a distinctive feature of an atheromatous plaque, representing 6.3% of ACS. CN was more common in NSTE-ACS than in STEMI patients (9.4% vs. 6.6%). CN was also chiefly observed in the left anterior descendant artery (48%), followed by the right coronary (40.4%) and left circumflex (14.5%) arteries. Higher prevalence of hypertension (78.8%), diabetes mellitus (50.8%), multivessel disease (71.7%), and kidney disease (26.43%) were noted in CN compared to non-CN patients. CN-associated ACS also 6-fold increased the risk of target lesion revascularization compared to those without CN.

[Looking back on 100 years of board certification for urology in Germany : Formation of a medical subject in the context of specialization and professionalization]. / 100 Jahre Facharzt für Urologie : Zur Ausbildung eines medizinischen Faches im Kontext von Spezialisierung und Professionalisierung.

This article examines the development of urology as an independent medical discipline in Germany, with a particular focus on professionalization and specialization in the 19th and 20th centuries. Based on historical sources, the text illuminates the importance of the German medical profession's further training regulations as an instrument of medical self-administration and the classification of urology as a medical specialty in the Bremen guidelines of 1924, which established board certification in diseases of the urinary organs (urology).

Targeted dephosphorylation of TFEB promotes its nuclear translocation.

Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.

Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic ß-cells.

KCNQ1/Kv7, a low-voltage-gated K+ channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and ß-cell survival in hereditary diabetes pathology.

Mapping the Locations of Medical Specialists in the Ministry of Health's Hospitals in Malaysia by Specialty, Subspecialty and Area of Interest.

Mapping the distribution of medical specialists in the Ministry of Health (MOH) Malaysia facilities is expected to be more complex as the demand for specialty and subspecialty services increases in the future. A more robust and definitive gap analysis is needed to facilitate planning and resource allocation. The Medical Development Division developed a master list of framework of specialties, subspecialties and areas of interest, and Specialist Database Module in the Medical Programme Information System (MPIS) as tools to facilitate mapping of services. Relational database of specialists' location, facilities, workload, population profile and other relevant parameters were developed to provide data visualisation in specific dashboard. Needs versus supply ratio is proposed as one of parameters to visualise specialised medical services distribution by geographical localities.

Integrated single cell-RNA sequencing and Mendelian randomization for ischemic stroke and metabolic syndrome.

Although more and more evidence has supported that metabolic syndrome (MS) is linked to ischemic stroke (IS), the molecular mechanism and genetic association between them has not been investigated. Here, we combined the existing single-cell RNA sequencing (scRNA-seq) data and mendelian randomization (MR) for stroke to understand the role of dysregulated metabolism in stroke. The shared hub genes were identified with machine learning and WGCNA. A total of six upregulated DEGs and five downregulated genes were selected for subsequent analyses. Nine genes were finally identified with random forest, Lasso regression, and XGBoost method as a potential diagnostic model. scRNA-seq also show the abnormal glycolysis level in most cell clusters in stroke and associated with the expression level of hub genes. The genetic relationship between IS and MS was verified with MR analysis. Our study reveals the common molecular profile and genetic association between ischemic stroke and metabolic syndrome.

Cerebrospinal fluid and plasma concentrations of the inflammatory marker soluble CD27 in a large surgical population.

Soluble CD27 (sCD27) is a potential biomarker for diseases involving immune dysfunction. As there is currently little data on cerebrospinal fluid (CSF) sCD27 concentrations in the general population we measured CSF and plasma concentrations in 486 patients (age range 18-92 years, 57% male) undergoing spinal anesthesia for elective surgery. Across the complete cohort the median [range] sCD27 concentrations were 163 [<50 to 7474] pg/mL in CSF and 4624 [1830 to >400,000] pg/mL in plasma. Plasma sCD27, age and Qalb were the factors most strongly associated with CSF sCD27 levels. Reference sCD27 concentration intervals (central 95% of values) in a sub-group without the indication of neuropsychiatric, inflammatory or systemic disease (158 patients) were <50 pg/mL - 419 pg/mL for CSF and 2344-36422 pg/mL for plasma. These data provide preliminary reference ranges that could inform future studies of the validity of sCD27 as a biomarker for neuro- and systemic inflammatory disorders.

Zanubrutinib delays selinexor resistance evolution in biopsy sample-derived primary central nervous system lymphoma models.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma of the brain with poor prognosis. The scarcity of cell lines established using PCNSL makes it difficult to conduct preclinical studies on new drugs. We aimed to explore the effect of selinexor combined with zanubrutinib in PCNSL using established PCNSL cells and an orthotopic PCNSL model. Primary PCNSL cells were successfully cultured. Selinexor inhibited proliferation, induced G1 phase arrest, and promoted apoptosis, however, induced drug resistance in PCNSL. Selinexor combined with zanubrutinib had a synergistic effect on PCNSL and prevented the onset of selinexor resistance in PCNSL by inhibiting AKT signaling. Moreover, selinexor combined with zanubrutinib notably slowed tumor growth and prolonged survival compared to that of the control. Overall, the addition of zanubrutinib to selinexor monotreatment had a synergistic effect in vitro and prolonged survival in vivo.

