Tropical Origin, Global Diversification and Dispersal in the Pond Damselflies (Coenagrionoidea) Revealed by a New Molecular Phylogeny.

The processes responsible for the formation of Earth's most conspicuous diversity pattern, the latitudinal diversity gradient (LDG), remain unexplored for many clades in the Tree of Life. Here, we present a densely-sampled and dated molecular phylogeny for the most speciose clade of damselflies worldwide (Odonata: Coenagrionoidea), and investigate the role of time, macroevolutionary processes and biome-shift dynamics in shaping the LDG in this ancient insect superfamily. We used process-based biogeographic models to jointly infer ancestral ranges and speciation times, and to characterise within-biome dispersal and biome-shift dynamics across the cosmopolitan distribution of Coenagrionoidea. We also investigated temporal and biome-dependent variation in diversification rates. Our results uncover a tropical origin of pond damselflies and featherlegs ~ 105 Ma, while highlighting uncertainty of ancestral ranges within the tropics in deep time. Even though diversification rates have declined since the origin of this clade, global climate change and biome-shifts have slowly increased diversity in warm- and cold-temperate areas, where lineage turnover rates have been relatively higher. This study underscores the importance of biogeographic origin and time to diversify as important drivers of the LDG in pond damselflies and their relatives, while diversification dynamics have instead resulted in the formation of ephemeral species in temperate regions. Biome-shifts, although limited by tropical niche conservatism, have been the main factor reducing the steepness of the LDG in the last 30 Myr. With ongoing climate change and increasing northward range expansions of many damselfly taxa, the LDG may become less pronounced. Our results support recent calls to unify biogeographic and macroevolutionary approaches to increase our understanding of how latitudinal diversity gradients are formed and why they vary across time and among taxa.

Clinical impact of analgesic-sedative agents and peri-operative clinical status on white matter brain injury in preterm infants following surgical NEC.

BACKGROUND: The potential influence of exposure to analgesic-sedative agents (ASA) before, during, and after surgical NEC and peri-operative clinical status on white matter injury (WMI) in preterm infants has not been fully defined, and a comprehensive evaluation may inform future research and clinical interventions. METHODS: A retrospective study comparing ASA exposure before/during /after surgical NEC and peri-operative clinical status in neonates with and without WMI. RESULTS: Infants with any WMI (grade 2-4, n = 36/67, 53.7%) had a higher number of surgical procedures receiving ASA (5 [IQR: 3, 8] vs. 3 [2, 4]; p = 0.002) and had a longer duration of hypotension during their first (48.0 hours [26.0, 48.0] vs. 15.5 [6, 48]; p = 0.009) and second surgery (20 hours [0, 48h] vs. 0 [0, 22]; p = 0.017), received more hydrocortisone (35% vs.13.3%,p = 0.04) than those without any WMI. There were no differences in fentanyl/morphine/midazolam exposure before/during/after the NEC onset in the two groups.Infants with severe WMI (19/67, 28.3%, grade 3/4) had a higher incidence of AKI (P = 0.004), surgical morbidity (p = 0.047), more surgical procedures (6.5 [3, 10] vs. 4 [2, 5]; p = 0.012), and received higher mean fentanyl doses(p = 0.03) from birth until NEC onset than those without severe WMI. The univariate associations between these factors and severe WMI remained insignificant after multivariable logistic regression. CONCLUSION: Infants with WMI had more surgical procedures receiving ASA and had a longer duration of hypotension during surgeries. A large multicenter prospective study is needed to understand the full impact of ASA.

Correlation of placental pathology with the postoperative outcomes and white matter injury in preterm infants following necrotizing enterocolitis.

