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Abstract Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2–5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

Abstract While biallelic POLR3A loss‐of‐function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent‐onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A‐related disorder with c.1909+22 variant. One of these patients showed expanded phenotypic spectrum of generalised dystonia and her sister remained asymptomatic except for hypodontia. Two patients with dystonic arm tremor responded to deep brain stimulation. In our systemic literature review, we found that POLR3A‐related disorder with c.1909+22 variant has attenuated disease severity but frequency of dystonia and upper limb tremor did not differ among genotypes.

Pathogenic and antimicrobial-resistant (AMR) microorganisms are continually transmitted between human, animal, and environmental reservoirs, contributing to the high burden of infectious disease and driving the growing global AMR crisis. The sheer diversity of pathogens, AMR mechanisms, and transmission pathways connecting these reservoirs create the need for comprehensive cross-sectoral surveillance to effectively monitor risks. Current approaches are often siloed by discipline and sector, focusing independently on parts of the whole. Here we advocate that integrated surveillance approaches, developed through transdisciplinary cross-sector collaboration, are key to addressing the dual crises of infectious diseases and AMR. We first review the areas of need, challenges, and benefits of cross-sectoral surveillance, then summarise and evaluate the major detection methods already available to achieve this (culture, quantitative PCR, and metagenomic sequencing). Finally, we outline how cross-sectoral surveillance initiatives can be fostered at multiple scales of action, and present key considerations for implementation and the development of effective systems to manage and integrate this information for the benefit of multiple sectors. While methods and technologies are increasingly available and affordable for comprehensive pathogen and AMR surveillance across different reservoirs, it is imperative that systems are strengthened to effectively manage and integrate this information.

Abstract Background The effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk. Methods This study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined. Results There was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs.

Abstract In the last decade, bat conservation guidance has received increasing attention, as many United States bat species are in decline due to white‐nose syndrome and have been listed or considered for federal endangered species status. Research on how these species are impacted by forestry management decisions has advanced to provide specific conservation actions for these imperiled species. We set out to better understand the level of knowledge land managers had in relation to forestry techniques and their impact on wildlife conservation in order to more effectively strategize how we can efficiently provide educational resources. We surveyed 78 land managers in Illinois to identify their priorities for management and how familiar they were with forestry management guidelines for bat conservation. We followed up with a subset of voluntary participants with semistructured phone interviews to generate more in‐depth responses. Using these tools, we reveal that a top priority for most managers in Illinois is invasive species management. Most have some familiarity with bat conservation actions, but few were confident in their knowledge of threatened and endangered species. Thirteen of the twenty phone interviews identified a preference for talking to/hearing from experts to receive information on bat conservation. These results highlighted where there are information gaps on best practices for forestry management from a conservation perspective, and identified how we can best address these through partnerships with land managers. Implementation of these practices is likely how recovery of these vulnerable species will happen—through protection of their basic needs, including availability of roosts, abundance of prey, and access to uncontaminated water resources.

Abstract The range expansion of ticks to higher latitudes poses a severe threat to human health exposing human populations who had no prior contact with ticks to several harmful tick‐borne diseases. Early detection of ticks in new areas is critical to help inform the public and medical professionals of the dangers associated with tick encounters. Environmental DNA represents a novel survey method that could provide reliable records of tick occurrences and timely warnings of their range expansions. In this study, we designed novel eDNA qPCR assays for three common North American tick species (Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis) and tested them on 51 samples of grasses and leaf litter collected from 12 grassland and forest sites in central and southern Illinois. We provide in silico and in vitro validation of all three assays; however, we were unable to generate any positive detections from field samples. Our lack of eDNA detections likely stems from low eDNA deposition rates coupled with rapid degradation in grasslands and forests, a problem exacerbated by terrestrial eDNA sampling methods limited by volume of substrate. We provide recommendations for improving sample collection methods to increase detection probability in future efforts. Continued research should focus on the viability of eDNA to detect small terrestrial invertebrates, like ticks, and it potential as early warning indicator of the spread of vector‐borne diseases.

