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Abstract Introduction The novel Confirm Rx™ implantable cardiac monitor (ICM) with SharpSense™ technology incorporates a new P‐wave discriminator designed to improve AF detection. This study aimed to evaluate the diagnostic performance of the Confirm Rx™ ICM in detecting AF episodes of varying durations. Methods We conducted a multicenter retrospective analysis of consecutive patients implanted with a Confirm Rx™ ICM (v1.2) across nine UK hospitals, all with documented AF lasting at least 6 min. Electrocardiograms (ECGs) were manually adjudicated by cardiologists. To account for intra‐ and inter‐reviewer variability, a random sample of 10% of ECGs underwent additional review. Disagreements were resolved by a third reviewer. Diagnostic performance was determined by calculating the gross and patient‐averaged positive predictive value (PPV) for AF episodes of different duration. The source of false positive (FP) detection was also categorized. Results Overall, 16,230 individual ECGs from 232 patients were included. The median AF episode duration was 14 min. R‐wave amplitude remained stable during follow‐up (0.52 ± 0.27 mV [initial] vs. 0.54 ± 0.29 mV [end of follow‐up], p = .10). The gross and patient‐averaged PPV were 75.0% and 67.0%, respectively. Diagnostic performance (gross) increased with progressively longer AF episodes: 88.0% for ≥1 h, 97.3% for 6 h, and 100% for 24 h. The main source of FP during tachycardia was T‐wave oversensing (54.2%), while in non‐tachycardic episodes it was predominantly ectopy (71.2%). The AF burden precision was excellent (93.3%). Conclusion The Confirm Rx™ ICM diagnostic performance was modest for all AF episodes (75%), with accuracy increasing for longer AF episodes.

Abstract Background Alzheimer’s disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. Methods The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. Results We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. Conclusions We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. Trial registration The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23–09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.

CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy. Results from a panel of in vivo and ex vivo 3D tumor models imply that, beyond driving CD8+ T cells into T-cell exhaustion, a major role of PD-1 and CTLA-4 is in limiting the CXCR3-based self-feeding mechanism of T cell potentiation. This may explain why patients that are CXCL9/CXCL10high tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10low. It also suggests a therapeutic role for CXCL9-Fc or CXCL10-Fc therapy; herein we demonstrate significant anti-tumor activity in multiple murine tumor models with such agents.

The brain-derived neurotrophic factor (BDNF) gene plays an important role in modulating the stress-response axis and inflammation, which can be regulated by epigenetic mechanisms. BNDF methylation has been associated with stress-related psychiatric disorders such as depression, anxiety and post-traumatic stress. Previous studies have reported that stressful events are involved with long-lasting alterations in DNA methylation (DNAm) of the BNDF exon IV promoter, suggesting that glucocorticoids and inflammatory cytokines can regulate this process. We previously found that perceived psychological stress is modulated by inflammatory cytokines, such as interleukin (IL)-6, IL-8 and IL-10, and IL-12p70, suggesting their role in mediating the stress response. However, the epigenetic mechanism mediating this response has yet to be fully understood. In this study, we propose that high perceived stress and high serum levels of inflammatory cytokines may correlate with specific methylation sites within the BNDF exon IV promoter. To address these questions, we conducted a cross-sectional study of 82 adult women teachers working in basic education in Brazil. The perceived stress scale was used to assess stress and blood samples were collected for the measurement of inflammatory markers and BNDF methylation through flow cytometry assay and DNA pyrosequencing, respectively. We detected differentially methylated CpG sites in the BNDF gene, where 5 CpG sites were directly correlated with high stress levels. However, 4 CpG sites showed inverse effects, indicating that changes in methylation levels in those sites could lead to a protective effect on perceived stress. About inflammatory markers, IL-6 and IL-8 were associated with high perceived stress. However, only IL-8 and IL-10 showed simultaneous modulation of perceived stress, while IL-10 and IL12p70 correlated with DNAm. We found that higher levels in IL-10 and IL-12p70 serum decrease methylation in CpG11. A direct relationship was also found to IL-12p70, where higher levels in serum increase methylation in CpG5 and 13, respectively. Taken as a whole, our findings reinforce the hypothesis regarding stress-sensitive regions within the BDNF gene, mainly for CpG5, 11, and 13. In addition to these results, CpG7 and 9 may be regarded as stress-protective regions. Our data suggest that BDNF DNAm in the blood may represent a novel biomarker for early detection of adverse effects of chronic exposure to stress in healthy individuals.

Governance of the ocean and its biodiversity is deeply entangled within social, political and cultural histories. The evolution of marine science has been subject to similar influences, and we (the authors) consider these factors to create, embed and reinforce knowledge hierarchies in ocean governance processes and associated research that set societal patterns of prioritisation and exclusion. Such knowledge hierarchies have constructed dominant Western-oriented knowledge systems as ‘rational’ and ‘objective’ approaches to environmental governance in contrast to non-Western knowledge systems and have led to a dominance of natural (normal) sciences over centralised biodiversity governance. The extraction and incorporation of traditional knowledge into the Western-oriented scientific canon through myriad historical and contemporary processes in ocean biodiversity governance often reproduce knowledge hierarchies, do not benefit knowledge holders and are often considered incomplete, inappropriate or absent. As we address current ocean biodiversity and conservation challenges, researchers must be aware of the history of knowledge extraction, impositions and assumptions within their fields. Researchers must also actively acknowledge and address these histories in their work to avoid marginalisation and support ethical, empathetic, and rigorous knowledge production that meets the needs of society. In this paper, through a development of the concept of knowledge hierarchies, we explore case studies of research diverse in geography and discipline ranging from action research in Namibia, the application of arts-based methodologies in legal proceedings to research focused at an international level, and the concept of ocean literacies, all of which are located under the umbrella of a project specifically targeting transformative ocean governance. It becomes evident that knowledge hierarchies are multi-layered, perpetuating, and often reproduced even when attempting to address hierarchies through such methods as the integration or ‘bringing together’ of diverse knowledge systems. Effective change will therefore require sensitive and multi-faceted approaches to knowledge hierarchies, including processes of embracing discomfort, which will be important to work with, as well as through. While there will be continued tensions between hierarchies, it is a sine qua non that researchers need to build a commitment to understanding where powers lie, rather than ignoring such imbalances or, similarly, by idealising approaches.

Background Reversible airway obstruction is common in children with primary ciliary dyskinesia. However, the diagnostic value of adding bronchodilator (BD) response testing to routine spirometry is unclear. Methods This is a retrospective analysis of pulmonary function test results obtained from children with primary ciliary dyskinesia seen as outpatients at the Hospital for Sick Children, Toronto. Spirometry results were collected for every appointment with BD response testing (“Visit”, with pre-BD and post-BD measurements) as well as for the previous (“Baseline”) and following (“Follow-up”) encounters. Results A positive BD response was seen in 86 out of 474 (18.1%) of the pulmonary function tests from 82 children with primary ciliary dyskinesia. BD responsiveness was associated with a significant absolute change (±sd) in % predicted forced expiratory volume in 1 s (FEV1) from Baseline to Visit pre-BD (−6.5±10.3%, p

The COVID-19 pandemic has highlighted the need for priority setting in health financing and resource allocation, spotlighting the limitations of traditional health financing strategies. This commentary explores the relevance of mathematical modeling in enhancing allocative efficiency within the health sector, especially in the aftermath of the pandemic. We draw from the World Bank’s experiences in supporting over 20 countries to employ mathematical optimization models for priority setting, aiming to achieve optimal health outcomes within constrained budgets. The pandemic’s impact on economic growth, revenue collection, debt stress, and the overall fiscal space available for health financing has necessitated a paradigm shift toward prioritizing efficiency improvements in health service delivery. We outline lessons learned from such modeling and chart future directions to enhance efficiency gains, including for integrated, patient-centered approaches to health service delivery. We advocate for flexible and effective localized priority-setting, leveraging data-driven insights to navigate the complexities of health financing in a post-COVID era.