BACKGROUND: To determine the association of placental pathologic lesions with postoperative outcomes, survival, and white matter injury (WMI) in preterm infants with NEC. METHODS: A retrospective chart review of 107 neonates with NEC (Bell stage > IIa) from Jan 2013- June 2020 was completed. Demographic, clinical, and outcome data were compared between infants with or without placental pathologic lesions. RESULTS: In this cohort, 59/107 (55%) infants had medical NEC, and 48 (45%) had surgical NEC. The infants had a mean gestational age of 28.1±3.7 weeks and a birth weight of 1103±647 g. Maternal vascular malperfusion (82/107, 76.6%) and acute histological chorioamnionitis (42, 39.3%) were the most common pathological placental lesions. Acute histologic chorioamnionitis with fetal inflammatory response was more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p = 0.02). The NEC Infants with WMI on brain MRI scans had a significantly higher incidence of acute histological chorioamnionitis (52% vs. 27.8%; P = 0.04). No significant differences in mortality, length of stay and postoperative outcomes in neonates with and without acute histologic chorioamnionitis with fetal inflammatory response were noted. On unadjusted logistic regression, acute histologic chorioamnionitis without fetal inflammatory response was also associated with higher odds of WMI (OR 2.81; 95% CI 1.05-7.54; p = 0.039). CONCLUSION: Acute histological chorioamnionitis without fetal inflammatory response was associated with higher odds of WMI in infants with NEC, with no significant impact on mortality and other postoperative outcomes.

The black summer bushfires: impacts and risk factors for livestock bushfire injury in south-eastern Australia.

BACKGROUND: The 2019/2020 Australian bushfires were the largest bushfire event in modern Australian history. While actions to mitigate risk to homes from bushfires are well reported, there is very little research reported on the impacts of bushfires on livestock. With an increasing incidence of bushfires predicted, there is an urgent need to identify how farmers can best protect their livestock. OBJECTIVES: Compare bushfire affected farms with and without injured livestock to identify associations between risk factors and bushfire injury. Infer management approaches that can be used to reduce bushfire injury in livestock. METHOD: A case-control study using a structured interview questionnaire, delivered in late 2020 to cattle and sheep farmers in south-eastern Australia (New South Wales and Victoria) whose farmland was burnt in the 2019/2020 Australian bushfires. Case farms were farms with bushfires injured or killed livestock. Control farms were farms that had no bushfire injured livestock but that still had fire present on the farm. Interview responses were summarised and information theoretical approaches were used to identify potential risk factors for livestock bushfire injury and protective actions that could inform future fire-preparation recommendations. RESULTS AND DISCUSSION: Of 46 farms in the case-control study, 21 (46%) reported bushfire injured or killed livestock. Apparent protective factors identified included: preparation (having a bushfire plan and more than two farm bushfire fighting units), backburning and receiving assistance from fire authorities. Combined beef and sheep grazing enterprises appeared to have an increased risk of bushfire injury to livestock.

Clinical likelihood ratios and balanced accuracy for 44 in silico tools against multiple large-scale functional assays of cancer susceptibility genes.

PURPOSE: Where multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio of ~2. However, limited availability of "clinical truth sets" and prior use in tool training limits their utility for evaluation of tool performance. METHODS: We created a truth set of 9,436 missense variants classified as deleterious or tolerated in clinically validated high-throughput functional assays for BRCA1, BRCA2, MSH2, PTEN, and TP53 to evaluate predictive performance for 44 recommended/commonly used in silico tools. RESULTS: Over two-thirds of the tool-threshold combinations examined had specificity of <50%, thus substantially overcalling deleteriousness. REVEL scores of 0.8-1.0 had a Positive Likelihood Ratio (PLR) of 6.74 (5.24-8.82) compared to scores <0.7 and scores of 0-0.4 had a Negative Likelihood Ratio (NLR) of 34.3 (31.5-37.3) compared to scores of >0.7. For Meta-SNP, the equivalent PLR = 42.9 (14.4-406) and NLR = 19.4 (15.6-24.9). CONCLUSION: Against these clinically validated "functional truth sets," there was wide variation in the predictive performance of commonly used in silico tools. Overall, REVEL and Meta-SNP had best balanced accuracy and might potentially be used at stronger evidence weighting than current ACMG/AMP prescription, in particular for predictions of benignity.

