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Space Infrared Telescope for Cosmology and Astrophysics (SPICA), the cryogenic infrared space telescope recently pre-selected for a ‘Phase A’ concept study as one of the three remaining candidates for European Space Agency (ESA's) fifth medium class (M5) mission, is foreseen to include a far-infrared polarimetric imager [SPICA-POL, now called B-fields with BOlometers and Polarizers (B-BOP)], which would offer a unique opportunity to resolve major issues in our understanding of the nearby, cold magnetised Universe. This paper presents an overview of the main science drivers for B-BOP, including high dynamic range polarimetric imaging of the cold interstellar medium (ISM) in both our Milky Way and nearby galaxies. Thanks to a cooled telescope, B-BOP will deliver wide-field 100–350
m images of linearly polarised dust emission in Stokes Q and U with a resolution, signal-to-noise ratio, and both intensity and spatial dynamic ranges comparable to those achieved by Herschel images of the cold ISM in total intensity (Stokes I). The B-BOP 200
m images will also have a factor
30 higher resolution than Planck polarisation data. This will make B-BOP a unique tool for characterising the statistical properties of the magnetised ISM and probing the role of magnetic fields in the formation and evolution of the interstellar web of dusty molecular filaments giving birth to most stars in our Galaxy. B-BOP will also be a powerful instrument for studying the magnetism of nearby galaxies and testing Galactic dynamo models, constraining the physics of dust grain alignment, informing the problem of the interaction of cosmic rays with molecular clouds, tracing magnetic fields in the inner layers of protoplanetary disks, and monitoring accretion bursts in embedded protostars.
We aimed to provide comprehensive estimates of laboratory-confirmed respiratory syncytial virus (RSV)-associated hospitalisations. Between 2012 and 2015, active surveillance of acute respiratory infection (ARI) hospitalisations during winter seasons was used to estimate the seasonal incidence of laboratory-confirmed RSV hospitalisations in children aged <5 years in Auckland, New Zealand (NZ). Incidence rates were estimated by fine age group, ethnicity and socio-economic status (SES) strata. Additionally, RSV disease estimates determined through active surveillance were compared to rates estimated from hospital discharge codes. There were 5309 ARI hospitalisations among children during the study period, of which 3923 (73.9%) were tested for RSV and 1597 (40.7%) were RSV-positive. The seasonal incidence of RSV-associated ARI hospitalisations, once corrected for non-testing, was 6.1 (95% confidence intervals 5.8–6.4) per 1000 children <5 years old. The highest incidence was among children aged <3 months. Being of indigenous Māori or Pacific ethnicity or living in a neighbourhood with low SES independently increased the risk of an RSV-associated hospitalisation. RSV hospital discharge codes had a sensitivity of 71% for identifying laboratory-confirmed RSV cases. RSV infection is a leading cause of hospitalisation among children in NZ, with significant disparities by ethnicity and SES. Our findings highlight the need for effective RSV vaccines and therapies.
This is a copy of the slides presented at the meeting but not formally written up for the volume.
Many important oxidative reactions, such as CO oxidation, take place on metal surfaces at high temperatures and partial pressures. Understanding the atomic processes involved in these catalyzed reactions are of great importance and may be achievable by observations of the adsorbate-induced surface structure under temperatures and pressures relevant to working catalysts. Many of the prior studies, however, have only considered quenched-in structures with no dynamic interaction between the metal surface and the gas phase. This presentation describes in-situ synchrotron x-ray studies of the Cu (001) surface as a function of pO2, the oxygen partial pressure, and temperature. We utilize a controlled-flow reaction chamber specially constructed to mount onto an eight-circle diffractometer at the Advanced Photon Source. The chamber allows the flow of oxygen, hydrogen, and argon mixtures with pO2 ranging from 760 to 1×10-12 Torr and sample temperatures variable from 25 to 1000 °C. After reaching a critical pO2, oxygen adsorbs onto the initially clean Cu (001) surface, resulting in the rapid nucleation and growth of c(2×2)-O domains. Domain formation is concurrent with a small in-plane surface contraction and a large out-of-plane surface expansion associated with a compressive adsorbate-induced surface stress. The often reported (2√2×√2)R45 reconstruction is observed only below ~ 150 °C. Relationships between the different surface structures, subsurface oxygen, surface stress, and surface reactivity will be discussed.
We sought to retrospectively report our outcomes using post-operative stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) in place of whole-brain radiation therapy (WBRT) following resection of brain metastases from our hospital-based community practice.