Abstract Introduction Suicide is a major public health problem in Pakistan, accounting to approximately 19,331 deaths every year. Many are due to consumption of acutely toxic pesticides; however, there is a lack of national suicide data, limiting knowledge and potential for intervention. In this paper, we aimed to review the literature on pesticide self-poisoning in Pakistan to identify the most problematic pesticides in relation to national pesticide regulations. Methods Information on the currently registered and banned pesticides was obtained from Ministry of National Food Security and Research while data on pesticide import and use was extracted from FAOSTAT. We searched the following sources for articles and research papers on poisoning in Pakistan: Cumulative Index to Nursing and Allied Health (CINAHL), Google Scholar, Applied Social Sciences Index and Abstracts (ASSIA), Excerpta Medica (EMBASE), National Library of Medicine’s MEDLINE (PUBMED), PS102YCHINFO and Pakmedinet.com using the search terms ‘self-poisoning’, ‘deliberate self-harm’, ‘suicide’, ‘methods and means of suicide’, ‘organophosphate’, ‘wheat pill’, ‘aluminium phosphide’, ‘acute poisoning’, OR ‘pesticides’, AND ‘Pakistan’. Results As of May 2021, 382 pesticide active ingredients (substances) were registered in Pakistan, of which five were WHO hazard class Ia (extremely hazardous) and 17 WHO hazard class Ib (highly hazardous). Twenty-six pesticides, four formulations, and seven non-registered pesticides had been banned, of which two were WHO class Ia and five Ib. We identified 106 hospital-level studies of poisoning conducted in Pakistan, of which 23 did not mention self-poisoning cases and one reported no suicidal poisoning cases. We found no community or forensic medicine studies. Of 52,323 poisoning cases identified in these papers, 24,546 [47%] were due to pesticides. The most commonly identified pesticide classes were organophosphorus (OP) insecticides (13,816 cases, 56%) and the fumigant aluminium phosphide (3 g 56% tablets, often termed ‘wheat pills’; 686 cases, 2.7%). Few studies identified the particular pesticides involved or the resulting case fatality. Conclusion We found pesticide poisoning to be a major cause of poisoning in Pakistan, with OP insecticides and the fumigant aluminium phosphide the main pesticides identified. Withdrawal of Class I pesticides (as proposed to occur nationally in 2022) and high concentration aluminium phosphide tablets should rapidly reduce suicidal deaths by reducing the case fatality for low-intention poisoning cases. National cause of death data and forensic toxicology laboratory data identifying the pesticides responsible for deaths will be important to assess impacts of the proposed national ban.

Abstract Expansions of short tandem repeats (STRs) cause many rare diseases. Expansion detection is challenging with short-read DNA sequencing data since supporting reads are often mapped incorrectly. Detection is particularly difficult for “novel” STRs, which include new motifs at known loci or STRs absent from the reference genome. We developed STRling to efficiently count k-mers to recover informative reads and call expansions at known and novel STR loci. STRling is sensitive to known STR disease loci, has a low false discovery rate, and resolves novel STR expansions to base-pair position accuracy. It is fast, scalable, open-source, and available at: github.com/quinlan-lab/STRling .

BackgroundSphingosine phosphate lyase insufficiency syndrome (SPLIS) is associated with biallelic variants in SGPL1, comprising a multisystemic disease characterized by steroid resistant nephrotic syndrome, primary adrenal insufficiency, neurological problems, skin abnormalities and immunodeficiency in described cases. Signal transducer and activator of transcription 1 (STAT1) plays an important role in orchestrating an appropriate immune response through JAK-STAT pathway. Biallelic STAT1 loss of function (LOF) variants lead to STAT1 deficiency with a severe phenotype of immunodeficiency with increased frequency of infections and poor outcome if untreated.Case presentationWe report novel homozygous SGPL1 and STAT1 variants in a newborn of Gambian ethnicity with clinical features of SPLIS and severe combined immunodeficiency. The patient presented early in life with nephrotic syndrome, severe respiratory infection requiring ventilation, ichthyosis, and hearing loss, with T-cell lymphopenia. The combination of these two conditions led to severe combined immunodeficiency with inability to clear respiratory tract infections of viral, fungal, and bacterial nature, as well as severe nephrotic syndrome. The child sadly died at 6 weeks of age despite targeted treatments.ConclusionWe report the finding of two novel, homozygous variants in SGPL1 and STAT1 in a patient with a severe clinical phenotype and fatal outcome early in life. This case highlights the importance of completing the primary immunodeficiency genetic panel in full to avoid missing a second diagnosis in other patients presenting with similar severe clinical phenotype early in life. For SPLIS no curative treatment is available and more research is needed to investigate different treatment modalities. Hematopoietic stem cell transplantation (HSCT) shows promising results in patients with autosomal recessive STAT1 deficiency. For this patient’s family, identification of the dual diagnosis has important implications for future family planning. In addition, future siblings with the familial STAT1 variant can be offered curative treatment with HSCT.

Carbon Fiber Composites (CFCs) recycling has received increasing interest by the composites industry, but it is still in its early stages as an industry. There are two primary challenges that need to be addressed in order to achieve full property retention during CFC recycling: (1) the ability to recover the fiber content without property loss; and (2) conversion of the recycled, short fiber material back into high-performance CFC structures. The ability to manufacture high fiber volume fraction CFCs with end-of-life products would provide an opportunity to reduce material cost and lifetime-embodied energy. In this paper, recycled, short carbon fibers are processed via solvolysis and converted into high-performance CFCs with fiber volume fraction of ~50% and excellent composite property retention. This is enabled through alignment of the discontinuous, recycled fiber feedstock using the Tailorable universal Feedstock for Forming (TuFF) process. The paper introduces the necessary steps to process the fibers in the wet-laid process and explores the resulting mechanical and microstructural properties. The importance of incoming fiber surface quality and the effect of surface contamination from residue left by the recycling process on both the TuFF process and final composite properties is discussed in detail. A pyrolytic process has been adopted to remove the residue that is a by-product of the recycling process from the incoming recycled fiber surface. The approach presents a promising pathway for the recycling of high-performance CFCs.