Early success of the arthroscopic-assisted locked loop suprapectoral biceps tenodesis.

Background: There is wide variability in surgical technique for biceps tenodesis. Prior biomechanical studies have demonstrated superior ultimate and fatigue strength with a Krakow-type locked loop when compared with simple suture and lasso-loop configurations; however, this had not yet been clinically studied. The purpose of this study was to assess the short-term results an arthroscopic-assisted locked loop (ALL) suprapectoral biceps tenodesis technique. Methods: All patients who underwent an ALL suprapectoral biceps tenodesis by a single surgeon from 2012 and 2019 with a minimum of 12-month follow-up were analyzed. Data collected included demographics, surgical indications, concomitant operative procedures, and postoperative complications of anterior shoulder "groove" pain, "Popeye deformity," biceps muscle cramping pain, and need for revision surgery. Results: Forty patients who underwent an ALL suprapectoral biceps tenodesis met inclusion criteria. Patients were 55.6 ± 8.6 years of age, consisting of 28 men (57%) and 21 women (43%). The median follow-up was 19.3 months. At the latest follow-up, 1 (2%) patient had anterior shoulder "groove" pain, and no patients had a Popeye deformity or biceps muscle cramping. There were no revision biceps tenodesis procedures. Conclusion: The ALL suprapectoral biceps tenodesis technique results in a low incidence of postoperative complications. At a short-term follow-up of 1 year, no patients had reoperations or revisions for failed biceps tenodesis. Groove pain was nearly absent in this series of patients.

Sleep apnea and kidney transplant outcomes: findings from a 20-year (1997-2017) historical cohort study.

OBJECTIVE/BACKGROUND: A historic cohort single-center study of kidney transplant recipients with graft loss examined the associations between sleep apnea and two transplant outcomes, death with a functioning graft (DWFG), and graft survival time. PATIENT/METHODS: Adult patients who received transplants and experienced graft failure or DWFG from January 1, 1997 to January 1, 2017 constituted the cohort (n = 322). Data for the study were obtained by merging two secondary data sources: the Organ Procurement and Transplantation Network (OPTN) database and the transplant center's medical records. A Cox regression modeled the association of diagnosed sleep apnea, stratified by year-of transplant surgery, with graft survival time. Using backward elimination, this model was adjusted for recipient age, race/ethnicity, gender, functional status, donor age, and antigen mismatch. RESULTS: No statistically significant differences were found for proportions of DWFG in those with, versus without, sleep apnea, informing our censoring approach. When examining graft survival time, the Cox regression model was stratified given a sleep apnea and year-of-transplant interaction (p < 0.01, adjusted model). For patients transplanted between 1997 and 2008, sleep apnea was statistically significantly associated with a decreased risk of graft failure or cardiovascular-related DWFG [adjusted Hazard Ratio (aHR) = 0.63, 95%CI, 0.42-0.94]. For patients transplanted between 2009 and 2017, sleep apnea statistically significantly increased the risk of graft failure or cardiovascular-related DWFG (aHR = 2.61, 95%CI, 1.13-6.00). CONCLUSIONS: In a cohort of transplant recipients with graft loss, sleep apnea increased the risk of graft loss nearly three-fold among patients transplanted between 2009 and 2017. Similar DWFG proportions by sleep apnea presence indicate this risk is likely driven by renal failure, not mortality. Further research on whether treatment of sleep apnea can improve graft survival is warranted.

Intrinsic modifiable risk factors in ballet dancers: Applying evidence based practice principles to enhance clinical applications.

