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Doctoral researchers and early career researchers (ECRs) are crucial to producing scientific advancements and represent the future of academic leadership. Their research endeavours were changed radically by lockdowns in response to the COVID-19 pandemic. The aim of this study was to explore the perceived benefits and challenges of the national lockdown in the UK from the perspective of doctoral researchers and ECRs. We present analysis of qualitative survey data from 1,142 doctoral researchers and ECRs on their experiences of the first UK lockdown collected from April 16, 2020-May 14, 2020. Our findings suggest considerable heterogeneity in how the pandemic impacted this key group of academic workers. Challenges arising from the lockdown largely cohered around a poor work environment, limited access to resources, perceptions of pressure, and negative psychological outcomes. Conversely, respondents also highlighted several benefits in the early stages of the pandemic, with the change to working from home creating more time, resulting in greater productivity and a better work-life balance. Collectively, findings indicate the importance of considering the personal circumstances and needs of individual researchers. We discuss the implications for support these researchers require to rebuild their careers in the wake of the initial disruption., Author(s): Patricia C. Jackman [sup.1] , Rebecca Sanderson [sup.2] , Tandy J. Haughey [sup.3] , Caroline E. Brett [sup.4] , Naomi White [sup.5] , Amy Zile [sup.6] , Katie Tyrrell [...]

Despite introduction and recommendation of the capsular polysaccharide pneumococcal vaccine in Canada during 1989 to persons >65 years of age, Streptococcus pneumoniae is still a cause of major illness and [...]

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.

Qualitative platelet disorders remain rare and varied. We describe here 2 additional patients with giant platelets, thrombocytopenia, deficiency in alpha granules and the presence of membranous inclusions within the cytoplasm. Collectively known as Medich syndrome, we further elucidated structural and clinical features of this rare syndrome. Platelets obtained from 2 patients with macro-thrombocytopenia were evaluated by electron microscopy. Structural findings were correlated with clinical characteristics. The defining morphologic feature found in the platelets of these patients is the presence of long, tubular inclusions consisting of several layers of membrane wrapped around a core of cytoplasm. These inclusions may deform the discoid shape of the platelet. In addition, abnormal giant alpha granules are present. Clinically all patients in the current report and review of the literature had mucosal bleeding and were often misdiagnosed as having immune related thrombocytopenia. To date five cases of Medich giant platelet syndrome have been reported. The cases are unified by the ultrastructural findings of abnormal alpha granules and unusual cytoplasmic scrolls. All patients experienced mucosal bleeding, however many clinical, biologic and genetic characteristics of this rare disorder remain to be determined.

Background and aims – Rhipidocladum, a woody bamboo genus distributed from Mexico to Argentina, has raceme like synflorescences of multiple spikelets. Six of the 21 known species occur in Mexico. In this study, we present a full description, distribution map, illustrations, and photographs of an unusual new Rhipidocladum species endemic to Jalisco, Mexico. Additionally, we provide an updated key to the species of Rhipidocladum in Mexico. Material and methods – This study was based on fieldwork, literature, and herbarium specimens review. Specimens collected were analysed and photographed during fieldwork. The conservation assessment is based on spatial analyses, following the IUCN guidelines and criteria. Results – This is the first species in the genus Rhipidocladum that has synflorescences with only a single, terminal spikelet. Rhipidocladum singuliflorum occurs only in three localities in the municipality of Puerto Vallarta, Jalisco, Mexico. This species inhabits the canyon slopes of rivers in subdeciduous and tropical dry forests, at 6–150 m a.s.l. According to our IUCN assessment, this new species should be considered Critically Endangered.

Abstract Background Patient engagement is an important tool for quality improvement (QI) and optimizing the uptake of research findings. The Plan-Do-Study-Act (PDSA) model is a QI tool that encourages ongoing evaluation of clinical care, thus improving various aspects of patient care. Ascertaining pediatric patient priorities for a pain questionnaire in the post-acute, or transitional pain, setting is important to guide clinical care since active engagement with the population of interest can optimize uptake. We used the PDSA model to adapt a chronic pain questionnaire for the pediatric transitional pain setting to reflect pediatric patient and parent/guardian preferences and to form an example of how the PDSA model can be used to improve clinical care through patient engagement. Methods This project employed the PDSA model to adapt the pediatric Ontario Chronic Pain Questionnaire for use in the pediatric Transitional Pain Service (pedTPS) setting. Plan: Following reviewing the Ontario Chronic Pain Questionnaire and literature on pain questionnaire development, goal-based questions, questions on pain location, relevant Patient-Reported Outcomes Measurement Information System (PROMIS®) measures and the Pain Catastrophizing Scale, child (PCS-C) and parent (PCS-P), informed the questionnaire. Do: The questionnaire and a satisfaction survey were sent to patients and families through Research Electronic Data Capture (REDCap™). Study: Results from the satisfaction survey were analyzed. Act: Using descriptive statistics employing ordinal mixed-models with random effects, ANOVA, and double-blinded qualitative thematic coding, questionnaire preferences were analyzed and the questionnaire was adapted accordingly before implementation into the (pedTPS). Results Eighty-eight questionnaires and satisfaction surveys were analyzed from 69 respondents (32 patients; 37 parents/guardians). Sixty-six (75.00%) surveys indicated satisfaction with the questionnaire. A combined 77 (87.50%) “strongly agreed” (25/88) or “agreed” (52/88) that the questionnaire language was clear. The application of suggested changes to the questionnaire resulted in four versions across the project timeline, which reflected patient and parent/guardian preferences for questions that reflect the themes, “Story”; “Time-Optimal”; and “Pertinent” (“STOP”). There were no statistically significant differences in satisfaction across the versions due to sample size. Conclusion Most respondents were satisfied with the questionnaire and prefer “STOP” questions. Future studies will focus on testing the questionnaire for validity and reliability across pedTPS populations.