Materials and Methods:
A retrospective review of 23 patients who underwent post-operative SRS at our single institution from 2013 to 2017 was undertaken. Patient records, treatment plans and diagnostic images were reviewed. Local failure, distant intracranial failure and overall survival were studied. Categorical variables were analyzed using Fisher’s exact tests. Continuous variables were analyzed using Mann–Whitney tests. The Kaplan–Meier method was used to estimate survival times.
16 (70%) were single-fraction SRS, whereas the remaining 7 patients received a five-fraction treatment course. The median single-fraction dose was 16 Gy (range, 16–18). The median total dose for fractionated treatments was 25 Gy (range, 25–35). Overall survival at 6 and 12 months was 95 and 67%, respectively. Comparison of SRS versus SRT local control rates at 6 and 12 months revealed control rates of 92 and 78% versus 29 and 14%, respectively. Every patient with dural/pial involvement at the time of surgery had distant intracranial failure at the 12-month follow-up.
Single-fraction frameless SRS proved to be an effective modality with excellent local control rates. However, the five-fraction SRT course was associated with an increased rate of local recurrence. Dural/pial involvement may portend a high risk for distant intracranial disease; therefore, it may be prudent to consider alternative approaches in these cases.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
Depression is a common, serious, but under-recognised problem in multiple sclerosis (MS). The primary objective of this study was to assess whether a rapid visual analogue screening tool for depression could operate as a quick and reliable screening method for depression, in patients with MS.
Patients attending a regional MS outpatient clinic completed the Emotional Thermometer 7 tool (ET7), the Hospital Anxiety and Depression Scale – Depression Subscale (HADS-D) and the Major Depression Inventory (MDI) to establish a Diagnostic and Statistical Manual, 4th edition (DSM-IV) diagnosis of Major Depression. Full ET7, briefer subset ET4 version and depression and distress thermometers alone were compared with HADS-D and MDI. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and receiver operating characteristic (ROC) curve were calculated to compare the performance of all the screening tools.
In total, 190 patients were included. ET4 performed well as a ‘rule-out’ screening step (sensitivity 0.91, specificity 0.72, NPV 0.98, PPV 0.32). ET4 performance was comparable to HADS-D (sensitivity 0.96, specificity 0.77, NPV 0.99, PPV 0.37) without need for clinician scoring. The briefer ET4 performed as well as the full ET7.
ET are quick, sensitive and useful screening tools for depression in this MS population, to be complemented by further questioning or more detailed psychiatric assessment where indicated. Given that ET4 and ET7 perform equally well, we recommend the use of ET4 as it is briefer. It has the potential to be widely implemented across busy neurology clinics to assist in depression screening in this under diagnosed group.
Depression frequently co-occurs with disorders of glucose and insulin homeostasis (DGIH) and obesity. Low-grade systemic inflammation and lifestyle factors in childhood may predispose to DGIH, obesity and depression. We aim to investigate the cross-sectional and longitudinal associations among DGIH, obesity and depression, and to examine the effect of demographics, lifestyle factors and antecedent low-grade inflammation on such associations in young people.
Using the Avon Longitudinal Study of Parents and Children birth cohort, we used regression analyses to examine: (1) cross-sectional and (2) longitudinal associations between measures of DGIH [insulin resistance (IR); impaired glucose tolerance] and body mass index (BMI) at ages 9 and 18 years, and depression (depressive symptoms and depressive episode) at age 18 years and (3) whether sociodemographics, lifestyle factors or inflammation [interleukin-6 (IL-6) at age 9 years] confounded any such associations.
We included 3208 participants. At age 18 years, IR and BMI were positively associated with depression. These associations may be explained by sociodemographic and lifestyle factors. There were no longitudinal associations between DGIH/BMI and depression, and adjustment for IL-6 and C-reactive protein did not attenuate associations between IR/BMI and depression; however, the longitudinal analyses may have been underpowered.
Young people with depression show evidence of DGIH and raised BMI, which may be related to sociodemographic and lifestyle effects such as deprivation, smoking, ethnicity and gender. In future, studies with larger samples are required to confirm this. Preventative strategies for the poorer physical health outcomes associated with depression should focus on malleable lifestyle factors.