AbstractIntroduction The aim of this study was to assess the safety of bronchoscopic microwave ablation (MWA) of peripheral lung parenchyma using the NEUWAVE™ FLEX Microwave Ablation System, and robotic-assisted bronchoscopy (RAB) using the MONARCH™ Platform in a swine model.Methods Computed tomography (CT)-guided RAB MWA was performed in the peripheral lung parenchyma of 17 Yorkshire swine (40–50 kg) and procedural adverse events (AEs) documented. The acute group (day 0, n = 5) received 4 MWAs at 100 W for 1, 3, 5, and 10 min in 4 different lung lobes. Subacute and chronic groups (days 3 and 30, n = 6 each) received one MWA (100 W, 10 min) per animal.Results The study was completed without major procedural complications. No postprocedural AEs including death, pneumothorax, bronchopleural fistula, hemothorax, or pleural effusions were observed. No gross or histological findings suggestive of thromboembolism were found in any organ. One 3-Day and one 30-Day swine exhibited coughing that required no medication (minor AEs), and one 30-Day animal required antibiotic medication (major AE) for a suspected lower respiratory tract infection that subsided after two weeks. CT-based volumetric estimates of ablation zones in the acute group increased in an ablation time-dependent (1–10 min) manner, whereas macroscopy-based estimates showed an increasing trend in ablation zone size.Conclusion The NEUWAVE FLEX and MONARCH devices were safely used to perform single or multiple RAB MWAs. The preclinical procedural safety profile of RAB MWA supports clinical research of both devices to investigate efficacy in select patients with oligometastatic disease or primary NSCLC.

This research examines the prevalence of research software as independent records of output within UK academic institutional repositories (IRs). There has been a steep decline in numbers of research software submissions to the UK’s Research Excellence Framework from 2008 to 2021, but there has been no investigation into whether and how the official academic IRs have affected the low return rates. In what we believe to be the first such census of its kind, we queried the 182 online repositories of 157 UK universities. Our findings show that the prevalence of software within UK Academic IRs is incredibly low. Fewer than 28% contain software as recognised academic output. Of greater concern, we found that over 63% of repositories do not currently record software as a type of research output and that several Universities appeared to have removed software as a defined type from default settings of their repository. We also explored potential correlations, such as being a member of the Russell group, but found no correlation between these metadata and prevalence of records of software. Finally, we discuss the implications of these findings with regards to the lack of recognition of software as a discrete research output in institutions, despite the opposite being mandated by funders, and we make recommendations for changes in policies and operating procedures.

BackgroundLong-lasting insecticidal nets (LLINs) are a key vector control tool used for the prevention of malaria. Active ingredient (AI) measurements in LLINs are essential for evaluating their quality and efficacy. The main aim of the present study was to determine the utility of X-ray fluorescence (XRF) spectroscopy as a suitable field-deployable tool for total AI quantification in LLINs.MethodsNew and unused LLIN samples containing deltamethrin (PermaNet® 2.0, n = 35) and alpha-cypermethrin (SafeNet®, n = 43) were obtained from batches delivered to Papua New Guinea (PNG) for mass distribution. Insecticides were extracted from the LLINs using a simple extraction technique and quantified using liquid chromatography mass spectrometry (LC-MS). The LC-MS results were correlated with XRF spectroscopy measurements on the same nets. Operators were blinded regarding the type of net. Bioefficacy of the LLIN samples was tested using WHO cone bioassays and test results were correlated with total AI content.ResultsThe results indicate correlation between quantitative XRF and LC-MS. Interestingly, the total AI content was negatively correlated with bioefficacy in PermaNet® 2.0 (especially in recently manufactured nets). In contrast, AI content was positively correlated with bioefficacy in SafeNet®. These results indicate that the chemical content analysis in predelivery inspections does not always predict bioefficacy.ConclusionXRF is a promising field-deployable tool for quantification of both deltamethrin- and alpha-cypermethrin-coated LLINs. Because total AI content is not always a predictor of the efficacy of LLINs to kill mosquitoes, bioefficacy measurements should be included in predelivery inspections.

Since peatlands cover around 20 % of the land area in the Republic of Ireland, their management is of particular significance in reducing national greenhouse gases (GHG) emissions. We reviewed peatland carbon (C) flux studies within Ireland, extracting data for carbon dioxide, methane, and nitrous oxide fluxes, as well as fluvial losses and here propose preliminary country-specific emission factors (EFs) for various peatland land uses and management practices. Using our derived EFs and latest areal estimates, national emissions from peatlands (excluding horticulture and combustion) amount to 1.9 Mt C y-¹ (± 0.4–3.4 Mt C y-¹), with more than half of all peatland GHG emissions coming from grasslands on organic soils and over one-third from domestic extraction drained peatlands. Our analyses suggest that peatland management through rewetting and restoration has the potential to substantially reduce emissions from drained peatlands, and this article attempts to quantify this reduction. This is critically important given the large areas of degraded peatlands that have been earmarked for rewetting in the next decade.

Abstract Background Mouse is probably the most important model organism to study mammal biology and human diseases. A better understanding of the mouse genome will help understand the human genome, biology and diseases. However, despite the recent progress, the characterization of the regulatory sequences in the mouse genome is still far from complete, limiting its use to understand the regulatory sequences in the human genome. Results Here, by integrating binding peaks in ~ 9,000 transcription factor (TF) ChIP-seq datasets that cover 79.9% of the mouse mappable genome using an efficient pipeline, we were able to partition these binding peak-covered genome regions into a cis-regulatory module (CRM) candidate (CRMC) set and a non-CRMC set. The CRMCs contain 912,197 putative CRMs and 38,554,729 TF binding sites (TFBSs) islands, covering 55.5% and 24.4% of the mappable genome, respectively. The CRMCs tend to be under strong evolutionary constraints, indicating that they are likely cis-regulatory; while the non-CRMCs are largely selectively neutral, indicating that they are unlikely cis-regulatory. Based on evolutionary profiles of the genome positions, we further estimated that 63.8% and 27.4% of the mouse genome might code for CRMs and TFBSs, respectively. Conclusions Validation using experimental data suggests that at least most of the CRMCs are authentic. Thus, this unprecedentedly comprehensive map of CRMs and TFBSs can be a good resource to guide experimental studies of regulatory genomes in mice and humans.

Abstract European hedgehogs, Erinaceus europaeus (Linnaeus, 1758), are small mammals found in western Europe and also in parts of northern Europe. They can be seen in rural, suburban and urban areas, but are usually found in grassland with edge habitats. These animals are omnivorous and serve as definitive or paratenic hosts for several parasites, including acanthocephalans (phylum Acanthocephala). During necropsy of a European hedgehog, a single adult parasite was collected from the intestinal lumen and preserved in 70% ethanol. After morphological evaluation of the specimen, it was identified as Moniliformis cestodiformis (von Linstow, 1904) (Acanthocephala: Moniliformidae). This is the first report of M. cestodiformis in a European hedgehog, as well as in Europe. More epidemiological studies need to be carried out to map the location and prevalence of this parasite in Portugal and the European continent.

Abstract Background Therapeutic agents stimulating the process of myelination could be beneficial for the treatment of demyelinating diseases, such as multiple sclerosis. The efficient translation of compounds promoting myelination in vitro to efficacy in vivo is inherently time-consuming and expensive. Thyroid hormones accelerate the differentiation and maturation of oligodendrocytes, thereby promoting myelination. Systemic administration of the thyroid hormone thyroxine (T4) accelerates brain maturation, including myelination, during early postnatal development. The objective of this study was to validate an animal model for rapid testing of promyelinating therapeutic candidates for their effects on early postnatal development by using T4 as a reference compound. Methods Daily subcutaneous injections of T4 were given to Sprague Dawley rat pups from postnatal day (PND) 2 to PND10. Changes in white matter were determined at PND10 using diffusion tensor magnetic resonance imaging (DTI). Temporal changes in myelination from PND3 to PND11 were also assessed by quantifying myelin basic protein (MBP) expression levels in the brain using the resonance Raman spectroscopy/enzyme-linked immunosorbent assay (RRS-ELISA) and quantitative immunohistochemistry. Results DTI of white matter tracts showed significantly higher fractional anisotropy in the internal capsule of T4-treated rat pups. The distribution of total FA values in the forebrain was significantly shifted towards higher values in the T4-treated group, suggesting increased myelination. In vivo imaging data were supported by in vitro observations, as T4 administration significantly potentiated the developmental increase in MBP levels in brain lysates starting from PND8. MBP levels in the brain of animals that received treatment for 9 days correlated with the FA metric determined in the same pups in vivo a day earlier. Furthermore, accelerated developmental myelination following T4 administration was confirmed by immunohistochemical staining for MBP in coronal brain sections of treated rat pups. Conclusions T4-treated rat pups had increased MBP expression levels and higher MRI fractional anisotropy values, both indications of accelerated myelination. This simple developmental myelination model affords a rapid test of promyelinating activity in vivo within several days, which could facilitate in vivo prescreening of candidate therapeutic compounds for developmental hypomyelinating diseases. Further research will be necessary to assess the utility of this platform for screening promyelination compounds in more complex demyelination disease models, such us multiple sclerosis.

