A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures.

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.

Tractography patterns of pedunculopontine nucleus deep brain stimulation.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson's disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = -0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Management of complicated pediatric rhinosinusitis in the COVID-19 era.

With the ongoing development of the COVID-19 pandemic, research continues to emerge regarding the pathophysiology, characteristics, and treatment considerations for patients with COVID-19. No reports have highlighted the specific challenges posed in the management of pediatric patients with COVID-19 who present with complicated rhinosinusitis. In this report, we discuss our preoperative, intraoperative, and postoperative multidisciplinary treatment strategy for these cases and provide two examples of complicated rhinosinusitis cases in COVID-19 patients, treated with two different approaches. Pearls, insights, and a brief review of the literature are discussed.

Avian functional responses to landscape recovery.

Restoring native vegetation in agricultural landscapes can reverse biodiversity declines via species gains. Depending on whether the traits of colonizers are complementary or redundant to the assemblage, species gains can increase the efficiency or stability of ecological functions, yet detecting these processes is not straightforward. We propose a new conceptual model to identify potential changes to complementarity and redundancy in response to landscape change via relative changes in taxonomic and functional richness. We applied our model to a 14-year study of birds across an extensive agricultural region. We found compelling evidence that high levels of landscape-scale tree cover and patch-scale restoration were significant determinants of functional change in the overall bird assemblage. This was true for every one of the six traits investigated individually, indicating increased trait-specific functional complementarity and redundancy in the assemblage. Applying our conceptual model to species diversity data provided new insights into how the return of vertebrates to restored landscapes may affect ecological function.

Australian songbird body size tracks climate variation: 82 species over 50 years.

The observed variation in the body size responses of endotherms to climate change may be explained by two hypotheses: the size increases with climate variability (the starvation resistance hypothesis) and the size shrinks as mean temperatures rise (the heat exchange hypothesis). Across 82 Australian passerine species over 50 years, shrinking was associated with annual mean temperature rise exceeding 0.012°C driven by rising winter temperatures for arid and temperate zone species. We propose the warming winters hypothesis to explain this response. However, where average summer temperatures exceeded 34°C, species experiencing annual rise over 0.0116°C tended towards increasing size. Results suggest a broad-scale physiological response to changing climate, with size trends probably reflecting the relative strength of selection pressures across a climatic regime. Critically, a given amount of temperature change will have varying effects on phenotype depending on the season in which it occurs, masking the generality of size patterns associated with temperature change. Rather than phenotypic plasticity, and assuming body size is heritable, results suggest selective loss or gain of particular phenotypes could generate evolutionary change but may be difficult to detect with current warming rates.

The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.

Using ideal distributions of the time since habitat was disturbed to build metrics for evaluating landscape condition.

Developing a standardized approach to measuring the state of biodiversity in landscapes undergoing disturbance is crucial for evaluating and comparing change across different systems, assessing ecosystem vulnerability and the impacts of destructive activities, and helping direct species recovery actions. Existing ecosystem metrics of condition fail to acknowledge that a particular community could be in multiple states, and the distribution of states could worsen or improve when impacted by a disturbance process, depending on how far the current landscape distribution of states diverges from pre-anthropogenic impact baseline conditions. We propose a way of rapidly assessing regional-scale condition in ecosystems where the distribution of age classes representing increasing time since last disturbance is suspected to have diverged from an ideal benchmark reference distribution. We develop two metrics that (1) compare the observed mean time since last disturbance with an expected mean and (2) quantify the summed shortfall of vegetation age-class frequencies relative to a reference age-class distribution of time since last disturbance. We demonstrate the condition metrics using two case studies: (1) fire in threatened southwestern Australian proteaceaous mallee-heath and (2) impacts of disturbance (fire and logging) in the critically endangered southeastern Australian mountain ash Eucalyptus regnans forest on the yellow-bellied glider Petaurus australis. We explore the effects of uncertainty in benchmark time since last disturbance, and evaluate metric sensitivity using simulated age-class distributions representing alternative ecosystems. By accounting for and penalizing too-frequent and too-rare disturbances, the summed shortfall metric is more sensitive to change than mean time since last disturbance. We find that mountain ash forest is in much poorer condition (summed shortfall 38.5 out of 100 for a 120-yr benchmark disturbance interval) than indicated merely by loss of extent (84% of vegetation remaining). Proteaceaous mallee-heath is in worse condition than indicated by loss of extent for an upper benchmark interval of 80 yr, but condition almost doubles for the minimum tolerable time since last disturbance interval of 20 yr. To fully describe ecosystem degradation, we recommend that our summed shortfall metric, focused on habitat quality and informed by biologically meaningful baselines, be added to existing condition measures focused on vegetation extent. This will improve evaluation of change in ecosystem states and enhance management of ecosystems in poor condition.

