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Proton‐beam therapy (PBT) is a cutting‐edge radiation therapy modality that is currently not available in Australia. Comparative photon‐proton (CPP) planning is required for the medical treatment overseas programme (MTOP) and will be required for access to PBT in Australia in the future. Comparative planning brings professional development benefits to all members of the radiation therapy team. This service was also created to support future proposals for a PBT facility in Victoria. We report our experience developing an in‐house CPP service at Peter MacCallum Cancer Centre. A set of resources to support CPP planning was established. Training of relevant staff was undertaken after which an in‐house training programme was developed. A standard protocol for PBT planning parameters was established. All CPP plans were reviewed. Future goals for the CPP planning programme were described. In total, 62 cases were comparatively planned over 54 months. Of these, 60% were paediatric cases, 14% were adolescents and young adults (15–25 years) and 26% were adults. The vast majority (over 75%) of patients comparatively planned required irradiation to the central nervous system including brain and cranio‐spinal irradiation. A variety of proton plans were reviewed by international PBT experts to confirm their deliverability. Our team at Peter MacCallum Cancer Centre has gained significant experience in CPP planning and will continue to develop this further. Local expertise will help support decentralisation of patient selection for proton treatments in the near future and the PBT business case in Victoria. Comparative planning brings professional development benefits to all members of the radiation therapy team. This service was also created to support future proposals for a Proton‐beam therapy facility in Victoria. We report our experience developing an in‐house comparative photon‐proton planning service at Peter Mac.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Dual-energy CT imaging has many potential uses in abdominal imaging. It also has unique requirements for protocol creation depending on the dual-energy scanning technique that is being utilized. It also generates several new types of images which can increase the complexity of image creation and image interpretation. The purpose of this article is to review, for rapid switching and dual-source dual-energy platforms, methods for creating dual-energy protocols, different approaches for efficiently creating dual-energy images, and an approach to navigating and using dual-energy images at the reading station all using the example of a pancreatic multiphasic protocol. It will also review the three most commonly used types of dual-energy images: “workhorse” 120kVp surrogate images (including blended polychromatic and 70 keV monochromatic), high contrast images (e.g., low energy monochromatic and iodine material decomposition images), and virtual unenhanced images. Recent developments, such as the ability to create automatically on the scanner the most common dual-energy images types, namely new “Mono+” images for the DSDECT (dual-source dual-energy CT) platform will also be addressed. Finally, an approach to image interpretation using automated “hanging protocols” will also be covered. Successful dual-energy implementation in a high volume practice requires careful attention to each of these steps of scanning, image creation, and image interpretation.

Cyclooxygenase-2 (COX-2) plays a critical role in regulating innate immunity and metabolism by producing prostaglandins (PGs) and other lipid mediators. However, the implication of adipose COX-2 in obesity remains largely unknown. Using adipocyte-specific COX-2 knockout (KO) mice, we showed that depleting COX-2 in adipocytes promoted white adipose tissue development accompanied with increased size and number of adipocytes and predisposed diet-induced adiposity, obesity, and insulin resistance. The increased size and number of adipocytes by COX-2 KO were reversed by the treatment of prostaglandin E2 (PGE2) but not PGI2 and PGD2 during adipocyte differentiation. PGE2 suppresses PPARγ expression through the PKA pathway at the early phase of adipogenesis, and treatment of PGE2 or PKA activator isoproterenol diminished the increased lipid droplets in size and number in COX-2 KO primary adipocytes. Administration of PGE2 attenuated increased fat mass and fat percentage in COX-2 deficient mice. Taken together, our study demonstrated the suppressing effect of adipocyte COX-2 on adipogenesis and reveals that COX-2 restrains adipose tissue expansion via the PGE2-mediated paracrine mechanism and prevents the development of obesity and related metabolic disorders.

BackgroundPathogenic variants in TGFB3 may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in TGFB3-related disease but there are limited outcomes data on vascular events in this condition.MethodsClinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) TGFB3 variants enrolled in the Montalcino Aortic Consortium registry were reviewed.Results34 individuals (56% male, median age 42 years, IQR 17–49, range 3–74 years) with P/LP TGFB3 variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32–69 years) with aortic root dilation (41–49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred.ConclusionsTGFB3-related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with TGFB3-related HTAD compared with HTAD due to TGFBR1 or TGFBR2 variants.

