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Background Mild traumatic brain injuries receive voluminous attention in the research literature, but this is confined almost entirely to sports and military contexts. As an occupation, performing stunts in film, television, and entertainment places the head at high risk of repetitive impact and whiplash, but stunt performers do not enjoy the same level of healthcare supervision and access as that provided to sports participants. Therefore, the aim of this study was to evaluate stunt performers’ qualitative perceptions of reporting and management of head trauma in their industry. Methods After giving their informed consent, 87 motion picture and television stunt performers responded to a query about their views of ways to improve how stunt performers’ occupational head trauma—specifically head impacts and head whips that could cause a concussion—are reported and managed. We analyzed their responses via content and thematic analyses. Two researchers independently marked and categorized key words, phrases, and texts to identify codes that described participants’ comments. They then revised, discussed, and resolved coding discrepancies through consensus to establish inter-coder reliability. Next, we identified thematic patterns that described participants’ understanding of the stunt performer industry and what must change to facilitate reporting of head trauma. We derived themes from data that occurred multiple times, both within and across short answer responses. Results We identified three primary themes cited by the stunt performers as needs in their industry: (1) Need to Reduce the Stigma of Reporting a Stunt-Related Injury, (2) Need to Eliminate the “Cowboy Culture,” and (3) Need to Improve the Quality of the Work Environment. Conclusions Stunt performers are crucial members of a global entertainment industry valued at approximately US$100 billion annually. A large segment of the world’s population consumes their work in motion pictures, television, and live entertainment. When they are given an anonymous opportunity to speak, stunt performers offer insight into and recommendations for industry changes—primarily cultural and educational in nature—that could improve their physical and mental health, career longevity, and employability when they are confronted with head trauma.

In this trial, high-frequency oscillatory ventilation was compared with conventional ventilation with a lung-protective protocol. When the study was stopped early, hospital mortality was 47% with HFOV versus 35% with the control ventilation strategy. The acute respiratory distress syndrome (ARDS) is a common complication of critical illness. 1 , 2 Mortality is high, and survivors often have long-term complications. 3 , 4 Although mechanical ventilation is life-sustaining for patients with ARDS, it can perpetuate lung injury. Basic research suggests that repetitive overstretching or collapse of lung units with each respiratory cycle can generate local and systemic inflammation, contributing to multiorgan failure and death. 5 Consistent with these findings are data from clinical trials that support the use of smaller tidal volumes (6 vs. 12 ml per kilogram of predicted body weight) 6 and higher levels of positive end-expiratory pressure (PEEP). . . .

Objectives To determine if coronary computed tomographic angiography enhances prediction of perioperative risk in patients before non-cardiac surgery and to assess the preoperative coronary anatomy in patients who experience a myocardial infarction after non-cardiac surgery.Design Prospective cohort study.Setting 12 centers in eight countries.Participants 955 patients with, or at risk of, atherosclerotic disease who underwent non-cardiac surgery.Interventions Coronary computed tomographic angiography was performed preoperatively; clinicians were blinded to the results unless left main disease was suspected. Results were classified as normal, non-obstructive (<50% stenosis), obstructive (one or two vessels with ≥50% stenosis), or extensive obstructive (≥50% stenosis in two vessels including the proximal left anterior descending artery, three vessels, or left main).Main outcome measure Composite of cardiovascular death and non-fatal myocardial infarction within 30 days after surgery (primary outcome). This was the dependent variable in Cox regression. The independent variables were scores on the revised cardiac risk index and findings on coronary computed tomographic angiography.Results The primary outcome occurred in 74 patients (8%). The model that included both scores on the revised cardiac risk index and findings on coronary computed tomographic angiography showed that coronary computed tomographic angiography provided independent prognostic information (P=0.014; C index=0.66). The adjusted hazard ratios were 1.51 (95% confidence interval 0.45 to 5.10) for non-obstructive disease; 2.05 (0.62 to 6.74) for obstructive disease; and 3.76 (1.12 to 12.62) for extensive obstructive disease. For the model with coronary computed tomographic angiography compared with the model based on the revised cardiac risk index alone, with 30 day risk categories of <5%, 5-15%, and >15% for the primary outcome, the results of risk reclassification indicate that in a sample of 1000 patients that coronary computed tomographic angiography would have resulted appropriately in 17 net patients receiving a higher risk estimation among the 77 patients who would have experienced the primary outcome (P<0.001). Coronary computed tomographic angiography, however, would have resulted inappropriately in 98 net patients receiving a higher risk estimation, among the 923 patients who would not have experienced the primary outcome (P<0.001). Among patients who had a perioperative myocardial infarction, preoperative coronary anatomy showed extensive obstructive disease in 31% (22/71), obstructive disease in 41% (29/71), non-obstructive disease in 24% (17/71), and normal findings in 4% (3/71).Conclusions Though findings on coronary computed tomographic angiography can improve estimation of risk for patients who will experience perioperative cardiovascular death or myocardial infarction, findings are more than five times as likely to lead to an inappropriate overestimation of risk among patients who will not experience these outcomes. Perioperative myocardial infarction occurs across the spectrum of coronary artery disease, suggesting that there could be several pathophysiologic mechanisms.

The SARS-CoV-2 Omicron BA.1 variant emerged in 2021 1 and has multiple mutations in its spike protein 2 . Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2 , and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways 3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis. The spike protein of the Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 than Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic and vaccine-elicited neutralizing antibodies.

Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1 , which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas. Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Overwintering success is an important determinant of arthropod populations that must be considered as climate change continues to influence the spatiotemporal population dynamics of agricultural pests. Using a long-term monitoring database and biologically relevant overwintering zones, we modeled the annual and seasonal population dynamics of a common pest, Helicoverpa zea (Boddie), based on three overwintering suitability zones throughout North America using four decades of soil temperatures: the southern range (able to persist through winter), transitional zone (uncertain overwintering survivorship), and northern limits (unable to survive winter). Our model indicates H. zea population dynamics are hierarchically structured with continental-level effects that are partitioned into three geographic zones. Seasonal populations were initially detected in the southern range, where they experienced multiple large population peaks. All three zones experienced a final peak between late July (southern range) and mid-August to mid-September (transitional zone and northern limits). The southern range expanded by 3% since 1981 and is projected to increase by twofold by 2099 but the areas of other zones are expected to decrease in the future. These changes suggest larger populations may persist at higher latitudes in the future due to reduced low-temperature lethal events during winter. Because H. zea is a highly migratory pest, predicting when populations accumulate in one region can inform synchronous or lagged population development in other regions. We show the value of combining long-term datasets, remotely sensed data, and laboratory findings to inform forecasting of insect pests.

Results from retrospective studies indicate that selecting individuals for low-dose CT lung cancer screening on the basis of a highly predictive risk model is superior to using criteria similar to those used in the National Lung Screening Trial (NLST; age, pack-year, and smoking quit-time). We designed the Pan-Canadian Early Detection of Lung Cancer (PanCan) study to assess the efficacy of a risk prediction model to select candidates for lung cancer screening, with the aim of determining whether this approach could better detect patients with early, potentially curable, lung cancer. We did this single-arm, prospective study in eight centres across Canada. We recruited participants aged 50–75 years, who had smoked at some point in their life (ever-smokers), and who did not have a self-reported history of lung cancer. Participants had at least a 2% 6-year risk of lung cancer as estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Risk variables in the model were age, smoking duration, pack-years, family history of lung cancer, education level, body-mass index, chest x-ray in the past 3 years, and history of chronic obstructive pulmonary disease. Individuals were screened with low-dose CT at baseline (T0), and at 1 (T1) and 4 (T4) years post-baseline. The primary outcome of the study was incidence of lung cancer. This study is registered with ClinicalTrials.gov, number NCT00751660. 7059 queries came into the study coordinating centre and were screened for PanCan risk. 15 were duplicates, so 7044 participants were considered for enrolment. Between Sept 24, 2008, and Dec 17, 2010, we recruited and enrolled 2537 eligible ever-smokers. After a median follow-up of 5·5 years (IQR 3·2–6·1), 172 lung cancers were diagnosed in 164 individuals (cumulative incidence 0·065 [95% CI 0·055–0·075], incidence rate 138·1 per 10 000 person-years [117·8–160·9]). There were ten interval lung cancers (6% of lung cancers and 6% of individuals with cancer): one diagnosed between T0 and T1, and nine between T1 and T4. Cumulative incidence was significantly higher than that observed in NLST (4·0%; p<0·0001). Compared with 593 (57%) of 1040 lung cancers observed in NLST, 133 (77%) of 172 lung cancers in the PanCan Study were early stage (I or II; p<0·0001). The PanCan model was effective in identifying individuals who were subsequently diagnosed with early, potentially curable, lung cancer. The incidence of cancers detected and the proportion of early stage cancers in the screened population was higher than observed in previous studies. This approach should be considered for adoption in lung cancer screening programmes. Terry Fox Research Institute and Canadian Partnership Against Cancer.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3′ untranslated region of VHL , nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23–3.30). In cis -expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals. A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.

ObjectivesTo determine the stance duration and ground reaction forces (GRF) of horses with deep digital flexor (DDF) tendinopathy at the level of the foot and compare the stance duration and GRF to those of clinically sound horses.DesignProspective clinical study.AnimalsSixteen horses (seven horses with bilateral forelimb lameness, four horses with unilateral forelimb lameness, and five horses with no lameness).ProceduresAnalyses of kinetic variables were performed on both forelimbs from sound horses and horses diagnosed with chronic DDF tendinopathy. Stance duration and longitudinal and vertical components of the GRF were determined for the limbs of clinically sound horses and limbs of horses with DDF tendinopathy. Separate Spearman correlation analyses were used to assess potential association within groups (combined left and right forelimbs of clinically sound horses, lamest limbs of horses with DDF tendinopathy, and contralateral limbs of horses with DDF tendinopathy) and with the set of kinetic variables. Analysis of variance on mean ranks of tied values was used to determine differences in kinetic variables between groups (PROC GLIMMIX) using the kinetic values of the clinically sound horses as the reference group.ResultsThere were a total of 11 lame horses. Seven horses had bilateral forelimb lameness and four had unilateral lameness. Of the 11 horses, there were 15 DDF tendinopathies. There were eight dorsal border DDF tendinopathies, five core DDF tendinopathies, and two sagittal/parasagittal splits DDF tendinopathies. The most lame limbs of horses with DDF tendinopathy had significantly smaller values for peak vertical force and time of peak braking force than did forelimbs of clinically sound horses. Also, the most lame limbs of horses with DDF tendinopathy had significantly larger values for the time of peak vertical force than did forelimbs of clinically sound horses.Conclusions and Clinical RelevanceHorses with chronic DDF tendinopathies develop certain alterations of GRF parameters. This information can be used in future studies to determine if particular kinetic variable changes in horses with DDF tendinopathies differ from those of horses with other pathologies within the foot and therefore could be diagnostic.