A randomised double-blind placebo-controlled trial investigating the behavioural effects of vitamin, mineral and n-3 fatty acid supplementation in typically developing adolescent schoolchildren.

Nutrient deficiencies have been implicated in anti-social behaviour in schoolchildren; hence, correcting them may improve sociability. We therefore tested the effects of vitamin, mineral and n-3 supplementation on behaviour in a 12-week double-blind randomised placebo-controlled trial in typically developing UK adolescents aged 13-16 years (n 196). Changes in erythrocyte n-3 and 6 fatty acids and some mineral and vitamin levels were measured and compared with behavioural changes, using Conners' teacher ratings and school disciplinary records. At baseline, the children's PUFA (n-3 and n-6), vitamin and mineral levels were low, but they improved significantly in the group treated with n-3, vitamins and minerals (P=0·0005). On the Conners disruptive behaviour scale, the group given the active supplements improved, whereas the placebo group worsened (F=5·555, d=0·35; P=0·02). The general level of disciplinary infringements was low, thus making it difficult to obtain improvements. However, throughout the school term school disciplinary infringements increased significantly (by 25 %; Bayes factor=115) in both the treated and untreated groups. However, when the subjects were split into high and low baseline infringements, the low subset increased their offences, whereas the high-misbehaviour subset appeared to improve after treatment. But it was not possible to determine whether this was merely a statistical artifact. Thus, when assessed using the validated and standardised Conners teacher tests (but less clearly when using school discipline records in a school where misbehaviour was infrequent), supplementary nutrition might have a protective effect against worsening behaviour.

Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.

Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial.

OBJECTIVES: To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI. PATIENTS AND METHODS: Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15-2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31-3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16-3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11-1.83; EV 9; P = 0.26). CONCLUSIONS: Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.

Identifying the location of fire refuges in wet forest ecosystems.

The increasing frequency of large, high-severity fires threatens the survival of old-growth specialist fauna in fire-prone forests. Within topographically diverse montane forests, areas that experience less severe or fewer fires compared with those prevailing in the landscape may present unique resource opportunities enabling old-growth specialist fauna to survive. Statistical landscape models that identify the extent and distribution of potential fire refuges may assist land managers to incorporate these areas into relevant biodiversity conservation strategies. We used a case study in an Australian wet montane forest to establish how predictive fire simulation models can be interpreted as management tools to identify potential fire refuges. We examined the relationship between the probability of fire refuge occurrence as predicted by an existing fire refuge model and fire severity experienced during a large wildfire. We also examined the extent to which local fire severity was influenced by fire severity in the surrounding landscape. We used a combination of statistical approaches, including generalized linear modeling, variogram analysis, and receiver operating characteristics and area under the curve analysis (ROC AUC). We found that the amount of unburned habitat and the factors influencing the retention and location of fire refuges varied with fire conditions. Under extreme fire conditions, the distribution of fire refuges was limited to only extremely sheltered, fire-resistant regions of the landscape. During extreme fire conditions, fire severity patterns were largely determined by stochastic factors that could not be predicted by the model. When fire conditions were moderate, physical landscape properties appeared to mediate fire severity distribution. Our study demonstrates that land managers can employ predictive landscape fire models to identify the broader climatic and spatial domain within which fire refuges are likely to be present. It is essential that within these envelopes, forest is protected from logging, roads, and other developments so that the ecological processes related to the establishment and subsequent use of fire refuges are maintained.

Variability in surgical quality in a phase III clinical trial of radical cystectomy in patients with organ-confined, node-negative urothelial carcinoma of the bladder.

BACKGROUND AND OBJECTIVES: Previous studies have shown that variability in surgical technique can affect the outcomes of cooperative group trials. We analyzed measures of surgical quality and clinical outcomes in patients enrolled in the p53-MVAC trial. METHODS: We performed a post-hoc analysis of patients with pT1-T2N0M0 urothelial carcinoma of the bladder following radical cystectomy (RC) and bilateral pelvic and iliac lymphadenectomy (LND). Measures of surgical quality were examined for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: We reviewed operative and/or pathology reports for 440 patients from 35 sites. We found that only 31% of patients met all suggested trial eligibility criteria of having ≥15 lymph nodes identified in the pathologic specimen (LN#) and having undergone both extended and presacral LND. There was no association between extent of LND, LN#, or presacral LND and TTR or OS after adjustment for confounders and multiple testing. CONCLUSIONS: We demonstrated that there was substantial variability in surgical technique within a cooperative group trial. Despite explicit entry criteria, many patients did not undergo per-protocol LNDs. While outcomes were not apparently affected, it is nonetheless evident that careful attention to study design and quality monitoring will be critical to successful future trials.

