This qualitative study examined parents' experiences of supporting their children during the COVID-19 pandemic. Eighteen parents of children aged 2-16 years from diverse backgrounds, living in the ...UK, were interviewed one-to-one about their experiences. Ten professionals working with children and families were also interviewed to gain a broader perspective of parents' experiences. Using Reflexive Thematic Analysis, four themes were developed: (a) worries and uncertainties; (b) mental exhaustion; (c) resources available to cope with the challenges; and (d) finding the positives. Findings revealed the worries and uncertainties that parents faced regarding how best to support their child and the long-term consequences of the pandemic, as well as feelings of mental exhaustion from juggling multiple responsibilities. The impact of COVID-19 on parents' wellbeing was varied and parents identified several factors that determined their ability to support their children, such as space in the home environment, support networks and their personal mental health. Despite the challenges, some parents reported positive experiences, such as strengthened family bonds during the pandemic. Our study emphasizes the importance of flexible work arrangements and family-friendly employment policies, as well as support for parents to enable them to support their children and look after their own wellbeing.
Abstract Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the ...MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. Methods To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Results Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. Conclusions We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
Cultures of governance and peace Burgess, J. Peter; Richmond, Oliver P; Samaddar, Ranabir
2016, 2016., 20160910, 2016-09-10
eBook
This volume brings together insights which look at the intersection of governance, culture and conflict resolution in India and the European Union. Two very different but connected epistemic, ...cultural and institutional settings, which have been divided by distance, colonialism and culture; yet have recently been brought closer together by ideas and practices of what is known as liberal peace, neoliberal state and development projects. The differences are obvious in terms of geography, culture, the nature and shape of institutions, and historical forces: and yet the commonalities between the two are surprising. This is the first book to compare contemporary Indian and European Union approaches to peace and is based on strong case studies and rigorous analysis. Postgraduate students, peace and conflict researchers, policy-makers and practitioners will benefit immensely from insights provided in this book.
There is emerging evidence of the detrimental impact of the pandemic and associated restrictions on young people’s mental health in the UK but to date, these data have been largely quantitative. The ...aim of the current study was to gain a deeper understanding of young people’s experiences in relation to their mental health and wellbeing during the pandemic. Seventeen young people, aged 11 to 16 years, sampled for diverse characteristics, and living in the UK, were interviewed virtually between December 2020 and February 2021. Reflexive thematic analysis was carried out by the research team, which included two young people, and five themes were developed: (1) positives; (2) worries and anxiety; (3) sadness and anger about losses; (4) mental exhaustion; and (5) support from others. Aspects of young people’s individual circumstances (e.g., pre-existing mental health difficulties; special educational needs and neurodevelopmental disorders) appeared to play a role in their experiences. Continued measurement of young people’s mental health, initiatives to identify young people who have been struggling and the provision of support (including evidence-based and accessible interventions) will be important for protecting young people from future adversities as we emerge from the pandemic.
Objective: To comparatively evaluate hypertonic sodium (HTS) and mannitol in patients following acute traumatic brain injury (TBI) on the outcomes of all-cause mortality, neurological disability, ...intracranial pressure (ICP) change from baseline, ICP treatment failure, and serious adverse events. Data Sources: PubMed, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and WHO ICTRP (World Health Organization International Clinical Trials Registry Platform) were searched (inception to November 2015) using hypertonic saline solutions, sodium chloride, mannitol, osmotic diuretic, traumatic brain injury, brain injuries, and head injury. Searches were limited to humans. Clinical practice guidelines and bibliographies were reviewed. Study Selection and Data Extraction: Prospective, randomized trials comparing HTS and mannitol in adults (≥16 years) with severe TBI (Glasgow Coma Scale score ≤8) and elevated ICP were included. ICP elevation, ICP reduction, and treatment failure were defined using study definitions. Data Synthesis: Of 326 articles screened, 7 trials enrolling a total of 191 patients met inclusion criteria. Studies were underpowered to detect a significant difference in mortality or neurological outcomes. Due to significant heterogeneity and differences in reporting ICP change from baseline, this outcome was not meta-analyzed. No difference between HTS and mannitol was observed for mean ICP reduction; however, risk of ICP treatment failure favored HTS (risk ratio RR = 0.39; 95% CI = 0.18-0.81). Serious adverse events were not reported. Conclusions: Based on limited data, clinically important differences in mortality, neurological outcomes, and ICP reduction were not observed between HTS or mannitol in the management of severe TBI. HTS appears to lead to fewer ICP treatment failures.
Abstract Objective To examine longitudinal associations of participation in regular family meals (≥ 5 meals/week) with eating habits and dietary intake during adolescence. Design Population-based, ...longitudinal study (Project EAT: Eating Among Teens). Surveys were completed in Minnesota classrooms at Time 1 (1998-1999) and by mail at Time 2 (2003-2004). Setting Baseline surveys were completed in Minneapolis/St. Paul, Minnesota, schools and by mail at follow-up. Participants 677 adolescents (303 males and 374 females) who were in middle school at Time 1 (mean age = 12.8 ± 0.74 years) and high school at Time 2 (mean age = 17.2 ± 0.59 years). Main Outcome Measures Dietary intake, frequency of meals, and fast-food intake patterns. Analysis Generalized linear modeling stratified by gender and adjusted for race/ethnicity, socioeconomic status, and the Time 1 outcome. Results Regular family meals were positively associated with Time 2 frequency of breakfast, lunch, and dinner meals for males and breakfast and dinner meals for females. Among males, regular family meals were negatively associated with Time 2 fast-food intake. Regular family meals were also positively associated with Time 2 mean daily intakes of vegetables, calcium-rich food, fiber, calcium, magnesium, potassium, iron, zinc, folate, and vitamins A and B6 among both genders. Conclusions and Implications Regular family meals during early adolescence may contribute to the formation of healthful eating habits 5 years later. Parents should be made aware of the importance of shared mealtime experiences.
