Miracle-dz/UniFAR-FTUs huggingface dataset:
Activity landscape of DNA methyltransferase inhibitors bridges chemoinformatics with epigenetic drug discovery

Introduction: Activity landscapes are valuable tools for exploring systematically the structure–activity relationships (SAR) of chemical databases. Their application to analyze the SAR of DNA methyltransferase (DNMT) inhibitors, which are attractive compounds as potential epi-drugs or epi-probes, provides useful information to identify pharmacophoric regions and plan the development of predictive models and virtual screening. Areas covered: This paper highlights different approaches for conducting SAR analysis of datasets with a particular focus on the activity landscape methodology. SAR information of DNMT inhibitors (DNMTi), stored in a public database, is surveyed to further illustrate concepts and generalities of activity landscape modeling with a special emphasis on structure–activity similarity (SAS) maps. Expert opinion: The increasing SAR information reported for DNMTi opens up avenues to implement activity landscape methods. Despite several activity landscape methods, such as SAS maps, being well established, these need further refinement. For instance, novel combinations of multiple representations, such as the addition of Z-values of similarity (fusion-Z), lead to more robust representations of consensus SAS maps. Density SAS maps improve the visualization of the SAR. A survey of activity cliffs (i.e., pairs of compounds with high structural similarity but high differences in potency) of DNMTi available in a public database suggest that it is feasible to develop predictive models for non-nucleoside DNMTi using approaches such as quantitative structure-activity relationships and that non-nucleoside DNMTi in ChEMBL can be used as query molecules in similarity-based virtual screening.
Rethinking Leading: The directive, non-directive divide

There is a dearth of legal and psychological consideration of leading questions during the trial process. This article argues the current approach to leading questions does not assist or promote the accuracy of witness evidence. Witness here is taken to mean anyone giving oral testimony, whether for the prosecution, defence or indeed the defendant him or herself. We advance a revised definition of leading, differentiating between directive and non-directive questions. Directive questioning is the primary mischief to eliciting accurate witness testimony; we propose here its reform. Nondirective leading is of less concern and should be the leading form open to use in cross-examination.
Asthma in Preschool Children: A Review of the Diagnostic Challenges

Family physicians face many challenges when diagnosing asthma in preschool children. These diagnostic challenges are compounded by variations in the natural history of early stage asthma, which are not fully understood, since early childhood wheezing and asthma are heterogeneous disorders with many phenotypic and variable expressions. Since no standard definition for the type, severity, or frequency of symptoms exist for this age group, clear evidence-based recommendations are lacking. Without adequate guidance, family physicians are left to make diagnostic and treatment decisions, which can lead to undertreatment of asthmatics and overtreatment of transient wheezers. New guidelines that specifically address the challenges of diagnosing asthma in this particular age group (Global Initiative for Asthma, British Thoracic Society/Scottish Intercollegiate Guidelines Network) have recently been published, and researchers are actively seeking new methods and techniques through epidemiological studies to assist primary care clinicians in the diagnostic process. This review has wide application in primary care. By recognizing the diagnostic challenges and understanding the related best practices, family physicians will be better placed to treat, manage, and control asthma symptoms, resulting in lower morbidity rates and reduced health system costs, as well as enhancing the overall quality of life and well-being of the children affected.
Tricuspid regurgitation is a predictor of mortality after percutaneous mitral valve edge-to-edge repair.

AIMS The aim of this study was to determine the impact of tricuspid regurgitation (TR) on mortality after edge-to-edge percutaneous mitral valve repair (PMVR), and also to analyse whether there is a difference in outcome between patients with improvement of TR after PMVR compared to patients without. METHODS AND RESULTS Out of 197 consecutive patients who underwent PMVR, 139 patients with available follow-up (mean 428±386 days) were included in the study. Concomitant moderate/severe TR was present in 58.3% of patients. Kaplan-Meier analysis showed significantly reduced overall survival for patients with moderate/severe TR, compared to patients with none/mild TR (p=0.003). Cox multivariate regression analysis revealed severe TR at baseline as the strongest independent predictor of mortality (HR 4.367, p=0.003). An improvement of the baseline moderate/severe TR was observed in 45.5% of patients at 30-day follow-up. Patients with no improvement of TR after PMVR had a higher midterm mortality compared to patients in whom TR improved (40.5% versus 11.4%, p=0.005). CONCLUSIONS More than half of patients undergoing PMVR have concomitant moderate/severe TR, which is associated with a worse outcome. Among predictors of mortality after edge-to-edge PMVR, severe TR at baseline is the most important. Patients with no improvement of TR at 30 days after PMVR have a significantly higher mortality at follow-up.
When is a meta‐analysis conclusive? A guide to Trial Sequential Analysis with an example of remote ischemic preconditioning for renoprotection in patients undergoing cardiac surgery: Clinical Epidemiology in Nephrology

