Miracle-dz/UniFAR-FTUs huggingface dataset:
Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker

Background: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia. Methods: We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis. Results: We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of preeclamptic placentas. Levels of DLX5 correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation. Conclusions: Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of DLX5 might help explain certain aspects of preeclampsia.
National Women’s Knowledge of Stroke Warning Signs, Overall and by Race/Ethnic Group

Background and Purpose— Recognition of stroke warning signs may reduce treatment delays. The purpose of this study was to evaluate contemporary knowledge of stroke warning signs and knowledge to call 9-1-1, among a nationally representative sample of women, overall and by race/ethnic group. Methods— A study of cardiovascular disease awareness was conducted by the American Heart Association in 2012 among English-speaking US women ≥25 years identified through random-digit dialing (n=1205; 54% white, 17% black, 17% Hispanic, and 12% other). Knowledge of stroke warning signs, and what to do first if experiencing stroke warning signs, was assessed by standardized open-ended questions. Results— Half of women surveyed (51%) identified sudden weakness/numbness of face/limb on one side as a stroke warning sign; this did not vary by race/ethnic group. Loss of/trouble talking/understanding speech was identified by 44% of women, more frequently among white versus Hispanic women (48% versus 36%; P<0.05). Fewer than 1 in 4 women identified sudden severe headache (23%), unexplained dizziness (20%), or sudden dimness/loss of vision (18%) as warning signs, and 1 in 5 (20%) did not know 1 stroke warning sign. The majority of women said that they would call 9-1-1 first if they thought they were experiencing signs of a stroke (84%), and this did not vary among black (86%), Hispanic (79%), or white/other (85%) women. Conclusions— Knowledge of stroke warning signs was low among a nationally representative sample of women, especially among Hispanics. In contrast, knowledge to call 9-1-1 when experiencing signs of stroke was high.
Efficacy, chondrotoxicity and plasma concentrations of tramadol following intra-articular administration in horses undergoing arthroscopy: preliminary findings

Abstract Intra-articular administration of analgesics is performed to ensure good perioperative pain management avoiding undesirable systemic effects. To evaluate the effect of intra-articular injection of tramadol on postoperative pain after arthroscopy in horses and to determine whether tramadol had a local effect. Before the in vivo study, an in vitro test was performed aiming to evaluate the viability of equine chondrocytes after exposure to various concentrations of tramadol. The concentration identified as most appropriate was used to treat the horses’ joints. Twelve horses affected by osteochondrosis were randomly assigned to two groups that were treated intra-articularly at the end of surgery with tramadol (4 mg/mL) and saline, respectively. At predetermined time-points a Composite Pain Scale was applied and blood samples were collected in order to define the extent of tramadol absorption into the systemic circulation. The Mann-Whitney test was used for statistical analysis. Serum of four out of six treated horses revealed traces of tramadol (range 10.6–19.3 ng/mL) sporadically between 0.5 and 4 hours post-treatment, while in the other two horses, no trace of drug was found. Findings suggested that any eventual effect was probably due to local action rather than systemic absorption. The pain scores obtained in tramadol-treated horses were lower between 1 and 6 hours post-administration, than those obtained in the control group, but the differences were not statistically significant. These preliminary results suggest that tramadol, at this concentration, is only mildly beneficial in the pain management of horses after arthroscopy.
Total anatomical reconstruction during robot‐assisted radical prostatectomy: focus on urinary continence recovery and related complications after 1000 procedures

To present the functional and oncological outcomes after ≥1 year of follow‐up, following an experience of >1000 robot‐assisted radical prostatectomies (RARPs) with our standardised total anatomical reconstruction (TAR) technique. To evaluate which factors influence postoperative continence recovery in order to obtain a nomogram to predict the risk of postoperative urinary incontinence (UI).
Five Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with no Detectable Immunity.

