Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

[Automatic classification of immune-mediated glomerular diseases based on multi-modal multi-instance learning].

OBJECTIVE: To develop a multi-modal deep learning method for automatic classification of immune-mediated glomerular diseases based on images of optical microscopy (OM), immunofluorescence microscopy (IM), and transmission electron microscopy (TEM). METHODS: We retrospectively collected the pathological images from 273 patients and constructed a multi-modal multi- instance model for classification of 3 immune-mediated glomerular diseases, namely immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN). This model adopts an instance-level multi-instance learning (I-MIL) method to select the TEM images for multi-modal feature fusion with the OM images and IM images of the same patient. By comparing this model with unimodal and bimodal models, we explored different combinations of the 3 modalities and the optimal methods for modal feature fusion. RESULTS: The multi-modal multi-instance model combining OM, IM, and TEM images had a disease classification accuracy of (88.34±2.12)%, superior to that of the optimal unimodal model [(87.08±4.25)%] and that of the optimal bimodal model [(87.92±3.06)%]. CONCLUSION: This multi- modal multi- instance model based on OM, IM, and TEM images can achieve automatic classification of immune-mediated glomerular diseases with a good classification accuracy.

Multifaceted approach toward mapping out the anticancer properties of small molecules via in vitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing.

Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in-silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK-MEL-28, A431, and SCC-12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC-12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC50 = 5.0 µM, SCC-12: IC50 = 2.9 µM, SKMEL-28: IC50 = 4.9 µM, A375: IC50 = 6.7 µM) and 13 (A431: IC50 = 5.0 µM, SCC-12: IC50 = 3.3 µM, SKMEL-28: IC50 = 13.8 µM, A375: IC50 = 17.1 µM), significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells, as evidenced by the suppression of Bcl-2 and upregulation of Bax, cleaved caspase-3, caspase-9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web-based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure-activity relationship through the preparation and biological evaluation of analogs.

CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS.

ABSTRACT: In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.

Is value-based healthcare a strategy to achieve universal health coverage that includes oral health? An Australian case study.

The 2021 Resolution on Oral Health by the 74th World Health Assembly supports an important health policy direction: inclusion of oral health in universal health coverage. Many healthcare systems worldwide have not yet addressed oral diseases effectively. The adoption of value-based healthcare (VBHC) reorients health services towards outcomes. Evidence indicates that VBHC initiatives are improving health outcomes, client experiences of healthcare, and reducing costs to healthcare systems. No comprehensive VBHC approach has been applied to the oral health context. Dental Health Services Victoria (DHSV), an Australian state government entity, commenced a VBHC agenda in 2016 and is continuing its efforts in oral healthcare reform. This paper explores a VBHC case study showing promise for achieving universal health coverage that includes oral health. DHSV applied the VBHC due to its flexibility in scope, consideration of a health workforce with a mix of skills, and alternative funding models other than fee-for-service.

A shared accretion instability for black holes and neutron stars.

Accretion disks around compact objects are expected to enter an unstable phase at high luminosity1. One instability may occur when the radiation pressure generated by accretion modifies the disk viscosity, resulting in the cyclic depletion and refilling of the inner disk on short timescales2. Such a scenario, however, has only been quantitatively verified for a single stellar-mass black hole3-5. Although there are hints of these cycles in a few isolated cases6-10, their apparent absence in the variable emission of most bright accreting neutron stars and black holes has been a continuing puzzle11. Here we report the presence of the same multiwavelength instability around an accreting neutron star. Moreover, we show that the variability across the electromagnetic spectrum-from radio to X-ray-of both black holes and neutron stars at high accretion rates can be explained consistently if the accretion disks are unstable, producing relativistic ejections during transitions that deplete or refill the inner disk. Such a new association allows us to identify the main physical components responsible for the fast multiwavelength variability of highly accreting compact objects.

Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

INTRODUCTION: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC). We aimed to demonstrate the utility of a PrEP quality improvement intervention in pinpointing and addressing barriers to PrEP use among transgender women in Vietnam. METHODS: We applied a real-world participatory continuous quality improvement (CQI) and Plan-Do-Study-Act (PDSA) methodology to ascertain barriers to PrEP uptake among transgender women and determine priority actions for quality improvement. A CQI team representing transgender women leaders, key population (KP)-clinic staff, public-sector HIV managers and project staff applied PDSA to test solutions to identified barriers that addressed the primary quality improvement outcome of the monthly change in PrEP uptake among transgender women and secondary outcomes, including month-3 PrEP continuation, the impact of offering PHC on PrEP uptake and unmet PrEP need. We utilized routine programmatic data and a descriptive cross-sectional study enrolling 124 transgender women to measure these outcomes from October 2018 to September 2021. RESULTS: Five key barriers to PrEP uptake among transgender women were identified and corresponding solutions were put in place: (1) offering gender-affirming care training to KP-clinics and community-based organizations; (2) integrating gender-affirming services into 10 KP-clinics; (3) offering PHC through five one-stop shop (OSS) clinics; (4) implementing a campaign addressing concerns related to hormone use and PrEP interactions; and (5) developing national HIV and transgender healthcare guidelines. New PrEP enrolment and month-3 PrEP continuation increased significantly among transgender women. Of 235 transgender women who initially sought healthcare other than PrEP at OSS clinics, 26.4% subsequently enrolled in PrEP. About one-third of transgender women reported unmet PrEP need, while two-thirds indicated an interest in long-acting cabotegravir. CONCLUSIONS: Offering gender-competent, integrated PHC can increase PrEP enrolment and continuation, and can be an entry-point for PrEP among those seeking care within PHC clinics. More work is needed to expand access to transgender women-led and -competent healthcare in Vietnam.

A persistent ultraviolet outflow from an accreting neutron star binary transient.

All disc-accreting astrophysical objects produce powerful disc winds. In compact binaries containing neutron stars or black holes, accretion often takes place during violent outbursts. The main disc wind signatures during these eruptions are blue-shifted X-ray absorption lines, which are preferentially seen in disc-dominated 'soft states'1,2. By contrast, optical wind-formed lines have recently been detected in 'hard states', when a hot corona dominates the luminosity3. The relationship between these signatures is unknown, and no erupting system has as yet revealed wind-formed lines between the X-ray and optical bands, despite the many strong resonance transitions in this ultraviolet (UV) region4. Here we report that the transient neutron star binary Swift J1858.6-0814 exhibits wind-formed, blue-shifted absorption lines associated with C IV, N V and He II in time-resolved UV spectroscopy during a luminous hard state, which we interpret as a warm, moderately ionized outflow component in this state. Simultaneously observed optical lines also display transient blue-shifted absorption. Decomposing the UV data into constant and variable components, the blue-shifted absorption is associated with the former. This implies that the outflow is not associated with the luminous flares in the data. The joint presence of UV and optical wind features reveals a multi-phase and/or spatially stratified evaporative outflow from the outer disc5. This type of persistent mass loss across all accretion states has been predicted by radiation-hydrodynamic simulations6 and helps to explain the shorter-than-expected duration of outbursts7.

[Efficacy and safety of percutaneous transluminal pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension].

Objective: To explore the efficacy and safety of percutaneous transluminal pulmonary angioplasty (PTPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: This prospective single arm study included 19 CTEPH patients (7 male, age(56.3±12.5)years) admitted to Wuhan Asia Heart Hospital from January 2017 to June 2019 and received PTPA interventional therapy. Baseline data, including age, sex, WHO functional class, 6-minute walk distance (6MWD), NT-proBNP, right heart catheterization values, were collected. Patients received single or repeated PTPA. Number of dilated vessels from each patient was analyzed, patients were followed up for 24 weeks and right heart catheterization was repeated at 24 weeks post initial PTPA. All-cause death, perioperative complications, and reperfusion pulmonary edema were reported. WHO functional class, 6MWD, NT-proBNP, right heart catheterization values were compared between baseline and at 24 weeks follow up. Results: Nineteen CTEPH patients received a total of 56 PTPA treatments. The pulmonary artery pressure (mPAP) decreased from (40.11±7.55) mmHg (1 mmHg=0.133 kPa) to (27.53±4.75) mmHg (P<0.001), and the total pulmonary resistance (TPR) decreased from (13.00±3.56) Wood U to (5.48±1.56) Wood U (P<0.001), cardiac output increased from (3.19±0.63) L/min to (5.23±0.94) L/minutes (P<0.01) at 24 weeks post PTPA. The WHO functional class improved significantly (P<0.001), 6MWD increased from (307.08±129.51) m to (428.00±112.64) m (P=0.002), the NT-proBNP decreased at 24 weeks post PTPA (P=0.002). During the follow-up period, there was no death; hemoptysis occurred in 4 patients during the operation, none of which resulted in serious adverse clinical consequences. One patient developed reperfusion pulmonary edema and recovered after treatment. Conclusion: PTPA treatment is safe and can significantly improve the hemodynamics and WHO functional class of patients with CTEPH.

