Antidepressant drugs and risk of developing glioma: a national registry-based case control study and a meta-analysis.

The aim of the present study was to investigate if use of antidepressants is related to the risk of developing lower (WHO grade 2-3) and higher grade (WHO grade 4) glioma. A registry-based case-control study was performed using 1283 glioma cases and 6400 age-, sex- and geographically matched controls, diagnosed in Sweden 2009-2013. Conditional logistic regression was used to analyze whether Selective Serotonin Reuptake Inhibitors (SSRIs) or non-SSRIs were associated with the risk of developing lower- or higher-grade glioma in the study population. Our results show that use of antidepressant medication was not associated with the risk of developing glioma. We also performed a meta-analysis in which the dataset from the present study was combined with results from two previous epidemiological studies to answer the same questions. The meta-analysis showed a modest risk reduction of developing glioma in relation to antidepressant treatment (OR 0.90 [95% CI 0.83-0.97]), when all glioma subgroups and all forms of antidepressant medications were combined. In conclusion, it remains possible that antidepressants may have common monoaminergic mechanism(s) that reduce the risk of developing glioma.

The Prevalence of Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-analysis.

It is increasingly recognized that cognitive symptoms are a common sequelae of relapsing-remitting multiple sclerosis and are associated with adverse functional consequences. However, estimates of cognitive impairment (CIm) prevalence vary widely. This study aimed to determine the pooled prevalence of CIm among adults with RRMS and investigate moderators of prevalence rates. Following prospective registration (PROSPERO; CRD42021281815), electronic databases (Embase, Scopus, Medline, and PsycINFO) were searched from inception until March 2023. Eligible studies reported the prevalence of CIm among adults with RRMS, as determined through standardized neuropsychological testing and defined as evidence of reduced performance across at least two cognitive domains (e.g., processing speed, attention) relative to normative samples, healthy controls, or premorbid estimates. The electronic database search yielded 8695 unique records, of which 50 met selection criteria. The pooled prevalence of cognitive impairment was 32.5% (95% confidence interval 29.3-36.0%) across 5859 participants. Mean disease duration and age were significant predictors of cognitive impairment prevalence, with samples with longer disease durations and older age reporting higher prevalence rates. Studies which administered more extensive test batteries also reported significantly higher cognitive impairment prevalence. Approximately one third of adults with RRMS experience clinical levels of CIm. This finding supports the use of routine cognitive testing to enable early detection of CIm, and to identify individuals who may benefit from additional cognitive and functional support during treatment planning.

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts.

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.

A phase II, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesis-generating, phase II, prospective, open-label, randomized study (clinicaltrials gov. Identifier: NCT03339297) compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age 57 years; range, 2-69 years) or SOC arm (n=73; median age 56 years; range, 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8%, 90% confidence interval [CI]: -22.5 to 4.9). The difference noted at day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2%; 90% CI: -41.8 to 7.5). Overall survival rates at day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.

Pharmacogenetic profiling via genome sequencing in children with medical complexity.

BACKGROUND: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear. METHODS: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC. RESULTS: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors. CONCLUSION: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC. IMPACT: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.

Durable response to afatinib in advanced lung adenocarcinoma harboring a novel NPTN-NRG1 fusion: a case report.

BACKGROUND: NRG1 fusions are rare oncogenic drivers in solid tumors, and the incidence of NRG1 fusions in non-small cell lung cancer (NSCLC) was 0.26%. It is essential to explore potential therapeutic strategies and efficacy predictors for NRG1 fusion-positive cancers. CASE PRESENTATION: We report an advanced lung adenocarcinoma patient harboring a novel NPTN-NRG1 fusion identified by RNA-based next-generation sequencing (NGS), which was not detected by DNA-based NGS at initial diagnosis. Transcriptomics data of the tissue biopsy showed NRG1α isoform accounted for 30% of total NRG1 reads, and NRG1ß isoform was undetectable. The patient received afatinib as fourth-line treatment and received a progression-free survival (PFS) of 14 months. CONCLUSIONS: This report supports afatinib can provide potential benefit for NRG1 fusion patients, and RNA-based NGS is an accurate and cost-effective strategy for fusion detection and isoform identification.

Integration of arts and humanities in medicine to develop well-rounded physicians: the roles of health sciences librarians.

