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α1-Adrenergic receptors (ARs) are catecholamine-activated G protein-coupled receptors (GPCRs) that are expressed in mouse and human myocardium and vasculature, and play essential roles in the regulation of cardiovascular physiology. Though α1-ARs are less abundant in the heart than β1-ARs, activation of cardiac α1-ARs results in important biologic processes such as hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicate that nonselectively blocking α1-ARs is associated with a twofold increase in adverse cardiac events, including heart failure and angina, suggesting that α1-AR activation might also be cardioprotective in humans. Mounting evidence implicates the α1A-AR subtype in these adaptive effects, including prevention and reversal of heart failure in animal models by α1A agonists. In this review, we summarize recent advances in our understanding of cardiac α1A-ARs.

BACKGROUND AND AIMS Estimates of racial disparity in cirrhosis have been limited by lack of large-scale, longitudinal data, which track patients from diagnosis to death and/or transplant. APPROACH AND RESULTS We analyzed a large, metropolitan, population-based electronic health record data set from seven large health systems linked to the state death registry and the national transplant database. Multivariate competing risk analyses, adjusted for sex, age, insurance status, Elixhauser score, etiology of cirrhosis, HCC, portal hypertensive complication, and Model for End-Stage Liver Disease-Sodium (MELD-Na), examined the relationship between race, transplant, and cause of death as defined by blinded death certificate review. During the study period, 11,277 patients met inclusion criteria, of whom 2,498 (22.2%) identified as Black. Compared to White patients, Black patients had similar age, sex, MELD-Na, and proportion of alcohol-associated liver disease, but higher comorbidity burden, lower rates of private insurance, and lower rates of portal hypertensive complications. Compared to White patients, Black patients had the highest rate all-cause mortality and non-liver-related death and were less likely to be listed or transplanted (P

Monte Carlo-based project risk models are essential tools in project risk management, particularly for large, complex projects in which it is difficult to glean intuitively the importance of individual risks to the overall project. Conventional correlation-based methods for measuring the importance of contributing risks in such models are argued here to be both statistically flawed and unintuitive in the importance metrics they produce. Drawing on and adapting methods more traditionally associated with engineering risk models, Risk Reduction Worth (RRW) is introduced as an importance measure. RRW is shown to be statistically robust and provide an easily interpretable, quantitative measure of the importance of a risk to the overall performance of a project; specifically, measuring the extent to which removal of a risk would improve confidence in project outcomes. To ensure practicality of the method, an approach is described in which RRWs can be produced for all contributing risks based on a single Monte Carlo sample. This is demonstrated through application to a large, complex project risk model from which intuitive risk importance insights provide a robust, transparent basis for the allocation of risk management resources.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

Bacterial biofilms are difficult to inactivate due to their high antimicrobial resistance. Therefore, new approaches are required for more effective bacterial biofilm inactivation. Airborne acoustic ultrasound improves bactericidal or bacteriostatic activity which is safe and environmentally friendly. While, plasma activated water (PAW) is attracting increasing attention due to its strong antimicrobial properties. This study determined efficacy of combined airborne acoustic ultrasound and plasma activated water from both cold and thermal plasma systems in inactivating Escherichia coli K12 biofilms. The application of airborne acoustic ultrasound (15 min) alone was significantly more effective in reducing E. coli counts in 48 and 72 h biofilms compared to 30 min treatment with PAW. The effect of airborne acoustic ultrasound was more pronounced when used in combination with PAW. Airborne acoustic ultrasound treatment for 15 min of the E. coli biofilm followed by treatment with PAW significantly reduced the bacterial count by 2.2—2.62 Log10 CFU/mL when compared to control biofilm treated with distilled water. This study demonstrates that the synergistic effects of airborne acoustic ultrasound and PAW for enhanced antimicrobial effects. These technologies have the potential to prevent and control biofilm formation in food and bio-medical applications.

One remarkable characteristic of eukaryotic cells is the complexity of their membrane systems [...]

The field of tissue engineering is increasingly recognizing that gene therapy can be employed for modulating in vivo cellular response thereby guiding tissue regeneration. However, the field lacks a versatile and biocompatible gene delivery platform capable of efficiently delivering transgenes to mesenchymal stem cells (MSCs), a cell type often refractory to transfection. Herein, we describe the extensive and systematic exploration of three architectural variations of star-shaped poly(l-lysine) polypeptide (star-PLL) with varying number and length of poly(l-lysine) arms as potential nonviral gene delivery vectors for MSCs. We demonstrate that star-PLL vectors are capable of self-assembling with pDNA to form stable, cationic nanomedicines. Utilizing high content screening, live cell imaging, and mechanistic uptake studies we confirm the intracellular delivery of pDNA by star-PLLs to MSCs is a rapid process, which likely proceeds via a clathrin-independent mechanism. We identify a star-PLL composition with 64 poly(l-lysine) arms and five l-lysine subunits per arm as a particularly efficient vector that is capable of delivering both reporter genes and the therapeutic transgenes bone morphogenetic protein-2 and vascular endothelial growth factor to MSCs. This composition facilitated a 1000-fold increase in transgene expression in MSCs compared to its linear analogue, linear poly(l-lysine). Furthermore, it demonstrated comparable transgene expression to the widely used vector polyethylenimine using a lower pDNA dose with significantly less cytotoxicity. Overall, this study illustrates the ability of the star-PLL vectors to facilitate efficient, nontoxic nucleic acid delivery to MSCs thereby functioning as an innovative nanomedicine platform for tissue engineering applications.

