Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC.

Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1ß, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-ß and PD-L1 enhances antitumor responses.

T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-ß play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-ß inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-ß, termed AxF (scFv)2, under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv)2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv)2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-ß by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression.

Impact and cost-effectiveness of SARS-CoV-2 self-testing strategies in schools: a multicountry modelling analysis.

OBJECTIVES: To determine the most epidemiologically effective and cost-effective school-based SARS-CoV-2 antigen-detection rapid diagnostic test (Ag-RDT) self-testing strategies among teachers and students. DESIGN: Mathematical modelling and economic evaluation. SETTING AND PARTICIPANTS: Simulated school and community populations were parameterised to Brazil, Georgia and Zambia, with SARS-CoV-2 self-testing strategies targeted to teachers and students in primary and secondary schools under varying epidemic conditions. INTERVENTIONS: SARS-CoV-2 Ag-RDT self-testing strategies for only teachers or teachers and students-only symptomatically or symptomatically and asymptomatically at 5%, 10%, 40% or 100% of schools at varying frequencies. OUTCOME MEASURES: Outcomes were assessed in terms of total infections and symptomatic days among teachers and students, as well as total infections and deaths within the community under the intervention compared with baseline. The incremental cost-effectiveness ratios (ICERs) were calculated for infections prevented among teachers and students. RESULTS: With respect to both the reduction in infections and total cost, symptomatic testing of all teachers and students appears to be the most cost-effective strategy. Symptomatic testing can prevent up to 69·3%, 64·5% and 75·5% of school infections in Brazil, Georgia and Zambia, respectively, depending on the epidemic conditions, with additional reductions in community infections. ICERs for symptomatic testing range from US$2 to US$19 per additional school infection averted as compared with symptomatic testing of teachers alone. CONCLUSIONS: Symptomatic testing of teachers and students has the potential to cost-effectively reduce a substantial number of school and community infections.

Risk Screening Tools Could Potentially Miss HIV-Positive Individuals Who Seek Testing Services: A Secondary Program Data Analysis on the Performance Characteristics of an Adolescent and Adult HIV Risk Screening Tool in Uganda.

Improving HIV testing efficiency saves financial and material resources for health. We conducted a secondary data analysis of routinely collected HIV risk-screening program data in Uganda, from October to November 2019, to determine the performance characteristics of the adolescent and adult HIV risk screening tools in public health facilities. A total of 19,854 clients had been screened for HIV testing eligibility and tested for HIV. The overall positivity rate (cluster-weighted prevalence of HIV) among those screened was 4.5% (95% CI: 4.1-4.8) versus 3.71% (95% CI: 3.06-4.50) among those not screened. The sensitivity and specificity of the risk screening tool were 91% (95% CI: 89-93) and 25% (24.2-26), respectively. With screening, the number needed to test to identify one PLHIV was reduced from 27 to 22. Although risk screening would have led to a 24.5% (4825/19,704) reduction in testing volume, 9.3% (68/732) of PLHIV would have been missed and be misclassified as not eligible for testing. The cost saving per PLHIV identified was minimally reduced by 3% from USD 69 without screening to USD 66.9 with screening. Since the treatment-adjusted prevalence of HIV is dropping globally, overzealous use of risk screening tools to determine who to test or not carries the potential of missing PLHIV due to their limited specificity. We recommend the use of scientifically validated HIV risk screening tools, and a need to explore the use of HIV self-testing as a test for tirage to minimize misclassification of people who seek HIV testing services.

Recent Advances of Transition Metal Dichalcogenides-Based Materials for Energy Storage Devices, in View of Monovalent to Divalent Ions.

The fast growth of electrochemical energy storage (EES) systems necessitates using innovative, high-performance electrode materials. Among the various EES devices, rechargeable batteries (RBs) with potential features like high energy density and extensive lifetime are well suited to meet rapidly increasing energy demands. Layered transition metal dichalcogenides (TMDs), typical two dimensional (2D) nanomaterial, are considered auspicious materials for RBs because of their layered structures and large specific surface areas (SSA) that benefit quick ion transportation. This review summarizes and highlights recent advances in TMDs with improved performance for various RBs. Through novel engineering and functionalization used for high-performance RBs, we briefly discuss the properties, characterizations, and electrochemistry phenomena of TMDs. We summarised that engineering with multiple techniques, like nanocomposites used for TMDs receives special attention. In conclusion, the recent issues and promising upcoming research openings for developing TMDs-based electrodes for RBs are discussed.

2D MXenes Nanosheets for Advanced Energy Conversion and Storage Devices: Recent Advances and Future Prospects.