Epidemiology of 369 diseases and injuries attributable to 84 risk factors: 1990-2019 with 2040 projection.

The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990-2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

Evolution of interconsultal activity to endocrinology and nutrition in hospitalization floor in a third level hospital.

INTRODUCTION: Endocrinology and Nutrition (EyN) is an outpatient and hospital medical specialty. This study aims to understand the evolution of the activity of interdepartmental consultation (IC) carried out by EyN in hospitalization floor of a third level hospital, comparing its evolution with other medical specialties, and comparing endocrine IC with nutritional IC. MATERIAL AND METHODS: Longitudinal and retrospective study which analyzes IC notes of EyN and other medical specialties between 01-01-2013 and 31-12-2022. RESULTS: A total of 76093 IC notes (12623 patients) were performed by the EyN service (average age 65.4 years; 59% male) with an average of 4.8 notes per patient. Average annual growth was 7% in notes and 4% in patients (versus 6% and 3% of all other medical services, differences statistically significant). Of all patients hospitalized for 4 or more days, EyN went from attending 7.9% (2013) to 12.3% (2022). 66% of the IC performed by EyN was for nutritional cause and 34% for other pathologies. CONCLUSIONS: The EyN service is the one that most patients attend in hospital IC activity, with growth over the last few years greater than other medical specialties. Nutritional pathology is the main reason for IC.

Gender Inequity in Clinical Clerkships and its Influence on Career Selection: A Cross-Sectional Survey.

Objective: The aim of this study was to identify the frequency, form, and underlying factors contributing to gender inequity experienced by medical undergraduates and assess its influence on their career choices. Method: This was a cross-sectional, retrospective survey with a 100% response rate. This survey was distributed among medical students of clinical years in Karachi's private and government medical colleges from September 10th, 2021-March 30th, 2022. 430 participants were enrolled using a simple-random-sampling-technique. Chi-square/Fisher's Exact tests are employed to assess the relationships between gender and gender-based inequity in various specialties, including their characteristics, influence on career choices, adverse psychological effects, and potential mitigation strategies. Results: Among 430 respondents, 28.6% were male, and 71.4% were female. 89.1% reported gender inequity, evenly distributed in government (80.4%) and private institutions (88.1%). The general surgery and gynecology disciplines stood out, each with a 56% prevalence. In gynecology and surgery clinical-clerkships, both genders experienced similar rates, with females at 54.5% and 42.3%, and males at 56.7% and 61.6%, respectively (P-value = .000*). Disrespect from staff/professors/patients (48.8%) was the most common manifestation, driven by factors like preferences (73.7%), gender superiority (62.6%), societal attitudes (54%), and cultural norms (50.9%). Furthermore, 82.6% of students reported that gender inequity had a negative impact on their career decision (Male = 82.9%;Female = 82.4%, P-value = .899). Additionally, gender inequity also caused demotivation (78.1%), poor self-esteem (67.2%), helplessness/hopelessness (48.6%), and frustration (45.8%). Conclusions: Gender inequity is widely prevalent in the clinical-clerkships, affecting medical students' career decisions and mental health, stressing the need to prioritize and implement solutions at the undergraduate clinical-clerkship level.

The Effect of the COVID-19 Pandemic on the Factors Influencing Iranian Medical Residents' Specialty Selection: A Qualitative Study.

Background: Medical students' specialty selection influences the composition of the physician workforce and the effectiveness of health systems. Therefore, the identification of factors that influence the choice of specialty is critical for an evidence-based health policy. This study aimed to investigate the effect of the Coronavirus Disease 2019 (COVID-19) pandemic on the determinants of specialty choice among Iranian medical residents. Methods: In early 2022, this qualitative study was conducted among Iranian medical residents in seven provinces, including Tehran, Isfahan, Fars, Khorasan Razavi, Kerman, Kermanshah, and Khuzestan. The participants were selected using a purposeful sampling method. Data were collected using 74 semi-structured in-depth face-to-face interviews. Finally, a thematic content analysis (conventional content analysis) method was applied for data synthesis. Results: The participant's mean age was 28.7±2.5 years, and more than 52% (N=39) were men. Following data synthesis, 10 sub-themes and four main themes were identified, including educational aspects affected by the pandemic, career-related hazards, personal and professional lifestyles affected by the disease, and experiences and beliefs regarding the pandemic. Conclusion: The COVID-19 pandemic has had a significant impact on medical students' educational, professional, and personal aspects of specialty choices. This study demonstrated how the disease affected the choice of specialty. Therefore, the findings could be used for developing national health policy and planning.