Miracle-dz/UniFAR-FTUs huggingface dataset:
Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis

Significance Previous work has shown that foamy macrophages accumulate desmosterol, a cholesterol biosynthetic intermediate. However, the participation of desmosterol in regulating the functions of cholesterol-laden macrophages in the physiological context of atherosclerosis has remained elusive. In this work, we selectively deplete desmosterol by overexpressing DHCR24, the enzyme that catalyzes the conversion of desmosterol into cholesterol, in myeloid cells and demonstrate that desmosterol content in atherosclerotic plaque macrophages controls their function and activation. Molecular analysis of macrophages isolated from lesions revealed that depletion of desmosterol increases the expression of interferon-regulated genes and genes associated with “classical” macrophage activation. Together, our work provides molecular insights into the intimate links between cholesterol metabolism and inflammatory responses of macrophages during atherogenesis. Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)–dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.
Epidemiology, treatment and preventive strategy in Diwali-related burns

Introduction : Diwali is one of the most important festivals in India, but it also sees lots of people suffering from burns due to fire crackers. Methodology : This is a prospective study of 120 cases of Diwali-related burns in a period of 3 years. The data in the prescribed format were collected from two hospitals of Guwahati, the capital city of Assam. Results : There were 85 males and 35 females in the series. While 90 patients were directly involved in the use of the crackers, 30 were passersby or onlookers. The most common offending agent was the Flower pot (Kalgach) - 84 cases, while fire crackers were responsible for 23 cases, eight cases were due to chakari and five cases were due to the flame of earthen lamps. Majority of the cases (112) had burns between 2% and 6%, while six cases had 10-15% burns and two other cases sustained 45% and 60% burns. Seventy percent of the cases burnt their right hands, 10% burnt their left hand, 5% had burns in both the hands, 4% had burns of the trunk and limbs to a variable extent and 6% sustained facial burns. There were six cases (5%) of eye injuries. While 112 cases were treated as outpatients, 18 cases required indoor treatment. Most of the cases were treated with Collagen dry sheet dressing. A few cases (n = 5) were subjected to Early Excision and Grafting, while three cases required delayed grafting. Burn Prevention programs before Diwali were also undertaken in both the hospitals during the study period. The effect of the Burn Prevention Program on the incidence is also discussed in this paper. Conclusions : Awareness among the masses and strict implementation of government legislation may help in bringing down the incidence of Diwali-related burns.
Single-center study: evaluation of sonography in Budd-Chiari syndrome

Abstract Purpose Budd-Chiari syndrome (BCS) is a rare disease characterized by hepatic venous outflow tract obstruction. The study aimed to evaluate the diagnostic utility of ultrasound in confirming the diagnosis of BCS and to provide an overview of the clinical picture. Materials and method In this retrospective single-center study, patients with an initial diagnosis of BCS were included. The files were analyzed concerning the ultrasound images and compared to computed tomography (CT) and magnetic resonance imaging (MRI). Main clinical signs of BCS were collected. Results Data of 25 patients were analyzed. Doppler sonography showed the highest sensitivity (78.9%) with the highest specificity 97.4 (%) in confirming the correct diagnosis of BCS. Main imaging signs were obstruction in the hepatic veins (68.0%, 17/25 thrombotic), collaterals (91.7%, 11/12 intrahepatic), inhomogeneous liver parenchyma (7/21), and a hypertrophied lobus caudatus (18/21) (p < 0.01). All imaging signs could be detected with sonography. Hypertrophied lobus caudatus was seen exclusively in BCS. Furthermore, portal hypertension (9/25), liver cirrhosis (9/25), and ascites (19/25) can be diagnosed as non-specific signs of BCS (p < 0.01). The main clinical findings were elevated γ-GT levels in the laboratory (92.0%, 23/25, p < 0.01) and esophageal varices in endoscopy (12/25 p < 0.01). An association with myeloproliferative neoplasia (MPN) was frequently seen (10/25) (p < 0.01). Conclusion The present study demonstrates that sonography is an appropriate tool for the diagnosis of BCS and should be used as the first imaging procedure.
Intermittent wind generation in optimal power flow dispatching