X-ray microscopy is a field that has developed rapidly in recent years. Two different approaches have been used. Zone plates have been employed to produce focussed beams with sizes as low as 0.07 pm for x-ray energies below 1 keV. Images of biological materials and elemental maps for major and minor low Z have been produced using above and below absorption edge differences. At higher energies collimators and focussing mirrors have been used to make small diameter beams for excitation of characteristic K— or L-x rays of all elements in the periodic
While beneficial for sow reproductive efficiency and biosecurity, segregated early weaning (SEW) leads to a systemic immune response that adversely affects the digestive physiology and post-weaning growth of pigs. Two experiments were conducted to evaluate the effects of a glucocorticoid receptor agonist (GA) on growth performance, measures of immune function and intestinal integrity of SEW pigs. In both experiments, pigs were fed corn-soybean meal-based starter diets. In the first experiment, 48 pigs (initial BW 4.8 ± 0.7 kg) were weaned at 21 ± 1 days and randomly assigned to three GA treatment groups: 0, 0.2 and 0.6 mg GA/kg of BW injected intramuscularly. Treatments were administered one day before weaning. Pigs in the 0 mg GA group received sterile saline in place of GA. Body weight was measured daily from one day before to 7 days post-weaning, and then weekly until 28 days post-weaning. Piglets treated with 0.2 mg GA had a higher BW than piglets in other treatment groups during the 28-day course of the study (P <0.02). To further explore the mechanisms behind this result, a second experiment was performed in which a total of 18 gilts (BW 5.6 ± 0.85 kg) were randomly assigned into three treatment groups: suckling plus saline (UWS), weaned treated with GA (WGA; 0.2 mg GA/kg BW) and weaned plus saline (CON). Treatments were administered one day before and 3 days post-weaning. The WGA and CON groups were weaned at 23 ± 2 days, while the UWS group remained with sow for the duration of the study. Body weight was measured daily and blood plasma was collected at 0, 1, 4 and 5 days post-weaning. All gilts were euthanized 5 days after weaning and jejunum samples were collected for mucosal scrapings, histomorphological analysis and gene expression analysis. Plasma levels of interleukin-1β (IL-1β) and haptoglobin were lower in WGA pigs compared with CON (P <0.02), while plasma total antioxidant capacity was higher in WGA pigs compared with both CON and UWS groups (P <0.01). Relative to CON, GA downregulated IL-18 gene expression in the jejunum, as assessed by both tissue homogenate and mucosal scrapings, but it upregulated claudin-IV gene expression only in the tissue homogenate (P <0.01). These results suggest that GA treatment improves the growth performance of SEW pigs in part by mitigating the negative effects of systemic inflammation. However, the effect of GA on barrier integrity requires further investigation.
Despite their high value and importance for various glaciological applications, detailed ice thickness measurements of alpine glaciers are still very limited. Knowledge of bedrock topography is essential for paleoglaciological studies. The Guliya ice cap located on the Tibetan Plateau is one of the highest and largest ice caps in mid-low latitude regions. A detailed ground-penetrating radar (GPR) survey was conducted on the Guliya ice cap in 2015 using 20 and 40 MHz frequency antennas. An empirical Bayesian kriging method was used for ice thickness interpolation and uncertainty assessment. GPR measurements revealed complex basal topography of the Guliya glacier with a maximum thickness of 371.12 ± 13 m. The internal reflections caused by changes in the dielectric properties were registered on the 40 MHz radargrams at the summit and were attributed to density variations. As a result of this fieldwork, one of the largest ice thickness datasets in High Mountain Asia was obtained. Guliya glacier elevation changes were assessed by differencing digital elevation models. The glacier gained mass from 2000 to 2015 with an average rate of 0.270 ± 0.11 m w.e. a−1 at the summit and 0.279 ± 0.11 m w.e. a−1 at the lower elevations.
Limited research has suggested that higher lambing densities increase interference from foreign ewes at lambing which disrupts the ewe-lamb bond and compromises lamb survival. This may be particularly evident in mobs of twin-bearing ewes compared to single-bearing ewes because a greater number of lambs are born per day. Therefore, we hypothesised that; (i) decreasing the mob size of ewes at lambing has a greater impact on the survival of twin-born lambs than single-born lambs; (ii) the relationship between mob size and lamb survival can be explained by differences in the rate of interaction with foreign ewes and lambs at lambing; and (iii) ewes will utilise a limited area of the paddock at lambing and thus lambing density will be defined by the distribution of ewes in the paddock rather than the paddock area. Merino ewes were allocated into a 2×2 factorial combination of ewe pregnancy status (single- or twin-bearing) and mob size (high (n=130 ewes) or low (n=50 ewes)) on day 140 from the start of joining. Each treatment had two replicates excepting the low mob size for twins which had a third replicate. Ewes lambed at a stocking rate of 11 ewes/ha. Feed-on-offer during lambing exceeded 2400 kg dry matter (DM)/ha. Ewe-lamb behaviour was observed and dead lambs were autopsied over 11 days during the peak of lambing. The distribution of ewes in each paddock was recorded every 2 h during daylight hours by counting the number of ewes occupying 2500 m2 grids. The proportion of ewes and their newborn progeny which interacted with foreign ewes at lambing did not differ between the high and low mob sizes for single- (24.9% v. 20.8%) or twin-bearing ewes (14.3% v. 19.6%; P=0.74). Similarly, interaction with foreign lambs did not differ between the high and low mob sizes for single- (14.5% v. 25.2%) and twin-bearing ewes (34.5% v. 26.4%; P=0.44). The distribution of ewes within the paddock did not differ between treatments (P=0.95). On average, single-bearing ewes which lambed at the high and low mob sizes occupied 34% and 36% of the paddock during daylight hours, and the corresponding values for twin-bearing ewes were 40% and 43%. Survival of twin-born lambs was lower than single-born lambs (75.3% v. 87.9%; P<0.01), however, lamb survival was not influenced by mob size regardless of birth type. These results suggest that higher mob sizes may not compromise lamb survival when feed-on-offer during lambing exceeds 2400 kg DM/ha.
