Development of a full aperture backscatter system for the Orion laser.

A full aperture backscatter system (FABS) is currently in development on the Orion laser at AWE to measure scattered light from the stimulated Brillouin scattering (SBS) and stimulated Raman scattering (SRS) processes. The light is to be collected through the full aperture of the final optic assembly and traverse back down the beam path, with fractions of this light being directed to an optics table. By measuring the energy of this backscattered light, it is possible to gain insight into some of the laser-plasma instabilities that are present on the laser system and should give an indication of some of the scattered light losses due to the SBS and SRS processes. The uncontrolled scattered light can lead to hotter electrons, which then preheat the target causing a degradation in compression and can inhibit ignition in inertial confinement fusion experiments, as well as secondary instabilities whereby the scattered light may in itself cause further LPIs, such as two-ion decay or the Langmuir decay instability. The FABS diagnostic on Orion is planned to enhance the plasma diagnostics suite available and provide quantitative guidance on increasing the energy coupling. Current progress includes the characterization of filters and, hence, a broadband xenon lamp to be used in measuring the transmission efficiency of the optics chain, desktop alignment of the backscatter optics, and characterization of the streak cameras.

A COVID-19 monitoring process for healthcare workers utilizing occupational health.

BACKGROUND: Hospital-based occupational health (HBOH) is uniquely positioned to not only prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, but to care for healthcare workers (HCWs) sick with coronavirus disease 2019 (COVID-19). AIMS: The primary objective of this study is to describe a system where HBOH services were adapted to provide a monitoring programme whereby HCWs with SARS-CoV-2 received daily evaluations and treatment options in order to improve access to care, and to report the clinical outcomes and predictors of hospitalization in HCWs enrolled in the programme. A secondary objective is to compare clinical outcomes to data on national HCWs with COVID-19. METHODS: This retrospective cohort study used survey data collected on HCWs at a university health system with COVID-19 from 1 March 2020 through 1 December 2021. A firth regression model was used to examine the unadjusted and adjusted association between clinical factors and hospitalization. RESULTS: The study cohort included 4814 HCWs with COVID-19. Overall hospitalizations were 119 (2%), and there were six deaths (0.12%). Predictors of hospitalization include several co-morbidities and symptoms. A total of 1835 HCWs monitored before vaccine or monoclonal antibody availability were compared with data on U.S. HCWs in a similar time period. The monitored HCWs had a lower rate of co-morbidities (19% versus 44%, P < 0.001), a lower hospitalization rate (3% versus 8% P < 0.001) and case-fatality rate (0.11% versus 0.95% P < 0.001). CONCLUSIONS: This monitoring strategy for COVID-19 may be feasible for HBOH systems to implement and improve access to care, but more data are needed to determine if it improves outcomes.

Measuring for primary prevention: An online survey of local community perspectives on family and domestic violence in regional Australia.

BACKGROUND: Family and domestic violence, encompassing diverse behaviours including physical, sexual, emotional and financial abuse, is endemic worldwide and has multiple adverse health and social consequences. Principal drivers include traditional gender values that disempower women. Changing these is a key prevention strategy. In Australia, high-quality national surveys provide data on public perspectives concerning family and domestic violence but may not capture community-level diversity. As part of a project for primary prevention family and domestic violence in outer regional Australia, our aims were to develop and administer a questionnaire-based survey suitable for the local community encompassing knowledge about, attitudes towards, and personal experiences of family and domestic violence, to describe and to investigate the theoretical (factor) structure and local socio-demographic predictors of responses, and to determine the extent to which the survey findings are locally distinctive. METHODS: The online community survey for local residents (≥15 years), comprised items on respondents' sociodemographic characteristics plus questions abridged from pre-existing national instruments on knowledge about, attitudes towards, and personal experiences of family and domestic violence. Responses were rake-weighted to correct census-ascertained sample imbalance and investigated using exploratory factor analysis, with sociodemographic predictors determined using multiple linear regression and dominance analysis. RESULTS: Among 914 respondents, males (27.0%), those from age-group extremes, and less-educated persons were underrepresented. Familiarity with diverse family and domestic violence behaviours was high among all subgroups. Poorer knowledge of the FDV behaviour continuum and attitudes supporting traditional gender roles and FDV were disproportionately evident among males, older respondents and those with lower education levels. Both the factor structure of extracted composite measures reflecting community perspectives and sociodemographic predictors of responses generally aligned with patterns evident in national data. CONCLUSIONS: Local reinforcement of existing nationwide findings on community understanding of and attitudes towards family and domestic violence provides salience for targeted interventions.

