Miracle-dz/UniFAR-FTUs huggingface dataset:
Chromosomal Variability among Allopatric Populations of Erythrinidae Fish Hoplias malabaricus: Mapping of Three Classes of Repetitive DNAs

Karyotype and chromosomal characteristics from 3 allopatric populations of Hoplias malabaricus, cytogenetically the most studied Erythrinidae taxon, were investigated using different staining techniques (C-, Ag-, and CMA3 banding) as well as fluorescent in situ hybridization (FISH) to detect 18S rDNA, 5S rDNA, and 5SHindIII satellite DNA sites. The isolation, cloning and characterization of an 18S rDNA probe from H. malabaricus genome were also performed for the first time in order to develop a more specific probe. The 3 populations, named PR, CR, and DR, showed identical karyotypes, with 2n = 42 chromosomes composed of 11 m pairs and 10 sm pairs, without heteromorphic sex chromosomes, which characterize the populations as belonging to karyomorph A. In all populations C-positive heterochromatin was situated in the centromeric/pericentromeric regions of the chromosomes, as well as in the telomeric region of several pairs. A conspicuous proximal heterochromatic block on the long arm of pair No. 16 was the only GC-rich segment in the karyotypes. 5SHindIII satellite DNA was always mapped in the centromeric region of several chromosomes. The 18S rDNA sites were situated on the telomeric or centromeric regions, whereas the 5S rDNA showed an interstitial or proximal location in some pairs. Several chromosomes bearing these repetitive DNA sequences were shared by the 3 populations, alongside with some exclusive chromosomal markers. In this sense, population CR was the most differentiated one, including a syntenic condition for the 18S and 5S rDNA probes, as confirmed by double FISH. Thus, despite their inclusion in the same major karyotypic group, the distinct populations cannot be considered an absolute evolutionary unit, as evidenced by their inner chromosomal differentiations.
Personalizing Second-Line Type 2 Diabetes Treatment Selection: Combining Network Meta-analysis, Individualized Risk, and Patient Preferences for Unified Decision Support

Background. Personalizing medical treatment often requires practitioners to compare multiple treatment options, assess a patient’s unique risk and benefit from each option, and elicit a patient’s preferences around treatment. We integrated these 3 considerations into a decision-modeling framework for the selection of second-line glycemic therapy for type 2 diabetes. Methods. Based on multicriteria decision analysis, we developed a unified treatment decision support tool accounting for 3 factors: patient preferences, disease outcomes, and medication efficacy and safety profiles. By standardizing and multiplying these 3 factors, we calculated the ranking score for each medication. This approach was applied to determining second-line glycemic therapy by integrating 1) treatment efficacy and side-effect data from a network meta-analysis of 301 randomized trials (N = 219,277), 2) validated risk equations for type 2 diabetes complications, and 3) patient preferences around treatment (e.g., to avoid daily glucose testing). Data from participants with type 2 diabetes in the U.S. National Health and Nutrition Examination Survey (NHANES 2003–2014, N = 1107) were used to explore variations in treatment recommendations and associated quality-adjusted life-years given different patient features. Results. Patients at the highest microvascular disease risk had glucagon-like peptide 1 agonists or basal insulin recommended as top choices, whereas those wanting to avoid an injected medication or daily glucose testing had sodium-glucose linked transporter 2 or dipeptidyl peptidase 4 inhibitors commonly recommended, and those with major cost concerns had sulfonylureas commonly recommended. By converting from the most common sulfonylurea treatment to the model-recommended treatment, NHANES participants were expected to save an average of 0.036 quality-adjusted life-years per person (about a half month) from 10 years of treatment. Conclusions. Models can help integrate meta-analytic treatment effect estimates with individualized risk calculations and preferences, to aid personalized treatment selection.
Aberrant expression of sperm-specific glycolytic enzymes are associated with poor sperm quality

