Miracle-dz/UniFAR-FTUs huggingface dataset:
A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia

Background Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment. Methodology/Principal findings An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45–87%) in the unadjusted analysis, and 50% (95% CI 27–73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67–90%) and 67% (95% CI 48–82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32–78%) in the monotherapy arm, and 88% (95% CI 79–98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication. Conclusions/Significance The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa. Trial registration number www.clinicaltrials. gov NCT02011958.
Fabrication, Optimization, and Evaluation of Rotigotine-Loaded Chitosan Nanoparticles for Nose-To-Brain Delivery

The objective of the present study was to develop, optimize, and evaluate rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery. Rotigotine-loaded chitosan nanoparticles were prepared by the ionic gelation method and optimized for various parameters such as the effect of chitosan, sodium tripolyphosphate, rotigotine concentration on particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The prepared nanoparticles were characterized using photon correlation spectroscopy, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, fourier-transform infrared spectroscopy, and X-ray diffraction. The developed RNPs showed a small hydrodynamic particle size (75.37 ± 3.37 nm), small PDI (0.368 ± 0.02), satisfactory zeta potential (25.53 ± 0.45 mV), and very high entrapment efficiency (96.08 ± 0.01). The 24-h in vitro release and ex vivo nasal permeation of rotigotine from the nanoparticles were 49.45 ± 2.09% and 92.15 ± 4.74% while rotigotine solution showed corresponding values of 95.96 ± 1.79%and 58.22 ± 1.75%, respectively. The overall improvement ratio for flux and permeability coefficient were found to be 4.88 and 2.67 when compared with rotigotine solution. A histopathological study showed that the nanoparticulate formulation produced no toxicity or structural damage to nasal mucosa. Our results indicated that rotigotine-loaded chitosan nanoparticles provide an efficient carrier for nose-to-brain delivery.
Meta‐analysis of the mental health status of left‐behind children in China

The aims of this study were to systematically evaluate and comparatively analyse the mental health status of left‐behind children (LBC) in China and to provide a scientific basis for mental intervention and healthy education for LBC. Six electronic databases were searched for studies (published from 1 January 2010 to 5 March 2018) of the mental health of LBC using the Mental Health Test scale. We only selected original articles that either reported the incidence of serious mental health status or the means and standard deviations of each factor score of the scale. The pooled rates and weighted mean difference were calculated. The results indicated that the incidence of serious mental health status of LBC is nearly 2.7 times higher than that of non‐LBC. The scores for most of the factors analysed by the Mental Health Test of LBC were higher than those of non‐LBC. In addition, the mental health status of left‐behind girls is worse than that of left‐behind boys. Except for impulsive tendency, there was no significant difference in the mental health status of LBC in primary and junior high schools. In terms of the different types of guardianship, the mental health status of LBC under a grandparent's guardianship and parental peer' guardianship is more serious than that of LBC under a single‐parent guardianship. The mental health status of LBC is poor, particularly for left‐behind girls. The primary mental problems faced by LBC are learning anxiety, social anxiety and physical symptoms. It is necessary to develop more targeted measures to prevent and manage LBC.
The Pulsatile Gonadorelin Pump Induces Earlier Spermatogenesis Than Cyclical Gonadotropin Therapy in Congenital Hypogonadotropic Hypogonadism Men

The objective of this study was to compare the effect of pulsatile gonadorelin pump (PGP) and cyclical gonadotropin (human chorionic gonadotropin [HCG]/human menopausal gonadotropin [HMG]) therapy (CGT) on spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) men. Twenty-eight azoospermic CHH males were included in this nonrandomized study. Ten received PGP and 18 received CGT. The primary endpoint was the earliest time spermatogenesis occurred during 24 months of treatment. Spermatogenesis time was significant earlier in the PGP group than the CGT group (median of 6 and 14 months, respectively, χ2 = 6.711, p = .01). Spermatogenesis occurred in 90% of the PGP group and 83.3% of the CGT group and showed statistically insignificant difference in the superiority analysis and the no-inferior test. Contributing factors significant for spermatogenesis were previous HCG/or testosterone treatment and the peak serum luteinizing hormone level of triptorelin stimulation test at baseline. Although testis volume and penile length increased significantly from baseline, the differences between the two therapies were not significant. There was a tendency for high serum testosterone level, associated with more facial acne and breast tenderness in the CGT group. Skin allergic erythema scleroma was a common side effect of the PGP. In summary, PGP resulted in earlier spermatogenesis and more desirable testosterone levels than CGT.
Reduced Perceptual Specialization in Autism: Evidence From the Other-Race Face Effect