INTRODUCTION: The risk of musculoskeletal injury is multifactorial (Bahr 2005). Injury risk is a composite of intrinsic and extrinsic risk factors that can be modifiable or non-modifiable. Ballet dancers have unique risk factors, due to the nature of their art and sport. The purpose of this literature review is to identify intrinsic modifiable risk factors for injury in ballet dancers. The secondary purpose is to investigate potential screening tools which can be used to identify these risk factors. METHODS: The authors performed a review of the literature in October 2017 within the databases of MEDLINE Complete, SPORTDiscus, and PubMed Central following a list of inclusion and exclusion criteria. RESULTS: A review of the available literature identified seven intrinsic modifiable factors specifically for ballet dancers and seven appropriate screening tools. DISCUSSION: The literature identified the most common intrinsic modifiable risk factors associated with ballet dancers to be: hypermobility, fatigue, overuse, neuromuscular dysfunction, degree of turnout, weakness of core and lower extremity musculature, and lower extremity range of motion (ROM) discrepancies. CONCLUSION: Sports medicine professionals who manage these performing artists can use this literature review to help develop injury prevention programs and enhance return to sport decision.

A 12-item short form of the Knee injury and Osteoarthritis Outcome Score (KOOS-12): tests of reliability, validity and responsiveness.

OBJECTIVE: To evaluate reliability, validity and responsiveness of KOOS-12, a 12-item short form of the 42-item Knee injury and Osteoarthritis Outcome Score (KOOS) that provides Pain, Function and Quality of Life (QOL) scale scores and a summary knee impact score. DESIGN: Data from 1,392 knee osteoarthritis (OA) patients from the FORCE-TJR research cohort who completed KOOS before and 6 and 12 months after total knee replacement (TKR) were analyzed. KOOS-12 includes a pain frequency item and three items measuring pain during increasingly difficult (sitting/lying, walking, stairs) activities; function items about standing, rising from sitting, getting in/out of a car, and twisting/pivoting; and the 4-item KOOS QOL scale. Percent computable scale scores, floor and ceiling effects, internal consistency reliability, validity (scale correlations, tests of known groups validity using one-way analysis of variance (ANOVA)) and responsiveness (effect sizes, standardized response means) were compared for the KOOS-12, full-length KOOS, KOOS-PS and KOOS, JR. RESULTS: Internal consistency reliability was above 0.70 for all KOOS-12 scales and ≥0.90 for the KOOS-12 Summary score. Validity and responsiveness of KOOS-12 Pain, Function and QOL scales was satisfactory and reached similar conclusions as comparable full-length KOOS scales. The KOOS-12 Summary score was most responsive in discriminating between groups who differed in global ratings of post-TKR change in physical capabilities and had the highest effect sizes and standardized response means. CONCLUSIONS: KOOS-12 was a reliable and valid alternative to KOOS in TKR patients with moderate to severe OA and provided three domain-specific and summary knee impact scores with substantially reduced respondent burden.

Item selection for 12-item short forms of the Knee injury and Osteoarthritis Outcome Score (KOOS-12) and Hip disability and Osteoarthritis Outcome Score (HOOS-12).

OBJECTIVE: To develop 12-item short forms (KOOS-12, HOOS-12) of the 42-item Knee injury and Osteoarthritis Outcome Score (KOOS) and 40-item Hip disability and Osteoarthritis Outcome Score (HOOS) that represent the full-length instruments sufficiently to provide joint-specific pain, function and quality of life (QOL) domain and summary joint impact scores. This paper describes KOOS-12 and HOOS-12 item selection. Subsequent papers will examine KOOS-12 and HOOS-12 reliability, validity and responsiveness. DESIGN: Items were selected based on qualitative information from patients, clinicians and KOOS/HOOS translators and analysis of data from 1,395 knee osteoarthritis (OA) and 1,281 hip OA patients from the FORCE-TJR cohort who completed KOOS or HOOS before and after total joint replacement (TJR). Item response theory models and computerized adaptive test (CAT) simulations were used to identify items that best measured patients' levels of pain and function pre- and post-TJR. KOOS-12/HOOS-12 items were selected based on content, coverage of a wide measurement range, high item information, item usage in CAT simulations, scale-level properties (reliability, validity, responsiveness), and qualitative information. RESULTS: KOOS-12 and HOOS-12 each included a pain frequency item and three items measuring pain during increasingly difficult activities (sitting/lying, walking, up/down stairs); function items about standing, rising from sitting, getting in/out of a car, and twisting/pivoting (KOOS-12) or walking on an uneven surface (HOOS-12); and the original 4-item QOL scale. CONCLUSIONS: This study demonstrated the benefits of examining patient-reported outcome measures using modern psychometric methods, to create short forms with diverse content that provide domain-specific and summary joint impact scores.

