A solar cycle clock for extreme space weather.

The variable solar cycle of activity is a long-standing problem in physics. It modulates the overall level of space weather activity at earth, which in turn can have significant societal impact. The Hilbert transform of the sunspot number is used to map the variable length, approximately 11 year Schwabe cycle onto a uniform clock. The clock is used to correlate extreme space weather seen in the aa index, the longest continuous geomagnetic record at earth, with the record of solar active region areas and latitudes since 1874. This shows that a clear switch-off of the most extreme space weather events occurs when > 90 % of solar active region areas have moved to within about 15° of the solar equator, from regions of high gradient in solar differential rotation which can power coronal mass ejections, to a region where solar differential rotation is almost constant with latitude. More moderate space weather events which coincide with 27 day solar rotation recurrences in the aa index, consistent with stable, persistent source regions of high speed streams, commence when the centroid of solar active region areas moves to within 15° of the solar equator. This offers a physical explanation for the longstanding identification of a two component cycle of activity in the aa index.

Identification and treatment of Strongyloides stercoralis infection in a Boston Terrier dog from south-eastern Australia.

Strongyloides stercoralis, the causative agent of strongyloidiasis, is a potentially zoonotic intestinal nematode endemic to northern Australia. Strongyloidiasis is typically observed in immunocompromised hosts and is characterised by gastrointestinal signs, respiratory symptoms and a failure to thrive. In immunocompromised hosts, hyperinfection syndrome and disseminated infections can prove life-threatening. A 24-month-old Boston Terrier dog was referred for investigation of chronic small and large intestinal watery hematochezic diarrhoea, emaciation and hematemesis. Small intestinal histology identified a nematode despite consecutive negative faecal flotations. A real-time polymerase chain reaction and Baermann test subsequently confirmed infection with S. stercoralis. The dog had received an oral parasiticide comprising milbemycin oxime and afoxolaner every month for the 11 months prior to this diagnosis. Despite fenbendazole being reported as successful in the treatment of canine strongyloidiasis, a course of fenbendazole failed to clear the infection. Eradication of S. stercoralis infection was confirmed after the administration of off-label ivermectin fortnightly for 12 doses. Attention should be paid to this nematode as the failure of routine copromicroscopic methods to diagnose S. stercoralis infections can result in misdiagnosis, mistreatment and progression of the disease. Off-label ivermectin may be an alternative to fenbendazole for the treatment of Strongyloides spp. infection in dogs.

Motility-Induced Phase Separation Mediated by Bacterial Quorum Sensing.

We study motility-induced phase separation (MIPS) in living active matter, in which cells interact through chemical signaling, or quorum sensing. In contrast to previous theories of MIPS, our multiscale continuum model accounts explicitly for genetic regulation of signal production and motility. Through analysis and simulations, we derive a new criterion for the onset of MIPS that depends on features of the genetic network. Furthermore, we identify and characterize a new type of oscillatory instability that occurs when gene regulation inside cells promotes motility in higher signal concentrations.

Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis.

During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC-fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells.

Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk.

Primary myelofibrosis is an untreatable age-related disorder of haematopoiesis in which a break in the crosstalk between progenitor Haematopoietic Stem Cells (HSCs) and neighbouring mesenchymal stem cells causes HSCs to rapidly proliferate and migrate out of the bone marrow. Around 90% of patients harbour mutations in driver genes that all converge to overactivate haematopoietic JAK-STAT signalling, which is thought to be critical for disease progression, as well as microenvironment modification induced by chronic inflammation. The trigger to the initial event is unknown but dysregulated thrombopoietin (TPO) and Toll-Like Receptor (TLR) signalling are hypothesised to initiate chronic inflammation which then disrupts stem cell crosstalk. Using a systems biology approach, we have constructed an intercellular logical model that captures JAK-STAT signalling and key crosstalk channels between haematopoietic and mesenchymal stem cells. The aim of the model is to decipher how TPO and TLR stimulation can perturb the bone marrow microenvironment and dysregulate stem cell crosstalk. The model predicted conditions in which the disease was averted and established for both wildtype and ectopically JAK mutated simulations. The presence of TPO and TLR are both required to disturb stem cell crosstalk and result in the disease for wildtype. TLR signalling alone was sufficient to perturb the crosstalk and drive disease progression for JAK mutated simulations. Furthermore, the model predicts probabilities of disease onset for wildtype simulations that match clinical data. These predictions might explain why patients who test negative for the JAK mutation can still be diagnosed with PMF, in which continual exposure to TPO and TLR receptor activation may trigger the initial inflammatory event that perturbs the bone marrow microenvironment and induce disease onset.

