Search

Physical inactivity is an important modifiable risk factor for non-communicable diseases (NCDs) and mental health conditions. We aimed to estimate the public health-care costs associated with these diseases because of physical inactivity, which will help policy makers to prioritise investment in policy actions to promote and enable more people to be more active.We used a population-attributable fraction formula to estimate the direct public health-care costs of NCDs and mental health conditions for 2020-30. The disease outcomes that we included were incident cases of coronary heart disease, stroke, type 2 diabetes, hypertension, cancer (breast, colon, bladder, endometrial, oesophageal, gastric, and renal), dementia, and depression in adults aged at least 18 years. We used the most recent health and economic data evidence available for 194 countries.499·2 million new cases of preventable major NCDs would occur globally by 2030 if the prevalence of physical inactivity does not change, with direct health-care costs of INT$520 billion. The global cost of inaction on physical inactivity would reach approximately $47·6 billion per year. Although 74% of new cases of NCDs would occur in low-income and middle-countries, high-income countries would bear a larger proportion (63%) of the economic costs. The cost of treatment and management of NCDs varied-although dementia accounted for only 3% of new preventable NCDs, the disease corresponded to 22% of all costs; type 2 diabetes accounted for 2% of new preventable cases but 9% of all costs; and cancers accounted for 1% of new preventable cases but 15% of all costs.This health and economic burden of physical inactivity is avoidable. Further investments in and implementation of known and effective policy interventions will support countries to reach the Sustainable Development Goal of reduction of NCD mortality by 2030.None.

Aedes aegypti (Diptera: Culicidae) is the principal vector of dengue and other viruses that cause disease among 100 to 400 million people each year. The recent development of widespread insecticidal resistance has led to the rapid development of biological control solutions aimed at larval control. While the efficacy of Metarhizium brunneum has been shown against Aedes larvae, the impact of larval population dynamics will need to be determined to formulate effective control strategies. In this study, larvae were subjected to four concentrations of M. brunneum (105, 106, 107, 108 conidia ml−1). Larvae were found to be susceptible to M. brunneum with dose-dependent efficacy. When constant larval immigration was added as a parameter, peak mortality was consistently found to occur on the fourth day, before a significant reduction in control efficacy linked to a decline in conidial availability within the water column. This suggests that M. brunneum treatments should be applied at a concentration 1 × 107 conidia ml−1 every four days to effectively control mosquito larvae in the field, regardless of the fungal formulation, water volume, or larval density. Understanding fungal-mosquito dynamics is critical in developing appropriate control programs as it helps optimize the fungal control agent’s dose and frequency of application.

ObjectiveTo investigate cost-effectiveness and costs of fall prevention exercise programmes for older adults.DesignSystematic review.Data sourcesMedline, Embase, Web of Science, Scopus, National Institute for Health Research Economic Evaluation Database, Health Technology Assessment database, Tufts Cost-Effectiveness Analysis Registry, Research Papers in Economics and EconLit (inception to May 2022).Eligibility criteria for study selectionEconomic evaluations (trial-based or model-based) and costing studies investigating fall prevention exercise programmes versus no intervention or usual care for older adults living in the community or care facilities, and reporting incremental cost-effectiveness ratio (ICER) for fall-related outcomes or quality-adjusted life years (QALY, expressed as cost/QALY) and/or intervention costs.Results31 studies were included. For community-dwelling older adults (21 economic evaluations, 6 costing studies), results ranged from more effective and less costly (dominant) interventions up to an ICER of US$279 802/QALY gained and US$11 986/fall prevented (US$ in 2020). Assuming an arbitrary willingness-to-pay threshold (US$100 000/QALY), most results (17/24) were considered cost-effective (moderate certainty). The greatest value for money (lower ICER/QALY gained and fall prevented) appeared to accrue for older adults and those with high fall risk, but unsupervised exercise appeared to offer poor value for money (higher ICER/QALY). For care facilities (two economic evaluations, two costing studies), ICERs ranged from dominant (low certainty) to US$35/fall prevented (moderate certainty). Overall, intervention costs varied and were poorly reported.ConclusionsMost economic evaluations investigated fall prevention exercise programmes for older adults living in the community. There is moderate certainty evidence that fall prevention exercise programmes are likely to be cost-effective. The evidence for older adults living in care facilities is more limited but promising.PROSPERO registration numberPROSPERO 2020 CRD42020178023.

