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[This corrects the article DOI: 10.1371/journal.pone.0276532.].

In this paper, we analyze double modal use in American English based on a multi-billion-word corpus of geolocated posts from the social media platform Twitter. We identify and map 76 distinct double modals totaling 5,349 examples, many more types and tokens of double modals than have ever been observed. These descriptive results show that double modal structure and use in American English is far more complex than has generally been assumed. We then consider the relevance of these results to three current theoretical debates. First, we demonstrate that although there are various semantic tendencies in the types of modals that most often combine, there are no absolute constraints on double modal formation in American English. Most surprisingly, our results suggest that double modals are used productively across the US. Second, we argue that there is considerable dialect variation in double modal use in the southern US, with double modals generally being most strongly associated with African American Language, especially in the Deep South. This result challenges previous sociolinguistic research, which has often highlighted double modal use in White Southern English, especially in Appalachia. Third, we consider how these results can help us better understand the origins of double modals in America English: although it has generally been assumed that double modals were introduced by Scots-Irish settlers, we believe our results are more consistent with the hypothesis that double modals are an innovation of African American Language.

The Step Pyramid of Djoser in Saqqara, Egypt, is considered the oldest of the seven monumental pyramids built about 4,500 years ago. From transdisciplinary analysis, it was discovered that a hydraulic lift may have been used to build the pyramid. Based on our mapping of the nearby watersheds, we show that one of the unexplained massive Saqqara structures, the Gisr el-Mudir enclosure, has the features of a check dam with the intent to trap sediment and water. The topography beyond the dam suggests a possible ephemeral lake west of the Djoser complex and water flow inside the 'Dry Moat' surrounding it. In the southern section of the moat, we show that the monumental linear rock-cut structure consisting of successive, deep compartments combines the technical requirements of a water treatment facility: a settling basin, a retention basin, and a purification system. Together, the Gisr el-Mudir and the Dry Moat's inner south section work as a unified hydraulic system that improves water quality and regulates flow for practical purposes and human needs. Finally, we identified that the Step Pyramid's internal architecture is consistent with a hydraulic elevation mechanism never reported before. The ancient architects may have raised the stones from the pyramid centre in a volcano fashion using the sediment-free water from the Dry Moat's south section. Ancient Egyptians are famous for their pioneering and mastery of hydraulics through canals for irrigation purposes and barges to transport huge stones. This work opens a new line of research: the use of hydraulic force to erect the massive structures built by Pharaohs.

Salmon are an essential component of the ecosystem in Tsleil-Waututh Nation's traditional, ancestral, and contemporary unceded territory, centred on present-day Burrard Inlet, BC, Canada, where Tsleil-Waututh people have been harvesting salmon, along with a wide variety of other fishes, for millennia. Tsleil-Waututh Nation is a Coast Salish community that has called the Inlet home since time immemorial. This research assesses the continuity and sustainability of the salmon fishery at təmtəmíxʷtən, an ancestral Tsleil-Waututh settlement in the Inlet, over thousands of years before European contact (1792 CE). We apply Zooarchaeology by Mass Spectrometry (ZooMS) analysis to 245 archaeological salmon vertebrae to identify the species that were harvested by the ancestral Tsleil-Waututh community that lived at təmtəmíxʷtən. The results demonstrate that Tsleil-Waututh communities consistently and preferentially fished for chum salmon (Oncorhynchus keta) over the period of almost 3,000 years. The consistent abundance indicates a sustainable chum salmon fishery over that time, and a strong salmon-to-people relationship through perhaps 100 generations. This research supports Tsleil-Waututh Nation's stewardship obligations under their ancestral legal principles to maintain conditions that uphold the Nation's way of life.

BackgroundLung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed within the first 48 hours of non-critical patients with suspected COVID-19 would identify those with a high-risk of worsening.MethodsPOCUSCO was a prospective, multicenter study. Non-critical adult patients who presented to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following ED presentation. The lung damage severity was assessed using a previously developed score reflecting both the extension and the intensity of lung damage. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion.ResultsAmong 296 patients, 8 (2.7%) met the primary outcome. The area under the curve (AUC) of L-POCUS was 0.80 [95%CI:0.60-0.94]. The score values which achieved a sensibility >95% in defining low-risk patients and a specificity >95% in defining high-risk patients were ConclusionL-POCUS performed within the first 48 hours following ED presentation allows risk-stratification of patients with non-severe COVID-19.

Both common pain and anxiety problems are widespread, debilitating and often begin in childhood-adolescence. Twin studies indicate that this co-occurrence is likely due to shared elements of risk, rather than reciprocal causation. A joint genome-wide investigation and pathway/network-based analysis of adolescent anxiety and pain problems can identify genetic pathways that subserve shared etiopathogenetic mechanisms. Pathway-based analyses were performed in the independent samples of: The Quebec Newborn Twin Study (QNTS; 246 twin pairs and 321 parents), the Longitudinal Study of Child Development in Quebec (QLSCD; n = 754), and in the combined QNTS and QLSCD sample. Multiple suggestive associations (p

Background and purposeLimited data is available on sex differences in young stroke patients describing discrepant findings. This study aims to investigate the sex differences in young stroke patients.MethodsProspective cohort study comparing risk factors, etiology, stroke localization, severity on admission, management and outcome in patients aged 16-55 years with acute ischemic stroke consecutively included in the Bernese stroke database between 01/2015 to 12/2018 with subgroup analyses for very young (16-35y) and young patients (36-55y).Results689 patients (39% female) were included. Stroke in women dominated in the very young (53.8%, pConclusionsThe main finding of this study is that sex specific risk factors in women may contribute to a large extent to the higher incidence of stroke in the very young in women. Important modifiable stroke risk factors, such as arterial hypertension, diabetes mellitus and atrial fibrillation did not differ in women and men, either in the young as well as in the very young. These findings have major implications for primary preventive strategies of stroke in young people.

IntroductionUrsus americanus Pallas 1780 is the largest carnivore and the only ursid in Mexico. It is considered an endangered species in the country because its distribution and population have been reduced by up to 80% because of habitat loss or furtive hunting. These problems can lead to a diet change, which could result in metabolic disorders, such as fatty acid β-oxidation defects or organic acid metabolism disorders. In our study, a free amino acid and acylcarnitine profile was characterized.MethodsPeripheral blood samples were drawn from nine free-ranging black bears in a period of five months, from June to October of 2019 in Northeastern Mexico, and 12 amino acids and 30 acylcarnitines were determined and quantified. Age differences were observed in the samples through ANOVA and post-hoc Tukey test.ResultsOnly three metabolites showed a significant difference with age: alanine (Ala) [cubs vs juvenile], free-carnitine (C0) [juvenile vs cubs] and acetylcarnitine (C2) [cubs vs adults and juvenile vs cubs].ConclusionMetabolites with variability due to age were identified, making them potential biomarkers to monitor metabolic status as early diagnosis in endangered species. This is the first study of black bear amino acid and acylcarnitine profiles, and the values found could be used as reference for free amino acid and acylcarnitine concentrations in further studies of the species.

