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Introduction Little is known regarding long-term mortality outcomes after non-fatal suicide attempts among Veterans Health Administration (VHA) patients, which may inform services delivery and program evaluation. Methods For 4,601,081 Veterans with 2005 VHA encounters, we assessed unadjusted and age-adjusted all-cause and cause-specific mortality through 2017, overall and for Veterans with (N = 8243) versus without (N = 4,592,838) 2005 VHA suicide attempt documentation. Standardized mortality ratios compared mortality rates by suicide attempt status. Multivariable proportional hazards regression models assessed age- and gender-adjusted mortality risk. Results Among Veteran VHA users with non-fatal suicide attempt diagnoses, 1.6% died of suicide, 4.6% of non-suicide external causes, and 30.7% of any cause. In age- and gender-adjusted analyses, Veterans who attempted suicide had increased suicide (hazard ratio [HR] = 4.52, 95% confidence interval [CI] = 3.82-5.36), non-suicide external cause (HR = 3.75, 95% CI = 3.38-4.17), and all-cause (separate due to non-proportional hazards: 2006, HR = 2.05, 95% CI = 1.81-2.31; 2007-2017, HR = 1.72, 95% CI = 1.65-1.80) mortality through 2017. Conclusion Over 12 years, Veteran VHA patients with non-fatal suicide attempt diagnoses had increased risk of suicide, non-suicide external cause, and all-cause mortality. Over 98% of Veteran VHA users who had a diagnosed non-fatal attempt did not die by suicide, highlighting additional program evaluation outcomes and opportunities to support physical and mental health.

The current study investigated the impact of birth order on vocabulary and social language development in 1338 first-born and 1049 s-born autistic youth (M age = 9.03 years, SD = 3.57; 86.4% male) from the Simons Simplex Collection. Frequentist and Bayesian analyses revealed mixed findings in language development. There were no differences in vocabulary or social language between first-born and second-born children. However, birth order and income together predicted expressive vocabulary and inappropriate speech such that birth order had a greater impact on language in lower-income families. This is the first study to investigate the impact of birth order on language outcomes in autistic youth and has implications for early intervention in lower-resourced communities.

Stroke remains a leading global cause of death and disability. In the last decade, the therapeutic window for mechanical thrombectomy has increased from a maximum of 6 to 24 h and beyond. While endovascular advancements have improved rates of recanalization, no post-stroke pharmacotherapeutics have been effective in enhancing neurorepair and recovery. New experimental models are needed to closer mimic the human patient. Our group has developed a model of transient 5-h occlusion in rats to mimic stroke patients undergoing thrombectomy. Our procedure was designed specifically in aged rats and was optimized based on sex in order to keep mortality and extent of injury consistent between aged male and female rats. This model uses a neurological assessment modeled after the NIH Stroke Scale. Finally, the potential for translation between our rat model of stroke and humans was assessed using comparative gene expression for key inflammatory genes. This model will be useful in the evaluation of therapeutic targets to develop adjuvant treatments for large vessel occlusion during the thrombectomy procedure.

During the COVID-19 pandemic, a major educational shift took place-the transition from face-to-face instruction to remote learning. Although this transition impacted all learners, it is speculated that groups of vulnerable youth (i.e., those with neurodevelopmental disorders, in rural areas, from low-income families) would demonstrate significant difficulties with remote instruction. However, no work to date has investigated remote learning in these groups in rural settings. Accordingly, the aim of this study was to characterize remote learning experiences in youth with neurodevelopmental disorders from rural Appalachia. Forty-nine youth (aged 6-17 years) and caregivers who had previously completed a comprehensive psychoeducational assessment were contacted to participate in an online study during COVID-19 stay-at-home orders. Youth and caregivers reported on psychopathology, emotion regulation and coping strategies, remote learning experiences, and demographics. A majority (87%) of students in rural Appalachia were not receiving the recommended amount of direct remote instruction. Indeed, a majority of school services received pre-COVID were not continued during remote learning. Greater child emotion dysregulation and parent psychopathology were predictive of remote learning difficulties and less engagement. Youth's adaptive coping abilities were predictive of greater total schoolwork per day. Parent employment was associated with greater difficulty with remote learning, but Individualized Education Program (IEP)/504 status and family income were not related to remote learning experiences. Results identified intervention leverage points, including improving adaptive coping and emotion regulation abilities, and reducing parent psychopathology and stress, to improve remote learning outcomes for youth in rural settings with neurodevelopmental disorders. (PsycInfo Database Record (c) 2021 APA, all rights reserved) Impact Statement Public Health Significance Statement-The transition from face-to-face instruction to remote learning during the COVID-19 stay-at-home orders significantly impacted all students and likely impacted vulnerable youth at a disproportionate rate. Students with neurodevelopmental disorders (e.g., autism, attention-deficit/hyperactivity disorder, and learning disorders) in rural Appalachia were receiving less than the recommended amount of direct instruction and few of their pre-COVID school services (e.g., therapy, tutoring, and test accommodations). Improving emotion regulation and adaptive coping strategies in youth and decreasing parental psychopathology symptoms (i.e., anxiety and depression) and stress could improve student remote learning outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Individuals with mental or substance use disorders have higher mortality rates than people in the general population. How excess mortality varies across health care facilities is unknown. The authors sought to investigate facility-level mortality rates among Veterans Health Administration (VHA) patients who had received diagnoses of mental or substance use disorders.An electronic medical records-based retrospective cohort study was conducted, encompassing 8,812,373 unique users of 139 VHA facilities from 2011 to 2016. Covariates included age, sex, and past-year diagnoses of serious mental illness, posttraumatic stress disorder, major depressive disorder, other mental health conditions, or substance use disorders. The outcome was all-cause mortality per comprehensive Veterans Affairs/Department of Defense searches of the National Death Index. Proportional hazards regression was used to calculate overall and facility-specific hazard ratios (HRs) for each diagnosis group, adjusted for age, sex, and comorbid medical conditions.Overall, all-cause mortality was statistically significantly elevated among VHA users with mental health diagnoses (HR=1.21, 95% confidence interval=1.20-1.22). HRs varied across facilities consistently over time. At the VHA facility level, diagnostic groups were significantly correlated with the degree of excess mortality. Results were similar in sensitivity analyses that excluded deaths from suicide or drug or alcohol overdose.VHA users with mental or substance use disorder diagnoses had elevated mortality rates. Correlation in excess mortality across two periods indicated that facility differences in excess mortality were persistent and therefore potentially associated with facility- and community-level factors, which may help inform quality improvement efforts to reduce mortality rates.

The use of two attending surgeons during posterior spinal fusion (PSF) for cerebral palsy (CP) patients has been shown to improve perioperative outcomes. This study aims to determine if the use of two surgeons is associated with an increase in the number of subsequent surgeries that can be performed in the same operating room (OR) during business hours. Patients with scoliosis and CP treated with PSF with minimum 90-day follow-up were included. Patients were grouped based on whether one or two attending surgeons performed the case. The primary outcome was the number of surgeries that followed in the same OR before 5 PM. Secondary outcomes included operative time, estimated blood loss (EBL), length of stay, rate of surgical site infection, and rate of unplanned return to the operating room. Thirty-six patients were included (10 with 1 surgeon and 26 with 2 surgeons). The two surgeon group had a significant increase in the average number of surgeries subsequently performed in the same OR during business hours (1.1 vs. 0.3, p = 0.01), as well as shorter mean operative time (159 vs. 307 min, p = 0.007) and EBL (554 vs. 840 cc, p = 0.01; 26 vs. 39%EBV, p = 0.03). The use of two attending surgeons was associated with a significant increase in the number of cases subsequently performed in the same OR during business hours, and significant decreases in operative time and EBL. Hospitals should consider the patient care and potential system-level improvements when considering implementation of two surgeon teams for PSF in CP patients. Therapeutic Level III.

Measurement-based care (MBC), an evidence-based approach that has demonstrated efficacy for improving treatment outcomes, has yet to be investigated in clients with Autism Spectrum Disorder. The current paper investigates the use of MBC in autistic (n = 20) and non-autistic (n = 20) clients matched on age, sex, and presenting problem. Results of change score analysis indicated that utilizing routine symptom monitoring can enhance treatment evaluation. Autistic clients participated in significantly more sessions, made significantly less progress, and were less compliant with MBC than non-autistic clients. Though hierarchical linear modeling demonstrated no significant differences in treatment slope, results indicated moderate effect size. These results inform the use of MBC in community clinics, highlighting policy implications and need for targeted measurement.

Thoracic organs from hepatitis C virus (HCV) positive donors are not commonly used for transplantation. The development of direct-acting antivirals (DAA) for HCV treatment has led to renewed interest in using HCV-positive organs. We evaluated HCV transmission rates, viremia clearance, and short-term outcomes in HCV-negative patients who received HCV-positive thoracic organs at our institution. From January 1, 2018 to May 31, 2019, 38 patients underwent HCV-positive thoracic organ transplantation (16 lungs and 22 hearts). Heart recipients were started on glecaprevir/pibrentasvir, a pangenotypic DAA, when they developed HCV viremia. Lung recipients were empirically started on glecaprevir/pibrentasvir within the first 3 post-transplant days. The primary outcome was cure of HCV defined as sustained virologic response at 12 weeks (SVR12). All heart recipients developed HCV viremia with median initial viral load of 64,565 IU/mL (interquartile range: 1660–473,151). The median time from DAA initiation to viremia clearance was 19 days (confidence interval: 15–27 days). Eleven out of 16 (68.8%) lung recipients developed HCV viremia with median initial viral load of 26 IU/mL (interquartile range: 15–143). The median time from DAA initiation to viremia clearance was 10 days (confidence interval: 6–17 days). Five out of 16 (31.3%) lung recipients never became viremic. All patients demonstrated SVR12. Thoracic organ transplantation from HCV viremic donors is safe with excellent short-term survival. Early initiation of HCV treatment results in rapid viremia clearance and SVR12. Long-term outcomes and optimal timing of DAA initiation remains to be determined.

Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in attention-deficit/hyperactivity disorder (ADHD). Little is known about how RRBs manifest in ADHD. We quantified and compared factor structures of RRBs in children with ASD (n = 634) or ADHD (n = 448), and related factors to sex and IQ. A four-factor solution emerged, including Stereotypy, Self-Injury, Compulsions, and Ritualistic/Sameness. Factor structures were equivalent across diagnoses, though symptoms were more severe in ASD. IQ negatively correlated with Stereotypy, Self-Injury, and Compulsions in ASD, and negatively correlated with Compulsions and Ritualistic/Sameness behaviors in ADHD. In ASD only, females exhibited higher Self-Injury. Thus, patterns of RRBs are preserved across ASD and ADHD, but severity and relationship with IQ differed.

