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Radiation therapy, one of the most effective methods for cancer treatment, is still limited by the tolerances of normal tissues surrounding the tumor. Innovative techniques like spatially fractionated radiation therapy (SFRT) have been shown to increase normal tissue dose resistance. Heavy ions also offer high-dose conformity and increased relative biological effectiveness (RBE) when compared to protons and X-rays. The alliance of heavy ions and spatial fractionation of the dose has the potential to further increase the therapeutic index for difficult-to-treat cases today. In particular, the use of β-delayed multiple-particle emitters might further improve treatment response, as it holds the potential to increase high linear energy transfer (LET) decay products in the valleys of SFRT (low-dose regions) at the end of the range. To verify this hypothesis, this study compares β-delayed multiple-particle emitters (8Li, 9C, 31Ar) with their respective stable isotopes (7Li, 12C, 40Ar) to determine possible benefits of β-delayed multiple-particle emitters minibeam radiation therapy (β-MBRT). Monte Carlo simulations were performed using the GATE toolkit to assess the dose distributions of each ion. RBE-weighted dose distributions were calculated and used for the aforementioned comparison. No significant differences were found among carbon isotopes. In contrast, 8Li and 31Ar exhibited improved RBE-weighted dose distributions with an approximately 12–20% increase in the Bragg-peak-to-entrance dose ratio (BEDR) for both peaks and valleys, which favors tissue sparing. Additionally, 8Li and 31Ar exhibited a lower peak-to-valley dose ratio (PVDR) in normal tissues and higher PVDR in the tumor than 7Li and 40Ar. Biological experiments are needed to conclude whether the differences observed make β-delayed multiple-particle emitters advantageous for MBRT.

Abstract Our planet is facing increasing challenges: climate change, biodiversity loss, pandemics, poverty, and many other problems closely linked to a deteriorating environment. Meanwhile, one of our most important assets, rangers working in protected and conserved areas responsible for managing large tracts of the planet's lands and waters, are often underutilized, underrecognized and underequipped. They are generally left out of the debate about conservation and sustainable development policy, despite being central to the success of those policies. This paper outlines the need for global leaders across multiple sectors to recognize the profession of rangers as essential planetary health workers and to position rangers more effectively within global conservation and environmental policy mechanisms. It introduces the challenges facing rangers, the emerging diversity of roles within the ranger profession and the important contribution of rangers to conservation and sustainable development. It presents policy and implementation avenues to improve recognition and professionalization of rangers as key executors of conservation and development policy, particularly considering the recent Global Biodiversity Framework ambitions.

Objectives To develop a physiotherapist-led consensus statement on the definition and provision of high-value care for people with musculoskeletal conditions.Design We performed a three-stage study using Research And Development/University of California Los Angeles Appropriateness Method methodology. We reviewed evidence about current definitions through a rapid literature review and then performed a survey and interviews with network members to gather consensus. Consensus was finalised in a face-to-face meeting.Setting Australian primary care.Participants Registered physiotherapists who are members of a practice-based research network (n=31).Results The rapid review revealed two definitions, four domains of high value care and seven themes of high-quality care. Online survey responses (n=26) and interviews (n=9) generated two additional high-quality care themes, a definition of low-value care, and 21 statements on the application of high value care. Consensus was reached for three working definitions (high value, high-quality and low value care), a final model of four high value care domains (high-quality care, patient values, cost-effectiveness, reducing waste), nine high-quality care themes and 15 statements on application.Conclusion High value care for musculoskeletal conditions delivers most value for the patient, and the clinical benefits outweigh the costs to the individual or system providing the care. High-quality care is evidence based, effective and safe care that is patient-centred, consistent, accountable, timely, equitable and allows easy interaction with healthcare providers and healthcare systems.

Mean voided volume (MVV) is a non-invasive indicator of urinary bladder capacity and frequently used as secondary or even primary endpoint in clinical studies of bladder function, particularly in the context of overactive bladder syndrome. We have analyzed previously reported results from two large, non-interventional studies (n = 1335 and 745 patients with overactive bladder syndrome treated with 30–45 mg propiverine ER) to address two questions: How does MVV relate to other typically used parameters of overactive bladder syndrome (primary aim)? Is MVV a normally distributed variable (secondary aim)? We found that distribution of MVV at baseline and after treatment exhibits a skewed distribution and deviates from a normal distribution, albeit not to a major extent. Basal MVV was weakly to moderately inversely correlated to numbers of urgency, incontinence and nocturia episodes (Spearman’s correlation coefficient 0.2224–0.2960) and somewhat stronger but still only moderately to micturition frequency (0.3296–0.3505). Associations of similar strength were found for absolute and % treatment-associated changes of MVV. MVV was not associated with age and only inconsistently with gender. We conclude that MVV should not be treated as a normally distributed variable and propose that at least partly different (patho)physiological factors may regulate MVV as compared to urgency, incontinence, frequency and nocturia. This should be considered in the choice of primary endpoint in clinical studies.

Abstract Background Personal social capital, which refers to the scope and quality of an individual’s social networks within a community, has received increasing attention as a potential sociological factor associated with better individual health; yet, the mechanism relating social capital to health is still not fully understood. This study examined the associations between social capital and self-rated health while exploring the roles of leisure-time physical activity (LTPA) and socioeconomic status (SES) among middle-aged and older adults. Methods Cross-sectional data were collected from 662 middle-aged and older adults (Mean age: 58.11 ± 10.59 years old) using the Qualtrics survey panel. Personal Social Capital Scale was used to measure bonding and bridging social capital and the International Physical Activity Questionnaire was used to assess LTPA levels. SES was assessed by education and household income levels. Self-rated health was assessed using a single item, by which the participants were categorized into the two groups, having ‘good’ vs. ‘not good’ self-rated health. A series of univariate and multivariate logistic regression models were established to examine the independent and adjusted associations of social capital with self-rated health and to test mediating and moderating roles of LTPA and SES, respectively. Results Bonding and bridging social capital were positively associated with self-rated health (Odds ratios = 1.11 and 1.09; P’s

Multidomain RNA-binding proteins recognize specific target sequences through mechanisms that are not well understood. Here the authors present an integrated approach to define the RNA-binding specificity and RNP topology and apply it to the analysis of the prototypical multidomain RNA-binding protein IMP3.