Mallee related maalok ecosystems are unique to southern Australia, having no direct analogue on other land masses. They straddle the interface between the Mediterranean-type and arid climate zones. The key environmental factors that shape mallee ecosystem functions and traits are severe summer water deficits, nutritional poverty, and fire regimes. These processes interact with herbivores, which are critical to regeneration of woody perennials in the postfire period. Approximately 30% of mallee ecosystems were converted to cropping and exotic pasture in the past 200 years. Future sustainability depends on a more representative protected area network, regulation of land use change, conservative livestock management, avoidance of short fire-return intervals, minimizing risks of recruitment failure, and approaches that build resilience to climate change.

Worldwide, one in three people do not have access to safe drinking water [1], resulting in the deaths of nearly 1000 children every day. Standard tests can take several days to produce a result [2], by which time it is often too late since the contaminated and polluted water has already been used. Hence, there is a clear need for rapid and specific testing that can produce results in real time. Here, we focus on microplastics pollution in drinking water. A typical pollution pathway is shown in Fig. 1 [3]. Published version

OBJECTIVES/HYPOTHESIS To 1) examine the characteristics of patients who develop second primary malignancies (SPMs) from an index human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) and HPV-unrelated HNSCC and to 2) compare overall survival between those with HPV-related and HPV-unrelated index HNSCC among patients who develop SPM. STUDY DESIGN Retrospective cohort analysis. METHODS A retrospective study was conducted of 113,259 patients who were diagnosed with HNSCC from 2000 to 2014. SPM was defined as the first subsequent primary cancer occurring at least 2 months after index cancer diagnosis, and HPV-relatedness was based on whether patients' index HNSCC was potentially HPV-related or HPV-unrelated. Multivariable Fine and Gray (FG) competing-risks regression models were used to estimate factors associated with risk of SPM by HPV-relatedness. Among patients with SPM, an adjusted Cox proportional hazards (PH) regression model was used to assess the association between HPV-relatedness and survival. RESULTS Approximately 13,900 patients (12.3%) developed SPM. In the FG model, patients with HPV-unrelated HNSCC had a 15% higher risk of developing SPM (adjusted hazard ratio: 1.15, 95% confidence interval: 1.10-1.20) than those with potentially HPV-related HNSCC, but the same characteristics were associated with SPM development. In the Cox PH model, patients with SPM whose index HNSCC was HPV-unrelated had higher risk of death than those whose index HNSCC was potentially HPV-related (adjusted hazard ratio: 1.06; 95% confidence interval: 1.02-1.11). CONCLUSIONS Patients with HPV-unrelated HNSCC have a higher risk of SPM development than do those with HPV-related HNSCC. Effective secondary disease-prevention strategies should be established to improve long-term patient outcomes. LEVEL OF EVIDENCE NA Laryngoscope, 129:1828-1835, 2019.

Objective To determine if there are differences in mortality from oral cavity squamous cell carcinoma (OCSCC) based on oral cavity (OC) subsites. Methods Using the Surveillance, Epidemiology, and End Results Program (SEER) 9 database, patients with sequence number 0 or 1 squamous cell OCSCC were analyzed by OC subsite for 5-year cause-specific mortality (CSM) from OCSCC. Proportional hazards regression determined the association between 5-year CSM and OC subsites while controlling for treatment modality, stage, and demographic characteristics using hazard ratios. Significance was set at alpha = 0.05. Results 20,647 OC patients were included in the regression analysis. The most commonly diagnosed sites were floor of mouth (34.4%) and oral tongue (34.3%). Floor of mouth, upper gum, and retromolar trigone were associated with lower CSM compared to oral tongue. Not receiving surgery and receiving radiation were associated with increased CSM, and CSM increased with cancer staging when distant or regional disease was compared to localized disease. Also, patients diagnosed at 60 years or older and black patients had increased CSM. Conclusion Among OCSCC patients, those with oral tongue cancer are more likely to experience CSM than patients with floor of mouth, upper gum, and retromolar trigone cancer. It is important to understand these mortality related differences in the management of OCSCC patients. Understanding subsite-specific mortality may benefit prognosis counseling of OCSCC patients and elicit subsite-directed research as a means to improve outcomes. Level of evidence NA Laryngoscope, 129:1400-1406, 2019.

Background Cancer survivors face psychosocial issues that increase their risk of suicide. This study examined the risk of suicide across cancer sites, with a focus on survivors of head and neck cancer (HNC). Methods The Surveillance, Epidemiology, and End Results 18-registry database (from 2000 to 2014) was queried for the top 20 cancer sites in the database, including HNC. The outcome of interest was suicide as a cause of death. The mortality rate from suicide was estimated for HNC sites and was compared with rates for 19 other cancer sites that were included in the study. Poisson regression was used to estimate adjusted rate ratios (aRRs) and 95% confidence intervals (CIs) for 1) HNC versus non-HNC sites (the other 19 cancer sites combined), and 2) HNC versus each individual cancer site. Models were stratified by sex, controlling for race, marital status, age, year, and stage at diagnosis. Results There were 404 suicides among 151,167 HNC survivors from 2000 to 2014, yielding a suicide rate of 63.4 suicides per 100,000 person-years. In this timeframe, there were 4493 suicides observed among 4219,097 cancer survivors in the study sample, yielding an incidence rate of 23.6 suicides per 100,000 person-years. Compared with survivors of other cancers, survivors of HNC were almost 2 times more likely to die from suicide (aRR, 1.97; 95% CI, 1.77-2.19). There was a 27% increase in the risk of suicide among HNC survivors during the period from 2010 to 2014 (aRR, 1.27; 95% CI, 1.16-1.38) compared with the period from 2000 to 2004. Conclusions Although survival rates in cancer have improved because of improved treatments, the risk of death by suicide remains a problem for cancer survivors, particularly those with HNC.