A stochastic model of wind generation in an optimal power flow (OPF) dispatching program is presented. The model includes the error in wind power forecasts using a probability or relative frequency histogram. Compared with the deterministic OPF, the proposed model allows the coordination of wind and thermal power while accounting for (i) the expected penalty cost for not using all available wind power and (ii) the expected cost of calling up power reserves because of wind power shortage. The stochastic model is integrated in an extended conic quadratic OPF program in which wind driven generators are represented as induction machines. Simulation results are presented for cases where the forecasting error histogram is either derived from historical data or estimated by a bimodal normal distribution. The effect of the skewness of the error distribution on the optimal dispatch policy is studied.
Higher blood urea nitrogen level is independently linked with the presence and severity of neonatal sepsis

Abstract Background Previous studies have demonstrated that blood urea nitrogen (BUN) is strongly associated with sepsis. However, no data are currently available regarding the association of BUN levels and neonatal sepsis. Thus, this study aimed to investigate the role of BUN in predicting the presence and severity of neonatal sepsis. Methods In this study, we enrolled 925 neonates. Among them, 737 neonates were diagnosed with sepsis, including 426 neonates with severe sepsis. Neonates with hyperbilirubinemia (n = 188) served as controls. We collected complete clinical and laboratory data were collected. Multivariate logistic regression analysis was performed to identify the potential independent risk factor for neonatal sepsis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy of BUN in predicting neonatal sepsis. All statistical analyses were performed using the statistical package SPSS 24.0. Results Neonates with sepsis and severe sepsis had a higher level of BUN. The prevalence of neonates with severe sepsis was dramatically increased according to BUN tertiles. Correlation analysis showed that BUN levels were positively correlated with the levels of infection marker procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP). Multiple logistic regression analysis showed that BUN was an independent risk factor for the presence and severity of neonatal sepsis. ROC curve analysis showed that BUN had a well discriminatory power in predicting sepsis (area under curve (AUC) = 0.69, 95% CI, 0.66–0.74, p < . 001) and severe sepsis (AUC = 0.72, 95% CI, 0.67–0.78, p < .001). Conclusion Higher BUN level is independently linked with the presence and severity of neonatal sepsis.
Fibrinogen β chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism

Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha‐chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) −455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE).
Psychosocial interventions for older people with intellectual disabilities and the role of support staff: A systematic review

Abstract Background The life expectancy of people with intellectual disabilities has increased. The implications of ageing have resulted in changes in their support needs and challenges to support staff. Access to evidence based strategies for support staff providing care to elderly with intellectual disabilities remains scarce. A systematic review was conducted to provide an overview of available psychosocial interventions. Methods Four databases were searched and assessed according to the PRISMA guidelines. A narrative, integrative method of analysis was conducted to synthesise quantitative and qualitative data. Results The 36 studies included in the review reported on interventions aimed at either identifying and meeting the needs or perceptions of older individuals or at improving their behaviour and skills. Furthermore, the role of support staff in the implementation of interventions was either active, assisting or undefined. Conclusions This overview of studies could contribute to the existing body of knowledge and help to optimise psychosocial support for a growing population.
High‐definition transcranial direct current stimulation modulates performance and alpha/beta parieto‐frontal connectivity serving fluid intelligence

Fluid intelligence (Gƒ) includes logical reasoning abilities and is an essential component of normative cognition. Despite the broad consensus that parieto‐prefrontal connectivity is critical for Gƒ (e.g. the parieto‐frontal integration theory of intelligence, P‐FIT), the dynamics of such functional connectivity during logical reasoning remains poorly understood. Further, given the known importance of these brain regions for Gƒ, numerous studies have targeted one or both of these areas with non‐invasive stimulation with the goal of improving Gƒ, but to date there remains little consensus on the overall stimulation‐related effects. To examine this, we applied high‐definition direct current anodal stimulation to the left and right dorsolateral prefrontal cortex (DLPFC) of 24 healthy adults for 20 min in three separate sessions (sham, left, and right active). Following stimulation, participants completed a logical reasoning task during magnetoencephalography (MEG). Significant neural responses at the sensor‐level were imaged using a beamformer, and peak task‐induced activity was subjected to dynamic functional connectivity analyses to evaluate the impact of distinct stimulation montages on network activity. We found that participants responded faster following right DLPFC stimulation vs. sham. Moreover, our neural findings followed a similar trajectory of effects such that left parieto‐frontal connectivity decreased following right and left DLPFC stimulation compared to sham, with connectivity following right stimulation being significantly correlated with the faster reaction times. Importantly, our findings are consistent with P‐FIT, as well as the neural efficiency hypothesis (NEH) of intelligence. In sum, this study provides evidence for beneficial effects of right DLPFC stimulation on logical reasoning.
Cluster headache: a single tertiary center study