Prospective studies suggest that child maltreatment substantially increases the risk for depression in adulthood. However, the mechanisms underlying this association require further elucidation. In recent years, DNA methylation has emerged as a potential mechanism by which maltreatment experiences (a) could partly explain the emergence or aggravation of depressive symptoms (i.e., mediation) and/or (b) could increase (or decrease) the risk for depressive symptoms (i.e., moderation). The present study tested whether the methylation levels of nine candidate genes mediated and/or moderated the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. The sample comprised 156 men aged between 18 and 35 years. Maltreatment experiences and depressive symptoms were assessed retrospectively using self-reported questionnaires. Methylation levels of nine candidate genes (COMT, FKBP5, IL6, IL10, MAOA, NR3C1, OXTR, SLC6A3 and SLC6A4), previously reported to be sensitive to early-life stress, were quantified from saliva samples. Maltreatment experiences in childhood were significantly associated with depressive symptoms in emerging adulthood. Both maltreatment experiences and depressive symptoms were associated with the methylation levels of two genomic sites, which cumulatively, but not individually, explained 16% of the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. Moreover, maltreatment experiences in childhood interacted with the methylation levels of fourteen genomic sites, which cumulatively, but not individually, modulated the level of depressive symptoms in young male adults who were maltreated as children. However, none of these effects survived multiple testing correction. These findings bring attention to the cumulative effects of DNA methylation measured in several candidate genes on the risk of reporting depressive symptoms following maltreatment experiences in childhood. Nonetheless, future studies need to clarify the robustness of these putative cumulative effects in larger samples and longitudinal cohorts.

BackgroundMeningiomas are stratified according to tumor grade and extent of resection, often in isolation of other clinical variables. Here, we use machine learning (ML) to integrate demographic, clinical, radiographic and pathologic data to develop predictive models for meningioma outcomes.Methods and findingsWe developed a comprehensive database containing information from 235 patients who underwent surgery for 257 meningiomas at a single institution from 1990 to 2015. The median follow-up was 4.3 years, and resection specimens were re-evaluated according to current diagnostic criteria, revealing 128 WHO grade I, 104 grade II and 25 grade III meningiomas. A series of ML algorithms were trained and tuned by nested resampling to create models based on preoperative features, conventional postoperative features, or both. We compared different algorithms' accuracy as well as the unique insights they offered into the data. Machine learning models restricted to preoperative information, such as patient demographics and radiographic features, had similar accuracy for predicting local failure (AUC = 0.74) or overall survival (AUC = 0.68) as models based on meningioma grade and extent of resection (AUC = 0.73 and AUC = 0.72, respectively). Integrated models incorporating all available demographic, clinical, radiographic and pathologic data provided the most accurate estimates (AUC = 0.78 and AUC = 0.74, respectively). From these models, we developed decision trees and nomograms to estimate the risks of local failure or overall survival for meningioma patients.ConclusionsClinical information has been historically underutilized in the prediction of meningioma outcomes. Predictive models trained on preoperative clinical data perform comparably to conventional models trained on meningioma grade and extent of resection. Combination of all available information can help stratify meningioma patients more accurately.

The present study documented in two distinct population-based samples the contribution of preschool fluid and crystallized cognitive abilities to school achievement in primary school and examined the mediating role of crystallized abilities in this sequence of predictive associations. In both samples, participants were assessed on the same cognitive abilities at 63 months (sample 1, n = 1072), and at 41 and 73 months (sample 2, n = 1583), and then with respect to their school achievement from grade 1 (7 years) to grade 6 (12 years). Preschool crystallized abilities were found to play a key role in predicting school achievement. They contributed substantially to school achievement in the early school years, but more modestly in the later years, due to the strong auto-regression of school achievement. They also mediated the association between fluid abilities and later school achievement in the early grades of school, with the former having modest direct contribution to the latter in the later grades. These findings are discussed regarding their implication for preventive interventions.

Mammals have evolved several physiological mechanisms to cope with changes in ambient temperature. Particularly critical among them is the process of keeping the membrane of cells in a fluid phase to prevent metabolic dysfunction. In this paper, we examine variation in the fatty acid composition of bone marrow and muscle tissues in the cold-adapted caribou (Rangifer tarandus caribou) to determine whether there are systematic differences in fatty acid profiles between anatomical regions that could potentially be explained by thermal adaptation as influenced by cell function, including hematopoiesis. Our results indicate that the bone marrow and muscle tissues from the appendicular skeleton are more unsaturated than the same tissues in the axial skeleton, a finding that is consistent with physiological adaptation of the appendicular regions to thermal challenges. Because mechanisms of thermal adaptation appear to be widely shared among terrestrial mammals, we suggest that the same patterns may prevail in other species, possibly including humans.

This study examines how unique audience segments within the Canadian population think and act toward climate change, and explores whether and how the level of audience engagement moderates the effect of various messages on support for climate policy. Drawing on a random probability sample of Canadian residents (N = 1207) conducted in October 2017, we first identify and describe five distinct audiences that vary in their attitudes, perceptions and behaviours with respect to climate change: the Alarmed (25%), Concerned (45%), Disengaged (5%), Doubtful (17%) and Dismissive (8%). We then explore how each segment responds to different messages about carbon pricing in Canada. We find that messages alluding to earmarking (i.e., "Invest in solutions") or leveling the playing field for alternative energy sources (i.e., "Relative price") increase support for a higher carbon price among the population as a whole. However, these messages decreased support for carbon pricing among more engaged audiences (e.g., Alarmed) when a low carbon price was specified to the respondent. Meanwhile, the "Relative price" is the only message that increased policy support among less engaged audiences-the Concerned and the Doubtful. In addition to highlighting the importance of tailoring and targeting messages for differently engaged segments, these results suggest that communicating around the specific consequences of carbon taxes for the prices of some goods may be a fruitful way to enhance support for carbon taxes among relatively less engaged audiences.

Polar microalgae face two major challenges: 1- growing at temperatures (-1.7 to 5°C) that limit enzyme kinetics; and 2- surviving and exploiting a wide range of irradiance. The objective of this study is to understand the adaptation of an Arctic diatom to its environment by studying its ability to acclimate to changes in light and temperature. We acclimated the polar diatom Chaetoceros neogracilis to various light levels at two different temperatures and studied its growth and photosynthetic properties using semi-continuous cultures. Rubisco content was high, to compensate for low catalytic rates, but did not change detectably with growth temperature. Contrary to what is observed in temperate species, in C. neogracilis, carbon fixation rate (20 min 14C incorporation) equaled net growth rate (μ) suggesting very low or very rapid (