The interferon response is a critical component response to SARS-CoV-2 infection and prior studies have established a role for the administration of PEGylated interferon-lambda1 and its impact on viral clearance. Here the authors show that PEGylated interferon-lambda1 accelerates the clearance of SARS-CoV-2 despite the negative impact of age on the host T cell response.

The relationship between increased short-term mortality rates after invasive pneumococcal disease (IPD) has been frequently studied. However, the relationship between IPD and long-term mortality rates is unknown. IPD patients in Alberta, Canada, had clinical data collected that were linked to administrative databases. We used Cox proportional hazards modeling, and the primary outcome was time to all-cause deaths. First IPD events were identified in 4,522 patients, who had a median follow-up of 3.2 years (interquartile range 0.8‒9.1 years). Overall all-cause mortality rates were consistently higher among cases than controls at 30 days (adjusted hazard ratio [aHR] 3.75, 95% CI 3.29–4.28), 30‒90 days (aHR 1.56, 95% CI 1.27‒1.93), and >90 days (aHR 1.43, 95% CI 1.33–1.54). IPD increases risk for short, intermediate, and long-term mortality rates regardless of age, sex, or concurrent conditions. These findings can help clinicians focus on postdischarge patient plans to limit long-term effects after acute IPD infection.

The stratosphere can be a source of predictability for surface weather on timescales of several weeks to months. However, the potential predictive skill gained from stratospheric variability can be limited by biases in the representation of stratospheric processes and the coupling of the stratosphere with surface climate in forecast systems. This study provides a first systematic identification of model biases in the stratosphere across a wide range of subseasonal forecast systems. It is found that many of the forecast systems considered exhibit warm global-mean temperature biases from the lower to middle stratosphere, too strong/cold wintertime polar vortices, and too cold extratropical upper-troposphere/lower-stratosphere regions. Furthermore, tropical stratospheric anomalies associated with the Quasi-Biennial Oscillation tend to decay toward each system's climatology with lead time. In the Northern Hemisphere (NH), most systems do not capture the seasonal cycle of extreme-vortex-event probabilities, with an underestimation of sudden stratospheric warming events and an overestimation of strong vortex events in January. In the Southern Hemisphere (SH), springtime interannual variability in the polar vortex is generally underestimated, but the timing of the final breakdown of the polar vortex often happens too early in many of the prediction systems. These stratospheric biases tend to be considerably worse in systems with lower model lid heights. In both hemispheres, most systems with low-top atmospheric models also consistently underestimate the upward wave driving that affects the strength of the stratospheric polar vortex. We expect that the biases identified here will help guide model development for subseasonal-to-seasonal forecast systems and further our understanding of the role of the stratosphere in predictive skill in the troposphere.

Abstract Objectives Unlike in adult rheumatology, for most forms of juvenile idiopathic arthritis (JIA) no reliable biomarkers currently exist to assess joint and disease activity. However, electrophoresis is frequently found changed in active juvenile arthritis. The objective of this study was to evaluate the α2-fraction of serum electrophoresis and its main components as biomarkers for JIA, categories extended/persistent oligoarthritis and seronegative polyarthritis, in comparison with the conventionally used erythrocyte sedimentation rate and C-reactive protein. Methods Serum samples and clinical data from 181 patients with JIA were collected. Serum electrophoresis and α2-fraction and its components were determined using standard methods. Relationship between calculated α2-fraction of serum electrophoresis (CA2F) and its components, acute-phase parameters and cJADAS27 was assessed using Pearson’s correlation coefficient and linear regression modelling, adjusting for confounding effects. Results were confirmed in a second cohort with 223 serum samples from 37 patients, using a mixed model to account for repeated measures. Results Compared to ESR and CRP, CA2F showed higher correlation to cJADAS27, in particular for persistent oligoarthritis. Of the three components of the α2-fraction, haptoglobin showed the highest correlation to cJADAS27. Regression analysis demonstrated higher ability to predict cJADAS27 for CA2F, and especially for haptoglobin as a component thereof, than for CRP and ESR. Conclusion Compared to conventional methods, α2-fraction of serum electrophoresis and specifically, haptoglobin show higher correlations with disease activity in common subtypes of JIA, representing excellent candidates as biomarkers for disease activity. Further studies are necessary to determine diagnostic value and correlations in other subtypes.