Backgound The scaphoid is the most commonly fractured carpal bone and often presents as a diagnostic challenge. Fractures can often go unnoticed on initial radiographic evaluation and clinical presentation can vary significantly among patients. Awareness of high-risk cohorts assists practitioners in making the appropriate clinical diagnosis of acute scaphoid fracture.Materials and Methods The National Trauma Data Bank is the world's largest trauma data repository. Utilizing the 2016 public use file, we isolated scaphoid fractures by anatomic fracture location by utilizing International Classification of Diseases, 10th revision coding. Reported cases of distal pole (S62.01), waist (S62.02), and proximal pole (S62.03) were included. This data was then queried to determine trends in mechanism of injury, demographic information, and associated injuries.Results There were a total of 968,665 patients with 2,769 cases of reported scaphoid fractures resulting in 286 scaphoid fractures per 100,000 person-years. Males were more likely to sustain a scaphoid fracture than females. The most commonly encountered associated injuries were distal radius fractures, distal ulnar fractures, and nonscaphoid carpal bone fractures, respectively.Conclusions Scaphoid fractures presenting to trauma centers are more commonly reported among males and those involved in motor vehicle accidents or falls. Appropriate scaphoid-specific radiographic imaging should be obtained as well as wrist and elbow images to evaluate for concomitant injuries, especially distal radius fractures.

Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs).In this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs.A total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT- recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT- group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8-45) in the NAT+ group vs 65 (IQR: 44-84) days in the NAT-. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004).Transient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.

Background Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. Methods In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. Results Forty‐eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty‐five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. Conclusion CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. Level of evidence 1b; individual prospective cohort study., Circulating tumors cells (CTCs) were detected in 6/25 patients with locoregionally advanced disease (24%) and 4/11 with metastatic squamous cell carcinoma of the head and neck (36%). On univariate analysis, smoking was associated with CTCs.

OBJECTIVE: To evaluate the strength of associations between single-task and dual-task gait measures and Posterior Cingulate Gyrus (PCG) neurochemicals in acutely concussed collegiate athletes. SETTING: Participants were recruited from a NCAA Division 1 University. PARTICIPANTS: Nineteen collegiate athletes acutely (< 4 days) following sports-related concussion. DESIGN: We acquired Magnetic Resonance Spectroscopy (MRS) in the PCG and gait performance measurements in the participants, acutely following concussion. Linear mixed-effects models were constructed in order to measure the effect of gait performance, in the single and dual task settings, and sex on the six neurochemicals quantified with MRS in mmol. Correlation coefficients were also calculated to determine the direction and strength of the relationship between MRS neurochemicals and gait performance, post-concussion symptom score, and number of previous concussions. MAIN MEASURES: Average gait speed, average cadence, N-acetyl aspartate, choline, myo-inositol, glutathione, glutamate plus glutamine, creatine. RESULTS: Single-task gait speed (p=0.0056) and cadence (p=0.0065) had significant effects on myo-Inositol concentrations in the PCG, independent of sex, in concussed collegiate athletes. Single-task cadence (p=0.047) also had a significant effect on glutathione in the PCG. No significant effects were observed between dual-task gait performance and PCG neurochemistry. CONCLUSIONS: These findings indicate that increased concentrations of neuroinflammatory markers in the PCG are associated with slower single-task gait performance within four days of sport-related concussion.

Social anxiety disorder (SAD) is commonly comorbid with autism spectrum disorder (ASD). Here, in a sample of 86 children and adolescents (MAGE = 12.62 years; 68.6% male), 28 of whom were diagnosed with ASD, 34 with SAD, and 24 with comorbid ASD and SAD, we compared parent-reported scores from the Social Responsiveness Scale-Second Edition (SRS-2; Constantino and Gruber in Social Responsiveness Scale (SRS; Constantino and Gruber 2012) to determine the sensitivity and specificity of the measure in cases of differential diagnosis between SAD and ASD. Results suggest that neither the subscales, nor the SRS-2 total score, consistently differed between ASD and SAD. Sensitivity and specificity analyses suggested that the SRS-2 total poorly discriminated ASD from SAD. When screening socially anxious youth for possible ASD, caution should be taken.

Accurately replicating and analyzing cellular responses to mechanical cues is vital for exploring metastatic disease progression. However, many of the existing in vitro platforms for applying mechanical stimulation seed cells on synthetic substrates. To better recapitulate physiological conditions, a novel actuating platform is developed with the ability to apply tensile strain on cells at various amplitudes and frequencies in a high-throughput multi-well culture plate using a physiologically-relevant substrate. Suspending fibrillar fibronectin across the body of the magnetic actuator provides a matrix representative of early metastasis for 3D cell culture that is not reliant on a synthetic substrate. This platform enables the culturing and analysis of various cell types in an environment that mimics the dynamic stretching of lung tissue during normal respiration. Metabolic activity, YAP activation, and morphology of breast cancer cells are analyzed within one week of cyclic stretching or static culture. Further, matrix degradation is significantly reduced in breast cancer cell lines with metastatic potential after actuation. These new findings demonstrate a clear suppressive cellular response due to cyclic stretching that has implications for a mechanical role in the dormancy and reactivation of disseminated breast cancer cells to macrometastases.

Background: An imbalanced gut microbial community, or dysbiosis, has been shown to occur following stroke. It is possible that this dysbiosis negatively impacts stroke recovery and rehabilitation. Species level resolution measurements of the gut microbiome following stroke are needed to develop and test precision interventions such as probiotic or fecal microbiota transplant therapies that target the gut microbiome following stroke. Previous studies have used 16S rRNA amplicon sequencing in young male mice to obtain broad profiling of the gut microbiome at the genus level following stroke, but further investigations will be needed with whole genome shotgun sequencing in aged rats of both sexes to obtain species level resolution in a model which will better translate to the demographics of human stroke patients.Results: 39 aged male and female rats underwent middle cerebral artery occlusion. Fecal samples were collected before stroke and three days post stroke to measure gut microbiome. Machine learning was used to identify the top ranked bacteria which were changed following stroke. MRI imaging was used to obtain infarct and edema size and cerebral blood flow (CBF). ELISA was used to obtain inflammatory markers. Dysbiosis was demonstrated by an increase in pathogenic bacteria such as Butyricimonas virosa (15.52 fold change, pConclusion: The species level resolution measurements found here can be used as a foundation to develop and test precision interventions targeting the gut microbiome following stroke. Probiotics that include Ruminococcus flavefaciens, Akkermansia muciniphila, and Lactobacillus murinus should be developed to target the deficit following stroke to measure the impact on stroke severity.

Among veterans in Veterans Health Administration (VHA) care, patients with mental health and substance use conditions experience elevated suicide rates. However, despite previously demonstrated high rates of suicidal behavior, little is known regarding suicide rates among veteran VHA users with personality disorders (PDs) as a whole, or by PD clusters (A: Eccentric; B: Dramatic; C: Fearful; and PD-not otherwise specified). PD prevalence and suicide rates were assessed through 2017; overall and by clusters for 5,517,024 veterans alive as of 12/31/2013 and with more than 2 VHA encounters in 2012-2013. In all, 46,050 (.83%) had a PD diagnosis in 2012-2013. Suicide risk was examined using proportional hazards regressions adjusted for age, sex, veteran status, clustering within a geographic region, and other mental health diagnoses. Patients with PDs had greater suicide risk than those without (156.5 vs. 46.7 per 100,000 person-years). Individuals in Cluster B, which includes borderline and antisocial PDs, were at the highest risk (178.5 per 100,000 person-years), followed by PD-not otherwise specified and Cluster C (152.6 and 121.4 per 100,000 person-years, respectively). Rates of PDs in the VHA system were lower than those usually found in community samples. Veterans with a PD diagnosis had an increased risk of suicide, which was especially elevated for those with Cluster B diagnoses. Study findings document the importance of enhancing diagnosis and treatment for veterans with PDs and targeted suicide prevention services. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Occupational exposures to volatile organic compounds (VOCs) have been associated with numerous health complications including steatohepatitis and liver cancer. However, the potential impact of environmental/residential VOC exposures on liver health and function is largely unknown. To address this knowledge gap, the objective of this cross-sectional study is to investigate associations between VOCs and liver injury biomarkers in community residents. Subjects were recruited from six Louisville neighborhoods, and informed consent was obtained. Exposure biomarkers included 16 creatinine-adjusted urinary metabolites corresponding to 12 parent VOCs. Serological disease biomarkers measured included cytokertain-18 (K18 M65 and M30), liver enzymes, and direct bilirubin. Associations between exposure and disease biomarkers were assessed using generalized linear models. Smoking status was confirmed through urinary cotinine levels. The population comprised of approximately 60% females and 40% males; White persons accounted 78% of the population; with more nonsmokers (n = 413) than smokers (n = 250). When compared with nonsmokers, males (45%) and Black persons (26%) were more likely to be smokers. In the overall population, metabolites of acrolein, acrylonitrile, acrylamide, 1,3-butadiene, crotonaldehyde, styrene, and xylene were positively associated with alkaline phosphatase. These associations persisted in smokers, with the exception of crotonaldehyde, and addition of N,N-dimethylformamide and propylene oxide metabolites. Although no positive associations were observed for K18 M30, the benzene metabolite was positively associated with bilirubin, irrespective of smoking status. Taken together, the results demonstrated that selected VOCs were positively associated with liver injury biomarkers. These findings will enable better risk assessment and identification of populations vulnerable to liver disease.

BACKGROUND Obesity rates continue to rise among children and adolescents across the globe. A multicenter research consortium composed of institutions in the Southern US, located in states endemic for childhood obesity, was formed to evaluate the effect of obesity on pediatric musculoskeletal disorders. This study evaluates the effect of body mass index (BMI) percentile and socioeconomic status (SES) on surgical site infections (SSIs) and perioperative complications in patients with adolescent idiopathic scoliosis (AIS) treated with posterior spinal fusion (PSF). METHODS Eleven centers in the Southern US retrospectively reviewed postoperative AIS patients after PSF between 2011 and 2017. Each center contributed data to a centralized database from patients in the following BMI-for-age groups: normal weight (NW, 5th to

Occupational exposures to volatile organic compounds (VOCs) have been associated with numerous health complications including steatohepatitis and liver cancer. However, the potential impact of environmental/residential VOC exposures on liver health and function is largely unknown. To address this knowledge gap, the objective of this cross-sectional study is to investigate associations between VOCs and liver injury biomarkers in community residents. Subjects were recruited from six Louisville neighborhoods, and informed consent was obtained. Exposure biomarkers included 16 creatinine-adjusted urinary metabolites corresponding to 12 parent VOCs. Serological disease biomarkers measured included cytokertain-18 (K18 M65 and M30), liver enzymes and direct bilirubin. Associations between exposure and disease biomarkers were assessed using generalized linear models. Smoking status was confirmed through urinary cotinine levels. The population comprised of approximately 60% females and 40% males; White persons accounted 78% of the population; with more nonsmokers (n=413) than smokers (n=250). When compared to nonsmokers, Males (45%) and Black persons (26%) were more likely to be smokers. In the overall population, metabolites of acrolein, acrylonitrile, acrylamide, 1,3-butadiene, crotonaldehyde, styrene and xylene were positively associated with alkaline phosphatase (ALP). These associations persisted in smokers, with the exception of crotonaldehyde, and addition of N,N dimethylformamide and propylene oxide metabolites. Although no positive associations were observed for K18 M30, the benzene metabolite was positively associated with bilirubin, irrespective of smoking status. Taken together, the results demonstrated that selected VOCs were positively associated with liver injury biomarkers. These findings will enable better risk assessment and identification of populations vulnerable to liver disease.

Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs., Functional assessment of under- and undescribed clinical STK11 variants highlights the limitations of current in silico predictive algorithms. Successful implementation of personalized genomic medicine will rely on rapid and accurate variant classification.

The Mycobacterium tuberculosis complex (MTBC) species includes both M. tuberculosis, the primary cause of human tuberculosis (TB), and M. bovis, the primary cause of bovine tuberculosis (bTB), as well as other closely related Mycobacterium species. Zoonotic transmission of M. bovis from cattle to humans was recognized more than a century ago, but transmission of MTBC species from humans to cattle is less often recognized. Within the last decade, multiple published reports from around the world describe human-to-cattle transmission of MTBC. Three probable cases of human-to-cattle MTBC transmission have occurred in the United States since 2013. In the first case, detection of active TB disease (M. bovis) in a dairy employee in North Dakota prompted testing and ultimate detection of bTB infection in the dairy herd. Whole genome sequencing (WGS) demonstrated a match between the bTB strain in the employee and an infected cow. North Dakota animal and public health officials concluded that the employee's infection was the most likely source of disease introduction in the dairy. The second case involved a Wisconsin dairy herd with an employee diagnosed with TB disease in 2015. Subsequently, the herd was tested twice with no disease detected. Three years later, a cow originating from this herd was detected with bTB at slaughter. The strain in the slaughter case matched that of the past employee based on WGS. The third case was a 4-month-old heifer calf born in New Mexico and transported to Texas. The calf was TB tested per Texas entry requirements and found to have M. tuberculosis. Humans are the suspected source of M. tuberculosis in cattle; however, public health authorities were not able to identify an infected human associated with the cattle operation. These three cases provide strong evidence of human-to-cattle transmission of MTBC organisms and highlight human infection as a potential source of introduction of MTBC into dairy herds in the United States. To better understand and address the issue, a multisectoral One Health approach is needed, where industry, public health, and animal health work together to better understand the epidemiology and identify preventive measures to protect human and animal health.

Multisensory integration, the process by which sensory information from different sensory modalities are bound together, is hypothesized to contribute to perceptual symptomatology in schizophrenia, in whom multisensory integration differences have been consistently found. Evidence is emerging that these differences extend across the schizophrenia spectrum, including individuals in the general population with higher levels of schizotypal traits. In the current study, we used the McGurk task as a measure of multisensory integration. We measured schizotypal traits using the Schizotypal Personality Questionnaire (SPQ), hypothesizing that higher levels of schizotypal traits, specifically Unusual Perceptual Experiences and Odd Speech subscales, would be associated with decreased multisensory integration of speech. Surprisingly, Unusual Perceptual Experiences were not associated with multisensory integration. However, Odd Speech was associated with multisensory integration, and this association extended more broadly across the Disorganized factor of the SPQ, including Odd or Eccentric Behaviour. Individuals with higher levels of Odd or Eccentric Behaviour scores also demonstrated poorer lip-reading abilities, which partially explained performance in the McGurk task. This suggests that aberrant perceptual processes affecting individuals across the schizophrenia spectrum may relate to disorganized symptomatology.

Timely care initiation is a priority within the Veterans Health Administration (VHA). Patients with serious mental illnesses (SMI) are a group that benefits from timely care initiation due to elevated risks of negative outcomes with delayed care. However, no evaluation has assessed whether VHA SMI patients disproportionately experience delays in mental health care initiation. VHA administrative care data were used to compare delays in mental health care initiation for VHA patients with and without SMI who had newly identified mental health needs. Analyses assessed rates of delayed initial mental health appointments within five settings (General Mental Health [GMH], Primary Care Mental Health Integration [PC-MHI], Post-Traumatic Stress Disorder [PTSD], Substance Use Disorder [SUD], and Psychosocial Rehabilitation clinics [PSR]). SMI patients were more likely to receive delayed initial appointments in three of five clinical settings (PTSD, SUD, PSR) and had significantly longer average wait times for an initial appointment when referred to the PTSD clinic for an initial appointment. Overall, SMI patients were equally as likely to receive delayed initial appointments. While VHA SMI patients were not more likely to experience delayed mental health care initiation overall, they were more likely to experience delays within three of the five treatment settings. Findings suggest that the majority of VHA SMI patients experience equivalent timeliness, though those with more complex needs, and particularly those with trauma-related care needs, may be more likely to experience treatment initiation delays. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Paratuberculosis (Johne’s disease) is caused by Mycobacterium avium ssp. paratuberculosis (MAP), and affects both domestic and wild ruminants, including cattle, goats, sheep, and deer. In cattle, most infections occur during calfhood followed by a prolonged incubation period of 1–2 y or more before cows shed culturable numbers of MAP bacilli in their feces. As disease progresses, infected animals develop protein-losing enteropathy, intractable diarrhea, and weight loss. In a cohort of 32 clinically normal deer from a herd with a history of periodic clinical paratuberculosis, we found that subclinical infection was characterized by high rates of infection, common involvement of mesenteric lymph nodes, minimal lesion formation, few intralesional acid-fast bacilli, and low-level fecal shedding of MAP. The characteristics of subclinical paratuberculosis in white-tailed deer resemble those of cattle and red deer, although microscopic lesions were less common in subclinical deer than reported for subclinical cattle, and we did not see necrotizing granulomas as described in subclinical red deer and elk.

Ameloblastic carcinoma is a rare odontogenic neoplasm that demonstrates the histologic characteristics of ameloblastoma, accompanied by the cytologic features of malignancy. The spindle-cell variant of ameloblastic carcinoma (SCAC) is exceptionally rare, with a total of 10 cases having been reported in the literature to date. Histologically, a prominent sarcomatoid cell population appears to originate from the epithelial (ameloblastic) component. Like conventional ameloblastic carcinoma, most cases of SCAC occur in individuals older than 40 years of age. Here, 3 additional cases of SCAC are reported, 2 of which occurred in young individuals. Diagnostic criteria to aid in the identification of SCAC are proposed. Finally, histologic and immunohistochemical evidence supporting the occurrence of epithelial-mesenchymal transition in SCAC is presented.

Restricted and repetitive behaviors and interests (RRBI) have garnered attention for their presenting sex differences in Autism Spectrum Disorder (ASD). Specifically, previous works have claimed that RRBI are less predictive of an ASD diagnosis for females relative to males. Previous reports have demonstrated mixed findings: females present with greater RRBI (e.g., compulsive behaviors), females present with fewer RRBI (e.g., restricted interests), and females are not distinguishable from males based on overall RRBI profiles. The following review details behavioral and neurophysiological RRBI findings to argue that female presentations are qualitatively and quantitatively unique and should be taken into consideration for diagnostic measures. Future directions will be suggested in under-explored areas including functional imaging, sensory profiles, and typically developing control groups.

The primary hurdle for diagnosis of some diseases is the long incubation required to culture and confirm the presence of bacteria. The concept of using microbial VOCs as “signature markers” could provide a faster and noninvasive diagnosis. Finding biomarkers is challenging due to the specificity required in complex matrices. The objectives of this study were to (1) build/test a lab-scale platform for screening of microbial VOCs and (2) apply it to Mycobacterium avium paratuberculosis; the vaccine strain of M. bovis Bacillus Calmette-Guérin; and M. kansasii to demonstrate detection times greater those typically required for culture. SPME-GC-MS was used for sampling, sample preparation, and analyses. For objective (1), a testing platform was built for headspace sampling of bacterial cultures grown in standard culture flasks via a biosecure closed-loop circulating airflow system. For (2), results show that the suites of VOCs produced by Mycobacteria ssp. change over time and that individual strains produce different VOCs. The developed method was successful in discriminating between strains using a pooled multi-group analysis, and in timepoint-specific multi- and pair-wise comparisons. The developed testing platform can be useful for minimally invasive and biosecure collection of biomarkers associated with human, wildlife and livestock diseases for development of diagnostic point-of-care and field surveillance.

