Miracle-dz/UniFAR-FTUs huggingface dataset:
Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan

Abstract This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.
Glucocorticoid Receptor α Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD

Background Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown. Methods To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast’s effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients. Results We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα’s transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone’s ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner. Discussion Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.
Teenage sleep and technology engagement across the week

Background Throughout the developed world, adolescents are growing up with increased access to and engagement with a range of screen-based technologies, allowing them to encounter ideas and people on a global scale from the intimacy of their bedroom. The concerns about digital technologies negatively influencing sleep are therefore especially noteworthy, as sleep has been proven to greatly affect both cognitive and emotional well-being. The associations between digital engagement and adolescent sleep should therefore be carefully investigated in research adhering to the highest methodological standards. This understood, studies published to date have not often done so and have instead focused mainly on data derived from general retrospective self-report questionnaires. The value of this work has been called into question by recent research showing that retrospective questionnaires might fail to accurately measure these variables of interest. Novel and diverse approaches to measurement are therefore necessary for academic study to progress. Methods This study analyses data from 11,884 adolescents included in the UK Millennium Cohort Study to examine the association between digital engagement and adolescent sleep, comparing the relative effects of retrospective self-report vs. time-use diary measures of technology use. By doing so, it provides an empirical lens to understand the effects of digital engagement both throughout the day and before bedtime and adds nuance to a research area primarily relying on retrospective self-report. Results The study finds that there is a small negative association relating digital engagement to adolescent sleep both on weekdays and weekend days (median standardized association βweekday = −0.06 and βweekend = −0.03). There is a more negative association between digital engagement and total sleep time on weekdays compared to weekend days (median standardized βweekday = −0.08, median standardized βweekend = −0.02), while there is no such difference when examining adolescents’ bedtime. Surprisingly, and contrary to our expectations, digital technology use before bedtime is not substantively associated with the amount of sleep and the tardiness of bedtime in adolescents. Conclusions Results derived from the use of transparent Specification Curve Analysis methods show that the negative associations in evidence are mainly driven by retrospective technology use measures and measures of total time spent on digital devices during the day. The effects are overall very small: for example, an additional hour of digital screen time per day was only related to a 9 min decrease in total time spent sleeping on weekdays and a 3 min decrease on weekends. Using digital screens 30 min before bed led to a 1 min decrease in total time spent sleeping on weekdays and weekends. The study shows that more work should be done examining how to measure digital screen time before interventions are designed.
Saturated Fatty Acids in Obesity-Associated Inflammation

Abstract Obesity is a major risk factor for the development of various pathological conditions including insulin resistance, diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Central to these conditions is obesity-associated chronic low-grade inflammation in many tissues including adipose, liver, muscle, kidney, pancreas, and brain. There is increasing evidence that saturated fatty acids (SFAs) increase the phosphorylation of MAPKs, enhance the activation of transcription factors such as nuclear factor (NF)-κB, and elevate the expression of inflammatory genes. This paper focuses on the mechanisms by which SFAs induce inflammation. SFAs may induce the expression inflammatory genes via different pathways including toll-like receptor (TLR), protein kinase C (PKC), reactive oxygen species (ROS), NOD-like receptors (NLRs), and endoplasmic reticulum (ER) stress. These findings suggest that SFAs act as an important link between obesity and inflammation.
Effect of Funding Source on “Spin” in Studies of Ocriplasmin Therapy for Vitreomacular Traction and Macular Hole

Purpose To examine the relationship between industry funding and “spin” in randomized controlled trials (RCTs) and meta-analyses investigating use of ocriplasmin for patients with vitreomacular traction (VMT) and macular hole (MH). Methods In this study, we examined all PubMed and Ovid MEDLINE RCTs and meta-analyses published in journals with impact factor ≥2 investigating effectiveness of ocriplasmin use for VMT and MH. The main outcome measure was correspondence between the studies’ main statistical outcome and their abstract conclusion wording. Each article was reviewed by three independent observers and was evaluated for source of funding, industry co-authorship, study methodology, statistical significance of main outcome measure, correspondence between results of main outcome measure and abstract conclusion, and journal impact factor. Funding was determined by public disclosure. Discrepancies were resolved by consensus. Results Twelve studies met inclusion criteria, of which 11 were industry funded and 1 was non-industry funded; 11 (91.67%) showed correspondence between outcome and abstract conclusion, without difference between industry-funded and non-industry funded publications or between publications in journals with high impact factor (≥3) versus low impact factor (≥2 and <3). Conclusion In RCTs and meta-analyses of ocriplasmin for VMT and MH, our results suggest that neither industry funding nor journal impact factor affected the rate of “spin” in study conclusions. This study helps physicians understand what challenges they face when learning about a newer, less-established drug.
Resident physicians’ and Midwives’ Knowledge of Preeclampsia and Eclampsia Reflected in Their Practice at a Clinical Hospital in Southern Romania

