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Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given.

Background: The Illawarra Shoalhaven Diabetes Service (ISDS), ISLHD, Australia provides diabetes care to approximately 400 women newly diagnosed with Gestational Diabetes (GD) each year. A dietitian facilitated service delivery model has been implemented where all women are seen by the dietitian ongoing throughout their GD journey with dietetic referral to the endocrinologist and diabetes nurse educator only if BGLs are above target and insulin required. This is different to many other diabetes services with a medical or nurse led approach often with minimal ongoing dietitian input. Summary: At ISDS, women are provided with face to face nutrition and diabetes education at diagnosis in a small group setting and then reviewed individually by the dietitian via telehealth one week post initial education, and again at 28 and 36 weeks gestation. Women with GD also phone the dietitian if they are experiencing elevated BGLs outside these scheduled appointments. The dietitian is responsible for checking recorded BGL results at each review and making a referral to the endocrinologist if diet modifications to lower BGLs are unsuccessful. Nutrition education is holistic and not only includes dietary management strategies for blood glucose management but also healthy eating and lifestyle advice for pregnancy, breastfeeding and Type 2 diabetes prevention. Pivoting to telehealth appointments during covid was evaluated favourably by women. They indicated that telehealth was convenient, saved time, their questions were answered, problems were dealt with effectively and that it was easier to access than conventional appointments especially if they also had work commitments, young children or multiple antenatal appointments. Telehealth was also valued as an environmentally sustainable healthcare strategy by clients and dietitians. Discussion: The dietitian as the facilitator of diabetes education for women with GD through the use of telehealth has been an effective and efficient method of service delivery for clients and clinicians at the ISDS.

Radiopaque and fluorescent embolic particles have been synthesized and characterised to match the size of vasculature found in tumours to ensure effective occlusion of the vessels. A literature search showed that the majority of vessels surrounding a tumour were less than 50 µm and therefore polydispersed polystyrene particles with a peak size of 50 µm have been synthesised. The embolic particles contain 5–8 nm amorphous tantalum oxide nanoparticles which provide X-ray contrast. Embolic particles containing up to 9.4 wt% tantalum oxide were prepared and showed significant contrast compared to the undoped polystyrene particles. The X-ray contrast of the embolic particles was shown to be linear (R2 = 0.9) with respect to the concentration of incorporated tantalum nanoparticles. A model was developed which showed that seventy-five 50 µm embolic particles containing 10 % tantalum oxide could provide the same contrast as 5 cm of bone. Therefore, the synthesized particles would provide sufficient X-ray contrast to enable visualisation within a tumour.

TODD RUNDGREN One of the most influential musicians and producers over the past three decades, Todd Rundgren is going to perform his 1973 masterwork A Wizard, A True Star...

LA quintet TATE are gearing up to conquer Britain after making serious headway in their home country.

Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies. Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.

Rheumatoid arthritis is an autoimmune condition that predominantly affects the synovial joints, causing joint destruction, pain, and disability. Historically, the standard for measuring the long-term efficacy of disease-modifying antirheumatic drugs has been the assessment of plain radiographs with scoring techniques that quantify joint damage. However, with significant improvements in therapy, current radiographic scoring systems may no longer be fit for purpose for the milder spectrum of disease seen today. We argue that artificial intelligence is an apt solution to further improve upon radiographic scoring, as it can readily learn to recognize subtle patterns in imaging data to not only improve efficiency, but can also increase the sensitivity to variation in mild disease. Current work in the area demonstrates the feasibility of automating scoring but is yet to take full advantage of the strengths of artificial intelligence. By fully leveraging the power of artificial intelligence, faster and more sensitive scoring could enable the ongoing development of effective treatments for patients with rheumatoid arthritis.

Hepatic precursor cells (HPCs) are known to be bipotent and to give rise to both new hepatocytes and cholangiocytes upon acute liver injury. Stuart J. Forbes and his colleagues now show that interactions of HPCs with local macrophages and myofibroblasts potentiate Wnt and Notch signaling, respectively, to determine fate specification of the HPCs. Together, these mechanisms help determine proper organ regeneration after liver injury. During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.