Habitat suitability modelling (HSM) is a tool that is increasingly being used to help guide decision making for conservation management. It can also be used to focus efforts of restoration in our oceans. To improve on model performance, the best available environmental data along with species distribution data are needed. Marine habitats tend to have ecological niches defined by physical environmental conditions and of particular importance for shallow water species is wave energy. In this study we examined the relative improvements to HSM outputs that could be achieved by producing high-resolution Delft-3D modelled wave height data to see if model predictions at a fine-scale can be improved. Seagrasses were used as an exemplar and comparisons at fine-scale showed considerable differences in the area predicted suitable for seagrass growth and greatly increased the importance of waves as a predictor variable when compared with open-source low resolution wave energy data.

Contains fulltext : 291986.pdf (Publisher’s version ) (Open Access) The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor ap2-g, is known to be influenced by host factors but a comprehensive model remains uncertain. Here, we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission. We examine markers of host immunity and metabolism, and markers of parasite growth and transmission investment. We find that inflammatory responses associated with reduced plasma lysophosphatidylcholine levels are associated with markers of increased investment in parasite sexual reproduction (i.e. transmission investment) and reduced growth (i.e. asexual replication). This association becomes stronger with falling transmission and suggests that parasites can rapidly respond to the within-host environment, which in turn is subject to changing transmission.

We explore the terahertz (THz) emission from CoFeB/Pt spintronic structures in the below-magnetic-saturation regime and reveal an orientation dependence in the emission, arising from in-plane uniaxial magnetic anisotropy (UMA) in the ferromagnetic layer. Maximizing the UMA during the film deposition process and aligning the applied magnetic field with the easy axis of the structure allow the THz emission to reach saturation under weaker applied fields. In addition, the THz emission amplitude remains at saturation levels when the applied field is removed. The development of CoFeB/Pt spintronic structures that can emit broadband THz pulses without the need for an applied magnetic field is beneficial to THz magneto-optical spectroscopy and facilitates the production of large-area spintronic emitters. Furthermore, by aligning the applied field along the hard axis of the structure, the linear polarization plane of the emitted THz radiation can be manipulated by changing the magnitude of the applied field. We, therefore, demonstrate THz polarization control without the need for mechanical rotation of external magnets.

Background Knowledge of which physical activity programs are most effective for older adults in different sub-populations and contexts is limited. The objectives of this rapid review were to: 1) Overview evidence evaluating physical activity programs/services for older adults; and 2) Describe impact on physical activity, falls, intrinsic capacity (physical domain), functional ability (physical, social, and cognitive/emotional domains), and quality of life. Methods We conducted a rapid review of primary studies from 350 systematic reviews identified in a previous scoping review (March 2021: PEDro, MEDLINE, CINAHL, Cochrane Database). For Objective 1, we included intervention studies investigating physical activity programs/services in adults ≥ 60 years. Of these, we included good quality (≥ 6/10 PEDro scale) randomised controlled trials (RCTs) with ≥ 50 participants per group in Objective 2. Results Objective 1: Of the 1421 intervention studies identified from 8267 records, 79% were RCTs, 87% were in high income countries and 39% were good quality. Objective 2: We identified 87 large, good quality RCTs (26,861 participants). Overall activity promotion, structured exercise and recreation/sport had positive impacts (≥ 50% between-group comparisons positive) across all outcome domains. For overall activity promotion (21 intervention groups), greatest impacts were on physical activity (100% positive) and social outcomes (83% positive). Structured exercise (61 intervention groups) had particularly strong impacts on falls (91% positive), intrinsic capacity (67% positive) and physical functioning (77% positive). Recreation/sport (24 intervention groups) had particularly strong impacts on cognitive/emotional functioning (88% positive). Multicomponent exercise (39 intervention groups) had strong impacts across all outcomes, particularly physical activity (95% positive), falls (90% positive) and physical functioning (81% positive). Results for different populations and settings are presented. Conclusion Evidence supporting physical activity for older adults is positive. We outline which activity types are most effective in different populations and settings.

Introduction Respiratory rate (RR) is a key marker of stress with evidence that raised RR is the vital sign most predictive of cardiac events. Respiratory monitoring is critical to detecting Sleep Disordered Breathing (SDB). COVID-19 highlighted the importance of infection control, and methods of detecting RR without direct airstream contact have wide application for diagnostic and monitoring in respiratory medicine. This scoping review aims to provide an up-to-date overview of indirect respiratory monitoring. Method Systematic literature searches were conducted according to PRISMA-ScR guidelines on PubMed, Embase, ProQuest and Scopus covering articles published between January 2012, until February 2022. Data was extracted into the following categories : physiological signal, sensor type, sensor location and field of use. Analysis methods and effectiveness of each method were also assessed. Results 10736 articles were screened, 236 articles were included for analysis. 61.9% (n=146) monitored respiration through periodic motion of the chest and abdomen, 22.5% (n=53) cardiorespiratory coupling 7.6% (n=18) airstream temperature, 2.5% (n=6) respiratory sounds, 0.4% (n=) remote airflow monitoring, and 5.1% (n=12) combined markers. Medical and clinical research accounted for 42.4% (n=100) of papers, health and exercise monitoring 28% (n=66), and sleep monitoring 16.9% (n=40).22 different sensor types were identified, the most common being remote radar monitoring 17.8% (n=42), photoplethysmography 14.8% (n=35), AI assisted video monitoring 9.7% (n=23) and thermal imaging 8.5% (n=20). Discussion Indirect RR monitoring technology that is typically unutilized in clinical settings. Continued development in AI assisted signal analysis will make these methods more accessible for clinical and consumer use.