Emerging accounts of autism suggest that flexible and broadly tuned perceptual representations, presumably resulting from reduced specialization, may underlie atypical perception. Here, we examined the other-race effect (ORE) to study face processing specialization arising from specific experience with own-race faces. Face discrimination was tested for own- and other-race faces in typically developed individuals and in individuals with autism spectrum disorder (ASD). For each race, faces were morphed to vary discrimination difficulty, and orientation was manipulated to examine inversion effects. The ASD group displayed overall lower sensitivity and reduced inversion effects in processing faces. Importantly, the processing advantage for own-race faces was substantially smaller in this group, resulting specifically from the reduced specialization for the own-race faces. Moreover, the typical larger inversion effect for Caucasian faces was not observed in the ASD group; sensitivity to orientation was smaller and equivalent for the two face races. These more broadly tuned representations in autism may account for the overall weaker representations of faces and suggest, more broadly, that a failure in perceptual specialization may underlie atypical perception in autism.
Differences in Sexual Identity Dimensions Between Bisexual and Other Sexual Minority Individuals: Implications for Minority Stress and Mental Health

Bisexual individuals experience poorer mental health than other sexual minority individuals. One explanation for this is that biphobia predisposes bisexual individuals to have a more ambiguous sexual identity and fewer opportunities for stress-ameliorating forms of coping and support. This study explores sexual identity and sexual identity dimensions—prominence, valence, integration, and complexity—in bisexual and other sexual minority individuals. We describe differences in sexual identity dimensions between bisexual and other sexual minority individuals and test two explanations for mental health disparities between them: whether sexual identity dimensions directly impact mental health and whether they moderate the impact of stress on mental health. Data came from a longitudinal study of a diverse sample of sexual minority individuals (N = 396, 71 bisexual respondents) sampled from community venues in New York City. Sexual identity was prominent for both bisexual and other sexual minority individuals, but bisexual individuals reported lower valence and integration of sexual identity in their identity structures. The hypothesis that sexual identity dimensions moderate the impact of minority stress on mental health was not supported. After several longitudinal assessments, however, we concluded that identity valence (but not integration or complexity) and depressive symptoms were bidirectionally associated so that differences in valence between bisexual and other sexual minority individuals explained, in part, disparities in depressive symptoms.
A Systematic Review and International Web-Based Survey of Randomized Controlled Trials in the Perioperative and Critical Care Setting: Interventions Reducing Mortality.

The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians' opinions and routine practices to understand the clinicians' response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (n = 13). The concordance between agreement and use (a positive answer both to "do you agree" and "do you use") showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location.
Healthy Lifestyle and Incidence of Metabolic Syndrome in the SUN Cohort

We assessed the relationship between a healthy lifestyle and the subsequent risk of developing metabolic syndrome. The “Seguimiento Universidad de Navarra” (SUN) Project is a prospective cohort study, focused on nutrition, lifestyle, and chronic diseases. Participants (n = 10,807, mean age 37 years, 67% women) initially free of metabolic syndrome were followed prospectively for a minimum of 6 years. To evaluate healthy lifestyle, nine habits were used to derive a Healthy Lifestyle Score (HLS): Never smoking, moderate to high physical activity (>20 MET-h/week), Mediterranean diet (≥4/8 adherence points), moderate alcohol consumption (women, 0.1–5.0 g/day; men, 0.1–10.0 g/day), low television exposure (<2 h/day), no binge drinking (≤5 alcoholic drinks at any time), taking a short afternoon nap (<30 min/day), meeting up with friends >1 h/day, and working at least 40 h/week. Metabolic syndrome was defined according to the harmonizing definition. The association between the baseline HLS and metabolic syndrome at follow-up was assessed with multivariable-adjusted logistic regressions. During follow-up, we observed 458 (4.24%) new cases of metabolic syndrome. Participants in the highest category of HLS adherence (7–9 points) enjoyed a significantly reduced risk of developing metabolic syndrome compared to those in the lowest category (0–3 points) (adjusted odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.47–0.93). Higher adherence to the Healthy Lifestyle Score was associated with a lower risk of developing metabolic syndrome. The HLS may be a simple metabolic health promotion tool.
Fluorescent cell tracer dye permits real‐time assessment of re‐epithelialization in a serum‐free ex vivo human skin wound assay

