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Abstract The Philippines are central to understanding the expansion of the Austronesian language family from its homeland in Taiwan. It remains unknown to what extent the distribution of Malayo-Polynesian languages has been shaped by back migrations and language leveling events following the initial Out-of-Taiwan expansion. Other aspects of language history, including the effect of language switching from non-Austronesian languages, also remain poorly understood. Here we apply Bayesian phylogenetic methods to a core-vocabulary dataset of Philippine languages. Our analysis strongly supports a sister group relationship between the Sangiric and Minahasan groups of northern Sulawesi on one hand, and the rest of the Philippine languages on the other, which is incompatible with a simple North-to-South dispersal from Taiwan. We find a pervasive geographical signal in our results, suggesting a dominant role for cultural diffusion in the evolution of Philippine languages. However, we do find some support for a later migration of Gorontalo-Mongondow languages to northern Sulawesi from the Philippines. Subsequent diffusion processes between languages in Sulawesi appear to have led to conflicting data and a highly unstable phylogenetic position for Gorontalo-Mongondow. In the Philippines, language switching to Austronesian in ‘Negrito’ groups appears to have occurred at different time-points throughout the Philippines, and based on our analysis, there is no discernible effect of language switching on the basic vocabulary.

BackgroundWhile smoking cessation has been linked to substantial weight gain, the potential influence of e-cigarettes on weight changes among individuals who use these devices to quit smoking is not fully understood. ObjectiveThis study aims to reanalyze data from the Evaluating the Efficacy of e-Cigarette Use for Smoking Cessation (E3) trial to assess the causal effects of e-cigarette use on change in body weight. MethodsThis is a secondary analysis of the E3 trial in which participants were randomized into 3 groups: nicotine e-cigarettes plus counseling, nonnicotine e-cigarettes plus counseling, and counseling alone. With adjustment for baseline variables and the follow-up smoking abstinence status, weight changes were compared between the groups from baseline to 12 weeks’ follow-up. Intention-to-treat and as-treated analyses were conducted using doubly robust estimation. Further causal analysis used 2 different propensity scoring methods to estimate causal regression curves for 4 smoking-related continuous variables. We evaluated 5 different subsets of data for each method. Selection bias was addressed, and missing data were imputed by the machine learning method extreme gradient boosting (XGBoost). ResultsA total of 257 individuals with measured weight at week 12 (mean age: 52, SD 12 y; women: n=122, 47.5%) were included. Across the 3 treatment groups, of the 257 participants, 204 (79.4%) who continued to smoke had, on average, largely unchanged weight at 12 weeks, with comparable mean weight gain ranging from –0.24 kg to 0.33 kg, while 53 (20.6%) smoking-abstinent participants gained weight, with a mean weight gain ranging from 2.05 kg to 2.70 kg. After adjustment, our analyses showed that the 2 e-cigarette arms exhibited a mean gain of 0.56 kg versus the counseling alone arm. The causal regression curves analysis also showed no strong evidence supporting a causal relationship between weight gain and the 3 e-cigarette–related variables. e-Cigarettes have small and variable causal effects on weight gain associated with smoking cessation. ConclusionsIn the E3 trial, e-cigarettes seemed to have minimal effects on mitigating the weight gain observed in individuals who smoke and subsequently quit at 3 months. However, given the modest sample size and the potential underuse of e-cigarettes among those randomized to the e-cigarette treatment arms, these results need to be replicated in large, adequately powered trials. Trial RegistrationClinicalTrials.gov NCT02417467; https://www.clinicaltrials.gov/study/NCT02417467

Abstract Languages vary in how they signal “who does what to whom”. Three main strategies to indicate the participant roles of “who” and “whom” are case, verbal indexing, and rigid word order. Languages that disambiguate these roles with case tend to have either verb-final or flexible word order. Most previous studies that found these patterns used limited language samples and overlooked the causal mechanisms that could jointly explain the association between all three features. Here we analyze grammatical data from a Grambank sample of 1705 languages with phylogenetic causal graph methods. Our results corroborate the claims that verb-final word order generally gives rise to case and, strikingly, establish that case tends to lead to the development of flexible word order. The combination of novel statistical methods and the Grambank database provides a model for the rigorous testing of causal claims about the factors that shape patterns of linguistic diversity.

