Miracle-dz/UniFAR-FTUs huggingface dataset:
The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol‐3 (PI3) kinase‐δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B‐cell receptor‐signalling pathway. IBL‐202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan‐PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL‐202 in CLL. Importantly, IBL‐202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL‐202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL‐202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug‐resistance.
Moral Judgment

The past decade has seen a renewed interest in moral psychology. A unique feature of the present endeavor is its unprecedented interdisciplinarity. For the first time, cognitive, social, and developmental psychologists, neuroscientists, experimental philosophers, evolutionary biologists, and anthropologists collaborate to study the same or overlapping phenomena. This review focuses on moral judgments and is written from the perspective of cognitive psychologists interested in theories of the cognitive and affective processes underlying judgments in moral domains. The review will first present and discuss a variety of different theoretical and empirical approaches, including both behavioral and neuroscientific studies. We will then show how these theories can be applied to a selected number of specific research topics that have attracted particular interest in recent years, including the distinction between moral and conventional rules, moral dilemmas, the role of intention, and sacred/protected values. One overarching question we will address throughout the chapter is whether moral cognitions are distinct and special, or whether they can be subsumed under more domain-general mechanisms.
Herpes zoster complicated by unilateral pleural effusion

546 EJD, vol. 28, n◦ 4, July-August 2018 on patch testing. Though the number of diagnosed irritant reactions was noted to be equal in a comparison of the Finn Chambers and TRUE Test, this was for irritant reactions that were recognized and not for those inadvertently misread [7]. In many comparative studies, the TRUE Test underscores comparator systems for total number of allergic positives, leading to the assumption that the TRUE Test can give more false negatives than other methods [4, 8]. However, this may be an over-simplification. The TRUE Test may be a better system for detecting some relevant allergens (e.g. nickel and neomycin) whilst other systems are superior for others (e.g. fragrance mix I and thiuram mix) [8, 9]. Reproducibility in terms of obtaining the same result on successive testing is a useful measure of the reliability of a patch test system to show true allergic positives. The demonstration of a dose-response relationship using serial dilutions is the ideal discriminator for this, but it is impractical in clinical work. The TRUE Test shows a higher degree of reproducibility compared to other patch test methods. Non-reproducibility was 18% for the TRUE Test, compared to 38% for the Finn Chambers [4]. However, simultaneous right-versus-left testing using the TRUE Test revealed a discrepancy of 5% for the TRUE Test and 4.2% for the Epiquick Test [6, 10]. These predictable variabilities (known unknowns) exist for any system and have to be taken into account in methodological comparison. They may explain some of the disparity observed by Kwon et al. [1]. A demonstration of relevance is the gold standard for the applicative interpretation of results in the patch test clinic. Kwon et al. did not incorporate relevance into their analysis, concentrating on gross results, but others have examined it in comparative studies and found conflicting results [1]. Systems tended to have different strengths for different allergens. For example, more relevant allergic positives to methylisothiazolinone and nickel were found using the TRUE Test than with Finn Chambers, though the latter exceeded the former for fragrance mix I, wool alcohols, and Myroxylon pereriae, and findings were conflicted for para-phenylenediamine and neomycin [5, 9]. The message from Kwon et al. is that all patch test systems have their advantages and disadvantages and none at present is perfect [1]. Whether one methodology is preferred over another depends on local expertise, tradition, and availability of trained technical and nursing staff. There will be instances when the TRUE Test is the most appropriate method for assessing the possibility of contact allergy, as it has been well tested and validated.
Efficacy and tolerance of photodynamic therapy for vulvar Paget’s disease: a multicentric retrospective study

BackgroundExtra-mammary Paget’s disease is a rare form of intraepithelial adenocarcinoma with a variable pattern of invasion, sometimes associated with distant malignancy. Vulvar Paget’s disease (VPD) represents 1% of all vulvar cancers. Standard treatment is surgical excision, however, the recurrence rate is high and surgery leads to anatomical, functional, and sexual morbidity. Some case series suggest efficacy of photodynamic (PDT) as treatment for this indication.ObjectivesOur aim was to assess the efficacy and tolerance of PDT in women suffering from VPD.Materials & MethodsA retrospective study was conducted on all patients suffering from VPD, treated with PDT at six hospitals in France. Clinical data, histopathological reports at diagnosis, therapeutic history, PDT schedule, tolerance, and clinical response were reported.ResultsThirteen women were included, with a mean age of 70.1 years. Ten women had an in situ disease, two had <1-mm dermal involvement, and one had adnexal involvement. All PDT courses were carried out using the same light source and photosensitizing agent. Complete response was achieved in two patients (15%) and partial response in five patients (38%). Five patients (38%) had stable disease and one (7%) had progressive disease. Ten of the 13 patients underwent pain evaluation; in six cases (60%), pain was described as moderate to intense.ConclusionPDT appears to be a therapeutic option for patients with VPD, with a response rate similar to that of other therapies usually recommended, such as surgery and imiquimod. There is a need to harmonise PDT procedures and pain assessment.
Assessing epidemiology of leprosy and socio-economic distribution of cases