Total hip arthroplasty in Cambodia - Our experience of two hundred and fifty six consecutive total hip arthroplasties in a low-income country & the challenge of service delivery in this setting.

The Children's Surgical Centre has performed 256 THAs since 2007, We aim to assess the outcome of arthroplasty in a LMIC. Primary outcome: all cause of re-operation, Secondary outcome: any other complication. A retrospective review of all consecutive THA since 2007 was conducted. Electronic and physical case notes were reviewed. Statistical analysis was performed using MedCalc. 256 THA. Mean age: 43, gender M2:1F. Common pathologies include (1) AVN (44%), (2) OA (11%) and (3) DDH (11%). Revision rate 13%. Time to revision was 2.8 years (0-9). Common revision reasons: (1) stem fracture (5.8%), (2) aseptic loosening (4.8%) and (3) infection (2.7%). Complications were identified in 85 patients (33.2%). Common complications included (1) aseptic loosening (10.5%) (2) stem fracture (5.8%) and (3) dislocation (5.8%). Patients at CSC benefit from THA, the complication rates at CSC are declining suggesting the apex of the 'learning curve' has passed. Cheap poorly manufactured implants continue to cause catastrophic failure.

Yak miR-2285o-3p attenuates hypoxia-induced apoptosis by targeting caspase-3.

miRNAs are a class of hairpin-derived RNAs, 21-24 nucleotides in length, which are involved in a range of biological processes. The bta-miR-2285 family has over 40 members spanning the entire bovine genome. We previously found that bta-miR-2285o-3p was highly expressed in yak heart and lung when compared with cattle, which prompted us to investigate its potential function in high-altitude adaptation of yaks. In this study, we detected wide-spread high expression of bta-miR-2285o-3p in yak tissues. Further experiments revealed that the protein tyrosine phosphatase receptor type M (PTPRM) gene was the host gene of bta-miR-2285o-3p and that two linked SNPs in bta-mir-2285o precursor affected the biogenesis of mature miRNA (bta-miR-2285o-3p). Functional analysis in vitro indicated that bta-miR-2285o-3p attenuated hypoxia-induced apoptosis by targeting very low-density lipoprotein receptor (VLDLR), phosphatase and tensin homolog (PTEN) and caspase-3. Expression level analysis in vivo revealed the high negative Pearson's correlation between bta-miR-2285o-3p and caspase3 in yak, highlighting the potential important roles of bta-miR-2285o-3p in yak high-altitude adaptation. Our study provides a typical model for deciphering the function of miRNAs in environmental adaptation.

Soft elasticity optimises dissipation in 3D-printed liquid crystal elastomers.

Soft-elasticity in monodomain liquid crystal elastomers (LCEs) is promising for impact-absorbing applications where strain energy is ideally absorbed at constant stress. Conventionally, compressive and impact studies on LCEs have not been performed given the notorious difficulty synthesizing sufficiently large monodomain devices. Here, we use direct-ink writing 3D printing to fabricate bulk (>cm3) monodomain LCE devices and study their compressive soft-elasticity over 8 decades of strain rate. At quasi-static rates, the monodomain soft-elastic LCE dissipated 45% of strain energy while comparator materials dissipated less than 20%. At strain rates up to 3000 s-1, our soft-elastic monodomain LCE consistently performed closest to an ideal-impact absorber. Drop testing reveals soft-elasticity as a likely mechanism for effectively reducing the severity of impacts - with soft elastic LCEs offering a Gadd Severity Index 40% lower than a comparable isotropic elastomer. Lastly, we demonstrate tailoring deformation and buckling behavior in monodomain LCEs via the printed director orientation.