Anti-transgene immune responses elicited after intramuscular (i.m.) delivery of recombinant adeno-associated virus (rAAV) have been shown to hamper long-term transgene expression in large-animal models of rAAV-mediated gene transfer. To overcome this hurdle, an alternative mode of delivery of rAAV vectors in nonhuman primate muscles has been described: the locoregional (LR) intravenous route of administration. Using this injection mode, persistent inducible transgene expression for at least 1 year under the control of the tetracycline-inducible Tet-On system was previously reported in cynomolgus monkeys, with no immunity against the rtTA transgene product. The present study shows the long-term follow-up of these animals. It is reported that LR delivery of a rAAV2/1 vector allows long-term inducible expression up to at least 5 years post gene transfer, with no any detectable host immune response against the transactivator rtTA, despite its immunogenicity following i.m. gene transfer. This study shows for the first time a long-term regulation of muscle gene expression using a Tet-On-inducible system in a large-animal model. Moreover, these findings further confirm that the rAAV LR delivery route is efficient and immunologically safe, allowing long-term skeletal muscle gene transfer.
Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors.

BACKGROUND Recent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations. However, timely and efficient identification of neoantigens is still one of the major obstacles to using personalized neoantigen-based cancer immunotherapy. METHODS Two different pipelines of neoantigens identification were established in this study: (1) Clinical grade targeted sequencing was performed in patients with refractory solid tumor, and mutant peptides with high variant allele frequency and predicted high HLA-binding affinity were de novo synthesized. (2) An inventory-shared neoantigen peptide library of common solid tumors was constructed, and patients' hotspot mutations were matched to the neoantigen peptide library. The candidate neoepitopes were identified by recalling memory T-cell responses in vitro. Subsequently, neoantigen-loaded dendritic cell vaccines and neoantigen-reactive T cells were generated for personalized immunotherapy in six patients. RESULTS Immunogenic neo-epitopes were recognized by autologous T cells in 3 of 4 patients who utilized the de novo synthesis mode and in 6 of 13 patients who performed shared neoantigen peptide library, respectively. A metastatic thymoma patient achieved a complete and durable response beyond 29 months after treatment. Immune-related partial response was observed in another patient with metastatic pancreatic cancer. The remaining four patients achieved the prolonged stabilization of disease with a median PFS of 8.6 months. CONCLUSIONS The current study provided feasible pipelines for neoantigen identification. Implementing these strategies to individually tailor neoantigens could facilitate the neoantigen-based translational immunotherapy research.TRIAL REGSITRATION. ChiCTR.org ChiCTR-OIC-16010092, ChiCTR-OIC-17011275, ChiCTR-OIC-17011913; ClinicalTrials.gov NCT03171220. FUNDING This work was funded by grants from the National Key Research and Development Program of China (Grant No. 2017YFC1308900), the National Major Projects for "Major New Drugs Innovation and Development" (Grant No.2018ZX09301048-003), the National Natural Science Foundation of China (Grant No. 81672367, 81572329, 81572601), and the Key Research and Development Program of Jiangsu Province (No. BE2017607).
Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens.

Telomeres and ribosomal RNA genes (rDNA) are essential for cell survival and particularly sensitive to factors affecting genome stability. Here, we examine the role of RAD51 and its antagonist, RTEL1, in the moss Physcomitrella patens. In corresponding mutants, we analyse their sensitivity to DNA damage, the maintenance of telomeres and rDNA, and repair of double-stranded breaks (DSBs) induced by genotoxins with various modes of action. While the loss of RTEL1 results in rapid telomere shortening, concurrent loss of both RAD51 genes has no effect on telomere lengths. We further demonstrate here the linked arrangement of 5S and 45S rRNA genes in P. patens. The spacer between 5S and 18S rRNA genes, especially the region downstream from the transcription start site, shows conspicuous clustering of sites with a high propensity to form quadruplex (G4) structures. Copy numbers of 5S and 18S rDNA are reduced moderately in the pprtel1 mutant, and significantly in the double pprad51-1-2 mutant, with no progression during subsequent cultivation. While reductions in 45S rDNA copy numbers observed in pprtel1 and pprad51-1-2 plants apply also to 5S rDNA, changes in transcript levels are different for 45S and 5S rRNA, indicating their independent transcription by RNA polymerase I and III, respectively. The loss of SOL (Sog One-Like), a transcription factor regulating numerous genes involved in DSB repair, increases the rate of DSB repair in dividing as well as differentiated tissue, and through deactivation of G2/M cell-cycle checkpoint allows the cell-cycle progression manifested as a phenotype resistant to bleomycin.
Voluntary increase of acoustic middle ear impedances with simultaneous sound attenuation associated with mild hyperacusis (VIMH)