In 2016, imported Zika virus (ZIKV) infections and the presence of a potentially competent mosquito vector (Aedes albopictus) implied that ZIKV transmission in New York City (NYC) was possible. The NYC Department of Health and Mental Hygiene developed contingency plans for a urosurvey to rule out ongoing local transmission as quickly as possible if a locally acquired case of confirmed ZIKV infection was suspected. We identified tools to (1) rapidly estimate the population living in any given 150-m radius (i.e. within the typical flight distance of an Aedes mosquito) and (2) calculate the sample size needed to test and rule out the further local transmission. As we expected near-zero ZIKV prevalence, methods relying on the normal approximation to the binomial distribution were inappropriate. Instead, we assumed a hypergeometric distribution, 10 missed cases at maximum, a urine assay sensitivity of 92.6% and 100% specificity. Three suspected example risk areas were evaluated with estimated population sizes of 479–4,453, corresponding to a minimum of 133–1244 urine samples. This planning exercise improved our capacity for ruling out local transmission of an emerging infection in a dense, urban environment where all residents in a suspected risk area cannot be feasibly sampled.
We investigated risk factors for severe acute lower respiratory infections (ALRI) among hospitalised children <2 years, with a focus on the interactions between virus and age. Statistical interactions between age and respiratory syncytial virus (RSV), influenza, adenovirus (ADV) and rhinovirus on the risk of ALRI outcomes were investigated. Of 1780 hospitalisations, 228 (12.8%) were admitted to the intensive care unit (ICU). The median (range) length of stay (LOS) in hospital was 3 (1–27) days. An increase of 1 month of age was associated with a decreased risk of ICU admission (rate ratio (RR) 0.94; 95% confidence intervals (CI) 0.91–0.98) and with a decrease in LOS (RR 0.96; 95% CI 0.95–0.97). Associations between RSV, influenza, ADV positivity and ICU admission and LOS were significantly modified by age. Children <5 months old were at the highest risk from RSV-associated severe outcomes, while children >8 months were at greater risk from influenza-associated ICU admissions and long hospital stay. Children with ADV had increased LOS across all ages. In the first 2 years of life, the effects of different viruses on ALRI severity varies with age. Our findings help to identify specific ages that would most benefit from virus-specific interventions such as vaccines and antivirals.
OBJECTIVES/SPECIFIC AIMS: Immuno-oncology (IO) strategies are promising new approaches for the treatment of a variety of malignancies, including multiple myeloma (MM). Regulatory T cells (Tregs), which suppress effector T cell function, are a limitation to durable IO responses. The transcription factor FOXP3 is critical for the mature Treg phenotype. FOXP3 homodimerization is required for DNA binding and transcriptional activity, and mutations mapping to the dimerization region are associated with IPEX syndrome, resulting in dysfunctional Tregs in humans. We therefore hypothesize that inhibitors of FOXP3 dimerization will repress Treg suppression and enhance the anti-MM activity of IO. METHODS/STUDY POPULATION: To discover FOXP3 dimerization inhibitors, we are modeling FOXP3 homodimerization in vitro. Currently, we are optimizing an ALPHA screen and an ELISA-based dimerization assay using recombinant full length and truncated versions of FOXP3 to discover peptidomimetics that inhibit homodimerization. Induced Tregs expanded from human PBMCs will be treated with lead biologics and functional assays will be performed. RESULTS/ANTICIPATED RESULTS: Here we demonstrate Treg suppression of T cell proliferation and IFN-γ secretion after 5 days of co-culture under basal conditions. Additionally, we developed a MM/T cell co-culture system to measure anti-MM T cell responses and show decreased anti-MM T cell activity in the presence of Tregs. We expect to exploit the assays outlined here to demonstrate defective Treg suppression when FOXP3 dimerization is inhibited. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies support drug discovery efforts that will ultimately improve IO therapies for patients with MM.
Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.