Purpose: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world., Methods: We performed a secondary analysis of data from the prospective ICON audit, in which all adult ( >16 years ) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - 80 years. Sepsis was defined as infection plus at least one organ failure., Results: A total of 2963 patients had sepsis, with similar proportions across the age groups (80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients 70 years was independently associated with increased risk of dying., Conclusions: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years. (C) 2019 Elsevier Inc. 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Valcoreanu] Spitalul Cf 2 Bucuresti, Bucharest, Romania., [Slavcovici, A.] Iuliu Hatieganu Univ Med & Pharm, Teaching Hosp Infect Dis, Cluj Napoca, Romania., [Bagin, V] City Clin Hosp 40, St Petersburg, Russia., [Belsky, D.] City Hosp 40, St Petersburg, Russia., [Palyutin, S.] Clin Hosp NVNV Solovyev, Yaroslavl, Russia., [Shlyapnikov, S.] Emergency Res Inst NA Djanelidze, St Petersburg, Russia., [Bikkulova, D.] Fed Res Ctr Paediat Haematol Oncol & Immunol, Moscow, Russia., [Gritsan, A.] Krasnoyarsk State Med Univ, Krasnoyarsk Reg Hosp, Krasnoyarsk, Russia., [Natalia, G.] Med Assoc Novaya Bolnitsa, Ekaterinburg, Russia., [Makarenko, E.] Mil Med Acad, Ekaterinburg, Russia., [Kokhno, V] Novosibirsk Med Univ, Novosibirsk, Russia., [Tolkach, A.] Omsk Reg Clin Hosp, Omsk, Russia., [Kokarev, E.] Railway Hosp Khabarovsk, Khabarovsk, Russia., [Belotserkovskiy, B.] St Alexy Hosp, St Louis, France., [Zolotukhin, K.] State Dist Hosp, Moscow, Russia., [Kulabukhov, V] Vishnevsky Inst Surg, Moscow, Russia., [Soskic, L.] Clin Ctr Serbia, Clin Cardiac Surg, Belgrade, Serbia., [Palibrk, I] Clin Ctr Serbia, Clin Digest Surg, Belgrade, Serbia., [Jankovic, R.; Jovanovic, B.] Clin Ctr Nis, Clin Vasc Surg, Nish, Serbia., [Pandurovic, M.] Clin Ctr Serbia, Emergency Ctr, Belgrade, Serbia., [Bumbasirevic, V] Clin Ctr Belgrade, Emergency Ctr, Belgrade, Serbia., [Uljarevic, B.] Gen Univ Hosp, Belgrade, Serbia., [Surbatovic, M.] Mil Med Acad, Belgrade, Serbia., [Ladjevic, N.] Urol Hosp, Belgrade, Serbia., [Slobodianiuk, G.] Dist Hosp, Bratislava, Slovakia., [Sobona, V] Fac Hosp, Bratislava, Slovakia., [Cikova, A.] Univ Hosp Bratislava, Hosp Ruzinov ICU, Bratislava, Slovakia., [Gebhardtova, A.] Univ Hosp Ruzinov Bratislava, Bratislava, Slovakia., [Jun, C.] Qingdao Univ, Tertiary Hosp, Qingdao, Shandong, Peoples R China., [Yunbo, S.] Qingdao Univ, Affiliated Hosp, Med Coll, Qingdao, Shandong, Peoples R China., [Dong, U.] Beijing Canc Hosp, Beijing Inst Canc Res, Beijing, Peoples R China., [Feng, S.] Beijing Chaoyang Hosp, Beijing, Peoples R China., [Duan, M.] Beijing Friendship Hosp, Beijing, Peoples R China., [Xu, Y.] Capital Med Univ, Beijing Tongren Hosp, Beijing, Peoples R China., [Xue, X.] Beijing Univ Peoples Hosp, Beijing, Peoples R China., [Gao, T.] Beijing Luhe Hosp, Beijing, Peoples R China., [Xing, X.] Chinese Acad Med Sci, Canc Hosp, Beijing, Peoples R China., [Zhao, X.] China Acad Chinese Med Sci, Guang An Men Hosp, Beijing, Peoples R China., [Li, C.] Peoples Hosp, Chuxiong, Yunnan, Peoples R China., [Gengxihua, G.] Donge Cty Peoples Hosp Shandong Prov, Liaocheng, Shandong, Peoples R China., [Tan, H.] Chinese Acad Med Sci, Fu Wai Hosp, Beijing, Peoples R China., [Xu, J.] Fujian Prov Hosp, Fuzhou, Fujian, Peoples R China., [Jiang, L.] Capital Med Univ, Fuxing Hosp, Beijing, Peoples R China., [Tiehe, Q.] Guangdong Gen Hosp, Guangzhou, Guangdong, Peoples R China., [Bingyu, Q.] Henan Prov Peoples Hosp, Zhengzhou, Henan, Peoples R China., [Shi, Q.] Xi An Jiao Tong Univ, Coll Med, Xian, Shaanxi, Peoples R China., [Lv, Z.] Kunming Third Peoples Hosp, Kunming, Yunnan, Peoples R China., [Zhang, L.] Lanzhou Univ, Hosp 2, Lanzhou, Gansu, Peoples R China., [Jingtao, L.] 309th Hosp, Beijing, Peoples R China., [Zhen, Z.] China Med Univ, Hosp 1, Beijing, Peoples R China., [Wang, Z.] Peking Univ, Shougang Hosp, Beijing, Peoples R China., [Wang, T.] Peking Univ, Hosp 3, Beijing, Peoples R China., [Yuhong, L.] Pla Navy Gen Hosp, Beijing, Peoples R China., [Zhai, Q.] Shandong Univ, Qilu Hosp, Jinan, Shandong, Peoples R China., [Chen, Y.] Jiaotong Univ, Affiliated Med Sch, Ruijin Hosp, Shanghai, Peoples R China., [Wang, C.] Shandong Prov Hosp, Jinan, Shandong, Peoples R China., [Jiang, W.] Shanghai 10th Peoples Hosp, Shanghai, Peoples R China., [Ruilan, W.] Shanghai First Peoples Hosp, Shanghai, Peoples R China., [Chen, Y.; Xiaobo, H.] Sichuan Prov Peoples Hosp, Chengdu, Sichuan, Peoples R China., [Ge, H.] Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China., [Yan, T.] Affiliated Guiyang Med Coll, Guiyang, Guizhou, Peoples R China., [Yuhui, C.] Fudan Univ, Peoples Hosp Shanghai 5, Shanghai, Peoples R China., [Zhang, J.] Dalian Med Univ, Affiliated Hosp 1, Dalian, Peoples R China., [Jian-Hong, F.] Suzhou Univ, Affiliated Hosp 1, Suzhou, Peoples R China., [Zhu, H.] Xinjiang Med Univ, Affiliated Hosp 1, Urumqi, Peoples R China., [Huo, F.; Wang, Y.] Jilin Univ, Hosp 1, Changchun, Jilin, Peoples R China., [Li, C.] First Peoples Hosp Kunming, Kunming, Yunnan, Peoples R China., [Zhuang, M.] Gen Hosp Shenyang Mil Reg, Shenyang, Liaoning, Peoples R China., [Ma, Z.] Peoples Hosp Cangzhou, Cangzhou, Peoples R China., [Sun, J.] Jilin Univ, Hosp 2, Changchun, Jilin, Peoples R China., [Liuqingyue, L.] Second Peoples Hosp Liaocheng City Shandong Prov, Liaocheng, Shandong, Peoples R China., [Yang, M.] Third Xiangya Hosp, Changsha, Hunan, Peoples R China., [Meng, J.] Tongde Hosp Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China., [Ma, S.] Tongji Univ, Shanghai East Hosp, Shanghai, Peoples R China., [Kang, Y.] West China Hosp, Scu, Peoples R China., [Yu, L.] Wuhan Ctr Hosp, Wuhan, Hubei, Peoples R China., [Peng, Q.] Xiangya Hosp, Changsha, Hunan, Peoples R China., [Wei, Y.] Yantai Yuhuangding Hosp, Yantai, Peoples R China., [Zhang, W.] Yantaishan Hosp, Yantai, Shandong, Peoples R China., [Sun, R.] Zhejiang Prov Peoples Hosp, Hangzhou, Zhejiang, Peoples R China., [Yeung, A.] Pamela Youde Nethersole Eastern Hosp, Hong Kong, Peoples R China., [Wan, W.] Princess Margaret Hosp, Hong Kong, Peoples R China., [Sin, K.] Queen Elizabeth Hosp, Hong Kong, Peoples R China., [Lee, K.] United Christian Hosp Hong Kong SAR, Hong Kong, Peoples R China., [Wijanti, M.] Anestesi, Yogyakarta, Indonesia., [Widodo, U.] Pku Muhammadiyah Bantu, Yogyakarta, Indonesia., [Samsirun, H.] Rd Mattaher Hosp Jambi, Jambi City, Indonesia., [Sugiman, T.] Rumah Sakit Pantai Lndah Kapuk, North Jakarta, Indonesia., [Wisudarti, C.] Sardjito Hosp, Yogyakarta, Indonesia., [Maskoen, T.] Sch Med Unpad, Hasan Sadikin Hosp, Bandung, Indonesia., [Hata, N.] Nippon Med Sch, Chiba Hokusoh Hosp, Inzai, Japan., [Kobe, Y.] Chiba Univ Hosp, Chiba, Japan., [Nishida, O.] Fujita Hlth Univ, Sch Med, Toyoake, Aichi, Japan., [Miyazaki, D.] Japanese Red Cross Maebashi Hosp, Maebashi, Gumma, Japan., [Nunomiya, S.] Jichi Med Univ Hosp, Shimotsuke, Japan., [Uchino, S.] Jikei Univ, Sch Med, Tokyo, Japan., [Kitamura, N.] Kimitsu Chuo Hosp, Kisarazu, Japan., [Yamashita, K.] Kochi Med Sch, Nankoku, Kochi, Japan., [Hashimoto, S.] Kyoto Prefectural Univ Med, Kyoto, Japan., [Fukushima, H.] Nara Med Univ Hosp, Kashihara, Nara, Japan., [Adib, N. Nik] Hosp Sultanah Nur Zahirah, Kuala Terengganu, Terengganu, Malaysia., [Tai, L.] Kuala Lumpur Hosp, Kuala Lumpur, Malaysia., [Tony, B.] Queen Elizabeth Hosp 2, Kota Kinabalu, Malaysia., [Bigornia, R.] Cebu Velez Gen Hosp, Cebu, Philippines., [Bigornia, R.] Perpetual Succour Hosp, Cebu, Philippines., [Palo, J.] Med City, Pasig, Philippines., [Chatterjee, S.] Alexandra Hosp, Singapore, Singapore., [Tan, B.] Natl Univ Hlth Syst, Singapore, Singapore., [Kong, A.] Singapore Gen Hosp, Singapore, Singapore., [Goh, S.] Tan Tock Seng Hosp, Singapore, Singapore., [Lee, C.] Natl Taiwan Univ Hosp, Taipei, Taiwan., [Pothirat, C.] Chiaingmai Univ, Maharaj Nakorn Chiangmai Hosp, Chiang Mai, Thailand., [Khwannimit, B.] Prince Songkla Univ, Hat Yai, Thailand., [Theerawit, P.] Ramathibodi Hosp, Bangkok, Thailand., [Pornsuriyasak, P.] Ramathibodi Hosp, Somdech Phra Debaratana Med Ctr, Bangkok, Thailand., [Piriyapatsom, A.] Mahidol Univ, Siriraj Hosp, Bangkok, Thailand., [Mukhtar, A.] Cairo Univ, Giza, Egypt., [Dsicu] Demerdash Surg Intens Care Unit, Cairo, Egypt., [Hamdy, A. Nabil] Ain Shams Fac Med, Cairo, Egypt., [Hosny, H.] Zaitoun Specialized Hosp, Cairo, Egypt., [Ashraf, A.] Gums, Tehran, Iran., [Mokhtari, M.] Sbums, Imam Hossein Hosp, Tehran, Iran., [Nowruzinia, S.] Imamreza Hosp, Mashhad, Razavi Khorasan, Iran., [Lotfi, A.] Laleh Hosp, Tehran, Iran., [Zand, F.] Shiraz Anesthesiol & Crit Care Res Ctr, Shiraz, Iran., [Nikandish, R.] Shiraz Univ Med Sci, Shiraz, Iran., [Moghaddam, O. Moradi] Tehran Med Sci Univ, Tehran, Iran., [Cohen, J.] Rabin Med Ctr, Petah Tiqwa, Israel., [Sold, O.] Sourasky Tel Aviv Med Ctr, Tel Aviv, Israel., [Sfeir, T.] Ctr Hosp Nord, Ettelbruck, Luxembourg., [Hasan, A.] Sohar Hosp, Sohar, Oman., [Abugaber, D.] Specialized Arab Hosp, Nablus, Palestine., [Ahmad, H.] Almana Gen Hosp, Khobar, Saudi Arabia., [Tantawy, T.] KFSHRC, Riyadh, Saudi Arabia., [Baharoom, S.] King Abdulaziz Med City Riyadh, Riyadh, Saudi Arabia., [Algethamy, H.] King Abdulaziz Univ, Jeddah, Saudi Arabia., [Amr, A.] King Saud Med City, Riyadh, Saudi Arabia., [Almekhlafi, G.] Riyadh Mil Hosp, Riyadh, Saudi Arabia., [Coskun, R.] Erciyes Univ, Med Fac, Kayseri, Turkey., [Sungur, M.] Erciyes Univ, Med Sch, Kayseri, Turkey., [Cosar, A.] Gulhane Mil Med Acad, Ankara, Turkey., [Gucyetmez, B.] Int Hosp, Istanbul, Turkey., [Demirkiran, O.] Istanbul Univ, Cerrahpasa Med Sch Hosp, Istanbul, Turkey., [Senturk, E.] Istanbul Univ, Istanbul Med Fac, Istanbul, Turkey., [Ulusoy, H.] Karadeniz Tech Univ, Med Fac, Trabzon, Turkey., [Atalan, H.] Mem Atasehir Hosp, Istanbul, Turkey., [Serin, S.] Pamukkale Univ, Denizli, Turkey., [Kati, I] Yuzuncu Yil Univ, Med Fac, Van, Turkey., [Alnassrawi, Z.] Dubai Hosp, Dubai, U Arab Emirates., [Almemari, A.] Mafraq Hosp, Abu Dhabi, U Arab Emirates., [Krishnareddy, K.] Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates., [Kashef, S.] Tawam Hosp, Al Ain, U Arab Emirates., [Alsabbah, A.] City Hosp, Dubai, U Arab Emirates., [Poirier, G.] Hop Charles Lemoyne, Longueuil, PQ, Canada., [Marshall, J.] St Michaels Hosp, Toronto, ON, Canada., [Herridge, M.] Toronto Gen Hosp, Toronto, ON, Canada., [Herridge, M.] Toronto Western Hosp, Toronto, ON, Canada., [Fernandez-Medero, R.] San Juan Hosp, San Juan, PR USA., [Fulda, G.] Christiana Care Hlth Syst, Newark, DE USA., [Banschbach, S.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA., [Quintero, J.] El Camino Hosp, Mountain View, CA USA., [Schroeder, E.] George Washington Hosp, Washington, DC USA., [Sicoutris, C.] Hosp Univ Penn, Philadelphia, PA 19104 USA., [Gueret, R.] John H Stroger Hosp Cook Cty, Chicago, IL USA., [Kashyap, R.] Mayo Clin, CCM, Rochester, MN USA., [Bauer, P.] Mayo Clin, PCC, Rochester, MN USA., [Nanchal, R.] Med Coll Wisconsin, Milwaukee, WI 53226 USA., [Wunderink, R.] Northwestern Mem Hosp, Chicago, IL 60611 USA., [Jimenez, E.] Orlando Reg Med Ctr Inc, Orlando, FL USA., [Ryan, A.] Washington Hosp Ctr, Washington, DC 20010 USA., [Ryan, A.] Washington Hosp Ctr, 2H, Washington, DC USA., [Ryan, A.] Washington Hosp Ctr, 2G, Washington, DC USA., [Ryan, A.] Washington Hosp Ctr, 3H, Washington, DC USA., [Ryan, A.] Washington Hosp Ctr, 3G, Washington, DC USA., [Ryan, A.] Washington Hosp Ctr, 4H, Washington, DC USA., [Ryan, A.] Washington Hosp Ctr, CVRR, Washington, DC USA., [Prince, D.] Armadale Hlth Serv, Mount Nasura, WA, Australia., [Edington, J.] Bendigo Hosp, Bendigo, Vic, Australia., [Van Haren, F.] Canberra Hosp, Canberra, ACT, Australia., [Bersten, A.] Flinders Med Ctr, Bedford Pk, SA, Australia., [Hawkins, D. J.] Joondalup Hlth Campus, Joondalup, WA, Australia., [Kilminster, M.] Lismore Base Hosp, Lismore, NSW, Australia., [Sturgess, D.] Mater Adult Hosp, South Brisbane, Qld, Australia., [Ziegenfuss, M.] Prince Charles Hosp, Brisbane, Qld, Australia., [O'Connor, S.] Royal Adelaide Hosp, Adelaide, SA, Australia., [Lipman, J.] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia., [Campbell, L.] Royal Darwin Hosp, Tiwi, NT, Australia., [Mcallister, R.] Royal Hobart Hosp, Hobart, Tas, Australia., [Roberts, B.] Sir Charles Gairdner Hosp, Nedlands, WA, Australia., [Williams, P.] Queen Elizabeth Hosp, Woodville, SA, Australia., [Parke, R.] Auckland Dist Hlth Board, Auckland, New Zealand., [Seigne, P.] Christchurch Hosp, Christchurch, New Zealand., [Freebairn, R.] Hawkes Bay Hosp, Hastings, New Zealand., [Nistor, D.] Palmerston North Hosp, Midcent Hlth, Palmerston North, New Zealand., [Oxley, C.] Middlemore Hosp, Auckland, New Zealand., [Young, P.] Wellington Hosp, Wellington, New Zealand., [Valentini, R.] Cemic, Buenos Aires, DF, Argentina., [Wainsztein, N.] Fleni, Buenos Aires, DF, Argentina., [Comignani, P.] Hosp Aleman, Buenos Aires, DF, Argentina., [Casaretto, M.] Hosp Cent San Isidro, Buenos Aires, DF, Argentina., [Sutton, G.] Hosp Fernandez, Buenos Aires, DF, Argentina., [Villegas, P.] Hosp Francisco Lopez Lima Area Programa Gen Roca, Gen Roca, Argentina., [Galletti, C.] Sanatorio Allende, Cordoba, Argentina., [Neira, J.] Sanatorio Trinidad Palermo, Buenos Aires, DF, Argentina., [Rovira, D.] Sanatorio Julio Corzo Rosario, Rosario, Santa Fe, Argentina., [Hidalgo, J.] Karl Heusner Mem Hosp, Belize City, Belize., [Hidalgo, J.] Belize Healthcare Partner, Belize City, Belize., [Sandi, F.] Hosp Obrero 1, La Paz, Bolivia., [Caser, E.] Cias Unimed Vitoria, Vitoria, ES, Brazil., [Thompson, M.] Evangelical Hosp Cachoeiro De Itapemirim, Cachoeiro De Itapemirim, Brazil., [D'agostino Dias, M.] Hosp 9 Julho, Sao Paulo, Brazil., [Fontes, L.] Hosp Alcides Carneiro, Petropolis, Brazil., [Lunardi, M.] Hosp Clin Luzia De Pinho Melo, Mogi Das Cruzes, Brazil., [Youssef, N.] Hosp Nacoes Curitiba, Curitiba, Parana, Brazil., [Lobo, S.] Hosp Base Famerp, Sao Jose Do Rio Preto, Brazil., [Silva, R.] Hosp Clin Niteroi, Niteroi, RJ, Brazil., [Sales Jr, J.] Hosp Clin Padre Miguel, Rio De Janeiro, Brazil., [Madeira Campos Melo, L.] Hosp Terapia Intens, Sao Paulo, Brazil., [Oliveira, M.] Hosp Trabalhador, Curitiba, Parana, Brazil., [Fonte, M.] Hosp Esperanza, Olinda, PE, Brazil., [Grion, C.] Hosp Evangel Londrina, Londrina, Brazil., [Feijo, C.] Hosp Geral Fortaleza, Fortaleza, Ceara, Brazil., [Rezende, V] Hosp Geral Roraima, Boa Vista, Brazil., [Assuncao, M.] Hosp Israelita Albert Einstein, Sao Paulo, Brazil., [Neves, A.] Hosp Mater Dei, Belo Horizonte, MG, Brazil., [Gusman, P.; Dalcomune, D.] Hosp Meridional, Cariacica, ES, Brazil., [Teixeira, C.] Hosp Moinhos Vento, Porto Alegre, RS, Brazil., [Kaefer, K.] Hosp Municipal Ruth Cardoso, Balneario, Brazil., [Maia, I] Hosp Nereu Ramos, Florianopolis, SC, Brazil., [Souza Dantas, V] Hosp Pasteur, Rio De Janeiro, Brazil., [Costa Filho, R.] Hosp Pro Cardiaco, Rio De Janeiro, Brazil., [Amorim, F.] Hosp Reg Samambaia, Brasilia, DF, Brazil., [Assef, M.] Hosp Reg Hans Dieter Schmidt, Joinville, Brazil., [Schiavetto, P.] Hosp Santa Casa Campo Mourao, Campo Mourao, PR, Brazil., [Houly, J.] Hosp Santa Paula, Sao Paulo, SP, Brazil., [Houly, J.] Hosp Santapaula, Sao Paulo, Brazil., [Bianchi, F.] Hosp Sao Jose Avai, Itaperuna, RJ, Brazil., [Dias, F.] Hosp Sao Lucas Pucrs, Porto Alegre, RS, Brazil., [Avila, C.] Hosp Sao Vicente Paula, Rio De Janeiro, RJ, Brazil., [Gomez, J.] Hosp Sao Vicente Paulo, Rio De Janeiro, Brazil., [Rego, L.] Hosp Saude Mulher, Belem, Para, Brazil., [Castro, P.] Hosp Tacchini, Bento Goncalves, RS, Brazil., [Passos, J.] Hosp Unimed Costa Do Sol Macae Rj, Macae, RJ, Brazil., [Mendes, C.] Hosp Univ Ufpb Joao Pessoa, Joao Pessoa, Paraiba, Brazil., [Grion, C.] Hosp Univ Londrina, Londrina, Brazil., [Colozza Mecatti, G.] Hosp Univ Sao Francisco, Braganca Paulista, SP, Brazil., [Ferrreira, M.] Santa Casa Caridade Diamantina, Diamantina, MG, Brazil., [Irineu, V] Santa Casa Misericordia Tatui, Tatui, Brazil., [Guerreiro, M.] Sao Francisco de Paula Hosp, Sao Francisco De Paula, RS, Brazil., [Ugarte, S.] Clin Indisa, Providencia, Chile., [Tomicic, V] Clin Las Lilas, Providencia, Chile., [Godoy, C.] Hosp Carlos Van Buren, Valparaiso, Chile., [Samaniego, W.] Hosp Trabajador Santiago, Santiago, Chile., [Escamilla, I] Hosp El Pino, San Bernardo, Chile., [Escamilla, I] Hosp Mutual De Seguridad, Santiago, Chile., [Castro Castro, L.] Ctr Med Imbanaco, Valle Del Cauca, Colombia., [Libreros Duque, G.] Clin Colombia Cali, Cali, Colombia., [Diaz-Guio, D.] Clin Del Cafe, Armenia, Colombia., [Benitez, F.] Clin La Estancia SA, Popayan, Colombia., [Guerra Urrego, A.] Clin Medellin, Medellin, Colombia., [Buitrago, R.] Fdn Clin Shaio, Bogota, Colombia., [Ortiz, G.] Hosp Santa Clara, Bogota, Colombia., [Villalba Gaviria, M.] Hosp Univ Fdn Santa Fe De Bogota, Bogota, Colombia., [Salas, D.] Calderon Guardia Hosp, San Jose, Costa Rica., [Ramirez-Arce, J.] Hosp Dr Rafael Angel Varlderon Guardia Ccss, San Jose, Costa Rica., [Salgado, E.] Clin La Merced, Quito, Ecuador., [Morocho, D.] Hosp Eugenio Espejo, Quito, Ecuador., [Vergara, J.] Hosp Luis Vernaza, Quito, Ecuador., [Chung Sang, M.] Shdug Sistema Hosp Docente De La Univ Guayaquil, Quito, Ecuador., [Orellana-Jimenez, C.] Gen Hosp, San Salvador, El Salvador., [Garrido, L.] Hosp Ctr Med, Guatemala City, Guatemala., [Diaz, O.] Inst Hondureno Seguro Social, La Ceiba, Honduras., [Resiere, D.] Ctr Hosp Univ Ft De France, Fort De France, Martinique, France., [Osorio, C.] Ctr Estatal Cuidados Crit, Salamanca, Mexico., [De La Vega, A.] Ctr Med Nacl 20 Noviembre Issste, Mexico City, DF, Mexico., [Carrillo, R.] Fdn Clin Med Sur, Mexico City, DF, Mexico., [Sanchez, V] Hosp San Jose TEC Monterrey, Monterrey, Mexico., [Villagomez, A.] Hosp 1 Octubre, Issste, Mexico., [Martinez Zubieta, R.] Hosp Espanol Mexico, Mexico City, DF, Mexico., [Sandia, M.] Hosp Gen Ajusco Medio, Mexico City, DF, Mexico., [Zalatiel, M.] Hosp Gen Guadalupe Victoria, Texcoco, Mexico., [Poblano, M.] Hosp Juarez Mexico, Mexico City, DF, Mexico., [Rodriguez Gonzalez, D.] Hosp Civil Guadalajara, Hspitaljuan I Menchaca, Guadalajara, Jalisco, Mexico., [Arrazola, F.; Juan Francisco, L.] Inst Mexicano Seguro Social, Mexico City, DF, Mexico., [Liamendys-Silva, S. A.] Inst Nacl Cancerol, Mexico City, DF, Mexico., [Hernandez, M.] ISSSTE Guerra Moya, Mexico City, DF, Mexico., [Hernandez, M.] Med Ctr ISSEMYM Toluca, Mexico City, DF, Mexico., [Rodriguez Cadena, D.] Mixta, Mexico City, DF, Mexico., [Lopez Islas, I.] Secretaria Salud Dist Fed, Mexico City, DF, Mexico., [Ballesteros Zarzavilla, C.] Hosp Santo Comas, Panama City, Panama., [Matos, A.] Social Secur Hosp, La Chorrera, Panama., [Oyanguren, I] Clin Anglo Amer, Lima, Peru., [Cerna, J.] Essalud, Lima, Peru., [Quispe Sierra, R.] Hosp Nacl Dos De Mayo, Lima, Peru., [Jimenez, R.] Hosp Rebagliati, Lince Dist, Peru., [Castillo, L.] Inst Nacl Enfermedades Neoplas, Surquillo, Peru., [Ocal, R.] Gulhane Med Fac, Istanbul, Turkey., [Sencan, A.] Izmir Ataturk Educ & Res Hosp, Izmir, Turkey., [Gianoni, S. Mareque] CAMS, Montevideo, Uruguay., [Deicas, A.] CASMU, Montevideo, Uruguay., [Hurtado, J.] Hosp Espanol Asse, Montevideo, Uruguay., [Burghi, G.] Hosp Maciel, Montevideo, Uruguay., [Martinelli, A.] Ctr Med Caracas, Caracas, Venezuela., [Von der Osten, I] Hosp Miguel Perez Carreno, Caracas, Venezuela., [Du Maine, C.] MSF Trauma Hosp Kunduz, Kunduz, Afghanistan., [Bhattacharyya, M.] Amri Hosp, Kolkata, India., [Bandyopadhyay, S.] Amri Hosp Salt Lake, Kolkata, W Bengal, India., [Yanamala, S.] Apollo Hosp, Hyderabad, India., [Gopal, P.] Apollo Hosp, Bangalore, Karnataka, India., [Sahu, S.] Apollo Hosp, Bhubaneswar, India., [Ibrahim, M.] Apollo Special Hosp, Chennai, Tamil Nadu, India., [Rathod, D.] Asian Heart Inst, Mumbai, Maharashtra, India., [Mukundan, N.] Baby Mem Hosp Ltd, Calicut, Kerala, India., [Dewan, A.] Batra Hosp & Mrc, New Delhi 110062, India., [Amin, P.] Bombay Hosp Inst Med Sci, Mumbai, Maharashtra, India., [Samavedam, S.] Care Hosp, Hyderabad, India., [Shah, B.] Cims Hosp, Ahmadabad, Gujarat, India., [Gurupal, D.] Columbiaasia Hosp, Mysore, Karnataka, India., [Lahkar, B.] Dispur Hosp, Gauhati, India., [Mandal, A.] Fortis Hosp, Bangalore, Karnataka, India., [Sircar, M.] Fortis Hosp, Noida, India., [Ghosh, S.] Fortis Escorts Hosp, Faridabad, India., [Balasubramani, V] Ganga Med Ctr & Hosp P Ltd, Coimbatore, Tamil Nadu, India., [Kapadia, F.] Hinduja Hosp, Mumbai, Maharashtra, India., [Vadi, S.] KDAH, Mumbai, Maharashtra, India., [Nair, K.] Kerala Inst Med Sci, RMCC, Thiruvananthapuram, Kerala, India., [Tripathy, S.] Kalinga Inst Med Sci, DTEM, Bhubaneswar, Odisha, India., [Nandakumar, S.] Kovai Med Ctr & Hosp, Coimbatore, Tamil Nadu, India., [Sharma, J.] Medanta Medic, Gurgaon, India., [Kar, A.] Med Superspecialty Hosp, Kolkata, W Bengal, India., [Jha, S.] Metro Heart Inst Multispecial, Faridabad, India., [Gurav, K. Zirpe] Ruby Hall Pune, Pune, Maharashtra, India., [Patel, M.] Saifee Hosp, Mumbai, Maharashtra, India., [Bhaysar, A.] Spandan Multispecial Hosp, Vadodara, India., [Samaddar, D.] Tata Main Hosp, Jamshedpur, Jharkhand, India., [Kulkarni, A.] Tata Mem Hosp, Mumbai, Maharashtra, India., [Hashmi, M.] Aga Khan Univ, Karachi, Pakistan., [Ali, W.] Hearts Int Hosp, Rawalpindi, Pakistan., [Nadeem, S.] Liaquat Natl Hosp, Karachi, Pakistan., [Indraratna, K.] Sri Jayewardenepura Gen Hosp, Sri Jayawardenepura Kott, Sri Lanka., [Margarit, A.] Hosp Nostra Senyora Meritxell, Les Escaldes, Andorra., [Urbanek, P.] Akh Wien, Vienna, Austria., [Schlieber, J.] Allgemeines & Orthopad Landeskrankenhaus Stolzalp, Stolzalpe, Austria., [Reisinger, J.] Barmherzige Schwestern Linz, Linz, Austria., [Auer, U.] Gen Hosp Braunau, Braunau, Austria., [Hartjes, A.] Krankenhaus D Barmherzigen Schwestern Ried II, Ried Im Innkreis, Austria., [Lerche, A.] Krankenhaus Floridsdorf, Vienna, Austria., [Janous, T.] LK Gmund Waidhofen Thaya Zwettl, Standort Zwettl, Austria., [Kink, E.] LKH Horgas Enzenbach, Gratwein, Austria., [Krahulec, W.] LKH West, Graz, Austria., [Smolle, K.] Univ Hosp, Graz, Austria., [Van der Schueren, M.] AZ Groeninge Kortrijk, Kortrijk, Belgium., [Thibo, P.] AZ Jan Palfijn Gent, Ghent, Belgium., [Vanhoof, M.] AZ Turnhout, Turnhout, Belgium., [Ahmet, I] Bracops Anderlecht, Anderlecht, Belgium., [Gadisseux, P.] Ctr Hosp Mouscron, Mouscron, Belgium., [Dufaye, P.] CH Peltzer La Tourelle, Verviers, Belgium., [Jacobs, O.] Chirec Edith Cavell, Auderghem, Belgium., [Fraipont, V] CHR Citadelle, Liege, Belgium., [Biston, P.] CHU Charleroi, Charleroi, Belgium., [Dive, A.] CHU Mt Godinne, Yvoir, Belgium., [Bouckaert, Y.] CHU Tivoli, La Louviere, Belgium., [Gilbert, E.] CHwapi, Tournai, Belgium., [Gressens, B.] Clin St Pierre Ottignies, Ottignies, Belgium., [Pinck, E.] Clin Maternite St Elisabeth, Namur, Belgium., [Collin, V] Clin Europe St Michel, Etterbeek, Belgium., [Vincent, J. L.] Erasme Univ Hosp, Anderlecht, Belgium., [De Waele, J.] Ghent Univ Hosp, Ghent, Belgium., [Rimachi, R.] Moliere Hosp, Forest, Belgium., [Gusu, D.] Notre Dame, Brussels, Belgium., [De Decker, K.] Onze Lieve Vrouw Hosp, Aalst, Belgium., [Mandianga, K.] Ixelles Hosp, Ixelles, Belgium., [Heytens, L.] Sint Augustinus, Antwerp, Belgium., [Wittebole, X.] St Luc Univ Hosp UCL, Brussels, Belgium., [Spapen, H.] UZ Brussel, Brussels, Belgium., [Olivier, V] Vivalia Site Libramt, Libramont, Belgium., [Vandenheede, W.] VZW Gezondheidszorg Oostkust Knokke Heist, Knokke Heist, Belgium., [Rogiers, P.] ZNA Middelheim, Antwerp, Belgium., [Kolodzeike, P.] Herning Hosp, Herning, Denmark., [Kruse, M.] Hjoerring Hosp, Hjorring, Denmark., [Andersen, T.] Vejle Hosp, Vejle, Denmark., [Harjola, V] Helsinki Univ Cent Hosp, Helsinki, Finland., [Saarinen, K.] Seinajoki Cent Hosp, Seinajoki, Finland., [Leone, M.] Aix Marseille Univ, Hop Nord, Marseille, France., [Durocher, A.] Calmette Hosp, Lille, France., [Moulront, S.] Ctr Hosp Dunkerque, Dunkerque, France., [Lepape, A.] Ctr Hosp Lyon Sud, Lyon, France., [Losser, M.] CHU Nancy Brabois, Nancy, France., [Cabaret, P.] CH St Philibert, GHICL, Lille, France., [Kalaitzis, E.] CHR Dax, Dax, France., [Zogheib, E.] CHU Amiens, Amiens, France., [Charve, P.] CHU Dijon, Dijon, France., [Francois, B.] CHU Dupuytren, Limoges, France., [Lefrant, J. Y.] CHU Nimes, Nimes, France., [Beilouny, B.] Ctr Hosp Troyes, Troyes, France., [Forceville, X.] Ctr Hosp Meaux, Grp Hosp Est Francilien, Meaux, France., [Misset, B.] Grp Hosp Paris St Joseph, Paris, France., [Jacobs, F.] Hop Antoine Beclere, Clamart, France., [Floccard, B.] Hop Edouard Herriot, Lyon, France., [Payen, D.] Hop Lariboisere, AP HP, Paris, France., [Wynckel, A.] Hop Maison Blanche, Reims, France., [Castelain, V] Hop Univ Strasbourg, Strasbourg, France., [Faure, A.] Hosp Civils Lyon, Lyon, France., [Lavagne, P.] CHU Grenoble, Grenoble, France., [Thierry, I] CHU Nantes, Nantes, France., [Moussa, M.] CHRU Lille, Reanimat Chirurg Cardiovasc, Lille, France., [Vieillard-Baron, A.] Univ Hosp Ambroise Pare, Boulogne, France., [Durand, M.] Univ Hosp Grenoble, La Tronche, France., [Gainnier, M.] Univ Hosp Marseille, Marseille, France., [Ichai, C.] Univ Nice, Nice, France., [Arens, S.] Alexianer Krefeld Gmbh, Krefeld, Germany., [Hoffmann, C.] Charite Hochschulmed Berlin, Berlin, Germany., [Kaffarnik, M.] Charite, Berlin, Germany., [Scharnofske, C.] Diakoniekrankenhaus Henriettenstiftung Gmbh, Hannover, Germany., [Voigt, I] Elisabeth Krankenhaus Essen, Essen, Germany., [Peckelsen, C.] Munich Municipal Hosp Grp, Harlaching Hosp, Munich, Germany., [Weber, M.] Helios St Johannes Klin, Duisburg, Germany., [Gille, J.] Hosp St Georg Leipzig, Leipzig, Germany., [Lange, A.] Klin Hennigsdorf Oberhavel Kliniken Gmbh, Hennigsdorf, Germany., [Schoser, G.] Klin Tettnang, Tettnang, Germany., [Sablotzki, A.] Klinikum St Georg Leipzig, Leipzig, Germany., [Jaschinski, U.; Bluethgen, A.] Klinikum Augsburg, Augsburg, Germany., [Vogel, F.] Klinikum Bremen Mitte, Bremen, Germany., [Tscheu, A.] Klinikum Bremen Ost, Bremen, Germany., [Fuchs, T.] Klinikum Heidenheim, Heidenheim, Germany., [Wattenberg, M.] Klinikum Links Weser Gmbh, Bremen, Germany., [Helmes, T.] Klinikum Luedenscheid, Luedenscheid, Germany., [Scieszka, S.] Krankenhaus Neuwerk, Monchengladbach, Germany., [Heintz, M.] Marienkrankenhaus Schwerte, Schwerte, Germany., [Sakka, S.] Med Ctr Cologne Merheim, Cologne, Germany., [Kohler, J.] Schwarzwald Baar Klinikum Villingen Schwenningen, Villingen Schwenningen, Germany., [Fiedler, F.] St Elisabeth Krankenhaus Koln Hohenlind, Cologne, Germany., [Danz, M.] St Martinus Hosp Olpe, Olpe, Germany., [Sakr, Y.] Uniklinikum Jena, Jena, Germany., [Riessen, R.] Univ Klinikum Tubingen, Tubingen, Germany., [Kerz, T.] Univ Med Mainz, Mainz, Germany., [Kersten, A.] Univ Hosp Aachen, CPACC, Aachen, Germany., [Tacke, F.] Univ Hosp Aachen, DMIII, Aachen, Germany., [Marx, G.] Univ Hosp Aachen, OIC, Aachen, Germany., [Volkert, T.] Univ Hosp Muenster, Munster, Germany., [Schmutz, A.] Univ Med Ctr Freiburg, Fr