Abstract Background Removing highly hazardous pesticides from agricultural practice in low- and middle-income countries is crucial to ensuring community and environmental health and occupational safety of farmers. However, the approach has been challenged as threatening food production, despite evidence from Asian countries that curbing agricultural use of highly hazardous pesticides does not affect crop yields. In 2011, the state of Kerala, India, banned 14 highly hazardous pesticides resulting in a marked reduction in deaths from pesticide poisoning. Objective We aimed to determine whether the Kerala pesticide bans impacted agricultural yields. Methods We collected data on agricultural production, area under cultivation, and rainfall, published by the Kerala state agricultural department from 2004 to 2018 for eight key crops that had been treated with the banned pesticides. Trends in crop yields (total production/area under cultivation) and rainfall across 14 districts in Kerala were aggregated and analysed using joinpoint regression. These trends were evaluated to ascertain possible associations with the pesticide bans. Results The joinpoint regression analyses showed no evidence for any change in yield trends for any of the eight crops in the year of the pesticide bans (2011), or the subsequent year (2012), suggesting a negligible impact of the bans on crop yields. Steady trends of predominately reductions in overall rainfall, without any change around the time of the pesticide bans, was observed in Kerala throughout the period. No evidence of district-level changes in rainfall that might have offset any potential adverse impacts of the pesticide bans on crop yields was noted. Fluctuations in yield until 2018 could be explained by variation in rainfall, changes in land use, and agricultural policies. Conclusion We found no evidence of an adverse effect on agricultural yields in Kerala that could be attributed to bans of highly hazardous pesticides. This work provides further evidence that such pesticides can be withdrawn from agricultural use without affecting yields. Further studies are required for the whole of India after the national bans of 12 pesticides in 2018 to identify state-level effects of the bans.

The DES gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic DES variants produce a range of skeletal and cardiac muscle disorders collectively known as the desminopathies. We report three desminopathy cases which highlight the phenotypic heterogeneity of this disorder and discuss various factors that may contribute to the clinical differences seen between patients with different desmin variants and also between family members with the same variant.

Significant changes in public procurement are underway in the UK. Post-Brexit, the UK government is in the process of modifying the procurement rulebook. The new regime will be guided by the procurement strategy priorities of social value, jobs and net zero; however, the new approach to procurement foresees minimal rules and significant guidance. This paper explores implications of changing procurement legislation on the delivery of net zero at a local level in the UK. Particular focus lies on the many contracting authorities, such as county, city and district councils, that have declared climate emergencies and ambitions to decarbonise. Two case studies depicting the procurement of local net zero solutions, one on the Energy Efficient Scotland Programme and the other on place-based finance instruments, such as community municipal investments (CMIs), are used to identify existing opportunities and barriers to procure local net zero solutions with a particular focus on institutional governance. This paper concludes with a set of questions that need to be addressed to ensure that the changes to public procurement legislation are understood and that the institutional governance of intermediation can lead to outcomes that balance economic, social and environmental considerations across multiple scales. 'Practice relevance' The absence of a rich approach to multilevel governance in the UK means that procurement is one of the few options currently available to many local authorities to deliver net zero at the local level. Given the scale of investments necessary to reach net zero, institutional governance is necessary to align top-down procurement and bottom-up finance with many other laws, policies and regulations. This paper explores the implications of changing procurement legislation on the delivery of net zero at a local level. Two case studies depicting the procurement of local net zero solutions (the Energy Efficient Scotland Programme and place-based finance instruments, 'e.g.' CMIs) are used to identify existing opportunities and barriers to procure local net zero solutions. Guidance on understanding public procurement legislation is provided to ensure that the institutional governance of intermediation can lead to outcomes that balance economic, social and environmental considerations (especially decarbonisation) across multiple scales.