Abstract Background: Acoustic impedances, as measured with tympanometers, change with the pressure in the middle ears, or reflexively as a response to a range of stimuli. A few persons are able to influence their acoustic impedances voluntarily. Aims/objectives: To describe this phenomenon and its clinical consequences. Material and methods: Presentation of five case reports with measurements of the acoustic impedances, hearing thresholds, and otoacoustic emissions (TEOAE) in the relaxed state and while the change in acoustic impedance was invoked. Results: All five subjects were able to voluntarily increase the acoustic impedance of their ears for short periods of time. While the change was active, TEOAE levels decreased by 0.8–9.7 dB and a mild transient conductive hearing loss in the low frequencies occurred. Four out of the five subjects reported a mild hyperacusis when the voluntary change was not invoked and showed unusual features in their acoustically evoked reflex. Conclusions and significance: Subjects who can control their acoustic impedances voluntarily seem to have an increased prevalence of mild hyperacusis. Our results suggest interference of the voluntary control with the acoustic stapes reflex as a mechanism and we propose to name this phenomenon ‘Voluntary Impedance increase with Mild Hyperacusis’, or VIMH.
Five-year Efficacy and Safety of Tocilizumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Methotrexate- and Biologic-naive or Free of Methotrexate for 6 Months: the AMBITION Study

Objective. To report on the 5-year efficacy and safety results of the AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) monotherapy study (ClinicalTrials.gov: NCT00109408, NCT00720798). Methods. Patients with rheumatoid arthritis for whom biologics had not failed or who did not discontinue methotrexate because of lack of efficacy or tolerability were followed up for 5 years to assess the efficacy and serious adverse events (SAE) of tocilizumab (TCZ) monotherapy. Results. Longterm efficacy results showed that efficacy was maintained or improved for up to 264 weeks in patients receiving TCZ monotherapy. Serious infection was the most frequent SAE; no new safety signals were reported. Conclusion. Longterm monotherapy with TCZ demonstrated continuing efficacy and safety.
Predictors of Assertive and Nonassertive Styles of Self-Defense Behavior During a Lab-Based Sexual Assault Scenario

The current study examined how psychological factors influence hypothetical behavioral responses to threat (BRTT). College women (n = 113) with a history of sexual victimization completed a standardized lab-based self-defense scenario. Interpersonal skills, coping style, and assertive and nonassertive BRTT during a prior assault predicted assertive BRTT during the task. The use of nonassertive BRTT during past assaults no longer predicted assertive BRTT during the task when accounting for rape acknowledgment. Findings regarding rape acknowledgment demonstrate the complexity of recovery from sexual assault. Our results highlight interpersonal skills as an intervention target for innovative sexual assault risk reduction interventions.
Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method

Previous research showed that scaling drug clearance from adults to children based on body weight alone is not accurate for all hepatically cleared drugs in very young children. This study systematically assesses the accuracy of scaling methods that, in addition to body weight, also take age-based variables into account for drugs undergoing hepatic metabolism in children younger than five years, namely scaling with (1) a body weight-based function using an age-dependent exponent (ADE) and (2) a body weight-based function with fixed exponent of 0.75 (AS0.75) combined with isoenzyme maturation functions (MFPBPK) similar to those implemented in physiologically based pharmacokinetic (PBPK) models (AS0.75 + MFPBPK). A PBPK-based simulation workflow was used, including hypothetical drugs with a wide range of properties and metabolized by different isoenzymes. Adult clearance values were scaled to seven typical children between one day and four years. Prediction errors of ± 50% were considered reasonably accurate. Isoenzyme maturation was found to be an important driver of changes in hepatic metabolic clearance in children younger than five years, which prevents the systematic accuracy of ADE scaling. AS0.75 + MFPBPK, when accounting for maturation of isoenzymes and microsomal protein per gram of liver (MPPGL), can reasonably accurately scale hepatic metabolic clearance for all low and intermediate extraction ratio drugs except for drugs binding to alpha-1-acid glycoprotein in neonates. As differences in the impact of changes in system-specific parameters on drugs with different properties yield differences in clearance ontogeny, it is unlikely that for the remaining drugs, scaling methods that do not take drug properties into account will be systematically accurate.
Epigenetic alterations associated with childhood trauma and adult mental health outcomes: A systematic review

