SyncMRT: a solution to image-guided synchrotron radiotherapy for quality assurance and pre-clinical trials.

In this work, a new image guidance system and protocols for delivering image-guided radiotherapy (IGRT) on the Imaging and Medical Beamline (IMBL) at the ANSTO Australian Synchrotron are introduced. The image guidance methods used and the resulting accuracy of tumour alignment in in vivo experiments are often under-reported. Image guidance tasks are often complex, time-consuming and prone to errors. If unchecked, they may result in potential mis-treatments. We introduce SyncMRT, a software package that provides a simple, image guidance tool-kit for aligning samples to the synchrotron beam. We have demonstrated sub-millimetre alignment using SyncMRT and the small-animal irradiation platform (the DynamicMRT system) on the IMBL. SyncMRT has become the standard for carrying out IGRT treatments on the IMBL and has been used in all pre-clinical radiotherapy experiments since 2017. Further, we introduce two quality assurance (QA) protocols to synchrotron radiotherapy on the IMBL: the Winston-Lutz test and hidden target test. It is shown that the presented QA tests are appropriate for picking up geometrical setup errors and assessing the end-to-end accuracy of the image guidance process. Together, these tools make image guidance easier and provide a mechanism for reporting the geometric accuracy of synchrotron-based IGRT treatments. Importantly, this work is scalable to other delivery systems, and is in continual development to support the upcoming veterinary radiotherapy trials on the IMBL.

Universal drug coverage and income-related disparities in glycaemic control.

AIMS: To examine whether income-related disparities in glycaemic control decline after the age of 65 years, when publicly funded universal drug insurance is acquired in Ontario, Canada. METHODS: We conducted a population-based cross-sectional study using linked administrative healthcare databases. Adults with diabetes, aged 40-89 years, with available HbA1c data were included (N = 716 297). Income was based on median neighbourhood household income. Multiple linear regression was used to test for effect modification of age ≥65 years on the relationship between income and HbA1c . RESULTS: There was a significant inverse association between income and HbA1c level. After adjusting for baseline factors, the effect of income on HbA1c level was significantly greater for individuals aged <65 years (mean difference HbA1c for lowest vs highest income group +2.5 mmol/mol, 95% CI +2.3 to +2.7 [+0.23%, 95% CI 0.21 to 0.24]) than for those aged ≥65 years (+1.2 mmol/mol, 95% CI +1.0 to +1.3 [+0.11%, 95% CI 0.10 to 0.12]; P < 0.0001 for interaction). CONCLUSIONS: Despite universal access to healthcare, people with diabetes with lower incomes had significantly worse glycaemic control compared with their counterparts on higher incomes. However, income gradients in glycaemic control were markedly reduced after the age of 65 years, possibly as a result of access to prescription drug coverage.

Correlation between in vitro and in vivo data on food digestion. What can we predict with static in vitro digestion models?

During the last decade, there has been a growing interest in understanding food's digestive fate in order to strengthen the possible effects of food on human health. Ideally, food digestion should be studied in vivo on humans but this is not always ethically and financially possible. Therefore, simple in vitro digestion models mimicking the gastrointestinal tract have been proposed as alternatives to in vivo experiments. Thus, it is no surprise that these models are increasingly used by the scientific community, although their various limitations to fully mirror the complexity of the digestive tract. Therefore, the objective of this article was to call upon the collective experiences of scientists involved in Infogest (an international network on food digestion) to review and reflect on the applications of in vitro digestion models, the parameters assessed in such studies and the physiological relevance of the data generated when compared to in vivo data. The authors provide a comprehensive review in vitro and in vivo digestion studies investigating the digestion of macronutrients (i.e., proteins, lipids, and carbohydrates) as well as studies of the bioaccessibility and bioavailability of micronutrients and phytochemicals. The main conclusion is that evidences show that despite the simplicity of in vitro models they are often very useful in predicting outcomes of the digestion in vivo. However, this has relies on the complexity of in vitro models and their tuning toward answering specific questions related to human digestion physiology, which leaves a vast room for future studies and improvements.