ABSTRACT Object The characteristics of cluster headache (CH) patients in many countries and the diagnostic and therapeutic approach have been described in several publications, but so far no clinical data have been published from Turkey. Material methods This is a cross-sectional retrospective study that includes all patients who were diagnosed with CH and referred to our headache clinic, Dokuz Eylül University Faculty of Medicine, Neurology Department from 1991 to January 2018. Results We included 114 patients (24 females and 90 males) in our study. The mean age at onset was 31.68 ± 12.72 (range 13–68). Eighty-six (78.18%) patients had episodic cluster headache (ECH) and 24 (21.82%) patients had chronic cluster headache (CCH). The age at onset was significantly higher in the patients with CCH than with ECH (p = 0.002). The most common location was orbitotemporal for both genders. The most common accompanying symptoms were lacrimation (80.73%). The male:female ratio in all patients was 3:7, 3.8:1 in those with CCH and 4:1 in those with ECH. Eighty-nine (87.25%) patients had prophylactic treatment and 60 of them received verapamil. Conclusion In our study, some clinical features of our patients were similar to those of Europe and America or the Asian countries and some of them not. There are regional differences in cluster headache patients. With more awareness of cluster headache and research from many countries, clinical differences can be revealed more objectively in the future.
Disability, a priority area for health research in South Africa: an analysis of the burden of disease study 2017

Abstract Purpose Disabilities are increasing globally, which is attributed to the overall ageing of populations in affluent countries. This trend may differ in low and middle-income countries. This paper assesses the change over time in Years Lived with Disability (YLD) for South Africa and how this compares to regional and global trends. Materials and methods This secondary analysis of the Global Burden of Disease Study 2017 dataset describes the observed contribution of YLD to Disability-Adjusted Life Years (DALYs) per 100 000 people over the period 1990–2016, and forecast to 2030 using simple linear prediction. South African trends are compared to global and sub-Saharan African (SSA) trends to highlight the effect of HIV and policy implications. Results Globally, the contribution of YLD to DALYs has increased from ±21.7% in 1990 to ±34% by 2016, with high socio-demographic index countries having a higher contribution (49%). HIV, mental health, musculoskeletal, neurological, and sense organ disorders are the five main contributors to YLD in South Africa (54%). Removing the effects of HIV/AIDS and sexually transmitted infections on YLD, South Africa’s trend appears similar to the global trend, yet opposite to the SSA trend. Conclusion Our analysis shows there is a growing burden of disability in South Africa. Differences in trends with the regional and global patterns can be attributed to the high burden of HIV and non-communicable diseases in South Africa. Therefore, strategies are urgently needed to increase integration of disability and rehabilitation services into chronic HIV and non-communicable disease management. This calls for disability screening to identify functional limitations in routine data collection and case management. IMPLICATIONS FOR REHABILITATION South Africa has experienced an increase in disability prevalence over time. This requires strengthening of services such as mental health interventions, physiotherapy, optometry, and audiology, and linking major disease clusters, such as HIV and the NCDs, to rehabilitation services. The greatest contributors towards disability adjusted life years in South Africa are currently mental disorders (13.8%), HIV and sexually transmitted infections (11.8%), musculoskeletal disorders (10.4%), neurological disorders (8.2%), and sense organ diseases (7.5%). Routine data collection and case management needs to include disability screening to identify developing functional limitations.
Human FKBP5 Negatively Regulates Transcription through Inhibition of P-TEFb Complex Formation

