Miracle-dz/UniFAR-FTUs huggingface dataset:
High GDF-8 in follicular fluid is associated with a low pregnancy rate in IVF patients with PCOS.

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility. Growth differentiation factor-8 (GDF-8) is expressed in the ovary and can be detected in human follicular fluid which provides an important microenvironment for maintaining physiological functions of the ovarian follicle. To date, the relationship between GDF-8 levels in follicular fluid and the risk of PCOS is completely unknown. In the present study, we show that during the process of the controlled ovarian hyperstimulation (COH), serum GDF-8 levels are higher on the day of gonadotropin administration and 14 days after embryo transfer in in vitro fertilization (IVF) patients with PCOS than they are in IVF patients without PCOS. Importantly, GDF-8 levels in follicular fluid at oocyte retrieval are also higher in PCOS patients than in non-PCOS patients. Treatment of primary human granulosa-lutein (hGL) cells with GDF-8 downregulates steroidogenic acute regulatory protein (StAR) expression and the inhibition is more pronounced in hGL cells from PCOS patients than it is in cells from non-PCOS patients. Importantly, high GDF-8 levels and low progesterone (P4) levels were associated with poor pregnancy outcomes in PCOS patients. Our results provide the first evidence that aberrant expression of GDF-8 in the follicular fluid of PCOS patients results in abnormal P4 expression, which leads to poor pregnancy outcomes.
Should Infants Be Separated from Mothers with COVID-19? First, Do No Harm

The COVID-19 pandemic has affected every facet of life, beginning with the first hours and days after birth. In an effort to ‘‘bend the curve,’’ some have argued that the prudent course is to isolate infants from mothers with suspected or confirmed COVID-19 in order to reduce the risk of transmission from mother to baby. Data are limited, and recommendations for the first days after birth differ. The World Health Organization (WHO) recommends that infants and mothers with suspected or confirmed COVID-19 ‘‘should be enabled to remain together and practice skin-to-skin contact, kangaroo care and to remain together and to practice rooming in throughout the day and night. ’’ Breastfeeding is strongly recommended, given its known lifelong importance for maternal and child health. Mothers are encouraged to wash their hands, wear a mask if they have a cough, and routinely disinfect surfaces that they have touched. The United States Centers for Disease Control and Prevention (CDC) advises that facilities ‘‘consider temporarily separating the mother from her infant’’ until the mother is no longer considered contagious. During separation, the CDC recommends that women express breast milk, to be fed to the newborn by a healthy caregiver. If rooming in is preferred by the mother or unavoidable due to facility limitations, steps to reduce risk are described. The CDC further suggests that ‘‘the risks and benefits of temporary separation should be discussed by the healthcare team,’’ but does not elaborate. New data are emerging daily, and by the time this commentary is published, the landscape may have changed dramatically. But as of late March 2020, what might be the benefits and risks of temporary separation? The benefit of separation is that it minimizes the risk of transmission of SARS-CoV-2 from mother to infant during the hospital stay. However, if the goal is the health and wellbeing of mother and child in the months following birth, there are additional considerations.
Update to U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Updated Recommendations for the Use of Contraception Among Women at High Risk for HIV Infection

"U.S. Medical Eligibility Criteria for Contraceptive Use" (U.S. MEC) 2016 provides evidence-based guidance for the safe use of contraceptive methods among U.S. women with certain characteristics or medical conditions (1). The U.S. MEC is adapted from global guidance from the World Health Organization (WHO) and kept up to date through continual review of published literature (1). CDC recently evaluated the evidence and the updated WHO guidance on the risk for human immunodeficiency virus (HIV) acquisition among women using hormonal contraception and intrauterine devices (IUDs) (2). After careful review, CDC adopted WHO's 2019 updated guidance for inclusion in the U.S. MEC guidance; CDC's updated guidance states that progestin-only injectable contraception (including depot medroxyprogesterone acetate [DMPA]) and IUDs (including levonorgestrel-releasing and copper-bearing) are safe for use without restriction among women at high risk for HIV infection (U.S. MEC category 1 [previously U.S. MEC category 2, advantages outweigh risks]) (Box). CDC's guidance also adds an accompanying clarification for women who wish to use IUDs, which states "Many women at a high risk for HIV infection are also at risk for other sexually transmitted diseases (STDs). For these women, refer to the recommendations in the 'U.S. Medical Eligibility Criteria for Contraceptive Use' for women with other factors related to STDs, and the 'U.S. Selected Practice Recommendations for Contraceptive Use' on STD screening before IUD insertion" (1,3). Recommendations for other hormonal contraceptive methods (including combined hormonal methods, implants, and progestin-only pills) remain the same; there is also no restriction for their use among women at high risk for HIV infection (U.S. MEC category 1). Finally, CDC clarified that the U.S. MEC recommendations for concurrent use of hormonal contraceptives or IUDs and antiretroviral use for treatment of HIV infection also apply to use of antiretrovirals for prevention of HIV acquisition (preexposure prophylaxis [PrEP]).
Requirements engineering issues causing software development outsourcing failure