Drivers of global change are creating strongly contrasting early life conditions for developing offspring, which may have carry-over effects on lifetime fitness. We tested for “silver-spoon” effects of natal conditions (environmental conditions and maternal quality) and individual quality (pre-fledging) on the lifetime reproductive success (LRS) of aerial insectivorous adult tree swallows (Tachycineta bicolor) hatched in distinct populations with contrasting environments in Saskatchewan and British Columbia, Canada. In both populations, LRS of adults was influenced by environmental conditions they experienced as developing nestlings, but silver-spoon effects were context-dependent, indicating population-specific responses to the local environment. Higher natal temperature in Saskatchewan had positive silver-spoon effects on the LRS of adult swallows, but the opposite was observed in British Columbia, likely because the highest temperatures local recruits experienced as nestlings occurred during heat extremes. In Saskatchewan, where wetter conditions reflect higher wetland abundance and food supply, we detected a negative effect of good natal wetland conditions on adult LRS, contrary to our hypothesis. However, since current breeding wetland conditions are a strong driver of adult fitness, and adults experiencing high natal wetland abundance generally bred when wetland abundance was lower, we suspect any potential benefits of natal wetland abundance on LRS were overridden by wetland conditions during breeding. As hypothesized, wetter natal conditions in British Columbia, which reflect an unfavorable environment for developing nestlings, had negative silver-spoon effects on the LRS of adults. No maternal or pre-fledging quality effects were detected at either site. Therefore, LRS of individuals within distinct populations is influenced, at least in part, by carry-over effects of the natal environment that vary locally. Consequently, natal environmental conditions that affect fitness, with putative population-level consequences, may underly spatially-varying population trends of regionally distinct populations within a species’ range.

IntroductionRegulatory agencies generate a vast amount of textual data in the review process. For example, drug labeling serves as a valuable resource for regulatory agencies, such as U.S. Food and Drug Administration (FDA) and Europe Medical Agency (EMA), to communicate drug safety and effectiveness information to healthcare professionals and patients. Drug labeling also serves as a resource for pharmacovigilance and drug safety research. Automated text classification would significantly improve the analysis of drug labeling documents and conserve reviewer resources.MethodsWe utilized artificial intelligence in this study to classify drug-induced liver injury (DILI)-related content from drug labeling documents based on FDA’s DILIrank dataset. We employed text mining and XGBoost models and utilized the Preferred Terms of Medical queries for adverse event standards to simplify the elimination of common words and phrases while retaining medical standard terms for FDA and EMA drug label datasets. Then, we constructed a document term matrix using weights computed by Term Frequency-Inverse Document Frequency (TF-IDF) for each included word/term/token.ResultsThe automatic text classification model exhibited robust performance in predicting DILI, achieving cross-validation AUC scores exceeding 0.90 for both drug labels from FDA and EMA and literature abstracts from the Critical Assessment of Massive Data Analysis (CAMDA).DiscussionMoreover, the text mining and XGBoost functions demonstrated in this study can be applied to other text processing and classification tasks.

Abstract Self‐selection studies assess participants' ability to use label information to decide if a proposed nonprescription drug is appropriate for their use. The optimal use of information from participants' responses in these trials has not been studied. Data from a self‐selection study for a progestogen‐only contraceptive pill (norgestrel 0.075 mg tablets, Opill) were analyzed. Participants (1772 evaluable participants) were provided with the proposed drug facts label and asked sequentially: (1) Given what you have read on the label and your own health history, is this product okay or not okay for you to take home today and start to use?; (2) Why or why not?; (3) Would you like to purchase Opill today to take home for your own use?; (4) Why or why not? The Per Guidance Analysis based on the US Food and Drug Administration's Guidance considered only the response to the first question as defining a selector. The Complete Analysis considered the responses to all four questions to determine a selector. The Per Guidance Analysis characterized 1597 participants as selectors, whereas the Complete Analysis identified 1180 participants as selectors. The decrease in selectors reflected participants who responded “okay” to the initial question but “no” to purchase question while providing rational explanations for their shift in responses. The results support the use of all available information when assessing a participant's intent in self‐selection studies for nonprescription drug candidates. The findings are discussed in the context of findings from the social cognitive and communication sciences.

Globally, human house types are diverse, varying in shape, size, roof type, building materials, arrangement, decoration and many other features. Here we offer the first rigorous, global evaluation of the factors that influence the construction of traditional (vernacular) houses. We apply macroecological approaches to analyse data describing house features from 1900 to 1950 across 1000 societies. Geographic, social and linguistic descriptors for each society were used to test the extent to which key architectural features may be explained by the biophysical environment, social traits, house features of neighbouring societies or cultural history. We find strong evidence that some aspects of the climate shape house architecture, including floor height, wall material and roof shape. Other features, particularly ground plan, appear to also be influenced by social attributes of societies, such as whether a society is nomadic, polygynous or politically complex. Additional variation in all house features was predicted both by the practices of neighouring societies and by a society's language family. Collectively, the findings from our analyses suggest those conditions under which traditional houses offer solutions to architects seeking to reimagine houses in light of warmer, wetter or more variable climates.