Since the initial MXenes were discovered in 2011, several MXene compositions constructed using combinations of various transition metals have been developed. MXenes are ideal candidates for different applications in energy conversion and storage, because of their unique and interesting characteristics, which included good electrical conductivity, hydrophilicity, and simplicity of large-scale synthesis. Herein, we study the current developments in two-dimensional (2D) MXene nanosheets for energy storage and conversion technologies. First, we discuss the introduction to energy storage and conversion devices. Later, we emphasized on 2D MXenes and some specific properties of MXenes. Subsequently, research advances in MXene-based electrode materials for energy storage such as supercapacitors and rechargeable batteries is summarized. We provide the relevant energy storage processes, common challenges, and potential approaches to an acceptable solution for 2D MXene-based energy storage. In addition, recent advances for MXenes used in energy conversion devices like solar cells, fuel cells and catalysis is also summarized. Finally, the future prospective of growing MXene-based energy conversion and storage are highlighted.

Telluride-Based Materials: A Promising Route for High Performance Supercapacitors.

As supercapacitor (SC) technology continues to evolve, there is a growing need for electrode materials with high energy/power densities and cycling stability. However, research and development of electrode materials with such characteristics is essential for commercialization the SC. To meet this demand, the development of superior electrode materials has become an increasingly critical step. The electrochemical performance of SCs is greatly influenced by various factors such as the reaction mechanism, crystal structure, and kinetics of electron/ion transfer in the electrodes, which have been challenging to address using previously investigated electrode materials like carbon and metal oxides/sulfides. Recently, tellurium and telluride-based materials have garnered increasing interest in energy storage technology owing to their high electronic conductivity, favorable crystal structure, and excellent volumetric capacity. This review provides a comprehensive understanding of the fundamental properties and energy storage performance of tellurium- and Te-based materials by introducing their physicochemical properties. First, we elaborate on the significance of tellurides. Next, the charge storage mechanism of functional telluride materials and important synthesis strategies are summarized. Then, research advancements in metal and carbon-based telluride materials, as well as the effectiveness of tellurides for SCs, were analyzed by emphasizing their essential properties and extensive advantages. Finally, the remaining challenges and prospects for improving the telluride-based supercapacitive performance are outlined.

Iron oxide-coupled CRISPR-nCas9-based genome editing assessment in mucopolysaccharidosis IVA mice.

Mucopolysaccharidosis (MPS) IVA is a lysosomal storage disorder caused by mutations in the GALNS gene that leads to the lysosomal accumulation of keratan sulfate (KS) and chondroitin 6-sulfate, causing skeletal dysplasia and cardiopulmonary complications. Current enzyme replacement therapy does not impact the bone manifestation of the disease, supporting that new therapeutic alternatives are required. We previously demonstrated the suitability of the CRISPR-nCas9 system to rescue the phenotype of human MPS IVA fibroblasts using iron oxide nanoparticles (IONPs) as non-viral vectors. Here, we have extended this strategy to an MPS IVA mouse model by inserting the human GALNS cDNA into the ROSA26 locus. The results showed increased GALNS activity, mono-KS reduction, partial recovery of the bone pathology, and non-IONPs-related toxicity or antibody-mediated immune response activation. This study provides, for the first time, in vivo evidence of the potential of a CRISPR-nCas9-based gene therapy strategy for treating MPS IVA using non-viral vectors as carriers.

Exploring the electrochemical properties of CuSe-decorated NiSe2 nanocubes for battery-supercapacitor hybrid devices.

Chalcogenides, a promising class of electrode materials, attracted massive popularity owing to their exciting features of high conductive nature, high capacity, rich redox activities, and structural functionalities, making them the first choice for the electrochemical energy domain. This paper reported a new NiSe2-CuSe nanocomposite prepared via a wet-chemical synthesis followed by a low-cost and simple hydrothermal reaction. The physical characterization showed cubes and nanoparticles type morphological features of NiSe2 and CuSe products, while their composite reveals a combined morphological characteristic. The electrochemical properties were tested in an aqueous solution, demonstrating that the NiSe2-CuSe nanocomposite exhibits a high capacity of 376 C g-1, low resistance, good reversibility and rate capability in a three-electrode mode than bulk counterparts. For practical aspects, a battery-hybrid supercapacitor (BHSC) is developed with NiSe2-CuSe nanocomposite, and activated carbon (AC) serves as cathode and anode in two-cell mode operation. The built NiSe2-CuSe||AC/KOH BHSC expanded the voltage to 1.8 V and delivered the highest capacitance of 148 F g-1 and 55 F g-1 from 1 to 10 A g-1, suppressing most of the previously existing literature reports. Also, our built NiSe2-CuSe||AC/KOH BHSC displayed a high-power delivery of 8928 W kg-1 at a maximum energy density of 66.6 W h kg-1 and retained 91.7% capacitance after a long way of 10,000 cycles. These outstanding results demonstrate that metal selenides can be effectively utilized as alternative electrodes with high energy, rate performance, and long-term durability for advanced energy conversion and storage devices.