Mandibular advancement therapy (MAS) is a recognised second-line therapy for obstructive sleep apnoea (OSA). However, MAS treatment outcomes vary and are difficult to predict. Recent studies have investigated the role of OSA endotypes to predict MAS therapy outcomes. However, whether OSA endotype predictors differ between obese and non-obese people with OSA is unknown. Thus, this study aimed to compare OSA endotypes between responders and non-responders to MAS therapy in obese and non-obese individuals. 90 people with OSA (AHI>10events/h) were studied. OSA was confirmed via in-laboratory polysomnography. A detailed physiology night was subsequently performed prior to MAS therapy. OSA endotypes were estimated from the detailed physiology polysomnography using a custom-designed, validated, semiautomated script. OSA endotypes were compared between responders (residual AHI Responders to MAS therapy had a less collapsible upper airway; Vpassive: 93[88,96]vs.85[62,94]%Veupnea,p=0.003); Vactive: 103[95,112]vs.98[16,104] %Veupnea,p=0.008), better pharyngeal muscle compensation Vcomp: 9.8[4.3,19.6]vs.3.3[-19.1,18.6]%Veupnea,p=0.02), lower arousal threshold (114[109,144]vs. 142 [117, 177]%Veupnea,p=0.006) and tended to also have lower loop gain (0.48 ±0.1vs. 0.42±0.1,p=0.05). . These findings were similar in obese versus non-obese individuals although loop gain was significantly lower in responders versus non-responders in the non-obese (p=0.01) but not the obese group (0.97). MAS therapy was most beneficial in people with a less collapsible upper airway, good pharyngeal muscle compensation, lower arousal threshold and loop gain at baseline. Prospective assessment of OSA endotypic traits may therefore help guide treatment decisions and improve MAS therapy outcomes.

Coastal ecosystems, including coral reefs, mangroves, and seagrass, are in global decline. Mitigation approaches include restoration and other managed recovery interventions. To maximise success, these should be guided by an understanding of the environmental niche and geographic limits of foundational species. However, the choices of data, variables, and modelling approaches can be bewildering when embarking on such an exercise, and the biases associated with such choices are often unknown. We reviewed the current available knowledge on methodological approaches and environmental variables used to model and map habitat suitability for coastal ecosystems. While our focus is on seagrass, we draw on information from all marine macrophyte studies for greater coverage of approaches at different scales around the world. We collated 75 publications, of which 35 included seagrasses. Out of all the publications, we found the most commonly used predictor variables were temperature (64%), bathymetry (61%), light availability (49%), and salinity (49%), respectively. The same predictor variables were also commonly used in the 35 seagrass Habitat Suitability Models (HSM) but in the following order: bathymetry (74%), salinity (57%), light availability (51%), and temperature (51%). The most popular method used in marine macrophyte HSMs was an ensemble of models (29%) followed by MaxEnt (17%). Cross-validation was the most commonly used selection procedure (24%), and threshold probability was the favoured model validation (33%). Most studies (87%) did not calculate or report uncertainty measures. The approach used to create an HSM was found to vary by location and scale of the study. Based upon previous studies, it can be suggested that the best approach for seagrass HSM would be to use an ensemble of models, including MaxEnt along with a selection procedure (Cross-validation) and threshold probability to validate the model with the use of uncertainty measures in the model process.

There are numerous examples of phenological shifts that are recognized both as indicators of climate change and drivers of ecosystem change. A pressing challenge is to understand the causal mechanisms by which climate affects phenology. We combined annual population census data and individual longitudinal data (1992–2018) on grey seals,Halicheorus grypus, to quantify the relationship between pupping season phenology and sea surface temperature. A temperature increase of 2°C was associated with a pupping season advance of approximately seven days at the population level. However, we found that maternal age, rather than sea temperature, accounted for changes in pupping date by individuals. Warmer years were associated with an older average age of mothers, allowing us to explain phenological observations in terms of a changing population age structure. Finally, we developed a matrix population model to test whether our observations were consistent with changes to the stable age distribution. This could not fully account for observed phenological shift, strongly suggesting transient modification of population age structure, for example owing to immigration. We demonstrate a novel mechanism for phenological shifts under climate change in long-lived, age- or stage-structured species with broad implications for dynamics and resilience, as well as population management.