OBJECTIVE The literature on nasopharyngeal carcinoma survival in the United States has focused mostly on Whites or Asians and not much is known about survivorship in other minority racial and ethnic groups. We aimed to determine the disease-specific survival rate and prognostic factors for nasopharyngeal carcinoma survival across the minority United States population. DESIGN A retrospective cohort study. SETTING The Surveillance, Epidemiology and End Results (SEER) 13 database from 1992 to 2014 was queried for adult cases of nasopharyngeal carcinoma (n = 2549). PARTICIPANTS Eligible cases were Blacks, Hispanics, Asians/Pacific Islanders, American Indians/Alaska Natives; White patients were excluded. MAIN OUTCOMES MEASURE A multivariable competing risk survival analysis yielded hazard ratios (HR) for competing mortality and was used to identify independent prognostic factors for survival. RESULTS Non-Hispanic American Indians/Alaska Natives consistently had the worst cause-specific survival of any group and that non-Hispanic Asians/Pacific Islanders consistently had the best survival (P < 0.001). Even after adjusting for other poor prognostic factors in the study, including older age, keratinising histology, and lack of radiation treatment, non-Hispanic American Indians/Alaska Natives had more than double hazards of death from nasopharyngeal cancer compared with non-Hispanic Asians/Pacific Islanders (aHR = 2.63, 95% CI 1.67, 4.13). CONCLUSIONS There are disparities in nasopharyngeal carcinoma survival among racial and ethnic minority groups in the United States, with American Indians/Alaskan Natives faring worst. It is critical that future research focuses on nasopharyngeal carcinoma among this population to improve survivorship and mitigate cancer-related health disparities.

Objectives/hypothesis Head and neck squamous cell carcinoma (HNSCC) prognosis strongly correlates with demographic factors. This study aimed to determine whether demographic predictors of HNSCC survival differ between age cohorts, with an emphasis on the growing elderly demographic. Study design Outcomes research. Methods Adults with squamous cell carcinoma of the upper aerodigestive tract were identified from the Surveillance, Epidemiology and End Results 18 database. Demographic and oncologic factors were compared between three age groups: 18 to 49, 50 to 74, and >75 years. Factors associated with cancer-specific survival were assessed in each cohort using subdistribution hazard ratio (sHR) and 95% confidence interval (CI) produced by multivariate competing risk models. Results A cohort of 69,098 patients included 10,588 (15.3%) 75 years or older and 9,882 (14.3%) less than 50 years old. Older patients were more often female (35.4% vs. 25.1% aged 18-49 years and 20.4% aged 50-74 years), white (78.7% vs. 69.4% and 75.9%), insured (63.5% vs. 46.5% and 56.8%), and married (56.6% vs. 53% and 51.1%), but received adequate treatment less often (72.0% vs. 86.3% and 82.7%). In the older cohort, male sex was associated with lower mortality (sHR: 0.92, 95% CI: 0.85-1.00), and unlike the younger cohorts, black race was no longer associated with mortality (sHR: 1.07, 95% CI: 0.94-1.22). Marriage was associated with lower mortality in all age groups but with diminishing effects (single sHR: young 1.52, middle 1.31, older 1.14). Conclusions Elderly HNSCC patients have distinct effects from demographic prognostic factors and should be considered a separate subgroup with unique epidemiology, risks, and preferences. Level of evidence 2c Laryngoscope, , 129:146-153, 2018.

Weight suppression (WS), the difference in one's highest and current adult weight excluding pregnancy, is associated with eating disorder (ED) symptom onset and maintenance. There is increasing evidence that WS is related to ED symptoms in non-clinical samples, but there are no known studies examining the interaction of WS and current body mass index (BMI) in this group. History of overweight is common in those with EDs, and higher weight status often delays identification and treatment. This study examined the interaction of WS and current BMI on body dissatisfaction and eating pathology in undergraduate men and women. Undergraduates (N = 476) completed online surveys assessing current height and weight, weight history, and eating attitudes and behaviors. In women (n = 333), both BMI and WS were positively associated with body dissatisfaction, restraint, and global ED symptoms. In men (n = 143), there were no significant associations with BMI, but WS was related to greater body dissatisfaction, restraint, global ED symptoms, and loss-of-control eating. Moderation analyses revealed that the effect of current BMI on shape concern (p = .005), weight concern (p = .002), global ED symptoms (p = .01), and purging behaviors (p = .04) in women and restraint (p = .03) in men weakened at the highest levels of WS. Results suggest that WS is salient in a non-clinical sample and underscore the need to evaluate both weight history and the presence of disordered eating in individuals across the BMI spectrum.

