Miracle-dz/UniFAR-FTUs huggingface dataset:
Raltegravir (RAL) in neonates: Dosing, pharmacokinetics (PK), and safety in HIV-1 exposed neonates at risk of infection (IMPAACT P1110).

BACKGROUND Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor (INSTI) available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection. METHODS IMPAACT P1110 is a phase 1, multicenter non-comparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A two-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received two single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2. RESULTS A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N=16); and cohort 2 (N=36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through Day 7; 3 mg/kg twice daily from Days 8 to 28 of life; 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks. CONCLUSIONS Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. A modified regimen will be studied in premature infants in a new version of P1110.
Academic outcome in pediatric ischemic stroke

ABSTRACT An important cause of acquired brain injury in children, pediatric ischemic stroke can cause sequelae across a wide range of cognitive domains, including verbal reasoning and processing speed. As a result, survivors are especially vulnerable to academic difficulties and face unique challenges compared to their peers. Despite this knowledge, pediatric stroke remains an understudied neurological condition, and its impact on school functioning poorly understood. The present clinical study addressed academic outcome in this population using a multifaceted approach. Patients were recruited for participation from the Children’s Stroke Program at the Hospital for Sick Children in Toronto, Canada. A battery of standardized neuropsychological tests was administered, and additional data was collected through parent-rated measures and review of recent academic report cards. Compared to peers, youth with stroke exhibited deficits in processing speed, verbal reasoning, and core academic skills spanning reading, reading comprehension, writing, and math. Lesion laterality did not affect cognitive and academic scores. Youth with a combined cortical-subcortical lesion scored lower on a test of nonverbal reasoning compared to youth with either cortical or subcortical lesions. Compared to healthy peers, the pediatric stroke group was more likely to report requiring extra help at school, accommodations, individual education plans, and assistive technology. They were also more likely to be diagnosed with a learning disability, but not Attention Deficit/Hyperactivity Disorder. Nonverbal reasoning skills, school grades, and school-related quality of life were comparable between groups. The present study contributed to a more nuanced understanding of the impact of pediatric stroke on academic outcome.
A retrospective evaluation of reliability and reproducibility of Arbeitsgemeinschaftfür Osteosynthesefragen classification and Fernandez classification for distal radius fracture

Abstract This is a retrospective evaluated. The objective of this study was to test the interobserver reliability and intraobserver reproducibility of fracture classification with Arbeitsgemeinschaftfür Osteosynthesefragen (AO) system and Fernandez system used by 5 senior orthopedic surgeons. Anteroposterior and lateral radiographs of 160 patients hospitalized for displaced distal radius fracture were examined. Independently, 5 orthopedic surgeons evaluated the radiographs according to 2 different distal radius classification systems (3 types of results). Three statistical tools were used to measure interobserver reliability and intraobserver reproducibility. The intraclass correlation coefficient and kappa coefficient (k) were used to assess both interobserver and intraobserver agreement of AO and Fernandez. Kappa value indicated poor agreement (<0), slight (0–0.20), fair (0.21–0.40), moderate (0.41–0.60), good (0.61–0.80), and perfect (0.81–1.00). The intraobserver reproducibility of AO system (9 types) and Fernandez system were moderate with a value of 0.577 and 0.438. The intraobserver reproducibility of AO system (27 subtypes) was 0.286. The interobserver reliability of AO system (9 types) was moderate with a value of 0.469 and that of Fernandez was moderate with a value of 0.435. The interobserver reliability of AO system (27 subtypes) was 0.299. Neither of the 2 systems can give us a satisfactory agreement between interobserver reliability and intraobserver reproducibility. In AO system, the interobserver reliability and intraobserver reproducibility of the 9 types decreased with the increase of subgroups.
The prevalence of gout and hyperuricemia in middle-aged and elderly people in Tibet Autonomous Region, China

Abstract Objective: Gout and hyperuricemia are common public health problem. There has been no epidemiological survey of gout and hyperuricemia in Tibet Autonomous Region, the southwest of China. Therefore, we estimated the prevalence of gout and hyperuricemia in Luoma Town, Naqu City, Tibet Autonomous Region of China. Methods: A population-based cross-sectional survey was conducted among 1458 residents of Luoma Town, Tibet Autonomous Region, age ≥40 years. We used questionnaires in face-to-face interviews, anthropometric measurements and serum uric acid test. Hyperuricemia was defined as serum uric acid level ≥7 mg/dl in men and ≥6 mg/dl in women. The definition of gout in this study was on the basis of new 2015ACR/EULAR classification criteria. Results: Nine hundred eighty-nine participants completed all items of gout and 818 participants attended to be taken blood samples for serum UA levels test. The overall crude prevalence of gout and hyperuricemia was 0.30% and 1.83% respectively. It was more prevalent in men than in women (2.86% vs 0.75%, P = .034) in hyperuricemia group. Tibetan had a lower age-standardized prevalence of gout 0.26% (95% confidence interval (CI): 0%–0.60%) and hyperuricemia 2.05% (95% confidence interval (CI): 0.99%–3.44%) compared with the China Health and Retirement Longitudinal Study results. Conclusion: This is the first large-scale population-based survey to demonstrate the prevalence of gout and hyperuricemia of the middle-aged and elderly population in Tibet Autonomous Region, China. The prevalence of gout and hyperuricemia is relatively lower than other places in China, and that might be influenced by ethnicity, genetic and environment factors. These findings will be useful for the future researches and health care strategies.
Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility)

