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Risk-based catastrophe bonds require the estimation of losses from the convolution of hazard, exposure and vulnerability models. These models are affected by different uncertainties that arise from the definition of their input parameters. In this paper, we propose a stochastic approach to treat the uncertainty in the asset location and attributes of the exposure model. The proposed method uses the Monte Carlo sampling approach to generate a stochastic exposure database, where each asset location is generated randomly within the geometric bound of the administration, while the asset attributes (i.e. construction type and material, number of storey, building activity type and number of dwelling) are sampled from distributions built from census data. Finally, a sensitivity analysis is performed to investigate the influence of the spatial resolution of the exposure model on the average annual losses (AAL) and catastrophe bond prices. To this end, we implement four exposure models, with spatial resolution at the asset, municipality and province levels, on a study region comprising ten provinces in southern Italy. Compared to the proposed model, the exposure model where assets are relocated and aggregated at the geometric centroid of the municipality underestimates AAL by $$8\%$$ 8 % , while a higher difference (up to $$20\%$$ 20 % ) is observed for the exposure model where assets are relocated and aggregated at the geometric centroid of the province. We also consider an exposure model whose asset locations are extracted from publicly available building footprints. Yet, this latter model was incomplete for some provinces resulting in underestimation of AAL up to $$90\%$$ 90 % . Differences in catastrophe bond prices obtained from the four exposure models are less evident, with the exposure model built based on the building footprints showing a difference up to $$9.5\%$$ 9.5 % .

BACKGROUNDA salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT), and it is not known whether it is related to individual treatments,GBAgenotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies.OBJECTIVEPrompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.METHODSLongitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy,GBA1genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.RESULTSThe patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, pCONCLUSIONSThere is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related toGBAgenotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.FundingLSD Training Fellowship from Sanofi to MB.

Expression of recombinant proteins in mammalian cell factories relies on synthetic assemblies of genetic parts to optimally control flux through the product biosynthetic pathway. In comparison to other genetic part-types, there is a relative paucity of characterized signal peptide components, particularly for mammalian cell contexts. In this study, we describe a toolkit of signal peptide elements, created using bioinformatics-led and synthetic design approaches, that can be utilised to enhance production of biopharmaceutical proteins in Chinese Hamster Ovary cell factories. We demonstrate, for the first time in a mammalian cell context, that machine learning can be used to predict how discrete signal peptide elements will perform when utilised to drive ER translocation of specific single chain protein products. For more complex molecular formats, such as multichain monoclonal antibodies, we describe how a combination of in silico and targeted design rule-based in vitro testing can be employed to rapidly identify product-specific signal peptide solutions from minimal screening spaces. The utility of this technology is validated by deriving vector designs that increase product titres ≥ 1.8x, compared to standard industry systems, for a range of products, including a difficult-to-express monoclonal antibody. The availability of a vastly expanded toolbox of characterised signal peptide parts, combined with streamlined in silico/in vitro testing processes, will permit efficient expression vector re-design to maximise titres of both simple and complex protein products.

The social worlds of young children primarily revolve around parents and caregivers, who play a key role in guiding children's social and cognitive development. However, a hallmark of adolescence is a shift in orientation toward nonfamilial social targets, an adaptive process that prepares adolescents for their independence. Little is known regarding neurobiological signatures underlying changes in adolescents' social orientation. Using functional brain imaging of human voice processing in children and adolescents (ages 7-16), we demonstrate distinct neural signatures for mother's voice and nonfamilial voices across child and adolescent development in reward and social valuation systems, instantiated in nucleus accumbens and ventromedial prefrontal cortex. While younger children showed greater activity in these brain systems for mother's voice compared with nonfamilial voices, older adolescents showed the opposite effect with increased activity for nonfamilial compared with mother's voice. Findings uncover a critical role for reward and social valuative brain systems in the pronounced changes in adolescents' orientation toward nonfamilial social targets. Our approach provides a template for examining developmental shifts in social reward and motivation in individuals with pronounced social impairments, including adolescents with autism.SIGNIFICANCE STATEMENTChildren's social worlds undergo a transformation during adolescence. While socialization in young children revolves around parents and caregivers, adolescence is characterized by a shift in social orientation toward nonfamilial social partners. Here we show that this shift is reflected in neural activity measured from reward processing regions in response to brief vocal samples. When younger children hear their mother's voice, reward processing regions show greater activity compared with when they hear nonfamilial, unfamiliar voices. Strikingly, older adolescents show the opposite effect, with increased activity for nonfamilial compared with mother's voice. Findings identify the brain basis of adolescents' switch in social orientation toward nonfamilial social partners and provides a template for understanding neurodevelopment in clinical populations with social and communication difficulties.