Complexity and health functionality of plant cell wall fibers from fruits and vegetables.

The prevalence of lifestyle-related diseases is increasing in developing countries with the causes for death starting to follow the same pattern in the developed world. Lifestyle factors including inadequate dietary intake of fruits and vegetables and over consumption of nutrient-poor processed foods, are considered to be major causal risk factors associated with increased susceptibility to developing certain diseases (Alldrick, 1998 ; Kiani, 2007 ). Recent epidemiological evidence confirms a strong association between dietary fiber and reduced all-cause mortality risk, as well as a risk reduction for a number of non-communicable diseases (Chuang et al., 2012 ). The relationship between dietary fiber and mortality has been described as "convincing observations that call for mechanistic investigations" (Landberg, 2012 ). In particular, the health protective roles played by dietary fibers of different origin are not well understood. Whilst Hippocrates was the earliest known physician to study the health benefits of fiber derived from grains (Burkitt, 1987 ), the functionality of fruit and vegetable fiber, especially in association with other compounds such as polyphenols and carotenoids, is an area of more recent interest. Hence the objective of this review is to assess the complexity and health-related functional role of plant cell wall (PCW) fibers from fruits and vegetables with a particular emphasis on interactions between cell walls and phytonutrients.

Trends in fall-related hospitalisations in older people living in aged care facilities.

UNLABELLED: The aim is to describe the trends in fall-related hospitalisations for older people living in aged care facilities. Over the 9-year period investigated, there were dramatic increases in fall-related hospitalisations. This worrying trend highlights that we may not be addressing falls in aged care facilities sufficiently. INTRODUCTION: The purposes of this study are to describe the trends in fall-related hospitalisations in older people living in aged care facilities and to compare these trends across different demographic groups and injury types. METHODS: This study was conducted in Australia's second most populous state, Victoria. Aged care facilities in Australia provide high- and low-level nursing care for people who can no longer live independently. Included in this study were hospital admitted episodes of care which met the following criteria: age 65+ years at admission, an admission source indicating a transfer from an aged care facility, an external cause indicating a fall, a care type of 'acute', a Victorian postcode of residence, and an admission date between July 1, 2003 and June 30, 2012 (inclusive). Rate denominator data were Victorian aged care bed years. RESULTS: Over the last 9 years, 7098 episodes of care met the inclusion criteria. The age-standardised rate of hospitalisation increased by 11% (95% confidence interval [CI] 9%, 12%) per year. Serious injury increased at a slower pace than less serious injury. The slowest rate increase was for hip fracture (incidence rate ratio: 1.03 (95% CI 1.00, 1.06), the most common fracture type. CONCLUSIONS: Rates of fall-related hospitalisations in older people living in aged care facilities increased at a dramatic pace in the period studied. The relative slower increase in hip fracture may point towards changing referral practices, possible success in osteoporosis management, body mass index increases in older people living in aged care facilities or a combination of these factors.

Structural differences between bovine A(1) and A(2) ß-casein alter micelle self-assembly and influence molecular chaperone activity.

Within each milk protein there are many individual protein variants and marked alterations to milk functionality can occur depending on the genetic variants of each protein present. Bovine A(1) and A(2) ß-casein (ß-CN) are 2 variants that contribute to differences in the gelation performance of milk. The A(1) and A(2) ß-CN variants differ by a single AA, the substitution of histidine for proline at position 67. ß-Casein not only participates in formation of the casein micelle but also forms an oligomeric micelle itself and functions as a molecular chaperone to prevent the aggregation of a wide range of proteins, including the other caseins. Micelle assembly of A(1) and A(2) ß-CN was investigated using dynamic light scattering and small-angle X-ray scattering, whereas protein functionality was assessed using fluorescence techniques and molecular chaperone assays. The A(2) ß-CN variant formed smaller micelles than A(1) ß-CN, with the monomer-micelle equilibrium of A(2) ß-CN being shifted toward the monomer. This shift most likely arose from structural differences between the 2 ß-CN variants associated with the adoption of greater polyproline-II helix in A(2) ß-CN and most likely led to enhanced chaperone activity of A(2) ß-CN compared with A(1) ß-CN. The difference in micelle assembly, and hence chaperone activity, may provide explain differences in the functionality of homozygous A(1) and A(2) milk. The results of this study highlight that substitution of even a single AA can significantly alter the properties of an intrinsically unstructured protein such as ß-CN and, in this case, may have an effect on the functionality of milk.