Secondhand smoke in public places in Vietnam: An assessment 5 years after implementation of the tobacco control law.

OBJECTIVES: This study quantified the secondhand smoke (SHS) concentration in a sample of public places in Vietnam to determine changes in SHS levels 5 years after a public smoking ban was implemented. METHODS: Two monitoring campaigns, one in 2013 (before the tobacco control law was implemented) and another in 2018 (5 years after the implementation of the law) were conducted in around 30 restaurants, cafeterias and coffee shops in major cities of Vietnam. Concentrations of PM2.5, as an indicator of SHS, were measured by portable particulate matter monitors (TSI SidePak AM510 and Air Visual Pro). RESULTS: The geometric mean PM2.5 concentration of all monitored venues was 87.7 µg/m3 (83.7-91.9) in the first campaign and 55.2 µg/m3 (53.7-56.7) in the second campaign. Pairwise comparison showed the PM2.5 concentrations in the smoking observed area was triple and double those in the non-smoking area and the outdoor environment. After adjusting for sampling locations and times, the SHS concentration 5 years after the implementation of the tobacco control law reduced roughly 45%. CONCLUSION: The study results indicate an improvement in air quality in public places in Vietnam via both the reduction in PM2.5 levels and the number of people observed smoking. However, greater enforcement of the free-smoke legislation is needed to eliminate SHS in public places in Vietnam.

Monitoring the levels of brominated and organophosphate flame retardants in passenger cars: Utilisation of car air filters as active samplers.

Filters in residential and office air conditioning (A/C) systems have been used as sampling devices for monitoring different pollutants. However, cabin air filters (CAFs) in the A/C system of passenger cars have not been utilised for this purpose. In this study, we collected 22 used CAFs from passenger cars in Hanoi, Vietnam to analyse for 8 polybrominated diphenyl ethers (PBDEs) and 10 organophosphate esters (OPEs). All the analytes were detected in more than 50% of samples with the exception of BDE153 and BDE154. The average concentrations of ∑10OPEs and ∑8BDEs in the captured dust were 2600 and 40 ng/g, respectively with Tris (1-chloro-2-propyl) phosphate (TCIPP) and BDE209 as the dominant congener in OPE and BDE groups, respectively. CAFs are a potential tool to qualitatively assess the levels of semi-volatile chemicals in suspended dust in cars as a screening step for exposure assessment of those chemicals.

Health-related quality of life, service utilization and costs of low language: A systematic review.

BACKGROUND: Low language (LL) is a common childhood condition affecting 7-17% of children. It is associated with life-long adverse outcomes and can affect various aspects of a child's life. However, the literature on its impact on health-related quality of life (HRQoL), service use and costs are limited. To date, there has been no systematic review of the overall economic burden of LL. A systematic review regarding the economic burden of LL is important for clinical, educational, policy decision-making and theoretical aspects. We adopted the term 'low language' to refer to children whose language performance falls below well-recognized cut-points regardless of known or unknown aetiology. AIMS: To review the literature systematically on how LL is associated with HRQoL, service utilization and costs. METHODS & PROCEDURES: A systematic search was conducted across various databases, including MEDLINE, Embase, PsycINFO, CINAHL, up to July 2017. Data on study design, population and outcomes were extracted and screened by two pairs of reviewers with the revision of other experts in the panel on any discrepancies. The Effective Public Health Practice Project tool was used to assess the risk of bias of the included studies. The findings of the included studies were summarized in a narrative synthesis. OUTCOMES & RESULTS: We identified 22 relevant articles, of which 12 reported HRQoL and 11 reported service utilization and costs associated with LL. Preference-based instruments, which include the relative importance attached to different aspects of HRQoL, were less employed in the literature. Most studies found poorer HRQoL in children with LL compared with their peers. About half the families having children with LL did not actively seek professional help, and many families felt they did not receive sufficient services when needed. Healthcare costs associated with LL were substantial. Non-healthcare costs were largely unexplored. CONCLUSIONS & IMPLICATIONS: LL was associated with reduced children's HRQoL, higher service use and costs. Under-servicing was evident in children with LL. LL also imposed large costs on the healthcare system. Further research is required to examine (1) the overall HRQoL of children with LL, in particular studies using and testing the performance of preference-based instruments; and (2) the service use and costs specific to LL, especially non-healthcare costs.