Objectives In this study, we aimed to describe and evaluate the codesign of an intervention in general practice setting to help address navigation problems faced by the patients from the culturally and linguistically diverse (CALD) community in Australia. Methods An experience-based codesign (EBCD) methodology was adopted using the Double Diamond design process. Two codesign workshops were conducted online with 13 participants including patients, their caregivers, health service providers, researchers, and other stakeholders. Workshops were audio-recorded, transcribed, and thematically analyzed. Results The codesign participants identified several navigation problems among CALD patients such as inadequate health literacy, cultural and language barriers, and difficulties with navigating health and social services. They believed that bilingual community navigators (BCNs; lay health workers from the same language or cultural background) could help them address these problems. However, this depended on BCNs being trained and supervised, with a clear role definition and manageable workloads, and not used as an interpreter. In undertaking the codesign process, we found that pre-workshop consultations were useful to ensure engagement, especially for consumers who participated more actively in group activities with service providers after these and their own separate small group discussions during the workshop. Conclusion Overall, participants identified that BCNs could offer help in addressing the problems faced by the CALD patients in accessing care in general practice setting. The codesign process provided new insights into the navigation problems faced by CALD patients in accessing care and collaboratively developed a strategy for further testing and evaluation.

Introduction The impact of SARS-CoV-2 in rare disease populations has been underreported. Gaucher disease (GD) is a prototype rare disease that shares with SARS-CoV-2 a disruption of the lysosomal pathway. Materials-methods Retrospective analysis of 11 patients with Type 1 GD who developed COVID-19 between March 2020 and March 2021. Results Seven male and 4 female patients with Type 1 GD developed COVID-19. One was a pediatric patient (8 years old) while the remainder were adults, median age of 44 years old (range 21 to 64 years old). Two patients required hospitalization though none required intensive care or intubation. All 11 patients recovered from COVID-19 and there were no reported deaths. Conclusions Our case series suggests that GD patients acquired COVID-19 at a similar frequency as the general population, though experienced a milder overall course despite harboring underlying immune system dysfunction and other known co-morbidities that confer high risk of adverse outcomes from SARS-CoV-2 infection.

A novel combination of advanced gas-chromatography and detection systems coupled to a buffer-gas cell was characterized on-line to allow gas-phase chemical studies of accelerator-produced short-lived α -decaying mercury, francium, and astatine isotopes. These were produced in 40Ar- and 48Ca-induced nuclear fusion–evaporation reactions, subsequently isolated in the recoil separators MARS at Texas A&M University, USA, and TASCA at GSI Darmstadt, Germany, before being thermalized in a buffer-gas-stopping cell. From the latter, the nuclear reaction products were extracted into gas-phase chromatographic systems, suitable for registering α -decaying short-lived radionuclides, such as isotopes of superheavy elements. Efficiencies of 21(3)% for 204-209Fr were reached for the extraction into the optimized miniCOMPACT gas-chromatography setup, indicating that this technique enables the identification of isotopes of volatile as well as non-volatile elements. These studies guide the path towards chemical investigations of superheavy elements beyond flerovium, which are out of reach with currently used setups.

Globally, the COVID-19 pandemic seriously affected both physical and mental health conditions. This study aims to assess changes in the prevalence of depression among older adults during the COVID-19 pandemic in Bangladesh and explore the correlates of depression in pooled data.This study followed a repeated cross-sectional design and was conducted through telephone interviews on two successive occasions during the COVID-19 pandemic (October 2020 and September 2021) among 2077 (1032 in 2020-survey and 1045 in 2021-survey) older Bangladeshi adults aged 60 years and above. Depression was measured using the 15-item Geriatric Depression Scale (GDS-15). The binary logistic regression model was used to identify the factors associated with depression in pooled data.A significant increase in the prevalence of depression was noted in the 2021 survey compared to the 2020 survey (47.2% versus 40.3%; adjusted odds ratio (aOR): 1.40, 95% confidence interval (CI): 1.11-1.75). Depression was significantly higher among participants without a partner (aOR 1.92, 95% CI 1.45-2.53), with a monthly family income of5000 BDT (aOR: 2.65, 95% CI 1.82-3.86) or 5000-10 000 BDT (aOR: 1.30, 95% CI 1.03-1.65), living alone (aOR 2.24, 95% CI 1.40-3.61), feeling isolated (aOR 3.15, 95% CI 2.49-3.98), with poor memory/concentration (aOR 2.02, 95% CI 1.58-2.57), with non-communicable chronic conditions (aOR 1.34, 95% CI 1.06-1.69), overwhelmed by COVID-19 (aOR 1.54, 95% CI 1.18-2.00), having difficulty earning (aOR 1.49, 95% CI 1.15-1.92) or obtaining food (aOR 1.56, 95% CI 1.17-2.09) during COVID-19 pandemic, communicating less frequently (aOR 1.35, 95% CI 1.07-1.70) and needing extra care (aOR 2.28, 95% CI 1.75-2.96) during the pandemic.Policymakers and public health practitioners should provide immediate mental health support initiatives for this vulnerable population during the COVID-19 pandemic and beyond. Policymakers should also invest in creating safe places to practise mindful eating, exercise, or other refuelling activities as a means of preventing and managing depression.