Ex vivo wounded human skin organ culture is an invaluable tool for translationally relevant preclinical wound healing research. However, studies incorporating this system are still underutilized within the field because of the low throughput of histological analysis required for downstream assessment. In this study, we use intravital fluorescent dye to lineage trace epidermal cells, demonstrating that wound re‐epithelialization of human ex vivo wounds occurs consistent with an extending shield mechanism of collective migration. Moreover, we also report a relatively simple method to investigate global epithelial closure of explants in culture using daily fluorescent dye treatment and en face imaging. This study is the first to quantify healing of ex vivo wounds in a longitudinal manner, providing global assessments for re‐epithelialization and tissue contraction. We show that this approach can identify alterations to healing with a known healing promoter. This methodological study highlights the utility of human ex vivo wounds in enhancing our understanding of mechanisms of human skin repair and in evaluating novel therapies to improve healing outcome.
Assessment of a Bidirectional Association Between Major Depressive Disorder and Alopecia Areata

Importance Alopecia areata (AA) is an autoimmune disease characterized by hair loss that can impose a substantial psychological burden on patients, including major depressive disorder (MDD), yet many patients report mental health symptoms prior to the onset of AA. As such, there may be an association between MDD and AA that acts in both directions. Objective To assess the bidirectional association between MDD and AA. Design, Setting, and Participants This population-based retrospective cohort study included patients 10 to 90 years of age registered with The Health Improvement Network in general practices in the United Kingdom between January 1, 1986, and May 16, 2012. Statistical analysis was conducted from August 17, 2017, to April 23, 2018. To assess the risk of AA, the following 2 cohorts were defined: patients with an incident diagnosis of MDD (exposure) and a reference general population cohort. To assess the risk of MDD, the following 2 cohorts were defined: patients with an incident diagnosis of AA (exposure) and a reference general population cohort. Person-time was partitioned into unexposed and exposed time in the exposure cohorts. Main Outcomes and Measures In the analysis of the risk of AA, development of incident AA during follow-up was considered the main outcome measure. In the analysis of the risk of MDD, development of incident MDD during follow-up was considered the primary outcome measure. Results In the analysis of the risk of AA, 405 339 patients who developed MDD (263 916 women and 141 423 men; median age, 36.7 years [interquartile range, 26.6-50.5 years]) and 5 738 596 patients who did not develop MDD (2 912 201 women and 2 826 395 men; median age, 35.8 years [interquartile range, 25.3-52.6 years]) were followed up for 26 years. After adjustment for covariates, MDD was found to increase the risk of subsequently developing AA by 90% (hazard ratio, 1.90; 95% CI, 1.67-2.15; P < .001). Antidepressants demonstrated a protective effect on the risk of AA (hazard ratio, 0.57; 95% CI, 0.53-0.62; P < .001). In the analysis of the risk of MDD, 6861 patients who developed AA (3846 women and 3015 men; median age, 31.5 years [interquartile range, 18.2 years]) and 6 137 342 patients who did not develop AA (3 172 371 women and 2 964 971 men; median age, 35.9 years [interquartile range, 27.0 years]) were followed up for 26 years. After adjustment for covariates, AA was found to increase the risk of subsequently developing MDD by 34% (hazard ratio, 1.34; 95% CI, 1.23-1.46; P < .001). Conclusions and Relevance These temporal analyses suggest that, while patients with AA are at risk for subsequently developing MDD, having MDD also appears to be a significant risk factor for development of AA, with antidepressant use confounding this risk.
Space Use and Leadership Modify Dilution Effects on Optimal Vigilance under Food-Safety Trade-Offs

Dilution of predation risk within groups allows individuals to be less vigilant and forage more while still facing lower risk than if they were alone. How group size influences vigilance when individuals can also adjust their space use and whether this relationship differs among individuals contributing differently to space use decisions remain unknown. We present a model-based study of how dilution affects the optimal antipredator behavior of group members in groups where all individuals determine their vigilance level while group leaders also determine space use. We showed that optimal vigilance did not always decrease with group size, as it was sometimes favorable for individuals in larger groups to use riskier patches while remaining vigilant. Followers were also generally less vigilant than leaders. Indeed, followers needed to acquire more resources than leaders, as only the latter could decide when to go to richer patches. Followers still benefit from dilution of predation risk compared with solitary individuals. For leaders, keeping their leadership status can be more important than incorporating new group members to increase dilution. We demonstrate that risk dilution impacts both optimal vigilance and space use, with fitness reward being tied to a member’s ability to influence group space use.
Association of Education Outside the Classroom and Pupils' Psychosocial Well-Being: Results From a School Year Implementation.