Abstract Leprosy still represents a serious health problem in a number of countries, including Brazil. Although leprosy has been associated with poverty for a long time, it is still difficult to accurately define this relationship. Here, we evaluated in an endemic municipality the progress from 1995 to 2015 of epidemiological indicators to establish if there were any strong associations between social indicators and the occurrence of leprosy. An ecological study was conducted using the SINAN database (Brazilian leprosy-national notifiable diseases information system) in combination with georeferencing of leprosy cases. The georeferencing used the ArcGis programme and occurrence of cases was evaluated in relation to the Health Vulnerability Index (HVI), an indicator that categorises socio-economic and sanitation factors. The data identified a marked decrease in the overall prevalence of leprosy, a reduction in the new case-detection rate and a reduction in the number of cases with grade 2 disabilities (albeit with transient peaks in 2007 and 2015). Logistic regression analysis showed association of detection rates with elevated HVI. Thus, while the epidemiological indicators point to the elimination of leprosy, there is evidence of hidden cases and an association between higher rates of leprosy detection and greater social vulnerability remain.
Patterns of poisoning exposure at different ages: the 2015 annual report of the Australian Poisons Information Centres

OBJECTIVES To characterise the types of calls received by Australian Poisons Information Centres (PICs) in Australia, and to analyse poisoning exposures by age group, circumstances of exposure, and the types of substances involved. Design, setting: Retrospective analysis of call records from all four Australian PICs (national coverage). MAIN OUTCOME MEASURES Basic demographic information; exposure circumstances, substance types involved in each age group; recommendations for management (eg, stay at home, go to hospital). RESULTS There were 204 906 calls to Australian PICs in 2015, 69.0% from the general public, 27.9% from health professionals; 16.2% of calls originated from hospitals. 170 469 calls (including re-calls about an exposure) related to 164 363 poison exposure events; 64.4% were unintentional, 18.1% were the consequences of medication error, and 10.7% involved deliberate self-poisoning. Most exposures were of 20-74-year-old adults (40.1%) or 1-4-year-old toddlers (36.0%). The PICs advised callers to stay at home for 67.4% of exposures, and to present to hospital for 10.9%. The most common substances involved in exposures overall were household cleaners (10.2%) and paracetamol-containing analgesics (7.3%). Exposures of infants and toddlers were most frequently to household cleaning substances (17.8%, 15.3% respectively) and personal care items (6.6%, 7.3%); callers were usually advised to stay at home (88.5%, 86.4%). Deliberate self-poisoning (49.1%) and hospital referral (23.9%) were most frequent for adolescents. Exposures of adults (20-74 years) frequently involved psychotropic pharmaceuticals (17.8%) or painkillers (15.1%). Exposures in adults over 74 were typically medication errors involving cardiovascular (23.6%), anticoagulant (4.6%), or antidiabetic (4.1%) medications. CONCLUSIONS Poisoning is a significant public health problem throughout life, but the nature of the hazards differs markedly between age groups. PIC data could inform strategic public health interventions that target age-specific poisoning hazards.
Wait…What??? Guiding Intervention Principles for Students With Verbal Working Memory Limitations.

Purpose The purpose of this clinical focus article is to present 5 guiding principles for the development of interventions for children with limited verbal working memory abilities. Method Summarizing and synthesizing previously reported theories and empirical data, we present a framework intended to guide working memory interventions. Results Existing research and theory support a comprehensive, multidimensional treatment model that considers the knowledge and abilities of the student and the language-learning demands they face in the various contexts of a school day. Conclusion The clinical framework for which we are advocating is one that embodies the characteristics of complex interventions-those made up of many individual components that work synchronously in conjunction with each other.
People with Serious Mental Illness Compeer Friends: a Qualitative Study of a Volunteer Friendship Programme for