Direct mass measurements in the region of the heaviest elements were performed with the Penning-trap mass spectrometer SHIPTRAP at GSI Darmstadt. Utilizing the phase-imaging ion-cyclotron-resonance massspectrometry technique, the atomic masses of 251No (Z = 102), 254Lr (Z = 103), and 257Rf (Z = 104) available at rates down to one detected ion per day were determined directly for the first time. The ground-state masses of 254No and 255,256Lr were improved by more than one order of magnitude. Relative statistical uncertainties as low as δm/m ≈ 10−9 were achieved. Mass resolving powers of 11 000 000 allowed resolving long-lived low-lying isomeric states from their respective ground states in 251,254No and 254,255Lr. This provided an unambiguous determination of the binding energies for odd-A and odd-odd nuclides previously determined only indirectly from decay spectroscopy., Federal Ministry of Education & Research (BMBF) 05P15HGFNA 05P19HGFNA 05P21HGFN1 05P15UMFNA 05P21UMFN1, Max Planck Society, Foundation CELLEX, Netherlands Organization for Scientific Research (NWO) 680-91-103, European Commission under Marie Sklodowska-Curie Action FP7 MSC COFUND scheme European Research Council (ERC) 819957, Ministry of Science and Innovation, Spain (MICINN) Spanish Government FPA2015-67694-P PID2019-104093GB-I00/AEI

Debilitating bone complications are common among patients with Gaucher disease type 1 (GD1). We analyzed changes in bone parameters among 393 GD1 patients treated with oral eliglustat for 4–8 years in 4 Sanofi Genzyme-sponsored clinical trials (Phase 2/NCT00358150 [N=26]; Phase 3: ENGAGE/NCT00891202 [N=40]; ENCORE/NCT00943111 [N=157]; EDGE/NCT01074944 [N=170]. In treatment-naïve patients (Phase 2/ ENGAGE), mean spine T-scores moved from the osteopenic range at baseline to the healthy range after 2–3 years. Mean±SEM spine T score increased from 1.55±0.28 to 0.59±0.34 (n=14) after 8 years in Phase 2, and increased to 0.53±0.27 in ENGAGE after 4.5 years (n=9). In both trials, spine Z-scores improved and femur T- and Z-scores remained normal. In ENCORE (patients stabilized after a mean of 10 years of enzyme replacement therapy [ERT]), T- and Z-scores remained in reference ranges for up to 4 years; least-square mean spine Z-scores improved by 0.29 (P

Lysosomal storage disorders (LSD) are rare diseases, caused by inherited deficiencies of lysosomal enzymes/transporters, that affect 1 in 7000 to 1 in 8000 newborns. Individuals with LSDs face long diagnostic journeys during which debilitating and life-threatening events can occur. Clinical trials and classical descriptions of LSDs typically focus on common manifestations, which are not representative of the vast phenotypic heterogeneity encountered in real-world experience. Additionally, recognizing that there was a limited understanding of the natural history, disease progression, and real-world clinical outcomes of rare LSDs, a collaborative partnership was pioneered 30 years ago to address these gaps. The Rare Disease Registries (RDR) (for Gaucher, Fabry, Mucopolysaccharidosis type I, and Pompe), represent the largest observational database for these LSDs. Over the past thirty years, data from the RDRs have helped to inform scientific understanding and the development of comprehensive monitoring and treatment guidelines by creating a framework for data collection and establishing a standard of care, with an overarching goal to improve the quality of life of affected patients. Here, we highlight the history, process, and impact of the RDRs, and discuss the lessons learned and future directions.