Background A large proportion of gynecological cancer survivors suffer from pain during sexual intercourse, also known as dyspareunia. Following a multimodal pelvic floor physical therapy (PFPT) treatment, a reduction in pain and improvement in psychosexual outcomes were found in the short term, but no study thus far has examined whether these changes are sustained over time. Purpose To examine the improvements in pain, sexual functioning, sexual distress, body image concerns, pain anxiety, pain catastrophizing, painful intercourse self-efficacy, depressive symptoms and pelvic floor disorder symptoms in gynecological cancer survivors with dyspareunia after PFPT, and to explore women’s perceptions of treatment effects at one-year follow-up. Methods This mixed-method study included 31 gynecological cancer survivors affected by dyspareunia. The women completed a 12-week PFPT treatment comprising education, manual therapy and pelvic floor muscle exercises. Quantitative data were collected using validated questionnaires at baseline, post-treatment and one-year follow-up. As for qualitative data, semi-structured interviews were conducted at one-year follow-up to better understand women’s perception and experience of treatment effects. Results Significant improvements were found from baseline to one-year follow-up on all quantitative outcomes (P ≤ 0.028). Moreover, no changes were found from post-treatment to one-year follow-up, supporting that the improvements were sustained at follow-up. Qualitative data highlighted that reduction in pain, improvement in sexual functioning and reduction in urinary symptoms were the most meaningful effects perceived by participants. Women expressed that these effects resulted from positive biological, psychological and social changes attributable to multimodal PFPT. Adherence was also perceived to influence treatment outcomes. Conclusions Findings suggest that the short-term improvements following multimodal PFPT are sustained and meaningful for gynecological cancer survivors with dyspareunia one year after treatment.

Naphthalene is an environmental toxicant to which humans are exposed. Naphthalene causes dose-dependent cytotoxicity to murine airway epithelial cells but a link between exposure and human pulmonary disease has not been established. Naphthalene toxicity in rodents depends on P450 metabolism. Subsequent biotransformation results in urinary elimination of several conjugated metabolites. Glucuronide and sulfate conjugates of naphthols have been used as markers of naphthalene exposure but, as the current studies demonstrate, these assays provide a limited view of the range of metabolites generated from the parent hydrocarbon. Here, we present a liquid chromatography tandem mass spectrometry method for measurement of the glucuronide and sulfate conjugates of 1-naphthol as well as the mercapturic acids and N-acetyl glutathione conjugates from naphthalene epoxide. Standard curves were linear over 2 log orders. On column detection limits varied from 0.91 to 3.4 ng; limits of quantitation from 1.8 to 6.4 ng. The accuracy of measurement of spiked urine standards was -13.1 to + 5.2% of target and intra-day and inter-day variability averaged 7.2 (± 4.5) and 6.8 (± 5.0) %, respectively. Application of the method to urine collected from mice exposed to naphthalene at 15 ppm (4 hrs) showed that glutathione-derived metabolites accounted for 60-70% of the total measured metabolites and sulfate and glucuronide conjugates were eliminated in equal amounts. The method is robust and directly measures several major naphthalene metabolites including those derived from glutathione conjugation of naphthalene epoxide. The assays do not require enzymatic deconjugation, extraction or derivatization thus simplifying sample work up.

IntroductionNIMH Project Accept (HPTN 043) is a community- randomized trial to test the safety and efficacy of a community-level intervention designed to increase testing and lower HIV incidence in Tanzania, Zimbabwe, South Africa and Thailand. The evaluation design included a longitudinal study with community members to assess attitudinal and behavioral changes in study outcomes including HIV testing norms, HIV-related discussions, and HIV-related stigma.MethodsA cohort of 657 individuals across all sites was selected to participate in a qualitative study that involved 4 interviews during the study period. Baseline and 30-month data were summarized according to each outcome, and a qualitative assessment of changes was made at the community level over time.ResultsMembers from intervention communities described fewer barriers and greater motivation for testing than those from comparison communities. HIV-related discussions in intervention communities were more grounded in personal testing experiences. A change in HIV-related stigma over time was most pronounced in Tanzania and Zimbabwe. Participants in the intervention communities from these two sites attributed community-level changes in attitudes to project specific activities.DiscussionThe Project Accept intervention was associated with more favorable social norms regarding HIV testing, more personal content in HIV discussions in all study sites, and qualitative changes in HIV-related stigma in two of five sites.

BackgroundIn preparation for full Affordable Care Act implementation, California has instituted two healthcare initiatives that provide comprehensive coverage for previously uninsured or underinsured individuals. For many people living with HIV, this has required transition either from the HIV-specific coverage of the Ryan White program to the more comprehensive coverage provided by the county-run Low-Income Health Programs or from Medicaid fee-for-service to Medicaid managed care. Patient advocates have expressed concern that these transitions may present implementation challenges that will need to be addressed if ambitious HIV prevention and treatment goals are to be achieved.Methods30 semi-structured, in-depth interviews were conducted between October, 2012, and February, 2013, with policymakers and providers in 10 urban, suburban, and rural California counties. Interview topics included: continuity of patient care, capacity to handle payer source transitions, and preparations for healthcare reform implementation. Study team members reviewed interview transcripts to produce emergent themes, develop a codebook, build inter-rater reliability, and conduct analyses.ResultsRespondents supported the goals of the ACA, but reported clinic and policy-level challenges to maintaining patient continuity of care during the payer source transitions. They also identified strategies for addressing these challenges. Areas of focus included: gaps in communication to reach patients and develop partnerships between providers and policymakers, perceived inadequacy in new provider networks for delivering quality HIV care, the potential for clinics to become financially insolvent due to lower reimbursement rates, and increased administrative burdens for clinic staff and patients.ConclusionsCalifornia's new healthcare initiatives represent ambitious attempts to expand and improve health coverage for low-income individuals. The state's challenges in maintaining quality care and treatment for people living with HIV experiencing these transitions demonstrate the importance of setting effective policies in anticipation of full ACA implementation in 2014.

Alpine ski racers require diverse physical capabilities. While enhanced force production is considered key to high-level skiing, its relevance is convoluted. The aims of this study were to i) clarify the association between performance path length and velocity, ii) test the importance of radial force, and iii) explore the contribution of force magnitude and orientation to turn performance. Ski athletes (N = 15) were equipped with ski-mounted force plates and a global navigation satellite system to compute the following variables over 14 turns: path length (L), velocity normalized energy dissipation [Δemech/vin], radial force [Fr], total force (both limbs [Ftot], the outside limb, and the difference between limbs), and a ratio of force application (RF = Fr/Ftot). Data were course-averaged or separated into sectional turn groupings, averaged, and entered into stepped correlation and regression models. Our results support Δemech/vin as a discriminative performance factor (R2 = 0.50-0.74, p < .003), except in flat sections. Lower course times and better Δemech/vin were associated with greater Fr (R2 = 0.34-0.69 and 0.31-0.52, respectively, p < .032), which was related to both Ftot and RF (β = 0.92-1.00 and 0.63-0.81, respectively, p < .001) which varied in predictive order throughout the sections. Ftot was associated with increased outside limb force and a more balanced contribution of each limb (β = 1.04-1.18 and -0.65- -0.92, respectively, p < .001). Fr can be improved by either increasing total force output or by increasing technical effectiveness (i.e., proportionally more force radially) which should increase the trajectories available to the skier on the ski course.