Abstract Objectives: Multiple, chronic and repeated trauma exposure in childhood is associated with adverse mental health outcomes in adulthood. In this paper we synthesise the literature on epigenetic modifications in childhood trauma (CT) and the mediating effects of differential epigenetic mechanisms on the association between CT and the later onset of psychiatric disorders. Methods: We reviewed the literature up to March 2018 in four databases: PubMed, Web of Science, EBSCOhost and SCOPUS. Non-human studies were excluded. All studies investigating CT exposure both in healthy adults (18 years and older) and adults with psychiatric disorders were included. Results: Thirty-six publications were included. For mood disorders, methylation of the glucocorticoid receptor NR3C1 gene, specifically at the NGFI-A binding site in exon 1F, and correlation with CT was a robust finding. Several studies documented differential methylation of SLC6A4, BDNF, OXTR and FKBP5 in association with CT. Common pathways identified include neuronal functioning and maintenance, immune and inflammatory processes, chromatin and histone modification, and transcription factor binding. Conclusions: A variety of epigenetic mediators that lie on a common pathway between CT and psychiatric disorders have been identified, although longitudinal studies and consistency in methodological approach are needed to disentangle cause and effect associations.
Validation of an algorithm for identifying MS cases in administrative health claims datasets

Objective To develop a valid algorithm for identifying multiple sclerosis (MS) cases in administrative health claims (AHC) datasets. Methods We used 4 AHC datasets from the Veterans Administration (VA), Kaiser Permanente Southern California (KPSC), Manitoba (Canada), and Saskatchewan (Canada). In the VA, KPSC, and Manitoba, we tested the performance of candidate algorithms based on inpatient, outpatient, and disease-modifying therapy (DMT) claims compared to medical records review using sensitivity, specificity, positive and negative predictive values, and interrater reliability (Youden J statistic) both overall and stratified by sex and age. In Saskatchewan, we tested the algorithms in a cohort randomly selected from the general population. Results The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT claims within a 1-year time period; a 2-year time period provided little gain in performance. Algorithms including DMT claims performed better than those that did not. Sensitivity (86.6%–96.0%), specificity (66.7%–99.0%), positive predictive value (95.4%–99.0%), and interrater reliability (Youden J = 0.60–0.92) were generally stable across datasets and across strata. Some variation in performance in the stratified analyses was observed but largely reflected changes in the composition of the strata. In Saskatchewan, the preferred algorithm had a sensitivity of 96%, specificity of 99%, positive predictive value of 99%, and negative predictive value of 96%. Conclusions The performance of each algorithm was remarkably consistent across datasets. The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT use within 1 year. We recommend this algorithm as the standard AHC case definition for MS.
Effectiveness of a short message service intervention to motivate people with positive results in preliminary colorectal cancer screening to undergo colonoscopy: A randomized controlled trial

Colonoscopy adherence among populations at high risk for colorectal cancer (CRC) is crucial for the early diagnosis and treatment of CRC, but the adherence rate has been found to be poor. A short message service (SMS) is effective in promoting cancer screening, but its effectiveness in promoting colonoscopy among populations at high risk for CRC has not been well studied.
The Malocclusion Impact Questionnaire (MIQ): Cross-Sectional Validation in a Group of Young People Seeking Orthodontic Treatment in New Zealand

The aim of the study was to test the validity of the Malocclusion Impact Questionnaire (MIQ) in a NZ sample and to evaluate possible cross-cultural differences in MIQ data between a NZ and a UK sample. A cross-sectional, non-random sample of young people, aged 10–16 years, attending their first appointment at the orthodontic clinic of New Zealand’s National Centre for Dentistry were asked to complete a questionnaire. This consisted of the 17 item MIQ, the short form CPQ11-14-ISF16 and two global questions. Some basic demographic and clinical data were collected. Sixty-six participants completed the questionnaire; however, the data for 2 were excluded due to the number of incomplete responses. MIQ was found to have excellent internal consistency (Cronbach’s alpha 0.924), good construct validity (Spearman’s rho, 0.661 global Q1 ‘Overall, how much do your teeth bother you? ’; 0.583 global Q2 ‘Overall, how much do your teeth affect your life? ’). MIQ also demonstrated good criterion validity with CPQ11-14-ISF16 (Pearson rho, 0.625). The Rasch analysis confirmed that the questionnaire performed similarly and there was no differential item functioning between the two populations. The main differences between the samples were that the young people in NZ were less concerned about their malocclusion and reported lower item-impact scores compared with the young people in the UK.