Kodani et al. identify a role for the mammalian homologue of yeast SFI1 as a regulator of centriole duplication. They show that SFI1 localizes USP9X to the centrosome to stabilize the microcephaly protein STIL to promote centriole duplication., In mammals, centrioles participate in brain development, and human mutations affecting centriole duplication cause microcephaly. Here, we identify a role for the mammalian homologue of yeast SFI1, involved in the duplication of the yeast spindle pole body, as a critical regulator of centriole duplication in mammalian cells. Mammalian SFI1 interacts with USP9X, a deubiquitylase associated with human syndromic mental retardation. SFI1 localizes USP9X to the centrosome during S phase to deubiquitylate STIL, a critical regulator of centriole duplication. USP9X-mediated deubiquitylation protects STIL from degradation. Consistent with a role for USP9X in stabilizing STIL, cells from patients with USP9X loss-of-function mutations have reduced STIL levels. Together, these results demonstrate that SFI1 is a centrosomal protein that localizes USP9X to the centrosome to stabilize STIL and promote centriole duplication. We propose that the USP9X protection of STIL to facilitate centriole duplication underlies roles of both proteins in human neurodevelopment.

Objective: Marriage is consistently associated with better health outcomes. Spouses' attempts to influence partners' lifestyle and general health behaviors may contribute to this effect, although partners may not be aware of this influence. Spousal worry of a cancer diagnosis for an at-risk partner may factor into attempts to influence. An examination of spousal worry and influence on lifestyle choices, general health behaviors, and cancer screening adherence for partners at higher risk of colorectal cancer may shed light on spousal influence and partners' perceptions of influence. Methods: A mixed-method design assessed cancer worry and spousal influence for risk-reducing behavior in first-degree relatives of colorectal cancer patients following personalized genetic counseling. Couples discussed current and future ways to reduce risk. Results: Both the at-risk partner and the spouses had moderately high cancer worries. Spouses reported exerting influence for healthier behavior and cancer screening adherence but at-risk partners did not always recognize it. Qualitative data demonstrated partners' perceptions of spousal influence toward better health decisions, and against better health decisions. Conclusions: Future research should examine how and when spouses choose to exert influence, type of influence, what strategies they use, and to what effect.