Although a large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorders, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor, and AKT signaling pathways, other functional roles (if any) are unclear. Here, we report an antiproliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. ABSTRACT Although a large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorders, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor, and AKT signaling pathways, other functional roles (if any) are unclear. Here, we report an antiproliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. Mechanistically, we show that, owing to the same region of interaction on cyclin-dependent kinse 9 (CDK9), human FKBP5 directly competes with cyclin T1 for functional positive transcription elongation factor b (P-TEFb) complex formation. In vitro biochemical assays, coupled with cell-based assays, showed a strong negative effect of FKBP5 on P-TEFb-mediated phosphorylation of diverse substrates. Consistently, FKBP5 knockdown showed enhanced P-TEFb complex formation that led to increased global RNA polymerase II C-terminal domain (CTD) phosphorylation, expression of proliferation-related genes, and subsequent proliferation. Thus, our results show an important role for FKBP5 in negative regulation of P-TEFb functions within mammalian cells.
Reexamining Remission Definitions in Rheumatoid Arthritis: Considering Disease Activity Score in 28 Joints, C‐Reactive Protein, and Patient Global Assessment

ACR Open Rheumatology Vol. 4, No. 2, February 2022, pp 123–127 DOI 10.1002/acr2.11345 © 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creat ive Commo ns Attri butio nNonCo mmerc ialNoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made.
Bemcentinib and gilteritinib inhibit cell growth and impair the endo-lysosomal and autophagy systems in an AXL-independent manner.

AXL, a receptor tyrosine kinase from the TAM (TYRO3 AXL and MER) subfamily, and its ligand growth arrest specific 6 (GAS6) are implicated in pathogenesis of a wide array of cancers, acquisition of resistance to diverse anti-cancer therapies and cellular entry of viruses. The continuous development of AXL inhibitors for treatment of cancer and COVID-19 patients underscores the need to better characterize the cellular effects of AXL targeting. In the present study, we compared the cellular phenotypes of CRISPR-Cas9-induced depletion of AXL and its pharmacological inhibition with bemcentinib, LDC1267 and gilteritinib. Specifically, we evaluated GAS6-AXL signaling, cell viability and invasion, the endo-lysosomal system and autophagy in glioblastoma cells. We showed that depletion of AXL but not of TYRO3 inhibited GAS6-induced phosphorylation of downstream signaling effectors, AKT and ERK1/2, indicating that AXL is a primary receptor for GAS6. AXL was also specifically required for GAS6-dependent increase in cell viability but was dispensable for viability of cells grown without exogenous addition of GAS6. Furthermore, we revealed that LDC1267 is the most potent and specific inhibitor of AXL activation among the tested compounds. Finally, we found that, in contrast to AXL depletion and its inhibition with LDC1267, cell treatment with bemcentinib and gilteritinib impaired the endo-lysosomal and autophagy systems in an AXL-independent manner. Implications: Altogether, our findings are of high clinical importance as we discovered that two clinically advanced AXL inhibitors, bemcentinib and gilteritinib, may display AXL-independent cellular effects and toxicity.
Association of Polypharmacy with Kidney Disease Progression in Adults with CKD

Visual Abstract Background and objective Polypharmacy is common in patients with CKD and reportedly associated with adverse outcomes. However, its effect on kidney outcomes among patients with CKD has not been adequately elucidated. Hence, this investigation was aimed at exploring the association between polypharmacy and kidney failure requiring KRT. Design, setting, participants, and measurements We retrospectively examined 1117 participants (median age, 66 years; 56% male; median eGFR, 48 ml/min per 1.73 m2) enrolled in the Fukushima CKD Cohort Study to investigate the association between the number of prescribed medications and adverse outcomes such as kidney failure, all-cause mortality, and cardiovascular events in Japanese patients with nondialysis-dependent CKD. Polypharmacy and hyperpolypharmacy were defined as the regular use of 5–9 and ≥10 medications per day, respectively. Results The median number of medications was eight; the prevalence of polypharmacy and hyperpolypharmacy was each 38%. During the observation period (median, 4.8 years), 120 developed kidney failure, 153 developed cardiovascular events, and 109 died. Compared with the use of fewer than five medications, adjusted hazard ratios (95% confidence intervals) associated with polypharmacy and hyperpolypharmacy were 2.28 (1.00 to 5.21) and 2.83 (1.21 to 6.66) for kidney failure, 1.60 (0.85 to 3.04) and 3.02 (1.59 to 5.74) for cardiovascular events, and 1.25 (0.62 to 2.53) and 2.80 (1.41 to 5.54) for all-cause mortality. Conclusions The use of a high number of medications was associated with a high risk of kidney failure, cardiovascular events, and all-cause mortality in Japanese patients with nondialysis-dependent CKD under nephrology care.