Federal seafood safety response to the Deepwater Horizon oil spill.

Following the 2010 Deepwater Horizon oil spill, petroleum-related compounds and chemical dispersants were detected in the waters of the Gulf of Mexico. As a result, there was concern about the risk to human health through consumption of contaminated seafood in the region. Federal and Gulf Coast State agencies worked together on a sampling plan and analytical protocols to determine whether seafood was safe to eat and acceptable for sale in the marketplace. Sensory and chemical methods were used to measure polycyclic aromatic hydrocarbons (PAHs) and dispersant in >8,000 seafood specimens collected in federal waters of the Gulf. Overall, individual PAHs and the dispersant component dioctyl sodium sulfosuccinate were found in low concentrations or below the limits of quantitation. When detected, the concentrations were at least two orders of magnitude lower than the level of concern for human health risk. Once an area closed to fishing was free of visibly floating oil and all sensory and chemical results for the seafood species within an area met the criteria for reopening, that area was eligible to be reopened. On April 19, 2011 the area around the wellhead was the last area in federal waters to be reopened nearly 1 y after the spill began. However, as of November 9, 2011, some state waters off the Louisiana coast (Barataria Bay and the Delta region) remain closed to fishing.

Cross-sectional and temporal relationships between bird occupancy and vegetation cover at multiple spatial scales.

Scale is a key concept in ecology, but the statistically based quantification of scale effects has often proved difficult. This is exemplified by the challenges of quantifying relationships between biodiversity and vegetation cover at different spatial scales to guide restoration and conservation efforts in agricultural environments. We used data from 2002 to 2010 on 184 sites (viz., site scale) nested within 46 farms (the farm scale), nested within 23 landscapes (the landscape scale). We found cross-sectional relationships with the amount of vegetation cover that were typically positive for woodland birds and negative for open-country birds. However, for some species, relationships differed between spatial scales, suggesting differences in nesting and foraging requirements. There was a 3.5% increase in the amount of native vegetation cover in our study region between 2002 and 2010, and our analyses revealed that some open country species responded negatively to these temporal changes, typically at the farm and/or site scale, but not the landscape scale. Species generally exhibited stronger cross-sectional relationships with the amount of vegetation cover than relationships between changes in occupancy and temporal changes in vegetation cover. This unexpected result can be attributed to differences in habitat use by birds of existing vegetation cover (typically old-growth woodland) vs. plantings and natural regeneration, which are the main contributors to temporal increases in vegetation cover. By taking a multi-scaled empirical approach, we have identified species-specific, scale-dependent responses to vegetation cover. These findings are of considerable practical importance for understanding which species will respond to different scales of protection of existing areas of native vegetation, efforts to increase the amount of native vegetation over time, and both approaches together.

Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception.

Pain perception can be altered by activity in the periaqueductal gray (PAG). The PAG can decrease the incoming nociceptive signals at the level of the spinal dorsal horn, but it is not clear whether the PAG can also affect the sensory thalamus, ventral posterolateral and ventral posteromedial thalamic nuclei, to modulate pain. However, the PAG and the thalamus have direct connections with each other; so we postulated that the PAG may also modulate pain by inhibiting the sensory nuclei in the thalamus, and that these may also reciprocally influence the PAG. Here, by analyzing the local field potentials recorded from the sensory thalamus and the PAG in chronic pain patients with deep brain stimulation electrodes, we show that PAG stimulation inhibited the sensory thalamus with decreasing thalamic delta, theta, alpha and beta power, and sensory thalamus stimulation excited the PAG with increasing PAG delta and theta power. We demonstrate that the PAG and the sensory thalamus interact reciprocally at short latency, which may be related to pain modulation.

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia.

AIM: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. METHOD: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). RESULTS: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. INTERPRETATION: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals.

Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients.

RATIONALE: Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores. OBJECTIVES: To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients. METHODS: Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI. MEASUREMENTS AND MAIN RESULTS: Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI. CONCLUSIONS: Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.