Software development outsourcing is becoming more and more famous because of the advantages like cost abatement, process enhancement, and coping with the scarcity of needed resources. Studies confirm that unfortunately a large proportion of the software development outsourcing projects fails to realize anticipated benefits. Investigations into the failures of such projects divulge that in several cases software development outsourcing projects are failed because of the issues that are associated with requirements engineering process. The objective of this study is the identification and the ranking of the commonly occurring issues of the requirements engineering process in the case of software development outsourcing. For this purpose, contemporary literature has been assessed rigorously, issues faced by practitioners have been identified and three questionnaire surveys have been organized by involving experienced software development outsourcing practitioners. The Delphi technique, cut-off value method and 50% rule have also been employed. The study explores 150 issues (129 issues from literature and 21 from industry) of requirements engineering process for software development outsourcing, groups the 150 issues into 7 identified categories and then extricates 43 customarily or commonly arising issues from the 150 issues. Founded on ‘frequency of occurrence’ the 43 customarily arising issues have been ranked with respect to respective categories (category-wise ranking) and with respect to all the categories (overall ranking). Categories of the customarily arising issues have also been ranked. The issues’ identification and ranking contribute to design proactive software project management plan for dealing with software development outsourcing failures and attaining conjectured benefits of the software development outsourcing.
Dietary Puerarin Supplementation Alleviates Oxidative Stress in the Small Intestines of Diquat-Challenged Piglets

Simple Summary The oxidant stress which piglets suffer from during the weaning period has caused huge losses to the pig farm industry. It is important for scientists to find an effective way to alleviate the oxidant stress in weaned piglets. This study was designed to test the hypothesis that dietary puerarin supplementation alleviates oxidative stress in the small intestine of diquat-challenged piglets. Interestingly, dietary puerarin supplementation improved intestinal morphology, cell proliferation, barrier function, and increased Nrf2 and its downstream enzymes in diquat-challenged piglets, which shows that puerarin has potent protective effects against diquat-induced oxidative stress. These findings will be very beneficial to the pig industry, especially to the development of antibiotic-free diets, new anti-inflammatory drugs and the application of puerarin in piglets. Abstract This study was conducted to demonstrate that dietary puerarin supplementation alleviates oxidative stress in the small intestine of diquat-challenged piglets. The results showed that puerarin administration markedly alleviated diquat-induced intestinal injury, which was indicated by the improvement of intestinal morphology, cell proliferation and barrier function. One of the potential mechanisms responsible for this was the decrease in oxidative stress, as evidenced by the increase in activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in the small intestine. Puerarin increased the protein expression levels of NF-E2-related factor 2 (Nrf2) and its downstream enzymes, including heme oxygenase 1 (HO-1), glutamate–cysteine ligase catalytic and its modifier subunit (GCLc and GCLm) in the jejunal mucosa of diquat-induced piglets. Puerarin administration improved intestinal morphology, cell proliferation, and barrier function, and increased Nrf2 and its downstream enzymes. These findings indicate that the dietary supplementation of puerarin attenuates the oxidative stress involving Nrf2 signaling pathways in diquat-challenged piglets.
NFE2L2/KEAP1 mutations correlate with higher TMB value/PD-L1 expression and potentiate improved clinical outcome with immunotherapy.

