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Background Oxygen (O2) is a mainstay of treatment in acute severe asthma but how it is administered varies widely. The objectives were to examine whether a trial comparing humidified O2 to standard O2 in children is feasible, and specifically to obtain data on recruitment, tolerability and outcome measure stability. Methods Heated humidified, cold humidified and standard O2 treatments were compared for children (2–16 years) with acute severe asthma in a multi-centre, open, parallel, pilot randomised controlled trial (RCT). Multiple outcomes were assessed. Results Of 258 children screened, 66 were randomised (heated humidified O2 n = 25; cold humidified O2 n = 21; standard O2 n = 20). Median (IQR) length of stay (hours) in hospital was 37.9 (29.1), 52 (35.4) and 49.1 (29.7) for standard, heated humidified and cold humidified respectively and time (hours) on O2 was 15.9 (9.4), 13.6 (14.9) and 13.1 (14.9) for the three groups respectively. The mean (standard deviation) time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3), 35.1 (28.2) and 32.7 (20.1). Asthma Severity Score decreased in all three groups similarly, although missing data prevented complete analysis. Humidified O2 was least well tolerated with eight participants discontinuing their randomised treatment early. An important barrier to recruitment was research nurse availability. Conclusion Although, the results of this pilot study should not be extrapolated beyond the study sample and inferential conclusions should not be drawn from the results, this is the first RCT to compare humidified and standard O2 therapy in acute severe asthmatics of any age. These findings and accompanying screening data show that a large RCT of O2 therapy is feasible. However, challenges associated with randomisation and data collection should be addressed in any future trial design.

Tillering and secondary branching are two plastic traits with high agronomic importance, especially in terms of the ability of plants to adapt to changing environments. We describe a quantitative trait analysis of tillering and secondary branching in two novel BC1F2 populations totaling 246 genotypes derived from backcrossing two Sorghum bicolor x S. halepense F1 plants to a tetraploidized S. bicolor. A two-year, two-environment phenotypic evaluation in Bogart, GA and Salina, KS permitted us to identify major effect and environment specific QTLs. Significant correlation between tillering and secondary branching followed by discovery of overlapping sets of QTLs continue to support the developmental relationship between these two organs and suggest the possibility of pleiotropy. Comparisons with two other populations sharing S. bicolor BTx623 as a common parent but sampling the breadth of the Sorghum genus, increase confidence in QTL detected for these two plastic traits and provide insight into the evolution of morphological diversity in the Eusorghum clade. Correspondence between flowering time and vegetative branching supports other evidence in suggesting a pleiotropic effect of flowering genes. We propose a model to predict biomass weight from plant architecture related traits, quantifying contribution of each trait to biomass and providing guidance for future breeding experiments.

[This corrects the article DOI: 10.1371/journal.pone.0233279.].

Cost-effectiveness analysis (CEA) is a well-known, but resource intensive, method for comparing the costs and health outcomes of health interventions. To build on available evidence, researchers are developing methods to transfer CEA across settings; previous methods do not use all available results nor quantify differences across settings. We conducted a meta-regression analysis of published CEAs of human papillomavirus (HPV) vaccination to quantify the effects of factors at the country, intervention, and method-level, and predict incremental cost-effectiveness ratios (ICERs) for HPV vaccination in 195 countries. We used 613 ICERs reported in 75 studies from the Tufts University’s Cost-Effectiveness Analysis (CEA) Registry and the Global Health CEA Registry, and extracted an additional 1,215 one-way sensitivity analyses. A five-stage, mixed-effects meta-regression framework was used to predict country-specific ICERs. The probability that HPV vaccination is cost-saving in each country was predicted using a logistic regression model. Covariates for both models included methods and intervention characteristics, and each country’s cervical cancer burden and gross domestic product per capita. ICERs are positively related to vaccine cost, and negatively related to cervical cancer burden. The mean predicted ICER for HPV vaccination is 2017 US$4,217 per DALY averted (95% uncertainty interval (UI): US$773–13,448) globally, and below US$800 per DALY averted in 64 countries. Predicted ICERs are lowest in Sub-Saharan Africa and South Asia, with a population-weighted mean ICER across 46 countries of US$706 per DALY averted (95% UI: $130–2,245), and across five countries of US$489 per DALY averted (95% UI: $90–1,557), respectively. Meta-regression analyses can be conducted on CEA, where one-way sensitivity analyses are used to quantify the effects of factors at the intervention and method-level. Building on all published results, our predictions support introducing and expanding HPV vaccination, especially in countries that are eligible for subsidized vaccines from GAVI, the Vaccine Alliance, and Pan American Health Organization.