Aims/hypothesisThere is conflicting evidence about the obesity paradox—the counterintuitive survival advantage of obesity among certain subpopulations of individuals with chronic conditions. It is believed that results supporting the obesity paradox are due to methodological flaws, such as collider bias. The aim of this study was to examine the association between obesity and mortality in Australian men and women. In addition, we explored whether obesity would appear to be protective if the analysis was restricted to a subpopulation with disease, and to discuss the potential role of collider bias in producing such a result.MethodsThe examined cohort included 10,575 Australian adults (4844 men and 5731 women) aged 25–91 years who were recruited for the AusDiab baseline survey in 1999 and followed-up through 2014. The main predictor variable was BMI categorised as normal weight (18.5 to <25 kg/m2), overweight (25 to <30 kg/m2) and obese (≥30 kg/m2), and the outcome of interest was all-cause mortality. Hazard ratios were estimated from Cox proportional hazards regression models in the entire cohort and then in subpopulations with and without diabetes.ResultsA total of 1477 deaths occurred during 145,384 person-years (median 14.6 years) of follow-up. Mortality was higher in obese than in normal-weight individuals for the full population (HR 1.18; 95% CI 1.05, 1.32). When an interaction between diabetes status and BMI category was added to the model, there was no evidence of an interaction between BMI and diabetes status (p = 0.92). When participants with and without diabetes were analysed separately, there was no evidence of an association between obesity and mortality in those with diabetes (HR 0.91; 95% CI 0.62, 1.33).Conclusions/interpretationIn the entire AusDiab cohort, we found a significantly higher mortality among obese participants as compared with their normal-weight counterparts. We found no difference in the obesity–mortality association between individuals with and without diabetes.

We examined the developmental processes involved in peer problems among children (M age = 10.41 years) previously diagnosed with attention-deficit/hyperactivity disorder (ADHD) at study entry (N = 536) and a comparison group (N = 284). Participants were followed over a 6-year period ranging from middle childhood to adolescence. At four assessment periods, measures of aggression, social skills, positive illusory biases (in the social and behavioral domains), and peer rejection were assessed. Results indicated that children from the ADHD group exhibited difficulties in each of these areas at the first assessment. Moreover, there were vicious cycles among problems over time. For example, peer rejection was related to impaired social skills, which in turn predicted later peer rejection. Problems also tended to spill over into other areas, which in turn compromised functioning in additional areas across development, leading to cascading effects over time. The findings held even when controlling for age and were similar for males and females, the ADHD and comparison groups, and among ADHD treatment groups. The results suggest that the peer problems among children with and without ADHD may reflect similar processes; however, children with ADHD exhibit greater difficulties negotiating important developmental tasks. Implications for interventions are discussed.

PurposeIn several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world.MethodsThis federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8–25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis.Results29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059–1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027–1.088).ConclusionOur findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP–T2D associations were confirmed.

Assessing the spatial distribution of organisms across landscapes is a key step toward determining processes that produce observed patterns. The spatial distribution of an invasive aquatic mollusk, the zebra mussel (Dreissena polymorpha), was examined in two lake-rich areas (Belarus and midwestern United States) with contrasting invasion histories. Spatial distribution patterns of invaded lakes were determined using Ripley's K. Aggregation of invaded lakes was found at similar spatial extents (<50 km) in both regions; segregation was found at spatial extents > 120 km in Belarus. The observed spatial extent of aggregation likely reflected the scale of secondary geographic spread, whereas the scale of long-distance dispersal events was reflected by the spatial extent of segregation. Isolated Belarus lakes were less likely to be invaded than those connected by waterways. Although one-dimensional aggregation of invaded lakes along connected Belarus waterways was not observed, nearest neighbor analysis indicated that zebra mussel dispersal occurred at distances <15 km within these waterways. Based on observed spatial pattern, we concluded that zebra mussels have not yet saturated European and North American lake landscapes, including many suitable lakes. Similar distribution patterns of invaded lakes in Belarus and North America suggest that similar processes have influenced zebra mussel spread in both landscapes.

The invasion of the freshwaters of Belarus by the zebra mussel, Dreissena polymorpha (Pallas), began at least 200 years ago by the opening of shipping canals linking the Black Sea and Baltic Sea drainage basins. However, zebra mussels have invaded only 93 (16.8%) of 553 studied lakes; at least 20 of these lakes were invaded within in the past 30 years. Zebra mussels were found disproportionately in lakes that were mesotrophic, larger, and had some commercial fishing. Although larger lakes have more intensive fisheries with larger catches, the intensity of the fishery and average catch did not affect the probability of zebra mussel invasion. Zebra mussels were not found in dystrophic lakes (10% of the lakes studied), probably due to their low pH and calcium content. Zebra mussels became locally extinct in one lake due to anthropogenic eutrophication and pollution. Many ecologically suitable lakes have yet to be invaded, which suggests that natural vectors of overland dispersal, e.g., waterfowl, have been ineffective in Belarus. Thus, future spread of this species will continue to depend on human activities such as commercial fishing.[PUBLICATION ABSTRACT]