Anatomy of a Transcatheter Mitral Valve Service.

Transcatheter mitral therapies offer treatment options to selected patients who are unable to undergo open procedures due to prohibitive surgical risk. Data detailing the design and structure of transcatheter mitral services to ensure appropriate patient selection and tailored management strategies is lacking. We report our initial experience of developing and running a purpose-built transcatheter mitral service. The nature and number of referral sources, the multi-disciplinary make-up of the dedicated Mitral Heart Team and the use of integrative imaging assessment with incorporation of computational solutions are discussed. In addition, a summary of the clinical decision-making process is presented. This report sets out a framework from which future clinics can evolve to improve and streamline the delivery of transcatheter mitral therapies.

Quantitative Immunohistochemistry to Measure Regional Expression of Nurr1 in the Brain and the Effect of the Nurr1 Heterozygous Genotype.

The transcription factor Nurr1 is a member of the steroid hormone nuclear receptor superfamily. Ablation of Nurr1 expression arrests mesencephalic dopamine neuron differentiation while attenuation of Nurr1 in the subiculum and hippocampus impairs learning and memory. Additionally, reduced Nurr1 expression has been reported in patients with Parkinson's disease and Alzheimer's disease. In order to better understand the overall function of Nurr1 in the brain, quantitative immunohistochemistry was used to measure cellular Nurr1 protein expression, across Nurr1 immunoreactive neuronal populations. Additionally, neuronal Nurr1 expression levels were compared between different brain regions in wild-type mice (+/+) and Nurr1 heterozygous mice (+/-). Regional Nurr1 protein was also investigated at various time points after a seizure induced by pentylenetetrazol (PTZ). Nurr1 protein is expressed in various regions throughout the brain, however, a wide range of Nurr1 expression levels were observed among various neuronal populations. Neurons in the parietal and temporal cortex (secondary somatosensory, insular, auditory, and temporal association cortex) had the highest relative Nurr1 expression (100%) followed closely by the claustrum/dorsal endopiriform cortex (85%) and then subiculum (76%). Lower Nurr1 protein levels were found in neurons in the substantia nigra pars compacta and ventral tegmental area (39%) followed by CA1 (25%) and CA3 (19%) of the hippocampus. Additionally, in the parietal and temporal cortex, two distinct populations of high and medium Nurr1 expressing neurons were observed. Comparisons between +/- and +/+ mice revealed Nurr1 protein was reduced in +/- mice by 27% in the parietal/temporal cortex, 49% in the claustrum/dorsal endopiriform cortex, 25% in the subiculum, 33% in substantia nigra pars compacta, 22% in ventral tegmental area, and 21% in CA1 region of the hippocampus. Based on these data, regional mechanisms appear to exist which can compensate for a loss of a Nurr1 allele. Following a single PTZ-induced seizure, Nurr1 protein in the dentate gyrus peaked around 2 h and returned to baseline by 8 h. Since altered Nurr1 expression has been implicated in neurologic disorders and Nurr1 agonists have showed protective effects, understanding regional protein expression of Nurr1, therefore, is necessary to understand how changes in Nurr1 expression can alter brain function.

Nurr1 deficiency shortens free running period, enhances photoentrainment to phase advance, and disrupts circadian cycling of the dopamine neuron phenotype.

