Miracle-dz/UniFAR-FTUs huggingface dataset:
Fatigue numeric rating scale validity, discrimination and responder definition in patients with psoriatic arthritis

Objectives This study assessed the psychometric properties of the fatigue numeric rating scale (NRS) and sought to establish values for clinically meaningful change (responder definition). Methods Using disease-specific clinician-reported and patient-reported data from two randomised clinical trials of patients with psoriatic arthritis (PsA), the fatigue NRS was evaluated for test–retest reliability, construct validity and responsiveness. A responder definition was also explored using anchor-based and distribution-based methods. Results Test–retest reliability analyses supported the reproducibility of the fatigue NRS in patients with PsA (intraclass correlation coefficient=0.829). Mean (SD) values at baseline and week 2 were 5.7 (2.2) and 5.7 (2.4), respectively. Supporting construct validity of the fatigue NRS, moderate-to-large correlations with other assessments measuring similar concepts as measured by Sackett’s conventions were demonstrated. Fatigue severity was reduced when the underlying disease activity was improved and reductions remained consistent at week 12 and 24. A 3-point improvement was identified as being optimal for demonstrating a level of clinically meaningful improvement in fatigue NRS after 12–24 weeks of treatment. Conclusions Fatigue NRS is a valid and responsive patient-reported outcome instrument for use in patients with PsA. The established psychometric properties from this study support the use of fatigue NRS in clinical trials and in routine clinical practice. Robust validation of reliability for use in routine clinical practice in treating patients with active PsA in less active disease states and other more diverse ethnic groups is needed.
Safe and effective digestive endoscopic resection in patients with cirrhosis: a single-center experience

Abstract Background Endoscopic resection has developed over the years. The main complications are perforation and bleeding. This study aimed to evaluate safety and effectiveness of digestive endoscopic resection in patients with cirrhosis. Methods This retrospective, open-label, single-center study included all consecutive patients with cirrhosis who were admitted for endoscopic resection between 2009 and 2016. Safety, efficacy, and risk factors for delayed bleeding were analyzed. Results 126 patients undergoing 164 procedures were included: 65 endoscopic resections (49 patients) in the upper gastrointestinal tract (esophagus 34, stomach 20, duodenum 11) and 99 in the lower gastrointestinal tract (77 patients). Mean Model for End-Stage Liver Disease score was 9.9 (standard deviation 4.5). Esophageal varices were present in 50 patients, and 21 patients had decompensated cirrhosis. The overall curative rate of endoscopic resection was 84.0 %. No patients died during 30-day follow-up. Immediate overall morbidity was 6.1 %, with two postoperative fevers and eight bleeds. Risk factors for delayed bleeding were duodenal location (P < 0.01), antiplatelet medication (P = 0.02), and lower glomerular filtration rate (GFR) (P = 0.01) in univariate analysis. Duodenal location and lower GFR remained statistically significant in multivariate analysis, with respective odds ratios for bleeding of 52.12 and 1.04. No liver decompensation occurred after endoscopic resection. Conclusions Endoscopic resection was safe and effective in patients with mild (Child – Pugh class A/B) cirrhosis, and should be proposed as a first option for treatment of superficial neoplasia. Additional data in patients with severe cirrhosis are needed to confirm the safety in this population.
Targeting survivin sensitizes cervical cancer cells to radiation treatment

ABSTRACT Survivin is an inhibitor of apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. It is selectively up-regulated in many human tumors and implicated in cellular radiation response through its role in apoptosis, cell division, and DNA damage response. This study aimed to investigate the effect and mechanisms of targeting survivin radiosensitivity in cervical cancer C33A cells. Here, the authors designed a small interfering RNA (siRNA) or plasmid-based small hairpin RNA (shRNA) targeting survivin and tested its effects on radiosensitivity to ionizing radiation (IR) treatment of C33A cells in vitro, as well as on the tumorigenicity of C33A cells in nude mice in vivo. Transient transfection of survivin siRNA into C33A cells suppressed survivin expression, induced cell apoptosis and G2/M arrest and reduced cell proliferation, clone formation ability after IR, followed by p53 upregulated modulator of apoptosis (PUMA) upregulation. But, transient transfection of survivin siRNA alone has no significant effect on cell growth and apoptosis. To confirm that PUMA upregulation is necessary for survivin silencing -induced radiosensitivity to IR treatment, the effect of targeting PUMA in survivin sliencing cells was observed. The results showed that targeting PUMA in survivin sliencing cells rescued C33A cells’ radioresistance. Furthermore, knocking down survivin expression combined with IR treatment significantly slowed tumor growth and promoted tumor cell apoptosis in C33A xenografted tumors. It was concluded that survivin played a role in radiotherapy resistance. Targeting survivin increased the radiosensitivity of C33A cells through induction of PUMA expression. Graphical Abstract
Bottom-up and top-down neural signatures of disordered multi-talker speech perception in adults with normal hearing