Casein polymorphism heterogeneity influences casein micelle size in milk of individual cows.

Milk samples from individual cows producing small (148-155 nm) or large (177-222 nm) casein micelles were selected to investigate the relationship between the individual casein proteins, specifically κ- and ß-casein phenotypes, and casein micelle size. Only κ-casein AA and ß-casein A1A1, A1A2 and A2A2 phenotypes were found in the large casein micelle group. Among the small micelle group, both κ-casein and ß-casein phenotypes were more diverse. κ-Casein AB was the dominant phenotype, and 3 combinations (AA, AB, and BB) were present in the small casein micelle group. A considerable mix of ß-casein phenotypes was found, including B and I variants, which were only found in the small casein micelle group. The relative amount of κ-casein to total casein was significantly higher in the small micelle group, and the nonglycosylated and glycosylated κ-casein contents were higher in the milks with small casein micelles (primarily with κ-casein AB and BB variants) compared with the large micelle group. The ratio of glycosylated to nonglycosylated κ-casein was higher in the milks with small casein micelles compared with the milks with large casein micelles. This suggests that although the amount of κ-casein (both glycosylated and nonglycosylated) is associated with micelle size, an increased proportion of glycosylated κ-casein could be a more important and favorable factor for small micelle size. This suggests that the increased spatial requirement due to addition of the glycosyl group with increasing extent of glycosylation of κ-casein is one mechanism that controls casein micelle assembly and growth. In addition, increased electrostatic repulsion due to the sialyl residues on the glycosyl group could be a contributory factor.

Natural variation of bovine milk fat globule size within a herd.

Native milk fat globule (MFG) size, pH, total fat, protein, and lactose composition in milk from individual cows was examined in autumn and spring 2012 and autumn 2013. Mean MFG diameters ranged between 2.5 and 5.7 µm. Some cows were observed to consistently produce small or large MFG throughout the sampling period, though trends were not consistent across all cows. Small-MFG milk contained more total polar lipids; however, the relative proportion of individual polar lipids did not differ with MFG size, with the exception of phosphatidylcholine, which was greater in small-MFG milk. No significant correlation between MFG size and proximate composition, including calculated fat yield or pH, was found. This work revealed a natural cow-to-cow variation in MFG size exists, which could potentially be exploited to improve the functionality of milk for manufacturing and some products.

Analysis of fibrinolytic shutdown in trauma patients with traumatic brain injury.