Abstract Titanium alloys, in particular, medical-grade Ti-6Al-4 V, are heavily used in orthopaedic applications due to their high moduli, strength, and biocompatibility. Implant infection can result in biofilm formation and failure of prosthesis. The formation of a biofilm on implants protects bacteria from antibiotics and the immune response, resulting in the propagation of the infection and ultimately resulting in device failure. Recently, slippery liquid-infused surfaces (LIS) have been investigated for their stable liquid interface, which provides excellent repellent properties to suppress biofilm formation. One of the current limitations of LIS coatings lies in the indistinctive repellency of bone cells in orthopaedic applications, resulting in poor tissue integration and bone ingrowth with the implant. Here, we report a chitosan impregnated LIS coating that facilitates cell adhesion while preventing biofilm formation. The fabricated coating displayed high contact angles (108.2 ± 5.2°) and low sliding angles (3.56 ± 4.3°). Elemental analysis obtained using X-ray photoelectron spectroscopy (XPS) confirmed the availability of fluorine and nitrogen, indicating the presence of fluorosilane and chitosan in the final coating. Furthermore, our results suggest that chitosan-conjugated LIS increased cell adhesion of osteoblast-like SaOS-2 cells and significantly promoted proliferation (a fourfold increase at 7-day incubation) compared to conventional titanium liquid-infused surfaces. Furthermore, the chitosan conjugated LIS significantly reduced biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) by up to 50% and 75% when compared to untreated titanium and chitosan-coated titanium, respectively. The engineered coating can be easily modified with other biopolymers or capture molecules to be applied to other biomaterials where tissue integration and biofilm prevention are needed.

The Karner blue butterfly (Lycaeides melissa samuelis, or Kbb), a federally endangered species under the U.S. Endangered Species Act in decline due to habitat loss, can be further threatened by climate change. Evaluating how climate shapes the population trend of the Kbb can help in the development of adaptive management plans. Current demographic models for the Kbb incorporate in either a density-dependent or density-independent manner. We instead created mixed density-dependent and -independent (hereafter "endo-exogenous") models for Kbbs based on long-term count data of five isolated populations in the upper Midwest, United States during two flight periods (May to June and July to August) to understand how the growth rates were related to previous population densities and abiotic environmental conditions, including various macro- and micro-climatic variables. Our endo-exogenous extinction risk models showed that both density-dependent and -independent components were vital drivers of the historical population trends. However, climate change impacts were not always detrimental to Kbbs. Despite the decrease of population growth rate with higher overwinter temperatures and spring precipitations in the first generation, the growth rate increased with higher summer temperatures and precipitations in the second generation. We concluded that finer spatiotemporally scaled models could be more rewarding in guiding the decision-making process of Kbb restoration under climate change.

Abstract Background Body weight (BW) is an economically important trait in the broiler (meat-type chickens) industry. Under the assumption of polygenicity, a “large” number of genes with “small” effects is expected to control BW. To detect such effects, a large sample size is required in genome-wide association studies (GWAS). Our objective was to conduct a GWAS for BW measured at 35 days of age with a large sample size. Methods The GWAS included 137,343 broilers spanning 15 pedigree generations and 392,295 imputed single nucleotide polymorphisms (SNPs). A false discovery rate of 1% was adopted to account for multiple testing when declaring significant SNPs. A Bayesian ridge regression model was implemented, using AlphaBayes, to estimate the contribution to the total genetic variance of each region harbouring significant SNPs (1 Mb up/downstream) and the combined regions harbouring non-significant SNPs. Results GWAS revealed 25 genomic regions harbouring 96 significant SNPs on 13 Gallus gallus autosomes (GGA1 to 4, 8, 10 to 15, 19 and 27), with the strongest associations on GGA4 at 65.67–66.31 Mb (Galgal4 assembly). The association of these regions points to several strong candidate genes including: (i) growth factors (GGA1, 4, 8, 13 and 14); (ii) leptin receptor overlapping transcript (LEPROT)/leptin receptor (LEPR) locus (GGA8), and the STAT3/STAT5B locus (GGA27), in connection with the JAK/STAT signalling pathway; (iii) T-box gene (TBX3/TBX5) on GGA15 and CHST11 (GGA1), which are both related to heart/skeleton development); and (iv) PLAG1 (GGA2). Combined together, these 25 genomic regions explained ~ 30% of the total genetic variance. The region harbouring significant SNPs that explained the largest portion of the total genetic variance (4.37%) was on GGA4 (~ 65.67–66.31 Mb). Conclusions To the best of our knowledge, this is the largest GWAS that has been conducted for BW in chicken to date. In spite of the identified regions, which showed a strong association with BW, the high proportion of genetic variance attributed to regions harbouring non-significant SNPs supports the hypothesis that the genetic architecture of BW35 is polygenic and complex. Our results also suggest that a large sample size will be required for future GWAS of BW35.

Bird and bat turbine collision fatalities are a principal biodiversity impact at wind energy facilities. Raptors are a group at particular risk and often the focus of post-construction fatality monitoring programs. To estimate fatalities from detected carcasses requires correction for biases, including for carcasses that are removed or decompose before the following search. This is addressed through persistence trials, where carcasses are monitored until no longer detectable or the trial ends. Sourcing sufficient raptor carcasses for trials is challenging and surrogates that are typically used often have shorter persistence times than raptors. We collated information from raptor carcass persistence trials to evaluate consistencies between trials and assess the implications of using persistence values from other studies in wind facility fatality estimates. We compiled individual raptor carcass persistence times from published sources along with information on methods and location, estimated carcass persistence using GenEst and ran full fatality estimates using the carcass persistence estimates and mock datasets for other information. We compiled results from 22 trials from 17 sites across four terrestrial biomes, with trials lasting between 7 and 365 days and involving between 11 and 115 carcasses. Median carcass persistence was estimated at 420 days (90% confidence interval (CI) of 290 to 607 days) for the full dataset. Persistence time varied significantly between trials (trial-specific persistence estimates of 14 (5–42) days to 1,586 (816–3,084) days) but not between terrestrial biomes. We also found no significant relationship between either the number of carcasses in the trial or trial duration and estimated carcass persistence. Using a mock dataset with 12 observed fatalities, we estimated annual fatalities of 25 (16–33) or 26 (17–36) individuals using a 14- or 28-day search interval respectively using global dataset. When using trial-specific carcass persistence estimates and the same mock dataset, estimated annual fatalities ranged from 22 (14–30) to 37 (21–63) individuals for a 14-day search interval, and from 22 (15–31) to 47 (26–84) individuals for a 28-day search interval. The different raptor carcass persistence rates between trials translated to small effects on fatality estimates when using recommended search frequencies, since persistence rates were generally much longer than the search interval. When threatened raptor species, or raptors of particular concern to stakeholders are present, and no site-specific carcass persistence estimates are available, projects should use the lowest median carcass persistence estimate from this study to provide precautionary estimates of fatalities. At sites without threatened species, or where the risk of collision to raptors is low, the global median carcass persistence estimate from this review could be used to provide a plausible estimate for annual raptor fatalities.