In social settings, speech waveforms from nearby speakers mix together in our ear canals. Normally, the brain unmixes the attended speech stream from the chorus of background speakers using a combination of fast temporal processing and cognitive active listening mechanisms. Of >100,000 patient records,~10% of adults visited our clinic because of reduced hearing, only to learn that their hearing was clinically normal and should not cause communication difficulties. We found that multi-talker speech intelligibility thresholds varied widely in normal hearing adults, but could be predicted from neural phase-locking to frequency modulation (FM) cues measured with ear canal EEG recordings. Combining neural temporal fine structure processing, pupil-indexed listening effort, and behavioral FM thresholds accounted for 78% of the variability in multi-talker speech intelligibility. The disordered bottom-up and top-down markers of poor multi-talker speech perception identified here could inform the design of next-generation clinical tests for hidden hearing disorders.
Plant hemoglobins: a journey from unicellular green algae to vascular plants.

Globins (Glbs) are widely distributed in archaea, bacteria and eukaryotes. They can be classified into proteins with 2/2 or 3/3 α-helical folding around the heme cavity. Both types of Glbs occur in green algae, bryophytes and vascular plants. The Glbs of angiosperms have been more intensively studied and several protein structures have been solved. They can be hexacoordinate or pentacoordinate, depending on whether a histidine is coordinating or not at the sixth position of the iron atom. The 3/3 Glbs of class 1 and the 2/2 Glbs (also called class 3 in plants) are present in all angiosperms, whereas the 3/3 Glbs of class 2 have been only found in early angiosperms and eudicots. The three Glb classes are expected to play different roles. Class 1 Glbs are involved in hypoxia responses and modulate NO concentration, which may explain their roles in plant morphogenesis, hormone signaling, cell fate determination, nutrient deficiency, nitrogen metabolism and plant-microorganism symbioses. Symbiotic Glbs derive from class 1 or class 2 Glbs and transport O2 in nodules. The physiological roles of class 2 and 3 Glbs are poorly defined but could involve O2 and NO transport and/or metabolism, respectively. More research is warranted on these intriguing proteins to determine their non-redundant functions.
Plasma monoamines change under dopamine supersensitivity psychosis in patients with schizophrenia: A comparison with first-episode psychosis

Background: Patients with first-episode psychosis respond well to initial antipsychotic treatment, but among patients experiencing a relapse of psychosis, the response rate falls to approximately 30%. The mechanism of this discrepancy has not been clarified, but the development of dopamine supersensitivity psychosis with the underlying up-regulation of post-synaptic dopamine D2 receptors could be involved in this lesser response. It is uncertain whether elevated dopamine synthesis and release occurs in patients with dopamine supersensitivity psychosis, in contrast to those with first-episode psychosis. Patients and methods: We examined a first-episode psychosis group (n=6) and a chronic schizophrenia group, i.e. patients experiencing relapse (n=23) including those who relapsed due to dopamine supersensitivity psychosis (n=18). Following the initiation of treatment, we measured the patients’ blood concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol at two weeks and four weeks after the baseline measurements. Results: The first-episode psychosis group tended to show decreased homovanillic acid, accompanied by an improvement of symptoms. The chronic schizophrenia group showed no alteration of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol over the treatment period. These results were the same in the dopamine supersensitivity psychosis patients alone. Conclusions: Our findings suggest that unlike first-episode psychosis, the release of dopamine from presynaptic neurons did not increase in relapse episodes in the patients with dopamine supersensitivity psychosis. This indirectly indicates that the development of supersensitivity of post-synapse dopamine D2 receptor is involved in relapse in dopamine supersensitivity psychosis patients.
Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