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat‐treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9‐month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open‐label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3–6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109/L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T‐score increased from −1.07 (osteopenia) to −0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well‐tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.

Restricted and repetitive behaviors (RRBs) are a defining clinical feature of autism spectrum disorders (ASD). RRBs are highly heterogeneous with variable expression of circumscribed interests (CI), insistence of sameness (IS) and repetitive motor actions (RM), which are major impediments to effective functioning in individuals with ASD; yet, the neurobiological basis of CI, IS and RM is unknown. Here we evaluate a unified functional brain circuit model of RRBs and test the hypothesis that CI and IS are associated with aberrant cognitive control circuit dynamics, whereas RM is associated with aberrant motor circuit dynamics. Using task-free fMRI data from 96 children, we first demonstrate that time-varying cross-network interactions in cognitive control circuit are significantly reduced and inflexible in children with ASD, and predict CI and IS symptoms, but not RM symptoms. Furthermore, we show that time-varying cross-network interactions in motor circuit are significantly greater in children with ASD, and predict RM symptoms, but not CI or IS symptoms. We confirmed these results using cross-validation analyses. Moreover, we show that brain-clinical symptom relations are not detected with time-averaged functional connectivity analysis. Our findings provide neurobiological support for the validity of RRB subtypes and identify dissociable brain circuit dynamics as a candidate biomarker for a key clinical feature of ASD., Restricted and repetitive behaviors (RRBs) are a core clinical feature of autism, yet the brain basis of RRBs is unknown. Here, the authors demonstrate that aberrant cognitive control and motor circuit dynamics differentially predict three distinct symptom clusters that define RRBs.

Background: Low- and middle-income countries (LMICs) have a disproportionately high burden of chronic diseases, with inequalities in health care access and quality services. This study aimed to assess patients' preferences for healthcare services for chronic disease management among adult patients in Bangladesh. Methods: The present analysis was conducted among 10,385 patients suffering from chronic diseases, drawn from the latest Household Income and Expenditure Survey 2016-2017. We used the multinomial logistic regression to investigate the association of chronic comorbid conditions and healthcare service-related factors with patients' preferences for healthcare services. Results: The top four dimensions of patient preference for healthcare services in order of magnitude were quality of treatment (30.3%), short distance to health facility (27.6%), affordability of health care (21.7%) and availability of doctors (11.0%). Patients with heart disease had a 29% significantly lower preference for healthcare affordability than the quality of healthcare services (relative risk ratio [RRR] = 0.71; 0.56-0.90). Patients who received healthcare services from pharmacies or dispensaries were more likely to prefer a short distance to a health facility (RRR = 6.99; 4.80-9.86) or affordability of healthcare services (RRR = 3.13; 2.25-4.36). Patients with comorbid conditions were more likely to prefer healthcare affordability (RRR = 1.39; 1.15-1.68). In addition, patients who received health care from a public facility had 2.93 times higher preference for the availability of medical doctors (RRR = 2.93; 1.70-5.04) than the quality of treatment in the health facility, when compared with private service providers. Conclusions: Patient preferences for healthcare services in chronic disease management were significantly associated with the type of disease and its magnitude and characteristics of healthcare providers. Therefore, to enhance service provision and equitable distribution and uptake of health services, policymakers and public health practitioners should consider patient preferences in designing national strategic frameworks for chronic disease management. Patient or Public Contribution: Our research team includes four researchers (co-authors) with chronic diseases who have experience of living or working with people suffering from chronic conditions or diseases. Refereed/Peer-reviewed

Background:Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features; however, the role of GBA in individual cell types and involvement of microglia, blood-derived macrophages, and immune infiltrates in nGD pathophysiology remains enigmatic.Methods:Here, using single-cell resolution of mouse nGD brains, lipidomics, and newly generated biomarkers, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons.Results:Targeted rescue of Gba in microglia and neurons, respectively, in Gba-deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced serum neurofilament light chain (Nf-L), and improved survival. Serum GlcSph concentration was correlated with serum Nf-L and ApoE in nGD mouse models as well as in GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, which was further enhanced upon treatment with brain-permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis, and reversal of neuroinflammation involving activation of microglia, brain macrophages, and NK cells.Conclusions:Together, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation. Brain-permeant small-molecule inhibitor of glucosylceramide synthase reduced the accumulation of bioactive glycosphingolipids, concomitant with amelioration of neuroinflammation involving microglia, NK cells, astrocytes, and neurons. Our findings advance nGD disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials, and illuminate therapeutic targets.Funding:Research grant from Sanofi; other support includes R01NS110354, Yale Liver Center P30DK034989, pilot project grant.