Genetic adaptation to captivity influences the reproductive success of hatchery-reared steelhead (Oncorhynchus mykiss) spawning in the wild, but the mechanism by which adaptation occurs is not well understood. Because body size-at-release is positively correlated with post-release survival in hatchery-reared smolts, one hypothesis is that hatcheries select for physiological and/or behavioral traits that promote fast growth in captivity. If those juvenile growth traits are maladaptive for spawning or offspring survival in the wild, then that could explain why hatchery fish quickly evolve to have lower reproductive success than natural-origin fish in the wild environment. First-generation hatchery-reared steelhead from the Hood River, (Oregon) have lower reproductive success in the wild than do natural-origin fish, and substantial evidence suggests the fitness difference is genetically based and due to genetic adaptation to captivity. Here we ask whether the ‘selection on size-at-release’ hypothesis could explain the rapid genetic adaptation observed in this well-studied steelhead population. Using scale analysis, we back-calculated length at ocean entrance to test whether size-selective survival occurred in two cohorts (brood year [BY] 1997 and 2009). In BY 2009, we found evidence of weak size-selective survival (difference of 9 mm between pre-release average length and back-calculated length from surviving adults), but in BY 1997, strong (37 mm difference) size-selective survival was observed. Family identity explained 33% of the variance in fork length before release, and fork length was highly heritable in both BY cohorts. Thus, the requisite genetic variation for response to selection on size-at-release exists in this population. Our results support the hypothesis that size-selective survival does occur after release, and that selection for traits promoting fast growth in the hatchery could be a mechanism by which rapid adaptation to captivity has occurred in the Hood River winter steelhead hatchery program.

The field of tissue engineering is increasingly recognizing that gene therapy can be employed for modulating in vivo cellular response thereby guiding tissue regeneration. However, the field lacks a versatile and biocompatible gene delivery platform capable of efficiently delivering transgenes to mesenchymal stem cells (MSCs), a cell type often refractory to transfection. Herein, we describe the extensive and systematic exploration of three architectural variations of star-shaped poly(l-lysine) polypeptide (star-PLL) with varying number and length of poly(l-lysine) arms as potential nonviral gene delivery vectors for MSCs. We demonstrate that star-PLL vectors are capable of self-assembling with pDNA to form stable, cationic nanomedicines. Utilizing high content screening, live cell imaging, and mechanistic uptake studies we confirm the intracellular delivery of pDNA by star-PLLs to MSCs is a rapid process, which likely proceeds via a clathrin-independent mechanism. We identify a star-PLL composition with 64 poly(l-lysine) arms and five l-lysine subunits per arm as a particularly efficient vector that is capable of delivering both reporter genes and the therapeutic transgenes bone morphogenetic protein-2 and vascular endothelial growth factor to MSCs. This composition facilitated a 1000-fold increase in transgene expression in MSCs compared to its linear analogue, linear poly(l-lysine). Furthermore, it demonstrated comparable transgene expression to the widely used vector polyethylenimine using a lower pDNA dose with significantly less cytotoxicity. Overall, this study illustrates the ability of the star-PLL vectors to facilitate efficient, nontoxic nucleic acid delivery to MSCs thereby functioning as an innovative nanomedicine platform for tissue engineering applications.

Aim. To describe the top five causes of preventable health conditions among Pacific children (Cook Island, Fijian, Niuean, Samoan, Tongan, Tokelauan) aged 0-4 years living in New Zealand (NZ), and to make comparisons of these rates with NZ’s population who were of neither Maori nor Pacific ethnicity (NMNP). Method. This study is a retrospective analysis of preschool Ambulatory Sensitive Hospitalisations (ASH) by ethnicity. The data, from 2010 to 2014, was extracted from The National Minimum Dataset. Results. The top five preventable health conditions among Pacific under 5’s were asthma and wheeze, gastroenteritis, dental, skin infections and pneumonia. Rates for all Pacific children with any of the ASH conditions were four to five times higher among Pacific, than among NMNP, from 2000 to 2014. Pacific children were also significantly more likely to present with bronchiectasis and rheumatic fever or rheumatic heart disease (RR 25.7 and 26.4 respectively). Conclusion. Pacific children aged 0-4 years are more likely to be exposed to health conditions that are considered preventable . The most common preventable health conditions experienced by Pacific children were asthma and wheeze, gastroenteritis, dental, skin infections and pneumonia. These findings highlight the importance of investing in effective prevention strategies to further investigate and address the underlying causes of these conditions.

Importance Patients with head and neck cancer (HNC) are known to be at increased risk of suicide compared with the general population, but there has been insufficient research on whether this risk differs based on patients’ rural, urban, or metropolitan residence status. Objective To evaluate whether the risk of suicide among patients with HNC differs by rural vs urban or metropolitan residence status. Design, Setting, and Participants This cross-sectional study uses data from the Surveillance, Epidemiology, and End Results database on patients aged 18 to 74 years who received a diagnosis of HNC from January 1, 2000, to December 31, 2016. Statistical analysis was conducted from November 27, 2020, to June 3, 2021. Exposures Residence status, assessed using 2013 Rural Urban Continuum Codes. Main Outcomes and Measures Death due to suicide was assessed byInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revisioncodes (U03, X60-X84, and Y87.0) and the cause of death recode (50220). Standardized mortality ratios (SMRs) of suicide, assessing the suicide risk among patients with HNC compared with the general population, were calculated. Suicide risk by residence status was compared using Fine-Gray proportional hazards regression models. Results Data from 134 510 patients with HNC (101 142 men [75.2%]; mean [SE] age, 57.7 [10.3] years) were analyzed, and 405 suicides were identified. Metropolitan residents composed 86.6% of the sample, urban residents composed 11.7%, and rural residents composed 1.7%. The mortality rate of suicide was 59.2 per 100 000 person-years in metropolitan counties, 64.0 per 100 000 person-years in urban counties, and 126.7 per 100 000 person-years in rural counties. Compared with the general population, the risk of suicide was markedly higher among patients with HNC in metropolitan (SMR, 2.78; 95% CI, 2.49-3.09), urban (SMR, 2.84; 95% CI, 2.13-3.71), and rural (SMR, 5.47; 95% CI, 3.06-9.02) areas. In Fine-Gray competing-risk analyses that adjusted for other covariates, there was no meaningful difference in suicide risk among urban vs metropolitan residents. However, compared with rural residents, residents of urban (subdistribution hazard ratio, 0.52; 95% CI, 0.29-0.94) and metropolitan counties (subdistribution hazard ratio, 0.55; 95% CI, 0.32-0.94) had greatly lower risk of suicide. Conclusions and Relevance The findings of this cross-sectional study suggest that suicide risk is elevated in general among patients with HNC but is significantly higher for patients residing in rural areas. Effective suicide prevention strategies in the population of patients with HNC need to account for rural health owing to the high risk of suicide among residents with HNC in rural areas.