Introduction With limited resources, attaining maximal average health service coverage can be at odds with maximising equity which attempts to promote greater reach among underserved populations. In this study, we examined the trade-offs in immunisation coverage levels and equity for children under 5 years of age in Pakistan across various subpopulations who can be targeted with different combinations of immunisation service modalities.Methods We conducted a detailed costing exercise across 16 geographically and demographically diverse districts in Pakistan. These data were the basis for (a) technical efficiency benchmarking via Data Envelopment Analysis to identify potential efficiency gains by location, delivery model and cost ingredient; (b) allocative efficiency optimisation modelling to understand how resource allocations could be optimised and to devise recommended budget allocations and operational metrics. Finally, the hypothetical overall efficiency gains attainable were estimated if available resources were allocated with the optimal emphases, and if service delivery models operated at productivity levels at the benchmarked frontier of efficiency.Results Benchmarking suggests that ~44% of delivery models are running efficiently and 37% are highly inefficient. While coverage and equity are usually at odds, surprisingly, the optimisation modelling revealed that substantial improvements in equity between subpopulations does not necessarily cost very much in overall immunisation coverage: theoretically, equity can be achieved while still attaining close to maximal immunisation coverage. Overall, analyses suggest greater emphases should be placed on outreach delivery models which particularly target rural areas and slum populations.Conclusion The unit cost differentials within districts are not sufficiently large for there to be a large reduction in potential Fully Immunised Children coverage if one focuses on maximising equity. However, reallocations of programme budgets can have a significant impact on equity outcomes, particularly at current low spending amounts. Therefore, it is recommended to address equity as the key objective in national immunisation programming.

Introduction Incentives conditional on school attendance or on remaining free of sexually transmitted infections have produced mixed results in reducing HIV incidence.Methods HIV-negative adolescent girls and young women aged 15–22%–50% of whom were out of school—were recruited from 293 clusters in Eswatini from urban (30%) and rural areas (70%).Financial incentives conditional on education attendance were randomly allocated at the cluster level. All participants were further individually randomised into eligibility for a raffle incentive conditional on random selection into the raffle, on negative tests for syphilis and Trichomonas vaginalis and on being a raffle winner, creating four subarms in a 2×2 factorial design: no-intervention, raffle incentive, education incentive and raffle & education incentive. Randomisation was unblinded to participants.Logistic regressions were used in intention-to-treat analysis of HIV incidence over 3 years to estimate the impact of incentives conditional on school attendance and raffle incentives conditional on remaining sexually transmitted infection free.Results The study recruited 4389 HIV-negative participants, who were distributed into four subarms: no intervention (n=1068), raffle incentive (n=1162), education incentive (n=1088) and raffle and education incentive (n=1071).At endline, 272 participants from 3772 for whom endline data were collected, tested positive for HIV. HIV incidence among participants in education treatment arm was significantly lower than in the education control arm, 6.34% (119/1878) versus 8.08% (153/1894) (p=0.041); OR: 0.766 (0.598 to 0.981); adjusted OR (aOR): 0.754 (0.585 to 0.972). Compared with the no intervention subarm, HIV incidence in the raffle and education incentive subarm was significantly lower, 5.79% (54/878) versus 8.84% (80/905); OR: 0.634 (0.443 to 0.907); aOR: 0.622 (0.433 to 0.893), while it was not significantly lower in the raffle incentive subarm.Conclusion Financial incentives conditional on education participation significantly reduced HIV infection among adolescent girls and young women in Eswatini and appear to be a promising tool for prevention in high HIV prevalence settings.Trial registration number Western Institutional Review Board—protocol number 20 141 630.Eswatini National Health Research Review Board—FWA00026661.Pan African Clinical Trials Registry—PACTR201811609257043.

Abstract Background Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. Methods Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. Results Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). Conclusion The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. Trial registration details Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

The pelvis is a common site of metastatic bone disease. Peri-acetabular lesions are particularly challenging and can cause severe pain, disability and pathologic fractures. Surgical management of these lesions has historically consisted of cementoplasty for contained lesions and Harrington reconstructions for larger, more destructive lesions. Due to the limitations of these procedures, a number of novel procedures have been developed to manage this challenging problem. Percutaneous techniques—including acetabular screw fixation and cementoplasty augmented with screws—have been developed to minimize surgical morbidity. Recent literature has demonstrated a reliable reduction in pain and improvement in function in appropriately selected patients. Several adjuncts to the Harrington procedure have been utilized in recent years to reduce complication rates. The use of constrained liners and dual mobility bearings have reduced the historically high dislocation rates. Cage constructs and porous tantalum implants are becoming increasingly common in the management of large bony defects and destructive lesions. With novel and evolving surgical techniques, surgeons are presented with a variety of surgical options to manage this challenging condition. Physicians must take into account the patients’ overall health status, oncologic prognosis and anatomic location and extent of disease when developing an appropriate surgical plan.

Keynote panel from the 2012 National Outreach Scholarship Consortium Conference

Synovial sarcomas (SS) represent a unique subset of soft tissue sarcomas (STS) and account for 5–10% of all STS. Synovial sarcoma differs from other STS by the relatively young age at diagnosis and clinical presentation. Synovial sarcomas have unique genomic characteristics and are driven by a pathognomonic t(X;18) chromosomal translocation and subsequent formation of the SS18:SSX fusion oncogenes. Similar to other STS, diagnosis can be obtained from a combination of history, physical examination, magnetic resonance imaging, biopsy and subsequent pathology, immunohistochemistry and molecular analysis. Increasing size, age and tumor grade have been demonstrated to be negative predictive factors for both local disease recurrence and metastasis. Wide surgical excision remains the standard of care for definitive treatment with adjuvant radiation utilized for larger and deeper lesions. There remains controversy surrounding the role of chemotherapy in the treatment of SS and there appears to be survival benefit in certain populations. As the understanding of the molecular and immunologic characteristics of SS evolve, several potential systematic therapies have been proposed.

Abstract Introduction The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) randomized controlled trial (RCT) was the first study to prospectively enroll and randomize orthopedic oncology patients in multiple centers internationally. The objective of this study was to describe recruitment patterns, to examine the differences in enrollment across different PARITY sites, and to identify variables associated with differing levels of recruitment. Methods Data from this study was obtained from the PARITY trial Methods Center and records of correspondence between the Methods Center and recruiting sites. We performed descriptive statistics to report the recruitment patterns over time. We compared recruitment, time to set up, and time to enroll the first patient between North American and international sites, private and public healthcare models, and the presence or absence of research personnel. Two-tailed non-paired t tests were performed to test average monthly recruitment rates between groups. Results A total of 602 patients from 36 North American and 12 international sites were recruited from 2013 to 2019. North American sites were able to become fully enrollment-ready at an average of 19.5 months and international sites at an average of 27 months. Once enrolling, international sites were able to enroll 0.59 patients per/month whereas North American sites averaged a monthly recruitment rate of 0.2 patients/month once enrolling. Sites with research personnel reached enrollment-ready status at an average of 19.3 months and sites without research support at an average of 30.3 months. Once enrolling, the recruitment rate was 0.28 patients/month and 0.2 patients per month for sites with and without research support, respectively. Publicly funded sites had a monthly enrollment of 0.4 patients/month whereas privately funded sites had a monthly enrollment rate of 0.17 patients/month. Conclusions As a collaborative group, the PARITY investigators increased the pace of recruitment throughout the trial, likely by increasing the number of active sites. The longer time to start-up at international sites may be due to the complex governing regulations of pharmaceutical trials. Nevertheless, international sites should be considered essential as they recruited significantly more patients per month once active. The absence of research support personnel may lead to delays in the time to start-up. The results of the current study will provide guidance for choosing which sites to recruit for participation in future collaborative clinical trials in orthopedic oncology and other surgical specialties. Trial registration ClinicalTrials.gov NCT01479283 . Prospectively registered on November 24, 2011

Point absorber wave energy converter (WEC) control strategies often require accurate models for maximum energy extraction. While linear models are suitable for small motions, the focus is on the nonlinear model of an hour-glass shaped buoy undergoing large vertical displacements. Closed-form expressions for the static and dynamic Froude–Krylov forces are developed. It is shown that, in general, the dynamic and static forces are of similar magnitude, which is not the case for a spherical buoy. While the dynamic force reduces the amplitude of the net buoy force, its shape predicts a larger buoy response than if neglected, causing the nonlinear terms to have an even more significant effect. An input-state feedback linearizing controller is developed to show how the nonlinear model can be used in a control law. A 2.5 m buoy example is simulated to illustrate the approach of tracking an arbitrary displacement reference. For the case considered, the extracted power is 30% larger when the nonlinear dynamic FK force is used in the control law. The hourglass buoy is also compared to a spherical buoy to illustrate differences in their response to regular waves and energy extraction when using the same control laws. A spherical buoy diameter of 7.5 m was required to obtain the same power output as a 5 m tall hourglass buoy. A power-force-amplitude (PFA) metric is introduced to compare energy extraction performance and power take-off requirements. The hourglass buoy’s PFA was 13% larger than the spherical buoy implying that it can produce similar power but with less control effort.