Neurological and neuropsychiatric disorders, including addiction, schizophrenia, and Parkinson's disease (PD), involve dysfunction in midbrain dopamine (DA) neurotransmission with severity of disease symptoms and progression associated with disrupted circadian rhythms. The nuclear transcription factor Nurr1, essential for DA neuron (DAN) development, survival, and maintenance, is also known to interact with circadian rhythm regulating clock proteins. In the Nurr1-null heterozygous (+/-) mice, a Nurr1 deficient model which reproduces some of the alterations in DA function found in schizophrenia and PD, we measured, using wheel-running activity, the free running period (tau) and photoperiod entrainment. Because Nurr1 has a role in regulating the DA phenotype, we also measured the circadian fluctuations in the number of DANs using tyrosine hydroxylase (TH) immunofluorescence. In Nurr1 +/- mice, tau was significantly shorter and entrainment to a 6 h earlier shift in the dark cycle was accelerated. The Nurr1 wild-type (+/+) mice cycled DAN numbers across time, with a significantly greater number (∼2-fold increase) of DANs at zeitgeber time (ZT) 0 than ZT12. The +/- mice, however, did not cycle the DA phenotype, as no differences in DAN numbers were observed between ZT0 and ZT12. Additionally, the +/- mice had significantly fewer DANs at ZT0 but not at ZT12 as compared to +/+ mice. Based these data, circadian rhythms and fluctuations in the DA phenotype requires normal Nurr1 function. A better understanding is needed of the mechanisms regulating the DA phenotype and subsequent neurotransmission across the circadian cycle and how this is altered in circadian rhythm and DA neurotransmission-associated disorders.

Imaging in Suspected Cardiac Sarcoidosis: A Diagnostic Challenge.

Cardiac Sarcoidosis (CS) represents a unique diagnostic dilemma. Guidelines have been recently revised to reflect the established role of sophisticated imaging techniques. Trans-thoracic Echocardiography (TTE) is widely adopted for initial screening of CS. Contemporary TTE techniques could enhance detection of subclinical Left Ventricular (LV) dysfunction, particularly LV global longitudinal strain assessment which predicts event-free survival (meta-analysis of 5 studies, hazard ratio 1.28, 95% confidence interval 1.18-1.37, p < 0.0001). However, despite the wide availability of TTE, it has limited sensitivity and specificity for CS diagnosis. Cardiac Magnetic resonance Imaging (CMR) is a crucial diagnostic modality for suspected CS. Presence of late gadolinium enhancement signifies myocardial scar and enables risk stratification. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) coupled with myocardial perfusion imaging can identify active CS and guide immunosuppressant therapy. Gallium scintigraphy may be considered although FDG-PET is often preferred. While CMR and FDG-PET provide complementary information in CS evaluation, current guidelines do not recommend which imaging modalities are essential in suspected CS and if so, which modality should be performed first. The utility of hybrid imaging combining both advanced imaging modalities in a single scan is currently being explored, although not yet widely available. In view of recent, significant advances in cardiac imaging techniques, this review aims to discuss changes in guidelines for CS diagnosis, the role of various cardiac imaging modalities and the future direction in CS.

"Between a rock and the mitral valve space": Transcatheter mitral valve-in-valve implantation for paravalvular leak and refractory hemolysis complicated by circumflex coronary occlusion.

Transcatheter mitral valve implantation (TMVI) is an emerging field in structural cardiology. A particularly difficult group to treat is high-risk patients requiring valve in mitral annular calcification (ViMAC) intervention, with overall poor procedural success and outcomes in recent registries. This case highlights an unusual complication of paravalvular regurgitation (PVL) through the uncovered stent frame of a balloon expandable transcatheter heart valve (THV) on the left ventricular side of the prosthesis, leading to mechanical hemolysis and subsequent anuric renal failure post a ViMAC procedure. Attempts to treat the PVL with an occlusion plug device were unsuccessful and led to left circumflex coronary occlusion secondary to mechanical compression of the vessel in the posterior mitral valve annulus, a previously unreported phenomenon. A repeat valve-in-valve procedure was performed to treat the PVL, and immediate angioplasty resolved the left circumflex occlusion. High-risk patients requiring TMVI pose multiple challenges to Heart Teams in the treatment of valve pathology. Optimal procedural planning, multimodality imaging, improved THVs, and the awareness of potential complications are fundamental in overcoming the learning curve of TMVI and improved outcome for patients requiring ViMAC.

Plasma levels of soluble membrane attack complex are elevated despite viral suppression in HIV patients with poor immune reconstitution.