Abstract The linear predictive coding pole processing (LPCPP) method proposed in our previous work overcomes the shortcomings of the LPC method, especially its sensitivity to noise and the filter order. The LPCPP method is a parameterised method that involves processing the LPC poles to produce a series of reduced‐order filter transfer functions to estimate the dominant frequency components of a signal. This paper analyses the ability of the LPCPP method to track the frequency changes of noisy, time‐varying signals in real‐time. Linear chirped frequency modulation signals are used in a series of experiments to simulate signals with different rates of frequency change. The results show that the LPCPP method can achieve real‐time tracking of the dominant frequency in the signal and outperforms the LPC method under different frequency change rates and different noise levels. Specifically, the valid estimate percentage of LPCPP is up to 41.3% higher than that of LPC which indicates that the LPCPP method significantly improves the validity of frequency estimates.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29–May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%–8.5% of persons did not seroconvert 3–6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Here we report on two unrelated adult patients presenting with Limb girdle muscular dystrophy who were found to have novel variants in ANO5. Both patients had prominent weakness of their proximal lower limbs with mild weakness of elbow flexion and markedly elevated creatine kinase. Next generation sequencing using a custom-designed neuromuscular panel was performed in both patients. In one patient, 336 genes were targeted for casual variants and in the other patient (using a later panel design), 464 genes were targeted. One patient was homozygous for a novel splice variant [c.294+5G>A; p.(Ala98Ins4*)] in ANO5. Another patient was compound heterozygous for two variants in ANO5; a common frameshift variant [c.191dupA; p.(Asn64fs)] and a novel missense variant [c.952G>C; p.(Ala318Pro)]. These findings support the utility of next generation sequencing in the diagnosis of patients presenting with a Limb girdle muscular dystrophy phenotype and extends the genotypic spectrum of ANO5 disease.

Abstract This paper proposes a new time‐resolved spectral analysis method based on a modification to the linear predictive coding (LPC) method for enhancing the identification of the dominant frequencies of a signal. The method described here is based on a z‐plane analysis of the LPC poles. These poles are used to produce a series of reduced order filter transfer functions which can accurately identify and estimate the frequency of the dominant spectral features. The standard LPC method has been shown to suffer from a sensitivity to noise and its performance is dependent on the filter order. The proposed method can accurately identify the dominant frequency components over a range of filter orders and is shown to be robust in the presence of noise. Compared with traditional time‐resolved methods, it is a parameterised method where the identification of the dominant frequency changes can be directly obtained in the form of frequency measurements. In a series of 10,000 Monte Carlo experiments on single component and multiple component signals, this LPC pole processing method outperforms the standard LPC method by accurately identifying the dominant frequency components in the signals.

The grand scale of GGR deployment now necessary to avoid dangerous climate change warrants the use of grand interpretive theories of how the global economy operates. We argue that critical social science should be able to name the global economy as “capitalism”; and instead of speaking about “transforming the global economy” as a necessary precondition for limiting climate change, instead speak about transforming, or even transcending, capitalism. We propose three principles are helpful for critical social science researchers willing to name and analyse the structural features of capitalism and their relation to greenhouse gas removal technology, policy, and governance. These principles are: (1) Greenhouse Gas Removal technologies are likely to emerge within capitalism, which is crisis prone, growth dependent, market expanding, We use a broad Marxist corpus to justify this principle. (2) There are different varieties of capitalism and this will affect the feasibility of different GGR policies and supports in different nations. We draw on varieties of capitalism and comparative political economy literature to justify this principle. (3) Capitalism is more than an economic system, it is ideologically and culturally maintained. Globally-significant issues such as fundamentalism, institutional mistrust, precarity, and populism, cannot be divorced from our thinking about globally significant deployment of greenhouse gas removal technologies. We use a broad Critical Theory body of work to explore the ideational project of maintaining capitalism and its relation to GGR governance and policy.

Antimicrobial resistance (AMR) is a global public health crisis that is now impacted by the COVID-19 pandemic. Little is known how COVID-19 risks influence people to consume antibiotics, particularly in contexts like Bangladesh where these pharmaceuticals can be purchased without a prescription. This paper identifies the social drivers of antibiotics use among home-based patients who have tested positive with SARS-CoV-2 or have COVID-19-like symptoms. Using qualitative telephone interviews, the research was conducted in two Bangladesh cities with 40 participants who reported that they had tested positive for coronavirus (n = 20) or had COVID-19-like symptoms (n = 20). Our analysis identified five themes in antibiotic use narratives: antibiotics as 'big' medicine; managing anxiety; dealing with social repercussions of COVID-19 infection; lack of access to COVID-19 testing and healthcare services; and informal sources of treatment advice. Antibiotics were seen to solve physical and social aspects of COVID-19 infection, with urgent ramifications for AMR in Bangladesh and more general implications for global efforts to mitigate AMR.

La financiarización es un proceso de cambio estructural e incompleto en las economías contemporáneas. El crecimiento del sistema financiero en las últimas décadas ha estado acompañado por una relación cada vez más compleja entre los actores socioeconómicos y los mercados financieros. En este artículo analizamos las causas y consecuencias de la financiarización con respecto a: la erosión de la relación capital-trabajo; el aumento de la desigualdad del ingreso laboral; y la comercialización de la vida cotidiana y los derechos sociales. Revisamos las principales conceptualizaciones de la financiarización en varios sitios de investigación correspondientes a los principales actores económicos, es decir: corporaciones no financieras; el estado y los individuos; y su compleja relación con los mercados financieros. Nuestro objetivo principal es evaluar las contribuciones y limitaciones de los estudios de financiarización en estos espacios de investigación.