In isolated or declining populations, viability may be compromised further by loss of genetic diversity. Therefore, it is important to understand the relationship between long-term ecological trajectories and population genetic structure. However, opportunities to combine these types of data are rare, especially in natural systems. Using an existing panel of 15 microsatellites, we estimated allelic diversity in seagrass, Zostera marina, at five sites around the Isles of Scilly Special Area of Conservation, UK, in 2010 and compared this to 23 years of annual ecological monitoring (1996–2018). We found low diversity and long-term declines in abundance in this relatively pristine but isolated location. Inclusion of the snapshot of genotypic, but less-so genetic, diversity improved prediction of abundance trajectories; however, this was spatial scale-dependent. Selection of the appropriate level of genetic organization and spatial scale for monitoring is, therefore, important to identify drivers of eco-evolutionary dynamics. This has implications for the use of population genetic information in conservation, management, and spatial planning.

BACKGROUND Slugs and snails constitute major crop pests. Withdrawal of metaldehyde has prompted a search for more environmentally friendly yet fast acting molluscicides. This study investigated the response of representative molluscs to conidia and volatile organic compounds (VOCs) of the insect pathogenic fungus Metarhizium brunneum Petch. RESULTS Conidia of M. brunneum had antifeedant/repellent properties with repellency being dependent upon the fungal strain and conidia concentration. Three commonly produced fungal VOCs, 1‐octene, 3‐octanone and 1‐octen‐3‐ol, were repellent at low doses (1–5 μL) but could kill slugs and snails on contact or fumigation. At the highest dose tested (10 μL), 100% mortality was achieved for Cornu aspersum Muller (garden snail) and Derocerus reticulatum Muller (grey field slug) within 1 h post‐treatment with the first deaths being recorded in, Slugs and snails avoid plants treated with conidia and VOCs of the insect pathogenic fungus Metarhizium brunneum. The VOCs show promise as mollusc repellents or molluscicides.

Structurally complex habitat is declining across temperate marine environments. This trend has been attributed to changes in land use and increasing coastal development, which are activities likely to continue with governments supporting ongoing economic growth within the marine realm. This can compromise biodiversity, and biodiversity offsetting is increasingly being heralded as a means to reduce the conflict between development and conservation. Offset schemes are often evaluated against targets of ‘ecological equivalence’ or ‘like-for-like’ but these terms can be difficult to define and quantify. Although targets of equivalence have been generally shown to be feasible in terrestrial environments, the complex and dynamic nature of the marine and coastal realms present difficulties when aiming for strict equivalence targets as measures of success. Here, we investigated four intertidal biogenic reef habitats formed by the tube worm Sabellaria alveolata within, and in proximity to, Swansea Bay (Wales, UK). The aim was to identify measurable biodiversity components for S. alveolata reef habitat, and to investigate the natural spatio-temporal variation in these components, to determine whether a target of equivalence was feasible. We also looked to identify the most important drivers of species assemblages within the reefs. Results showed that biodiversity both S. alveolata formation and tube aperture condition showed a significant interaction between site and season, with community composition varying significantly by site only. Site was found to explain the highest variation in community composition, followed by substrate type, and geographical position. These results highlight how widely coastal habitats can vary, in both space and time, and therefore calls into question a strict target of ecological equivalence when planning biodiversity offsets in coastal environments.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

The phenotypic plasticity of seagrasses enables them to adapt to changes in environmental conditions and withstand or recover from disturbance. This plasticity was demonstrated in the large variation recorded throughout a suite of bioindicators measured within Zostera marina meadows around Wales and SW England, United Kingdom. Short-term spatial data were analysed alongside long-term monitoring data to determine which bioindicators best described the status of eelgrass meadows subjected to a range of environmental and anthropogenic drivers. Shoot density, leaf length, leaf nutrients (C:N ratio, %N, %P) including stable isotope of δ13C and δ15N provided insight into the longer-term status of the meadows studied and a good indication of the causes of long-term decline. Meadows ranged from those in the Isles of Scilly with little evidence of impact to those in Littlewick in Milford Haven, Wales that showed the highest levels of impacts of all sites. Bioindicators at Littlewick showed clear warning signs of nutrient loading reflected in the long-term decline in shoot density, and prevalence of wasting disease. This study highlights the need for continuous consistent monitoring and the benefits of using extra tools in the form of shoot nutrient analysis to determine causes of decline.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics we screened 10,240 compounds, selecting those that protected against neomycin and gentamicin in zebrafish lateral-line hair cells and, when retested in mouse cochlear cultures, prevented gentamicin-induced death of outer hair cells (OHCs). Of 64 compounds that protected zebrafish hair cells, 8 protect OHCs from gentamicin in vitro. These hits share structural features and all block, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide-kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.