Particulate air pollution in Ho Chi Minh city and risk of hospital admission for acute lower respiratory infection (ALRI) among young children.

High levels of air pollutants in Vietnam, especially particulate matters including PM2.5, can be important risk factors for respiratory diseases among children of the country. However, few studies on the effects of ambient air pollution on human health have been conducted in Vietnam so far. The aim of this study is to examine the association between PM2.5 and hospital admission due to acute lower respiratory infection (ALRI) among children aged < 5 years old in Ho Chi Minh city, the largest city of Vietnam. Data relating PM2.5 and hospital admission were collected from February 2016-December 2017 and a time series regression analysis was performed to examine the relationship between PM2.5 and hospital admission including the delayed effect up to three days prior to the admission. We found that each 10 µg/m3 increase in PM2.5 was associated with an increase of 3.51 (95%CI: 0.96-6.12) risk of ALRI admission among children. According to the analysis, male children are more sensitive to exposure to PM2.5 than females, while children exposed to PM2.5 are more likely to be infected with acute bronchiolitis than with pneumonia. The study demonstrated that young children in HCMC are at increased risk of ALRI admissions due to the high level of PM2.5 concentration in the city's ambient air.

Environmental seasonality on predator-prey systems under nutrient and toxicant constraints.

Bioaccumulation of toxicants in aquatic food webs can pose risks to ecosystem function and human health. Toxicant models of aquatic ecosystems can be improved by incorporating realistic environmental impacts such as nutrient availability and seasonality. It is well known that the carrying capacity of predator-prey systems can vary seasonally due to environmental cycles resulting from natural and human activities. As such, incorporating seasonal variation in the carrying capacity of a predator-prey system provides a better understanding of the underlying population dynamics bioaccumulation of toxicants. Here, we develop a seasonally varied predator-prey model subject to concurrent nutrient and toxicant stressors. We investigate the effects of seasonality on population dynamics to increase understanding of the complex governing processes of the trophic transfer of nutrients, energy, and toxicants. We observe that the strength of seasonality can shift solutions from periodic to quasi-periodic and models that neglect environmental seasonality may be under-predicting adverse effects of toxicity.

Simulation of a radiobiology facility for the Centre for the Clinical Application of Particles.

The Centre for the Clinical Application of Particles' Laser-hybrid Accelerator for Radiobiological Applications (LhARA) facility is being studied and requires simulation of novel accelerator components (such as the Gabor lens capture system), detector simulation and simulation of the ion beam interaction with cells. The first stage of LhARA will provide protons up to 15 MeV for in vitro studies. The second stage of LhARA will use a fixed-field accelerator to increase the energy of the particles to allow in vivo studies with protons and in vitro studies with heavier ions. BDSIM, a Geant4 based accelerator simulation tool, has been used to perform particle tracking simulations to verify the beam optics design done by BeamOptics and these show good agreement. Design parameters were defined based on an EPOCH simulation of the laser source and a series of mono-energetic input beams were generated from this by BDSIM. The tracking results show the large angular spread of the input beam (0.2 rad) can be transported with a transmission of almost 100% whilst keeping divergence at the end station very low (<0.1 mrad). The legacy of LhARA will be the demonstration of technologies that could drive a step-change in the provision of proton and light ion therapy (i.e. a laser source coupled to a Gabor lens capture and a fixed-field accelerator), and a system capable of delivering a comprehensive set of experimental data that can be used to enhance the clinical application of proton and light ion therapy.