Jared Diamond suggested that the unique East–West orientation of Eurasia facilitated the spread of cultural innovations and gave it substantial political, technological and military advantages over other continental regions. This controversial hypothesis assumes that innovations can spread more easily across similar habitats, and that environments tend to be more homogeneous at similar latitudes. The resulting prediction is that Eurasia is home to environmentally homogenous corridors that enable fast cultural transmission. Despite indirect evidence supporting Diamond's influential hypothesis, quantitative tests of its underlying assumptions are currently lacking. Here we address this critical gap by leveraging ecological, cultural and linguistic datasets at a global scale. Our analyses show that although societies that share similar ecologies are more likely to share cultural traits, the Eurasian continent is not significantly more ecologically homogeneous than other continental regions. Our findings highlight the perils of single factor explanations and remind us that even the most compelling ideas must be thoroughly tested to gain a solid understanding of the complex history of our species.

Biomineralised remains of trilobites provide important insight into the evolutionary history of a diverse, extinct group of arthropods. Their exoskeletons are also ideal for recording malformations, including evidence of post-injury repair. Re-examination of historic collections and the study of new specimens is important for enhancing knowledge on trilobite malformations across this diverse clade. To expand the records of these abnormalities and present explanations for their formation, we document eight malformed trilobite specimens, as well as one carcass, housed within the Commonwealth Palaeontological Collection at Geoscience Australia in Canberra. We present examples of Asthenopsis, Burminresia, Centropleura, Coronocephalus, Dolicholeptus, Galahetes, Papyriaspis, and Xystridura from Cambrian, Ordovician, and Silurian deposits of Australia. Most of the malformed specimens show W-, U-, or L-shaped indentations that reflect injuries from either failed predation or complications during moulting, and a mangled carcass is ascribed to either successful predation or post-mortem scavenging. We also uncover examples of teratologies, such as bifurcated pygidial ribs and pygidial asymmetry, in addition to evidence of abnormal recovery (i.e., fusion of thoracic segments) from a traumatic incident.

Bottlenose dolphins (Tursiops spp.) inhabit bays, sounds, and estuaries (BSEs) throughout the southeast region of the U.S.A. and are sentinel species for human and ecosystem-level health. Dolphins are vulnerable to the bioaccumulation of contaminants through the coastal food chain because they are high-level predators. Currently, there is limited information on the spatial dynamics of mercury accumulation in these dolphins. Total mercury (THg) was measured in dolphin skin from multiple populations across the U.S. Southeast Atlantic and Gulf of Mexico coasts, and the influence of geographic origin, sex, and age class was investigated. Mercury varied significantly among sampling sites and was greatest in dolphins in St. Joseph Bay, Florida Everglades, and Choctawhatchee Bay (14,193 ng/g ± 2196 ng/g, 10,916 ng/g ± 1532 ng/g, and 7333 ng/g ± 1405 ng/g wet mass (wm), respectively) and lowest in dolphins in Charleston and Skidaway River Estuary (509 ng/g ± 32.1 ng/g and 530 ng/g ± 58.4 ng/g wm, respectively). Spatial mercury patterns were consistent regardless of sex or age class. Bottlenose dolphin mercury exposure can effectively represent regional trends and reflect large-scale atmospheric mercury input and local biogeochemical processes. As a sentinel species, the bottlenose dolphin data presented here can direct future studies to evaluate mercury exposure to human residents in St. Joseph Bay, Choctawhatchee Bay, and Florida Coastal Everglades, as well as additional sites with similar geographical, oceanographic, or anthropogenic parameters. These data may also inform state and federal authorities that establish fish consumption advisories to determine if residents in these locales are at heightened risk for mercury toxicity.

The 2019 African swine fever (ASF) outbreak in the Lao People’s Democratic Republic (Lao PDR or Laos) represented a major epidemiologic event where a transitioning lower-middle income nation (LMIC) experienced a viral epidemic in a naïve pig population. The diversity of pig management styles creates challenges for local and regional policymakers when formulating recommendations to control an ASF outbreak. The aim of this study were to investigate the management of pigs in villages of Oudomxay province that were affected by ASF in 2019, as a case study in a smallholder pig-rasing system in northern Laos. The frequencies of well known risk factors were measured in the affected villages and the timelines and household level stock losses due to the outbreak were investigated. These findings were compared to data available from a similar outbreak in the southern province of Savannakhet. Disease control implications of these findings are discussed. Mean losses were 3.0–23.3 pigs per household, with a mean lost herd value of USD 349, 95% CI (294–415). These pig losses reflect those estimated in Savannakhet (6.7 pigs per household). However, the financial loss estimated per household was higher, USD 349 versus USD 215, possibly due to higher pig values and a higher input/output management approach in Oudomxay. The investigation revealed the presence of numerous ASF risk factors, such as swill-feeding and free-ranging. In addition, poor biosecurity practices – such as inappropriate garbage disposal and slaughtering – that could contaminate the environment were present. ASF cases occurred across all villages between June and December 2019, with outbreak periods ranging from 22–103 days. These values are consistent with the outbreak in Savannakhet; however, notable differences in management styles were observed. These findings demonstrate the need for more disease control resources from the village to the Governmental level. Villages need support in enacting context appropriate biosecurity measures, whilst the ongoing surveillance and investigation of ASF require investment in logistical and veterinary resources at the Governmental level.