ObjectivesPrader-Willi syndrome (PWS) is a rare genetic disorder characterized by maladaptive behaviors, amongst which hyperphagia is a life-long concern for individuals with PWS and their caregivers. The current study examined the contribution of hyperphagia and other factors to caregiver burden across lifespan, in 204 caregivers of individuals with PWS living in the US, using the Zarit Burden Interview (ZBI) and the hyperphagia questionnaire (HQ-CT).ResultsWe found a strong relationship between ZBI and HQ-CT especially in individuals with PWS older than 4 y and showed that HQ-CT scores of individuals with PWS is positively correlated with ZBI scores of their caregivers. The weight status of individuals with PWS was not associated with HQ-CT and ZBI scores, except for obese individuals who had significantly higher HQ-CT scores when compared to normal weight PWS individuals. We looked at PWS symptoms and care-related issues that impacted individuals and caregivers the most. We found that care-related tasks had the biggest negative impact on caregivers of children aged 0-4 y, whereas anxiety, temper tantrums, and oppositional behaviors of older individuals with PWS had the biggest impact on their caregivers concomitant with their high caregiver burden. Finally, we assessed the variability of HQ-CT and ZBI over 6 months in a subgroup of 83 participants. Overall, neither measure differed between 6 months and baseline. Most individual's absolute HQ-CT score changes were between 0-2 units, whereas absolute ZBI score changes were between 0-6 points. Changes in the caregiver's or individual's life had little or no effect on HQ-CT and ZBI scores.ConclusionsThis study demonstrates a relationship between hyperphagia and caregiver burden and sheds light on predominant symptoms in children and adolescents that likely underly PWS caregiver burden. The stability and relationship between HQ-CT and ZBI support ZBI as an additional outcome measure in PWS clinical trials.

In oncology research, while xenograft tumor models are easily visualized and humane endpoints can be clearly defined, metastatic tumor models are often based on more subjective clinical observations as endpoints. This study aimed at identifying objective non-invasive criteria for predicting imminent distress and mortality in metastatic lung tumor-bearing mice. BALB/c and C57BL/6 mice were inoculated with CT26 or B16F10 cells, respectively. The mice were housed in Vium smart cages to continuously monitor and stream respiratory rate and locomotion for up to 28 days until scheduled euthanasia or humane endpoint criteria were met. Body weight and body temperature were measured during the study. On days 11, 14, 17 and 28, lungs of subsets of animals were microCT imaged in vivo to assess lung metastasis progression and then euthanized for lung microscopic evaluations. Beginning at day 21, most tumor-bearing animals developed increased respiratory rates followed by decreased locomotion 1-2 days later, compared with the baseline values. Increases in respiratory rate did not correlate to surface tumor nodule counts or lung weight. Body weight measurement did not show significant changes from days 14-28 in either tumor-bearing or control animals. We propose that increases in respiratory rate (1.3-1.5 X) can be used to provide an objective benchmark to signal the need for increased clinical observations or euthanasia. Adoption of this novel humane endpoint criterion would allow investigators time to collect tissue samples prior to spontaneous morbidity or death and significantly reduce the distress of mice in the terminal stages of these metastatic lung tumor models.

The first confirmed case of COVID-19 in Quebec, Canada, occurred at Verdun Hospital on February 25, 2020. A month later, a localized outbreak was observed at this hospital. We performed tiled amplicon whole genome nanopore sequencing on nasopharyngeal swabs from all SARS-CoV-2 positive samples from 31 March to 17 April 2020 in 2 local hospitals to assess viral diversity (unknown at the time in Quebec) and potential associations with clinical outcomes. We report 264 viral genomes from 242 individuals-both staff and patients-with associated clinical features and outcomes, as well as longitudinal samples and technical replicates. Viral lineage assessment identified multiple subclades in both hospitals, with a predominant subclade in the Verdun outbreak, indicative of hospital-acquired transmission. Dimensionality reduction identified two subclades with mutations of clinical interest, namely in the Spike protein, that evaded supervised lineage assignment methods-including Pangolin and NextClade supervised lineage assignment tools. We also report that certain symptoms (headache, myalgia and sore throat) are significantly associated with favorable patient outcomes. Our findings demonstrate the strength of unsupervised, data-driven analyses whilst suggesting that caution should be used when employing supervised genomic workflows, particularly during the early stages of a pandemic.

BackgroundThe association between obesity and fracture risk may be skeletal site- and sex-specific but results among studies are inconsistent. Whilst several studies reported higher bone mineral density (BMD) in patients with obesity, altered bone quality could be a major determinant of bone fragility in this population.ObjectivesThis systematic review and meta-analysis aimed to compare, in men, premenopausal women and postmenopausal women with obesity vs. individuals without obesity: 1) the incidence of fractures overall and by site; 2) BMD; and 3) bone quality parameters (circulating bone turnover markers and bone microarchitecture and strength by advanced imaging techniques).Data sourcesPubMed (MEDLINE), EMBASE, Cochrane Library and Web of Science were searched from inception of databases until the 13th of January 2021.Data synthesisEach outcome was stratified by sex and menopausal status in women. The meta-analysis was performed using a random-effect model with inverse-variance method. The risks of hip and wrist fracture were reduced by 25% (n = 8: RR = 0.75, 95% CI: 0.62, 0.91, P = 0.003, I2 = 95%) and 15% (n = 2 studies: RR = 0.85, 95% CI: 0.81, 0.88), respectively, while ankle fracture risk was increased by 60% (n = 2 studies: RR = 1.60, 95% CI: 1.52, 1.68) in postmenopausal women with obesity compared with those without obesity. In men with obesity, hip fracture risk was decreased by 41% (n = 5 studies: RR = 0.59, 95% CI: 0.44, 0.79). Obesity was associated with increased BMD, better bone microarchitecture and strength, and generally lower or unchanged circulating bone resorption, formation and osteocyte markers. However, heterogeneity among studies was high for most outcomes, and overall quality of evidence was very low to low for all outcomes.ConclusionsThis meta-analysis highlights areas for future research including the need for site-specific fracture studies, especially in men and premenopausal women, and studies comparing bone microarchitecture between individuals with and without obesity.Systematic review registration numberCRD42020159189.

BACKGROUND: National Institute of Mental Health Project Accept (HIV Prevention Trials Network [HPTN] 043) is a large, Phase III, community-randomized, HIV prevention trial conducted in 48 matched communities in Africa and Thailand. The study intervention included enhanced community-based voluntary counseling and testing. The primary endpoint was HIV incidence, assessed in a single, cross-sectional, post-intervention survey of >50,000 participants. METHODS: HIV rapid tests were performed in-country. HIV status was confirmed at a central laboratory in the United States. HIV incidence was estimated using a multi-assay algorithm (MAA) that included the BED capture immunoassay, an avidity assay, CD4 cell count, and HIV viral load. RESULTS: Data from Thailand was not used in the endpoint analysis because HIV prevalence was low. Overall, 7,361 HIV infections were identified (4 acute, 3 early, and 7,354 established infections). Samples from established infections were analyzed using the MAA; 467 MAA positive samples were identified; 29 of those samples were excluded because they contained antiretroviral drugs. HIV prevalence was 16.5% (range at study sites: 5.93% to 30.8%). HIV incidence was 1.60% (range at study sites: 0.78% to 3.90%). CONCLUSIONS: In this community-randomized trial, a MAA was used to estimate HIV incidence in a single, cross-sectional post-intervention survey. Results from this analysis were subsequently used to compare HIV incidence in the control and intervention communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203749.