Key design elements of successful acute ischemic stroke treatment trials.

PURPOSE: We review key design elements of positive randomized controlled trials (RCTs) in acute ischemic stroke (AIS) treatment and summarize their main characteristics. METHOD: We searched Medline, Pubmed and Cochrane databases for positive RCTs in AIS treatment. Trials were included if (1) they had a randomized controlled design, with (at least partial) blinding for endpoints, (2) they tested against placebo (or on top of standard therapy in a superiority design) or against approved therapy; (3) the protocol was registered and/or published before trial termination and unblinding (if required at study commencement); (4) the primary endpoint was positive in the intention to treat analysis; and (5) the study findings led to approval of the investigational product and/or high ranked recommendations. A topical approach was used, therefore the findings were summarized as a narrative review. FINDINGS: Seventeen positive RCTs met the inclusion criteria. The majority of trials included less than 1000 patients (n = 15), had highly selective inclusion criteria (n = 16), used the modified Rankin score as a primary endpoint (n = 15) and had a frequentist design (n = 16). Trials tended to be national (n = 12), investigator-initiated and performed with public funding (n = 11). DISCUSSION: Smaller but selective trials are useful to identify efficacy in a particular subgroup of stroke patients. It may also be of advantage to limit the number of participating countries and centers to avoid heterogeneity in stroke management and bureaucratic burden. CONCLUSION: The key characteristics of positive RCTs in AIS treatment described here may assist in the design of further trials investigating a single intervention with a potentially high effect size.

Understanding the musculoskeletal injury risk of women in combat: the effect of infantry training and sex on musculoskeletal injury incidence during British Army basic training.

INTRODUCTION: Until recently, women were excluded from British combat roles. Their risk for musculoskeletal injury during basic training is two to three times higher than men. To better understand the musculoskeletal injury risk of women in British Army infantry basic training, we compared injury incidence between (1) men in standard entry training and men in infantry training, to assess the risk of infantry training; and (2) men and women in both standard entry and officer basic training, to assess the risk in women compared with men. METHODS: The incidence of musculoskeletal injury was determined from defence medical records for all men entering infantry training, and for all men and women entering standard entry and officer training, between April 2015 and March 2016. RESULTS: 7390 men (standard entry, n=4229; infantry, n=2683; officer, n=478) and 696 women (standard entry, n=626; officer, n=70) entered basic training. Men in infantry training had a lower incidence of musculoskeletal injury (391 vs 417 per 1000 personnel, OR 0.90 (95% CI 0.81 to 0.99), p=0.028) and a higher incidence of stress fracture (14 vs 5 per 1000 personnel, OR 2.80 (95% CI 1.64 to 4.80), p<0.001) than men in standard entry training. Women had a higher incidence of musculoskeletal injury than men in standard entry training (522 vs 417 per 1000 personnel, OR 1.53 (95% CI 1.29 to 1.81), p<0.001) and a higher incidence of stress fracture than men in officer training (114 vs 19 per 1000 personnel, OR 6.72 (95% CI 2.50 to 18.07), p<0.001). CONCLUSION: Women in infantry training may be at similar risk for musculoskeletal injury, but at higher risk for stress fracture, compared with their non-infantry counterparts. Women in infantry training may be at higher risk for musculoskeletal injury and stress fracture compared with men in infantry training.

Age-specific information resources to address the needs of young people with stroke: a scoping review protocol.