Objective: To examine the effect of a mindfulness-based program specifically designed for teachers in reducing perceived stress and improving the quality of experienced emotion in female active working teachers. A second outcome evaluated is the associated change in cellular inflammatory activity, measured by peripheral blood levels of cytokines. Method: Eighty-eight female active teachers from public schools from São Paulo Municipality were recruited, and randomly allocated to an eight-week Mindfulness-Based Health Program for Educators (MBHP-Educa) or to Neuroscience for Education Program (Neuro-Educa: active control group). The venue of both programs were several public school facilities, where many of the teachers actually worked. Both groups received activities during eight weeks in a 2 ​h/week regimen, totalizing 16 ​h. Sixty-five participants completed the program and pre- and post-interventions measures were taken from the following scales: Interpersonal Multidimensional Reactivity Scale (IRI), Positive-and-Negative Affects Scale (PANAS), Perceived Stress Scale (PSS), Connor-Davidson Resilience Scale (CD-RISC), and a primary outcome in Ryff's Psychological Well-Being Scale (PBWS). At pre-and post-intervention, blood samples were collected for the measurement of several important inflammatory biomarkers, Tumor Necrosis Factor – α (TNF-α), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin 10 (IL-10) and Interleukin 12p70 (IL-12P70) through flow cytometry assay. Intervention effects were analyzed via Generalized mixed models (GLMM). Results: According to the GLMM, MBHP-Educa significantly reduced the scores of perceived stress (p ​

COVID-19 disease models have aided policymakers in low-and middle-income countries (LMICs) with many critical decisions. Many challenges remain surrounding their use, from inappropriate model selection and adoption, inadequate and untimely reporting of evidence, to the lack of iterative stakeholder engagement in policy formulation and deliberation. These issues can contribute to the misuse of models and hinder effective policy implementation. Without guidance on how to address such challenges, the true potential of such models may not be realised. The COVID-19 Multi-Model Comparison Collaboration (CMCC) was formed to address this gap. CMCC is a global collaboration between decision-makers from LMICs, modellers and researchers, and development partners. To understand the limitations of existing COVID-19 disease models (primarily from high income countries) and how they could be adequately support decision-making in LMICs, a desk review of modelling experience during the COVID-19 and past disease outbreaks, two online surveys, and regular online consultations were held among the collaborators. Three key recommendations from CMCC include: A ‘fitness-for-purpose’ flowchart, a tool that concurrently walks policymakers (or their advisors) and modellers through a model selection and development process. The flowchart is organised around the following: policy aims, modelling feasibility, model implementation, model reporting commitment. Holmdahl and Buckee (2020) A ‘reporting standards trajectory’, which includes three gradually increasing standard of reports, ‘minimum’, ‘acceptable’, and ‘ideal’, and seeks collaboration from funders, modellers, and decision-makers to enhance the quality of reports over time and accountability of researchers. Malla et al. (2018) A framework for “collaborative modelling for effective policy implementation and evaluation” which extends the definition of stakeholders to funders, ground-level implementers, public, and other researchers, and outlines how each can contribute to modelling. We advocate for standardisation of modelling processes and adoption of country-owned model through iterative stakeholder participation and discuss how they can enhance trust, accountability, and public ownership to decisions.

Recent research on growth machines, in a prominent theme, has focused on how mobilized discourses promote urban redevelopment projects. Pushed to the margins, in this work, has been the issue of how alternative growth visions and voices are silenced or muffled. This article examines the notion of “silencing” in urban growth discourses. Silencing, it is argued, should not be understood as censorship but rather as attempts by growth machines to relativize the importance of critical and dissent voices in redevelopment projects. We believe that to understand how redevelopment projects operate and transform (urban) spaces, such rhetorical peripherialization is as important as pro-growth discourses. In developing this argument, the article focuses on the case study of the Obama Presidential Center (OPC) on Chicago's Southeast Side. An OPC growth machine consisting of the Obama Foundation, the city mayor, the University of Chicago, and a coalition of local business and community organizations practices this simultaneity of offering their voice and undercutting alternative voices in adroit ways. Race, it is argued, is at the center of this systematic suppression. The OPC development provides an important example of how current redevelopment in cities across the global west currently proceeds.

Abstract Background Eswatini continues to have the highest prevalence of HIV in the world, and one of the highest HIV incidences among adult populations (aged 15–49). This analysis reports on both key elements of study design/protocol and baseline results from an impact evaluation of an intervention incentivizing (i) initiation, enrolment, attendance or completion of some form of education, and (ii) lower risk sexual behaviour. Methods The impact evaluation employs a two by two factorial design in which participants are enrolled in either the incentive for education arm (‘education treatment arm’ providing a conditional cash incentive) or the control arm (‘education control arm’). In each of these arms, 50% of participants were randomized to also be eligible for selection – three times a year – to participate in a conditional raffle conditional on testing negative for curable STIs (syphilis and Trichomonas vaginalis). Results Baseline recruitment and screening occurred in 2016 when a total of 6055 individuals were screened of which 4863 participated in the baseline survey, and 4819 individuals were randomized into one of the study arms. The baseline prevalence of HIV, Trichomonas vaginalis, and syphilis among adolescent girls and young women 8.20% (397/4840), 3.31% (150/4533) and 0.17% (8/4830) respectively. Conclusions An educational cash incentive and raffle incentive impact evaluation that addresses adolescent girls and young women who are in-education and out-of-education has the potential to reduce HIV risk in adolescent girls and young women in Eswatini. Trial registration Name of the registry: Pan African Clinical Trials Registry. Trial registration number: PACTR201811609257043 . Date of registration: May 11, 2018 ‘Retrospectively registered’. URL of trial registry record: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=4685

Abstract Background We describe the latest improvements to the long-range phasing (LRP) and haplotype library imputation (HLI) algorithms for successful phasing of both datasets with one million individuals and datasets genotyped using different sets of single nucleotide polymorphisms (SNPs). Previous publicly available implementations of the LRP algorithm implemented in AlphaPhase could not phase large datasets due to the computational cost of defining surrogate parents by exhaustive all-against-all searches. Furthermore, the AlphaPhase implementations of LRP and HLI were not designed to deal with large amounts of missing data that are inherent when using multiple SNP arrays. Methods We developed methods that avoid the need for all-against-all searches by performing LRP on subsets of individuals and then concatenating the results. We also extended LRP and HLI algorithms to enable the use of different sets of markers, including missing values, when determining surrogate parents and identifying haplotypes. We implemented and tested these extensions in an updated version of AlphaPhase, and compared its performance to the software package Eagle2. Results A simulated dataset with one million individuals genotyped with the same 6711 SNPs for a single chromosome took less than a day to phase, compared to more than seven days for Eagle2. The percentage of correctly phased alleles at heterozygous loci was 90.2 and 99.9% for AlphaPhase and Eagle2, respectively. A larger dataset with one million individuals genotyped with 49,579 SNPs for a single chromosome took AlphaPhase 23 days to phase, with 89.9% of alleles at heterozygous loci phased correctly. The phasing accuracy was generally lower for datasets with different sets of markers than with one set of markers. For a simulated dataset with three sets of markers, 1.5% of alleles at heterozygous positions were phased incorrectly, compared to 0.4% with one set of markers. Conclusions The improved LRP and HLI algorithms enable AlphaPhase to quickly and accurately phase very large and heterogeneous datasets. AlphaPhase is an order of magnitude faster than the other tested packages, although Eagle2 showed a higher level of phasing accuracy. The speed gain will make phasing achievable for very large genomic datasets in livestock, enabling more powerful breeding and genetics research and application.