New treatments are required for severe breathlessness in advanced disease. We conducted a randomised feasibility trial of mirtazapine over 28 days in adults with a modified medical research council breathlessness scale score ≥3. Sixty-four patients were randomised (409 screened), achieving our primary feasibility endpoint of recruitment. Most patients had COPD or interstitial lung disease; 52 (81%) completed the trial. There were no differences between placebo and mirtazapine in tolerability or safety, and blinding was maintained. Worst breathlessness ratings at day 28 (primary clinical activity endpoint) were, 7.1 (SD 2.3, placebo) and 6.3 (SD 1.8, mirtazapine). A phase III trial of mirtazapine is indicated. Trial registration: ISRCTN 32236160; European Clinical Trials Database (EudraCT no: 2015-004064-11).
Optical imaging and spectroscopy of atomically precise armchair graphene nanoribbons.

We report the optical imaging and absorption spectroscopy on atomically precise armchair graphene nanoribbons (GNRs) on insulating fused silica substrates. This is achieved by controlling light polarization on macroscopically aligned GNRs, which greatly enhances the sub-monolayer GNR optical contrast on the insulating substrates. We measured the linear absorption spectra of 7-armchair and 9-armchair GNRs in this study, and the experimental data agree qualitatively with ab inito calculation results.The polarization spectroscopy technique enables an unambiguous optical identification of GNR samples and provides a rapid tool to characterize the transferred film over large area.
Secondary-cell-wall release: a particular pattern of secretion in the mucilaginous seed coat of Magonia pubescens.

PREMISE Plant mucilages are composed of strongly hydrophilic polysaccharides and contribute to seed germination and seedling establishment. The myxospermic seeds of Magonia pubescens, a Cerrado (neotropical savanna) tree species, produces a voluminous mucilage capsule when hydrated. The development of the mucilaginous layer, the process of mucilage secretion and its role in seed germination was not previously studied so far. METHODS Morphological, anatomical, histochemical, and ultrastructural evaluations of the seed coat during seed development were undertaken. The formation of the mucilage capsule was followed using scanning electron microscopy, and the coat's effects on seed hydration and germination were evaluated after experimental manipulation of the seed coat. RESULTS The mucilaginous layer is contained in the outer coat of the seed. The mucilage-secreting cells accumulate proteins in the outer periclinal region and acidic polysaccharides in the inner periclinal region of the periplasmic space. Neutral polysaccharides, which form the loosely organized secondary wall, form a folding, basket-like structure surrounding the acidic polysaccharides. The protoplast collapses at maturity. With hydration, the mucilage expands, breaks the epidermal layer, and forms a mucilage capsule around the seed. The mucilaginous seed coat does not increase the germination rate. CONCLUSIONS Upon mucilage hydration, the secondary cell walls forming the network of neutral polysaccharides are released, along with proteins, and help retain the acidic polysaccharides-forming a peculiar architecture that imparts integrity and consistency to the mucilage capsule. As winged seeds are not usually buried, the mucilage capsule favors seedling hydration, contributing to its establishment on the soil surface.
Improving Early Infant Diagnosis Observations: Estimates of timely HIV testing and mortality among HIV-exposed infants.

BACKGROUND Improving efforts towards elimination of mother-to-child transmission of HIV requires timely early infant diagnosis (EID) among all HIV-exposed infants, but the occurrence of timely EID and infant survival may be under-ascertained in routine, facility-bound program data. METHODS From March-May 2015, we traced a random sample of HIV positive mother and HIV-exposed infant pairs lost to follow-up for EID in facility registers in Zimbabwe. We incorporated updated information into weighted survival analyses to estimate incidence of EID and death. Reasons for no EID were surveyed from caregivers. RESULTS Among 2,651 HIV-positive women attending antenatal care, 1,823 (68.8%) infants had no documented EID by 3 months of age. Among a random sample of 643 (35.3%) HIV-exposed infants lost to follow-up for EID, vital status was ascertained among 371 (57.7%) and updated care status obtained from 256 (39.8%) mothers traced. Among all HIV-infected mother HIV-exposed infant pairs, weighted estimates found cumulative incidence of infant death by 90 days of 3.9% (95%CI: 3.4% to 4.4%). Cumulative incidence of timely EID with death as a competing risk was 60%. The most frequently cited reasons for failure to uptake EID were 'my child died' and 'I didn't know I should have my child tested'. CONCLUSIONS Our findings indicate uptake of timely EID among HIV-exposed infants is underestimated in routine health information systems. High, early mortality among HIV-exposed infants underscores the need to more effectively identify HIV positive mother-HIV exposed infant pairs at high risk of adverse outcomes and loss to follow-up for enhanced interventions.
Promoter methylation of Bax and Bcl2 genes and their expression in patients with Behcet’s disease