¿Puede el crowdfunding contribuir al reequilibrio del sistema financiero mediante la democratización de la inversión? Este documento comienza a responder a esta pregunta estableciendo cómo y por qué los inversores confían en estos mercados. Ofrecemos dos contribuciones. Primero, a los debates teóricos sobre finanzas democráticas; y segundo, a un cuerpo más empírico de investigación interdisciplinar sobre inversión popular a través de un análisis cualitativo de 52 entrevistas originales con inversores en seis mercados de crowdfunding del Reino Unido. Nuestros datos se toman de un proyecto con la Autoridad de Conducta Financiera del Reino Unido para mejorar la protección de los inversores en estos mercados. Utilizando un enfoque de sociología económica, encontramos que los inversores: movilizan redes integradas para establecer confianza en el crowdfunding; están motivados por las expectativas de «rendimientos combinados»; prefieren herramientas de inversión automatizadas si carecen de experiencia; y típicamente invierten con fondos que han destinado a perder. Concluimos que se requiere una mayor protección de los inversores para la financiación colectiva para ayudar a democratizar las finanzas

The in situ differential scanning calorimetry (DSC) technique has been applied to investigate the solidification paths of a basaltic liquid. The starting glass was heated up to 1300°C, kept at this superliquidus temperature for 2 h and cooled at rates (ΔT/Δt) of 7, 60, 180, 1000, and 1800°C/h, down to 800 and 600°C. Glass transition temperature (Tg), crystallization temperature (Tx_HR) and melting temperature (Tm) were measured by in situ DSC spectra on heating. Tx measured along the cooling paths (Tx_CR) shows exothermic peaks that change from a single symmetric shape (7 and 60°C/h) to multi-component patterns (180, 1000, and 1800°C/h). The recovered products characterized by field emission gun source of the scanning electron microscopy and electron probe micro-analyzer-wavelength dispersive spectrometers show a phase assemblage of spinel (sp), clinopyroxene (cpx), melilite (mel), plagioclase (plg), and glass. Moreover, crystal size distributions (CSDs) and growth rates (Gmax and GCSD) were also determined. The crystal content slightly increases from 7 to 1800°C/h. Faceted sp are present in all the run products with an amount always

We apply deep kernel learning (DKL), which can be viewed as a combination of a Gaussian process (GP) and a deep neural network (DNN), to compression ignition engine emissions and compare its performance to a selection of other surrogate models on the same dataset. Surrogate models are a class of computationally cheaper alternatives to physics-based models. High-dimensional model representation (HDMR) is also briefly discussed and acts as a benchmark model for comparison. We apply the considered methods to a dataset, which was obtained from a compression ignition engine and includes as outputs soot and NOx emissions as functions of 14 engine operating condition variables. We combine a quasi-random global search with a conventional grid-optimization method in order to identify suitable values for several DKL hyperparameters, which include network architecture, kernel, and learning parameters. The performance of DKL, HDMR, plain GPs, and plain DNNs is compared in terms of the root mean squared error (RMSE) of the predictions as well as computational expense of training and evaluation. It is shown that DKL performs best in terms of RMSE in the predictions whilst maintaining the computational cost at a reasonable level, and DKL predictions are in good agreement with the experimental emissions data.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different proportions. The N-glycan repertoire is more diverse than previously reported. Bisected and LewisX structures are potential targets for diagnostics. hCG isolated from pregnancy urine inhibits NK cell cytotoxicity in vitro at nanomolar levels and bisected type glycans have previously been implicated in the suppression of NK cell cytotoxicity, suggesting that hCG-related bisected type N-glycans may directly suppress NK cell cytotoxicity.

Cell type deconvolution from bulk expression data rely on a reference expression matrix. Here, the authors introduce a basis matrix built using data from both healthy and diseased samples profiled on 42 platforms, reducing biases introduced by single-platform matrices built using healthy samples.

Abstract Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch.

Abstract Background Antimicrobial resistance (AMR) is a growing public health problem across the world. As the negative consequences of AMR become apparent at local, national and international levels, more attention is being focussed on the variety of mechanisms by which AMR is potentiated. We explore how interactions between pet owners and veterinarians represent a key arena in which AMR-related behaviours can be shaped. Methods In depth semi-structured interviews were carried out with pet owners (n = 23) and vets (n = 16) across the UK in 2017. A thematic analysis approach was taken, with inductively gathered data analysed deductively using a behavioural framework to identified key behaviours emerging from participant accounts which were amenable to change. Results Interactions between vets and pet owners were characterised by misunderstandings and misconceptions around antibiotics by pet owners, and a lack of clarity about the positions and intentions of the other party. Vets and pet owners had differing perceptions of where pressure to prescribe antibiotics inappropriately originated. Vets perceived it was mostly pet owners who pushed for inappropriate antibiotics, whereas pet owners reported they felt it was vets that overprescribed. Low levels of understanding of AMR in general were apparent amongst pet owners and understandings with regard to AMR in pets specifically were almost non-existent in the sample. Conclusions Improved use of antibiotics could be assisted by educating the pet owning public and by guideline development for companion animal vets, concurrent development of mandatory legislation, increased consultation time to facilitate better communication, development of vet training on antimicrobial therapy and stewardship led interactions with pet owners, and increased levels of knowledge of pet-related AMR amongst pet owners.

