snu-aidas/HVMap-dataset huggingface dataset:
IQ and non-clinical psychotic symptoms in 12-year-olds: results  from the ALSPAC birth cohort

BACKGROUND Non-clinical psychotic symptoms appear common in children, but it is possible that a proportion of reported symptoms result from misinterpretation. There is a well-established association between pre-morbid low IQ score and schizophrenia. Psychosis-like symptoms in children may also be a risk factor for psychotic disorder but their relationship with IQ is unclear. AIMS To investigate the prevalence, nature and frequency of psychosis-like symptoms in 12-year-old children and study their relationship with IQ. METHOD Longitudinal study using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. A total of 6455 children completed screening questions for 12 psychotic symptoms followed by a semi-structured clinical assessment. IQ was assessed at 8 years of age using the Wechsler Intelligence Scale for Children (3rd UK edition). RESULTS The 6-month period prevalence for one or more symptoms was 13.7% (95% CI 12.8-14.5). After adjustment for confounding variables, there was a non-linear association between IQ score and psychosis-like symptoms, such that only those with below average IQ score had an increased risk of reporting such symptoms. CONCLUSIONS Non-clinical psychotic symptoms occur in a significant proportion of 12-year-olds. Symptoms are associated with low IQ and also less strongly with a high IQ score. The pattern of association with IQ differs from that observed in schizophrenia.
Transposable elements have rewired the core regulatory network of human embryonic stem cells

Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only ∼5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.
Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands

Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence.
Neutrophilic infiltration within the airway smooth muscle in patients with COPD.

BACKGROUND COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. METHODS To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. RESULTS Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). CONCLUSIONS Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation.
Characteristics of service users and provider organisations associated with experience of out of hours general practitioner care in England: population based cross sectional postal questionnaire survey.

OBJECTIVE To investigate the experience of users of out of hours general practitioner services in England, UK. DESIGN Population based cross sectional postal questionnaire survey. SETTING General Practice Patient Survey 2012-13. MAIN OUTCOME MEASURES Potential associations between sociodemographic factors (including ethnicity and ability to take time away from work during working hours to attend a healthcare consultation) and provider organisation type (not for profit, NHS, or commercial) and service users' experience of out of hours care (timeliness, confidence and trust in the out of hours clinician, and overall experience of the service), rated on a scale of 0-100. Which sociodemographic/provider characteristics were associated with service users' experience, the extent to which any observed differences could be because of clustering of service users of a particular sociodemographic group within poorer scoring providers, and the extent to which observed differences in experience varied across types of provider. RESULTS The overall response rate was 35%; 971,232/2,750,000 patients returned surveys. Data from 902,170 individual service users were mapped through their registered practice to one of 86 providers of out of hours GP care with known organisation type. Commercial providers of out of hours GP care were associated with poorer reports of overall experience of care, with a mean difference of -3.13 (95% confidence interval -4.96 to -1.30) compared with not for profit providers. Asian service users reported lower scores for all three experience outcomes than white service users (mean difference for overall experience of care -3.62, -4.36 to -2.89), as did service users who were unable to take time away from work compared with service users who did not work (mean difference for overall experience of care -4.73, -5.29 to -4.17). CONCLUSIONS Commercial providers of out of hours GP care were associated with poorer experience of care. Targeted interventions aimed at improving experience for patients from ethnic minorities and patients who are unable to take time away from work might be warranted.
Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.
Increased CDK1 activity determines the timing of kinetochore-microtubule attachments in meiosis I

Chromosome segregation during cell division depends on stable attachment of kinetochores to spindle microtubules. Mitotic spindle formation and kinetochore-microtubule (K-MT) capture typically occur within minutes of nuclear envelope breakdown. In contrast, during meiosis I in mouse oocytes, formation of the acentrosomal bipolar spindle takes 3-4 h, and stabilization of K-MT attachments is delayed an additional 3-4 h. The mechanism responsible for this delay, which likely prevents stabilization of erroneous attachments during spindle formation, is unknown. Here we show that during meiosis I, attachments are regulated by CDK1 activity, which gradually increases through prometaphase and metaphase I. Partial reduction of CDK1 activity delayed formation of stable attachments, whereas a premature increase in CDK1 activity led to precocious formation of stable attachments and eventually lagging chromosomes at anaphase I. These results indicate that the slow increase in CDK1 activity in meiosis I acts as a timing mechanism to allow stable K-MT attachments only after bipolar spindle formation, thus preventing attachment errors.
Discontinuation and non-publication of surgical randomised controlled trials: observational study

OBJECTIVE To determine the rate of early discontinuation and non-publication of randomised controlled trials involving patients undergoing surgery. DESIGN Cross sectional observational study of registered and published trials. SETTING Randomised controlled trials of interventions in patients undergoing a surgical procedure. DATA SOURCES The ClinicalTrials.gov database was searched for interventional trials registered between January 2008 and December 2009 using the keyword "surgery". Recruitment status was extracted from the ClinicalTrials.gov database. A systematic search for studies published in peer reviewed journals was performed; if they were not found, results posted on the ClinicalTrials.gov results database were sought. Email queries were sent to trial investigators of discontinued and unpublished completed trials if no reason for the respective status was disclosed. MAIN OUTCOME MEASURES Trial discontinuation before completion and non-publication after completion. Logistic regression was used to determine the effect of funding source on publication status, with adjustment for intervention type and trial size. RESULTS Of 818 registered trials found using the keyword "surgery", 395 met the inclusion criteria. Of these, 21% (81/395) were discontinued early, most commonly owing to poor recruitment (44%, 36/81). The remaining 314 (79%) trials proceeded to completion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range 4.0-6.0) years from study completion to publication search. A further 6% (20/314) of studies presented results on ClinicalTrials.gov without a corresponding peer reviewed publication. Industry funding did not affect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) but was associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72). Investigators' email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trials and 83% (101/122) of unpublished studies. Only 43% (6/14) and 20% (25/122) replies were received. Email responses for completed trials indicated 11 trials in press, five published studies (four in non-indexed peer reviewed journals), and nine trials remaining unpublished. CONCLUSIONS One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable. This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks. To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns.
Efficient Generation of Fully Reprogrammed Human iPS Cells via Polycistronic Retroviral Vector and a New Cocktail of Chemical Compounds