Abstract Early malnutrition, the first environmental cause of intra-uterine growth restriction, impairs development of the thymus. Alterations of the thymic structure and function are reported at young ages in murine and ovine models. However, descriptions of thymic consequences of fetal malnutrition at adulthood are scarce. The present study investigates thymic structure, protein expression and cell selection process observed at postnatal day 180 (PND180) in male offspring of rats exposed to maternal low-protein diet (mLPD) compared with control diet during gestation. The thymic index was lower in adult offspring exposed to mLPD (P < 0·05). The thymic cortico-medullar ratio was lower in adult offspring exposed to mLPD (P < 0·05). At PND180, the protein expression of the lymphotoxin β receptor (P < 0·05), the autoimmune regulator (P < 0·05) and Forkhead Box P3 (FoxP3; P < 0·05) was all significantly lower in the mLPD group. The CD4+:CD8+ single-positive thymocyte subpopulation ratio and CD4+:CD8+ lymphocyte subpopulation ratio were increased in the mLPD group (P < 0·05). Among CD3+ lymphocytes, the proportions of CD4+CD8+ double-positive lymphocytes, CD31+ recent thymic emigrants and CD4+FoxP3+ lymphocytes were not significantly different between mLPD and control groups. These findings suggest mLPD during gestation induced long-lasting alterations in the development of thymic structure and thymic cell maturation and selection process in adult male rat offspring.
A Phase 1, Randomized, Placebo‐Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Subcutaneous Tezepelumab in Healthy Japanese Men

Tezepelumab, a human immunoglobulin G2 monoclonal antibody against thymic stromal lymphopoietin, is currently under clinical development for the treatment of severe, uncontrolled asthma. This phase 1, randomized, placebo‐controlled, single‐ascending‐dose study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Participants were assigned to 1 of 3 tezepelumab dose cohorts (35, 105, or 280 mg; n = 8 per cohort) and randomized (6:2) to receive a single subcutaneous dose of tezepelumab or placebo, with a follow‐up period of 84 to 112 days. The overall incidences and severities of treatment‐emergent adverse events were similar across tezepelumab doses and between the tezepelumab and placebo groups. Tezepelumab was absorbed slowly, reaching a maximum serum concentration (mean, 5.2‐39.7 µg/mL) after 7 to 10 days. Area under the concentration‐time curve (mean, 207.2‐1612.0 µg · day /mL) increased in an approximate dose‐proportional manner. Tezepelumab had a long terminal serum half‐life (mean, 23.9‐26.3 days) and a small apparent distribution volume, suggesting limited distribution into peripheral tissues. No participants developed anti‐tezepelumab antibodies. Single‐dose, subcutaneous administration of tezepelumab 35 to 280 mg resulted in an acceptable safety profile with linear pharmacokinetics in healthy Japanese men. No clear differences in tezepelumab safety and pharmacokinetics between Japanese and non‐Japanese populations were identified.
Burnout in consultants in child and adolescent mental health services (CAMHS) in Ireland: a cross-sectional study

Physician burnout has reached epidemic levels in many countries, contributing to adverse personal, patient and service outcomes. Adverse socioeconomic conditions, such as the economic downturn in the Ireland post 2008, contribute to a situation of increased demand but inadequate resources. Given a recent unprecedented increase in referrals to Irish child and adolescent mental health services (CAMHS), coupled with a fragmented and poorly resourced service, it is important to reflect on consultant child psychiatrists’ well-being. Objectives To report on the level of burnout among consultants working in CAMHS in Ireland using a cross-sectional design. Setting Community CAMHS in Ireland. Participants An online questionnaire was sent to all consultant child psychiatrists registered with the Irish Medical Council (n=112). Fifty-two consultants replied (46% response rate). Primary outcome measures Questions assessed demographic and occupational details, career satisfaction and perceived management, government and public support. The Copenhagen Burnout Inventory measured personal, work and patient-related burnout. Results The prevalence of moderate or higher levels of work-related and personal burnout was 75% and 72.3%, respectively. Fewer (n=14, 26.9%) experienced patient-related burnout. There was a strong correlation between work burnout and personal (r=0.851, n=52, p<0.001) and patient-related burnout (r=0.476, n=52, p<0.001). Lack of confidence in government commitment to investment in CAMHS (p<0.001) and perceived ineffective management by health authorities (p=0.002) were associated with higher burnout scores. Few consultants (n=11, 21%) felt valued in their job. The majority (n=36, 69%) had seriously considered changing jobs, and this was positively associated with higher burnout (p<0.001). Higher burnout scores were present in those (n=15, 28.8%) who would not retrain in child psychiatry (p=0.002). Conclusion The high level of burnout reported by respondents in this study, and ambivalence about child psychiatry as a career choice has huge professional and service implications. Urgent organisational intervention to support consultant psychiatrists’ well-being is required.
Chronic exposure to arsenite enhances influenza virus infection in cultured cells

Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well‐established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin‐Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3‐fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35‐fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite‐exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment‐positive cells (2 hours p.i.) and 224% increase in α‐2,3 sialic acid‐positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4‐fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS‐2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti‐influenza drug, oseltamivir, in arsenite‐exposed cells raises substantial public health concerns if this effect translates to arsenic‐exposed, influenza‐infected people.
A molecular‐level perspective on the frequency, distribution, and consequences of messenger RNA modifications

Cells use chemical modifications to alter the sterics, charge, and conformations of large biomolecules, modulating their biogenesis, function, and stability. Until recently post‐transcriptional RNA modifications were thought to be largely limited to nonprotein coding RNA species. However, this dogma has rapidly transformed with the discovery of a host of modifications in protein coding messenger RNAs (mRNAs). Recent advancements in genome‐wide sequencing technologies have enabled the identification of mRNA modifications as a potential new frontier in gene regulation—leading to the development of the epitranscriptome field. As a result, there has been a flurry of multiple groundbreaking discoveries, including new modifications, nucleoside modifying enzymes (“writers” and “erasers”), and RNA binding proteins that recognize chemical modifications (“readers”). These discoveries opened the door to understanding how post‐transcriptional mRNA modifications can modulate the mRNA lifecycle, and established a link between the epitranscriptome and human health and disease. Despite a rapidly growing recognition of their importance, fundamental questions regarding the identity, prevalence, and functional consequences of mRNA modifications remain to be answered. Here, we highlight quantitative studies that characterize mRNA modification abundance, frequency, and interactions with cellular machinery. As the field progresses, we see a need for the further integration of quantitative and reductionist approaches to complement transcriptome wide studies in order to establish a molecular‐level framework for understanding the consequences of mRNA chemical modifications on biological processes.
Gender-based Multilevel Analysis of Influential Factors for Suicide Attempts among At-risk Non-referred Adolescents in Korea

Objective Effective suicide prevention for at-risk adolescents requires increased access to medical treatment. Investigating the unique characteristics of suicide in this vulnerable at-risk non-referred sample can contribute to establishing effective suicide prevention policies. This study aimed to (a) examine at-risk non-referred adolescents’ suicide attempt rate, (b) investigate influential multilevel factors in predicting these adolescents’ suicide attempts, and (c) compare the results of (a) and (b) by gender. Methods A total of 401 samples (216 boys and 185 girls) were recruited through a school-based mental health project for at-risk adolescents. Multivariate hierarchical logistic regression analyses were performed at the individual-, contextual-, and protective levels to evaluate three multilevel models as well as to investigate predictabilities for the overall group and by gender. Results The suicide attempt rate of the overall sample was 29.4% (boys: 18.1%, girls: 42.7%), which was significantly higher than that of community samples. For boys, individual-level predictors (depression and conduct problems) had the most significant contribution in predicting suicide attempts. In contrast, for girls, protective-level predictors (family satisfaction) contributed the most to the prediction of suicide attempts, followed by contextual-level predictors (academic grades). Conclusion This study is an important step in understanding the unique characteristics of at-risk non-referred adolescents who have not yet been considered in mental health policies. Improving medical accessibility will be the first step in establishing effective suicide prevention policies for these vulnerable samples.
In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats.

A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: 1) the same day as EV administration; and 2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.
Revisiting Intergenerational Contact and Relationship Quality in Later Life: Parental Characteristics Matter

Contact and relationship quality between adult children and aging parents are two widely used indicators of intergenerational solidarity and are often assumed to be positively correlated. However, the association between the two may depend on characteristics of the parent involved. Using Family Exchanges Study Wave 1, this study assessed whether parental difficulties—measured as functional limitations and life problems—and gender moderated the associations between middle-aged adults’ contact and relationship quality with their parents. We found that more frequent email or phone contact was associated with worse relationship quality for fathers who had functional limitations. For life problems, however, more contact was not related to relationship quality for fathers with life problems. The associations did not differ by mother’s difficulties. These results suggest that frequent contact between middle-aged adult children and aging parents does not uniformly reflect better relationship quality but rather depends on parents’ characteristics.