Background Sleep Disordered Breathing (SDB) in children is characterised by snoring and breathing difficulties during sleep. Small clinical trials suggest intranasal corticosteroids reduce SDB severity as defined by polysomnography. We assessed the efficacy of intranasal corticosteroid for improving symptoms and quality of life (QOL) in children with SDB. Methods This is a double-blind, randomised, placebo-controlled trial of healthy children 3-12y referred to a specialist with SDB symptoms. Exclusions were previous adenotonsillectomy, obesity or severe SDB. Participants received daily intranasal mometasone furoate 50micrograms or normal saline for 6 weeks. The primary outcome was resolution of symptoms measured by SDB score. Secondary outcomes were SDB symptom scores, QOL, behaviour, parent and surgeon perceived need for surgery, and parent satisfaction with treatment. Results 276 participants were recruited; 138 in each group. 127 and 123 participants had primary outcome data at 6 weeks in the mometasone and saline groups respectively. Baseline age, atopic history, symptom severity and QOL were similar between groups. Resolution of SDB symptoms occurred in 44% [95%CI 35–53] of the mometasone group and 40% [95%CI 32–49] of the saline group; risk difference 4% [95%CI -0.8–16] p=0.511. Secondary outcomes were not different between groups. Discussion This large RCT, using clinical rather than polysomnographic outcomes to investigate the efficacy of mometasone on symptoms of SDB, found substantial rates of symptom resolution after 6 weeks in both groups. However, we found no difference in treatment effect between 6 weeks of intranasal mometasone over saline, for management of SDB symptoms in childhood.

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α1-adrenergic receptors (α1-ARs), in particular the α1A-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α1A-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg−1·day−1). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α1A-subtype is a potential therapeutic target to treat the failing RV. NEW & NOTEWORTHY Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α1A-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α1A-subtype is a therapeutic target to treat RV failure.

Scanning Wizard software helps scanning users improve the setup of their switch and scanning system. This study evaluated Scanning Wizard's effectiveness and usability. Ten people who use switch scanning and ten practitioners used Scanning Wizard in the initial session. Usability was high, based on survey responses averaging over 4.5 out of 5, and qualitative feedback was very positive. Five switch users were able to complete the multi-week protocol, using settings on their own scanning system that were recommended from the Scanning Wizard session. Using these revised settings, text entry rates improved by an average of 71%, ranging from 29% to 172% improvement. Results suggest that Scanning Wizard is a useful tool for improving the configuration of scanning systems for people who use switch scanning to communicate. Implications for Rehabilitation Some individuals with severe physical impairments use switch scanning for spoken and written communication. Scanning Wizard software helps scanning users improve the setup of their switch and scanning system. This study demonstrated high usability of Scanning Wizard (with 10 switch userpractitioner teams) and increased text entry rate by an average of 71% (for five switch users). Results suggest that Scanning Wizard is a useful tool for improving the configuration of scanning systems for people who use switch scanning to communicate.

The organization of cnidarian nerve nets is traditionally described as diffuse with randomly arranged neurites that show minimal reproducibility between animals. However, most observations of nerve nets are conducted using cross-reactive antibodies that broadly label neurons, which potentially masks stereotyped patterns produced by individual neuronal subtypes. Additionally, many cnidarians species have overt structures such as a nerve ring, suggesting higher levels of organization and stereotypy exist, but mechanisms that generated that stereotypy are unknown. We previously demonstrated that NvLWamide-like is expressed in a small subset of the Nematostella nerve net and speculated that observing a few neurons within the developing nerve net would provide a better indication of potential stereotypy. Here we document NvLWamide-like expression more systematically. NvLWamide-like is initially expressed in the typical neurogenic salt and pepper pattern within the ectoderm at the gastrula stage, and expression expands to include endodermal salt and pepper expression at the planula larval stage. Expression persists in both ectoderm and endoderm in adults. We characterized our NvLWamide-like::mCherry transgenic reporter line to visualize neural architecture and found that NvLWamide-like is expressed in six neural subtypes identifiable by neural morphology and location. Upon completing development the numbers of neurons in each neural subtype are minimally variable between animals and the projection patterns of each subtype are consistent. Furthermore, between the juvenile polyp and adult stages the number of neurons for each subtype increases. We conclude that development of the Nematostella nerve net is stereotyped between individuals. Our data also imply that one aspect of generating adult cnidarian nervous systems is to modify the basic structural architecture generated in the juvenile by increasing neural number proportionally with size.