BACKGROUND Abnormalities in the KEPA1-NRF2 pathway have a role in cancer progression, metastasis, and resistance to chemo-/radio-therapies. Persistent activation of NRF2 associates with poor prognosis across different cancer types. However, the beneficial therapeutic strategy to harness this pathway in cancer remains unclear. This study aimed to investigate the clinical outcome with immunotherapy in NFE2L2/KEAP1 mutant population. MATERIALS AND METHODS We investigated the correlation between NFE2L2/KEAP1 mutations and tumor mutational burden (TMB)/ programmed death-ligand 1 (PD-L1) expression status to identify the therapeutic vulnerability. For this purpose, relevance analysis with TMB value was performed in 9040 cancer patients, and relevance analysis with PD-L1 expression was performed in 3457 patients. The MSKCC database and real-world evidence were used to assess the immunotherapy response in NFE2L2/KEAP1 mutant subsets. RESULTS NFE2L2/KEAP1 mutations occurred in various cancers, and the highest mutation incidences occurred in lung squamous cell carcinoma (LUSC) as of 19.16% (NFE2L2) and 10.31% (KEAP1). We confirmed that higher TMB value and PD-L1 expression were associated with NFE2L2/KEAP1 mutations compared with wild-type, especially in non-small lung cancer (NSCLC). MSKCC database analysis showed the improved survival of NFE2L2/KEAP1 mutant patients with immunotherapy compared with other treatments (mOS 22.52 VS 12.89, P=0.0034). Real-world evidence further confirmed the efficacy of immunotherapy in the mutant population. CONCLUSION Our study revealed NFE2L2/KEAP1 mutant patients could achieve improved outcomes from immunotherapy than the other treatments. These findings may broaden the application of immune checkpoint blockade to patients harboring NFE2L2/KEAP1 mutations. IMPLICATIONS FOR PRACTICE NFE2L2/KEAP1 alterations occur frequently in multiple cancer types and associate with poor prognosis. However, the efficacious strategy to inhibit this pathway in cancer is poorly understood. In this study, we analyzed the mutational characteristics of NFE2L2/KEAP1 alterations in 9243 Chinese patients. The highest mutation incidences occurred in lung squamous cell carcinoma as of 19.16% (NFE2L2) and 10.31% (KEAP1). Relevance analysis showed the NFE2L2/KEAP1 mutant subsets were associated with higher TMB value and PD-L1 expression. Clinical data further confirmed NFE2L2/KEAP1 mutations correlate with improved outcome with immunotherapy. These findings suggest the clinical application of immunotherapy in NFE2L2/KEAP1 mutant population.
The Association between the Preference for Active Play and Neurological Development in Toddlers: A Register-Based Study

Active play is regarded as physical activity during early childhood. Physical activity has many benefits for children’s physical and psychosocial health and wellbeing, as well as for their cognitive development. The aim of this study was to investigate associations between the preference for active play and neurological development in toddlers. The study was conducted as a register-based study, and the data were collected from a public-health clinic’s electronic health records. The register data about active play used in this study were originally assessed by parents at home and by early years teachers at nurseries. Neurological development was assessed by the public health nurses in public child-health clinics. The data eligible for this study were available from 717 toddlers aged 2.5–3.0 years old (mean: 2.5 years ± 2 months). The majority of toddlers (85%) showed a preference for active play, both at home and at the nursery. The prevalence of delays in the neurological development of toddlers varied in different developmental areas (by 1–15%). Delays in gross motor competence, auditory perception, and self-help skills were associated with a lower preference for active play in nursery settings, but none of the neurodevelopmental items were found to be associated with toddlers’ preference for active play at home. Nurseries need to encourage children to actively play and support their gross motor competence and self-help skills.
Adipose Stem Cell–Derived Exosomes Decrease Fatty Infiltration and Enhance Rotator Cuff Healing in a Rabbit Model of Chronic Tears

Background: Fatty infiltration and poor tendon-bone healing in chronic rotator cuff tears (RCTs) are associated with unsatisfactory prognosis. Adipose stem cell–derived exosomes (ASC-Exos), having multiple biological effects, can prevent muscle degeneration in acute RCTs. However, the effects of ASC-Exos on fatty infiltration and tendon-bone healing in chronic RCTs remain unknown. Purpose: To study the effects of ASC-Exos on fatty infiltration and tendon-bone healing in a chronic RCT rabbit model. Study Design: Controlled laboratory study. Methods: At week 0, we randomly allocated 35 rabbits to receive sham surgery (14 rabbits) or establish a bilateral RCT model (21 rabbits, detachment of the supraspinatus tendon). At week 6, a total of 7 rabbits received sham surgery, and 7 rabbits with RCT were sacrificed for fatty infiltration assay. The remaining 14 rabbits with bilateral RCTs were randomly assigned to a saline group (7 rabbits that received local saline injection and rotator cuff repair) or an ASC-Exos group (7 rabbits that received local ASC-Exos injection and rotator cuff repair). At week 18, all rabbits were sacrificed for histological examination and biomechanical testing. Results: At week 18, the ASC-Exos group showed significantly lower fatty infiltration (14.01% ± 2.85%) compared with the saline group (21.79% ± 3.07%) (P < .001), and no statistical difference compared with the time of repair (10.88% ± 2.64%) (P = .127). For tendon-bone healing, the ASC-Exos group showed a higher histological score and more newly regenerated fibrocartilage at the repair site than did the saline group. Regarding biomechanical testing, the ASC-Exos group showed significantly higher ultimate load to failure, stiffness, and stress than the saline group. Conclusion: Local injection of ASC-Exos in chronic RCTs at the time of repair could prevent the progress of fatty infiltration, promote tendon-bone healing, and improve biomechanical properties. Clinical Relevance: ASC-Exos injection may be used as a cell-free adjunctive therapy to inhibit fatty infiltration and improve rotator cuff healing in the repair of chronic RCTs.
The effect of facemask in patients with unilateral cleft lip and palate: a systematic review and meta-analysis.