Romania has drastically improved an array of health indicators in recent years, including maternal mortality rates, which decreased from 1990 to 2015, but the mortality rates are still high, ranking among the first in Europe. Preeclampsia and eclampsia constitute one of the primary causes of maternal death in the country. The study was conducted from early January to the end of February 2019 to assess the current state of resident physicians’ and midwives’ knowledge of preeclampsia and eclampsia reflected in their practice at a clinical hospital in southern Romania. Self-administered questionnaires were used for data collection. Most of the investigated resident physicians and midwives (87.5%) answered correctly regarding the correct definition of preeclampsia. The first choice of procedure for the patient with preeclampsia (vaginal delivery or C-section) was chosen correctly by only 37.5% of the participants. Regarding the correct identification of the necessary paraclinical tests used for women with suspected preeclampsia, 58.3% of the participants answered correctly. As far as the correct identification of the possible risks of dexamethasone administration to mothers is concerned, only 29.2% of the participants answered correctly. Also, 58.3% of the participants answered correctly regarding the correct identification of contraindicated uterotonic drugs for women with diagnosed hypertension. Resident physicians and midwives are aware of pregnancy complications, but they hold limited knowledge specific to pregnancy complications as preeclampsia and eclampsia. It is imperative to promote studies to evaluate the impact of enhancing their training to include additional content related to the early detection and management of preeclampsia and eclampsia.
Effects of precipitation changes on soil bacterial community composition and diversity in the Junggar desert of Xinjiang, China

Variation in precipitation can markedly affect the structure and function of soil microbial communities, especially in arid areas which are limited by water resources. Therefore, it is critical to understand how soil bacterial community composition and diversity will respond to variation in precipitation. In this study, we examined the soil bacterial community structure and diversity between five precipitation treatments (60% decrease, 30% decrease, control, 30% increase and 60% increase in precipitation) in the same arid site, in the Junggar desert of Xinjiang, northern China. The dominant bacterial phyla, present at similar frequencies in plots with different precipitation levels, were Actinobacteria, Proteobacteria, Bacteroidetes, Acidobacteria and Chloroflexi. The Shannon-Wiener and Chao1 indices of soil bacterial α-diversity were both positively correlated with plant diversity. Our results indicated that (1) extreme drought significantly decreased bacterial abundance and diversity compared with increased precipitation; (2) variation in precipitation did not change the dominant components of the bacterial communities; and (3) soil pH and total nitrogen concentration were the key factors affecting soil bacterial composition in the Junggar desert.
On improving the implementation of automatic updating of systematic reviews

To the Editor, In their recent work, Martin et al. proposed an open source online tool to help update systematic reviews. The authors use a combination of machine learning and crowd-sourcing approaches to propose and assess trials that might need to be included in the update. Bibliographic databases and the ClinicalTrials.gov registry are searched for new trials to complement the updates proposed by registered users. We believe that this work provides a very useful tool for facilitating and automating some parts of the systematic review process, which are usually time-consuming. The proposed interface is clear, user-friendly, and easy to navigate; the authors make their data freely available for registered users, so that it can be re-used in future research. We believe that this work is of high importance, and we would like to ask for some clarifications and to provide some suggestions on how to improve the system.
Bioinformatics drives discovery in Biomedicine

Bioinformatics has evolved from providing basic solutions, such as sequence alignment, structure predictions, and phylogenetic analysis to an independent data-driven field. The unprecedented growth of genomic technologies and the enormous data have opened an avenue for bioinformaticians (Bioinformatics professionals) never been seen before in the history of mankind. The novel opportunity also requires creative solutions that need skills to deal with noisy, unstructured information to offer valuable biological insights. Currently, we are seeing only the tip of an iceberg and the future will revolve around big data sets in all forms of biological research. The emerging challenge is to unfold the hidden iceberg of data.
Systemic Arterial Stiffness in New Diagnosed Idiopathic Pulmonary Arterial Hypertension Patients