To determine differences in oropharyngeal squamous cell carcinoma (OPSCC) incidence between 1975 and 2014 stratified by race, sex, and age.We obtained age-adjusted OPSCC incidence rates for race and sex groups from 1975 to 2014 using the Surveillance, Epidemiology, and End Results 9 database. We defined OPSCC as cancers of the base of tongue, lingual/palatine tonsil, oropharynx, soft palate, uvula, and Waldeyer's ring. We used Joinpoint analyses to determine incidence trends for race/sex/age groupings.There were 38,624 oropharyngeal primary tumors in the analyses. Males accounted for 74% of sample population, and whites accounted for 84% of tumors. Overall, there was a 57.3% increase in incidence of oropharyngeal between 1975 and 2014. For blacks and whites, average incidence was lower for females than males. Rates for black males aged ≥50years was highest for most of the follow-up time but decreased sharply around 1988 and were surpassed by the significant increase in incidence in white males aged 50-59 (1995-2014 APC=4.07, p0.001) and ≥60years (2002-2014 APC=4.25, p0.001). For males aged ≥60, whites had higher rates than blacks starting in 2010. OPSCC incidence in White males (10.99 per 100,000 person-years) surpassed rates in Blacks (10.14 per 100,000 person-years) beginning in 2008.OPSCC has significantly increased in the United States in the last 40 years. This overall increase in OPSCC can primarily be attributed to white males. OPSCC prevention and early detection efforts could target these demographic factors to decrease rising OPSCC incidence.

IntroductionUncontrolled haemorrhage is the leading cause of death on the battlefield, and two-thirds of these deaths result from non-compressible haemorrhage. Blood salvage and autotransfusion represent an alternative to conventional blood transfusion techniques for austere environments, potentially providing blood to the casualty at point of injury. The aim of this paper is to describe the design, development and initial proof-of-concept testing of a portable blood salvage and autotransfusion technology to enhance survivability of personnel requiring major medical interventions in austere or military environments.MethodA manually operable, dual-headed pump was developed that removes blood from site of injury to a collection reservoir (upper pump) and back to casualty (lower pump). Theoretical flow rate calculations determined pump configuration and a three-dimensionally printed peristaltic pump was manufactured. Flow rates were tested with fresh bovine blood under laboratory conditions representative of the predicted clinical environment.ResultsMathematical modelling suggested flow rates of 3.6 L/min and 0.57 L/min for upper and lower pumps. Using fresh bovine blood, flow rates produced were 2.67 L/min and 0.43 L/min. To mimic expected battlefield conditions, upper suction pump flow rate was calculated using a blood/air mixture.ConclusionThe authors believe that this technology can potentially enhance survivability for casualties in austere and deployed military settings through autotransfusion and cell concentration. It reduces negative effects of blood donation on the conventional donor pool, and potentially negates the logistical constraints associated with allogenic transfusions.

A lack of longitudinal studies impedes the understanding of whether visual processing skills significantly influence reading performance. The present study assessed if multi-element processing (MEP), a visual processing task comprising only non-verbal stimuli, was predominantly related with decoding or sight-word reading. One hundred Spanish pre-reading children were evaluated on their MEP, naming speed (RAN), phonemic awareness (PA), letter knowledge (LK) and IQ. Early reading level was measured in first grade. In third grade, four reading lists consisting of short and long, high- and low-frequency words were administered. Results from path analyses revealed that, after controlling for RAN, PA, LK, IQ and early reading level, MEP was a significant predictor of the reading of long low-frequency words only. This result suggests that, in the transparent Spanish orthography, pre-reading MEP is significantly linked to future decoding skill. This is the first study to provide empirical evidence that pre-reading MEP predicts future reading.

The Golgi complex is the central unit of the secretory pathway, modifying, processing and sorting proteins and lipids to their correct cellular localisation. Changes to proteins at the Golgi complex can have deleterious effects on the function of this organelle, impeding trafficking routes through it, potentially resulting in disease. It is emerging that several Rho GTPase proteins, namely Cdc42, RhoBTB3, RhoA and RhoD are at least in part localised to the Golgi complex, and a number of studies have shown that dysregulation of their levels or activity can be associated with cellular changes which ultimately drive cancer progression. In this mini-review we highlight some of the recent work that explores links between form and function of the Golgi complex, Rho GTPases and cancer.

Objective A pattern of disordered eating involving a pathological fixation with healthy food consumption, labeled orthorexia nervosa (ON), has recently generated attention; however, research has not yet investigated perceptions of ON-related behaviors. This study examined potential stigmatization of ON, compared with DSM-5 ED diagnoses. Method Participants (N = 505) were randomly assigned to read a vignette depicting a woman with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), or ON. They then answered questions about the individual depicted in the vignette. A series of MANOVAs investigated whether opinions and beliefs about the person depicted varied as a function of the disorder described in the vignette. Results Individuals with ON were perceived as less likely to “improve with treatment” than individuals with BN, and less likely to “pull themselves together,” than individuals with BED. Individuals with ON and AN were viewed as “hard[er] to talk to” and more of a “danger to others” compared with individuals with BED. ON was viewed as less distressing, less likely to evoke sympathy, and more acceptable than the other disorders. Finally, “poor living choices” were perceived as contributing more substantially to ON. Participants' attributions of various personality characteristics did not differ based on ED diagnosis. Discussion Results suggest that ON is viewed as less severe, more desirable, and more often the result of personal life choices. However, findings also imply that ON is associated with stigma, similar to DSM-5 EDs. These negative attitudes might reinforce ON behaviors, and limit awareness of their potential complications.