The complement system is now a therapeutic target for the management of serious and life-threatening conditions such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, glomerulonephritis and other diseases caused by complement deficiencies or genetic variants. As complement therapeutics expand into more clinical conditions, monitoring complement activation is increasingly important, as is the baseline levels of complement activation fragments in blood or other body fluid levels. Although baseline complement levels have been reported in the literature, the majority of these data were generated using non-standard assays and with variable sample handling, potentially skewing results. In this study, we examined the plasma and serum levels of the soluble membrane attack complex of complement (sMAC). sMAC is formed in the fluid phase when complement is activated through the terminal pathway. It binds the regulatory proteins vitronectin and/or clusterin and cannot insert into cell membranes, and can serve as a soluble diagnostic marker in infectious disease settings, as previously shown for intraventricular shunt infections. Here we show that in healthy adults, serum sMAC levels were significantly higher than those in plasma, that plasma sMAC levels were similar between in African Americans and Caucasians and that plasma sMAC levels increase with age. Plasma sMAC levels were significantly higher in virally suppressed people living with HIV (PLWH) compared to non-HIV infected healthy donors. More specifically, PLWH with CD4+ T cell counts below 200 had even greater sMAC levels, suggesting diagnostic value in monitoring sMAC levels in this group.

Transcatheter aortic valve implantation for severe aortic stenosis in the Australian regional population.

OBJECTIVE: To compare clinical and functional outcomes of regional and urban patients after transcatheter aortic valve implantation for severe aortic stenosis. METHODS: Data were collected at patient follow-up post-transcatheter aortic valve implantation at 30 days and 12 months. Patients were stratified by residential postcodes into remoteness areas using the Australian Statistical Geography Standard. DESIGN: Retrospective cohort study. SETTING: Single-centre tertiary referral hospital. PARTICIPANTS: Patients undergoing transcatheter aortic valve implantation (n = 142) from 2009 to 2018 were analysed, with 77 patients (54.2%) residing in regional Victoria and New South Wales. MAIN OUTCOME MEASURES: Procedural success, adverse event rates, readmission rates, mortality rates, loss to follow-up and functional improvement. RESULTS: Patients residing in regional areas had a lower mean age (81.8 vs 83.7 years) and proportion of Stage 4 or 5 chronic kidney disease (1.3% vs 9.2%), compared with urban patients. Procedural characteristics and immediate post-procedural outcomes were similar between both groups. There was no statistically significant difference in mortality, readmission rates or loss to follow-up between the two cohorts. Regional patients demonstrated poorer rates of functional improvement at 30 days (50.7% vs 67.7%); however, this difference was not sustained at 12 months (79.2% vs 71.0%). Frailty was demonstrated to be an independent predictor of poor 30-day functional improvement. CONCLUSION: Regional patients treated with transcatheter aortic valve implantation for severe aortic stenosis have non-inferior 30-day and 12-month outcomes, when compared with urban patients. Frailty is a predictor of poor functional improvement post-transcatheter aortic valve implantation.

Contemporary review of severe aortic stenosis.

Severe aortic stenosis (AS) is the most common form of valvular heart disease in the developed world, with a rising prevalence due to an ageing Australian population. Transcatheter aortic valve implantation (TAVI) offers a less invasive option for the treatment of severe AS, with evidence supporting TAVI compared with medical therapy in inoperable patients and superior with surgical aortic valve replacement (SAVR) in high-risk patients. Equal outcomes have been observed in all-comer intermediate-risk populations. The Heart Team utilises a shared decision-making approach between physicians and surgeons in risk-stratifying patients and reduces the intrinsic bias that may occur if decisions are made in isolation. Geriatric assessment is useful for identifying preoperative frailty, a major risk factor for death post-aortic valve intervention. In severe AS, a decision can be made collaboratively to pursue TAVI, SAVR, a Ross Procedure or conservative management. The learning curve associated with TAVI has improved markedly, with overall complication rates decreasing around the world. Contemporary changes in practice, such as conscious sedation without general anaesthesia, expedited recovery and early discharge, will likely improve cost-effectiveness. In 2018, TAVI is a well-established procedure in Australia that has revolutionised the management of severe AS. In the future, with an expanding elderly population, the number of patients to benefit from transcatheter therapies for severe AS is hypothesised to increase 4-10-fold. Heart Team assessment is crucial in patients with severe AS to direct appropriate management.

International survey on growth indices and impacting factors in children with food allergies.