Objective: We suggested: 1) patients with idiopathic pulmonary hypertension (IPAH) have active factors which could damage not only the pulmonary but systemic arteries too as in arterial hypertensive patients; 2) if these changes were present, they might correlate with other parameters in ﬂ uencing on the prognosis. This study is the ﬁ rst attempt to use cardio-ankle vascular index (CAVI) for the evaluation of systemic arterial stiffness in patients with IPAH. Methods: A total of 112 patients were included in the study: group 1 consisted of 45 patients with new diagnosed IPAH, group 2 included 32 patients with arterial hypertension, and in the control group were 35 healthy persons adjusted by age. Right heart catheterization, ECG, a 6-minute walk test(6MWT),echocardiography,bloodpressure(BP)measurementandambulatoryBPmonitoring, pulse wave elastic artery stiffness (PWVe; segment carotid-femoral arteries) and muscular artery stiffness (PWVm; segment carotid-radial arteries), CAVI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level were provided. The Spearman correlation, a linear regression and multivariable binary logistic analysis were performed to indicate the predictors associated with PWVand CAVI. Results: The groups were adjusted for principal characteristics in ﬂ uenced on arterial stiffness. stiffening in IPAH patients, but the discovered changes and correlations suggest new directions for further studies, including pathogenesis and prognosis researches.
Effect of Low-Dose Nebivolol in Patients with Acute Myocardial Infarction: A Multi-Center Observational Study

The optimal dose of beta blockers after acute myocardial infarction (MI) remains uncertain. We evaluated the effectiveness of low-dose nebivolol, a beta1 blocker and a vasodilator, in patients with acute MI. A total of 625 patients with acute MI from 14 teaching hospitals in Korea were divided into 2 groups according to the dose of nebivolol (nebistol®, Elyson Pharmaceutical Co., Ltd., Seoul, Korea): low-dose group (1.25 mg daily, n=219) and usual- to high-dose group (≥2.5 mg daily, n=406). The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE, composite of death from any cause, non-fatal MI, stroke, repeat revascularization, rehospitalization for unstable angina or heart failure) at 12 months. After adjustment using inverse probability of treatment weighting, the rates of MACCE were not different between the low-dose and the usual- to high-dose groups (2.8% and 3.1%, respectively; hazard ratio: 0.92, 95% confidence interval: 0.38 to 2.24, p=0.860). The low-dose nebivolol group showed higher rates of MI than the usual- to high-dose group (1.2% and 0%, p=0.008). The 2 groups had similar rates of death from any cause (1.1% and 0.3%, p=0.273), stroke (0.4% and 1.1%, p=0.384), repeat PCI (1.2% and 0.8%, p=0.428), rehospitalization for unstable angina (1.2% and 1.0%, p=0.743) and for heart failure (0.6% and 0.7%, p=0.832). In patients with acute MI, the rates of MACCE for low-dose and usual- to high-dose nebivolol were not significantly different at 12-month follow-up.
Bacterial inoculations can perturb the growth trajectory of diatoms with an existing microbiome

Inoculation of axenic diatom monocultures with individual bacterial strains has been used effectively to examine the relationship between bacteria and a diatom host. Both beneficial and harmful effects on diatom fitness have been observed. Yet, diatoms commonly host a consortium of bacteria that could influence their response to perturbation by bacterial inoculations. In this study, diatom cultures with an existing microbiome were inoculated with individual bacterial strains. Strains of two genera of bacteria commonly found associated with diatoms (Alteromonas and Marinobacter) were isolated from a culture of the diatom Chaetoceros sp. KBDT20. To evaluate whether bacterial inoculations can impact the growth, peak abundance, or decline of diatoms with an intact microbiome, individual bacterial strains were inoculated into batch cultures of the original host as well as two non-origin diatom hosts (Chaetoceros sp. KBDT32 and Amphiprora sp. KBDT35). Inoculations were repeated under vitamin-replete and vitamin-deficient conditions to assess whether vitamin concentration modulates the impact of bacterial inoculations on the host. The origin Chaetoceros culture was largely unperturbed by bacterial inoculations. In contrast, non-origin hosts experienced long-term impacts on their growth trajectory, and those impacts were found to be dependent on the concentration of vitamins in the growth medium. For the non-origin Chaetoceros, all positive impacts were observed in vitamin-replete conditions and all negative impacts were observed in vitamin-deficient conditions. Amphiprora was only impacted by inoculation with Marinobacter strains in vitamin-deficient conditions, and the effect was negative. Neither individual bacterial strains nor genera resulted in exclusively beneficial nor detrimental impacts, and the magnitude of effect varied among bacterial strains. This study demonstrates that bacterial inoculations can have long-lasting impacts on the growth trajectory of diatoms with an existing microbiome, that this impact can differ even between congeneric diatoms, and that the impact can be significantly modulated by vitamin concentration.
Shock Waves as a Treatment Modality for Spasticity Reduction and Recovery Improvement in Post-Stroke Adults – Current Evidence and Qualitative Systematic Review