Summary: Alpha-1 adrenergic receptors (α1-ARs) play adaptive and protective roles in the heart. Dabuzalgron is an oral selective α1A-AR agonist that was well tolerated in multiple clinical trials of treatment for urinary incontinence, but has never been used to treat heart disease in humans or animal models. In this study, the authors administered dabuzalgron to mice treated with doxorubicin (DOX), a widely used chemotherapeutic agent with dose-limiting cardiotoxicity that can lead to heart failure (HF). Dabuzalgron protected against DOX-induced cardiotoxicity, likely by preserving mitochondrial function. These results suggest that activating cardiac α1A-ARs with dabuzalgron, a well-tolerated oral agent, might represent a novel approach to treating HF. Key Words: alpha adrenergic receptors, anthracyclines, cardioprotection, catecholamines, heart failure

BACKGROUND To describe sociodemographic factors associated with head and neck cancer (HNC) survival among patients with distant metastatic disease. METHODS We retrospectively analyzed national data for 2889 adult patients with metastatic HNC (2007-2015). We used Fine and Gray competing risks proportional hazard models, stratified by oropharyngeal cancer status, controlled for sociodemographic factors (age, sex, race/ethnicity, marital status, and insurance status), and accounted for multiple testing. RESULTS Median survival time was 11 months (15 months for patients married/partnered; 13 months for patients with non-Medicaid insurance; P

Importance Melanoma is one of the most common cancers worldwide, typically diagnosed in older adults. There is an increasing incidence in the younger population (age ≤40 years) in America. In addition, approximately 1 in 5 cases of melanoma affect the head and neck. However, there are limited data on the incidence of head and neck melanoma in the pediatric, adolescent, and young adult population in North America (United States and Canada). Objective To assess 20-year demographic and incidence changes associated with head and neck melanoma in the pediatric, adolescent, and young adult population in North America. Design, Setting, and Participants A descriptive analysis of retrospective data on head and neck melanoma from the North American Association of Central Cancer Registries’ Cancer in North America public use data set from 1995 to 2014 was conducted. The data set currently includes 93% of the United States and 64% of the Canadian populations. Eligible data were from 12 462 pediatric, adolescent, and young adult patients (aged 0-39 years) with a confirmed diagnosis of melanoma (International Classification of Diseases–Oncology 3histologic types 8720-8790) in primary head and neck sites: skin of lip, not otherwise specified (C44.0); eyelid (C44.1); external ear (C44.2); skin of other/unspecified parts of face (C44.3); and skin of scalp and neck (C44.4). The study was conducted from January 26 to July 21, 2019. Main Outcomes and Measures Log-linear regression was used to estimate annual percentage change in age-adjusted incidence rates (AAIRs) of head and neck melanoma. Results Of the 12 462 patients with head and neck melanoma included in the study, 6810 were male (54.6%). The AAIR was 0.51 per 100 000 persons (95% CI, 0.50-0.52 per 100 000 persons). In North America, the incidence of head and neck melanoma increased by 51.1% from 1995 to 2014. The rate was higher in the United States (AAIR, 0.52; 95% CI, 0.51-0.53 per 100 000 person-years) than Canada (AAIR, 0.43; 95% CI, 0.40-0.45 per 100 000 persons). In the United States, the incidence increased 4.68% yearly from 1995 to 2000 and 1.15% yearly from 2000 to 2014. In Canada, the incidence increased 2.18% yearly from 1995 to 2014. Male sex (AAIR, 0.55; 95% CI, 0.54-0.57 per 100 000 persons), older age (AAIR, 0.79; 95% CI, 0.79-0.80 per 100 000 persons), and non-Hispanic white race/ethnicity (AAIR, 0.79; 95% CI, 0.77-0.80 per 100 000 persons) were associated with an increased incidence of head and neck melanoma. Conclusions and Relevance The incidence of pediatric, adolescent, and young adult head and neck melanoma in North America appears to have increased by 51.1% in the past 2 decades, with males aged 15 to 39 years the main cohort associated with the increase.

The hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions whose characteristic feature is degeneration of the longest axons within the corticospinal tract which leads to progressive spasticity and weakness of the lower limbs. Though highly genetically heterogeneous, the majority of HSP cases are caused by mutations in genes encoding proteins that are responsible for generating and organizing the tubular endoplasmic reticulum (ER). Despite this, the role of the ER within neurons, particularly the long axons affected in HSP, is not well understood. Throughout axons, ER tubules make extensive contacts with other organelles, the cytoskeleton and the plasma membrane. At these ER contacts, protein complexes work in concert to perform specialized functions including organelle shaping, calcium homeostasis and lipid biogenesis, all of which are vital for neuronal survival and may be disrupted by HSP-causing mutations. In this article we summarize the proteins which mediate ER contacts, review the functions these contacts are known to carry out within neurons, and discuss the potential contribution of disruption of ER contacts to axonopathy in HSP.

The effort to characterise detector sensors and components for the High Luminosity upgrade of the CERN Large Hadron Collider requires collaboration between irradiation facilities around the world. By convention, the radiation damage following irradiation with particle beams is reported as the 1 MeV neutron equivalent fluence, obtained using the corresponding hardness factor. Measurements of proton hardness factors at three different kinetic energies are presented, by characterisation of commercially available diodes before and after irradiation, using irradiations at the University of Birmingham, the Karlsruhe Institute of Technology, and CERN. Possible future improvements to these measurements are also discussed.