BACKGROUND: Coagulation profiles following major trauma vary depending on injury pattern and degree of shock. The physiologic mechanisms involved in coagulation function at any given time are varied and remain poorly understood. Thromboelastography (TEG) has been used evaluate coagulation profiles in the trauma population with some reports demonstrating a spectrum of fibrinolysis to fibrinolytic shutdown on initial presentation. The objective of this study was to evaluate the fibrinolytic profile of patients with TBI using thromboelastography (TEG). We hypothesized that patients with TBI would demonstrate low fibrinolytic activity. METHODS: All trauma activations at an ACS-verified level 1 trauma center received a TEG analysis upon arrival from December 2019 to June 2021. A retrospective review of the results and outcomes was conducted, and TBI patients were compared to patients without TBI. Linear regression was used to evaluate the effect of patient and injury factors on fibrinolysis. Hyperfibrinolysis was defined as LY30 â€‹> â€‹7.7%, physiologic fibrinolysis as LY30 0.6-7.7%, and fibrinolytic shutdown as LY30 â€‹< â€‹0.6%. RESULTS: A total of 1369 patients received an admission TEG analysis. Patients with TBI had a significantly higher median ISS (16 vs. 8, p â€‹< â€‹0.001), lower median admission Glasgow Coma Scale (14 vs. 15, p â€‹< â€‹0.001), longer intensive care unit length of stay (3 vs. 2 days, p â€‹< â€‹0.0001), increased ventilator days (216 vs. 183, p â€‹< â€‹0.001), higher mortality (14.6% vs. 5.1%, p â€‹< â€‹0.001), but lower shock index (0.6 vs. 0.7, p â€‹< â€‹0.0001) compared to those without TBI. Median LY30 was found to be decreased in the TBI group (0.1 vs. 0.2, p â€‹= â€‹0.0006). Patients with TBI were found to have a higher rate of fibrinolytic shutdown compared those without TBI (68.7% vs. 63.5%, p â€‹= â€‹0.054). ISS, sex, and shock index were found to be predictive of LY30 on linear regression, but TBI was not (Β: 0.09, SE: 0.277, p â€‹= â€‹0.745). The rate of DVT/PE did not appear to be elevated in patients with TBI (0.8%) and without TBI (1.2%). CONCLUSIONS: Trauma patients with and without TBI were found to have high rates of fibrinolytic shutdown. Although there was a high incidence of fibrinolytic shutdown, it did not appear to have an impact on the rate of thrombotic complications. The clinical significance of these results is unclear and differs significantly from recent reports which demonstrated that TBI is associated with a 25% rate of fibrinolytic shutdown. Further investigation is needed to better define the fibrinolytic pathway in patients with trauma and TBI to develop optimal treatment algorithms.

Factors influencing the willingness to pay a price premium for red meat with potential to improve consumer wellness in Australia and the United States of America.

This study determined consumers' attitudes towards physical and mental wellness related to red meat consumption and their willingness to pay (WTP) more for the meat. In 2019, two online surveys of red meat eaters were conducted in the USA (n = 1000) and Australia (n = 523) using commercial platforms. Results showed that over 90% of respondents indicated interest in purchasing red meat to improve their wellness status. Additionally, about 85% indicated their WTP more for red meat for its wellness benefits, with Americans indicating stronger willingness than Australian respondents. The potential of meat consumption to improve overall wellness among red meat eaters was a dominant factor influencing consumers' WTP more. Other factors that increased WTP included frequency of meat consumption, physical exercise, sleep quality, number of children in a household, partnership status, and economic position. Outcomes from this study highlight a unique opportunity for the meat industry to position meat on its qualities that include wellness improvement if backed up with robust scientific evidence.

Developing a Patient-Centered Model of Prostate Cancer Care: Patient Satisfaction With a Survivorship Program Embedded in Urologic-Oncologic Care.

OBJECTIVE: To evaluate patients' and partners' satisfaction with a prostate cancer survivorship program embedded in urologic-oncologic care. As a part of quality improvement activity, we developed a patient and partner-centered, biopsychosocial support program for men and partners coping with the urinary and sexual side-effects of surgical treatment for prostate cancer. The program became a part of usual care for all prostate cancer patients. METHODS: Patients who saw both an advanced practice provider and a sex therapist between August 1, 2018 and July 31, 2019 were eligible. Surveys packets were sent to 146 patients with surveys included for partners (N = 292). We used descriptive statistics to characterize participant responses. RESULTS: Responses were received from 88 patients and 70 partners (56% response rate for the group). Patients and partners reported very high or fairly high satisfaction with the rehabilitation activities of the program (86-97% and 90%-100%, respectively); 91% of patients and 84% of partners thought having pre-operative education and post-operative rehabilitation was a good or fairly good idea; 83% of patients and 79% of partners would very much or somewhat recommend the program to a friend who was considering surgical treatment for prostate cancer. CONCLUSION: Embedding a patient and partner-centered prostate cancer survivorship support program in oncologic care can positively impact patients' and partners' engagement in and satisfaction with post-operative rehabilitation.

A commercial treatment planning system with a hybrid dose calculation algorithm for synchrotron radiotherapy trials.