Purpose This systematic review examines intervention studies using extracorporeal shock wave therapy (ESWT) application in post-stroke muscle spasticity with particular emphasis on the comparison of two different types of radial (rESWT) and focused shock waves (fESWT). Methods PubMed, PEDro, Scopus, and EBSCOhost databases were systematically searched. Studies published between the years 2000 and 2019 in the impact factor journals and available in the English full-text version were eligible for inclusion. All qualified articles were classified in terms of their scientific reliability and methodological quality using the PEDro criteria. The PRISMA guidelines were followed and the registration on the PROSPERO database was done. Results A total of 17 articles were reviewed of a total sample of 303 patients (age: 57.87±10.45 years and duration of stroke: 40.49±25.63 months) who were treated with ESWT. Recent data confirm both a subjective (spasticity, pain, and functioning) and objective (range of motion, postural control, muscular endurance, muscle tone, and muscle elasticity) improvements for post-stroke spasticity. The mean difference showing clinical improvement was: ∆=34.45% of grade for fESWT and ∆=34.97% for rESWT that gives a slightly better effect of rESWT (∆=0.52%) for spasticity (p<0.05), and ∆=38.83% of angular degrees for fESWT and ∆=32.26% for rESWT that determines the more beneficial effect of fESWT (∆=6.57%) for range of motion (p<0.05), and ∆=18.32% for fESWT and ∆=22.27% for rESWT that gives a slightly better effect of rESWT (∆=3.95%) for alpha motor neuron excitability (p<0.05). The mean PEDro score was 4.70±2.5 points for fESWT and 5.71±2.21 points for rESWT, thus an overall quality of evidence grade of moderate (“fair” for fESWT and “good” for rESWT). Three studies in fESWT and four in rESWT obtained Sackett’s grading system’s highest Level 1 of evidence. Conclusion The studies affirm the effectiveness of ESWT in reducing muscle spasticity and improving motor recovery after stroke.
Ultrasound-Guided Injection of High Molecular Weight Hyaluronic Acid versus Corticosteroid in Management of Plantar Fasciitis: A 24-Week Randomized Clinical Trial

Background and Aims Plantar fasciitis (PF) is the leading cause of heel pain in adults. This study was designed to evaluate the effect of hyaluronic acid (HA) injection in reducing the symptoms of PF, compared with corticosteroid (CS) injection as a conventional treatment. Methods In this triple-blind, randomized, clinical trial, 75 patients who had the symptoms of PF for at least 3 months were randomly divided into two groups of 38 and 37 individuals. Then, each patient received either a single injection of high molecular weight (>2000 kDa) HA (1 mL HA 20 mg + 1 mL lidocaine 2%) or CS (1 mL methylprednisolone 40 mg + 1 mL lidocaine 2%) under the ultrasonography (US) guidance. Visual analog scale (VAS), foot ankle ability index (FAAI), pressure pain threshold (PPT), functional foot index (FFI), and plantar fascia thickness (PFT) were measured using US at baseline, 6 weeks and 24 weeks after the injection. Eventually, at the end of the treatment period, the patients’ satisfaction was measured. Intention to treat analysis was used to assess the results. Results After 24 weeks of follow-up, results from 60 subjects were fully obtained; however, results of 73 patients included into intention to treat analysis in the sixth-week follow-up. In both groups, VAS, PFT and FFI decreased, while FAAI and PPT increased significantly (P <0.001). At the baseline and at the 24th-week, no significant difference between the two groups was observed in any of the variables. However, a comparison between the baseline and the sixth-week results shows a prominent decrease in PPT and PFT in the CS group compared to the HA group (P = 0.004 and P = 0.011). Finally, there were no statistical differences between the two groups in treatment satisfaction (P = 0.618). Conclusion Both CS and HA were effective modalities for PF and can improve pain and function with no superiority in 24th-week follow-ups, although CS seems to have a faster trend of improvement in the short term.