Partially Organised, Partially Successful? - A Case Study of the Partial Organisation of the COVAX Initiative

Master's Thesis in Public AdministrationAORG351MASV-PUBA

Hubble Space Telescope Wide Field Camera 3 Identifies an rpr_p = 1 Kpc Dual Active Galactic Nucleus in the Minor Galaxy Merger SDSS J0924+0510 at z = 0.1495

Kiloparsec-scale dual active galactic nuclei (AGNs) are active supermassive black hole pairs co-rotating in galaxies with separations of less than a few kpc. Expected to be a generic outcome of hierarchical galaxy formation, their frequency and demographics remain uncertain. We have carried out an imaging survey with the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) of AGNs with double-peaked narrow [O III] emission lines. HST/WFC3 offers high image quality in the near-infrared (NIR) to resolve the two stellar nuclei, and in the optical to resolve [O III] from ionized gas in the narrow-line regions. This combination has proven to be key in sorting out alternative scenarios. With HST/WFC3 we are able to explore a new population of close dual AGNs at more advanced merger stages than can be probed from the ground. Here we show that the AGN SDSS J0924+0510, which had previously shown two stellar bulges, contains two spatially distinct [O III] regions consistent with a dual AGN. While we cannot completely exclude cross-ionization from a single central engine, the nearly equal ratios of [O III] strongly suggest a dual AGN with a projected angular separation of 0."4, corresponding to a projected physical separation of $r_p$ = 1 kpc at redshift z = 0.1495. This serves as a proof of principle for combining high-resolution NIR and optical imaging to identify close dual AGNs. Our result suggests that studies based on low-resolution and/or low-sensitivity observations may miss close dual AGNs and thereby may underestimate their occurrence rate on $\lesssim$ kpc scales.Comment: 11 pages, 8 figures; ApJ in pres

Stress Urinary Incontinence post-Holmium Laser Enucleation of the Prostate: a Single-Surgeon Experience.

PURPOSE: To identify incidence and predictors of stress urinary incontinence (SUI) following Holmium laser enucleation of the prostate (HoLEP). MATERIALS AND METHODS: We performed a retrospective review of 589 HoLEP patients from 2012-2018. Patients were assessed at pre-operative and post-operative visits. Univariate and multivariate regression analyses were performed to identify predictors of SUI. RESULTS: 52/589 patients (8.8%) developed transient SUI, while 9/589 (1.5%) developed long-term SUI. tSUI resolved for 46 patients (88.5%) within the first six weeks and in 6 patients (11.5%) between 6 weeks to 3 months. Long-term SUI patients required intervention, achieving continence at 16.4 months on average, 44 men (70.9%) with incontinence were catheter dependent preoperatively. Mean prostatic volume was 148.7mL in tSUI patients, 111.6mL in long-term SUI, and 87.9mL in others (p \u3c 0.0001). On univariate analysis, laser energy used (p \u3c 0.0001), laser on time (p=0.0204), resected prostate weight (p \u3c 0.0001), overall International Prostate Symptom Score (IPSS) (p=0.0005), and IPSS QOL (p=0.02) were associated with SUI. On multivariate analysis, resected prostate weight was predictive of any SUI and tSUI, with no risk factors identified for long-term SUI. CONCLUSION: Post-HoLEP SUI occurs in ~10% of patients, with 1.5% continuing beyond six months. Most patients with tSUI recover within the first six weeks. Prostate size \u3e100g and catheter dependency are associated with increased risk tSUI. Larger prostate volume is an independent predictor of any SUI, and tSUI

Stereotactic Radiosurgery Practice Patterns for Brain Metastases in the United States: A National Survey

Background: Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treat- ment of multiple brain metastases. Methods: An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the US (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution. Results: 116 of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. 62% reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for \u3c10 brain metastases (73.7%; p\u3c.0001) and whole brain radiation therapy (WBRT) for \u3e10 brain metastases (82.5%; p\u3c.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1-4 (40.4%) and 5-10 (42.4%) (p\u3c.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p\u3c.0001) and performance status (p=.016). The most common margin for SRS was 0 mm (49.1%; p=.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p=.23). Most departments do not have a policy for brain metastases treatment (64.9%; p=.024). Conclusions: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS. Summary: This is among the first national surveys to assess the use of SRS for brain metastases in clinical practice. Specifically, radiation oncologist reported increasingly using SRS instead of WBRT for treating \u3c10 metastases, with the LINAC being the most common modality. Further, treatment parameters considered the most important included 0 mm margins, conformity index, brain V12, and mono- isocenter technique for multiple brain metastases. These results may provide context regarding the use of SRS for brain metastases in clinical practice

Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. We also review evidences that connect the phase separation property of TDP-43 and FUS to their functional roles in cells. Aberrant phase transition of TDP-43 and FUS leads to protein aggregation and disrupts their regular cell function. Therefore, restoration of functional protein phase of TDP-43 and FUS could be beneficial for neuronal cells. We discuss possible mechanisms for TDP-43 and FUS aberrant phase transition and aggregation while reviewing the methods that are currently being explored as potential therapeutic strategies to mitigate aberrant phase transition and aggregation of TDP-43 and FUS

NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4 −/− and Nlrp3 −/− mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis

Family caregiver challenges in dementia care in Australia and China: a critical perspective

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Both Australia and China have a large proportion of people with dementia and the prevalence will triple in Australia and increase five times in China by 2050. The majority of people with dementia are reliant on family caregivers to provide daily care and to maintain the dignity in both countries. As a consequence, caregiver burden has become a major concern because of the negative impact on the care recipients’ and the caregivers’ health. It is strongly recommended that cross-national collaboration should be conducted to share experiences in fighting dementia. The aim of this study was to compare socially and culturally constructed enablers and barriers pertinent to dementia caregivers in one capital city in Australia and one capital city in China through critical reflection on the caregivers’ subjective and objective experiences for the improvement of dementia care services in both countries. Methods: Giddens’ Structuration Theory was used as a framework to guide a concurrent mixed methods design with the qualitative strand as a priority. In the qualitative strand, data were collected by focus groups and in-depth interviews while in the quantitative strand, data were collected by questionnaire survey. Results: In total 148 caregivers participated in the project with 57 of them from Australia (26 and 31 in the qualitative and quantitative strands respectively) and 91 of them from China (23 and 68 in the qualitative and quantitative strands respectively). Findings from the qualitative and quantitative strands were presented as three categories: A higher objective burden in the Chinese cohort versus a higher subjective burden in the Australian cohort; Unmet need for caregiver support in Australia and China; and Expectations for improving dementia services in Australia and for developing dementia services in China. Conclusions: Dementia policy, services and resources need to be grounded on current research evidence in an ever-changing society like China. In Australia, dementia services need to have more components of preventing or reducing caregivers’ subjective burden. As subjective burden is mediate

Inflammasomes: mechanism of action, role in disease and therapeutics

The inflammasomes are innate immune system receptors/sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. It has been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research