BACKGROUND AND AIMS: Young people with stroke (YPwS) persistently experience challenges with disability, social reintegration, employment, and financial stability to provide for themselves and their families. The aims of this scoping review are to (1) identify and collate information resources for YPwS and evidence-based self-managements programs and (2) identify gaps in age-specific resources available for YPwS after traditional rehabilitation services have ended and/or who are returning to live in the community. METHODS: We will include both qualitative and quantitative studies, including all study designs. Participants will be community-dwelling adults aged between 18 and 65 years with a clinical diagnosis of stroke. We will include information resources and evidence-based self-managements programs for YPwS. Search terms will include stroke, young people, and community dwelling. We will search electronic databases such as MEDLINE. The reference lists of included studies, systematic reviews, and stroke guidelines and stroke-specific websites will also be searched. We will also contact Stroke Support Organizations and international/national allied health professional organisations to gather information resources about YPwS. We will also conduct a comprehensive environmental scan of additional resources using the search engine Google. The titles, abstracts, full-text articles, and contents of the resources identified by the search will be assessed against the inclusion and exclusion criteria to identify potentially relevant resources. RESULTS AND CONCLUSIONS: Existing resources and self-management programs will be collated and categorized according to the type of needs addressed such as physical, emotions, activities of daily living, information, relationships, and social needs as well as the key gaps identified.

Can Pediatric Primary Care Practices Afford Integrated Behavioral Health? A Comparison of 5 Pediatric Practices.

Licensed behavioral health providers (LBHPs) were integrated into 5 pediatric primary care practices in southeast and east Texas from October 2018 through March 2020. LBHPs Licensed behavioral health providers across the sites were 3 licensed clinical social workers (LCSW), 1 psychologist, and 1 nurse practitioner (NP). Practices provided data for 6 to 15 months. Overall, 2769 units of behavioral health services were provided to 746 children over 2243 hours. Across 4 sites, 44.3% of behavioral health patients were diagnosed with trauma disorders, 22.1% with anxiety, 19.3% with attention-deficit hyperactivity disorder, 15.1% with depression, and 10.9% with disruptive behavior disorders. Overall, the model was financially successful at 2 sites (LCSWs) and unsuccessful at 1 site (NP). The other 2 sites demonstrated potential for financial sustainability with increased behavioral health patient volume. Overall, this model is a financially viable option for pediatric primary care practices with adequate patient volumes to provide integrated behavioral health services.

Nutritional knowledge in British Army recruits during basic training.

BACKGROUND: Appropriate nutritional intake is essential to optimise both general health and performance in military recruits. General nutritional knowledge is a significant and modifiable determinant of dietary behaviour; however, the level of nutritional knowledge in British Army recruits undertaking basic training is poorly understood. METHODS: The Nutritional Knowledge Questionnaire for Athletes was completed by 29 male (age: 22.3±3.8 years) and 26 female (age: 22.0±3.0 years) standard-entry recruits at the end of basic training, and 15 male (age: 20.7±3.2 years) infantry recruits both at the start and end of basic training for the British Army. Between-group and within-group differences in total and subcomponent (ie, carbohydrate, protein, fat, vitamins and minerals, general nutrition, fluid intake, and sporting performance) scores were analysed. RESULTS: Standard-entry male recruits had more correct answers (52%) than standard-entry female recruits (38%) and male infantry recruits (40%) at the end of training. Infantry recruits had similar levels of nutritional knowledge at the start (39% correct) and end (40% correct) of training. Nutritional knowledge related to protein (range: 53%-75% correct answers) and vitamins and minerals (range: 42%-63% correct answers) were the two highest scoring subcomponents within each group. CONCLUSION: British Army recruits, in particular standard-entry female and infantry recruits, have poor nutritional knowledge, which did not improve throughout basic training. Better nutritional intervention, especially surrounding carbohydrate and fluid education, is required during British Army basic training to optimise career-long dietary behaviour.

Normal form for the onset of collapse: The prototypical example of the nonlinear Schrödinger equation.