ABSTRACTBackground: People with serious mental illness (SMI) experience numerous barriers to developing and maintaining friendships.Aims: To explore the beneﬁts and drawbacks of an intentional friendship programme (Compeer, Inc), which develops new social relationships for people with SMI by matching them in one-to-one relationships with community volunteers for weekly social activities.Methods: Twenty clients and volunteers, in Compeer friendships for different lengths of time, participated in individual semi-structured qualitative inter- views. Several volunteers were themselves current or former consumers of mental health services.Results: Participants reported numerous beneﬁts to participating in Compeer. Clients and volunteers spoke enthusiastically about the beneﬁts of gaining a friend. Many intentional relationships deepened over several years into mutually beneﬁcial friendships. Most clients became more outgoing, sociable and active, with increased self-esteem, self-worth and self-conﬁdence. Volunteers who had experienced mental illness themselves provided unique added beneﬁts to the relationship. Drawbacks were minimal and ﬁnancial and other costs to volunteers were low.Conclusions: Intentional friendships can be a potent yet cost-effective way to help people with SMI develop social skills, expand their social networks, and im-prove their quality of life. However, because relationships take several years to develop, quantitative evaluations using short follow-up periods may underestimate programme effectiveness.Key words: serious mental illness, intentional friendship, befriending, social support, community integration
Association of Thyroid Function With the Estimated Glomerular Filtration Rate in a Large Chinese Euthyroid Population

Background/Aims: We aimed to explore whether thyroid function within a normal range is associated with the estimated glomerular filtration rate (eGFR) and the incidence of chronic kidney disease (CKD) in a large Chinese population. Methods: We conducted a cross-sectional study that included 10,859 euthyroid individuals who underwent an annual regular health checkup in Jiangsu Province Official Hospital between August 2012 and August 2013. We measured the thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels using a Roche modular analytics E170 and then calculated the eGFR using the Chinese modified Modification of Diet in Renal Disease (CMDRD) equation. Results: In multiple linear regression models, TSH was negatively associated with eGFR after adjusting for confounding factors (β = -0.072, P = 1.994×10-22). The significance remained in both males and females. No significant association was observed between FT4 and eGFR. In the logistic regression model, we did not observe significant associations of TSH or FT3 with CKD. Participants in the highest quartile of FT4 versus the lowest quartile (reference) had an increased risk of CKD (OR = 1.763, P = 0.012). The risk of CKD was more pronounced in females with the highest quartile of FT4 (OR = 2.424, P = 0.029). Conclusion: Our findings suggest that TSH is associated with eGFR in euthyroid individuals and that higher FT4 is associated with an increased risk of CKD. More cohort studies are warranted to confirm whether the association is causal.
Preclinical human models and emerging therapeutics for advanced systemic mastocytosis

Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, the neoplastic cells carry activating mutations in KIT. Progress in mastocytosis research has long been hindered by the lack of suitable in vitro models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC-1, LAD1/2, LUVA, ROSA and MCPV-1. The HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34+ cells of non-mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSAKIT WT and MCPV-1) do not harbor KIT mutations, HMC-1 and ROSAKIT D816V cells exhibit activating KIT mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSAKIT D816V subclone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice. Such a model may allow in vivo validation of data obtained in vitro with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSAKIT D816V cells in preclinical therapeutic research in mastocytosis.
Immune sensitization during 1 year in the Antarctic high‐altitude Concordia Environment

Antarctica is a challenging environment for humans. It serves as a spaceflight ground analog, reflecting some conditions of long‐duration exploration class space missions. The French‐Italian Concordia station in interior Antarctica is a high‐fidelity analog, located 1000 km from the coast, at an altitude of 3232 m. The aim of this field study was to characterize the extent, dynamics, and key mechanisms of the immune adaptation in humans overwintering at Concordia for 1 year.
Prevalence and mortality of congenital heart disease in Korean adults

Abstract The aim of this study was to assess the age-standardized prevalence (prevalence) and age-standardized mortality (mortality) of congenital heart disease (CHD) by sex in Korean adults. Data were collected from the National Health Insurance Service in Korea from 2006 through 2016. The data consisted of main and secondary diagnoses related to CHD. We calculated the prevalence and mortality of CHD in adults with the direct method using the estimated Korean population in 2015 as the reference. The prevalence of CHD in Korean adults increased from 35.8 cases per 100,000 persons in 2006 to 65.6 cases in 2015. In 2015, the prevalence in the 20- to 44-year-old group, 45- to 64-year-old group, and the older than 65 years group was 54.6, 69.6, and 95.1 cases, respectively. Among women, the prevalence was 34.3 and 31.3 cases in men. The mortality of CHD in adults decreased from 3.061 persons per 100,000 persons in 2007 to 0.551 persons in 2015. The 5-year survival rate (SR) for people with CHD was 0.92 (95% confidence interval [CI] 0.91–0.93). The 5-year SR for the 20- to 44- and 45- to 64-year-old groups was more than 0.95; however, the 5-year SR of the older than 65 years group was only 0.73 (95% CI 0.72–0.74). The prevalence of CHD in Korean adults increased and the related mortality decreased during a decade. The 5-year SR of CHD for those over 65 years was lower than that for younger age groups.
Identification of the biological affection of long noncoding RNA BC200 in Alzheimer’s disease