Mycobacterium bovis is the cause of tuberculosis in most animals, most notably cattle. The stereotypical lesion of bovine tuberculosis is the granuloma; a distinct morphological lesion where host and pathogen interact and disease outcome (i.e., dissemination, confinement, or resolution) is determined. Accordingly, it is critical to understand host-pathogen interactions at the granuloma level. Host-pathogen interactions within individual granulomas at different stages of disease have not been examined in cattle. We examined bacterial burden and cytokine expression in individual pulmonary granulomas from steers at 30, 90, 180, and 270 days after experimental aerosol infection with M. bovis. Bacterial burdens within individual granulomas examined 30 days after infection were greater and more heterogenous (variable) than those examined 90 to 270 days after infection. Bacterial burdens did not correlate with expression of IFN-γ, TNF-α, TGF-β, granuloma stage, or lung lesion score, although there was a modest positive correlation with IL-10 expression. Granuloma stage did have modest positive and negative correlations with TNF-α and IL-10, respectively. Heterogeneity and mean expression of IFN-γ, IL-10 and TNF-α did not differ significantly over time, however, expression of TGF-β at 90 days was significantly greater than that seen at 30 days after infection.

Background This study will evaluate whether those who have completed a hand fellowship treat a disproportionate number of scaphoid fractures based on recent American Board of Orthopaedic Surgery (ABOS) data. We hypothesize that surgeons who have completed a fellowship in hand surgery will address most surgically treated scaphoid fractures, particularly those with fracture nonunions or requiring graft. Methods We queried the ABOS database for case log information submitted for part II of the ABOS examination. This search included all cases with Current Procedural Terminology codes for procedures related to scaphoid fixation. Demographic information, case volume, type of case, and complication rate were compared for hand fellowship–trained surgeons and those who had completed other fellowships as well as non-fellowship-trained surgeons. Results During the study period, 1686 surgeons reported treating 4244 scaphoid fractures. Of these surgeons, 1180 had completed a hand surgery fellowship. Hand fellowship–trained surgeons were shown to have operatively treated more scaphoid fractures both in total volume and on a per-surgeon basis. Hand fellowship–trained surgeons were also found to have performed a significantly higher proportion of difficult cases, which were those listed as being a malunion/nonunion or those incorporating a pedicle graft. There was no difference in the complication rate between the 2 groups. Conclusion Among those orthopedic surgeons reporting case information for part II of the ABOS certification examination, statistically significant differences exist in case volume and case difficulty among surgeons with different areas of fellowship training. Complication rates increase with patient age and examination year.

Background: Obese patients with adolescent idiopathic scoliosis (AIS) have been shown to present with larger curve magnitudes preoperatively. However, the effect of obesity on shoulder balance in AIS remains unknown. The purpose of our study was to determine if overweight and obese patients with AIS have worse radiographic shoulder balance on initial presentation when compared with normal weight patients. Methods: AIS patients Results: One hundred eighty-four patients (116 [63%] normal weight and 68 [37%] overweight/obese) were included. The mean age at surgery was 13.1 ± 2 years, and mean follow-up was 17.4 ± 13 months. Preoperative shoulder imbalance was significantly greater in the overweight/obese group compared to the normal weight group (1.9 ± 1 cm vs. 1.5 ± 1 cm, p = 0.04). The odds ratio of presenting with unbalanced shoulders was 2.0 (95% CI: 1.02–3.83, p = 0.04) for the overweight/obese group. No significant differences were found for postoperative shoulder balance, UIV selection, or major curve correction. Conclusions: Overweight and obese patients with AIS are twice as likely to present with unbalanced shoulders preoperatively; however, this difference is not clinically relevant with a mean difference of 0.4 cm between cohorts. Finally, the preoperative BMI percentile did not show a significant effect on the chosen UIV or curve magnitude correction. Level of Evidence: Level III: this is a retrospective case-control study.

Pump thrombosis remains a feared complication for patients implanted with durable left ventricular assist devices. Optimal treatment is unknown, but consists of either pharmacologic fibrinolysis or surgical pump exchange. Fibrinolysis is less invasive, but carries a significant risk of intracerebral hemorrhage. We present four cases of LVAD pump thrombosis successfully treated with a novel protocol that consists of low-dose four-factor prothrombin complex concentrate to reverse baseline INR elevation prior to alteplase administration to minimize the risk for intracerebral hemorrhage.

Background: Patients with cardiogenic shock after percutaneous coronary intervention (PCI) may require mechanical circulatory support (MCS). The combination of dual antiplatelet therapy with cangrelor and continuous anticoagulation required for MCS may increase the risk of bleeding. Objective: The objective of the study is to describe the complications and outcomes of patients who received cangrelor during MCS following PCI. Methods: This is a single-center, retrospective, observational case series of 17 patients who received cangrelor while on MCS from June 2017 to September 2019. Results: In a case series of 17 patients, 8 patients (47%) were supported with an Impella device and 4 patients (24%) with venoarterial (VA) extracorporeal membrane oxygenation (ECMO); 5 required (29%) concomitant VA ECMO and Impella support in the setting of cardiogenic shock. All patients received triple antithrombotic therapy with aspirin, heparin, and cangrelor. Cangrelor was commonly initiated at a median dose of 0.75 (range 0.5-4) µg/kg/min. Cangrelor dose adjustments included changes in increments up to 0.25 µg/kg/min with review of P2Y12 levels. A total of 10 patients (59%) experienced a bleeding event, most commonly located at the peripheral cannulation site (40%) and in the gastrointestinal tract (30%). Seven (70%) and 3 (30%) of the bleeding complications were classified as major and minor, respectively. No patient developed in-stent thrombosis during the hospitalization; 14 (82%) patients survived their MCS course. Conclusion and Relevance: This case series suggests that cangrelor doses less than 0.75 µg/kg/min may be beneficial. Larger studies should evaluate alternative dosing regimens.

Offspring born to diabetic or obese mothers have a higher lifetime risk of heart disease. Previously, we found that rat offspring exposed to late-gestational diabetes mellitus (LGDM) and maternal high-fat (HF) diet develop mitochondrial dysfunction, impaired cardiomyocyte bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combination-exposed newborn offspring. We hypothesized that PGDM exposure, similar to LGDM, causes mitochondrial dysfunction to play a central, pathogenic role in neonatal cardiomyopathy. We found that PGDM-exposed offspring, similar to LGDM-exposed offspring, have cardiac dysfunction at birth, but their isolated cardiomyocytes have seemingly less bioenergetics impairment. This finding was due to confounding by impaired viability related to poorer ATP generation, more lipid peroxidation, and faster apoptosis under metabolic stress. To mechanistically isolate and test the role of mitochondria, we transferred mitochondria from normal rat myocardium to control and exposed neonatal rat cardiomyocytes. As expected, transfer provides a respiratory boost to cardiomyocytes from all groups. They also reduce apoptosis in PGDM-exposed males, but not in females. Findings highlight sex-specific differences in mitochondria-mediated mechanisms of developmentally programmed heart disease and underscore potential caveats of therapeutic mitochondrial transfer.