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

We report results from a search for neutrino-induced neutral current (NC) resonant Δ(1232) baryon production followed by Δ radiative decay, with a ⟨0.8⟩ GeV neutrino beam. Data corresponding to MicroBooNE’s first three years of operations (6.80×1020 protons on target) are used to select single-photon events with one or zero protons and without charged leptons in the final state (1γ1p and 1γ0p, respectively). The background is constrained via an in situ high-purity measurement of NC π0 events, made possible via dedicated 2γ1p and 2γ0p selections. A total of 16 and 153 events are observed for the 1γ1p and 1γ0p selections, respectively, compared to a constrained background prediction of 20.5±3.65(syst) and 145.1±13.8(syst) events. The data lead to a bound on an anomalous enhancement of the normalization of NC Δ radiative decay of less than 2.3 times the predicted nominal rate for this process at the 90% confidence level (C.L.). The measurement disfavors a candidate photon interpretation of the MiniBooNE low-energy excess as a factor of 3.18 times the nominal NC Δ radiative decay rate at the 94.8% C.L., in favor of the nominal prediction, and represents a greater than 50-fold improvement over the world’s best limit on single-photon production in NC interactions in the sub-GeV neutrino energy range.

We present a measurement of νe interactions from the Fermilab Booster Neutrino Beam using the MicroBooNE liquid argon time projection chamber to address the nature of the excess of low energy interactions observed by the MiniBooNE Collaboration. Three independent νe searches are performed across multiple single electron final states, including an exclusive search for two-body scattering events with a single proton, a semi-inclusive search for pionless events, and a fully inclusive search for events containing all hadronic final states.With differing signal topologies, statistics, backgrounds, reconstruction algorithms, and analysis approaches, the results are found to be either consistent with or modestly lower than the nominal νe rate expectations from the Booster Neutrino Beam and no excess of νe events is observed., United States Department of Energy (DOE) DE-AC02-07CH11359 National Science Foundation (NSF), Swiss National Science Foundation (SNSF), European Commission, UK Research & Innovation (UKRI), Science & Technology Facilities Council (STFC), Royal Society of London

All over the globe, the generation of industrial waste has been increased due to the increasing demand for modern civilisation. In the developing countries like India, it is growing vigorously which eventually increases the production of vehicles and results in the more number of waste tyres. Despite the dumping such hazardous waste in landfills, stockpiling, and burning, their feasible utilisation in the modification of soil and concrete can be a good alternative option for their disposal. This paper enlightens the published work carried out by various researchers to enhance the mechanical properties of clayey soil using various forms of waste tyres. The effects of different forms of waste tyres on consistency limits, compaction characteristics, strength characteristics, compressibility characteristics, permeability and California-bearing ratio of cohesive soils have been reviewed. The review results show that the use of waste tyre products in ground improvement can be an economical solution for the construction industries and optimistic future as its disposal option. Still, further investigations and more research studies are required to consolidate the remarks drawn by the past researchers for its utilisation in the construction of highway/railway embankments and other field applications.

The manufacture of bispecific antibodies by Chinese hamster ovary (CHO) cells is often hindered by lower product yields compared to monoclonal antibodies. Recently, reactive oxygen species have been shown to negatively impact antibody production. By contrast, strategies to boost cellular antioxidant capacity appear to be beneficial for recombinant protein expression. With this in mind, we generated a novel hydrogen peroxide evolved host using directed host cell evolution. Here we demonstrate that this host has heritable resistance to hydrogen peroxide over many generations, displays enhanced antioxidant capacity through the upregulation of several, diverse antioxidant defense genes such as those involved in glutathione synthesis and turnover, and has improved glutathione content. Additionally, we show that this host has significantly improved transfection recovery times, improved growth and viability properties in a fed‐batch production process, and elevated expression of two industrially relevant difficult to express bispecific antibodies compared to unevolved CHO control host cells. These findings demonstrate that host cell evolution represents a powerful methodology for improving specific host cell characteristics that can positively impact the expression of difficult to express biotherapeutics., A novel H2O2 evolved CHO host was generated and characterised in this study. This host displays enhanced antioxidant capacity through the upregulation of several, diverse antioxidant defence genes such as those involved in glutathione synthesis and turnover and has improved glutathione content. Additionally, this host has significantly improved transfection recovery times, improved growth and viability properties in a fed batch production process and elevated expression of two industrially relevant difficult to express bispecific antibodies compared to unevolved CHO control host cells.