BackgroundA recent clinical trial demonstrated that a daily dose tenofovir disoproxil fumarate and emtricitabrine (TDF-FTC) can reduce HIV acquisition among men who have sex with men (MSM) and transgender (TG) women by 44%, and up to 90% if taken daily. We explored how medical and service providers understand research results and plan to develop clinical protocols to prescribe, support and monitor adherence for patients on PrEP in the United States.MethodsUsing referrals from our community collaborators and snowball sampling, we recruited 22 healthcare providers in San Francisco, Oakland, and Los Angeles for in-depth interviews from May-December 2011. The providers included primary care physicians seeing high numbers of MSM and TG women, HIV specialists, community health clinic providers, and public health officials. We analyzed interviews thematically to produce recommendations for setting policy around implementing PrEP. Interview topics included: assessing clinician impressions of PrEP and CDC guidance, considerations of cost, office capacity, dosing schedules, and following patients over time.ResultsLittle or no demand for PrEP from patients was reported at the time of the interviews. Providers did not agree on the most appropriate patients for PrEP and believed that current models of care, which do not involve routine frequent office visits, were not well suited for prescribing PrEP. Providers detailed the need to build capacity and were concerned about monitoring side effects and adherence. PrEP was seen as potentially having impact on the epidemic but providers also noted that community education campaigns needed to be tailored to effectively reach specific vulnerable populations.ConclusionsWhile PrEP may be a novel and clinically compelling prevention intervention for MSM and TG women, it raises a number of important implementation challenges that would need to be addressed. Nonetheless, most providers expressed optimism that they eventually could prescribe and monitor PrEP in their practice.

Our aim was to estimate the population of emperor penguins (Aptenodytes fosteri) using a single synoptic survey. We examined the whole continental coastline of Antarctica using a combination of medium resolution and Very High Resolution (VHR) satellite imagery to identify emperor penguin colony locations. Where colonies were identified, VHR imagery was obtained in the 2009 breeding season. The remotely-sensed images were then analysed using a supervised classification method to separate penguins from snow, shadow and guano. Actual counts of penguins from eleven ground truthing sites were used to convert these classified areas into numbers of penguins using a robust regression algorithm.We found four new colonies and confirmed the location of three previously suspected sites giving a total number of emperor penguin breeding colonies of 46. We estimated the breeding population of emperor penguins at each colony during 2009 and provide a population estimate of ~238,000 breeding pairs (compared with the last previously published count of 135,000-175,000 pairs). Based on published values of the relationship between breeders and non-breeders, this translates to a total population of ~595,000 adult birds.There is a growing consensus in the literature that global and regional emperor penguin populations will be affected by changing climate, a driver thought to be critical to their future survival. However, a complete understanding is severely limited by the lack of detailed knowledge about much of their ecology, and importantly a poor understanding of their total breeding population. To address the second of these issues, our work now provides a comprehensive estimate of the total breeding population that can be used in future population models and will provide a baseline for long-term research.

AIMS:The purpose of this study was to compare the effects of hamstring eccentric (NHE) strength training versus sprint training programmed as complements to regular soccer practice, on sprint performance and its mechanical underpinnings, as well as biceps femoris long head (BFlh) architecture. METHODS:In this prospective interventional control study, sprint performance, sprint mechanics and BFlh architecture variables were compared before versus after six weeks of training during the first six preseason weeks, and between three different random match-pair groups of soccer players: "Soccer group" (n = 10), "Nordic group" (n = 12) and "Sprint group" (n = 10). RESULTS:For sprint performance and mechanics, small to large pre-post improvements were reported in "Sprint group" (except maximal running velocity), whereas only trivial to small negative changes were reported in "Soccer group" and "Nordic group". For BFlh architecture variables, "Sprint" group showed moderate increase in fascicle length compared to smaller augment for the "Nordic" group with trivial changes for "Soccer group". Only "Nordic" group presented small increases at pennation angle. CONCLUSIONS:The results suggest that sprint training was superior to NHE in order to increase BFlh fascicle length although only the sprint training was able to both provide a preventive stimulus (increase fascicle length) and at the same time improve both sprint performance and mechanics. Further studies with advanced imaging techniques are needed to confirm the validity of the findings.

Old-growth forests play a major role in conserving biodiversity, protecting water resources, and sequestrating carbon, as well as serving as indispensable resources for indigenous societies. Novel silvicultural practices must be developed to emulate the natural dynamics and structural attributes of old-growth forests and preserve the ecosystem services provided by these boreal ecosystems. The success of these forest management strategies depends on developing an accurate understanding of natural regeneration dynamics. Our goal was therefore to identify the main patterns and drivers involved in the regeneration dynamics of old-growth forests with a focus on boreal stands dominated by black spruce (Picea mariana (L.) Mill.) and balsam fir (Abies balsamea (L.) Mill.) in eastern Canada. We sampled 71 stands in a 2 200 km2 study area located within Quebec's boreal region. For each stand, we noted tree regeneration (seedlings and saplings), structural attributes (diameter distribution, deadwood volume, etc.), and abiotic (slope and soil) factors. The presence of seed-trees located nearby and slopes having moderate to high angles most influenced balsam fir regeneration. In contrast, the indirect indices of recent secondary disturbances (e.g., insect outbreaks or windthrows) and topographic constraints (slope and drainage) most influenced black spruce regeneration. We propose that black spruce regeneration dynamics can be separated into distinct phases: (i) layering within the understory, (ii) seedling growth when gaps open in the canopy, (iii) gradual canopy closure, and (iv) production of new layers once the canopy is closed. These dynamics are not observed in paludified stands or stands where balsam fir is more competitive than black spruce. Overall, this research helps explain the complexity of old-growth forest dynamics, where many ecological factors interact at multiple temporal and spatial scales. This study also improves our understanding of ecological processes within primary old-growth forests and identifies the key factors to consider when ensuring the sustainable management of old-growth boreal stands.

Changing institutional culture to be more diverse and inclusive within the biomedical academic community is difficult for many reasons. Herein we present evidence that a collaborative model involving multiple institutions of higher education can initiate and execute individual institutional change directed at enhancing diversity and inclusion at the postdoctoral researcher (postdoc) and junior faculty level by implementing evidence-based mentoring practices. A higher education consortium, the Big Ten Academic Alliance, invited individual member institutions to send participants to one of two types of annual mentor training: 1) "Mentoring-Up" training for postdocs, a majority of whom were from underrepresented groups; 2) Mentor Facilitator training-a train-the-trainer model-for faculty and senior leadership. From 2016 to 2019, 102 postdocs and 160 senior faculty and administrative leaders participated. Postdocs reported improvements in their mentoring proficiency (87%) and improved relationships with their PIs (71%). 29% of postdoc respondents transitioned to faculty positions, and 85% of these were underrepresented and 75% were female. 59 out of the 120 faculty and administrators (49%) trained in the first three years provided mentor training on their campuses to over 3000 undergraduate and graduate students, postdocs and faculty within the project period. We conclude that early stage biomedical professionals as well as individual institutions of higher education benefited significantly from this collaborative mentee/mentor training model.

Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry mutations in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell types including the differentiation and function of immune cells. Hence, we postulated that, in addition to neurological and metabolic disorders, LSFC patients may show impaired immune activity. To gain insight into the quality of the immune response in LSFC patients, we examined the response to the measles, mumps and rubella (MMR) vaccine by measuring antibody titers to MMR in the plasma. In a cohort of eight LSFC patients, the response to the MMR vaccine was variable, with some individuals showing antibodies to all three viruses, while others had antibodies to two or fewer viruses. These results suggest that the mutations in the LRPPRC gene present in LSFC patients may affect the immune response to vaccines. Monitoring vaccine response in this fragile population should be considered to ensure full protection against pathogens.

ObjectiveThe objective of this study was to evaluate the relationship between individual characteristics and deep tissue infections in patients enrolled in opioid agonist treatment in Ontario, Canada.MethodsA retrospective cohort study was conducted on patients in opioid agonist treatment between January 1, 2011, and December 31, 2015 in Ontario, Canada. Patients were identified using data from the Ontario Health Insurance Plan Database, and the Ontario Drug Benefit Plan Database. We identified other study variables including all-cause mortality using data from the Registered Persons Database. Encrypted patient identifiers were used to link across databases. Logistic regression models were used to measure potential correlates of deep tissue infections.ResultsAn increase in the incidence of deep tissue infections was observed between 2011 and 2016 for patients on opioid agonist treatment. Additionally, age, sex, positive HIV diagnosis, and all-cause mortality was correlated with deep tissue infection in our study population.ConclusionThe study indicates factors that are associated with deep tissue infections in the opioid use disorder population and can be used to identify opportunities to reduce the incidence of new infections.

ObjectiveThe objective of this study was to evaluate the relationship between concurrent physician-based mental health services, all-cause mortality, and acute health service use for individuals enrolled in Opioid Agonist Treatment in Ontario, Canada.MethodsA cohort study of patients enrolled in opioid agonist treatment in Ontario was conducted between January 1, 2011, and December 31, 2015, in Ontario with an inverse probability of treatment weights using the propensity score to estimate the effect of physician-based mental health services. Treatment groups were created based on opioid agonist treatment patients' utilization of physician-based mental health services. Propensity score weighted odds ratios were calculated to assess the relationship between the treatment groups and the outcomes of interest. The outcomes included all-cause mortality using data from the Registered Persons Database, Emergency Department visits from the National Ambulatory Care Database, and hospitalizations using data from the Discharge Abstract Database. Encrypted patient identifiers were used to link across databases.ResultsA total of 48,679 individuals in OAT with mental disorders. Opioid agonist treatment alone was associated with reduced odds of all-cause mortality (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.3-0.4). Patients who received mental health services from a psychiatrist and primary care physician while engaged in OAT, the estimated rate of ED visits per year was higher (OR = 1.3, 95% CI 1.2-1.4) and the rate of hospitalizations (OR = 0.5, 95% CI 0.4-0.6) than in the control group.ConclusionOur findings support the view that opioid agonist treatment and concurrent mental health services can improve clinical outcomes for complex patients, and is associated with enhanced use of acute care services.

Several studies in humans indicate that low birth weight predisposes individuals to obesity in later life. Despite the constant increase in prevalence of obesity in the canine population and the major health consequences of this affection, few investigations have been carried out on the association between birth weight and the development of overweight in dogs. The purpose of the current study was to examine the association between birth weight and some other neonatal characteristics and overweight at adulthood in a population of purebred Labrador dogs. Information was collected about the sex, age, neuter status, birth weight, and growth rates (between 0-2 days and 2-15 days of age) in 93 Labrador dogs raised under similar environmental conditions until two months old. The body condition scores (BCS, scale of 1-9) of these dogs at adulthood were recorded, with BCS equal to or greater than 6 classified as overweight. Dogs were split into two groups based on the median birth weight in the population: lower than the median (LTM) and higher than the median (HTM). A logistic regression model was applied to analyse associations between the general characteristics of the dogs (sex, age, neuter status), early life parameters (birth weight, growth rates) and overweight at adulthood. Birth weight was the only early-life parameter found to be associated with overweight (p value = 0.032) with a prevalence of overweight of 70% among the dogs with LTM birth weight vs. 47% in dogs born with HTM birth weight. Overweight was also associated with age and neuter status (p value = 0.029 and 0.005 respectively). Our results suggest that, as in humans, dogs with the lowest birth weights are more likely to become overweight at adulthood. More studies are needed to further examine this relationship and to explore the underlying mechanisms. A subsequent objective could be to identify preventive strategies such as an adapted early nutrition programme for at-risk individuals.

Background and objectivesLess than 10 percent of the more than one million people vulnerable to HIV are using pre-exposure prophylaxis (PrEP). Practitioners are critical to ensuring the delivery of PrEP across care settings. In this study, we target a group of prescribers focused on providing HIV care and seeking up-to-date information about HIV. We assessed their experiences prescribing PrEP, whether these experiences differed by clinical specialty, and examined associations between willingness to prescribe PrEP as a "best first step" and different hypothetical prescribing scenarios.Setting and methodsBetween March and May 2015, we circulated a paper survey to 954 participants ((652 of whom met our inclusion criteria of being independent prescribers and 519 of those (80%) responded to the survey)) at continuing medical education advanced-level HIV courses in five locations across the US on practitioner practices and preferences of PrEP. We employed multivariable logistic regression analysis for binary and collapsed ordinal outcomes.ResultsAmong this highly motivated group of practitioners, only 54% reported ever prescribing PrEP. Internal medicine practitioners were 1.6 times more likely than infectious disease practitioners to have prescribed PrEP (95% CI: 0.99-2.60, p = .0524) and age, years of training, and sex were significantly associated with prescribing experience. Based on clinical vignettes describing different hypothetical prescribing scenarios, practitioners who viewed PrEP as the first clinical step for persons who inject drugs (PWID) were twice as likely to have also considered PrEP as the first clinical option for safer conception, and vice-a-versa (95% CI: 1.4-3.2, p < .001). Practitioners considering PrEP as the first preventive option for MSM were nearly six times as likely to also consider PrEP as the first clinical step for PWID, and vice-a-versa (95% CI: 2.28-13.56, p = .0002).ConclusionsOur findings indicate that even among a subset of HIV-focused practitioners, PrEP prescribing is not routine. This group of practitioners could be an optimal group to engage individuals that could most benefit from PrEP.