Mechanical stimulation, such as fluid-induced wall shear stress (WSS), is known that can influence the cellular behaviours. Therefore, in some tissue engineering experiments in vitro, mechanical stimulation is applied via bioreactors to the cells in cell culturing to study cell physiology and pathology. In 3D cell culturing, porous scaffolds are used for housing the cells. It is known that the scaffold porous geometries can influence the scaffold permeability and internal WSS in a bioreactor (such as perfusion bioreactor). To calculate the WSS generated on cells within scaffolds, usually computational fluid dynamics (CFD) simulation is needed. However, the limitations of the computational method for WSS calculation are: (i) the high time cost of the CFD simulation (in particular for the highly irregular geometries); (ii) accessibility to the CFD model for some cell culturing experimentalists due to the knowledge gap. To address these limitations, this study aims to develop an empirical model for calculating the WSS based on scaffold permeability. This model can allow the tissue engineers to efficiently calculate the WSS generated within the scaffold and/or determine the bioreactor loading without performing the computational simulations.

ABSTRACT Escherichia coli persistently colonizes the mammalian intestine by mechanisms that are not fully understood. Previously, we found when streptomycin-treated mice were fed E. coli MG1655, the intestine selected for envZ missense mutants that outcompeted the wild type. The better-colonizing envZ mutants had a higher level of OmpC and reduced OmpF. This suggested the EnvZ/OmpR two-component system and outer membrane proteins play a role in colonization. In this study, we show that wild-type E. coli MG1655 outcompetes an envZ-ompR knockout mutant. Moreover, ompA and ompC knockout mutants are outcompeted by the wild type, while an ompF knockout mutant colonizes better than the wild type. Outer membrane protein gels show the ompF mutant overproduces OmpC. An ompC mutant is more sensitive to bile salts than the wild type and ompF mutant. The ompC mutant initiates colonization slowly because it is sensitive to physiological concentrations of bile salts in the intestine. Overexpression of ompC under the control of a constitutive promoter confers a colonization advantage only when ompF is deleted. These results indicate that fine-tuning of OmpC and OmpF levels is needed to maximize competitive fitness in the intestine. RNA sequencing reveals the EnvZ/OmpR two-component system is active in the intestine: ompC is upregulated and ompF is downregulated. While other factors could also contribute to the advantage provided by OmpC, we provide evidence that OmpC is important for E. coli to colonize the intestine because its smaller pore size excludes bile salts or other unknown toxic substances, while OmpF is deleterious because its larger pore size allows bile salts or other unknown toxic substances to enter the periplasm. IMPORTANCE Every mammalian intestine is colonized with Escherichia coli. Although E. coli is one of the most studied model organisms, how it colonizes the intestine is not fully understood. Here, we investigated the role of the EnvZ/OmpR two-component system and outer membrane proteins in colonization of the mouse intestine by E. coli. We report that an ompC mutant is a poor colonizer, while an ompF mutant, which overproduces OmpC, outcompetes the wild type. OmpF has a larger pore size that allows toxic bile salts or other toxic compounds into the cell and is deleterious for colonization of the intestine. OmpC has a smaller pore size and excludes bile salts. Our findings provide insights into why E. coli fine-tunes the levels of OmpC and OmpF during colonization via the EnvZ/OmpR two-component system.

Introduction Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%–15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families.Method and analysis To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk.Ethics and dissemination By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients.Trial registration number NCT04903782.

Objetivo: analizar el perfil sociodemográfico y la situación de cuidado de los adultos mayores dependientes y sus cuidadores familiares en Brasil y Colombia. Método: investigación comparativa mixta y de tipo exploratorio, la cual sigue las fases de estudios comparativos propuestos por Bereday: descripción, interpretación, yuxtaposición y comparación. Se utilizó una entrevista semiestructurada. Se tuvieron en cuenta los principios éticos nacionales e internacionales dentro del estudio, con la aprobación de cada comité de ética en cada país. Resultados: fueron entrevistados 250 participantes: 52 adultos mayores dependientes en Brasil y 56 en Colombia, y 70 cuidadores familiares en Brasil y 72 en Colombia. El 68,5 % de los adultos mayores y el 83,8 % de los cuidadores eran mujeres. Se construyeron doce categorías a partir del discurso de los participantes, seis en los adultos mayores dependientes y seis en los cuidadores. Conclusión: hubo predominio de las mujeres e hijas como la mayoría de las cuidadoras familiares, así como la religión católica como la más prevalente en ambos países. Respecto a la situación de cuidado, en ambos países destaca que los adultos mayores dependientes y los cuidadores familiares sienten la presencia de un ser superior ayudándolos a superar los desafíos en las actividades de cuidado.

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of human coronaviruses to IFNs has been characterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3 activation effectively promotes transcription of antiviral genes during OC43 or 229E infection. Our study suggests that IRFs may be effective antiviral regulators against human coronavirus infection.