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that combines the normal tissue sparing of submillimetric, spatially fractionated beams with the improved dose deposition of protons. In contrast to conventional approaches which work with comparatively large beam diameters (5 mm to several centimetres) producing laterally homogeneous fields, pMBRT uses submillimetric minibeams to create a distinct spatial modulation of the dose featuring alternating regions of high dose (peaks) and low dose (valleys). This spatial fractionation can increase the tolerance of normal tissue and may allow a safe dose escalation in the tumour. Important quantities in this context are the valley dose as well as the peak-to-valley dose ratio (PVDR). Creating submillimetric proton beams for clinical applications is a challenging task that until now has been realized with mechanical collimators (metal blocks with thin slits or holes). However, this method is inherently inefficient, inflexible and creates undesirable secondary neutrons. We therefore recently proposed a method for obtaining clinical minibeams using only magnetic focusing. In this study, we performed Monte Carlo simulations in order to compare minibeams generated using the new method of magnetic focusing with two techniques involving mechanical collimators (collimator and broad beam irradiation, collimator and pencil beam scanning). The dose deposition in water was simulated and dosimetric aspects [beam broadening, depth-dose profiles, PVDR and Bragg-peak-to-entrance dose ratio (BEDR)] as well as irradiation efficiencies were evaluated. Apart from protons, we also considered helium ions which, due to their reduced lateral scattering and sharper Bragg peak, may present a promising alternative for minibeam radiation therapy. Magnetically focused minibeams exhibited a 20–60 times higher PVDR than mechanically collimated minibeams and yielded an increase in irradiation efficiency of up to two orders of magnitude. Compared to proton minibeams, helium ion minibeams were found to broaden at a slower rate and yield an even higher PVDR (at the same minibeam spacing) as well as a more favourable BEDR. Moreover, the simulations showed that methods developed for proton minibeams are suitable for the generation of helium ion minibeams.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs present in all eukaryotic cells investigated so far and generated by a special mode of alternative splicing of pre-mRNAs. Thereby, single exons, or multiple adjacent and spliced exons, are released in a circular form. CircRNAs are cell-type specifically expressed, are unusually stable, and can be found in various body fluids such as blood and saliva. Here we analysed circRNAs and the corresponding linear splice isoforms from human platelets, where circRNAs are particularly abundant, compared with other hematopoietic cell types. In addition, we isolated extracellular vesicles from purified and in vitro activated human platelets, using density-gradient centrifugation, followed by RNA-seq analysis for circRNA detection. We could demonstrate that circRNAs are packaged and released within both types of vesicles (microvesicles and exosomes) derived from platelets. Interestingly, we observed a selective release of circRNAs into the vesicles, suggesting a specific sorting mechanism. In sum, circRNAs represent yet another class of extracellular RNAs that circulate in the body and may be involved in signalling pathways. Since platelets are essential for central physiological processes such as haemostasis, wound healing, inflammation and cancer metastasis, these findings should greatly extend the potential of circRNAs as prognostic and diagnostic biomarkers.

Circular RNAs (circRNAs), an abundant class of noncoding RNAs in higher eukaryotes, are generated from pre-mRNAs by circularization of adjacent exons. Using a set of 15 circRNAs, we demonstrated their cell-type-specific expression and circular versus linear processing in mammalian cells. Northern blot analysis combined with RNase H cleavage conclusively proved a circular configuration for two examples, LPAR1 and HIPK3. To address the circularization mechanism, we analyzed the sequence requirements using minigenes derived from natural circRNAs. Both canonical splice sites are required for circularization, although they vary in flexibility and potential use of cryptic sites. Surprisingly, we found that no specific circRNA exon sequence is necessary and that potential flanking intron structures can modulate circularization efficiency. In combination with splice inhibitor assays, our results argue that the canonical spliceosomal machinery functions in circRNA biogenesis, constituting an alternative splicing mode.

This paper presents field tests of challenging flight applications obtained with a new family of lightweight low-power INS/GNSS (inertial navigation system/global satellite navigation system) solutions based on MEMS (micro-electro-mechanical- sensor) machined sensors, being used for UAV (unmanned aerial vehicle) navigation and control as well as for aircraft motion dynamics analysis and trajectory surveying. One key is a 42+ state extended Kalman-filter-based powerful data fusion, which also allows the estimation and correction of parameters that are typically affected by sensor aging, especially when applying MEMS-based inertial sensors, and which is not yet deeply considered in the literature. The paper presents the general system architecture, which allows iMAR Navigation the integration of all classes of inertial sensors and GNSS (global navigation satellite system) receivers from very-low-cost MEMS and high performance MEMS over FOG (fiber optical gyro) and RLG (ring laser gyro) up to HRG (hemispherical resonator gyro) technology, and presents detailed flight test results obtained under extreme flight conditions. As a real-world example, the aerobatic maneuvers of the World Champion 2016 (Red Bull Air Race) are presented. Short consideration is also given to surveying applications, where the ultimate performance of the same data fusion, but applied on gravimetric surveying, is discussed.