BACKGROUND: Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. METHODS: We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5-15 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. FINDINGS:15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34·5%) underwent appendicectomy. The normal appendicectomy rate was 15·9% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0·84 (95% CI 0·82-0·86). Applying score cutoffs of 3 points or lower for children aged 5-10 years and girls aged 11-15 years, and 2 points or lower for boys aged 11-15 years, the failure rate was 3·3% (95% CI 2·0-5·2; 18 of 539 patients), specificity was 44·3% (95% CI 41·4-47·2; 521 of 1176), and positive predictive value was 41·4% (38·5-44·4; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72·6%, 67·4-77·4) was similar to that of ultrasound scan (75·0%, 65·3-83·1). INTERPRETATION: The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. FUNDING: None.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

Graphical abstract, Highlights • M. hapla J2s are attracted to plant roots treated with Me. brunneum conidia. • J2s are attracted to roots treated with low doses of 1-octen-3-ol and 3-octanone. • High doses of 1-octen-3-ol and 3-octanone kill or repel J2 M. hapla. • The VOCs 1-octen-3-ol and 3-octanone show promise as nematicides., Root knot nematodes (RKNs) cause significant crop losses. Although RKNs and entomopathogenic fungi, such as Metarhizium brunneum, are associated with plant roots, very little is known about the interactions between these two organisms. This study showed that conidia and VOCs of Me. brunneum influenced the behaviour of M. hapla. The response was dependent on the fungal strain, VOC, concentration of both VOC and conidia, and time. Tomatoes planted in soil treated with the highest doses of conidia usually had a higher number of nematodes than untreated control plants. This was particularly obvious for Me. brunneum strain ARSEF 4556, 7 and 14-days post-treatment. The VOCs, 1-octen-3-ol and 3-octanone, lured M. hapla to plants when used at low doses and repelled them at high doses. In Petri dish assays. the VOCs 1-octen-3-ol and 3-octanone, caused 100% mortality of M. hapla at the highest dose tested (20 µl). Very few live M. hapla were recovered from soil treated with the VOC 1-octen-3-ol, especially at the highest doses tested.

Fishery catch records offer limited data to assess the status of rare, non-commercial species, including some sharks. Despite marine megafauna creating an important source of revenue though tourism, basic spatial information required to create conservation strategies is not available for many of these species. A cost-effective approach to assess the distribution of rare, non-commercial species is required to manage resources and inform conservation strategies in data-deficient areas. This study provides new information on the distribution and abundance of the zebra shark in southern Africa and examines if local ecological knowledge can be used to identify spatial and temporal trends of rare, non-commercial elasmobranchs. Trends identified from fisher interviews at two locations were compared to those collected using structured dive surveys. Both fisher interviews and structured surveys identified similar hotspot areas and temporal changes in the zebra shark population. Photographs of zebra sharks taken by researchers, dive operators, and recreational scuba divers between Pomene and Sodwana Bay were used to identify and provide information on the size, sex and movement of individuals. A combination of geo-located data gathered from one hundred interviews conducted with fishers at four different locations within Mozambique and sightings information from scuba divers were used in a species distribution model to determine the relative importance of environmental predictors and identify further areas of suitable habitat. Sea surface temperature was the most important factor in the coldest months, with distance from shore most limiting habitat suitability at other times of year. This approach could be applied in data-deficient regions to highlight areas of interest, prioritise research activities and inform conservation actions for rare, non-commercial marine megafauna.

Background Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. Methods Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. Findings Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers’ families, study staff and the research institution’s reputation more widely. Conclusion Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights.

Data from preclinical studies suggest a link between increased risk of breast cancer and exposure to bisphenols at doses below what the United States Food and Drug Administration (FDA) considers as safe for consumption. Bisphenols exert estrogenic effects and are found in canned and plastic wrapped foods, food packaging, and plasticware. Mechanistically, bisphenols bind to the estrogen receptor (ER) and activate the expression of genes associated with cell proliferation and breast cancer. In this paper, we present a narrative literature review addressing bisphenol A and chemical analogs including bisphenol AF, bisphenol F, and bisphenol S selected as prototype xenoestrogens; then, we discuss biological mechanisms of action of these bisphenols in breast cells and potential impact of exposure at different stages of development (i.e., perinatal, peripubertal, and adult). Finally, we summarize studies detailing interactions, both preventative and promoting, of bisphenols with food components on breast cancer risk. We conclude the review with a discussion of current controversies in interpretation of the above research and future areas for investigation, including the impact of bisphenols and food components on breast tumor risk.