Circular shell rings along the South Atlantic Coast of North America are the remnants of some of the earliest villages that emerged during the Late Archaic (5000–3000 BP). Many of these villages, however, were abandoned during the Terminal Late Archaic (ca 3800–3000 BP). We combine Bayesian chronological modeling with mollusk shell geochemistry and oyster paleobiology to understand the nature and timing of environmental change associated with the emergence and abandonment of circular shell ring villages on Sapelo Island, Georgia. Our Bayesian models indicate that Native Americans occupied the three Sapelo shell rings at varying times with some generational overlap. By the end of the complex’s occupation, only Ring III was occupied before abandonment ca. 3845 BP. Ring III also consists of statistically smaller oysters harvested from less saline estuaries compared to earlier occupations. Integrating shell biochemical and paleobiological data with recent tree ring analyses shows a clear pattern of environmental fluctuations throughout the period in which the rings were occupied. We argue that as the environment became unstable around 4300 BP, aggregation at villages provided a way to effectively manage fisheries that are highly sensitive to environmental change. However, with the eventual collapse of oyster fisheries and subsequent rebound in environmental conditions ca. post-3800 BP, people dispersed from shell rings, and shifted to non-marine subsistence economies and other types of settlements. This study provides the most comprehensive evidence for correlations between large-scale environmental change and societal transformations on the Georgia coast during the Late Archaic period.

Individual life expectancies provide information for individuals making retirement decisions and for policy makers. For couples, analogous measures are the expected years both spouses will be alive (joint life expectancy) and the expected years the surviving spouse will be a widow or widower (survivor life expectancy). Using individual life expectancies to calculate summary measures for couples is intuitively appealing but yield misleading results, overstating joint life expectancy and dramatically understating survivor life expectancies. This implies that standard "individual life cycle models" are misleading for couples and that “couple life cycle models” must be substantially more complex. Using the CDC life tables for 2010, we construct joint and survivor life expectancy measures for randomly formed couples. The couples we form are defined by age, race and ethnicity, and education. Due to assortative marriage, inequalities in individual life expectancies are compounded into inequalities in joint and survivor life expectancies. We also calculate life expectancy measures for randomly formed couples for the 1930–2010 decennial years. Trends over time show how the relative rate of decrease in the mortality rates of men and women affect joint and survivor life expectancies. Because our couple life expectancy measures are based on randomly formed couples, they do not capture the effects of differences in spouses’ premarital characteristics (apart from sex, age, race and ethnicity, and, in some cases, education) or of correlations in spouses’ experiences or behaviors during marriage. However, they provide benchmarks which have been sorely lacking in the public discourse.

ObjectivesGender-based violence is a global public health crisis, which has health, social, and economic impacts on survivors. In Ghana, responding to and preventing sexual violence on university campuses, has become a priority area. However, data are lacking on the healthcare provider response to students who have experienced sexual violence. The purpose of this study was to conduct a situational analysis to better understand the healthcare provider response to sexual violence in Cape Coast, Ghana.MethodsFirst, an observational facility assessment about healthcare services for survivors of sexual violence was conducted at two hospitals serving university students in Cape Coast, Ghana. Next, healthcare providers at the two hospitals completed: 1) a 113-item questionnaire about healthcare services, knowledge, and attitudes related to sexual violence and 2) in-depth semi-structured interviews describing their experiences providing healthcare to survivors of sexual violence. Descriptive statistics and frequencies were computed, and thematic analysis was used to analyze the qualitative data.ResultsBoth sites lacked supplies, including pre-packed rape kits, post-exposure HIV prophylaxis, and informational handouts on medications and support services for survivors. Further, healthcare providers lacked training on gender-based violence, including best practices for caring for survivors and evidence collection procedures. Providers described the clinical management for survivors of sexual violence, including providers' role in reporting sexual violence to authorities, medical forensic exams, reproductive and sexual health services, and referral for mental healthcare. Finally, providers described a number of barriers to survivors accessing post-assault healthcare, including stigma and structural barriers, such as cost of medical supplies and lack of privacy within the healthcare facilities.ConclusionsThe current healthcare response to sexual violence in Ghana is limited by lack of supplies, knowledge, and training for healthcare providers. Personal and structural barriers may prevent survivors from accessing needed healthcare following sexual violence.