Abstract Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15-year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413–$22,994) to USD$3706 (95% CI: $3086–$4453) for the neuromuscular disease panel and USD$5646 (95% CI: $4501–$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654–$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795–$17,135) per additional diagnosis. This study demonstrates the cost-effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access.

IntroductionPreconception carrier screening (PCS) identifies couples at risk of having children with recessive genetic conditions. New technologies have enabled affordable sequencing for multiple disorders simultaneously, including identifying carrier status for many recessive diseases. The aim of the study was to identify the most effective way of delivering PCS in Western Australia (WA) through the public health system.Methods and analysisThis is a multicentre cohort pilot study of 250 couples who have used PCS, conducted at three sites: (1) Genetic Services of Western Australia, (2) a private genetic counselling practice in Perth and (3) participating general practice group practices in the Busselton region of WA. The primary outcome of the pilot study was to evaluate the feasibility of implementing the comprehensive PCS programme in the WA healthcare system. Secondary outcome measures included evaluation of the psychosocial impact of couples, such as reproductive autonomy; identification of areas within the health system that had difficulties in implementing the programme and evaluation of tools developed during the study.Ethics and disseminationApproval was provided by the Women and Newborn Health Service Human Research Ethics Committee (HREC) at King Edward Memorial Hospital for Women (RGS0000000946) and the University of Western Australia (UWA) HREC (RA/4/20/4258). Participants may choose to withdraw at any time. Withdrawal will in no way affect participating couples' medical care. Study couples will be redirected to another participating health professional for consultation or counselling in the event of a health professional withdrawing. All evaluation data will be deidentified and stored in a password-protected database in UWA. In addition, all hard copy data collected will be kept in a locked cabinet within a secure building. All electronic data will be stored in a password-protected, backed-up location in the UWA Institutional Research Data Store. All evaluative results will be published as separate manuscripts, and selected results will be presented at conferences.

The effect of cooling on the degree of crystallinity, solid-state and dissolution properties of multi-component hot-melt extruded solid dispersions [SD] is of great interest for the successful formulation of amorphous SDs and is an area that is unreported, especially in the context of improving the stability of these specific systems. The thermal solid-state properties, degree of crystallinity, drug−polymer interactions, solubility and physical stability over time were investigated. X-ray powder diffraction [XRPD] and hyper differential scanning calorimetry [DSC] confirmed that indomethacin [INM] was converted to the amorphous state; however, the addition of poloxamer 407 [P407] had a significant effect on the degree of crystallinity and the solubility of the SD formulations. Spectroscopy studies identified the mechanism of interaction and solubility studies, showing a higher dissolution rate compared to amorphous and pure INM in pH 1.2 with a kinetic solubility of 20.63 µg/mL and 34.7 µg/mL after 3 and 24 h. XRPD confirmed that INM remained amorphous after 5 months stability testing in solid solutions with Poly(vinylpyrrolidone-co-vinyl acetate) [PVP VA64] and Plasdone S-630 [PL-S630]. Although cooling had a significant effect on the degree of crystallinity and on solubility of INM, the cooling method used did not have any significant effect on the amorphous stability of INM over time.

Following exposure to vaccines, antigen-specific CD8+ T cell responses develop as long-term memory pools. Vaccine strategies based on adenoviral vectors, e.g., those developed for HCV, are able to induce and sustain substantial CD8+ T cell populations. How such populations evolve following vaccination remains to be defined at a transcriptional level. We addressed the transcriptional regulation of divergent CD8+ T cell memory pools induced by an adenovector encoding a model antigen (beta-galactosidase). We observe transcriptional profiles that mimic those following infection with persistent pathogens, murine and human cytomegalovirus (CMV). Key transcriptional hallmarks include upregulation of homing receptors and anti-apoptotic pathways, driven by conserved networks of transcription factors, including T-bet. In humans, an adenovirus vaccine induced similar CMV-like phenotypes and transcription factor regulation. These data clarify the core features of CD8+ T cell memory following vaccination with adenovectors and indicate a conserved pathway for memory development shared with persistent herpesviruses.