Background: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have an increased risk of developing colorectal neoplasia (CRN) in the proximal colon. Objectives: To evaluate whether duration and severity of inflammation are linked to the development of CRN in this population. Design: Retrospective, case–control chart review of patients with PSC and IBD at a tertiary care center. Methods: Disease activity was scored per colonic segment at each colonoscopy prior to the first instance of observed CRN using a modified Mayo endoscopic sub-score and histologic assessment. Patients in the CRN-positive group were compared to controls that did not. Results: In all, 72 PSC-IBD patients with no history of CRN were identified, 13 of whom developed CRN after at least one colonoscopy at our institution. Patients in the CRN-positive group had significantly more endoscopic ( p

Abstract Background Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing. Methods An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs. Results Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively. Conclusions Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC.

Background and study aims Gastro-gastric fistulae (GGF) occur in 1.3 % to 6 % of Rouxy-en-Y gastric bypass (RYGB) patients and can be associated with abdominal pain, reflux, weight regain and onset of diabetes. Endoscopic and surgical treatments are available without prior comparisons. The study aim was to compare endoscopic and surgical treatment methods in RYGB patients with GGF. Patients and methods A retrospective matched cohort study of RYGB patients who underwent endoscopic closure (ENDO) or surgical revision (SURG) for GGF. One-to-one matching was performed based on age, sex, body mass index and weight regain. Patient demographics, GGF size, procedural details, symptoms and treatment-related adverse events (AEs) were collected. A comparison of symptom improvement and treatment-related AEs was performed. Fisher’s Exact, t-test and Wilcoxon Rank Sum tests were performed. Results Ninety RYGB patients with GGF (45 ENDO, 45 matched SURG) were included. GGF symptoms included weight regain (80 %), gastroesophageal reflux disease (71 %) and abdominal pain (67 %). At 6 months, the ENDO and SURG groups experienced 0.59 % and 5.5 % total weight loss (TWL) (P = 0.0002). At 12 months, the ENDO and SURG groups experienced 1.9 % and 6.2 % TWL (P = 0.007). Abdominal pain improved in 12 (52.2 %) ENDO and 5 (15.2 %) SURG patients at 12 months (P = 0.007). Diabetes and reflux resolution rates were similar between groups. Treatment-related AEs occurred in four (8.9 %) ENDO and 16 (35.6 %) SURG patients (P = 0.005), of which none and eight (17.8%), respectively, were serious (P = 0.006). Conclusions Endoscopic GGF treatment produces greater improvement in abdominal pain and fewer overall and serious treatment-related AEs. However, surgical revision appears to yield greater weight loss.

Solar energetic particle (SEP) events and their major subclass, solar proton events (SPEs), can have unfavorable consequences on numerous aspects of life and technology, making them one of the most harmful effects of solar activity. Garnering knowledge preceding such events by studying operational data flows is essential for their forecasting. Considering only solar cycle (SC) 24 in our previous study, we found that it may be sufficient to only utilize proton and soft X-ray (SXR) parameters for SPE forecasts. Here, we report a catalog recording ≥10 MeV ≥10 particle flux unit SPEs with their properties, spanning SCs 22–24, using NOAA’s Geostationary Operational Environmental Satellite flux data. We report an additional catalog of daily proton and SXR flux statistics for this period, employing it to test the application of machine learning (ML) on the prediction of SPEs using a support vector machine (SVM) and extreme gradient boosting (XGBoost). We explore the effects of training models with data from one and two SCs, evaluating how transferable a model might be across different time periods. XGBoost proved to be more accurate than SVMs for almost every test considered, while also outperforming operational SWPC NOAA predictions and a persistence forecast. Interestingly, training done with SC 24 produces weaker true skill statistic and Heidke skill scores _2 , even when paired with SC 22 or SC 23, indicating transferability issues. This work contributes toward validating forecasts using long-spanning data—an understudied area in SEP research that should be considered to verify the cross cycle robustness of ML-driven forecasts.