The study of nonlinear waves that collapse in finite time is a theme of universal interest, e.g., within optical, atomic, plasma physics, and nonlinear dynamics. Here we revisit the quintessential example of the nonlinear Schrödinger equation and systematically derive a normal form for the emergence of radially symmetric blowup solutions from stationary ones. While this is an extensively studied problem, such a normal form, based on the methodology of asymptotics beyond all algebraic orders, applies to both the dimension-dependent and power-law-dependent bifurcations previously studied. It yields excellent agreement with numerics in both leading and higher-order effects, it is applicable to both infinite and finite domains, and it is valid in both critical and supercritical regimes.

Magnetic Topology of Actively Evolving and Passively Convecting Structures in the Turbulent Solar Wind.

Multipoint in situ observations of the solar wind are used to identify the magnetic topology and current density of turbulent structures. We find that at least 35% of all structures are both actively evolving and carrying the strongest currents, actively dissipating, and heating the plasma. These structures are comprised of ∼1/5 3D plasmoids, ∼3/5 flux ropes, and ∼1/5 3D X points consistent with magnetic reconnection. Actively evolving and passively advecting structures are both close to log-normally distributed. This provides direct evidence for the significant role of strong turbulence, evolving via magnetic shearing and reconnection, in mediating dissipation and solar wind heating.

Network community structure of substorms using SuperMAG magnetometers.

Geomagnetic substorms are a global magnetospheric reconfiguration, during which energy is abruptly transported to the ionosphere. Central to this are the auroral electrojets, large-scale ionospheric currents that are part of a larger three-dimensional system, the substorm current wedge. Many, often conflicting, magnetospheric reconfiguration scenarios have been proposed to describe the substorm current wedge evolution and structure. SuperMAG is a worldwide collaboration providing easy access to ground based magnetometer data. Here we show application of techniques from network science to analyze data from 137 SuperMAG ground-based magnetometers. We calculate a time-varying directed network and perform community detection on the network, identifying locally dense groups of connections. Analysis of 41 substorms exhibit robust structural change from many small, uncorrelated current systems before substorm onset, to a large spatially-extended coherent system, approximately 10 minutes after onset. We interpret this as strong indication that the auroral electrojet system during substorm expansions is inherently a large-scale phenomenon and is not solely due to many meso-scale wedgelets.

Transparency in surgical randomized clinical trials: cross-sectional observational study.

BACKGROUND: RCTs provide the scientific basis upon which treatment decisions are made. To facilitate critical review, it is important that methods and results are reported transparently. The aim of this study was to explore transparency in surgical RCTs with respect to trial registration, disclosure of funding sources, declarations of investigator conflicts and data-sharing. METHODS: This was a cross-sectional review of published surgical RCTs. Ten high-impact journals were searched systematically for RCTs published in years 2009, 2012, 2015 and 2018. Four domains of transparency were explored: trial registration, disclosure of funding, disclosure of investigator conflicts, and a statement relating to data-sharing. RESULTS: Of 611 RCTs, 475 were eligible for analysis. Some 397 RCTs (83.6 per cent) were registered on a trial database, of which 190 (47·9 per cent) had been registered prospectively. Prospective registration increased over time (26 per cent in 2009, 33·0 per cent in 2012, 54 per cent in 2015, and 72·7 per cent in 2018). Funding disclosure was present in 55·0, 65·0, 69·4 and 75·4 per cent of manuscripts respectively. Conflict of interest disclosure was present in 49·5, 89·1, 94·6 and 98·3 per cent of manuscripts across the same time periods. Data-sharing statements were present in only 15 RCTs (3·2 per cent), 11 of which were published in 2018. CONCLUSION: Trial registration, disclosure of funding and disclosure of investigator conflicts in surgical RCTs have improved markedly over the past 10 years. Disclosure of data-sharing plans is exceptionally low. This may contribute to research waste and represents a target for improvement.