A 12-item short form of the Hip disability and Osteoarthritis Outcome Score (HOOS-12): tests of reliability, validity and responsiveness.

OBJECTIVE: To evaluate reliability, validity and responsiveness of HOOS-12, a 12-item short form of the 40-item Hip disability and Osteoarthritis Outcome Score (HOOS). HOOS-12 provides Pain, Function and Quality of Life (QOL) scale scores and a summary hip impact score. DESIGN: Data from 1,273 FORCE-TJR hip osteoarthritis (OA) patients who completed HOOS before and six and 12 months after total hip replacement (THR) were analyzed. HOOS-12 includes a pain frequency item and three items measuring pain during increasingly difficult (sitting/lying, walking, stairs) activities; function items about standing, rising from sitting, getting in/out of a car, and walking on an uneven surface; and the 4-item HOOS QOL scale. Percent computable scale scores, floor and ceiling effects, internal consistency reliability, validity (scale correlations, tests of known groups validity using one-way analysis of variance (ANOVA)), and responsiveness (effect sizes (ES), standardized response means (SRM)) were compared for HOOS-12, full-length HOOS, HOOS-PS and HOOS, JR. RESULTS: Internal consistency reliability was above 0.70 for all HOOS-12 scales and above 0.90 for the HOOS-12 Summary score. Validity and responsiveness of HOOS-12 Pain, Function and QOL scales were satisfactory and reached similar conclusions as comparable full-length HOOS scales. The HOOS-12 Summary score was highly responsive in discriminating between groups who differed in global ratings of post-THR change in physical capabilities and had high ES and SRM standardized response means. CONCLUSIONS: HOOS-12 was a reliable and valid alternative to HOOS in THR patients with moderate to severe OA and provided three domain-specific and summary hip impact scores with substantially reduced respondent burden.

The arcuate fracture: A descriptive radiographic study.

PURPOSE: To assess plain radiographic morphology of arcuate fractures in order to identify patterns and help shape treatment algorithm for proximal fibula fracture. METHODS: A search of radiographic reports at a level 1 trauma center from 2014 to 2016 using MONTAGE search software for the phrases "arcuate fracture", "fibular head avulsion", or "fibular head fracture" was conducted. Descriptive measurements were obtained including dimensions of the fragment, the displacement of the fragment from its anatomic position, and the orientation of the primary fracture line relative to the axis of the fibular diaphysis in both the sagittal and coronal plane. After review of the measurements and radiographs, fracture patterns were assessed based off previous knowledge previous knowledge of posterior lateral corner (PLC) anatomy. RESULTS: Radiographic reports of 48 knees (48 patients) met inclusion criteria. The distance of fractures from the proximal aspect of the fibula averaged 9.25 ± 5.53 mm on AP radiographs, and 9.42 ± 4.89 mm on lateral radiographs. The medial-to-lateral width of the proximal fragment averaged 20.09 ± 7.94 mm on AP radiographs, while the anterior-to-posterior width measured on lateral radiographs averaged 17.53 ± 8.48 mm. Orientation of the primary fracture line was calculated at an average of 23.04 ± 14.95° from the perpendicular on the AP view, and 21.55 ± 17.44° from the perpendicular on the lateral. Maximal displacement at the primary fracture line on the AP view was 4.95 ± 8.49 mm). Maximal displacement on the lateral measured 3.98 ± 7.01 mm. Recurring fracture patterns were identified and described. Assessment revealed 11 (22.9%) pattern 1 fractures, six (12.5%) pattern 2 fractures, 31 (64.58%) pattern 3 fractures, possibly correlating with anatomical features and fracture mechanism. CONCLUSIONS: These measurements and recurring patterns in our study shows the heterogeneity of the size and displacement of these fracture fragments and demonstrates the need for further studies in order to create an anatomic descriptive classification for arcuate fractures, which could be used for clinically for treatment.