BACKGROUND Education Outside the Classroom (EOtC) is a teaching method that is gaining traction, aiming to promote learning and well-being. However, research on the association between EOtC and well-being is limited. METHODS This quasi-experimental trial involved pupils (9-13 years) from 16 Danish public schools which implemented EOtC in some classes. Pupils (N = 511) from 27 classes were regularly exposed to EOtC (2-7 hours per week), and pupils (N = 120) from 7 parallel comparison classes were much less exposed (less than 2 hours per week). The pupils' psychosocial well-being was measured at the beginning and end of the school year using the Strengths and Difficulties Questionnaire. The results were compared between the groups. RESULTS Pupils regularly exposed to EOtC showed the greatest improvement in prosocial behavior. Negative associations were seen between EOtC and hyperactivity-inattention and peer problems in pupils of low socioeconomic status (SES). The observed improvements were smaller when the EOtC was spread over a larger number of sessions. Results were independent of sex. CONCLUSIONS Regular exposure to EOtC was found to promote social well-being, especially for pupils of low SES, and was most beneficial when concentrated in fewer, longer sessions.
Efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma

Abstract Objective: To determine the safety and efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma. Material and methods: We conducted an observational study in 156 patients with advanced renal cell carcinoma unsuitable for surgical treatment. Participants received cryoablation + sorafenib (n = 67) or sorafenib only (n = 89). Objective response rate (ORR), disease control rate (DCR), progression-free survival time (PFS), overall survival (OS), change in immune function after treatment, rate of adverse events, and quality of life were compared between the two groups. Results: In the cryoablation + sorafenib group, ORR and DCR were significantly higher and PFS and OS were significantly longer than in the sorafenib only group (both p < .05). Immune function-related indicators were significantly improved after treatment in the cryoablation + sorafenib group (p < .05), but no significant difference was found between before and after treatment in the sorafenib only group (p > .05). The incidence of targeted drug-related side effects was not significantly different between the groups (p > .05), and cryoablation did not increase the risk of side effects of targeted drugs. Conclusion: Cryoablation combined with sorafenib had superior clinical efficacy compared with sorafenib-only for the treatment of advanced renal cell carcinoma unsuitable for surgical treatment. Moreover, this combined therapy may enhance the body’s anti-tumor immunity and effectively prolong PFS and OS without compromising patient quality of life, thus representing a new treatment strategy for advanced renal cell carcinoma.
Pharmacokinetic and Metabolism Studies of Curculigoside C by UPLC-MS/MS and UPLC-QTOF-MS

Pharmacokinetic and metabolism studies were carried out on curculigoside C (CC), a natural product with good antioxidant and neuroprotective effects, with the purpose of investigating the effects of the hydroxyl group at C-3′ in curculigoside. A rapid and sensitive method with UPLC-MS was developed and fully validated for the first time in the pharmacokinetic analysis for quantification of CC in rat plasma. The assay was linear (R2 > 0.9984) over the concentration range of 1–2500 ng/mL, with the lower limit of quantification (LLOQ) being 1 ng/mL. The intra-day and inter-day precision (expressed as relative standard deviation, RSD) ranged from 4.10% to 5.51% and 5.24% to 6.81%, respectively. The accuracy (relative error, RE) ranged from −3.28% to 0.56% and −5.83% to −1.44%, respectively. The recoveries ranged from 92.14% to 95.22%. This method was then applied to a pharmacokinetic study of rats after intragastric administration of 15, 30 and 60 mg/kg CC. The results revealed that CC exhibited rapid oral absorption (Tmax = 0.106 h, 0.111 h, and 0.111 h, respectively), high elimination (t1/2 = 2.022 h, 2.061 h, and 2.048 h, respectively) and low absolute bioavailability (2.01, 2.13, and 2.39%, respectively). Furthermore, an investigation on the metabolism of CC was performed by UPLC-QTOF-MSE. Twelve metabolites of CC from plasma, bile, urine and faeces of rats were confirmed. The main metabolic pathways of CC, which involve dehydration, glucosylation, desaturation, formylation, cysteine conjugation, demethylation and sulfonation, were profiled. In conclusion, this research has developed a sensitive quantitative method and demonstrated the metabolism of CC in vivo.