ANTECEDENTES: Los ensayos clínicos aleatorizados y controlados (randomized controlled trials, RCT) proporcionan la base científica para la toma de decisiones terapéuticas. Es importante que los métodos y los resultados se presenten de forma transparente para facilitar la revisión crítica. El objetivo de este estudio fue investigar la transparencia en los RCTs del ámbito quirúrgico según su registro, declaraciones de las fuentes de financiación del estudio y conflicto de interés de los investigadores, así como información referente a compartir los datos. MÉTODOS: Revisión transversal de RCTs quirúrgicos publicados. Se realizó una búsqueda sistemática de los RCTs publicados en 10 revistas de alto impacto en los años 2009, 2012, 2015 y 2018. Se exploraron cuatro dominios de transparencia: el registro de los ensayos, la declaración de los fondos utilizados, la declaración de los conflictos de los investigadores y la información referente a la forma de compartir los datos. RESULTADOS: De 611 RCTs, se incluyeron en el análisis 475. Un total de 397 (83,6%) estudios se registraron en una base de datos de ensayos clínicos, de forma prospectiva en 190 (47,9%). El registro prospectivo aumentó a lo largo del tiempo (26,0% en 2009, 33,0% en 2012, 53,5% en 2015 y 72,7% en 2018). Se mencionaban las fuentes de financiación en el 55%, 65%, 69,4% y 75,4% de los manuscritos, respectivamente. La declaración de conflictos de interés estuvo presente en el 49,5%, 89,1%, 94,6% y 98,3% de los manuscritos en esos mismos períodos de tiempo. Las declaraciones relativas a compartir los datos de la investigación constaban en solo 15 (3,2%) RCTs, 11 de los cuales fueron publicados en el 2018. CONCLUSIÓN: En los últimos 10 años ha mejorado de forma notable el registro de los ensayos y las declaraciones de las fuentes de financiación y conflicto de interés en los RCTs quirúrgicos. La declaración referente a compartir los datos es excepcionalmente baja, lo que puede contribuir al desperdicio de la investigación y constituye un objetivo de mejora.

Patient education about recovery after colorectal surgery: systematic scoping review.

AIM: Enhanced recovery after surgery (ERAS) protocols aim to optimize recovery through a series of evidence-based recommendations. A key component of ERAS is the provision of patient education. Whilst the recommendation for this is strong, the evidence to inform its format, timing and delivery is unclear. The aim of this review was to describe previous educational interventions used to improve recovery after colorectal surgery and to explore opportunities for future research. METHODS: A systematic scoping review was performed. MEDLINE and Embase databases were searched between 1 January 1990 and 12 February 2020. Studies which described or assessed the effectiveness of a patient education or information resource to improve recovery after colorectal surgery were eligible. Outcomes of interest included the format, timing and delivery of interventions, as well as key features of intervention and study design. A narrative synthesis of data was produced through a process of charting and summarizing key results. RESULTS: A total of 1298 papers were inspected, and 11 were eligible for inclusion. Five papers were reports of randomized controlled trials, and others reported a mix of non-randomized and qualitative studies. The design of educational interventions included audio-visual resources (n = 3), smartphone device applications (n = 3) and approaches to facilitate person-to-person counselling (n = 5). Most of the counselling interventions reported positive outcomes (mainly in length of hospital stay), whereas the other types reported mixed results. Patients and the public were seldom involved as collaborators in the design of interventions. CONCLUSIONS: Patient education is generally advantageous, but there is insufficient evidence to optimize its design and delivery in the setting of colorectal surgery.

Modeling Osteocyte Network Formation: Healthy and Cancerous Environments.