Conservation and population management decisions often rely on population models parameterized using census data. However, the sampling regime, precision, sample size, and methods used to collect census data are usually heterogeneous in time and space. Decisions about how to derive population‐wide estimates from this patchwork of data are complicated and may bias estimated population dynamics, with important implications for subsequent management decisions.Here, we explore the impact of site selection and data aggregation decisions on pup survival estimates, and downstream estimates derived from parameterized matrix population models (MPMs), using a long‐term dataset on grey seal (Halichoerus grypus) pup survival from southwestern Wales. The spatiotemporal and methodological heterogeneity of the data are fairly typical for ecological census data and it is, therefore, a good model to address this topic.Data were collected from 46 sampling locations (sites) over 25 years, and we explore the impact of data handling decisions by varying how years and sampling locations are combined to parameterize pup survival in population‐level MPMs. We focus on pup survival because abundant high‐quality data are available on this developmental stage.We found that survival probability was highly variable with most variation being at the site level, and poorly correlated among sampling sites. This variation could generate marked differences in predicted population dynamics depending on sampling strategy. The sample size required for a confident survival estimate also varied markedly geographically.We conclude that for populations with highly variable vital rates among sub‐populations, site selection and data aggregation methods are important. In particular, including peripheral or less frequently used areas can introduce substantial variation into population estimates. This is likely to be context‐dependent, but these choices, including the use of appropriate weights when summarizing across sampling areas, should be explored to ensure that management actions are successful., Population management planning often uses models parameterised from survey data. These data are often aggregated across time and space. We illustrate how data aggregation decisions can influence inferences and highlight that these choices could have important consequences for future management.

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 106, 12.5 × 106 and 25 × 106 cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

Spatial learning is an ecologically important trait well studied in vertebrates and a few invertebrates yet poorly understood in crustaceans. We investigated the ability of European shore crabs, Carcinus maenas , to learn a complex maze over four consecutive weeks using food as a motivator. Crabs showed steady improvement during this conditioning period in both the time taken to find the food and in the number of wrong turns taken. Crabs also clearly remembered the maze as when returned two weeks later but without any food, they all returned to the end of the maze in under 8 min. Crabs that had not been conditioned to the maze (naive animals) took far longer to reach the end, and many (42%) did not venture to the end of the maze at all during the 1 h study period. This study provides an initial description of spatial learning in a benthic decapod; a better appreciation of this adaptive trait in these animals will develop our understanding of resource exploitation by benthic crustaceans and their ecological roles.

In sub-Saharan Africa, children below 5 years bear the greatest burden of severe malaria because they lack naturally acquired immunity that develops following repeated exposure to infections by Plasmodium falciparum. Antibodies to the surface of P. falciparum infected erythrocytes (IE) play an important role in this immunity. In children under the age of 6 months, relative protection from severe malaria is observed and this is thought to be partly due to trans-placental acquired protective maternal antibodies. However, the protective effect of maternal antibodies has not been fully established, especially the role of antibodies to variant surface antigens (VSA) expressed on IE. Here, we assessed the immune pressure on parasites infecting infants using markers associated with the acquisition of naturally acquired immunity to surface antigens. We hypothesized that, if maternal antibodies to VSA imposed a selection pressure on parasites, then the expression of a relatively conserved subset of var genes called group A var genes in infants should change with waning maternal antibodies. To test this, we compared their expression in parasites from children between 0 and 12 months and above 12 months of age. The transcript quantity and the proportional expression of group A var subgroup, including those containing domain cassette 13, were positively associated with age during the first year of life, which contrasts with above 12 months. This was accompanied by a decline in infected erythrocyte surface antibodies and an increase in parasitemia during this period. The observed increase in group A var gene expression with age in the first year of life, when the maternal antibodies are waning and before acquisition of naturally acquired antibodies with repeated exposure, is consistent with the idea that maternally acquired antibodies impose a selection pressure on parasites that infect infants and may play a role in protecting these infants against severe malaria.

Background Sarcomatoid carcinoma, or carcinosarcoma, is a neoplasm that contains both sarcomatous and carcinomatous elements. It is an extremely rare cancer most often arising from visceral organs. Here we report the seventh documented de novo case of carcinosarcoma of the bone, in a young female who showed initial clinical improvement with gemcitabine and docetaxel. Case presentation A 36-year-old Caucasian female presented with diffuse musculoskeletal pain that had progressed from her shoulder to her back, arm, and knee over 6 months. Imaging revealed diffuse sclerotic lesions of bilateral humeral heads, iliac and ischial bones, and thoracic and lumbar spine. Histopathologic examination of biopsies from the T9 vertebra and left femur showed mainly sarcomatous spindle cells with focal osteoid production. Immunostaining showed the cells to be OSCAR cytokeratin, patchy positive for pankeratin, and negative for CK7, GATA3, S100, SOX10, CD99, EMA, AE1/AE3, and HMW keratin indicative of an epithelial origin. After thorough clinical correlation, sarcomatoid carcinoma of a visceral organ was excluded and the diagnosis of primary sarcomatoid carcinoma of the bone was ultimately favored. She received chemotherapy with gemcitabine and docetaxel, and showed improvement at 6 months but ultimately passed 1 year post diagnosis. Conclusions Primary carcinosarcoma of the bone is an extremely rare malignancy. Early diagnosis is crucial as localized disease may be curable with resection. As shown in this case, combination chemotherapy with gemcitabine and docetaxel is a potential option in patients with unresectable or metastatic disease.