BCL2 and BAX genes are a group of signalling inducer and inhibitor genes playing a key role in the process of cellular physiological death (apoptosis). These genes, through the JAK/STAT signalling pathway, affect different cytokines on cell function and subsequently lead to the pathophysiology of diseases, especially autoimmune diseases. In addition, altering the methylation of genes can affect their expression. Since the aetiology and pathology of Behcet's disease is not fully understood, the aim of this study was to determine the methylation pattern of BCL2 and BAX genes in patients with Behcet's disease and compare it with those of control group. This was a case–control study on 51 patients with Behcet and 61 control subjects. Blood samples were received from all subjects. Subsequently, the peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll method and the methylation of the sites was investigated using quantitative methylation specific PCR (qMS‐PCR) technique after extraction of DNA by salting out method and its examination with Nano drop. The results of methylation and expression of Bax gene suggest that the methylation level in the patient group significantly increased compared to the healthy individuals (p‐value < .05). Furthermore, the results related to Bax gene expression revealed that the mean of gene expression in the patient group has decreased compared to the healthy group, and this decrease was statistically significant (p‐value < .05). The rate of expression and methylation of Bcl2 did not indicate any change in the two patient and healthy groups. Given the results of this study, it can be guessed that perhaps DNA methylation is involved in certain conditions of the disease and it may result in regulation of the expression of the involved genes such as Bax gene, in the pathogenesis of the disease.
Circulating miRNAs are associated with sleep duration in children/adolescents: Results of the I.Family Study

What is the central question of this study? Are differential patterns of circulating miRNAs associated with sleep duration in normal‐weight European children and adolescents? What is the main finding and its importance? Differences in the expression level of circulating miR‐26b‐3p and miR‐485‐5p are positively associated with total sleep duration in healthy normal‐weight children and adolescents.
Tesmin, Metallothionein-Like 5, is Required for Spermatogenesis in Mice†

Abstract In mammals, more than 2000 genes are specifically or abundantly expressed in testis, but gene knockout studies revealed several are not individually essential for male fertility. Tesmin (Metallothionein-like 5; Mtl5) was originally reported as a testis-specific transcript that encodes a member of the cysteine-rich motif containing metallothionein family. Later studies showed that Tesmin has two splicing variants and both are specifically expressed in male and female germ cells. Herein, we clarified that the long (Tesmin-L) and short (Tesmin-S) transcript forms start expressing from spermatogonia and the spermatocyte stage, respectively, in testis. Furthermore, while Tesmin-deficient female mice are fertile, male mice are infertile due to arrested spermatogenesis at the pachytene stage. We were able to rescue the infertility with a Tesmin-L transgene, where we concluded that TESMIN-L is critical for meiotic completion in spermatogenesis and indispensable for male fertility. Summary sentence TESMIN protein, a member of metallothionein family, is essential for mouse spermatogenesis, especially in the meiotic stage.
Disruption of the dimerization interface of the sensing domain in the dimeric heme-based oxygen sensor AfGcHK abolishes bacterial signal transduction

The heme-based oxygen sensor protein AfGcHK is a globin-coupled histidine kinase in the soil bacterium Anaeromyxobacter sp. Fw109-5. Its C-terminal functional domain exhibits autophosphorylation activity induced by oxygen binding to the heme-Fe(II) complex located in the oxygen-sensing N-terminal globin domain. A detailed understanding of the signal transduction mechanisms in heme-containing sensor proteins remains elusive. Here, we investigated the role of the globin domain's dimerization interface in signal transduction in AfGcHK. We present a crystal structure of a monomeric imidazole-bound AfGcHK globin domain at 1.8 Å resolution, revealing that the helices of the WT globin dimer are under tension and suggesting that Tyr-15 plays a role in both this tension and the globin domain's dimerization. Biophysical experiments revealed that whereas the isolated WT globin domain is dimeric in solution, the Y15A and Y15G variants in which Tyr-15 is replaced with Ala or Gly, respectively, are monomeric. Additionally, we found that although the dimerization of the full-length protein is preserved via the kinase domain dimerization interface in all variants, full-length AfGcHK variants bearing the Y15A or Y15G substitutions lack enzymatic activity. The combined structural and biophysical results presented here indicate that Tyr-15 plays a key role in the dimerization of the globin domain of AfGcHK and that globin domain dimerization is essential for internal signal transduction and autophosphorylation in this protein. These findings provide critical insights into the signal transduction mechanism of the histidine kinase AfGcHK from Anaeromyxobacter.
Foreign-born women’s lifestyle and health before and during early pregnancy in Sweden