BC200 is a long noncoding RNA expressed at high levels in the Alzheimer’s disease (AD), and blocking of BC200 by siRNA is assumed to be an effective method for various disease therapy. We have established an AD cell model overexpressing amyloid &bgr;-peptide (A&bgr;)1-42 to observe the effects of BC200 on the cell viability and apoptosis, and to investigate the associated underlying mechanisms. Efficient knockdown and overexpression of BC200 were established using BC200 siRNA and BC200 mimics, respectively. Cell viability following BC200 knockdown and overexpression was assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide assay, and cell apoptosis was monitored by flow cytometry. We successfully established an AD cell model overexpressing A&bgr;1-42 gene, and reported the results of change of BC200 on A&bgr;1-42 levels. Knockdown of BC200 significantly suppressed b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression, and overexpression of BC200 increased BACE1 expression. Besides, inhibition of BC200 significantly increased cell viability and reduced cell apoptosis in the AD model via directly targeting BACE1, which can be increased by overexpression of BC200. BC200 regulated AD cell viability and apoptosis via targeting BACE1, and it may be one of the putative target in AD development and provides potential new insights into genetic therapy against AD.
Targeted Multiplex Gene Expression Profiling to Measure High-Fat Diet and Metformin Effects on Fetal Gene Expression in a Mouse Model

Background: Maternal obesity and excessive gestational weight gain (GWG) are associated with delivery of a large-for-gestational-age infant. We used a high-fat diet (HFD) mouse model to separate the effect of maternal obesity from excessive GWG on fetal growth. Our objective was to identify fetal gene expression changes in an HFD and control diet (CD) mouse model with and without metformin exposure. Study Design: Normal weight timed-pregnant (Female Friend virus B) strain mice were allocated on day e0.5 to receive HFD or CD and either plain water or metformin (2.5 mg/mL in drinking water). Dams were euthanized on day e17.5 and fetal livers harvested and frozen at −80°C. RNA was extracted and hybridized to a customized 96-gene Nanostring panel focused on angiogenesis, inflammation, and growth gene expression. Fetal liver gene expression was compared between metformin and plain water groups using analysis of variance. Significant differences in gene expression, defined by a false discovery controlled q value <0.01, were then analyzed using Ingenuity pathway analysis (IPA). Results: In HFD-fed dams, compared to controls, the metformin-treated group had significantly lower fetal weight and 39 differentially expressed liver genes; 15 (38%) were in the growth/angiogenesis gene expression network. IPA predicted that fetal liver gene upregulation associated with metformin exposure is a result of metformin inhibition of the common upstream regulator, phosphatase and tensin homolog (PTEN). Conclusions: Metformin-exposed fetuses from dams fed HFD and CD have significant gene expression differences in genes specific to growth and angiogenesis pathways in the fetal liver. Diet alone did not alter fetal liver gene expression.
Associations of Family Demands and Work–Life Conflict with Musculoskeletal Disorders among Korean Workers

Although family-related demands play a role in the effect of psychosocial work characteristics on health, research on work-related health has neglected the family domain. The aim of the present study was to identify the effects of family demands and work–life conflict (WLC) on musculoskeletal disorders (MSDs) among Korean workers. We analyzed data from the nationally representative Korean Working Conditions Survey conducted with 50,007 workers in 2014. Logistic regression analyses stratified by gender were performed to identify gender differences, and interaction terms including WLCs and key covariates were also incorporated. Childcare demands (odds ratio (OR), 1.16) were related to MSD only in male workers, whereas homemaking (OR, 1.09) and eldercare (OR, 1.26) demands were related to MSDs only in female workers. WLC was also associated with MSDs among both male (OR, 1.50) and female (OR, 1.55) workers. We found no gender difference in the effect of WLC on MSDs (p = 0.91). Moreover, childcare demands may exacerbate the effect of WLC on MSDs. Our data suggest that family demands and WLC could be important targets of workplace interventions to prevent MSDs, and future research should evaluate the role of family demands and WLC as stressors in the workplace.