&NA; Regardless of whether a randomized trial finds a statistically significant effect for an intervention or not, readers often wonder if the trial was large enough to be conclusive. To answer this question, we can estimate the required sample size for a trial by considering how commonly the outcome occurs, the smallest effect of clinical importance and the acceptable risk of falsely detecting or rejecting that effect. But when is a meta‐analysis conclusive? We explain and illustrate the interpretation of Trial Sequential Analysis (TSA), a method increasingly used to answer this question. We conducted a conventional meta‐analysis which suggested that, in adults undergoing cardiac surgery, remote ischemic preconditioning does not provide a statistically significant reduction in acute kidney injury (AKI) [12 trials, 4230 patients; relative risk 0.87 (95% confidence interval 0.74‐1.02); P = 0.08; I2= 35%] or the risk of receiving acute dialysis [5 trials, 2111 patients; relative risk 1.15 (95% confidence interval 0.42‐3.19); P = 0.78; I2 = 59%]. TSA demonstrates that as little as a 20% relative risk reduction in AKI is unlikely. Reliably finding effects on acute dialysis and smaller effects on AKI would require much more evidence. Notably, conventional meta‐analyses conducted at one of the two earlier time points may have prematurely declared a statistically significant reduction in AKI, even though at no point in the TSA was there sufficient evidence to support such an effect. With this and other examples, we demonstrate that the TSA can prevent premature conclusions from meta‐analyses.
To compare the accuracy of prayer's sign and Mallampatti test in predicting difficult intubation in diabetic patients.

OBJECTIVE To determine the accuracy of Prayer's sign and Mallampatti test in predicting difficult endotracheal intubation in diabetic patients. METHODS The cross-sectional study was performed at Aga Khan University Hospital, Karachi, over a period from January 2009 to April 2010, and comprised 357 patients who required endotracheal intubation for elective surgical procedures. Prayer's sign and Mallampatti tests were performed for the assessment of airway by trained observers. Ease or difficulty of laryngoscopy after the patient was fully anaesthetised with standard technique were observed and laryngoscopic view of first attempt was rated according to Cormack-Lehan grade of intubation. SPSS 15 was used for statistical analysis. RESULTS Of the 357 patients, 125 (35%) were classified as difficult to intubate. Prayer's sign showed significantly lower accuracy, positive and negative predictive values than Mallampatti test. The sensitivity of Prayer's sign was lower 29.6 (95% Confidence Interval, 21.9-38.5) than Mallampatti test 79.3 (95% confidence interval, 70.8-85.7) while specificity of both the tests was not found to be significantly different. CONCLUSION Prayer's sign is not acceptable as a single best bedside test for prediction of difficult intubation.
Do Surgical Techniques Used in Groin Lymphadenectomy for Vulval Cancer Affect Morbidity Rates?

Objective: To determine the complication rates associated with differing surgical techniques for groin node dissection for vulval cancer. Materials and Methods: We performed a retrospective case note review of patients undergoing groin node dissection for vulval cancer between 2001 and 2009 at Nottingham University Hospitals NHS Trust. Results: Notes for 56 patients undergoing a total of 98 groin node dissections were examined. Sixty-four percent of the patients had at least one complication from surgery. The use of suction drains was not associated with an increase in complications. However, when drains were used, a short duration of use was associated with high rates of wound breakdown and a long duration of use was associated with higher rates of lymphedema. The use of staples for skin closure was associated with an increased risk of lymphocysts and chronic lymphedema. The greater the number of nodes collected at lymphadenectomy, the higher the risk of lymphocysts and lymphedema. Conclusions: We recommend the use of subcuticular suture for wound closure. Patients who undergo lymphadenectomy with a node count per groin of more than 7 should be closely monitored for lymphedema and referred promptly to specialist services. The prolonged use of suction drainage may increase the risk of lymphedema.
Resting-state brain correlates of cardiovascular complexity

