Surface dosimetry for breast radiotherapy in the presence of immobilization cast material

Curative breast radiotherapy typically leaves patients with varying degrees of cosmetic damage. One problem interfering with cosmetically acceptable breast radiotherapy is the external contour for large pendulous breasts which often results in high doses to skin folds. Thermoplastic casts are often employed to secure the breasts to maintain setup reproducibility and limit the presence of skin folds. This paper aims to determine changes in surface dose that can be attributed to the use of thermoplastic immobilization casts. Skin dose for a clinical hybrid conformal/IMRT breast plan was measured using radiochromic film and MOSFET detectors at a range ofwater equivalent depths representative of the different skin layers. The radiochromic film was used as an integrating dosimeter, while the MOSFETs were used for real-time dosimetry to isolate the contribution of skin dose from individual IMRT segments. Strips of film were placed at various locations on the breast and the MOSFETs were used to measure skin dose at 16 positions spaced along the film strips for comparison of data. The results showed an increase in skin dose in the presence of the immobilization cast of up to 45.7% and 62.3% of the skin dose without the immobilization cast present as measured with Gafchromic EBT film and MOSFETs, respectively. The increase in skin dose due to the immobilization cast varied with the angle of beam incidence and was greatest when the beam was normally incident on the phantom. The increase in surface dose with the immobilization cast was greater under entrance dose conditions compared to exit dose conditions

Trabecular bone organoids:a micron-scale ‘humanised’ prototype designed to study the effects of microgravity and degeneration

Bone is a highly responsive organ, which continuously adapts to the environment it is subjected to in order to withstand metabolic demands. These events are difficult to study in this particular tissue in vivo, due to its rigid, mineralised structure and inaccessibility of the cellular component located within. This manuscript presents the development of a micron-scale bone organoid prototype, a concept that can allow the study of bone processes at the cell-tissue interface. The model is constructed with a combination of primary female osteoblastic and osteoclastic cells, seeded onto femoral head micro-trabeculae, where they recapitulate relevant phenotypes and functions. Subsequently, constructs are inserted into a simulated microgravity bioreactor (NASA-Synthecon) to model a pathological state of reduced mechanical stimulation. In these constructs, we detected osteoclastic bone resorption sites, which were different in morphology in the simulated microgravity group compared to static controls. Once encapsulated in human fibrin and exposed to analogue microgravity for 5 days, masses of bone can be observed being lost from the initial structure, allowing to simulate the bone loss process further. Constructs can function as multicellular, organotypic units. Large osteocytic projections and tubular structures develop from the initial construct into the matrix at the millimetre scale. Micron-level fragments from the initial bone structure are detected travelling along these tubules and carried to sites distant from the native structure, where new matrix formation is initiated. We believe this model allows the study of fine-level physiological processes, which can shed light into pathological bone loss and imbalances in bone remodelling

Surface dosimetry for breast radiotherapy in the presence of immobilization cast material

Curative breast radiotherapy typically leaves patients with varying degrees of cosmetic damage. One problem interfering with cosmetically acceptable breast radiotherapy is the external contour for large pendulous breasts which often results in high doses to skin folds. Thermoplastic casts are often employed to secure the breasts to maintain setup reproducibility and limit the presence of skin folds. This paper aims to determine changes in surface dose that can be attributed to the use of thermoplastic immobilization casts. Skin dose for a clinical hybrid conformal/IMRT breast plan was measured using radiochromic film and MOSFET detectors at a range ofwater equivalent depths representative of the different skin layers. The radiochromic film was used as an integrating dosimeter, while the MOSFETs were used for real-time dosimetry to isolate the contribution of skin dose from individual IMRT segments. Strips of film were placed at various locations on the breast and the MOSFETs were used to measure skin dose at 16 positions spaced along the film strips for comparison of data. The results showed an increase in skin dose in the presence of the immobilization cast of up to 45.7% and 62.3% of the skin dose without the immobilization cast present as measured with Gafchromic EBT film and MOSFETs, respectively. The increase in skin dose due to the immobilization cast varied with the angle of beam incidence and was greatest when the beam was normally incident on the phantom. The increase in surface dose with the immobilization cast was greater under entrance dose conditions compared to exit dose conditions

Challenges and considerations of applying nature-based solutions in low- and middle-income countries in Southeast and East Asia

Low- and middle-income countries in Southeast and East Asia face a range of challenges related to the rapid pace of urbanisation in the region, the scale of pollution, climate change, loss of ecosystem services and associated difficulties for ecological restoration. Possible pathways towards a more sustainable future lie in the applications of nature-based solutions (NBS). However, there is relatively little literature on the application of NBS in the region, particularly Southeast Asia. In this paper we address this gap by assessing the socio-ecological challenges to the application of NBS in the region – one of the most globally biodiverse. We first provide an overview and background on NBS and its underpinnings in biodiversity and ecosystem services. We then present a typology describing five unique challenges for the application of NBS in the region: (1) Characteristics of urbanisation; (2) Biophysical environmental and climatic context; (3) Environmental risks and challenges for restoration; (4) Human nature relationships and conflicts; and (5) Policy and governance context. Exploiting the opportunities through South-South and North-South collaboration to address the challenges of NBS in Southeast and East Asia needs to be a priority for government, planners and academics.Peer reviewe

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health.