Direct reprogramming of human somatic cells into induced pluripotent stem (iPS) cells by defined transcription factors (TFs) provides great potential for regenerative medicine and biomedical research. This procedure has many challenges, including low reprogramming efficiency, many partially reprogrammed colonies, somatic coding mutations in the genome, etc. Here, we describe a simple approach for generating fully reprogrammed human iPS cells by using a single polycistronic retroviral vector expressing four human TFs in a single open reading frame (ORF), combined with a cocktail containing three small molecules (Sodium butyrate, SB431542, and PD0325901). Our results demonstrate that human iPS cells generated by this approach express human ES cells markers and exhibit pluripotency demonstrated by their abilities to differentiate into the three germ layers in vitro and in vivo. Notably, this approach not only provides a much faster reprogramming process but also significantly diminishes partially reprogrammed iPS cell colonies, thus facilitating efficient isolation of desired fully reprogrammed iPS cell colonies.
Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients.

SETTING Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh. OBJECTIVE To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a standardized regimen consisting of a minimum 9 months. DESIGN This was a prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance.
A Null Mutation in Inositol Polyphosphate 4-Phosphatase Type I Causes Selective Neuronal Loss in Weeble Mutant Mice

Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.
The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock.

Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1

Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection.
Malaria biology and disease pathogenesis: insights for new treatments

Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival.
Mutations among Italian mucopolysaccharidosis type I patients

A group of 27 Italian patients was screened for α-L-iduronidase mucopolysaccharidosis type I mutations. Mutations were found in 18 patients, with 28 alleles identified. The two most common mutations in northern Europeans (W402X and Q70X) accounted for 11% and 13% of the alleles, respectively. The R89Q mutation, uncommon in Europeans, was found only in one patient, accounting for 1 of 54 alleles (1.9%). The other mutations, P533R, A327P and G51D, accounted for 11%, 5.6% and 9.3% of the total alleles, respectively. Interestingly, the high frequency of the P533R mutation seems to be confined to Sicily and is higher than the 3% reported in a British/Australian study.
Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors

Abstract Pierce, D. A. and Preston, D. L. Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors. To clarify the information in the Radiation Effects Research Foundation data regarding cancer risks of low radiation doses, we focus on survivors with doses less than 0.5 Sv. For reasons indicated, we also restrict attention mainly to survivors within 3,000 m of the hypocenter of the bombs. Analysis is of solid cancer incidence from 1958–1994, involving 7,000 cancer cases among 50,000 survivors in that dose and distance range. The results provide useful risk estimates for doses as low as 0.05–0.1 Sv, which are not overestimated by linear risk estimates computed from the wider dose ranges 0–2 Sv or 0–4 Sv. There is a statistically significant risk in the range 0–0.1 Sv, and an upper confidence limit on any possible threshold is computed as 0.06 Sv. It is indicated that modification of the neutron dose estimates currently under consideration would not markedly change the conclusions.
Barriers and facilitators to implement shared decision making in multidisciplinary sciatica care: a qualitative study

BACKGROUND The Dutch multidisciplinary sciatica guideline recommends that the team of professionals involved in sciatica care and the patient together decide on surgical or prolonged conservative treatment (shared decision making [SDM]). Despite this recommendation, SDM is not yet integrated in sciatica care. Existing literature concerning barriers and facilitators to SDM implementation mainly focuses on one discipline only, whereas multidisciplinary care may involve other barriers and facilitators, or make these more complex for both professionals and patients. Therefore, this qualitative study aims to identify barriers and facilitators perceived by patients and professionals for SDM implementation in multidisciplinary sciatica care. METHODS We conducted 40 semi-structured interviews with professionals involved in sciatica care (general practitioners, physical therapists, neurologists, neurosurgeons, and orthopedic surgeons) and three focus groups among patients (six to eight per group). The interviews and focus groups were audiotaped and transcribed in full. Reported barriers and facilitators were classified according to the framework of Grol and Wensing. The software package Atlas.ti 7.0 was used for analysis. RESULTS Professionals reported 53 barriers and 5 facilitators, and patients 35 barriers and 18 facilitators for SDM in sciatica care. Professionals perceived most barriers at the level of the organizational context, and facilitators at the level of the individual professional. Patients reported most barriers and facilitators at the level of the individual professional. Several barriers and facilitators correspond with barriers and facilitators found in the literature (e.g., lack of time, motivation) but also new barriers and facilitators were identified. Many of these new barriers mentioned by both professionals and patients were related to the multidisciplinary setting, such as lack of visibility, lack of trust in expertise of other disciplines, and lack of communication between disciplines. CONCLUSIONS This study identified barriers and facilitators for SDM in the multidisciplinary sciatica setting, by both professionals and patients. It is clear that more barriers than facilitators are perceived for implementation of SDM in sciatica care. Newly identified barriers and facilitators are related to the multidisciplinary care setting. Therefore, an effective implementation strategy of SDM in a multidisciplinary setting such as in sciatica care should focus on these barriers and facilitators.