Abstract Background Diabetes is one of the leading causes of poor health and high care costs in Ukraine. To prevent diabetes complications and alleviate the financial burden of diabetes care on patients, the Ukrainian government reimburses diabetes medication and provides glucose monitoring, but there are significant gaps in the care continuum. We estimate the costs of providing diabetes care and the most cost-effective ways to address these gaps in the Poltava region of Ukraine. Methods We gathered data on the unit costs of diabetes interventions in Poltava and estimated expenditure on diabetes care. We estimated the optimal combination of facility-based and outreach screening and investigated how additional funding could best be allocated to improve glucose control outcomes. Results Of the ~ 40,000 adults in diabetes care, only ~ 25% achieved sustained glucose control. Monitoring costs were higher for those who did not: by 10% for patients receiving non-pharmacological treatment, by 61% for insulin patients, and twice as high for patients prescribed oral treatment. Initiatives to improve treatment adherence (e.g. medication copayment schemes, enhanced adherence counseling) would address barriers along the care continuum and we estimate such expenditures may be recouped by reductions in patient monitoring costs. Improvements in case detection are also needed, with only around two-thirds of estimated cases having been diagnosed. Outreach screening campaigns could play a significant role: depending on how well-targeted and scalable such campaigns are, we estimate that 10–46% of all screening could be conducted via outreach, at a cost per positive patient identified of US$7.12–9.63. Conclusions Investments to improve case detection and treatment adherence are the most efficient interventions for improved diabetes control in Poltava. Quantitative tools provide essential decision support for targeting investment to close the gaps in care.

Initial global-level estimates reported in June 2020 by the World Health Organization suggested that levels of disruption to TB service delivery could be as high as 25%-50% and result in an additional 6·3 million cases of tuberculosis (TB) and an additional 1·4 million TB-related deaths attributable to COVID-19 between 2020 and 2025. Quarterly epidemiological estimates and programmatic TB data capturing disruption levels to each TB service were collected by National TB Programmes in Indonesia, Kyrgyzstan, Malawi, Mozambique, and Peru. Data from 2019, for a pre-COVID-19 baseline, and throughout 2020, together with the NTP's COVID-19 response plans, were used within Optima TB models to project TB incidence and deaths over five years because of COVID-19-related disruptions, and the extent to which those impacts may be mitigated through proposed catch-up strategies in each country. Countries reported disruptions of up to 64% to demand-driven TB diagnosis. However, TB service availability disruptions were shorter and less severe, with TB treatment experiencing levels of disruption of up to 21%. We predicted that under the worse-case scenario cumulative new latent TB infections, new active TB infections, and TB-related deaths could increase by up to 23%, 11%, and 20%, respectively, by 2024. However, three of the five countries were on track to mitigate these increases to 3% or less by maintaining TB services in 2021 and 2022 and by implementing proposed catch-up strategies. Indonesia was already experiencing the worse-case scenario, which could lead to 270,000 additional active TB infections and 36,000 additional TB-related deaths by the end of 2024. The COVID-19 pandemic is projected to negatively affect progress towards 2035 End TB targets, especially in countries already off-track. Findings highlight both successful TB service delivery adaptions in 2020 and the need to proactively maintain TB service availability despite potential future waves of more transmissible COVID-19 variants.

Introduction More people are living with and beyond a cancer diagnosis. There is limited understanding of the long-term effects of cancer and cancer treatment on quality of life and personal and household finances when compared to people without cancer. In a separate protocol we have proposed to link de-identified data from electronic primary care and hospital records for a large population of cancer survivors and matched controls. In this current protocol, we propose the linkage of Patient Reported Outcomes Measures data to the above data for a subset of this population. The aim of this study is to investigate the full impact of living with and beyond a cancer diagnosis compared to age and gender matched controls. A secondary aim is to test the feasibility of the collection of Patient Reported Outcomes Measures (PROMS) data and the linkage procedures of the PROMs data to electronic health records data. Materials and methods This is a cross-sectional study, aiming to recruit participants treated at the Leeds Teaching Hospitals National Health Service Trust. Eligible patients will be cancer survivors at around 5 years post-diagnosis (breast, colorectal and ovarian cancer) and non-cancer patient matched controls attending dermatology out-patient clinics. They will be identified by running a query on the Leeds Teaching Hospitals Trust patient records system. Approximately 6000 patients (2000 cases and 4000 controls) will be invited to participate via post. Participants will be invited to complete PROMs assessing factors such as quality of life and finances, which can be completed on paper or online (surveys includes established instruments, and bespoke instruments (demographics, financial costs). This PROMs data will then be linked to routinely collected de-identified data from patient’s electronic primary care and hospital records. Discussion This innovative work aims to create a truly ‘comprehensive patient record’ to provide a broad picture of what happens to cancer patients across their cancer pathway, and the long-term impact of cancer treatment. Comparisons can be made between the cases and controls, to identify the aspects of life that has had the greatest impact following a cancer diagnosis. The feasibility of linking PROMs data to electronic health records can also be assessed. This work can inform future support offered to people living with and beyond a cancer diagnosis, clinical practice, and future research methodologies.

The demand for minerals has never been so high and is expected to increase in the coming decades [...]

Background: Despite the crucial role of educators in encourage students' academic learning, addressing educator stress inside the classroom remains a significant challenge in the educational context. Mindfulness Meditation training (MM) has been recommended as an environmental enrichment strategy in schools to help teachers cope with stress and cultivating a state of awareness in daily life. Although studies have shown that MM can improve immune system dynamics the biological mechanism underlying glutathione metabolism in a healthy human is unclear Objective: The purpose of this study was to determine whether MM training benefits psychological and behavioral response, immunological functions and glutathione metabolism in service healthy female teachers from public schools Methods: We randomly assigned 76 teachers to an 8-week Mindfulness-Based Health Program for Educators (MBHPEduca) or Neuroscience for Education program (Neuro-Educa; active control group). Using the quality of life as our primary outcome, perceived stress, negative affectivity, and resilience as our secondary outcome, and pro-inflammatory cytokines and glutathione levels as our third outcome at baseline and post-intervention that occurred in public schools. Blood samples were collected for the measurement of three proinflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) and three GSH metabolism, including Cysteine (Cys), Homocysteine (HCys) and GSH were conducted at pre-and post-intervention, with selfreported assessments over time. Treatment effects were analyzed using generalized estimating equations (GEE) with to intention to treat Results: We observed statistically significant improvements to the MBHP-Educa group compared to active control in perceived stress, resilience, positive and negative affect, and quality of life after 8-weeks MM (p ​

ABSTRACT Emergence of SARS-CoV-2 with high transmission and immune evasion potential, the so-called variants of concern (VOC), is a major concern. We describe the early genomic epidemiology of SARS-CoV-2 recovered from vaccinated health care professionals (HCP). Our postvaccination COVID-19 symptoms-based surveillance program among HCPs in a 17-hospital network identified all vaccinated HCPs who tested positive for COVID-19 after routine screening or after self-reporting. From 1 January 2021 to 30 April 2021, 23,687 HCPs received either mRNA-1273 or BNT162b2 mRNA vaccine. All available postvaccination SARS-CoV-2 samples and a random collection from nonvaccinated patients during the similar time frame were subjected to VOC screening and whole-genome sequencing (WGS). Sixty-two percent (23,697/37,500) of HCPs received at least one vaccine dose, with 60% (22,458) fully vaccinated. We detected 138 (0.58%, 138/23,697) COVID-19 cases, 105 among partially vaccinated and 33 (0.15%, 33/22,458) among fully vaccinated. Five partially vaccinated required hospitalization, four with supplemental oxygen. VOC screening from 16 fully vaccinated HCPs identified 6 (38%) harboring N501Y and 1 (6%) with E484K polymorphisms; percentage of concurrent nonvaccinated samples was 37% (523/1,404) and 20% (284/1,394), respectively. There was an upward trend from January to April for E484K/Q (3% to 26%) and N501Y (1% to 49%). WGS analysis from vaccinated and nonvaccinated individuals indicated highly congruent phylogenies. We did not detect an increased frequency of any receptor-binding domain (RBD)/N-terminal domain (NTD) polymorphism between groups (P > 0.05). Our results support robust protection by vaccination, particularly among recipients of both doses. Despite VOCs accounting for over 40% of SARS-CoV-2 from fully vaccinated individuals, the genomic diversity appears to proportionally represent VOCs among nonvaccinated populations. IMPORTANCE A number of highly effective vaccines have been developed and deployed to combat the COVID-19 pandemic. The emergence and epidemiological dominance of SARS-CoV-2 mutants with high transmission potential and immune evasion properties, the so-called variants of concern (VOC), continue to be a major concern. Whether these VOCs alter the efficacy of the administered vaccines is of great concern and a critical question to study. We describe the initial genomic epidemiology of SARS-CoV-2 recovered from partial/fully vaccinated health care professionals and probe specifically for VOC enrichment. Our findings support the high level of protection provided by full vaccination despite a steep increase in the prevalence of polymorphisms associated with increased transmission potential (N501Y) and immune evasion (E484K) in the nonvaccinated population. Thus, we do not find evidence of VOC enrichment among vaccinated groups. Overall, the genomic diversity of SARS-CoV-2 recovered postvaccination appears to proportionally represent the observed viral diversity within the community.