Angiosarcomas account about 2-3% of adult soft tissue sarcomas. This is a rare form of malignancy with remarkable clinical heterogeneity in term of presentation and behavior and can occur in any location of the body. Although radiation and chemotherapy are the usual form of therapy, frequent recurrence and metastasis is observed. The prognosis of angiosarcoma is relatively poor, and the overall 5-year survival rate is approximately 35%. Previous studies have shown the SDF-1 (stromal derived factor-1)/CXCR4 pathway is involved in the progression and the metastasis of angiosarcoma. CXCR4 is a chemokine receptor involved in metastatic spread of malignant tumors and is upregulated by many factors, including hypoxia and the histone methyltransferase EZH2. CXCR4 in turn activates the JAK/STAT3 pathway, which regulates the immune environment by inducing an infiltrate of tumor associated macrophages (TAMs) of the M2 (immunosuppressive) phenotype. Sarcomas in general have increased TAMs of the M2 phenotype and accumulating evidence indicates that a high number of TAMs are associated with an unfavorable prognosis in a variety of malignancies including angiosarcoma. The monocyte chemokine CCL2 has already been documented previously in canine hemangiosarcoma as one of the primary chemoattractants for M2 macrophages. The SDF-1/CXCR4 pathway has also been documented in other malignancies as a regulator of M2 macrophage infiltration and the immunosuppressive environment. It has also been reported that blockade of CXCR4 selectively reduces M2-polarized macrophages. We studied the expression of EZH2, p-STAT3, CXCR4, and CD163 (M2 macrophage marker), in four known cases of angiosarcoma. Two cases involved right lower leg soft tissue and two cases involved tissues from aortic wall. In all of our four cases the tumor cells of angiosarcoma stained positive for EZH2, p-STAT3, CXCR4, and CD163. This supports our hypothesis that indeed in angiosarcoma the M2 macrophages has an association with CXCR4 and pSTAT3. Clinical implications of this are that plerixafor or other CXCR4 antagonists could be used to treat angiosarcoma. By blocking CXCR4, the progression and metastasis of angiosarcoma could be abrogated and the immunosuppressive environment can be normalized. Our study indicates that CXCR4 could be considered a therapeutic target in angiosarcoma and the CXCR4 antagonist plerixafor should be further investigated as a potential agent to improve patient outcomes. Citation Format: Anindita Ghosh, Robert E. Brown, Joan M. Bull, Shaimaa M. Elzamly, Jamie J. Buryanek. CXCR4 as a therapeutic target in angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2692.

Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling. Observational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence. Overall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation. This is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.