Over the past ten years, there has been a growing interest in integrating arts and humanities in medicine to increase learners' empathy and resilience; improve personal well-being, communication, and observational skills; enhance self-reflection; and promote professionalism. These desired skills and qualities are becoming increasingly important for the physicians of tomorrow. Parallel to curricular interventions of integrating arts and humanities to medical education, there has been an increasing research interest in investigating the impact of such interventions on medical students with respect to improving and sustaining students' empathy as they progress in their medical education and develop their professional identity. Research has yielded interesting findings on the types and effect of the interventions in the medical curriculum. The Association of the American Medical Colleges (AAMC), recognizing the unique and unrealized role of arts and humanities in preparing and equipping physicians for twenty-first-century challenges, proposed seven recommendations for advancing arts and humanities integration into medical education to improve the education, practice, and well-being of physicians and physician learners across the spectrum of medical education. Institutional initiatives of arts and humanities integration in the medical curriculum in response to the AAMC's recommendations afford health sciences librarians expansive opportunities and a new landscape of playing an important role in these initiatives. With their diverse educational background in arts, humanities, social sciences, and many other disciplines and fields, health sciences librarians are poised for meaningful contributions to their institutional goals in developing a humanistic, compassionate workforce of future physicians.

Breast cancer screening and overdiagnosis.

Overdiagnosis is a harmful consequence of screening which is particularly challenging to estimate. An unbiased setting to measure overdiagnosis in breast cancer screening requires comparative data from a screened and an unscreened cohort for at least 30 years. Such randomised data will not become available, leaving us with observational data over shorter time periods and outcomes of modelling. This collaborative effort of the International Cancer Screening Network quantified the variation in estimated breast cancer overdiagnosis in organised programmes with evaluation of both observed and simulated data, and presented examples of how modelling can provide additional insights. Reliable observational data, analysed with study design accounting for methodological pitfalls, and modelling studies with different approaches, indicate that overdiagnosis accounts for less than 10% of invasive breast cancer cases in a screening target population of women aged 50 to 69. Estimates above this level are likely to derive from inaccuracies in study design. The widely discrepant estimates of overdiagnosis reported from observational data could substantially be reduced by use of a cohort study design with at least 10 years of follow-up after screening stops. In contexts where concomitant opportunistic screening or gradual implementation of screening occurs, and data on valid comparison groups are not readily available, modelling of screening intervention becomes an advantageous option to obtain reliable estimates of breast cancer overdiagnosis.

A scoping review of Q-methodology in healthcare research.

BACKGROUND: Q-methodology is an approach to studying complex issues of human 'subjectivity'. Although this approach was developed in the early twentieth century, the value of Q-methodology in healthcare was not recognised until relatively recently. The aim of this review was to scope the empirical healthcare literature to examine the extent to which Q-methodology has been utilised in healthcare over time, including how it has been used and for what purposes. METHODS: A search of three electronic databases (Scopus, EBSCO-CINAHL Complete, Medline) was conducted. No date restriction was applied. A title and abstract review, followed by a full-text review, was conducted by a team of five reviewers. Included articles were English-language, peer-reviewed journal articles that used Q-methodology (both Q-sorting and inverted factor analysis) in healthcare settings. The following data items were extracted into a purpose-designed Excel spreadsheet: study details (e.g., setting, country, year), reasons for using Q-methodology, healthcare topic area, participants (type and number), materials (e.g., ranking anchors and Q-set), methods (e.g., development of the Q-set, analysis), study results, and study implications. Data synthesis was descriptive in nature and involved frequency counting, open coding and the organisation by data items. RESULTS: Of the 2,302 articles identified by the search, 289 studies were included in this review. We found evidence of increased use of Q-methodology in healthcare, particularly over the last 5 years. However, this research remains diffuse, spread across a large number of journals and topic areas. In a number of studies, we identified limitations in the reporting of methods, such as insufficient information on how authors derived their Q-set, what types of analyses they performed, and the amount of variance explained. CONCLUSIONS: Although Q-methodology is increasingly being adopted in healthcare research, it still appears to be relatively novel. This review highlight commonalities in how the method has been used, areas of application, and the potential value of the approach. To facilitate reporting of Q-methodological studies, we present a checklist of details that should be included for publication.

Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons.