Background/Aims We assessed the effectiveness of anti-TNF agents and its associated factors to prevent endoscopic and clinical postoperative recurrence (POR) in Crohn’s disease (CD). Methods From a prospectively-maintained database, we retrieved 316 CD patients who underwent intestinal resection (2011–2017). Endoscopic (Rutgeerts index ≥ i2 at 6 months) and clinical (recurrence of symptoms leading to hospitalization or therapeutic escalation) POR were assessed. Results In 117 anti-TNF-naïve patients, anti-TNF therapy was more effective than immunosuppressive agents (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.8–43.9; P=0.008) and no medication/5-aminosalicylates (OR, 5.2; 95% CI, 1.0–27.9; P=0.05) to prevent endoscopic POR. In 199 patients exposed to anti-TNF prior to the surgery, combination with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02–5.31; P=0.046) to prevent endoscopic POR. Primary failure to anti-TNF agent prior to surgery was predictive of anti-TNF failure to prevent endoscopic POR (OR, 2.41; 95% CI, 1.10–5.32; P=0.03). When endoscopic POR despite anti-TNF prophylactic medication (n=55), optimizing anti-TNF and adding an immunosuppressive drug was the most effective option to prevent clinical POR (hazard ratio, 7.38; 95% CI, 1.54–35.30; P=0.012). Anti-TNF therapy was the best option to prevent clinical POR (hazard ratio, 3.10; 95% CI, 1.09–8.83; P=0.034) in patients with endoscopic POR who did not receive any biologic to prevent endoscopic POR (n=55). Conclusions Anti-TNF was the most effective medication to prevent endoscopic and clinical POR. Combination with anti-TNF and immunosuppressive agents should be considered in patients previously exposed to anti-TNF.

Measurement(s) expressions Technology Type(s) data aggregation Factor Type(s) none Sample Characteristic - Organism human language Sample Characteristic - Location global scale

Background/Aims Perianal fistulas are a debilitating manifestation of Crohn’s disease (CD). Despite the advent of anti-tumor necrosis factor (anti-TNF) therapy, the medical management of fistulizing CD continues to be challenged by unmet needs. We conducted a systematic review and meta-analysis of the effectiveness of vedolizumab for the management of perianal fistulizing CD. Methods A search of PubMed, EMBASE and the Cochrane Library was performed from inception to June 2020 for studies reporting rates of perianal fistula healing in CD patients treated with vedolizumab. The primary outcome of interest was complete healing of perianal fistulas and the secondary outcome was partial healing. The pooled fistula healing rates with 95% confidence intervals (CI) were calculated utilizing a random effects model. Results A total of 74 studies were initially identified, 4 of which met the inclusion criteria. A total of 198 patients with active perianal fistulas were included, 87% of whom had failed previous anti-TNF therapy. The pooled complete healing rate was 27.6% (95% CI, 18.9%–37.3%) with moderate heterogeneity (I2=49.4%) and the pooled partial healing rate was 34.9% (95% CI, 23.2%–47.7%) with high heterogeneity (I2=67.1%). Conclusions In a meta-analysis of 4 studies that included 198 patients with perianal fistulizing CD, the majority of whom had failed previous anti-TNF therapy, vedolizumab treatment led to healing of perianal fistulas in nearly one-third of the patients. The lack of high-quality data and significant study heterogeneity underscores the need for future prospective studies of fistula healing in patients receiving anti-integrin therapy.

In a 70-day study, 36 Jabbali and Sahrawi bucks, aged 11 months, were utilized to evaluate the effects of different levels of spirulina dietary supplement (SP) on carcass characteristics, fatty acid profile, and meat quality traits in Omani goat breeds. The goats were put into six groups of six bucks, each at random. The diet consisted of a conventional concentrate feed ration (CFR) without spirulina (CON), and the CFR diet supplemented with spirulina at the levels of 2 g/head daily (T1) and 4 g/head daily (T2). In general, Sahrawi bucks showed a highly significant response to SP feeding compared with Jabbali bucks. The treatment groups, especially T1, showed a significant increase in average daily gain and carcass traits (body length, leg length, and the rack weight) compared with the CON group of Sahrawi bucks. The weights of omental and kidney fat were also significantly higher in T1 compared with CON and T2 groups of Sahrawi goats, while they were significantly higher in T2 compared with CON and T1 groups of Jabbali goats. Carcass profile and meat quality, including ultimate ph and meat color lightness (L*) were increased significantly with dietary spirulina in both LD and SM muscles of Sahrawi goats. Most of the Sfa, Mufa, Pufa, Pufa n-6, Pufa n-3, and n-6/n-3 ratios of the LD showed significant differences in diets supplemented with SP compared with CON for Sahrawi bucks, while some of them were significant in Jabbali bucks. The LD muscle of Sahrawi goats fed diets supplemented with SP of the T1 group significantly decreased in the amounts of pentadecanoic and margaric acids compared with the T2 and CON groups. The study concluded that incorporating SP (2 g and 4 g/head daily) into the diet of Omani goats, especially Sahrawi goats, can increase growth performance, as well as improve fatty acid composition and meat quality.