Advanced cancers, such as prostate and breast cancers, commonly metastasize to bone. In the bone matrix, dendritic osteocytes form a spatial network allowing communication between osteocytes and the osteoblasts located on the bone surface. This communication network facilitates coordinated bone remodeling. In the presence of a cancerous microenvironment, the topology of this network changes. In those situations, osteocytes often appear to be either overdifferentiated (i.e., there are more dendrites than healthy bone) or underdeveloped (i.e., dendrites do not fully form). In addition to structural changes, histological sections from metastatic breast cancer xenografted mice show that number of osteocytes per unit area is different between healthy bone and cancerous bone. We present a stochastic agent-based model for bone formation incorporating osteoblasts and osteocytes that allows us to probe both network structure and density of osteocytes in bone. Our model both allows for the simulation of our spatial network model and analysis of mean-field equations in the form of integro-partial differential equations. We considered variations of our model to study specific physiological hypotheses related to osteoblast differentiation; for example predicting how changing biological parameters, such as rates of bone secretion, rates of cancer formation, and rates of osteoblast differentiation can allow for qualitatively different network topologies. We then used our model to explore how commonly applied therapies such as bisphosphonates (e.g., zoledronic acid) impact osteocyte network formation.

The outcome of pregnancy in women with cystic fibrosis: a UK population-based descriptive study.

OBJECTIVE: To estimate the incidence of cystic fibrosis in pregnancy and to explore obstetric and neonatal outcomes. DESIGN: A population-based descriptive study using the methodology of the UK Obstetric Surveillance System (UKOSS). SETTING: All consultant-led maternity units in the UK. POPULATION: All pregnant women with a diagnosis of cystic fibrosis who booked for antenatal care in a UK obstetric unit between March 2015 and February 2017. METHODS: Prospective case collection identified using UKOSS monthly notification. MAIN OUTCOME MEASURES: Incidence, maternal morbidity, maternal mortality, gestation at delivery, neonatal mortality, neonatal morbidity. RESULTS: We report 71 pregnancies over a 2-year period. There was one early miscarriage, four terminations and three sets of twins, resulting in the live birth of 69 infants. There were no maternal deaths. One infant died following spontaneous preterm birth at 29 weeks' gestation. The mean gestation at delivery was 36.2 completed weeks. The mean birthweight centile for gestational age was the 61st centile. We report a positive correlation between both maternal lung function (FEV1 ) and mean gestation at delivery, and between FEV1 and mean birthweight centile for gestational age. CONCLUSIONS: Pregnancy outcomes are generally good in women with cystic fibrosis. Successful pregnancy is possible even in those women with FEV1 <60% predicted, although such women have higher chance of preterm delivery and a smaller baby. TWEETABLE ABSTRACT: Pregnant women with cystic fibrosis who have poorer lung function at the beginning of pregnancy have a higher risk of having a premature or smaller baby.

Quality and effectiveness of osteoporosis treatment decision aids: a systematic review and environmental scan.

Decision aids (DAs) are evidence-based tools that support shared decision-making (SDM) implementation in practice; this study aimed to identify existing osteoporosis DAs and assess their quality and efficacy; and to gain feedback from a patient advisory group on findings and implications for further research. We searched multiple bibliographic databases to identify research studies from 2000 to 2019 and undertook an environmental scan (search conducted February 2019, repeated in March 2020). A pair of reviewers, working independently selected studies for inclusion, extracted data, evaluated each trial's risk of bias, and conducted DA quality assessment using the International Patient Decision Aid Standards (IPDAS). Public contributors (patients and caregivers with experience of osteoporosis and fragility fractures) participated in discussion groups to review a sample of DAs, express preferences for a new DA, and discuss plans for development of a new DA. We identified 6 studies, with high or unclear risk of bias. Across included studies, use of an osteoporosis DA was reported to result in reduced decisional conflict compared with baseline, increased SDM, and increased accuracy of patients' perceived fracture risk compared with controls. Eleven DAs were identified, of which none met the full set of IPDAS criteria for certification for minimization of bias. Public contributors expressed preferences for encounter DAs that are individualized to patients' own needs and risk. Using a systematic review and environmental scan, we identified 11 decision aids to inform patient decisions about osteoporosis treatment and 6 studies evaluating their effectiveness. Use of decision aids increased accuracy of risk perception and shared decision-making but the decision aids themselves fail to comprehensively meet international quality standards and patient needs, underpinning the need for new DA development.