Background Countries are recommended to progressively work towards universal health coverage (UHC), and to make explicit choices regarding the expansion of priority services. However, there is little guidance on how to manage the inclusion of vertical programmes, funded by external partners, in health benefits packages (HBP) in low and middle-income countries (LMICs).Objective We conducted a scoping review to map the inclusion of six vertical programmes (HIV, tuberculosis, malaria, maternal and child health, contraceptives, immunisation) in 26 LMICs.Methods We identified 26 LMICs with an HBP that was not aspirational (eg, with evidence of implementation or funding). For each HBP, we collected information on the corresponding UHC scheme, health financing at the time of establishment, revisions since inception and entitlements. For each vertical programme, we developed a list of tracer interventions based on the Disease Control Priorities 3 and the 100 Core Health Indicators List. We then used this list of tracer interventions to map the coverage of the six vertical programmes.Results The review shows that there is no common starting point for countries embarking into UHC. Some HBPs were almost three decades old. Whole package revisions are rare. The inclusion of vertical programme does not follow a given pattern based on health financing indicators or country’s income group. Maternal child health services are the most often included and family planning the least. Six countries in our sample covered all vertical programmes, while one covered only one of six.Conclusions This review has shown that there has been a long history of countries facing this question and we have provided the first mapping of inclusion of vertical programmes in UHC. The results of the mapping can inform decisions in countries embarking in UHC.

With solid tumor cancer survivorship increasing, the number of patients requiring post-treatment surveillance also continues to increase. This highlights the need for evidence-based cancer surveillance guidelines. Ideally, these guidelines would be based on combined high-quality data from randomized controlled trials (RCTs). We present a systematic review of published cancer surveillance RCTs in which we sought to determine the feasibility of data pooling for guideline development. We carried out a systematic search of medical databases for RCTs in which adult patients with solid tumors that had undergone surgical resection with curative intent and had no metastatic disease at presentation, were randomized to different surveillance regimens that assessed effectiveness on overall survival (OS). We extracted study characteristics and primary and secondary outcomes, and assessed risk of bias and validity of evidence with standardized checklist tools. Our search yielded 32,216 articles for review and 18 distinct RCTs were included in the systematic review. The 18 trials resulted in 23 comparisons of surveillance regimens. There was a highlevel of variation between RCTs, including the study populations evaluated, interventions assessed and follow-up periods for the primary outcome. Most studies evaluated colorectal cancer patients (11/18, [61%]). The risk of bias and validity of evidence were variable and inconsistent across studies. This review demonstrated that there is tremendous heterogeneity among RCTs that evaluate effectiveness of different postoperative surveillance regimens in cancer patients, rendering the consolidation of data to inform high-quality cancer surveillance guidelines unfeasible. Future RCTs in the field should focus on consistent methodology and primary outcome definition.

Maternal immunological dysregulation might affect the immunological development of the fetus. Here the authors show that decreased maternal acetate is associated with preeclampsia, impaired fetal thymic output and regulatory T cell development.

Abstract Background Post-stroke lower limb spasticity (PSLLS) has a prevalence of 28–37%. PSLLS can cause difficulty in walking and reduce quality of life (QOL). Post stroke spasticity impairs the ability to intervene to improve walking ability. Botulinum Toxin A (BT) is an effective intervention for focal spasticity, but its use is currently restricted in many countries by their reimbursement system stating that the evidence for improvement in walking and quality of life (QOL) is not robust for treatment in the lower limb. This randomized control trial (RCT) will investigate the effectiveness of BT in modifying spasticity, and improving functioning (mobility, walking, activities of daily living (ADL’s) and QOL. Methods/design A double-blind placebo-controlled trial injection will assess the effect of BT compared with a placebo (normal saline) in a sample of n = 94 patients. Following treatment of spasticity measured by Modified Ashworth Scale (MAS), the primary outcome of gait velocity will be measured by i) Gait Rite (Electronic Walkway); ii) walking by 2 Min Walk Test; iii) balance by Berg Balance Scale; mobility by iv) Timed Up and Go (TUG); v) lower limb function by ABILICO; vi) patient related goal by Goal Attainment Scale (GAS); vii) QOL by SF 12 (Rand version); viii) activities of daily living by the Functional Autonomy Measurement System (SMAF). There will be an associated health economic analysis. Discussion The study methodology is based on our systematic review 2026 studies, which concluded the evidence for improving mobility following use of BT to reduce spasticity was not robust. The results of this study could establish the use of BT in improving gait and lower limb function in PSLLS. This study could provide the evidence needed for reimbursement schemes to consider and changes to its funding policy for BT in PSLLS. Trial registration The trial is registered with the Australia New Zealand Clinical Trails Registry (ANZCTR)-ANZCTRN12617001603303. Registered 07/12/2017.

Mapping-by-sequencing strategies combine next-generation sequencing (NGS) with classical linkage analysis, allowing rapid identification of the causal mutations of the phenotypes exhibited by mutants isolated in a genetic screen. Computer programs that analyze NGS data obtained from a mapping population of individuals derived from a mutant of interest to identify a causal mutation are available; however, the installation and usage of such programs requires bioinformatic skills, modifying or combining pieces of existing software, or purchasing licenses. To ease this process, we developed Easymap, an open-source program that simplifies the data analysis workflows from raw NGS reads to candidate mutations. Easymap can perform bulked segregant mapping of point mutations induced by ethyl methanesulfonate (EMS) with DNA-seq or RNA-seq datasets, as well as tagged-sequence mapping for large insertions, such as transposons or T-DNAs. The mapping analyses implemented in Easymap have been validated with experimental and simulated datasets from different plant and animal model species. Easymap was designed to be accessible to all users regardless of their bioinformatics skills by implementing a user-friendly graphical interface, a simple universal installation script, and detailed mapping reports, including informative images and complementary data for assessment of the mapping results. Easymap is available at http://genetics.edu.umh.es/resources/easymap; its Quickstart Installation Guide details the recommended procedure for installation.

Crop monitoring and yield prediction are central to management decisions for farmers. One key task is counting the number of kernels on an ear of corn to estimate yield in a field. As ears of corn can easily have 400–900 kernels, manual counting is unrealistic; traditionally, growers have approximated the number of kernels on an ear of corn through a mixture of counting and estimation. With the success of deep learning, these human estimates can now be replaced with more accurate machine learning models, many of which are efficient enough to run on a mobile device. Although a conceptually simple task, the counting and localization of hundreds of instances in an image is challenging for many image detection algorithms which struggle when objects are small in size and large in number. We compare different detection-based frameworks, Faster R-CNN, YOLO, and density-estimation approaches for on-ear corn kernel counting and localization. In addition to the YOLOv5 model which is accurate and edge-deployable, our density-estimation approach produces high-quality results, is lightweight enough for edge deployment, and maintains its computational efficiency independent of the number of kernels in the image. Additionally, we seek to standardize and broaden this line of work through the release of a challenging dataset with high-quality, multi-class segmentation masks. This dataset firstly enables quantitative comparison of approaches within the kernel counting application space and secondly promotes further research in transfer learning and domain adaptation, large count segmentation methods, and edge deployment methods.