Preoperative KOOS and SF-36 Scores Are Associated With the Development of Symptomatic Knee Osteoarthritis at 7 Years After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Anterior cruciate ligament (ACL) tears are associated with the development of knee osteoarthritis despite ACL reconstruction surgery. However, little evidence is available to determine which patients will develop symptomatic knee osteoarthritis. PURPOSE: To determine if preoperative outcome measures-KOOS (Knee injury and Osteoarthritis Outcome Score) and SF-36 (36-item Short Form Health Survey)-were associated with the development of a symptomatic knee 7 years after ACL reconstruction. A secondary goal was to examine the relationship between imaging evidence of knee osteoarthritis and development of knee pain. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Prospectively collected data from 72 patients were reviewed with 7-year follow-up after unilateral ACL reconstruction. Patients were divided into symptomatic and asymptomatic groups based on the previously defined KOOS pain ≤72. Demographic variables and preoperative KOOS and SF-36 scores were compared between groups. Radiographic and magnetic resonance imaging data were used to evaluate differences in joint space width, Osteoarthritis Research Society International radiographic score, and the Whole-Organ Magnetic Resonance Imaging Score between groups. Univariate and multivariate analyses were performed to identify potential predictors of pain at 7-year follow-up. Wilcoxon sum rank and t tests were used to compare imaging findings between the symptomatic and asymptomatic patients at 7 years. RESULTS: According to KOOS pain, 7 of the 72 patients available at 7-year follow-up formed the symptomatic group. No differences were found between groups in regard to demographic variables or intraoperative findings. In multivariate analysis, lower preoperative scores for KOOS sports/recreation ( P = .005) and SF-36 mental health ( P = .025) were associated with a painful knee at 7 years, with increased odds of 82% and 68% per 10-unit decrease, respectively. The Whole-Organ Magnetic Resonance Imaging Score at 7 years showed evidence of osteoarthritic changes in the symptomatic group as compared with the asymptomatic group ( P = .047). However, there were no significant differences in the Osteoarthritis Research Society International radiographic score ( P = .051) or joint space width ( P = .488) between groups. CONCLUSION: Lower preoperative KOOS and SF-36 scores were associated with those patients who developed symptomatic knee osteoarthritis 7 years after ACL reconstruction.

Validation and determination of taselisib, a ß-sparing phosphoinositide 3-kinase (PI3K) inhibitor, in human plasma by LC-MS/MS.

A liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of taselisib (GDC-0032, RO5537381) concentrations in human plasma has been developed and validated to support bioanalysis of clinical samples. Solid phase extraction (SPE) was used to extract plasma samples (50µL) and the resulting samples were analyzed using reversed phase chromatography and mass spectrometry coupled with an atmospheric pressure chemical ionization interface. The mass analysis of taselisib was performed using multiple reaction monitoring transitions in positive ionization mode. The method was validated over the calibration curve range 0.400-400ng/mL using linear regression and 1/x(2) weighting. The within-run relative standard deviation (%RSD) ranged from 1.3 to 5.6%, while the between-run %RSD varied from 2.0 to 4.5% for LLOQ, low, medium, medium high and high QCs. The accuracy ranged from 94.7 to 100.3% of nominal for within-run and 96.0-99.0% of nominal for between-run for the same QCs. Extraction recovery of taselisib was between 83.8% and 92.9%. Stability of taselisib was established in human plasma for 977days at -20°C and -70°C and established in sample extracts for 96h when stored at 2 - 8°C. Stable-labeled internal standard was used to minimize matrix effects. Mean single dose pharmacokinetic parameters determined using this method for a phase I/II clinical trial were: Cmax=35.2ng/mL, AUC0-inf=1570ngh/mL, and T1/2=39.3h.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

The deterioration of driving performance over time in drivers with untreated sleep apnea.