Abstract Objectives: The aims of the study were to investigate foreign-born women’s lifestyle and health before and during early pregnancy and compare them with those of Nordic-born women. Methods: Women recruited at antenatal clinics in Sweden answered a questionnaire in Swedish, English or Arabic or by telephone interview with an interpreter. Questions covered pregnancy planning and periconceptional lifestyle and health. The responses of women born in or outside Europe were compared with those of Nordic-born women. The impact of religiousness and integration on periconceptional lifestyle and health was also investigated. Results: Twelve percent of participants (N = 3389) were foreign-born (n = 414). Compared with Nordic women, European and non-European women consumed less alcohol before conception (respectively, adjusted odds ratio [aOR] 0.38; 95% confidence interval [CI] 0.24, 0.58 and aOR 0.14; 95% CI 0.10, 0.19) and during early pregnancy (respectively, aOR 0.61; 95% CI 0.40, 0.91 and aOR 0.20; 95% CI 0.14, 0.29). Non-European women used less tobacco and were less physically active, but body mass index (BMI) did not differ between groups. Self-perceived health, stress and anxiety during early pregnancy did not differ, but non-European women more often had depressive symptoms (aOR 1.67; 95% CI 1.12, 2.51). Non-European women’s healthy lifestyle was associated with religiousness but not with the level of integration. Conclusions: Non-European women were overall less likely to engage in harmful lifestyle habits before and during early pregnancy but were more likely to suffer from depressive symptoms in comparison with Nordic women.
Determinants of object choice and object attachment: Compensatory consumption in compulsive buying–shopping disorder and hoarding disorder

Background and aims Individuals who meet criteria for compulsive buying–shopping disorder (i.e., acquiring problems only) or hoarding disorder (i.e., acquiring and discarding problems) may acquire possessions to compensate for unmet belonging needs, but may do so in different ways. Those with compulsive buying–shopping disorder may acquire objects that they believe will relieve the distress associated with unmet belonging needs (e.g., objects that distract or comfort), whereas those with hoarding disorder may acquire objects that they believe achieve belonging needs (e.g., objects that have interpersonal connotations). Accordingly, this study examined whether a belongingness threat would drive individuals who excessively acquire possessions to choose a human-like object (person-shaped tea holder) or a comfort item (box of chamomile tea). Methods One hundred seventy-five participants (57 self-reported excessive acquiring only; 118 self-reported excessive acquiring and difficulty discarding) recalled a time when they either felt supported or unsupported by a significant other before choosing an object to take home with them. Participants rated how anthropomorphic and comforting the objects were as well as how attached they became to their chosen object. Results Unsupported individuals were more likely to acquire the comfort item than supported individuals; however, individuals with both acquiring and discarding problems were more likely to acquire the human-like item than those with an acquiring problem only. Comfort and anthropomorphism ratings predicted object choice and attachment. Discussions and conclusion The current findings extend the Compensatory Consumer Behavior Model to include what factors determine strategy choice and object attachment.
Surrogate R-spondins for tissue-specific potentiation of Wnt Signaling

Secreted R-spondin1-4 proteins (RSPO1-4) orchestrate stem cell renewal and tissue homeostasis by potentiating Wnt/β-catenin signaling. RSPOs induce the turnover of negative Wnt regulators RNF43 and ZNRF3 through a process that requires RSPO interactions with Leucine-rich repeat-containing G-protein coupled receptors (LGRs), or through an LGR-independent mechanism that is enhanced by RSPO binding to heparin sulfate proteoglycans (HSPGs). Here, we describe the engineering of ‘surrogate RSPOs’ that function independently of LGRs to potentiate Wnt signaling on cell types expressing a target surface marker. These bispecific proteins were generated by fusing an RNF43- or ZNRF3-specific single chain antibody variable fragment (scFv) to the immune cytokine IL-2. Surrogate RSPOs mimic the function of natural RSPOs by crosslinking the extracellular domain (ECD) of RNF43 or ZNRF3 to the ECD of the IL-2 receptor CD25, which sequesters the complex and results in highly selective amplification of Wnt signaling on CD25+ cells. Furthermore, surrogate RSPOs were able substitute for wild type RSPO in a colon organoid growth assay when intestinal stem cells were transduced to express CD25. Our results provide proof-of-concept for a technology that may be adapted for use on a broad range of cell- or tissue-types and will open new avenues for the development of Wnt-based therapeutics for regenerative medicine.