BACKGROUND: Elimination diets required for the management of food allergies increase the risk for poor growth in children. Currently, no worldwide data exist on this topic and limited published data exist on the impact of atopic comorbidity, type of allergy and foods eliminated on growth. We therefore set out to perform a worldwide survey on growth and impacting factors in food allergic children. METHODS: A prospective growth survey was performed of children (aged 0-16 years) on an elimination diet with confirmed immunoglobulin (Ig)E and non-IgE mediated food allergies. Data collected included: weight-for-age, weight-for-height, height-for-age, head circumference, body mass index, type of food allergy and eliminated foods, allergic comorbidities and replacement milk/breast milk. Multivariable regression analysis was used to establish factors that affected growth. RESULTS: Data from 430 patients from twelve allergy centres were analysed: median age at diagnosis and data collection was 8 months and 23 months, respectively. Pooled data indicated that 6% were underweight, 9% were stunted, 5% were undernourished and 8% were overweight. Cow's milk elimination lead to a lower weight-for-height Z-scores than other food eliminations and mixed IgE and non-IgE mediated allergy had lower height-for-age Z-scores than IgE mediated allergy. Children with only non-IgE mediated allergies had lower weight-for-height and body mass index. Atopic comorbidities did not impact on growth. CONCLUSIONS: Stunting is more common in children with food allergies than low weight. Children particularly at risk of poor growth are those with non-IgE and mixed IgE and non-IgE mediated allergies, as well as those with cow's milk allergy.

A review of treatment options for behavioural manifestations of clinical anxiety as a comorbidity in dogs with idiopathic epilepsy.

Psychiatric comorbidities affect a large percentage of people with epilepsy and have a detrimental impact on their quality of life. Recently, behavioural comorbidities, with similar characteristics to human psychiatric diseases, have been identified in dogs with idiopathic epilepsy. In particular, behaviours motivated by the fear-anxiety emotional system have been found to be associated with the occurrence of idiopathic epilepsy in both dogs receiving anti-epileptic drugs, and drug-naïve dogs. There has been little research into the relationship between epilepsy and behavioural signs, and even less into potential treatment protocols. The following article will review available literature from human medicine to describe the current state of knowledge about the bi-directional relationship between anxiety and epilepsy, draw parallels from reported anxiogenic and anxiolytic properties of anti-epileptic drugs and attempt to provide pharmaceutical and behavioural guidance for veterinary patients with epilepsy and comorbid anxiety.

Bilateral quadriceps and hamstrings muscle volume asymmetries in healthy individuals.

Determining the magnitude of quadriceps and hamstring muscle volume asymmetries in healthy individuals is a critical first step toward interpreting asymmetries as compensatory or abnormal in pathological populations. The purpose of this study was to determine the magnitude of whole and individual muscle volume asymmetries, quantified as right-left volume differences, for the quadriceps and hamstring muscles in a young and healthy population. Twenty-one healthy individuals participated: Eleven females age = 22.6 ± 2.9 years and 10 males age = 23.2 ± 3.4 years. Whole muscle group and individual muscle volume asymmetries were quantified within the context of absolute measurement error using a 95% Limits of Agreement approach. Mean muscle asymmetries ranged from -3.0 to 6.0% for all individual and whole muscle groups. Whole muscle group 95% limits of agreements represented ±11.4% and ±8.8% volume asymmetries for the hamstrings and quadriceps, respectively. Individual muscle asymmetry 95% limits of agreements ranged from ∼ ± 11-13% for the vastii muscles while the biceps femoris short-head (±33.5%), long-head (±20.9%), and the rectus femoris (±21.4%) displayed the highest relative individual asymmetries. Individual muscle asymmetries exceeded absolute measurement error in 70% of all cases, with 26% of all cases exceeding 10% asymmetry. Although whole muscle group asymmetries appear to be near the 10% assumed clinical threshold of normality, the greater magnitude of individual muscle asymmetries highlights the subject- and muscle-specific variability in volume asymmetry. Future research is warranted to determine if volume asymmetry thresholds exist that discriminate between healthy and pathological populations. Statement of Clinical Significance: Muscle volume asymmetries displayed in healthy individuals provide a reference for interpreting asymmetries in pathological populations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:963-970, 2018.

Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy.

Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease.

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.