Background Risk stratification following an acute coronary syndrome (ACS) is of utmost importance, in order to identify patients at higher risk of subsequent cardiovascular events. Diabetic patients have a significantly worse prognosis, so new risk prediction tools are important to better identify and risk stratify high risk patients within this important ACS subpopulation. Aim The aim of this study was to identify the best predictors of a new ACS, in a single-center database of ACS, resorting to machine learning and artificial intelligence, and to compare the Global Registry of Acute Coronary Events (GRACE) risk score's relevance for risk discrimination in a general ACS population versus a subpopulation of diabetic patients. Methods In a single center, 5977 patients admitted due to ACS between 2004 and 2017 and alive at discharge were studied. In the subpopulation of diabetic patients (n=3429), each covariate present in the database was analyzed separately with a Cox proportional hazard model with three terms – subpopulation belonging indicator, covariate, interaction term. The p-value of the interaction term was used to rank variables. The more significant the interaction term, the stronger the change in relationship between patients in the subpopulation and the risk of a new ACS, compared to the one in the general population. Results During long term follow-up, 13% of patients (n=771) experienced a second event. Kaplan-Meier curve represents how ACS free-survival depends on the GRACE risk score and group of interest. In the general population and in the subpopulation of diabetic patients, the GRACE score was used to further divide patients into 3 terciles, of which only the lower and upper tercile are shown (GRACE ≤113 and GRACE >144, respectively). The solid lines represent Kaplan-Meier curves for diabetic patients, and the dotted lines in the general population. Pink or grey colour of the curves represent the stratification level of the covariate. Conclusions In our model, the GRACE risk score was found to be a better discriminator of risk of futher ACS in diabetic patients than in the general ACS population. Strikingly, a higher GRACE score predicts a lower rate of readmission, probably because many patients will die in the index hospitalization or out of hospital. This finding reinforces the usefulness of the GRACE score in high risk patients and may improve risk stratisfication in diabetic post-ACS patients, making sure that they are closely followed and submitted to optimal risk factor management, in order to improve their post-ACS prognosis.

Three dogs who were presented with cutaneous lesions and had histopathologic findings consistent with pemphigus foliaceus were treated with injectable polysulfated glycosaminoglycan as an adjunctive to systemic immune-modulatory therapy. These patients were not adequately controlled with oral glucocorticoids in conjunction with cyclosporine, azathioprine, and/or mycophenolate. Polysulfated glycosaminoglycan contributed to induction of remission and reduced glucocorticoid doses in all dogs.

Draft genomes of the fungal species Fusarium xylarioides, Teratosphaeria gauchensis and T. zuluensis are presented. In addition an annotation of the genome of Ceratocystis fimbriata is presented. Overall these genomes provide a valuable resource for understanding the molecular processes underlying pathogenicity and potential management strategies of these economically important fungi.

Artículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiera, y los autores pertenecientes a la UAM, Used for both proton decay searches and neutrino physics, large water Cherenkov (WC) detectors have been very successful tools in particle physics. They are notable for their large masses and charged particle detection capabilities. While current WC detectors reconstruct charged particle tracks over a wide energy range, they cannot efficiently detect neutrons. Gadolinium (Gd) has the largest thermal neutron capture cross section of all stable nuclei and produces an 8 MeV gamma cascade that can be detected with high efficiency. Because of the many new physics opportunities that neutron tagging with a Gd salt dissolved in water would open up, a large-scale R&D program called EGADS was established to demonstrate this technique’s feasibility. EGADS features all the components of a WC detector, chiefly a 200-ton stainless steel water tank furnished with 240 photo-detectors, DAQ, and a water system that removes all impurities from water while keeping Gd in solution. In this paper we discuss the milestones towards demonstrating the feasibility of this novel technique, and the features of EGADS in detail, This work was supported by the JSPS KAKENHI Grant Numbers JP21224004, JP26000003, JP24103004 and JP17H06365. Funding support was provided by Kavli IPMU (WPI), the University of Tokyo and the US Department of Energy. We thank the “Consorcio Laboratorio Subterraneo de Canfranc” (Spain) and the Boulby Underground Research Laboratory and in particular the staff of the BUGS facility (UK) for supporting the low-background materials screening work. Some of us have been supported by funds from the European Union H2020-MSCA-RISE-GA872549-SK2HK, the Spanish Ministry of Science and Innovation (grant PGC2018-099388-B-100), the Science and Technology Facilities Council (STFC) and GridPP, UK, and the European Union’s H2020 -MSCA-RISE-2018 JENNIFER2 grant agreement no. 822070

Background Since the number of cancer survivors is increasing, it is imperative that we better understand the long-term consequences of these survivors. We assessed the risk of developing a second primary malignant neoplasm (SPMN) after an index potentially-HPV-associated cancers (P-HPV-AC). Methods We constructed a population-based cohort of patients with P-HPV-AC using Surveillance, Epidemiology, and End Results registry data (2000–2015). We limited patients to those with invasive P-HPV-AC [cervical, vagina, vulva, penile, anal, and oropharynx] based on the International Classification of Diseases for Oncology, 3rd edition. Excess SPMN risks were calculated based on standardized incidence ratios (SIRs) and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). Results A total of 105,644 patients with an index P-HPV-AC were identified, and 7.8 % developed a SPMN. In all P-HPV-AC patients, the overall SIR was 1.73 (95 % CI: 1.69–1.77) and EAR of 70.72 per 10,000 PYR. All index P-HPV-AC sites showed statistically significant increases in the risk of SPMN, except for anal cancer among men, compared with the general population. The greatest increase in risk of SPMN was observed among patients diagnosed with an index P-HPV-oropharyngeal cancer (SIR = 1.83; 95 % CI, 1.70–1.82 and SIR = 2.29; 95 % CI, 2.12–2.47 for men and women, respectively). Men developed SPMN mostly in aero-digestive tract whiles women developed SPMN both in aero-digestive tract and other HPV-associated cancer sites. Conclusions P-HPV-AC survivors experienced excess risk of SPMN. These findings have the potential to affect future surveillance practices and improve preventive healthcare for survivors of P-HPV-ACs.