53 research outputs found
Assessing observational constraints on future European climate in an out-of-sample framework
Observations are increasingly used to constrain multi-model projections for future climate assessments. This study assesses the performance of five constraining methods, which have previously been applied to attempt to improve regional climate projections from CMIP5-era models. We employ an out-of-sample testing approach to assess the efficacy of these constraining methods when applied to “pseudo-observational” datasets to constrain future changes in the European climate. These pseudo-observations are taken from CMIP6 simulations, for which future changes were withheld and used for verification. The constrained projections are more accurate and broadly more reliable for regional temperature projections compared to the unconstrained projections, especially in the summer season, which was not clear prior to this study. However, the constraining methods do not improve regional precipitation projections. We also analysed the performance of multi-method projections by combining the constrained projections, which are found to be competitive with the best-performing individual methods and demonstrate improvements in reliability for some temperature projections. The performance of the multi-method projection highlights the potential of combining constraints for the development of constraining methods
Rare Copy Number Variants in \u3cem\u3eNRXN1\u3c/em\u3e and \u3cem\u3eCNTN6\u3c/em\u3e Increase Risk for Tourette Syndrome
Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (\u3c 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (\u3e 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS
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Assessing observational constraints on future European climate in an out-of-sample framework
Observations are increasingly used to constrain multi-model projections for future climate assessments. This study assesses the performance of five constraining methods, which have previously been applied to attempt to improve regional climate projections from CMIP5-era models. We employ an out-of-sample testing approach to assess the efficacy of these constraining methods when applied to “pseudo-observational” datasets to constrain future changes in European climate. These pseudo-observations are taken from CMIP6 simulations, for which future changes were withheld and used for verification. The constrained projections are more accurate and broadly more reliable for regional temperature projections compared to the unconstrained projections, especially in the summer season, which was not clear prior to this study. However, the constraining methods do not improve regional precipitation projections. We also analysed the performance of multi-method projections, by combining the constrained projections, which are found to be competitive with the best performing individual methods and demonstrate improvements in reliability for some temperature projections. The performance of the multi-method projection highlights the potential of combining constraints for the development of constraining methods
Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort
BACKGROUND:
Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice.
METHODS:
A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively.
RESULTS:
SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655.
CONCLUSIONS:
In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis
We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk
Synaptic processes and immune-related pathways implicated in Tourette syndrome
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS
Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Embolization for pediatric blunt splenic injury is an alternative to splenectomy when observation fails.
BACKGROUND: Management of splenic injury has shifted from operative to nonoperative management in both children and adults with reports of high success rates. Benefits of splenic conservation include decreased hospital stay, blood transfusion, and mortality, as well as avoidance of infectious complications. Angiography with embolization is an innovative adjunct to nonoperative management and has resulted in increased splenic salvage in adults; however, data in the pediatric population are scant.
METHODS: A retrospective comparative study of a single-hospital trauma registry reviewed from 1999 to 2009. Patients 18 years and younger admitted with injury to the spleen were included. Children with penetrating injury were excluded. Children were divided into three categories by initial treatment: observation, embolization, or splenectomy. Data recorded include age, radiographic grade of injury, and Injury Severity Score (ISS). Groups were analyzed for success of initial treatment, requirement for transfusion of packed red blood cells, splenic salvage, and mortality.
RESULTS: Registry review identified 259 children with blunt splenic injury. Initial treatment was observation in 227, embolization in 15, and splenectomy in 17. In the observation group, 9 (4%) of 227 children failed initial treatment; 8 of these underwent embolization, while 1 unerwent splenectomy. In the embolization group, 1 (7%) of 15 failed initial treatment and underwent splenectomy. Blood transfusion was required by 38 (17%) of 227 in the observation group, 6 (40%) of 15 (p = 0.02) in the embolization group, and 15 (88%) of 17 (p \u3c 0.01) in the splenectomy group. Overall splenic salvage rate was 237 (92%) of 259. Three children died in the observation group, and four children died in the splenectomy group. There was no death in the embolization group.
CONCLUSION: Splenic artery embolization for blunt trauma in children is associated with a higher blood transfusion rate compared with observation but offers a safe, intermediate alternative to splenectomy when observation fails.
LEVEL OF EVIDENCE: Therapeutic study, level IV
Soccer injuries in children requiring trauma center admission.
BACKGROUND: Soccer continues to gain popularity among youth athletes, and increased numbers of children playing soccer can be expected to result in increased injuries.
OBJECTIVE: We reviewed children with soccer injuries severe enough to require trauma activation at our Level I trauma center to determine injury patterns and outcome. Our goal is to raise awareness of the potential for injury in youth soccer.
METHODS: A retrospective review was performed using the trauma registry and electronic medical records at a Level I trauma center to identify children (\u3c 18 years old) treated for soccer injury from 1999-2009. Data reviewed include age, gender, mechanism, injury, procedures, and outcome.
RESULTS: Eighty-one children treated for soccer injury were identified; 38 (47%) were male. Of these, 20 had injury severe enough to require trauma team activation and 61 had minor injury. Mean age was 14 years old (range 5-17 years, SD 2.3). Lower extremity was the most common site of injury (57%), followed by upper extremity (17%), head (16%), and torso (10%). Mechanisms were: kicked or kneed in 27 patients (33%), collision with another player in 25 (31%), fall in 18 (22%), struck by ball in 10 (12%), and unknown in 1 (1%). Procedures included reduction of fractures, splenectomy, abdominal abscess drainage, and surgical feeding access. Long hospitalizations were recorded in some cases. There were no deaths.
CONCLUSION: Although less common, injury requiring prolonged hospital admission and invasive operative procedures exist in the expanding world of youth soccer. With increasing participation in the sport, we anticipate greater numbers of these child athletes presenting with serious injury
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