At present, global immunity to SARS-CoV-2 resides within a heterogeneous combination of susceptible, naturally infected and vaccinated individuals. The extent to which viral shedding and transmission occurs on re-exposure to SARS-CoV-2 is an important determinant of the rate at which COVID-19 achieves endemic stability. We used Sialodacryoadenitis Virus (SDAV) in rats to model the extent to which immune protection afforded by prior natural infection via high risk (inoculation; direct contact) or low risk (fomite) exposure, or by vaccination, influenced viral shedding and transmission on re-exposure. On initial infection, we confirmed that amount, duration and consistency of viral shedding, and seroconversion rates were correlated with exposure risk. Animals were reinfected after 3.7–5.5 months using the same exposure paradigm. 59% of seropositive animals shed virus, although at lower amounts. Previously exposed seropositive reinfected animals were able to transmit virus to 25% of naive recipient rats after 24-hour exposure by direct contact. Rats vaccinated intranasally with a related virus (Parker’s Rat Coronavirus) were able to transmit SDAV to only 4.7% of naive animals after a 7-day direct contact exposure, despite comparable viral shedding. Cycle threshold values associated with transmission in both groups ranged from 29–36 cycles. Observed shedding was not a prerequisite for transmission. Results indicate that low-level shedding in both naturally infected and vaccinated seropositive animals can propagate infection in susceptible individuals. Extrapolated to COVID-19, our results suggest that continued propagation of SARS-CoV-2 by seropositive previously infected or vaccinated individuals is possible.

Rates of chronic pain and daily opioid use are higher among veterans relative to civilian populations. Increasing physical activity can reduce pain severity and decrease opioid use among patients with chronic pain. Behavioral economic strategies can improve physical activity levels but have been undertested in veterans with chronic pain. The objective of this study was to evaluate if a financial incentive combined with a loss aversion component—a “regret lottery” in which veterans could win money if they met a set goal or told how much they could have won had they met their goal—would increase physical activity levels among veterans with chronic pain. A 12-week single-blinded randomized controlled trial (ClinicalTrials.gov: NCT04013529) was designed. Veterans with chronic pain (N = 40) receiving care at a specialty pain clinic were eligible for participation, and were randomly assigned (1:1) to either (a) activity trackers and daily text message reminders to increase physical activity (“control arm”), or (b) the same plus a weekly regret lottery (“intervention arm”). For those in the intervention arm, participants who met their activity goal, had a chance to win a small ($30) or large ($100) gift card incentive; those who did not meet their goals were informed of what they would have won had they met their goal. The primary outcome, physical activity, was measured using self-reported physical activity and step counts using activity trackers. Secondary outcomes included changes in physical function, chronic pain severity, depression and opioid use. The sample was primarily white, male and disabled, with an average age of 57 years. No between-arm differences were noted for physical activity, physical function, chronic pain severity, depression or opioid use. Regret lottery-based approaches may be ineffective at increasing physical activity levels in veterans with chronic pain. Trial Registry: NCT04013529.

The first documented Rift Valley hemorrhagic fever outbreak in the Arabian Peninsula occurred in northwestern Yemen and southwestern Saudi Arabia from August 2000 to September 2001. This Rift Valley fever outbreak is unique because the virus was introduced into Arabia during or after the 1997–1998 East African outbreak and before August 2000, either by wind-blown infected mosquitos or by infected animals, both from East Africa. A wet period from August 2000 into 2001 resulted in a large number of amplification vector mosquitoes, these mosquitos fed on infected animals, and the outbreak occurred. More than 1,500 people were diagnosed with the disease, at least 215 died, and widespread losses of domestic animals were reported. Using a combination of satellite data products, including 2 x 2 m digital elevation images derived from commercial satellite data, we show rainfall and potential areas of inundation or water impoundment were favorable for the 2000 outbreak. However, favorable conditions for subsequent outbreaks were present in 2007 and 2013, and very favorable conditions were also present in 2016–2018. The lack of subsequent Rift Valley fever outbreaks in this area suggests that Rift Valley fever has not been established in mosquito species in Southwest Arabia, or that strict animal import inspection and quarantine procedures, medical and veterinary surveillance, and mosquito control efforts put in place in Saudi Arabia following the 2000 outbreak have been successful. Any area with Rift Valley fever amplification vector mosquitos present is a potential outbreak area unless strict animal import inspection and quarantine proceedures are in place.