Synchrotron Radiotherapy (SyncRT) is a preclinical radiation treatment which delivers synchrotron x-rays to cancer targets. SyncRT allows for novel treatments such as Microbeam Radiotherapy, which has been shown to have exceptional healthy tissue sparing capabilities while maintaining good tumour control. Veterinary trials in SyncRT are anticipated to take place in the near future at the Australian Synchrotron's Imaging and Medical Beamline (IMBL). However, before veterinary trials can commence, a computerised treatment planning system (TPS) is required, which can quickly and accurately calculate the synchrotron x-ray dose through patient CT images. Furthermore, SyncRT TPS's must be familiar and intuitive to radiotherapy planners in order to alleviate necessary training and reduce user error. We have paired an accurate and fast Monte Carlo (MC) based SyncRT dose calculation algorithm with EclipseTM, the most widely implemented commercial TPS in the clinic. Using EclipseTM, we have performed preliminary SyncRT trials on dog cadavers at the IMBL, and verified calculated doses against dosimetric measurement to within 5% for heterogeneous tissue-equivalent phantoms. We have also performed a validation of the TPS against a full MC simulation for constructed heterogeneous phantoms in EclipseTM, and showed good agreement for a range of water-like tissues to within 5%-8%. Our custom EclipseTM TPS for SyncRT is ready to perform live veterinary trials at the IMBL.

A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins.

Mannose-binding proteins have been isolated from the liver of rats and humans and subsequently been found in the serum of rats, rabbits, and humans. We report the isolation of cDNA clones isolated from a human liver cDNA library that encodes a human mannose-binding protein. The primary structure has three domains: (a) an NH2-terminal cysteine-rich segment of 19 amino acids which appears to be involved in the formation of interchain disulfide bonds that would stabilize multimeric forms of the protein; (b) a collagen-like region consisting of 19 repeats of the sequence Gly-x-y; and (c) a COOH-terminal putative carbohydrate-binding domain consisting of 148 residues. This human mannose-binding protein bears 51% overall homology (allowing three gaps) with a rat mannose-binding protein C and 48% homology (allowing seven gaps) with a rat mannose-binding protein A. Like these homologous rat proteins, the human mannose-binding protein COOH-terminal sequences are homologous to the carbohydrate recognition portion of several other lectin-like proteins including mammalian hepatic receptors, an insect-soluble hemolymph, and a sea urchin lectin found in coelomic fluid. The apoproteins of dog and human surfactant and the human lymphocyte IgE Ec receptor have not been shown to have lectin-like properties, yet by homology are members of this family of lectin-like proteins. The human mannose-binding protein is preceded by a typical hydrophobic signal sequence and its hepatic secretion is induced as part of the acute-phase response consistent with its probable role in host defense.

The human mannose-binding protein gene. Exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10.

The human mannose-binding protein (MBP) plays a role in first line host defense against certain pathogens. It is an acute phase protein that exists in serum as a multimer of a 32-kD subunit. The NH2 terminus is rich in cysteines that mediate interchain disulphide bonds and stabilize the second collagen-like region. This is followed by a short intervening region, and the carbohydrate recognition domain is found in the COOH-terminal region. Analysis of the human MBP gene reveals that the coding region is interrupted by three introns, and all four exons appear to encode a distinct domain of the protein. It appears that the human MBP gene has evolved by recombination of an ancestral nonfibrillar collagen gene with a gene that encodes carbohydrate recognition, and is therefore similar to the human surfactant SP-A gene and the rat MBP gene. The gene for MBP is located on the long arm of chromosome 10 at 10q11.2-q21, a region that is included in the assignment for the gene for multiple endocrine neoplasia type 2A.

A Monte Carlo model of synchrotron radiotherapy shows good agreement with experimental dosimetry measurements: Data from the imaging and medical beamline at the Australian Synchrotron.