Objectives To determine the proportion of patients with extremity sarcoma who would be willing to participate in a clinical trial in which they would be randomised to one of four different postoperative sarcoma surveillance regimens. Additionally, we assessed patients’ perspectives on the burden of cancer care, factors that influence comfort with randomisation and the importance of cancer research.Design Prospective, cross-sectional patient survey.Setting Outpatient sarcoma clinics in Canada, the USA and Spain between May 2017 and April 2020. Survey data were entered into a study-specific database.Participants Patients with extremity sarcoma who had completed definitive treatment from seven clinics across Canada, the USA and Spain.Main outcome measures The proportion of patients with extremity sarcoma who would be willing to participate in a randomised controlled trial (RCT) that evaluates varying postoperative cancer surveillance regimens.Results One hundred thirty complete surveys were obtained. Respondents reported a wide range of burdens related to clinical care and surveillance. The majority of patients (85.5%) responded that they would agree to participate in a cancer surveillance RCT if eligible. The most common reason to participate was that they wanted to help future patients. Those that would decline to participate most commonly reported that participating in research would be too much of a burden for them at a time when they are already feeling overwhelmed. However, most patients agreed that cancer research will help doctors better understand and treat cancer.Conclusions These results demonstrate that most participants would be willing to participate in an RCT that evaluates varying postoperative cancer surveillance regimens. Participants’ motivation for trial participation included altruistic reasons to help future patients and deterrents to trial participation included the overwhelming burden of a cancer diagnosis. These results will help inform the development of patient-centred RCT protocols in sarcoma surveillance research.Level of evidence V.

Introduction: Medical students pursuing an emergency medicine (EM) residency are advised to obtain at least two Standardized Letters of Evaluation (SLOE). Students often complete one rotation at their home institution and at least one “away” rotation at a program separate from their home institution. The SLOE was introduced as an objective evaluation tool. The aim of this study was to determine whether there was a difference in scores between home rotation and away rotation SLOEs. Methods: We retrospectively reviewed the SLOEs of all applicants to an urban, academic EM residency program. For each SLOE, we calculated a composite score from rankings in seven “Qualifications for EM” (CS7), and converted comparative rank score (CRS) and estimated rank list position (ERP) to percentile scores. The CS7, CRS, and ERP on the home rotation SLOE were compared to those of the away SLOE using a paired t-test. Results: An evaluation of 721 applicants with at least one home SLOE and one away SLOE demonstrated a significant increase in the ERP of home rotators (P = 0.003). The data did not demonstrate a statistically significant difference in the CS7 (P = 0.69), or CRS (P = 0.97). Conclusion: Our study demonstrated that the only difference in SLOEs is that students are likely to be given a slightly higher estimated placement on the rank order list on a home SLOE. We hope this will help residency leadership with reviewing applications.

Mobile application (app) platforms have the potential to advance sexual and reproductive health (SRH). Yet there is a dearth of knowledge regarding global perspectives from healthcare providers on how SRH mobile apps are being leveraged in their healthcare practice. In 2019 the World Health Organization (WHO) developed a consolidated guideline on self-care interventions for SRH. To inform this guideline, we conducted a global values and preferences survey. This study aimed to (a) understand the awareness, access, and uptake of SRH mobile apps; (b) examine how many healthcare provider (HCP) participants provided linkages, referrals and information to clients regarding SRH mobile apps; and (c) among HCP, assess how many felt confident and informed regarding SRH mobile apps. We hosted a cross-sectional web-based survey on the WHO Department of Reproductive Health and Research website and shared the survey with SRHR listservs. There were 825 survey participants, 360 whom identified as healthcare providers (HCP). Approximately one-third of HCP participants had provided a referral/information to their clients about sexual or reproductive health apps. While 40.8% of HCP felt confident and informed about sexual health apps, half (47.4%) reported needing more information, and 15.6% expressed interest in receiving training to use in practice. While 42.6% of HCPs felt confident and informed about reproductive health apps, 45.7% needed more information, and 15.1% were interested in further training. There was also an open-ended question for HCP to share their thoughts about self-care SRH interventions. Specifically regarding SRH apps, HCP responses revealed the importance of considering: (a) security and confidentiality; (b) potential benefits of SRH apps for underserved groups (i.e. youth, rural communities); (c) community engagement; (d) health benefits; and (e) and online training for HCP on SRH mobile apps. Findings signal interest and opportunities for training and engaging HCP in using mobile apps to advance SRH.

One of the large-scale field waste rock experiments (test piles) conducted as part of the Diavik Waste Rock Project was deconstructed, providing a spatially located set of geochemical, mineralogical, and particle-size distribution samples. Geostatistical analyses were conducted for sulfur and carbon content and saturated hydraulic conductivity, which affect the geochemical evolution of waste rock, to investigate the spatial dependence of these parameters. Analyses included population statistics, experimental semi-variogram estimation, and theoretical semi-variogram fitting. Population statistics were calculated for additional data sets from samples collected during the construction of the test piles. The population statistical analyses indicated that log-normal distribution provided the best fit for all investigated data sets. Experimental semi-variograms were estimated for the spatially located data set (test pile deconstruction) using the classical estimator, and theoretical semi-variograms were fitted. This investigation showed that the spatial distribution of sulfur, carbon, and hydraulic conductivity within the core of the test-pile experiments can be approximated using a log-normal distribution with a mean and standard deviation calculated using the samples collected during construction of the piles, and that little to no spatial relationship was present for these parameters at the scale of sampling. That the saturated hydraulic conductivity of the matrix material can be represented by the same statistical distribution throughout the test pile is significant because water flow, as well as mineral surface area and reactivity are dominantly controlled within the matrix portion of the test pile. Reactive transport simulations are included to demonstrate the influence of the matrix material on effluent geochemistry.

Abstract Objective MRI derived spinal‐muscle morphology measurements have potential diagnostic, prognostic, and therapeutic applications in spinal health. Muscle morphology in the thoracic spine is an important determinant of kyphosis severity in older adults. However, the literature on quantification of spinal muscles to date has been limited to cervical and lumbar regions. Hence, we aim to propose a method to quantitatively identify regions of interest of thoracic spinal muscle in axial MR images and investigate the repeatability of their measurements. Methods Middle (T4‐T5) and lower (T8‐T9) thoracic levels of six healthy volunteers (age 26 ± 6 years) were imaged in an upright open scanner (0.5T MROpen, Paramed, Genoa, Italy). A descriptive methodology for defining the regions of interest of trapezius, erector spinae, and transversospinalis in axial MR images was developed. The guidelines for segmentation are laid out based on the points of origin and insertion, probable size, shape, and the position of the muscle groups relative to other recognizable anatomical landmarks as seen from typical axial MR images. 2D parameters such as muscle cross‐sectional area (CSA) and muscle position (radius and angle) with respect to the vertebral body centroid were computed and 3D muscle geometries were generated. Intra and inter‐rater segmentation repeatability was assessed with intraclass correlation coefficient (ICC (3,1)) for 2D parameters and with dice coefficient (DC) for 3D parameters. Results Intra and inter‐rater repeatability for 2D and 3D parameters for all muscles was generally good/excellent (average ICC (3,1) = 0.9 with ranges of 0.56‐0.98; average DC = 0.92 with ranges from 0.85‐0.95). Conclusion The guidelines proposed are important for reliable MRI‐based measurements and allow meaningful comparisons of muscle morphometry in the thoracic spine across different studies globally. Good segmentation repeatability suggests we can further investigate the effect of posture and spinal curvature on muscle morphology in the thoracic spine.

Quantitative analysis of plant and animal morphogenesis requires accurate segmentation of individual cells in volumetric images of growing organs. In the last years, deep learning has provided robust automated algorithms that approach human performance, with applications to bio-image analysis now starting to emerge. Here, we present PlantSeg, a pipeline for volumetric segmentation of plant tissues into cells. PlantSeg employs a convolutional neural network to predict cell boundaries and graph partitioning to segment cells based on the neural network predictions. PlantSeg was trained on fixed and live plant organs imaged with confocal and light sheet microscopes. PlantSeg delivers accurate results and generalizes well across different tissues, scales, acquisition settings even on non plant samples. We present results of PlantSeg applications in diverse developmental contexts. PlantSeg is free and open-source, with both a command line and a user-friendly graphical interface.