In 2006, six isolated hominin teeth were excavated from Middle Stone Age (MSA) deposits at the Magubike rockshelter in southern Tanzania. They comprise two central incisors, one lateral incisor, one canine, one third premolar, and one fourth premolar. All are fully developed and come from the maxilla. None of the teeth are duplicated, so they may represent a single individual. While there is some evidence of post-depositional alteration, the morphology of these teeth clearly shares features with anatomically modern Homo sapiens. Both metric and non-metric traits are compared to those from other African and non-African dental remains. The degree of biological relatedness between eastern and southern African Stone Age hunter-gatherers has long been a subject of interest, and several characteristics of the Magubike teeth resemble those of the San of southern Africa. Another notable feature is that the three incisors are marked on the labial crown by scratches that are much coarser than microwear striations. These non-masticatory scratches on the Magubike teeth suggest that the use of the front teeth as tools included regularly repeated activities undertaken throughout the life of the individual. The exact age of these teeth is not clear as ESR and radiocarbon dates on associated snail shells give varying results, but a conservative estimate of their minimum age is 45,000 years.

Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient's progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.

Inoculation theory offers a framework for protecting individuals against challenges to an existing attitude, belief, or state. Despite the prevalence and damaging effects of public speaking anxiety, inoculation strategies have yet to be used to help individuals remain calm before and during public speaking. We aimed to test the effectiveness of an inoculation message for reducing the onset of public speaking anxiety, and helping presenters interpret their speech-related anxiety more positively. Participants (Mage = 20.14, SD = 2.72) received either an inoculation (n = 102) or control (n = 128) message prior to engaging a public speaking task and reported a range of anxiety-related perceptions. Accounting for personality characteristics and perceptions of task importance, and relative to control participants, those who received the inoculation message reported significantly lower pre-task anxiety, and following the task, reported that they had experienced lower somatic anxiety, and that the inoculation message had caused them to view their nerves in a less debilitating light. Inoculation messages may be an effective strategy for helping participants reframe and reduce their apprehension about public speaking, and investigating their efficacy in other stress-inducing contexts may be worthwhile.

Historical extirpations have resulted in depauperate large herbivore assemblages in many northern forests. In eastern North America, most forests are inhabited by a single wild ungulate species, white-tailed deer (Odocoileus virginianus), and relationships between deer densities and impacts on forest regeneration are correspondingly well documented. Recent recolonizations by moose (Alces americanus) in northeastern regions complicate established deer density thresholds and predictions of browsing impacts on forest dynamics because size and foraging differences between the two animals suggest a lack of functional redundancy. We asked to what extent low densities of deer + moose would structure forest communities differently from that of low densities of deer in recently logged patch cuts of Massachusetts, USA. In each site, a randomized block with three treatment levels of large herbivores–no-ungulates (full exclosure), deer (partial exclosure), and deer + moose (control) was established. After 6–7 years, deer + moose reduced stem densities and basal area by 2-3-fold, Prunus pensylvanica and Quercus spp. recruitment by 3–6 fold, and species richness by 1.7 species (19%). In contrast, in the partial exclosures, deer had non-significant effects on stem density, basal area, and species composition, but significantly reduced species richness by 2.5 species on average (28%). Deer browsing in the partial exclosure was more selective than deer + moose browsing together, perhaps contributing to the decline in species richness in the former treatment and the lack of additional decline in the latter. Moose used the control plots at roughly the same frequency as deer (as determined by remote camera traps), suggesting that the much larger moose was the dominant browser species in terms of animal biomass in these cuts. A lack of functional redundancy with respect to foraging behavior between sympatric large herbivores may explain combined browsing effects that were both large and complex.

Johnsongrass (Sorghum halepense) is a striking example of a post-Columbian founder event. This natural experiment within ecological time-scales provides a unique opportunity for understanding patterns of continent-wide genetic diversity following range expansion. Microsatellite markers were used for population genetic analyses including leaf-optimized Neighbor-Joining tree, pairwise FST, mismatch analysis, principle coordinate analysis, Tajima’s D, Fu’s F and Bayesian clusterings of population structure. Evidence indicates two geographically distant introductions of divergent genotypes, which spread across much of the US in