Adolescents and young adults have high levels of forgone healthcare relative to other age groups, placing those who participate in action sports at particularly high risk for untreated injuries. Because skateboard injury data typically involves treated injuries, research to understand unmet health needs in non-clinical samples is needed. This exploratory study used qualitative content analysis of survey and structured interviews with young adult skateboarders (n = 26, mean age = 22.9 years) recruited at skate parks in a small U.S. city to examine the degree, type, and reported reasons for untreated skateboard injuries in that population. Participants completed a paper survey followed by a structured interview regarding their untreated skateboard injuries and reasons for avoiding medical treatment. A majority of respondents (80.8%) described at least one skateboarding injury that they did not have medically treated but now believe they should have done so. Injury types were deep soft tissue injuries (50.0% of respondents), bone fractures (15.4%), concussions (11.5%), and superficial soft tissue injuries (3.8%). Of respondents who avoided treatment, 76.2% considered treatment unnecessary at the time, 38.1% cited avoiding treatment due to cost, and 23.8% cited lack of knowledge. Findings suggest a need to address forgone injury care among young adult skateboarders through increased support and knowledge regarding when and how to seek affordable medical treatment.

Self-control underlies goal-directed behaviour in humans and other animals. Delayed gratification - a measure of self-control - requires the ability to tolerate delays and/or invest more effort to obtain a reward of higher value over one of lower value, such as food or mates. Social context, in particular, the presence of competitors, may influence delayed gratification. We adapted the 'rotating-tray' paradigm, where subjects need to forgo an immediate, lower-quality (i.e. less preferred) reward for a delayed, higher-quality (i.e. more preferred) one, to test social influences on delayed gratification in two corvid species: New Caledonian crows and Eurasian jays. We compared choices for immediate vs. delayed rewards while alone, in the presence of a competitive conspecific and in the presence of a non-competitive conspecific. We predicted that, given the increased risk of losing a reward with a competitor present, both species would similarly, flexibly alter their choices in the presence of a conspecific compared to when alone. We found that species differed: jays were more likely to select the immediate, less preferred reward than the crows. We also found that jays were more likely to select the immediate, less preferred reward when a competitor or non-competitor was present than when alone, or when a competitor was present compared to a non-competitor, while the crows selected the delayed, highly preferred reward irrespective of social presence. We discuss our findings in relation to species differences in socio-ecological factors related to adult sociality and food-caching (storing). New Caledonian crows are more socially tolerant and moderate cachers, while Eurasian jays are highly territorial and intense cachers that may have evolved under the social context of cache pilfering and cache protection strategies. Therefore, flexibility (or inflexibility) in delay of gratification under different social contexts may relate to the species' social tolerance and related risk of competition.

Abstract The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

Eurypterids (sea scorpions) are extinct aquatic chelicerates. Within this group, members of Pterygotidae represent some of the largest known marine arthropods. Representatives of this family all have hypertrophied, anteriorly-directed chelicerae and are commonly considered Silurian and Devonian apex predators. Despite a long history of research interest in these appendages, pterygotids have been subject to limited biomechanical investigation. Here, we present finite element analysis (FEA) models of four different pterygotid chelicerae—those of Acutiramus bohemicus, Erettopterus bilobus, Jaekelopterus rhenaniae, and Pterygotus anglicus—informed through muscle data and finite element models (FEMs) of chelae from 16 extant scorpion taxa. We find that Er. bilobus and Pt. anglicus have comparable stress patterns to modern scorpions, suggesting a generalised diet that probably included other eurypterids and, in the Devonian species, armoured fishes, as indicated by co-occurring fauna. Acutiramus bohemicus is markedly different, with the stress being concentrated in the proximal free ramus and the serrated denticles. This indicates a morphology better suited for targeting softer prey. Jaekelopterus rhenaniae exhibits much lower stress across the entire model. This, combined with an extremely large body size, suggests that the species likely fed on larger and harder prey, including heavily armoured fishes. The range of cheliceral morphologies and stress patterns within Pterygotidae demonstrate that members of this family had variable diets, with only the most derived species likely to feed on armoured prey, such as placoderms. Indeed, increased sizes of these forms throughout the mid-Palaeozoic may represent an ‘arms race’ between eurypterids and armoured fishes, with Devonian pterygotids adapting to the rapid diversification of placoderms.