Dynein structure and power stroke Burgess, Stan A; Walker, Matt L; Sakakibara, Hitoshi ...
Nature (London),
02/2003, Volume:
421, Issue:
6924
Journal Article
Peer reviewed
Open access
Dynein ATPases are microtubule motors that are critical to diverse processes such as vesicle transport and the beating of sperm tails; however, their mechanism of force generation is unknown. Each ...dynein comprises a head, from which a stalk and a stem emerge. Here we use electron microscopy and image processing to reveal new structural details of dynein c, an isoform from Chlamydomonas reinhardtii flagella, at the start and end of its power stroke. Both stem and stalk are flexible, and the stem connects to the head by means of a linker approximately 10 nm long that we propose lies across the head. With both ADP and vanadate bound, the stem and stalk emerge from the head 10 nm apart. However, without nucleotide they emerge much closer together owing to a change in linker orientation, and the coiled-coil stalk becomes stiffer. The net result is a shortening of the molecule coupled to an approximately 15-nm displacement of the tip of the stalk. These changes indicate a mechanism for the dynein power stroke.
Remodelling the contractile apparatus within smooth muscle cells allows effective contractile activity over a wide range of cell lengths. Thick filaments may be redistributed
via depolymerisation ...into inactive myosin monomers that have been detected
in vitro, in which the long tail has a folded conformation. Using negative stain electron microscopy of individual folded myosin molecules from turkey gizzard smooth muscle, we show that they are more compact than previously described, with heads and the three segments of the folded tail closely packed. Heavy meromyosin (HMM), which lacks two-thirds of the tail, closely resembles the equivalent parts of whole myosin. Image processing reveals a characteristic head region morphology for both HMM and myosin, with features identifiable by comparison with less compact molecules. The two heads associate asymmetrically: the tip of one motor domain touches the base of the other, resembling the blocked and free heads of this HMM when it forms 2D crystals on lipid monolayers. The tail of HMM lies between the heads, contacting the blocked motor domain, unlike in the 2D crystal. The tail of whole myosin is bent sharply and consistently close to residues 1175 and 1535. The first bend position correlates with a skip in the coiled coil sequence, the second does not. Tail segments 2 and 3 associate only with the blocked head, such that the second bend is near the C-lobe of the blocked head regulatory light chain. Quantitative analysis of tail flexibility shows that the single coiled coil of HMM has an apparent Young's modulus of about 0.5 GPa. The folded tail of the whole myosin is less flexible, indicating interactions between the segments. The folded tail does not modify the compact head arrangement but stabilises it, indicating a structural mechanism for the very low ATPase activity of the folded molecule.
Context: Scrutiny of hospital readmissions has led to the development and implementation of policies targeted at reducing readmission rates. Objective: To assess whether historic hospital readmission ...rates predict risk-adjusted patient readmission and to measure the costs of readmission, thus informing reimbursement policies under consideration by non-Veterans Health Administration payers. Design, Settings, and Participants: Multivariable hospital-fixed effects regression analyses of patients admitted to 129 Veterans Health Administration hospitals between 2005 and 2009 for 3 common conditions, acute myocardial infarction (AMI), community-acquired pneumonia (CAP), and congestive heart failure (CHF). Main Outcome Measures: We examined whether previous hospital readmission rates predicted risk-adjusted readmission or 30-day episode cost of care for subsequent patients. We then examined the 30-day inpatient hospitalization episode cost differences between those who had a readmission in the episode and those who did not. Results: Hospital readmission rates in the previous quarter are not predictive of individual patient risk-adjusted readmission or of patients' inpatient hospitalization episode cost in the subsequent quarter. Relative to those who were not readmitted within 30 days of index visit discharge, readmitted patients had 30-day episode costs that were 53.3% (P < 0.001), 82.8% (P < 0.001), and 79.8% (P < 0.001) higher for AMI, CAP, and CHF hospitalization episodes, respectively. Conclusions: Previous hospital readmission rates are poor predictors of readmission for future individual patients, therefore, policies using these measures to guide subsequent reimbursement are problematic for hospitals that are financially constrained. Our findings indicate current diagnosis related group payments would need to be raised by 10.0% for AMI, 11.5% for CAP, and 16.6% for CHF if these are to become 30-day bundled payments.
The myosin 2 family of molecular motors includes isoforms regulated in different ways. Vertebrate smooth-muscle myosin is activated by phosphorylation of the regulatory light chain, whereas scallop ...striated adductor-muscle myosin is activated by direct calcium binding to its essential light chain. The paired heads of inhibited molecules from myosins regulated by phosphorylation have an asymmetric arrangement with motor-motor interactions. It was unknown whether such interactions were a common motif for inactivation used in other forms of myosin-linked regulation. Using electron microscopy and single-particle image processing, we show that indistinguishable structures are indeed found in myosins and heavy meromyosins isolated from scallop striated adductor muscle and turkey gizzard smooth muscle. The similarities extend beyond the shapes of the heads and interactions between them: In both myosins, the tail folds into three segments, apparently at identical sites; all three segments are in close association outside the head region; and two segments are associated in the same way with one head in the asymmetric arrangement. Thus, these organisms, which have different regulatory mechanisms and diverged from a common ancestor >600 Myr ago, have the same quaternary structure. Conservation across such a large evolutionary distance suggests that this conformation is of fundamental functional importance.
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