Children who survive premature birth often exhibit reductions in hippocampal volumes and deficits in working memory. However, it is unclear whether synaptic plasticity and cellular mechanisms of learning and memory can be elicited or disrupted in the preterm fetal hippocampus. CA1 hippocampal neurons were exposed to two common insults to preterm brain: transient hypoxia-ischemia (HI) and hypoxia (Hx). We used a preterm fetal sheep model using both sexes in twin 0.65 gestation fetuses that reproduces the spectrum of injury and abnormal growth in preterm infants. Using Cavalieri measurements, hippocampal volumes were reduced in both Hx and HI fetuses compared with controls. This volume loss was not the result of neuronal cell death. Instead, morphometrics revealed alterations in both basal and apical dendritic arborization that were significantly associated with the level of systemic hypoxemia and metabolic stress regardless of etiology. Anatomical alterations of CA1 neurons were accompanied by reductions in probability of presynaptic glutamate release, long-term synaptic plasticity and intrinsic excitability. The reduction in intrinsic excitability was in part due to increased activity of the channels underlying the fast and slow component of the afterhyperpolarization in Hx and HI. Our studies suggest that even a single brief episode of hypoxemia can markedly disrupt hippocampal maturation. Hypoxemia may contribute to long-term working memory disturbances in preterm survivors by disrupting neuronal maturation with resultant functional disturbances in hippocampal action potential throughput. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in hippocampal maturation.SIGNIFICANCE STATEMENT Premature infants commonly sustain hypoxia-ischemia, which results in reduced hippocampal growth and life-long disturbances in learning and memory. We demonstrate that the circuitry related to synaptic plasticity and cellular mechanisms of learning and memory (LTP) are already functional in the fetal hippocampus. Unlike adults, the fetal hippocampus is surprisingly resistant to cell death from hypoxia-ischemia. However, the hippocampus sustains robust structural and functional disturbances in the dendritic maturation of CA1 neurons that are significantly associated with the magnitude of a brief hypoxic stress. Since transient hypoxic episodes occur commonly in preterm survivors, our findings suggest that the learning problems that ensue may be related to the unique susceptibility of the hippocampus to brief episodes of hypoxemia.

Mammography screening reduces rates of advanced and fatal breast cancers: Results in 549,091 women.

BACKGROUND: It is of paramount importance to evaluate the impact of participation in organized mammography service screening independently from changes in breast cancer treatment. This can be done by measuring the incidence of fatal breast cancer, which is based on the date of diagnosis and not on the date of death. METHODS: Among 549,091 women, covering approximately 30% of the Swedish screening-eligible population, the authors calculated the incidence rates of 2473 breast cancers that were fatal within 10 years after diagnosis and the incidence rates of 9737 advanced breast cancers. Data regarding each breast cancer diagnosis and the cause and date of death of each breast cancer case were gathered from national Swedish registries. Tumor characteristics were collected from regional cancer centers. Aggregated data concerning invitation and participation were provided by Sectra Medical Systems AB. Incidence rates were analyzed using Poisson regression. RESULTS: Women who participated in mammography screening had a statistically significant 41% reduction in their risk of dying of breast cancer within 10 years (relative risk, 0.59; 95% CI, 0.51-0.68 [P < .001]) and a 25% reduction in the rate of advanced breast cancers (relative risk, 0.75; 95% CI, 0.66-0.84 [P < .001]). CONCLUSIONS: Substantial reductions in the incidence rate of breast cancers that were fatal within 10 years after diagnosis and in the advanced breast cancer rate were found in this contemporaneous comparison of women participating versus those not participating in screening. These benefits appeared to be independent of recent changes in treatment regimens.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

INTRODUCTION: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. METHODS: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. RESULTS: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.

The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening.

BACKGROUND: Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? METHODS: To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease-specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39-year period (1977-2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958-1976). All patients received stage-specific therapy according to the latest national guidelines, irrespective of the mode of detection. RESULTS: The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34-0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44-0.63) compared with the corresponding risks for nonparticipants. CONCLUSIONS: Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study.

BACKGROUND: The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males. METHODS: Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case-Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings. RESULTS: The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample. CONCLUSIONS: These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.

Overdiagnosis in the population-based organized breast cancer screening program estimated by a non-homogeneous multi-state model: a cohort study using individual data with long-term follow-up.

BACKGROUND: Overdiagnosis, defined as the detection of a cancer that would not become clinically apparent in a woman's lifetime without screening, has become a growing concern. Similar underlying risk of breast cancer in the screened and control groups is a prerequisite for unbiased estimates of overdiagnosis, but a contemporary control group is usually not available in organized screening programs. METHODS: We estimated the frequency of overdiagnosis of breast cancer due to screening in women 50-69 years old by using individual screening data from the population-based organized screening program in Stockholm County 1989-2014. A hidden Markov model with four latent states and three observed states was constructed to estimate the natural progression of breast cancer and the test sensitivity. Piecewise transition rates were used to consider the time-varying transition rates. The expected number of detected non-progressive breast cancer cases was calculated. RESULTS: During the study period, 2,333,153 invitations were sent out; on average, the participation rate in the screening program was 72.7% and the average recall rate was 2.48%. In total, 14,648 invasive breast cancer cases were diagnosed; among the 8305 screen-detected cases, the expected number of non-progressive breast cancer cases was 35.9, which is equivalent to 0.43% (95% confidence interval (CI) 0.10%-2.2%) overdiagnosis. The corresponding estimates for the prevalent and subsequent rounds were 15.6 (0.87%, 95% CI 0.20%-4.3%) and 20.3 (0.31%, 95% CI 0.07%-1.6%), respectively. The likelihood ratio test showed that the non-homogeneous model fitted the data better than an age-homogeneous model (P <0.001). CONCLUSIONS: Our findings suggest that overdiagnosis in the organized biennial mammographic screening for women 50-69 in Stockholm County is a minor phenomenon. The frequency of overdiagnosis in the prevalent screening round was higher than that in subsequent rounds. The non-homogeneous model performed better than the simpler, traditional homogeneous model.

Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation.

The RefSeq project at the National Center for Biotechnology Information (NCBI) maintains and curates a publicly available database of annotated genomic, transcript, and protein sequence records (http://www.ncbi.nlm.nih.gov/refseq/). The RefSeq project leverages the data submitted to the International Nucleotide Sequence Database Collaboration (INSDC) against a combination of computation, manual curation, and collaboration to produce a standard set of stable, non-redundant reference sequences. The RefSeq project augments these reference sequences with current knowledge including publications, functional features and informative nomenclature. The database currently represents sequences from more than 55,000 organisms (>4800 viruses, >40,000 prokaryotes and >10,000 eukaryotes; RefSeq release 71), ranging from a single record to complete genomes. This paper summarizes the current status of the viral, prokaryotic, and eukaryotic branches of the RefSeq project, reports on improvements to data access and details efforts to further expand the taxonomic representation of the collection. We also highlight diverse functional curation initiatives that support multiple uses of RefSeq data including taxonomic validation, genome annotation, comparative genomics, and clinical testing. We summarize our approach to utilizing available RNA-Seq and other data types in our manual curation process for vertebrate, plant, and other species, and describe a new direction for prokaryotic genomes and protein name management.

Functional changes in hippocampal synaptic signaling in offspring survivors of a mouse model of intrauterine inflammation.

BACKGROUND: Recent evidence suggests that exposure to intrauterine inflammation causes acute fetal brain injury and is linked to a spectrum of neurobehavioral disorders. In a rodent model of intrauterine inflammation induced by lipopolysaccharide (LPS) exposure in utero, activated microglia can be detected in the hippocampus of offspring survivors, as late as 60 days postnatal (DPN). Given that the hippocampus is important for learning and memory, these results suggest that in utero inflammation underlies long-term cognitive deficits observed in children/survivors. METHODS: An established mouse model of LPS-induced intrauterine inflammation was used to study hippocampal function from offspring at 44-59 DPN. Microgliosis was examined at 45 DPN. Extracellular field recordings of synaptic transmission were performed on acute hippocampal slices. RESULTS: LPS offspring mice displayed persistent microglial activation and increased CA3-CA1 excitatory synaptic strength, which can be explained in part by an increase in the probability of glutamate release, and reduced long-term synaptic potentiation compared to control mice. CONCLUSIONS: These results offer a mechanistic explanation for the cognitive and behavioral deficits observed in survivors of preterm birth caused by intrauterine inflammation.

Initiators and promoters for the occurrence of screen-detected breast cancer and the progression to clinically-detected interval breast cancer.

BACKGROUND: The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. METHODS: We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. RESULTS: The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m2) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99-1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51-0.82). Dense breast (aRR 1.46; 95% CI, 1.12-1.91), triple-negative (aRR 2.07; 95% CI, 1.37-3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19-2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56-7.02) compared with the Luminal A subtype. DISCUSSION: We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individually-tailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage.

RefSeq: an update on mammalian reference sequences.

The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of annotated genomic, transcript and protein sequence records derived from data in public sequence archives and from computation, curation and collaboration (http://www.ncbi.nlm.nih.gov/refseq/). We report here on growth of the mammalian and human subsets, changes to NCBI's eukaryotic annotation pipeline and modifications affecting transcript and protein records. Recent changes to NCBI's eukaryotic genome annotation pipeline provide higher throughput, and the addition of RNAseq data to the pipeline results in a significant expansion of the number of transcripts and novel exons annotated on mammalian RefSeq genomes. Recent annotation changes include reporting supporting evidence for transcript records, modification of exon feature annotation and the addition of a structured report of gene and sequence attributes of biological interest. We also describe a revised protein annotation policy for alternatively spliced transcripts with more divergent predicted proteins and we summarize the current status of the RefSeqGene project.