Diabetic retinopathy, retinopathy of prematurity and retinal vein occlusion are potentially blinding conditions largely due to their respective neovascular components. The development of real-time in vivo molecular imaging methods, to assess levels of retinal neovascularization (NV), would greatly benefit patients afflicted with these conditions. mRNA hybridization techniques offer a potential method to image retinal NV. The success of these techniques hinges on the selection of a target mRNA whose tissue levels and spatial expression patterns correlate closely with disease burden. Using a model of oxygen-induced retinopathy (OIR), we previously observed dramatic increases in retinal endoglin that localized to neovascular structures (NV), directly correlating with levels of neovascular pathology. Based on these findings, we have investigated Endoglin mRNA as a potential marker for imaging retinal NV in OIR mice. Also of critical importance, is the application of innovative technologies capable of detecting mRNAs in living systems with high sensitivity and specificity. To detect and visualize endoglin mRNA in OIR mice, we have designed and synthesized a novel imaging probe composed of short-hairpin anti-sense (AS) endoglin RNA coupled to a fluorophore and black hole quencher (AS-Eng shRNA). This assembly allows highly sensitive fluorescence emission upon hybridization of the AS-Eng shRNA to cellular endoglin mRNA. The AS-Eng shRNA is further conjugated to a diacyl-lipid (AS-Eng shRNA–lipid referred to as probe). The lipid moiety binds to serum albumin facilitating enhanced systemic circulation of the probe. OIR mice received intraperitoneal injections of AS-Eng shRNA–lipid. Ex vivo imaging of their retinas revealed specific endoglin mRNA dependent fluorescence superimposed on neovascular structures. Room air mice receiving AS-Eng shRNA–lipid and OIR mice receiving a non-sense control probe showed little fluorescence activity. In addition, we found that cells in neovascular lesions labelled with endoglin mRNA dependent fluorescence, co-labelled with the macrophage/microglia-associated marker IBA1. Others have shown that cells expressing macrophage/microglia markers associate with retinal neovascular structures in proportion to disease burden. Hence we propose that our probe may be used to image and to estimate the levels of retinal neovascular disease in real-time in living systems.

Purpose: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time. Methods: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012. Results: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 ± 17.0 vs. 60.6 ± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35–0.59), p < 0.001]. Conclusions: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis., 0, info:eu-repo/semantics/published

Summary Infants of diabetic mothers are at risk of cardiomyopathy at birth and myocardial infarction in adulthood, but prevention is hindered because mechanisms remain unknown. We previously showed that maternal glucolipotoxicity increases the risk of cardiomyopathy and mortality in newborn rats through fuel-mediated mitochondrial dysfunction. Here we demonstrate ongoing cardiometabolic consequences by cross-fostering and following echocardiography, cardiomyocyte bioenergetics, mitochondria-mediated turnover, and cell death following metabolic stress in aged adults. Like humans, cardiac function improves by weaning with no apparent differences in early adulthood but declines again in aged diabetes-exposed offspring. This is preceded by impaired oxidative phosphorylation, exaggerated age-related increase in mitochondrial number, and higher oxygen consumption. Prenatally exposed male cardiomyocytes have more mitolysosomes indicating high baseline turnover; when exposed to metabolic stress, mitophagy cannot increase and cardiomyocytes have faster mitochondrial membrane potential loss and mitochondria-mediated cell death. Details highlight age- and sex-specific roles of mitochondria in developmentally programmed adult heart disease., Graphical Abstract, Highlights • Fetal exposures disrupt mitochondria, bioenergetics, & cardiac function at birth • First, bioenergetics & function improve until greater reliance on OXPHOS with age • At 6MO, poor respiration incites biogenesis & mitophagy, and then functional decline • Fetal exposures cause faster mitochondria-mediated cell death in aged adult hearts, Biological Sciences; Physiology; Animal Physiology; Molecular Biology; Diabetology; Cell Biology

Tacrolimus is a mainstay medication for graft-versus-host disease (GVHD) prophylaxis in combination with other immunosuppressive agents. Achieving therapeutic tacrolimus levels is vital in preventing acute GVHD (aGVHD), while supratherapeutic levels may increase risk of toxicity and relapse. We performed a single center retrospective chart review including all adult patients post-allogeneic hematopoietic stem-cell transplantation who received initial tacrolimus continuous intravenous infusion for GVHD prophylaxis between June 1, 2017 and December 31, 2019. The primary outcome was the percent of patients with an initial therapeutic tacrolimus level, defined as 5–12 ng/mL, after empiric weight-based dosing at 0.02 mg/kg/day. Secondary outcomes included evidence of tacrolimus toxicity within seven days of initiation, incidence of aGVHD by day 100, and relapse after six months. An initial therapeutic level was achieved in 47% of patients with a median initial level of 12.4 ng/mL. Fifty-two percent of patients had supratherapeutic levels. No significant nephrotoxicity, hepatotoxicity, or neurotoxicity occurred within a week of starting tacrolimus or at neutrophil engraftment. Grade II-IV aGVHD by day 100 was observed in 22% of patients, and relapse after six months was found in 16% of patients. These results have led to consideration of an empiric 20% dose reduction to 0.016 mg/kg/day or an expanded initial tacrolimus target of 5–15 ng/mL as there was low aGVHD incidence and no increased risk of toxicity.

Malignant melanoma is an aggressive cancer with a poor prognosis despite numerous advances in therapeutic strategies. Quercetin is a plant-derived flavonoid suggested to have potent anticancer properties. Quercetin has no demonstrable toxicity in humans, further supporting the possibility of using quercetin therapeutically. We chose to investigate quercetin efficacy against B16 murine melanoma cells and identify the mechanisms of anticancer activity. Treatment of B16 melanoma cells with 50 μg/mL quercetin resulted in a 75% reduction in viability from 6 through 48 h post-treatment. The reduction in cancer cell viability was comparable to or greater than what was observed with etoposide, an established chemotherapeutic. Specifically, we found Quercetin reduced the proliferation of B16 melanoma cells at 48 h as much or more than etoposide. Although quercetin reduced the proportion of cells in the S and G2/M stages of the cell cycle, this could largely be explained by an increase in the subG1 population in quercetin-treated cells (suggesting apoptosis). Quercetin-induced apoptosis was confirmed by flow cytometry analysis of Annexin V+ cells. Collectively, our findings demonstrate quercetin reduces proliferation and induces apoptosis of B16 melanoma cells

OBJECTIVE: Ongoing exploration of factors related to poor sleep in collegiate athletes is important as understanding of the risks and consequences of poor sleep in this specific population increases. DESIGN: Retrospective cohort study. SETTING: University in the Pacific Northwest. PARTICIPANTS: One-hundred thirty-seven male and female collegiate athletes across 5 collision, contact, and limited contact team sports. MEASUREMENTS: Depressive symptoms (Patient Health Questionnaire 9; PHQ-9), anxiety symptoms (General Anxiety Disorder 7; GAD-7), and somatic complaints (Patient Health Questionnaire 15; PHQ-15). Sleep quality (Pittsburgh Sleep Quality Index; PSQI) used both a cutoff score ≥6 and a cutoff score of ≥8, indicating “poor sleep quality” to reduce threats to divergent validity. RESULTS: Poor sleep quality as defined by PSQI ≥6 was present in 53% of athletes, and as defined by PSQI ≥8 was identified in 33.5% of the cohort. There were no differences in the incidence of poor sleepers between sport, race/ethnicity, or sex. Multiple regression analysis revealed that depressive symptoms, somatic complaints, Caucasian race, male sex, and number of concussions were significant predictors of poor sleep (P < .05). The model accounted for 43% of the variance in PSQI and primarily by depressive symptoms explaining 9% of reported sleep quality variability. Anxiety symptoms, sport category, and history of migraines were not significant predictors of poor sleep quality. CONCLUSIONS: A high incidence of poor sleep among collegiate athletes was observed regardless of sport, and may be related to depressive symptoms, somatic complaints, Caucasian race, male sex, and historical number of concussions.

The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19.

Preoperative testing to assess the physiologic impact of pectus excavatum is sometimes ordered to meet third-party payor preauthorization requirements. This study describes the utility of physiologic testing prior to minimally invasive repair of pectus excavatum (MIRPE).We retrospectively reviewed patients that underwent MIRPE from 1/2012-7/2016 at two academic children's hospitals. Data collected included demographics, insurance, Haller Index (HI), pulmonary function tests (PFTs) and echocardiograms (ECHO) obtained, and preauthorization denials.A total of 360 patients (mean age 15.7 ± 2.0 years; mean HI 4.5 ± 1.5) underwent MIRPE (Hospital 1: 189, Hospital 2: 171). Commercial insurers covered 84% of patients. Hospital 1 obtained more frequent preoperative testing (PFTs: 73% vs 6%, p 0.0001). Overall, 72% of PFTs were normal with abnormal studies limited to mild findings. Similarly, 85% of ECHOs were normal. Third-party payors more frequently denied preauthorization for MIRPE at Hospital 2 (11% vs. 5%, p = 0.03).More frequent preoperative testing may decrease initial preauthorization denials for MIRPE; however, this increased utilization of resources may not be necessary as the majority of test results are normal.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

Background Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Our previous work using chromatin immunoprecipitation sequencing revealed that late-gestation diabetes in combination with maternal high fat (HF) diet cause a distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to the combination of maternal diabetes and maternal HF diet. Methods Gene expression profiling from hearts of diabetes exposed, HF diet exposed, combination exposed and control newborn rats was compared for differential transcriptome expression. Functional annotation, pathway and network analysis was performed on statistically significant differentially expressed genes from the combination exposed group compared with controls. Downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β assays, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results Transcriptome analysis of newborn rat hearts showed significant changes in cardiac gene expression following exposure to maternal diabetes or HF diet individually, as well as the combination of diabetes + HF compared with controls. Reactome analyses identified expression changes in two key signaling cascades functionally prioritized in male control and combination exposed offspring hearts. These pathways included downregulation of the fibroblast growth factor (FGF) pathway and concomitant downstream PI3K/AKT activation canonically recognized as a regulator of cell metabolism, growth, and development. In contrast, the second pathway exhibited significant upregulation of mitoribosomal signaling that regulates mitochondrial biogenesis, mitophagy and cell fate. Focused bioinformatic analysis on mitochondrial genes enriched in the combination exposed dataset revealed genes associated with diverse aspects of mitochondrial structure, function, and dynamism. Functional biochemical, metabolic, and histochemical assays supported these transcriptome changes, confirming the essential role of mitochondrial energetics in facilitating diabetes- and diet-induced cardiac transcriptome remodeling and phenotype in offspring. Conclusions This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on intergenerational regulation of heart health.