Sleep apnea increases risk of driving crashes when left untreated. This study examined the driving performance decrements of untreated, undiagnosed sleep apnea drivers compared with healthy controls in a monotonous highway driving simulator task. It was hypothesized that the sleep apnea group would perform worse during a driving simulator test compared with the control group. A significant group by time interaction occurred indicating that sleep apnea participants' performance degraded more quickly over the course of the drive. In contrast with previous studies, this sleep apnea group did not include sleep disorder center patients, but rather community volunteers whose screening indicated a significant apnea/hypopnea index of 15 or greater. There may be inherent differences between patients and nonpatients with sleep apnea, as patients may have a more significant impact on their quality of life, causing them to seek treatment. Still, the results are clear that although the sleep apnea group drove similarly to the control group at the start of the drive, they are sensitive to time on task effects. These results support the need to diagnose and treat sleep apnea.

Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome.

BACKGROUND: With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). METHODS: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with ≥4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy (NCT00044304: registered at clinicaltrials.gov). The primary outcome was an eosinophil count <1.5 × 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. A retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily ≥ 1 month) were classified according to the criteria used in the prospective study. RESULTS: Overall, imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of ≥ 4 myeloid features was the sole predictor of response. After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36). CONCLUSIONS: Clinical features of MHES predict imatinib response in PDGFRA-negative HES.

Dimerization of glycoprotein Ibα is not sufficient to induce platelet clearance.

UNLABELLED: ESSENTIALS: Many anti-glycoprotein (GP)Ibα antibodies induce platelet clearance in a dimer-dependent manner. Characterization of monoclonal antibodies that bind the mechanosensitive domain (MSD) of GPIbα. An anti-MSD antibody binds two copies of GPIbα in platelets but does not induce platelet clearance. The prevailing clustering model of GPIbα signaling is incorrect or needs revision. BACKGROUND: The mechanism of platelet clearance is not clear. Many antibodies binding the membrane-distal ligand-binding domain of glycoprotein (GP)Ibα induce rapid clearance of platelets and acute thrombocytopenia, which requires the bifurcated antibody structure. It was thought that binding of these antibodies induced lateral dimerization or clustering of GPIbα in the plasma membrane, which leads to downstream signaling and platelet clearance. However, many antibodies targeting GPIbß and GPIX, which are associated with GPIbα in the GPIb-IX complex, do not induce platelet clearance, which is in contradiction to the clustering model. OBJECTIVES: To test whether dimerization or clustering of GPIbα is sufficient to transmit the signal that leads to platelet clearance. METHODS: We have recently raised several mAbs targeting the mechanosensitive domain (MSD) of GPIbα. Binding of these anti-MSD antibodies was characterized with biochemical methods. Their ability to stimulate platelets and induce platelet clearance in mice was assessed. RESULTS AND CONCLUSION: Infusion of anti-MSD antibodies does not cause thrombocytopenia in mice. These antibodies show no detectable effects on platelet activation and aggregation in vitro. Further biochemical investigation showed that the anti-MSD antibody 3D1 binds two copies of GPIbα on the platelet surface. Therefore, lateral dimerization of GPIbα induced by antibody binding is not sufficient to initiate GPIb-IX signaling and induce platelet clearance. Our results suggest that a factor other than or in addition to clustering of GPIbα is required to induce platelet clearance.

INSECT PHYLOGENOMICS. Response to Comment on "Phylogenomics resolves the timing and pattern of insect evolution".

Tong et al. comment on the accuracy of the dating analysis presented in our work on the phylogeny of insects and provide a reanalysis of our data. They replace log-normal priors with uniform priors and add a "roachoid" fossil as a calibration point. Although the reanalysis provides an interesting alternative viewpoint, we maintain that our choices were appropriate.