Analysis of data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL).

BACKGROUND: Analysis of Data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL) is a multi-site, multinational, observational cohort registry designed to collect data on the use of the magnetic resonance linear accelerator (MR-Linac) for radiation therapy and patient outcomes. The registry will provide a linked repository of technical and clinical data that will form a platform for prospective studies and technology assessment. METHODS: Design: This registry aims to include an estimated 10,000 eligible participants across Australia and other countries over a 7- to 10-year period. Participants will undergo treatment and assessments in accordance with standard practice. Toxicity and survival outcomes will be assessed at baseline, during treatment, and with 3 monthly follow-up until 24 months, patient reported outcome measures will also be collected. Participants with a variety of cancers will be included. DISCUSSION: Data obtained from the ADAPT-MRL registry is expected to provide evidence on the safety and efficacy of the MR-Linac, a new technical innovation in radiation oncology. We expect this registry will generate data that will be used to optimise treatment techniques, MR-Linac software algorithms, evaluate participants' outcomes and toxicities and to create a repository of adapted plans, anatomical and functional MR sequences linked to participants' outcomes.

Antithrombotic Agent Use in Elderly Patients Sustaining Low-Level Falls.

BACKGROUND: Elderly patients who are injured from a low-level fall comprise an increasing percentage of trauma admissions. We sought to evaluate the prevalence of antithrombotic (anticoagulant or antiplatelet) agent use, injury patterns, and outcomes in this population, focusing on intracranial hemorrhage (ICH). METHODS: We retrospectively reviewed the trauma registry at an American College of Surgeons-verified Level I trauma center for all patients aged 65 y or older admitted between 2007 and 2016 following a low-level fall. Medical records of patients on antithrombotic agents were examined in detail. Patients were divided into four groups based on the presence/absence of ICH and presence/absence of preadmission antithrombotic medication use. RESULTS: There were 4074 elderly patients admitted after a low-level fall, of which 1153 (28.3%) had a traumatic ICH, and 1238 (30.4%) were on antithrombotic agents. Notably, 35.9% of patients on antithrombotics had an ICH, as compared to 25.0% of 2836 patients not on antithrombotics other than aspirin (P < 0.001). The overall distribution of antithrombotic agent use differed significantly between the ICH and non-ICH groups; the ICH group had more coumadin usage. The mortality rate was significantly different across groups, with the group having ICH and a history of antithrombotics having the highest mortality at 14.2% (P < 0.001). Excluding the 27.8% of patients who were transferred into our hospital demonstrated that significantly more admissions on antithrombotics had ICH (22.4%) versus ICH admissions not on antithrombotics (14.7%, P < 0.001). The mortality rate was significantly different across groups, with the group having ICH and a history of antithrombotics having the highest mortality at 12.0% (P < 0.001). On multivariable analysis, anticoagulants, antiplatelets, and aspirin were all significantly associated with ICH; but only anticoagulants were significantly associated with mortality. CONCLUSIONS: Antithrombotic agent use was common in admitted elderly patients sustaining a low-level fall and is associated with an elevated rate of ICH. Anticoagulants were also associated with increased mortality.

BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans.

Body size is a tightly regulated phenotype in metazoans that depends on both intrinsic and extrinsic factors. While signaling pathways are known to control organ and body size, the downstream effectors that mediate their effects remain poorly understood. In the nematode Caenorhabditis elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. We investigated the transcriptional network through which the BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. We demonstrate that cuticle collagens can act as positive regulators (col-41), negative regulators (col-141), or dose-sensitive regulators (rol-6) of body size. Moreover, we find a requirement of BMP signaling for stage-specific expression of cuticle collagen genes. We show that the Smad signal transducers directly bind conserved Smad-binding elements in regulatory regions of col-141 and col-142, but not of col-41 Hence, cuticle collagen genes may be directly and indirectly regulated via the BMP pathway. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified. Since collagen mutations and misregulation are implicated in numerous human genetic disorders and injury sequelae, understanding how collagen gene expression is regulated has broad implications.

Validation of Suitable Housekeeping Genes for the Normalization of mRNA Expression for Studying Tumor Acidosis.

Similar to other types of cancer, acidification of tumor microenvironment is an important feature of osteosarcoma, and a major source of cellular stress that triggers cancer aggressiveness, drug resistance, and progression. Among the different effects of low extracellular pH on tumor cells, we have recently found that short-term exposure to acidosis strongly affects gene expression. This alteration might also occur for the most commonly used housekeeping genes (HKG), thereby causing erroneous interpretation of RT-qPCR data. On this basis, by using osteosarcoma cells cultured at different pH values, we aimed to identify the ideal HKG to be considered in studies on tumor-associated acidosis. We verified the stability of 15 commonly used HKG through five algorithms (NormFinder, geNorm, BestKeeper, ΔCT, coefficient of variation) and found that no universal HKG is suitable, since at least four HKG are necessary for proper normalization. Furthermore, according to the acceptable range of values, YWHAZ, GAPDH, GUSB, and 18S rRNA were the most stable reference genes at different pH. Our results will be helpful for future investigations focusing on the effect of altered microenvironment on cancer behavior, particularly on the effectiveness of anticancer therapies in acid conditions.

Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling.

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons.

Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes. LRRK2 G2019S iPSC-derived dopaminergic neuron cultures displayed unique abnormalities in mitochondrial distribution and trafficking, which corresponded to reduced sirtuin deacetylase activity and nicotinamide adenine dinucleotide levels despite increased sirtuin levels. These data indicate that mitochondrial deficits in the context of LRRK2 G2019S are not a global phenomenon and point to distinct sirtuin and bioenergetic deficiencies intrinsic to dopaminergic neurons, which may underlie dopaminergic neuron loss in PD.

Continuously moving table aorto-iliofemoral run-off contrast-enhanced magnetic resonance angiography: image quality analysis in comparison to the multistep acquisition.

BACKGROUND: Optimal vessel contrast is a prerequisite for vascular imaging. Consecutive stationary imaging of multiple fields of view is contrary to the continuous contrast material passage through the vascular tree. A continuous acquisition of a magnetic resonance (MR) sequence might overcome this limitation. PURPOSE: To investigate the image quality of a continuously moving table (CMT) acquisition compared with the established multistep approach for contrast-enhanced magnetic resonance angiography (CE-MRA) of the aorto-iliofemoral run-off. MATERIAL AND METHODS: Institutional review board approved this retrospective interindividual study of 60 consecutive patients referred to CE-MRA for peripheral arterial disease. Thirty patients underwent CE-MRA using the routine multistep acquisition and 30 patients were scanned using the CMT technique at 1.5 Tesla. All patients received a fixed contrast dose of 25 mL gadoterate meglumine. A quantitative analysis was performed to assess the relative contrast of 10 vascular segments from the proximal abdominal aorta to the distal calf arteries. A qualitative evaluation of three separate vascular regions (abdomen and pelvis, thighs, and calves) was performed. Two radiologists graded independently arterial vessel conspicuity, venous contamination, presence of artifacts, and diagnostic confidence on a 4-point scale. Overall scan time, including all localizer scans, was recorded. Statistical differences were tested using the Wilcoxon signed-rank test with Bonferroni correction. RESULTS: No significant differences were found between the continuously moving table acquisition and the multistep acquisition with regard to the relative vascular contrast and the qualitative image criteria. The agreement between both readers was significant (Kendall tau rank correlation coefficient, 0.373). The absolute reader agreement was 71.4%. The mean overall scan time was 12 min 44 s for the CMT protocol and 21 min 41 s for the multistep protocol. CONCLUSION: Aorto-iliofemoral run-off CE-MRA acquired with CMT technique provides a high image quality equivalent to a multistep technique at an overall scan time reduction of 41.3%.

Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial.

BACKGROUND: Aggressive challenging behaviour is frequently reported in adults with intellectual disability and it is often treated with antipsychotic drugs. However, no adequate evidence base for this practice exists. We compared flexible doses of haloperidol (a typical, first-generation antipsychotic drug), risperidone (an atypical, second-generation antipsychotic), and placebo, in the treatment of this behaviour. METHODS: 86 non-psychotic patients presenting with aggressive challenging behaviour from ten centres in England and Wales, and one in Queensland, Australia, were randomly assigned to haloperidol (n=28), risperidone (n=29), or placebo (n=29). Clinical assessments of aggression, aberrant behaviour, quality of life, adverse drug effects, and carer uplift (positive feelings about the care of the disabled person) and burden, together with total costs, were recorded at 4, 12, and 26 weeks. The primary outcome was change in aggression after 4 weeks' treatment, which was recorded with the modified overt aggression scale (MOAS). Analysis was by intention to treat. This study is registered as ISRCTN 11736448. FINDINGS: 80 patients had adherence of 80% or more to prescribed drug. Aggression decreased substantially with all three treatments by 4 weeks, with the placebo group showing the greatest change (median decrease in MOAS score after 4 weeks=9 [95% CI 5-14] for placebo, 79% from baseline; 7 [4-14] for risperidone, 58% from baseline; 6.5 [5-14] for haloperidol, 65% from baseline; p=0.06). Furthermore, although no important differences between the treatments were recorded, including adverse effects, patients given placebo showed no evidence at any time points of worse response than did patients assigned to either of the antipsychotic drugs. INTERPRETATION: Antipsychotic drugs should no longer be regarded as an acceptable routine treatment for aggressive challenging behaviour in people with intellectual disability.

Correlates of aggression in African American and Puerto Rican children.

The authors examined a cross-sectional interrelationship of psychosocial domains as they relate to aggression in a group of African American and English-speaking Puerto Rican children living in New York City. The population included 80 biological children of African American and Puerto Rican young adults who had been participating in the authors' ongoing longitudinal study, and 77 mothers or mother substitutes (rearing mothers) of those children. The authors performed hierarchical multiple regression analysis. The results indicated that (a) the child's personality and maternal attributes were significantly related to the child's aggression, despite control on all of the other domains and (b) the ethnic identification and discrimination domain was no longer related to the child's aggression with control on the mother-child relationship domain or on the child's personality domain. The findings have implications for clinical practice and public policy.