Zipf's law of abbreviation, relating more frequent signals to shorter signal lengths, applies to sounds in a variety of communication systems, both human and non-human. It also applies to writing systems: more frequent words tend to be encoded by less complex graphemes, even when grapheme complexity is decoupled from word length. This study documents an exception to this law of abbreviation. Observing European heraldic motifs, whose frequency of use was documented for the whole continent and over two large corpora (total N = 25115), one medieval, one early modern, we found that they do not obey a robust law of abbreviation. In our early modern corpus, motif complexity and motif frequency are positively, not negatively, correlated, a result driven by iconic motifs. In both our corpora, iconic motifs tend to be more frequent when more complex. They grew in popularity after the invention of printing. Our results suggest that lacking iconicity may be a precondition for a graphic code to exhibit Zipf's Law of Abbreviation.

Many modern crop varieties contain patented biotechnology traits, and an increasing number of these crops have multiple (stacked) traits. Fast and accurate determination of transgene levels is advantageous for a variety of use cases across the food, feed and fuel value chain. With the growing number of new transgenic crops, any technology used to quantify them should have robust assays that are simple to design and optimize, thereby facilitating the addition of new traits to an assay. Here we describe a PCR-based method that is simple to design, starts from whole seeds, and can be run to end-point in less than 5 minutes. Subsequent relative quantification (trait vs. non-trait) using capillary electrophoresis performed in 5% increments across the 0-100% range showed a mean absolute error of 1.9% (s.d. = 1.1%). We also show that the PCR assay can be coupled to non-optical solid-state nanopore sensors to give seed-to-trait quantification results with a mean absolute error of 2.3% (s.d. = 1.6%). In concert, the fast PCR and nanopore sensing stages demonstrated here can be fully integrated to produce seed-to-trait quantification results in less than 10 minutes, with high accuracy across the full dynamic range.

The forest floor of boreal forest stores large amounts of organic C that may react to a warming climate and increased N deposition. It is therefore crucial to assess the impact of these factors on the temperature sensitivity of this C pool to help predict future soil CO2 emissions from boreal forest soils to the atmosphere. In this study, soil warming (+2-4°C) and canopy N addition (CNA; +0.30-0.35 kg·N·ha-1·yr-1) were replicated along a topographic gradient (upper, back and lower slope) in a boreal forest in Quebec, Canada. After nine years of treatment, the forest floor was collected in each plot, and its organic C composition was characterized through solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Forest floor samples were incubated at four temperatures (16, 24, 32 and 40°C) and respiration rates (RR) measured to assess the temperature sensitivity of forest floor RR (Q10 = e10k) and basal RR (B). Both soil warming and CNA had no significant effect on forest floor chemistry (e.g., C, N, Ca and Mg content, amount of soil organic matter, pH, chemical functional groups). The NMR analyses did not show evidence of significant changes in the forest floor organic C quality. Nonetheless, a significant effect of soil warming on both the Q10 of RR and B was observed. On average, B was 72% lower and Q10 45% higher in the warmed, versus the control plots. This result implies that forest floor respiration will more strongly react to changes in soil temperature in a future warmer climate. CNA had no significant effect on the measured soil and respiration parameters, and no interaction effects with warming. In contrast, slope position had a significant effect on forest floor organic C quality. Upper slope plots had higher soil alkyl C:O-alkyl C ratios and lower B values than those in the lower slope, across all different treatments. This result likely resulted from a relative decrease in the labile C fraction in the upper slope, characterized by lower moisture levels. Our results point towards higher temperature sensitivity of RR under warmer conditions, accompanied by an overall down-regulation of RR at low temperatures (lower B). Since soil C quantity and quality were unaffected by the nine years of warming, the observed patterns could result from microbial adaptations to warming.

OBJECTIVE:To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia. METHODS:This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015-2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS. RESULTS:Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6-8.1) or metformin (OR = 5.0, CI 2.5-10.2), but less frequently OCP (OR = 0.5, CI 0.2-0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged 56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2-0.8). CONCLUSION:Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed.

AimsWe analysed the changes in force-velocity-power variables and jump performance in response to an individualized training program based on the force-velocity imbalance (FVimb). In particular, we investigated (i) the individual adaptation kinetics to reach the optimal profile and (ii) de-training kinetics over the three weeks following the end of the training program.MethodsSixty subjects were assigned to four sub-groups according to their initial FVimb: high or low force-deficit (FD) and high or low velocity-deficit (VD). The duration of training intervention was set so that each individual reached their "Optimal force-velocity (F-v) profile". Mechanical and performance variables were measured every 3 weeks during the program, and every week after the end of the individualized program.ResultsAll subjects in the FD sub-groups showed extremely large increases in maximal theoretical force output (+30±16.6% Mean±SD; ES = 2.23±0.28), FVimb reduction (-74.3±54.7%; ES = 2.17±0.27) and large increases in jump height (+12.4±7.6%; ES = 1.45±0.23). For the VD sub-groups, we observed moderate to extremely large increases in maximal theoretical velocity (+15.8±5.1%; ES = 2.72±0.29), FVimb reduction (-19.2±6.9%; ES = 2.36±0.35) and increases in jump height (+10.1±2.7%; ES = 0.93±0.09). The number of weeks needed to reach the optimal F-v profile (12.6 ± 4.6) was correlated to the magnitude of initial FVimb (r = 0.82, pConclusionsCollectively, these results provide useful insights into a more specific, individualized (i.e. based on the type and magnitude of FVimb) and accurate training prescription for jumping performance. Considering both training content and training duration together with FVimb may enable more individualized, specific and effective training monitoring and periodization.

Next generation RNA-sequencing (RNA-seq) is a flexible approach that can be applied to a range of applications including global quantification of transcript expression, the characterization of RNA structure such as splicing patterns and profiling of expressed mutations. Many RNA-seq protocols require up to microgram levels of total RNA input amounts to generate high quality data, and thus remain impractical for the limited starting material amounts typically obtained from rare cell populations, such as those from early developmental stages or from laser micro-dissected clinical samples. Here, we present an assessment of the contemporary ribosomal RNA depletion-based protocols, and identify those that are suitable for inputs as low as 1-10 ng of intact total RNA and 100-500 ng of partially degraded RNA from formalin-fixed paraffin-embedded tissues.

This study explores the association between specific insomnia symptoms (sleep onset, sleep maintenance and early morning awakenings symptoms) and self-efficacy (perceived self-confidence in the ability to use CPAP) with CPAP compliance in French patients with obstructive sleep apnea syndrome (OSAS). We performed a retrospective, cross-sectional analysis of CPAP compliance in a cohort of 404 patients diagnosed with OSAS. Patients completed mailed questionnaires on sleepiness (ESS), insomnia (ISI) and self-efficacy in sleep apnea (SEMSA). Linear regression modeling analyses were performed to explore the impact of measured variables on the number of hours of CPAP use. Of the initial pool of 404 patients, 288 returned the questionnaires (71% response rate). Their mean age was 63.16±12.73 yrs, 31% were females, mean BMI was 30.39±6.31 kg/m2, mean daily CPAP use was 6.19±2.03 h, mean number of years of use was 6.58±6.03 yrs, and mean initial AHI before CPAP use was 34.61±20.71 /h. Age (p

The present study is centered in adapting and validating a Spanish version of the Irrational Procrastination Scale (IPS). The sample consists of 365 adults aged 18-77 years (M = 37.70, SD = 12.64). Participants were administered two measures of procrastination, the IPS and the Decisional Procrastination Questionnaire, as well as the Big Five Inventory, and the Satisfaction With Life Scale. First, the factor and replication analysis revealed that the internal structure of the scale is clearly one-dimensional, supporting the idea that IPS seems to measure general procrastination as a single trait. Second, the internal consistency is satisfactory as is the temporal stability of the IPS scores. Third, the correlations encountered between the IPS scores and other measures of procrastination, personality traits and satisfaction with life are all in the expected direction and magnitude. Finally, consistent with previous research, procrastination is related to age, with the youngest being the most procrastinating group. This study represents the first attempt in adapting and validating the IPS measure of procrastination into Spanish. Results suggest that the Spanish version of the IPS offers valid and reliable scores when applied to adult population.