Experimental measurement of Synchrotron Radiotherapy (SyncRT) doses is challenging, especially for Microbeam Radiotherapy (MRT), which is characterised by very high dynamic ranges with spatial resolutions on the micrometer scale. Monte Carlo (MC) simulation is considered a gold standard for accurate dose calculation in radiotherapy, and is therefore routinely relied upon to produce verification data. We present a MC model for Australian Synchrotron's Imaging and Medical Beamline (IMBL), which is capable of generating accurate dosimetry data to inform and/or verify SyncRT experiments. Our MC model showed excellent agreement with dosimetric measurement for Synchrotron Broadbeam Radiotherapy (SBBR). Our MC model is also the first to achieve validation for MRT, using two methods of dosimetry, to within clinical tolerances of 5% for a 20×20 mm2 field size, except for surface measurements at 5 mm depth, which remained to within good agreement of 7.5%. Our experimental methodology has allowed us to control measurement uncertainties for MRT doses to within 5-6%, which has also not been previously achieved, and provides a confidence which until now has been lacking in MRT validation studies. The MC model is suitable for SyncRT dose calculation of clinically relevant field sizes at the IMBL, and can be extended to include medical beamlines at other Synchrotron facilities as well. The presented MC model will be used as a validation tool for treatment planning dose calculation algorithms, and is an important step towards veterinary SyncRT trials at the Australian Synchrotron.

Pf1 virus structure: helical coat protein and DNA with paraxial phosphates.

The helical path of the DNA in filamentous bacteriophage Pf1 was deduced from different kinds of existing structural information, including results from x-ray fiber diffraction. The DNA has the same pitch, 16 angstroms, as the surrounding helix of protein subunits; the rise and rotation per nucleotides are 6.1 angstroms and 132 degrees, respectively; and the phosphates are 2.5 angstroms from the axis. The DNA in Pf1 is, therefore, the most extended and twisted DNA structure known. On the basis of the DNA structure and extensive additional information about the protein, a model of the virion is proposed. In the model, the DNA bases reach out, into the protein, and the lysine and arginine side chains reach in, between the DNA bases, to stabilize the paraxial phosphate charges; the conformation of the protein subunit is a combination of alpha and 3(10) helices.

Cross-national comparison of population density.

The unresolved difficulties associated with defining and measuring population density strictly circumscribe the scope and nature of the conclusions that can be properly derived from differentials in man:land ratios. Any conclusions about human density will have meaning only to the extent that they are based on a recognition that this density must be viewed in both static and dynamic terms and that it cannot be isolated in analysis, from either the social and cultural setting, the demographic characteristics of the population, or the broader processes of social change within the society. In and of itself, the familiar man:land ratio says more about area than it does about either the human experience of density or the relation of population to resources. This ratio is therefore essentially meaningless as an indicator of comparative conditions of life among different countries and different geographic regions. The mere fact of having a relatively low average population density thus, does not automatically entitle a nation to complacency about its ability to adjust readily to future population change, either in terms of growth in numbers or in the geographic location of its people.

Automated identification of neurons in 3D confocal datasets from zebrafish brainstem.

Many kinds of neuroscience data are being acquired regarding the dynamic behaviour and phenotypic diversity of nerve cells. But as the size, complexity and numbers of 3D neuroanatomical datasets grow ever larger, the need for automated detection and analysis of individual neurons takes on greater importance. We describe here a method that detects and identifies neurons within confocal image stacks acquired from the zebrafish brainstem. The first step is to create a template that incorporates the location of all known neurons within a population - in this case the population of reticulospinal cells. Once created, the template is used in conjunction with a sequence of algorithms to determine the 3D location and identity of all fluorescent neurons in each confocal dataset. After an image registration step, neurons are segmented within the confocal image stack and subsequently localized to specific locations within the brainstem template - in many instances identifying neurons as specific, individual reticulospinal cells. This image-processing sequence is fully automated except for the initial selection of three registration points on a maximum projection image. In analysing confocal image stacks that ranged considerably in image quality, we found that this method correctly identified on average approximately 80% of the neurons (if we assume that manual detection by experts constitutes 'ground truth'). Because this identification can be generated approximately 100 times faster than manual identification, it offers a considerable time savings for the investigation of zebrafish reticulospinal neurons. In addition to its cell identification function, this protocol might also be integrated with stereological techniques to enhance quantification of neurons in larger databases. Our focus has been on zebrafish brainstem systems, but the methods described should be applicable to diverse neural architectures including retina, hippocampus and cerebral cortex.