The energy required for normal sperm function is mainly generated by glycolysis and oxidative phosphorylation. Testis-specific glycolytic enzymes are expressed in germ cells and present in mature spermatozoa. The objective of the present study was to investigate the association between aberrant expression of glycolytic enzymes and human sperm quality. In silico analysis of glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS), phosphoglycerate kinase 2 (PGK2) and lactate dehydrogenase (LDHC) identified that they were exclusively expressed in post-meiotic germ cells and this was validated in human testes using immunohistochemistry. Compared with the testes of young adults, markedly lower expression levels of these glycolytic enzymes were observed in the testes of elderly adults. Similarly, low levels were observed in immature and asthenozoospermic spermatozoa. The expression levels of GAPDHS, PGK2 and LDHC in the spermatozoa were closely correlated with progressive sperm motility. The results indicated that the expression of GAPDHS, PGK2 and LDHC in sperm may be associated with sperm quality, and there may be a similar molecular mechanism underlying sperm quality in immature and asthenozoospermic spermatozoa. This study reveals a close association of glycolytic enzymes with sperm quality. The data may greatly contribute to the molecular evaluation of sperm quality and the diagnosis and treatment of asthenozoospermia.
Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Compared With Leuprorelin Injections for Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE To investigate the noninferiority of relugolix compared with leuprorelin acetate in reducing heavy menstrual bleeding associated with uterine leiomyomas. METHODS In a double-blind, double-dummy trial, premenopausal women with uterine leiomyomas and heavy menstrual bleeding defined as a pictorial blood loss assessment chart score of at least 120 were randomized in a 1:1 ratio to relugolix (40 mg, oral, once daily) or leuprorelin acetate (1.88 mg or 3.75 mg, monthly injection) for 24 weeks. The primary endpoint was the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6-12. Secondary endpoints included myoma and uterine volumes, and hemoglobin levels. A sample size of 144 patients per group (n=288) was estimated to provide at least 90% power to demonstrate noninferiority (prespecified noninferiority margin -15%; one-sided 0.025 level of significance). RESULTS From March 2016 to September 2017, 281 patients were randomized (relugolix, n=139, leuprorelin n=142). Demographic and baseline characteristics were well balanced; mean pictorial blood loss assessment chart score was 254.3 in the relugolix group and 263.7 in the leuprorelin group. The proportion of patients with total pictorial blood loss assessment chart score of less than 10 for weeks 6-12 was 82.2% in the relugolix group and 83.1% in the leuprorelin group, demonstrating noninferiority of relugolix compared with leuprorelin (relugolix-leuprorelin difference -0.9%; 95% CI: -10.10 to 8.35; prespecified noninferiority margin -15%; P=.001). Reductions in myoma and uterine volumes and increases in hemoglobin levels were comparable in the two groups. Relugolix was associated with an earlier effect on menstrual bleeding than leuprorelin (pictorial blood loss assessment chart score of less than 10, 64.2% vs 31.7% [relugolix-leuprorelin difference 32.5%; 95% CI: 20.95-44.13%] for weeks 2-6 and pictorial blood loss assessment chart score of 0, 52.6% vs 21.8% [30.7%; 95% CI: 19.45-42.00%] for weeks 2-6) and faster recovery of menses after treatment discontinuation (relugolix median [Q1, Q3], 37 days [32.0, 46.0]; leuprorelin median, 65 days [54.0, 77.0]). Adverse events and bone mineral density loss were similar between relugolix and leuprorelin treatment groups. CONCLUSION In women with uterine leiomyomas, once-daily treatment with relugolix, an oral gonadotropin-releasing hormone antagonist, demonstrated noninferiority to monthly leuprorelin for improvement of heavy menstrual bleeding at 6-12 weeks of treatment, had a more rapid effect on menstrual bleeding, and was generally well tolerated. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02655237; JAPIC Clinical Trial Information, JapicCTI-163128. FUNDING SOURCE Takeda Pharmaceutical Company Limited and an affiliate of NovaQuest Capital Management LLC.
Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization

Background: Perioperative myocardial injury (PMI) seems to be a contributor to mortality after noncardiac surgery. Because the vast majority of PMIs are asymptomatic, PMI usually is missed in the absence of systematic screening. Methods: We performed a prospective diagnostic study enrolling consecutive patients undergoing noncardiac surgery who had a planned postoperative stay of ≥24 hours and were considered at increased cardiovascular risk. All patients received a systematic screening using serial measurements of high-sensitivity cardiac troponin T in clinical routine. PMI was defined as an absolute high-sensitivity cardiac troponin T increase of ≥14 ng/L from preoperative to postoperative measurements. Furthermore, mortality was compared among patients with PMI not fulfilling additional criteria (ischemic symptoms, new ECG changes, or imaging evidence of loss of viable myocardium) required for the diagnosis of spontaneous acute myocardial infarction versus those that did. Results: From 2014 to 2015 we included 2018 consecutive patients undergoing 2546 surgeries. Patients had a median age of 74 years and 42% were women. PMI occurred after 397 of 2546 surgeries (16%; 95% confidence interval, 14%–17%) and was accompanied by typical chest pain in 24 of 397 patients (6%) and any ischemic symptoms in 72 of 397 (18%). Crude 30-day mortality was 8.9% (95% confidence interval [CI], 5.7–12.0) in patients with PMI versus 1.5% (95% CI, 0.9–2.0) in patients without PMI (P<0.001). Multivariable regression analysis showed an adjusted hazard ratio of 2.7 (95% CI, 1.5–4.8) for 30-day mortality. The difference was retained at 1 year with mortality rates of 22.5% (95% CI, 17.6–27.4) versus 9.3% (95% CI, 7.9–10.7). Thirty-day mortality was comparable among patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction (280/397, 71%) versus those with at least 1 additional criterion (10.4%; 95% CI, 6.7–15.7, versus 8.7%; 95% CI, 4.2–16.7; P=0.684). Conclusions: PMI is a common complication after noncardiac surgery and, despite early detection during routine clinical screening, is associated with substantial short- and long-term mortality. Mortality seems comparable in patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction versus those patients who do. Clinical Trial Registration: URL: https://www.clinicaltrials. gov. Unique identifier: NCT02573532.
Fasting Versus Nonfasting and Low-Density Lipoprotein Cholesterol Accuracy

Background: Recent recommendations favoring nonfasting lipid assessment may affect low-density lipoprotein cholesterol (LDL-C) estimation. The novel method of LDL-C estimation (LDL-CN) uses a flexible approach to derive patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol. This adaptability may confer an accuracy advantage in nonfasting patients over the fixed approach of the classic Friedewald method (LDL-CF). Methods: We used a US cross-sectional sample of 1 545 634 patients (959 153 fasting ≥10–12 hours; 586 481 nonfasting) from the second harvest of the Very Large Database of Lipids study to assess for the first time the impact of fasting status on novel LDL-C accuracy. Rapid ultracentrifugation was used to directly measure LDL-C content (LDL-CD). Accuracy was defined as the percentage of LDL-CD falling within an estimated LDL-C (LDL-CN or LDL-CF) category by clinical cut points. For low estimated LDL-C (<70 mg/dL), we evaluated accuracy by triglyceride levels. The magnitude of absolute and percent differences between LDL-CD and estimated LDL-C (LDL-CN or LDL-CF) was stratified by LDL-C and triglyceride categories. Results: In both fasting and nonfasting samples, accuracy was higher with the novel method across all clinical LDL-C categories (range, 87%–94%) compared with the Friedewald estimation (range, 71%–93%; P⩽0.001). With LDL-C <70 mg/dL, nonfasting LDL-CN accuracy (92%) was superior to LDL-CF accuracy (71%; P<0.001). In this LDL-C range, 19% of fasting and 30% of nonfasting patients had differences ≥10 mg/dL between LDL-CF and LDL-CD, whereas only 2% and 3% of patients, respectively, had similar differences with novel estimation. Accuracy of LDL-C <70 mg/dL further decreased as triglycerides increased, particularly for Friedewald estimation (range, 37%–96%) versus the novel method (range, 82%–94%). With triglycerides of 200 to 399 mg/dL in nonfasting patients, LDL-CN <70 mg/dL accuracy (82%) was superior to LDL-CF (37%; P<0.001). In this triglyceride range, 73% of fasting and 81% of nonfasting patients had ≥10 mg/dL differences between LDL-CF and LDL-CD compared with 25% and 20% of patients, respectively, with LDL-CN. Conclusions: Novel adaptable LDL-C estimation performs better in nonfasting samples than the fixed Friedewald estimation, with a particular accuracy advantage in settings of low LDL-C and high triglycerides. In addition to stimulating further study, these results may have immediate relevance for guideline committees, laboratory leadership, clinicians, and patients. Clinical Trial Registration: URL: https://www.clinicaltrials. gov. Unique identifier: NCT01698489.
Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting. Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing. Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n = 30), median E2 methylation was significantly higher in patients who responded (P ≤ 0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n = 33), median E2 methylation was lower in patients who responded to treatment (P = 0.03; not significant after Bonferroni correction); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity. Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. Clin Cancer Res; 23(18); 5460–8. ©2017 AACR.
A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations

Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. Patients and Methods: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. Results: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Alan E. Kazdin: Award for Distinguished Scientific Applications of Psychology.

Presents Alan E. Kazdin, the 2011 winner of the American Psychological Association Award for Distinguished Scientific Applications of Psychology. "For outstanding and pathbreaking contributions to the understanding of the development, assessment, and treatment of psychopathology. Alan E. Kazdin's theoretically innovative, methodologically rigorous, and scientifically informed research has significantly advanced knowledge of child and adolescent psychopathologies such as depression and conduct problems. His writings on research strategies and methods have set a high standard for rigor in the field. His work and his ideas have had an enormous impact on the science, practice, and teaching of psychology, and his research has strengthened assessment and treatment of children and adolescents in scientific and clinical settings. His passion, energy, wisdom, and wit have inspired countless colleagues and students over the years, and his work will no doubt continue to do so for many generations to come. " (PsycINFO Database Record (c) 2011 APA, all rights reserved).
The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.
Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis

Bmi1 is a polycomb group proto-oncogene that has been implicated in multiple tumor types. However, its role in hepatocellular carcinoma (HCC) development has not been well studied. In this article, we report that Bmi1 is overexpressed in human HCC samples. When Bmi1 expression is knocked down in human HCC cell lines, it significantly inhibits cell proliferation and perturbs cell cycle regulation. To investigate the role of Bmi1 in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or an activated form of Ras (RasV12) in mouse liver. We found that while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, coexpression of Bmi1 and RasV12 promotes HCC formation in mice. Tumors induced by Bmi1/RasV12 resemble human HCC by deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. Intriguingly, we found no evidence that Bmi1 regulates Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development. In summary, our study shows that Bmi1 can cooperate with other oncogenic signals to promote hepatic carcinogenesis in vivo. Yet Bmi1 functions independent of Ink4A/Arf repression in liver cancer development. (Mol Cancer Res 2009;7(12):1937–45)
Scientific evidence on natural disasters and health emergency and disaster risk management in Asian rural-based area

Abstract Introduction Disaster epidemiological studies indicate that Asia has the highest frequency of natural disasters. Rural communities are heavily impacted by natural disasters and have different healthcare needs to urban ones. Referencing Asian countries, this paper’s objective is to provide an overview of health impacts and the current evidence for designing programmes and policies related to rural health emergency and disaster risk management (health-EDRM). Sources of data This paper uses published English-only reports and papers retrieved from PubMed, Google Scholar, Embase, Medline and PsycINFO on rural disaster and emergency responses and relief, health impact and disease patterns in Asia (January 2000–January 2018). Areas of agreement Earthquakes are the most studied natural disasters in rural communities. The medical burden and health needs of rural communities were most commonly reported among populations of extreme age. Most of the existing research evidence for rural interventions was reported in China. There lacks published peer-reviewed reports of programme impacts on personal and community preparedness. Areas of controversy There is a lack of evidence-based health-EDRM interventions to evaluate implementation effectiveness in rural areas despite vast volumes of health-related disaster literature. Growing points Climate change-related disasters are increasing in frequency and severity. Evidence is needed for disaster risk reduction interventions to address the health risks specific to rural populations. Areas timely for developing research To support global policy development, urgent evidence is needed on the intervention effectiveness, long-term health outcomes, local and cultural relevance as well as sustainability of health relief produced by Health-EDRM programmes in rural areas.