Strenuous exercise leads to a progressive reduction in the performance of voluntary physical exercise. This is due to a process described as fatigue and is defined as the failure to maintain the required or expected power output. While some of this is muscular in origin, there are data suggestive of how fatigue is modulated by cortical signals, leading to a concept of central fatigue. The previously reported fatigue-induced changes in cortical activity may have been due to blood oxygen-dependent (BOLD) signal drift and/or neural habituation alone. We implemented a functional magnetic resonance imaging paradigm to effectively isolate brain areas responsible for central (supraspinal) fatigue following exercise. Our data identify a large cluster that includes dominant the anterior ventral premotor cortex (aPMv), the insula and postcentral gyrus as critical nodes in the brain network where supraspinal fatigue might have their functional neural imprints. Findings here show that activity in the ipsilateral aPMv and the adjacent areas in the premotor cortex correlates with both localized fatigue (fatigue specific hand grip contraction), and generalized full body exhaustive fatigue. In addition, from a methodological standpoint, we have also shown that the effects of BOLD signal drift can be modeled and removed to arrive at specific brain activity patterns in our experiments. Once the loci of central fatigue are isolated in this way, treatments aimed at modulating activity in these premotor areas may reduce exercise-induced fatigue and perhaps also benefit various clinical conditions in which fatigue is a major symptom.

In this article, I examine the narrative-media nexus as it relates to pandemics. Communications feature in global public health efforts to address the emergence of a pandemic, an event typically marked by the proliferation of news stories. Pandemics are also a perennial subject of film, television, literature and online games and pandemic narratives travel across and blend the genres of science fiction, alien invasion and zombie horror. Underlining this genre-blending, public health communication on pandemics has appropriated the figure of the zombie to encourage interest in preparation for pandemic threats. Drawing on examples from public communications and popular culture in dialogue with interviews and focus groups conducted with health professionals and members of the general public, I advance an account of the transmediated knowledge and meanings of pandemic narrative. I examine how pandemics become objects of knowledge in narrative, the ways in which narrative is appropriated to communicate a pandemic's temporal and affective qualities, and how, in the circumstances of an actual outbreak, publics are invited to consider themselves as the ideal, "alert, but not alarmed" subjects of the pandemic storyworld. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1701187

This paper explores the understandings of antibiotics and antimicrobial resistance (AMR) among ethnically diverse informants in Melbourne, Australia. A total of 31 face-to-face semi-structured qualitative interviews were conducted with a sample of ethnic in-patients who were admitted with an acquired antimicrobial infection in a public hospital (n = 7); five hospital interpreters; and ethnic members of the general community (n = 19) as part of a broader study of lay understandings of AMR. Thematic analysis revealed there was poor understanding of AMR, even among informants being treated for AMR infections. Causes of the increasing incidence of AMR were attributed to: weather fluctuations and climate change; a lack of environmental cleanliness; and the arrival of new migrant groups. Asian informants emphasized the need for humoral balance. Antibiotics were viewed as ‘strong’ medicines that could potentially disrupt this balance and weaken the body. Travel back to countries of origin sometimes involved the use of medical services and informants noted that some community members imported antibiotics from overseas. Most used the internet and social media to source health information. There is a lack of information in their own languages. More attention needs to be given to migrant communities who are vulnerable to the development, transmission and infection with resistant bacteria to inform future interventions.

Switchgrass (Panicum virgatum L.) is a C4 perennial prairie grass and a lignocellulosic biofuels feedstock. Saccharification and biofuel yields are inhibited by the plant cell wall’s natural recalcitrance against enzymatic degradation. Plant hemicellulose polysaccharides such as arabinoxylans structurally support and crosslink other cell wall polymers. Grasses have predominately Type II cell walls that are abundant in arabinoxylan, which comprise nearly 25% of aboveground biomass. A primary component of arabinoxylan synthesis is uridine diphosphate (UDP) linked to arabinofuranose (Araf). A family of UDP-arabinopyranose mutase/reversible glycosylated polypeptides (UAM/RGPs) catalyze the interconversion between UDP-arabinopyranose (UDP-Arap) and UDP-Araf. In switchgrass we knocked down expression of the endogenous PvUAM1 gene via RNAi to investigate its role in cell wall recalcitrance in the feedstock. PvUAM1 encodes a switchgrass homolog of UDP-arabinose mutase, which converts UDP-Arap to UDP-Araf. Each transgenic line contained between one to at least seven T-DNA insertions, resulting in some cases, a 95% reduction of native PvUAM1 transcript in stem internodes. Transgenic plants had increased pigmentation in vascular tissues at nodes, but were otherwise morphologically similar to non-transgenics. There was decreased cell wall-associated arabinose in leaves and stems by over 50%, but there was an increase in cellulose in these organs. In addition, there was a commensurate change in arabinose side chain extension. Cell wall lignin composition was altered with a concurrent increase in lignin content and transcript abundance of lignin biosynthetic genes in mature tillers. Enzymatic saccharification efficiency was unchanged in the transgenic plants relative to the control, but had increased glucose in cell walls. The increased glucose detected in stems and leaves indicates that attenuation of PvUAM1 expression might have downstream effects on starch, cellulose and xyloglucan biosynthesis. A decrease in cell wall-associated arabinose was expected, which was likely caused by fewer Araf residues in the arabinoxylan. The decrease in arabinoxylan may cause a compensation response to maintain cell wall integrity by increasing cellulose and lignin biosynthesis. In cases in which increased lignin is desired, e.g., feedstocks for carbon fiber production, down-regulated UAM1 coupled with altered expression of other arabinoxylan biosynthesis genes might result in even higher production of lignin in biomass.