In their paper, Hughes et al. [...]

Polytetrafluoroethylene (PTFE) is an excellent diffuse reflector widely used in light collection systems for particle physics experiments. In noble element systems, it is often coated with tetraphenyl butadiene (TPB) to allow detection of vacuum ultraviolet scintillation light. In this work this dependence is investigated for PTFE coated with TPB in air for light of wavelengths of 200 nm, 260 nm, and 450 nm. The results show that TPB-coated PTFE has a reflectance of approximately 92% for thicknesses ranging from 5 mm to 10 mm at 450 nm, with negligible variation as a function of thickness within this range. A cross-check of these results using an argon chamber supports the conclusion that the change in thickness from 5 mm to 10 mm does not affect significantly the light response at 128 nm. Our results indicate that pieces of TPB-coated PTFE thinner than the typical 10 mm can be used in particle physics detectors without compromising the light signal.

Background and Aim: Salmonella enterica causes enteric disease in mammals and may potentially be transmitted from marine turtles that shed the pathogen in the environment. Marine turtle-associated human salmonellosis is a potential public health concern in Grenada, as the island supports populations of leatherback turtles (Dermochelys coriacea), hawksbill turtles (Eretmochelys imbricata), and green turtles (Chelonia mydas) that interface with veterinarians and conservation workers, the local population, and the thousands of visitors that frequent the island yearly. To date, the prevalence of S. enterica has only been examined in a small subset of marine turtles in the Caribbean and no studies have been conducted in Grenada. The aim of this study was to quantify the prevalence of S. enterica in leatherback, hawksbill and green turtles in Grenada, characterize phenotypes and DNA profiles, and explore the potential risk to human health in the region. Materials and Methods: A total of 102 cloacal swabs were obtained from nesting leatherback turtles and foraging hawksbill and green turtles. Samples were cultured on enrichment and selective media and isolates were phenotypically characterized using serotyping, pulsed-phase gel electrophoresis, and antibiotic susceptibility. Enrichment broths were additionally screened by polymerase chain reaction (PCR) using S. enterica-specific primers. Results: S. enterica was cultured from 15/57 (26.3%) leatherback turtles, 0/28 hawksbill, and 0/17 green turtles. This included S. enterica serovars Montevideo, S. I:4,5,12:i:-, Salmonella Typhimurium, Salmonella Newport, S. I:6,7:-:-, and S. I:4,5,12:-:-. Five/15 leatherback turtles carried multiple serovars. Eight pulsotype groups were identified with multiple clustering; however, there was no clear association between pulsotype group and serotype profile. Five/71 isolates showed resistance to streptomycin or ampicillin. Twenty-one/57 leatherback turtles, 14/28 hawksbill turtles, and 8/17 green turtles tested positive for S. enterica by quantitative PCR. Conclusion: Nesting leatherback turtles actively shed S. enterica and poses a risk for zoonosis; however, the presence of viable pathogen in green and hawksbill species is unclear. These findings help elucidate the role of marine turtles as potential sources of zoonotic S. enterica and provide baseline data for one health research in Grenada and the wider Caribbean region.

SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid β-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients.

BackgroundNeuronopathic Gaucher Disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in Gba, and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features, however the role of Gba in individual cell types and involvement of microglia, blood derived macrophages and immune infiltrates in nGD pathology remains enigmatic.MethodsHere, using single cell resolution of mouse nGD brains, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons.ResultsTargeted rescue of Gba in microglia and in neurons, respectively in Gba deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced level of serum neurofilament light chain (Nf-L) and improved survival. The levels of bioactive lipid, GlcSph was strongly correlated with serum Nf-L and ApoE in nGD mouse models as well as GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, that was further enhanced upon treatment with brain permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis and reversal of neuroinflammation involving activation of microglia, brain macrophages and NK cells.ConclusionsTogether, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation and the role of brain permeant small molecule glucosylceramide inhibitor in reversing complex multidimensional pathophysiology of nGD. Our findings advance disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials and illuminate therapeutic targets.Funding:Research grant from Sanofi Genzyme; other support includes R01NS110354.Yale Liver Center P30DK034989, pilot project grant.