While estimates of complex heartbeat dynamics have provided effective prognostic and diagnostic markers for a wide range of pathologies, brain correlates of complex cardiac measures in general and of complex sympatho-vagal dynamics in particular are still unknown. In this study we combine resting state functional Magnetic Resonance Imaging (fMRI) and physiological signal acquisition from 34 healthy subjects selected from the Human Connectome Project (HCP) repository with inhomogeneous point-process approximate and sample heartbeat entropy measures (ipApEn and ipSampEn) to investigate brain areas involved in complex cardiovascular control. Our results show that activity in the Temporal Gyrus, Frontal Orbital Cortex, Temporal Fusiform and Opercular cortices, Planum Temporale, and Paracingulate cortex are negatively correlated with ipApEn dynamics. Activity in the same cortical areas as well as in the Temporal Fusiform cortex are negatively correlated with ipSampEn dynamics. No significant positive correlations were found. These pioneering results suggest that cardiovascular complexity at rest is linked to a few specific cortical brain structures, including crucial areas connected with parasympathetic outflow. This corroborates the hypothesis of a multidimensional central network which controls nonlinear cardiac dynamics under a predominantly vagally-driven tone.
Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery

ObjectiveTo evaluate the impact of immune recovery induced by highly active antiretroviral therapy (HAART) on the survival of AIDS patients with primary central nervous system lymphoma (PCNSL). MethodsIn a multicentric retrospective analysis, 29 HIV-infected patients with histologically confirmed PCNSL were identified. To evaluate median survival, Kaplan–Meier statistics were used. To explore the effects of different variables on survival, a Weibull accelerated failure time regression analysis was performed. ResultsMedian age at manifestation of PCNSL was 39.1 years and median CD4 cell count was 11 × 106 cells/l. Seventy per cent of the patients had had a prior AIDS-defining illness. Cranial radiation (CR) was given to 12 out of 29 patients. Six patients were treated with HAART. Survival time of these patients and of the patients treated with CR alone differed significantly from those receiving neither CR nor HAART (median Kaplan–Meier survival estimate: 1093, 132, and 33 days, respectively). In the multivariate regression model, HAART and CR were identified as the only variables independently associated with prolonged survival. HAART versus no HAART and CR versus no CR increased the time to event by a factor of 6.1 (95% confidence interval, 2.4–16.0;P = 0.0002) and 3.1 (95% confidence interval, 1.5–6.3;P = 0.002), respectively. Four out of six patients on HAART showed a marked immune recovery and survived for more than 1.5 years, with two patients still alive. ConclusionData from this cohort indicate that immune recovery induced by HAART leads to dramatic improvement in survival of patients with AIDS-associated PCNSL. These findings may have important implications for future treatment strategies.
A flexible linear control algorithm for wireless sensor network synchronization

Time synchronization of wireless sensor network (WSN) nodes is essential to schedule orderly communication and monitoring tasks. In this paper, a synchronization algorithm based on linear control theory is used to compensate at run-time both time offsets and clock frequency skews. The proposed approach is innovative for two reasons. First of all, the controller correcting the local timers is able to work also in nonideal conditions (e.g., including random communication latencies and numerical quantization noise). Secondly, the computational burden of the algorithm and the amount of network traffic to transfer timing data are compatible with the requirements of typical low-cost WSN nodes. In fact, the time intervals between subsequent synchronizations tend to grows while the uncertainty decreases. As a consequence, each node is increasingly free to run other tasks. The correct operation of the proposed algorithm has been proved in a simulation framework modeling with great accuracy the behavior of a cluster of nodes.
Role of the Ca2+-Calcineurin-Nuclear Factor of Activated T cell Pathway in Mitofusin-2-Mediated Immune Function of Jurkat Cells