Background: Systemic inflammation has been implicated in tumor growth, symptoms of cancer including cachexia and pain, as well as shortened survival. Advanced Lung Cancer Inflammation Index (ALI) is a simple tool for assessing systemic inflammation and has been shown to predict outcome in variety of thoracic malignancies including NSCLC. The purpose of this study was to assess if ALI is a predictive biomarker for checkpoint inhibitors in patients with metastatic NSCLC. Methods: We evaluated all patients with metastatic NSCLC treated with checkpoint inhibitors (CPI) at our institute between Jan 1st 2015 and June 30th 2019. ALI was calculated (BMI x Alb / NLR) at the time of initiating CPI using patients Body Mass Index (BMI), serum Albumin (Alb), and Neutrophil Lymphocyte Ratio (NLR) to quantify the degree of systemic inflammation. Patients were divided into two groups, based on ALI: ALI < 15 (indicating a relatively high degree of systemic inflammation), and ALI > 15 (indicating a relatively low degree of systemic inflammation). Primary end point was progression-free survival (PFS). Secondary endpoint included overall survival (OS), response rates, and adverse events (AE) from immunotherapy. Chi-squared test was performed to compare clinical characteristics in different groups. Kaplan-Meier and Cox regression model were used to determine independent prognostic factors. Results: A total of 79 patients were included in the final analysis. The median age was 66. There were 39 males and 40 females. Ethnicities included White (n=40), African American (n=17), and Asian (n=6). Sixty-six had adenocarcinoma, 9 had Squamous cell carcinoma, 2 had neuroendocrine carcinoma, and 11 were NSCLC, Not otherwise specified NOS. Pembrolizumab was used in 43 patients with or without chemotherapy, nivolumab in 34 with and without chemotherapy and durvalumab in 2 patients. PDL-1 expression was available in forty-seven (59%) patients,14 had >50% PDL-1 expression, 27 had (1 - 49%), and 6 had < 1% or none. Thirteen patients had complete response (CR) on first assessment after immunotherapy, 23 had partial response (PR), 9 had stable disease or mixed response, 28 had progression, and 6 could not be assessed due to lack of follow up scan. Thirty-two had an ALI < 15, and 47 had ALI > 15. Patients with ALI > 15 had a significantly longer PFS compared to those with ALI < 15 (7.57 vs 3.17 months, p = 0.0018). Similarly, Patients with ALI > 15 had a significantly longer OS (17.60 vs 6.37 months, p = 0.002) than those with ALI < 15. Of the 43 patients who were treated with Pembrolizumab +/- chemotherapy, 18 had an ALI < 15 and 25 had an ALI > 15, there was no difference in PFS or OS based on ALI. In contrast, amongst those who received nivolumab +/- chemotherapy (n=34), patients with ALI > 15 (n=?) had significantly longer PFS (14.7 vs 6.22 months, p = 0.01), as well as OS (19.68 vs 9.75 months, p = 0.004). Thirty-seven patients had reported AE from immunotherapy. Most common was fatigue (n=17, 21.52%). Others included anorexia (n=4, 5.06%), elevated Liver Function Tests (n=2, 2.53%), and Thrombocytopenia (n=2, 2.53%). Conclusion: ALI is easy to calculate clinical tool which can help predict response to checkpoint inhibitors in patients with metastatic lung cancer especially in those receiving nivolumab. This should be further validated in a larger prospective study. Citation Format: Wei Yang, Avery M. Trudell, Joan M. Bull, Jafri H. Syed. Advanced lung cancer index at diagnosis is a predicative factor in immunotherapy recipients with stage IV non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 791.

Aims: The recently sequenced Burkholderia mesoacidophila (previously Pseudomonas mesoacidophila) is a soil organism and as such will be exposed to multiple concurrent stresses in the natural environment. The combinatorial stress potentially experienced by microbes in soil has not been investigated in detail. Methods and Results: The impact of combinatorial stress on growth was investigated using tripartite variables—temperature, nutritional environment and either osmotic or oxidative stress. In nutritionally stringent conditions, increasing diamide concentration had no effect on growth while increasing H2O2 concentration reduced both growth rate and maximum density. Metabolomic studies with oxidative stress revealed specific (unidentified) metabolites associated with diamide tolerance, and an overwhelming dominance of sugars and sugar alcohols in nutritionally stringent conditions with and without the additional stressor. Conclusions: Combinatorial stress tolerance is complex. Temperature had the greatest independent impact on growth, while the impact of the nutritional environment played a key role in oxidative stress tolerance. In nutritionally stringent conditions, the metabolome suggested different tolerance mechanisms for different types of oxidative stress. Significance and Impact of the Study: This work demonstrates the specificity of the stress response, and the need to consider multiple environmental factors to meaningfully investigate tolerance. Both environmental and clinical settings subject bacteria to combinatorial stress and this should be considered in the design of further studies.

Background: Although thousands of clinical isolates of Plasmodium falciparum are being sequenced and analysed by short read technology, the data do not resolve the highly variable subtelomeric regions of the genomes that contain polymorphic gene families involved in immune evasion and pathogenesis. There is also no current standard definition of the boundaries of these variable subtelomeric regions. Methods: Using long-read sequence data (Pacific Biosciences SMRT technology), we assembled and annotated the genomes of 15 P. falciparum isolates, ten of which are newly cultured clinical isolates. We performed comparative analysis of the entire genome with particular emphasis on the subtelomeric regions and the internal var genes clusters. Results: The nearly complete sequence of these 15 isolates has enabled us to define a highly conserved core genome, to delineate the boundaries of the subtelomeric regions, and to compare these across isolates. We found highly structured variable regions in the genome. Some exported gene families purportedly involved in release of merozoites show copy number variation. As an example of ongoing genome evolution, we found a novel CLAG gene in six isolates. We also found a novel gene that was relatively enriched in the South East Asian isolates compared to those from Africa. Conclusions: These 15 manually curated new reference genome sequences with their nearly complete subtelomeric regions and fully assembled genes are an important new resource for the malaria research community. We report the overall conserved structure and pattern of important gene families and the more clearly defined subtelomeric regions.