BACKGROUND:Pulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies. OBJECTIVES:To assess the effects of PH-targeted therapy on exercise capacity in HF patients. METHODS:MEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate. RESULTS:22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH-targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08-0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: -14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment. CONCLUSIONS:In conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies.

The BDNF Val66Met polymorphism is associated with impaired short-term plasticity in the motor cortex, short-term motor learning, and intermanual transfer of a procedural motor skill. Here, we investigated the impact of the Val66Met polymorphism on the modulation of cortical excitability and interhemispheric inhibition through sensorimotor practice of simple dynamic skills with the right and left first dorsal interosseous (FDI) muscles. To that end, we compared motor evoked potentials (MEP) amplitudes and short-interval intracortical inhibition (SICI) in the bilateral representations of the FDI muscle in the primary motor cortex (M1), and interhemispheric inhibition (IHI) from the left to right M1, before and after right and left FDI muscle training in an alternated sequence. Val66Met participants did not differ from their Val66Val counterparts on motor performance at baseline and following motor training, or on measures of MEP amplitude and IHI. However, while the Val66Val group displayed significant SICI reduction in the bilateral M1 in response to motor training, SICI remained unchanged in the Val66Met group. Further, Val66Val group's SICI decrease in the left M1, which was also observed following unimanual training with the right hand in the Control Right group, was correlated with motor improvement with the left hand. The potential interaction between left and right M1 activity during bimanual training and the implications of altered activity-dependent cortical excitability on short-term motor learning in Val66Met carriers are discussed.

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

At a multi-millennial scale, various disturbances shape boreal forest stand mosaics and the distribution of species. Despite the importance of such disturbances, there is a lack of studies focused on the long-term dynamics of spruce budworm (Choristoneura fumiferana (Clem.)) (SBW) outbreaks and the interaction of insect outbreaks and fire. Here, we combine macrocharcoal and plant macrofossils with a new proxy-lepidopteran scales-to describe the Holocene ecology around a boreal lake. Lepidopteran scales turned out to be a more robust proxy of insect outbreaks than the traditional proxies such as cephalic head capsules and feces. We identified 87 significant peaks in scale abundance over the last 10 000 years. These results indicate that SBW outbreaks were more frequent over the Holocene than suggested by previous studies. Charcoal accumulation rates match the established fire history in eastern Canada: a more fire-prone early and late Holocene and reduced fire frequency during the mid-Holocene. Although on occasion, both fire and insect outbreaks were coeval, our results show a generally inverse relationship between fire frequency and insect outbreaks over the Holocene.

BACKGROUND:Meningiomas are stratified according to tumor grade and extent of resection, often in isolation of other clinical variables. Here, we use machine learning (ML) to integrate demographic, clinical, radiographic and pathologic data to develop predictive models for meningioma outcomes. METHODS AND FINDINGS:We developed a comprehensive database containing information from 235 patients who underwent surgery for 257 meningiomas at a single institution from 1990 to 2015. The median follow-up was 4.3 years, and resection specimens were re-evaluated according to current diagnostic criteria, revealing 128 WHO grade I, 104 grade II and 25 grade III meningiomas. A series of ML algorithms were trained and tuned by nested resampling to create models based on preoperative features, conventional postoperative features, or both. We compared different algorithms' accuracy as well as the unique insights they offered into the data. Machine learning models restricted to preoperative information, such as patient demographics and radiographic features, had similar accuracy for predicting local failure (AUC = 0.74) or overall survival (AUC = 0.68) as models based on meningioma grade and extent of resection (AUC = 0.73 and AUC = 0.72, respectively). Integrated models incorporating all available demographic, clinical, radiographic and pathologic data provided the most accurate estimates (AUC = 0.78 and AUC = 0.74, respectively). From these models, we developed decision trees and nomograms to estimate the risks of local failure or overall survival for meningioma patients. CONCLUSIONS:Clinical information has been historically underutilized in the prediction of meningioma outcomes. Predictive models trained on preoperative clinical data perform comparably to conventional models trained on meningioma grade and extent of resection. Combination of all available information can help stratify meningioma patients more accurately.

In the current study we investigated the effects of resisted sprint training on sprinting performance and underlying mechanical parameters (force-velocity-power profile) based on two different training protocols: (i) loads that represented maximum power output (Lopt) and a 50% decrease in maximum unresisted sprinting velocity and (ii) lighter loads that represented a 10% decrease in maximum unresisted sprinting velocity, as drawn from previous research (L10).Soccer [n = 15 male] and rugby [n = 21; 9 male and 12 female] club-level athletes were individually assessed for horizontal force-velocity and load-velocity profiles using a battery of resisted sprints, sled or robotic resistance respectively. Athletes then performed a 12-session resisted (10 × 20-m; and pre- post-profiling) sprint training intervention following the L10 or Lopt protocol.Both L10 and Lopt training protocols had minor effects on sprinting performance (average of -1.4 to -2.3% split-times respectively), and provided trivial, small and unclear changes in mechanical sprinting parameters. Unexpectedly, Lopt impacted velocity dominant variables to a greater degree than L10 (trivial benefit in maximum velocity; small increase in slope of the force-velocity relationship), while L10 improved force and power dominant metrics (trivial benefit in maximal power; small benefit in maximal effectiveness of ground force orientation).Both resisted-sprint training protocols were likely to improve performance after a short training intervention in already sprint trained athletes. However, widely varied individualised results indicated that adaptations may be dependent on pre-training force-velocity characteristics.

OBJECTIVE:Although research on the physiological and psychological factors of endurance performance has been extensive, the factors related to dropping out of ultra-trail races have not been well documented. The aim of this study was to examine psychosocial factors as predictors of dropout in ultra-trail runners. METHODS:Two hundred and twenty-one volunteer athletes completed a survey that included measures of: (a) motivational variables (self-determined motivation, basic needs satisfaction, achievement goals), (b) theory of planned behavior constructs (attitudes, subjective norms, self-efficacy and intention to finish the race), and (c) coping strategies in sport. RESULTS:The results showed that finishers had higher scores for self-efficacy and intention to finish the race than withdrawers, whereas withdrawers had higher scores for avoidance coping. Multiple logistic regression showed that the number of started and finished ultra-trail races (OR, 0.44; 95% CI 0.22-0.88; p