Background: Mitofusin-2 (MFN2), a well-known mitochondrial fusion protein, has been shown to participate in innate immunity, but its role in mediating adaptive immunity remains poorly characterized. In this study, we explored the potential role of MFN2 in mediating the immune function of T lymphocytes. Methods: We manipulated MFN2 gene expression in Jurkat cells via lentiviral transduction of MFN2 small interfering RNA (siRNA) or full-length MFN2. After transduction, the immune response and its underlying mechanism were determined in Jurkat cells. One-way analysis of variance and Student's t-test were performed to determine the statistical significance between the groups. Results: Overexpression of MFN2 enhanced the immune response of T lymphocytes by upregulating Ca2+ (359.280 ± 10.130 vs. 266.940 ± 10.170, P = 0.000), calcineurin (0.513 ± 0.014 vs. 0.403 ± 0.020 nmol/L, P = 0.024), and nuclear factor of activated T cells (NFATs) activation (1.040 ± 0.086 vs. 0.700 ± 0.115, P = 0.005), whereas depletion of MFN2 impaired the immune function of T lymphocytes by downregulating Ca2+ (141.140 ± 14.670 vs. 267.060 ± 9.230, P = 0.000), calcineurin (0.054 ± 0.030 nmol/L vs. 0.404 ± 0.063 nmol/L, P = 0.000), and NFAT activation (0.500 ± 0.025 vs. 0.720 ± 0.061, P = 0.012). Furthermore, upregulated calcineurin partially reversed the negative effects of MFN2 siRNA on T cell-mediated immunity evidenced by elevations in T cell proliferation (1.120 ± 0.048 vs. 0.580 ± 0.078, P = 0.040), interleukin-2 (IL-2) production (473.300 ± 24.100 vs. 175.330 ± 12.900 pg/ml, P = 0.000), and the interferon-&ggr;/IL-4 ratio (3.080 ± 0.156 vs. 0.953 ± 0.093, P = 0.000). Meanwhile, calcineurin activity inhibitor depleted the positive effects of overexpressed MFN2 on T cells function. Conclusions: Our findings suggest that MFN2 may regulate T cell immune functions primarily through the Ca2+-calcineurin-NFAT pathway. MFN2 may represent a potential therapeutic target for T cell immune dysfunction-related diseases.
Novel filaggrin mutation but no other loss‐of‐function variants found in Ethiopian patients with atopic dermatitis

Background Filaggrin is a key protein involved in maintaining skin barrier function and hydration. Mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and are a major predisposing factor for atopic dermatitis (AD) in individuals of European and Asian descent. It has been proposed that FLG mutations are population specific and a difference in the spectra of mutations between different ancestral groups has been described. However, it is unknown whether FLG mutations in the African population are a causative genetic factor for IV and predispose to AD, or whether other mechanisms are more prominent.
Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet–induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low- (10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat–fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3&bgr;, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-&ggr; coactivator 1&agr; and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat–diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet–induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet–induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling.
Reverse Epidemiology in Systolic and Nonsystolic Heart Failure: Cumulative Prognostic Benefit of Classical Cardiovascular Risk Factors

Background—Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure (“reverse epidemiology”). We estimated the prognostic role of these risk factors in unselected patients with heart failure. Methods and Results—Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P=0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P=0.009). Conclusion—In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure.
Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease clinically characterized by manifestation of wheezing, pulmonary infiltrates and bronchiectasis and fibrosis which afflicts asthmatic and cystic fibrosis (CF) patients. The pathophysiologic mechanisms are mediated by a first and direct interaction of Aspergillus fumigatus (Af) antigens with airway epithelial cells, followed by an immunologic/allergic inflammatory response to Af antigens. In the first phase, Af proteases directly activate epithelial cells by damaging the epithelial integrity and by a direct interaction with epithelial cells, resulting in a rapid wave of pro-inflammatory cytokines and chemokines that initiates an inflammatory response. During the second phase, this fungus induces a strong Th2-type immunological response with markedly elevated Aspergillus-specific and total serum IgE levels and a strong eosinophilic inflammatory response. It is proposed that strong repair reactions, similar to that described for asthmatic patients, are induced by fungal proteinases followed by concurrent release of epithelial derived growth factors. Furthermore, Th2-type cytokines e.g. IL-4 and IL-13 and proteases from inflammatory cells and mast cells, will also promote the release of growth factors from airway epithelial cells driving a strong and irreversible remodeling reactions in airways of patient with ABPA, resulting in bronchiectatic lesions and fibrosis.