BACKGROUND Patients with cleft lip and palate usually present a Class III skeletal pattern. Facemask (FM) is one of the conventional orthodontic treatment modalities used to address the skeletal discrepancy in cleft patients. OBJECTIVE To investigate the potential effectiveness of FM in unilateral cleft lip and palate (UCLP) patients. SEARCH METHODS Search without restrictions except language in seven databases since inception and hand searching until January 2019 was conducted. Detailed search strategies were developed for each database which were based on the PubMed strategy and adapted accordingly. SELECTION CRITERIA Controlled studies assessing the effect of FM in UCLP patients were to be included. DATA COLLECTION AND ANALYSIS After retrieval and selection of the studies, data extraction was performed. Both angular and linear cephalometric measurements were collected. Weighted mean differences (WMDs) and 95% confidence intervals (CΙs) between treated and untreated UCLP patients concerning the pre- and post-treatment angular measurements of each group were calculated using a random-effects meta-analysis model. The risk of bias in individual studies was assessed using the ROBINS-I tool. RESULTS From nine eligible studies, five were included in the meta-analysis investigating the use of FM in patients and controls with UCLP (with and without maxillary expansion). Statistically significant differences were evident for SNA/S-N-ss, SNB/S-N-sm, ANB/ss-N-sm, and SN-MP. FM was found to induce an increase of SNA (WMD = 2.12 degrees, 95% CI: 1.58 to 2.66), ANB (WMD = 4.17 degrees, 95% CI: 3.60 to 4.74), and SN-MP angles (WMD = 2.60 degrees, 95% CI: 1.10 to 4.10) and a decrease of SNB angle (WMD = -1.94 degrees, 95% CI: -2.48 to -1.40) in UCLP patients. Low to moderate heterogeneity was observed. LIMITATIONS They emerge due to risk of bias, exclusion of non-English papers and methodological characteristics of the included papers. CONCLUSIONS According to the available data, FM seems to improve the sagittal skeletal relationships in UCLP patients, increasing the SNA and ANB angles and decreasing the SNB angle. Moreover, in the vertical dimension, FM increases the SN-MP angle. Regarding dental measurements, there are controversial results. More high-quality studies need to be conducted in order to further clarify the impact of FM on UCLP patients. REGISTRATION NUMBER PROSPERO: CRD42019131619.
Computational prioritization of cancer driver genes for precision oncology

Advances in high-throughput sequencing technologies has drastically increased the efficiency to access different alterations in the genome, transcriptome, proteome, and epigenome of a cancer cell. This has increased the computational burden to analyze these “big data” making the translation of the knowledge into insightful and impactful patient outcomes extraordinarily challenging. Among these alterations, only a few “driver” alterations are expected to confer crucial growth advantage. These are greatly outnumbered by functionally inconsequential “passenger” alterations. This poses a significant challenge for the identification of driver alterations, requiring solutions to novel algorithmic problems. Although, the insight on driver alterations is critical to guide selection of appropriate drug therapies for the patient, no specific tools exist to help clinicians contextualize the enormous genomic information when making therapeutic decisions. In this thesis we describe novel algorithms for the identification and prioritization of cancer driver genes. First we describe, HIT’nDRIVE, a combinatorial algorithm measuring the impact of genomic aberration to global changes of gene expression pattern to prioritize cancer driver genes. We also demonstrate its application on large multi-omics cancer datasets to guide precision oncology. We further describe integrative multi-omics characterization of peritoneal mesothelioma, a rare cancer of abdomen. Here using HIT’nDRIVE, we identified peritoneal mesothelioma with BAP1 loss to form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Finally, we describe, cd-CAP, a combinatorial algorithm to identify subnetworks with conserved molecular alteration pattern across a large subset of a tumor sample cohort. Notably, we demonstrate that many of the largest highly conserved subnetworks within a tumor type solely consist of genes that have been subject to copy number gain, typically located on the same chromosomal arm and thus likely a result of a single, large scale copy number amplification.
Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism

Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.