BACKGROUND: Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. PURPOSE: To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. METHODS: Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15-60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30-45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. RESULTS: Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. CONCLUSIONS: HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity

Child-care self-assessment to improve physical activity, oral health and nutrition for 2- to 4-year-olds:a feasibility cluster RCT

Background: The Nutrition And Physical Activity Self Assessment for Child Care (NAP SACC) intervention has shown evidence of effectiveness in the USA but not been adapted or assessed for effectiveness in the UK. Objectives: To evaluate the feasibility and acceptability of implementing NAP SACC in the UK. Design: Adaptation and development of NAP SACC and feasibility cluster randomised controlled trial (RCT) including process and economic evaluations. Substudies assessed mediator questionnaire test–retest reliability and feasibility of food photography methods. Setting: Nurseries, staff and parents in North Somerset, Cardiff, Gloucestershire and Bristol. Participants: Development – 15 early years/public health staff and health visitors, 12 nursery managers and 31 parents. RCT – 12 nurseries and 31 staff, four partners and 168 children/parents. Mediator substudy – 82 parents and 69 nursery staff. Food photography substudy – four nurseries, 18 staff and 51 children. Intervention: NAP SACC UK partners supported nurseries to review policies and practices and set goals to improve nutrition, oral health and physical activity (PA) over 5 months. Two workshops were delivered to nursery staff by local experts. A home component [website, short message service (SMS) and e-mails] supported parents. The control arm continued with usual practice. Main outcome measures: Feasibility and acceptability of the intervention and methods according to prespecified criteria. Data sources: Qualitative data to adapt the intervention. Measurements with children, parents and staff at baseline and post intervention (8–10 months after baseline). Interviews with nursery managers, staff, parents and NAP SACC UK partners; observations of training, workshops and meetings. Nursery environment observation, nursery Review and Reflect score, and resource log. Child height and weight, accelerometer-determined PA and sedentary time, screen time and dietary outcomes using the Child and Diet Evaluation Tool. Staff and parent questionnaires of knowledge, motivation and self-efficacy. Child quality of life and nursery, family and health-care costs. Food photography of everything consumed by individual children and staff questionnaire to assess acceptability. Results: Thirty-two per cent (12/38) of nurseries and 35.3% (168/476) of children were recruited; no nurseries withdrew. The intervention was delivered in five out of six nurseries, with high levels of fidelity and acceptability. Partners found it feasible but had concerns about workload. The child loss to follow-up rate was 14.2%. There was suggestion of promise in intervention compared with control nurseries post intervention for snacks, screen time, proportion overweight or obese and accelerometer-measured total PA and moderate to vigorous PA. Many parental and nursery knowledge and motivation mediators improved. The average cost of delivering the intervention was £1184 per nursery excluding partner training, and the average cost per child was £27. Fourteen per cent of parents used the home component and the mediator questionnaire had good internal consistency and test–retest reliability. Photography of food was acceptable and feasible. Limitations: Following nursery leavers was difficult. Accelerometer data, diet data and environmental assessment would have been more reliable with 2 days of data. Conclusions: The NAP SACC UK intervention and methods were found to be feasible and acceptable to participants, except for the home component. There was sufficient suggestion of promise to justify a definitive trial. Future work: A multicentre cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of NAP SACC UK has been funded by NIHR and will start in July 2019 (PHR NIHR 127551). Trial registration: Current Controlled Trials ISRCTN16287377

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Age dating of an early Milky Way merger via asteroseismology of the naked-eye star ν Indi

Over the course of its history, the Milky Way has ingested multiple smaller satellite galaxies1. Although these accreted stellar populations can be forensically identified as kinematically distinct structures within the Galaxy, it is difficult in general to date precisely the age at which any one merger occurred. Recent results have revealed a population of stars that were accreted via the collision of a dwarf galaxy, called Gaia–Enceladus1, leading to substantial pollution of the chemical and dynamical properties of the Milky Way. Here we identify the very bright, naked-eye star ν Indi as an indicator of the age of the early in situ population of the Galaxy. We combine asteroseismic, spectroscopic, astrometric and kinematic observations to show that this metal-poor, alpha-element-rich star was an indigenous member of the halo, and we measure its age to be 11.0±0.7 (stat) ±0.8 (sys) billion years. The star bears hallmarks consistent with having been kinematically heated by the Gaia–Enceladus collision. Its age implies that the earliest the merger could have begun was 11.6 and 13.2 billion years ago, at 68% and 95% confidence, respectively. Computations based on hierarchical cosmological models slightly reduce the above limits