Abstract Insectivorous birds breeding in seasonal environments provision their dependent young during periods when prey diversity and abundance vary. Consequently, the composition and nutritional value of diets parents feed to their offspring may differ within and among broods, potentially affecting the condition of nestlings. In a population of mountain bluebirds (Sialia currucoides), we used two methods to estimate diet composition for individual nestlings: direct observation of provisioning using video recordings at 5 and 9 days post‐hatch, and stable isotopes of the δ13C and δ15N in nestling feathers and prey followed by analysis with mixing models. We determined the macronutrient content (% fat and lean mass) and estimated the metabolized energy from each type of prey. We evaluated whether different methods of estimating diet composition would produce similar results, and whether the types of prey nestlings ate at one or both ages affected their morphology, growth rates, or blood ketone concentration. We found that bluebirds fed their young 5 main types of prey: beetles, cicadas, grasshoppers, insect larvae, and spiders. Both observational and mixing model estimates of diet composition indicated that larvae are traded off with grasshoppers and that fewer larvae are provided to nestlings as the season progresses. In evaluating how diet influences individual growth and condition, estimates from direct observations had greater explanatory power than those from mixing models, indicating that diets rich in the most energy‐dense prey (greatest fat content; cicadas and larvae) were associated with larger size and higher body condition, and faster rate of mass gain and growth of tarsus. Lower value prey had more limited, specific effects on nestlings, but may still be important dietary components. While isotopic methods produced estimates of diet composition that were generally informative, when applied to explain the growth and condition of nestlings they proved less useful.

Prenatal exposure to testosterone is implicated in the etiology of autism spectrum disorder (ASD). Hypertensive disorders of pregnancy and polycystic ovary syndrome are associated with both hyperandrogenism and increased risk for ASD. We examined whether increased maternal testosterone mediates the relationship between these hyperandrogenic disorders (HDs) during pregnancy and child communication and social skills. Maternal plasma was collected during the second trimester and parent-report measures of child communication and social skills were obtained at 4.5-6.5 years of age from 270 participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Our retrospective frequency-matched cohort study design identified 58 mothers with one or both of the HDs and 58 matched controls. Women diagnosed with an HD who carried a female had higher testosterone levels compared to those carrying a male (t(56) = -2.70, p = 0.01). Compared to females controls, females born to women with an HD had significantly higher scores on the Social Communication Questionnaire (t(114) = -2.82, p =0.01). Maternal testosterone partially mediated the relationship between a diagnosis of an HD and SCQ scores among females. These findings point to sex-specific associations of two HDs – hypertensive disorders of pregnancy and polycystic ovary syndrome – on child communication and social skills and a mediating effect of maternal testosterone during pregnancy. Further research is needed to understand placental-mediated effects of maternal testosterone on child brain development and neurodevelopmental outcomes.

Dystrophin plays a crucial role in maintaining sarcolemma stability during muscle contractions, and mutations that prevent the expression of a functional protein cause Duchenne muscular dystrophy (DMD). Antisense oligonucleotide-mediated manipulation of pre-messenger RNA splicing to bypass Duchenne-causing mutations and restore functional dystrophin expression has entered the clinic for the most common DMD mutations. The rationale of “exon skipping” is based upon genotype-phenotype correlations observed in Becker muscular dystrophy, a milder allelic disorder generally characterized by in-frame deletions and internally truncated but semi-functional dystrophin isoforms. However, there is a lack of genotype-phenotype correlations downstream of DMD exon 55, as deletions in this region are rare and most single exon deletions would disrupt the reading frame. Consequently, the amenability of mutations in this region of the DMD gene to exon skipping strategies remains unknown. Here, we induced “Becker muscular dystrophy-like” in-frame dystrophin isoforms in vivo by intraperitoneal injection of peptide-conjugated phosphorodiamidate morpholino oligomers targeting selected exons. The dystrophin isoform encoded by the transcript lacking exons 56+57 appears to be more functional than that encoded by the 58+59-deleted transcript, as determined by higher dystrophin expression, stabilized β-dystroglycan, and less severe dystrophic pathology, indicating some potential for the strategy to address Duchenne-causing mutations affecting these exons.

The hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis changes significantly during puberty in a variety of species, including humans. For example, stress-induced adrenocorticotropic hormone (ACTH) and corticosterone responses are greater in prepubertal compared to adult rats, yet the mechanisms that mediate these age-related differences are unclear. It is possible that the pituitary and adrenal glands have higher hormonal concentrations prior to puberty, thus enabling a greater hormonal response if a stressor were to occur. Thus, we tested the hypothesis that resting levels of ACTH, and its precursor, proopiomelanocortin (POMC), are higher in the pituitary, and corticosterone levels are higher in the adrenals, of prepubertal compared to adult rats. Furthermore, to investigate any potential sex differences in these parameters, both males and females were assessed. Here we report that despite similar circulating plasma ACTH and corticosterone levels, prepubertal males and females have greater ACTH levels in the pituitary and greater corticosterone concentrations in the adrenals compared to adult males and females. Moreover, we show that POMC protein levels are significantly greater in the pituitary gland of prepubertal than adult rats, particularly in prepubertal females. These data suggest that increased glandular production of ACTH and corticosterone during puberty in part mediate pubertal differences in hormonal stress reactivity and highlight how each node of the HPA axis may contribute to these developmental changes. Given the dramatic increase in stress-related dysfunctions during puberty, continued study of all parts of the HPA axis will be imperative.

Introduction: Severity and disease progression in people with Cystic Fibrosis (CF) is typically dependent on their genotype. One potential therapeutic strategy for people with specific mutations is exon skipping with antisense oligonucleotides (AO). CFTR exon 9 is an in-frame exon and hence the exclusion of this exon would excise only 31 amino acids but not alter the reading frame of the remaining mRNA. Splice mutations 1209 + 1 G > C and 1209 + 2 T > G were documented to cause CFTR exon 9 skipping and these variants were reported to manifest as a milder CF disease, therefore exon 9 skipping could be beneficial for people with class I mutations that affect exon 9 such as p.Trp401X. While the impact of exon 9 skipping on gene expression and cellular pathways can be studied in cells in vitro, trace amount of full-length normal or mutated material could confound the evaluation. To overcome this limitation, the impact of CFTR exon 9 skipping on disease phenotype and severity is more effectively evaluated in a small animal model. It was hypothesised that antisense oligonucleotide-mediated skipping this particular exon could result in a “mild mouse CF phenotype”.Methods:Cftr exon 9 deleted mice were generated using homologous recombination. Survival of homozygous (CftrΔ9/Δ9) and heterozygous (CftrΔ9/+) mice was compared to that of other CF mouse models, and lung and intestinal organ histology examined for any pathologies. Primary airway epithelial cells (pAECs) were harvested from CftrΔ9/Δ9 mice and cultured at the Air Liquid Interface for CFTR functional assessment using Ussing Chamber analysis.Results: A CftrΔ9/Δ9 mouse model presented with intestinal obstructions, and at time of weaning (21 days). CftrΔ9/Δ9 mice had a survival rate of 83% that dropped to 38% by day 50. Histological sections of the small intestine from CftrΔ9/Δ9 mice showed more goblet cells and mucus accumulation than samples from the CftrΔ9/+ littermates. Airway epithelial cell cultures established from CftrΔ9/Δ9 mice were not responsive to forskolin stimulation.Summary: The effect of Cftr exon 9 deletion on Cftr function was assessed and it was determined that the encoded Cftr isoform did not result in a milder “mouse CF disease phenotype,” suggesting that Cftr exon 9 is not dispensable, although further investigation in human CF pAECs would be required to confirm this observation.

Australian dinosaur research has undergone a renaissance in the last 10 years, with growing knowledge of mid-Cretaceous assemblages revealing an endemic high-paleolatitude Gondwanan fauna. One of its most conspicuous members is ankylosaurs, which are rare but nonetheless occur in most Australian dinosaur-bearing formations spanning the uppermost Barremian to lower Cenomanian. Here we describe a partial ankylosaur skull from the marine Toolebuc Formation exposed near Boulia in western Queensland, Australia. This skull represents the oldest ankylosaurian material from Queensland, predating the holotype of Kunbarrasaurus ieversi, which was found in the overlying Allaru Mudstone. The ankylosaur skull is encased in a limestone concretion with the maxillary tooth rows preserved only as impressions. Synchrotron radiation X-ray tomography was used to non-destructively image and reconstruct the specimen in 3D and facilitate virtual preparation of the separate cranial bones. The reconstruction of the skull revealed the vomer, palatines, sections of the ectopterygoids and maxillae, and multiple teeth. The palate has posteriorly positioned choanae that differs from the more anterior placement seen in most other ankylosaurians, but which is shared with K. ieversi, Akainacephalus johnsoni, Cedarpelta bilbeyhallorum, Gobisaurus domoculus, and Panoplosaurus mirus. Phylogenetic analyses place the new cranial material within the recently named basal ankylosaurian clade Parankylosauria together with K. ieversi. This result, together with the anatomical similarities to the holotype of K. ieversi, permits its referral to cf. Kunbarrasaurus sp. This specimen elucidates the palatal anatomy of Australian ankylosaurs and highlights one of the most ubiquitous components of Australian mid-Cretaceous dinosaur faunas.