Background Chronic Obstructive Pulmonary Disease (COPD) poses significant public health and economic challenges and performant prognostic models may be useful to direct treatment. The purpose of this study was to develop predictive models, validate the DOSE and updated ADO predictive models, and identify predictors of future hospitalisation and mortality in contemporary Australian COPD patients. Methods Data from 8,578 inpatients and outpatients diagnosed with COPD (via post-bronchodilator spirometry) between 2006 and 2021 at a large South Australian tertiary public hospital were analysed. Multivariate logistic models and Cox regression, utilising penalised regularisation in multiply imputed data, were used to investigate predictors of hospitalisation due to COPD exacerbation at 1-, 3-, and 5-years post-diagnosis, and COPD-specific mortality at 3- and 5-years. Haemoglobin-corrected DLCO (DLCOc) was used to extend the DOSE and updated ADO models. Results Locally developed models could predict COPD-specific 1-year hospitalisation risk with AUCs 0.80 (95% CI = [0.76, 0.83]) in males and 0.82 (95% CI = [0.78, 0.86]) in females on a temporally distinct hold-out set, with 3- and 5-year AUCs falling within this range. COPD-specific mortality was predicted with AUCs of 0.90 (95% CI = [0.85, 0.94]) and 0.89 (95% CI = [0.84, 0.92]) at 3 and 5 years in females, and 0.90 (95% CI = [0.86, 0.93]) and 0.88 (95% CI = [0.84, 0.92]) in males. Cox regression models predicted survival well in the test set for both females (C-index = 0.88, 95% CI = [0.85, 0.90]) and males (C-index = 0.86, 95% CI = [0.82, 0.88]). Local model performance was superior to that of the DOSE and updated ADO models for all outcomes, although not always significantly. Among the selected predictors, reduced DLCOc was strongly predictive of all outcomes. and acts as a short-term survival risk for follow-up durations less than 10 years. There was no significant difference in performance between sex, and there were differences in selected features and feature strength between sexes. Extending the extant clinical models with DLCOc significantly improved updated ADO and DOSE model fit and improved discriminatory performance, with the extended ADO index achieving AUC of 0.77 (95% CI = [0.75, 0.79]) and 0.87 (95% CI = [0.84, 0.89]) for predicting 5-year hospitalisation and mortality respectively across the full cohort. The extended DOSE index performed similarly with AUCs 0.77 (95% CI = [0.75, 0.79]) and 0.87 (95% CI = 0.83, 0.89)) for 5-year hospitalisation and mortality. Conclusions Ours is the only large clinical cohort and prognostic study of Australian COPD patients to date. Locally developed models achieved greater discriminative performance than the original updated ADO and DOSE models within our cohort. Extending the ADO and DOSE models with DLCOc significantly improved model fit in our cohort. We recommend further research into the use of DLCOc as a prognostic index for COPD, and its inclusion in future modelling attempts. Trial registration Retrospectively registered. Clinical trial number: Not Applicable.

Recent pulsar timing array (PTA) observations detected nanohertz gravitational waves, likely originating from massive black hole binaries (MBHBs). The detected amplitude is unexpectedly higher than inferred from the electromagnetic measurements. We present new gravitational-wave background (GWB) results from the ASTRID simulation. Its large volume and on-the-fly dynamics for massive black holes (MBHs) provide new insights into the MBHB population, offering a more accurate assessment of its contribution to the observed GWB. ASTRID predicts a GWB from MBHBs of hc = 2.8 × 10−15, or ∼45% of the observed amplitude at ∼4 nHz with a slope consistent with f−2/3, and hc = 2.5 × 10−16 with hc ∝ f−1.6 at ∼30 nHz. These predictions remain below current PTA constraints but align with empirical models based on the observed MBH mass functions. By comparison, TNG300 with postprocessed MBH dynamics yields a range between 70% and 90% (20% and 30%) of the observed levels at low (high) frequencies. At low frequencies, ASTRID predicts that the bulk of the GWB originates from MBHBs with masses Mtot = 1–3 × 109 M⊙ peaking at z ≈ 0.3, consistent with TNG300. Notably, both simulations predict significant contributions from minor mergers (q < 0.2) by up to ∼40%. By tracing the full merger trees of local MBHs in ASTRID, we show that they generate gravitational waves at ∼10%–80% of the maximum signal assuming no accretion and recent equal-mass mergers. Finally, we demonstrate the importance of on-the-fly MBH dynamics, the lack of which leads to 3–5 times excessive mass growth by merger, and a boost to the GWB prediction from this overestimated mass function, especially at high frequencies.