A greater understanding of the genetic regulation of plant cell wall remodeling and the impact of modified cell walls on plant performance is important for the development of sustainable biofuel crops. Here, we studied the impact of down-regulating KORRIGAN-like cell wall biosynthesis genes, belonging to the endo-β-1,4-glucanase gene family, on Populus growth, metabolism and the ability to interact with symbiotic microbes. The reductions in cellulose content and lignin syringyl-to-guaiacyl unit ratio, and increase in cellulose crystallinity of cell walls of PdKOR RNAi plants corroborated the functional role of PdKOR in cell wall biosynthesis. Altered metabolism and reduced growth characteristics of RNAi plants revealed new implications on carbon allocation and partitioning. The distinctive metabolome phenotype comprised of a higher phenolic and salicylic acid content, and reduced lignin, shikimic acid and maleic acid content relative to control. Plant sustainability implications of modified cell walls on beneficial plant-microbe interactions were explored via co-culture with an ectomycorrhizal fungus, Laccaria bicolor. A significant increase in the mycorrhization rate was observed in transgenic plants, leading to measurable beneficial growth effects. These findings present new evidence for functional interconnectedness of cellulose biosynthesis pathway, metabolism and mycorrhizal association in plants, and further emphasize the consideration of the sustainability implications of plant trait improvement efforts.

The present study examined how support providers' empathic dispositions (dispositional perspective taking, empathic concern, and personal distress) as well as their situational empathic reactions (interaction-based perspective taking, empathic concern, and personal distress) relate to the provision of spousal support during observed support interactions. Forty-five committed couples provided questionnaire data and participated in two ten-minute social support interactions designed to assess behaviors when partners are offering and soliciting social support. A video-review task was used to assess situational forms of perspective taking (e.g., empathic accuracy), empathic concern and personal distress. Data were analyzed by means of the multi-level Actor-Partner Interdependence Model. Results revealed that providers scoring higher on affective empathy (i.e., dispositional empathic concern), provided lower levels of negative support. In addition, for male partners, scoring higher on cognitive empathy (i.e., situational perspective taking) was related to lower levels of negative support provision. For both partners, higher scores on cognitive empathy (i.e., situational perspective taking) correlated with more instrumental support provision. Male providers scoring higher on affective empathy (i.e., situational personal distress) provided higher levels of instrumental support. Dispositional perspective taking was related to higher scores on emotional support provision for male providers. The current study furthers our insight into the empathy-support link, by revealing differential effects (a) for men and women, (b) of both cognitive and affective empathy, and

Right heart thrombi (RHT) are rare but well-described entity in literature. Their isolation has been considered as confirmatory for the diagnosis of venous thromboembolism (VTE). Even though their isolation aids the diagnosis, physicians are faced with a difficult management dilemma giving the paucity of data to support any treatment decision. We present a case of RHT in an 81-year-old man who presented to hospital with a large mobile right heart thrombus in transit seen on transthoracic echocardiogram (TTE). He was successfully treated with anticoagulation alone. This case highlights the importance of TTE in establishing the diagnosis and describes the interplay of factors influencing treatment decision.

OBJECTIVES:To examine the associations between volume and intensity of older peoples' physical activity, with their subsequent health service usage over the following four to five years. STUDY DESIGN:A prospective cohort design using baseline participant characteristics, objectively assessed physical activity and lower limb function provided by Project OPAL (Older People and Active Living). OPAL-PLUS provided data on numbers of primary care consultations, prescriptions, unplanned hospital admissions, and secondary care referrals, extracted from medical records for up to five years following the baseline OPAL data collection. PARTICIPANTS AND DATA COLLECTION:OPAL participants were a diverse sample of 240 older adults with a mean age of 78 years. They were recruited from 12 General Practitioner surgeries from low, middle, and high areas of deprivation in a city in the West of England. Primary care consultations, secondary care referrals, unplanned hospital admissions, number of prescriptions and new disease diagnoses were assessed for 213 (104 females) of the original 240 OPAL participants who had either consented to participate in OPAL-PLUS or already died during the follow-up period. RESULTS:In regression modelling, adjusted for socio-economic variables, existing disease, weight status, minutes of moderate-to-vigorous physical activity (MVPA) per day predicted subsequent numbers of prescriptions. Steps taken per day and MVPA also predicted unplanned hospital admissions, although the strength of the effect was reduced when further adjustment was made for lower limb function. CONCLUSIONS:Community-based programs are needed which are successful in engaging older adults in their late 70s and 80s in more walking, MVPA and activity that helps them avoid loss of physical function. There is a potential for cost savings to health services through reduced reliance on prescriptions and fewer unplanned hospital admissions.

Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1.