Bone Growth Induction in Mucopolysaccharidosis IVA Mouse.

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) enzyme, leading to the accumulation of glycosaminoglycans (GAG), keratan sulfate (KS) and chondroitin-6-sulfate (C6S), mainly in cartilage and bone. This lysosomal storage disorder (LSD) is characterized by severe systemic skeletal dysplasia. To this date, none of the treatment options for the MPS IVA patients correct bone pathology. Enzyme replacement therapy with elosulfase alpha provides a limited impact on bone growth and skeletal lesions in MPS IVA patients. To improve bone pathology, we propose a novel gene therapy with a small peptide as a growth-promoting agent for MPS IVA. A small molecule in this peptide family has been found to exert biological actions over the cardiovascular system. This work shows that an AAV vector expressing a C-type natriuretic (CNP) peptide induces bone growth in the MPS IVA mouse model. Histopathological analysis showed the induction of chondrocyte proliferation. CNP peptide also changed the pattern of GAG levels in bone and liver. These results suggest the potential for CNP peptide to be used as a treatment in MPS IVA patients.

Implementing SARS-CoV-2 antigen testing scale-up in Rwanda: retrospective analysis of national programme data and qualitative findings.

OBJECTIVES: Reverse transcriptase PCR is the most sensitive test for SARS-CoV-2 diagnosis. However, the scale-up of these tests in low-income and middle-income countries (LMICs) has been limited due to infrastructure and cost. Antigen rapid diagnostic tests are an alternative option for diagnosing active infection that may allow for faster, easier, less expensive and more widespread testing. We compared the implementation of antigen and PCR testing programmes in Rwanda. DESIGN: We retrospectively reviewed routinely collected PCR and antigen testing data for all reported tests conducted nationally. We administered semiquantitative surveys to healthcare workers (HCWs) involved in COVID-19 testing and care and clients receiving antigen testing. SETTING: Rwanda, November 2020-July 2021. PARTICIPANTS: National SARS-CoV-2 testing data; 49 HCWs involved in COVID-19 testing and care; 145 clients receiving antigen testing. INTERVENTIONS: None (retrospective analysis of programme data). PRIMARY AND SECONDARY OUTCOME MEASURES: Test volumes, turnaround times, feasibility and acceptability of antigen testing. RESULTS: Data from 906 204 antigen tests and 445 235 PCR tests were included. Antigen testing increased test availability and case identification compared with PCR and had a median results return time of 0 days (IQR: 0-0). In contrast, PCR testing time ranged from 1 to 18 days depending on the sample collection site/district. Both HCWs and clients indicated that antigen testing was feasible and acceptable. Some HCWs identified stockouts and limited healthcare staff as challenges. CONCLUSIONS: Antigen testing facilitated rapid expansion and decentralisation of SARS-CoV-2 testing across lower tier facilities in Rwanda, contributed to increased case identification, reduced test processing times, and was determined to be feasible and acceptable to clients and providers. Antigen testing will be an essential component of SARS-CoV-2 test and treat programmes in LMICs.

Hydrothermal assisted synthesis of hierarchical SnO2 micro flowers with CdO nanoparticles based membrane for energy storage applications.

Hierarchical nanostructures with appropriate morphology and surface functionalities are highly desired to achieve an optimized electrochemical property for active electrode materials. This work renders the facile hydrothermal synthesis of CdO, SnO2, and CdO-SnO2 nanocomposite, and their capacitive performance was tested. The formation of the pure samples and their composite was committed by low-temperature Raman spectroscopy and x-ray diffraction studies which revealed the tetragonal and cubic structures of CdO and SnO2 powder samples with good crystallinity and purity. The morphological postmortem reveals the formation of nanoparticles morphology of CdO with a highly smooth surface appearance. Besides, the SnO2 illustrates the morphology of the micro flowers composed of ultrathin nanosheets. More specifically, the electrochemical properties indicate the pseudocapacitive charge storage mechanism based on cyclic voltammetry and chronopotentiometry analysis. The CdO-SnO2 composite electrode displayed a higher capacitance due to additional pores/space offered for active sites and continuously allowed electrolyte ions to interact with the inner/outer surface of the electrode. These exciting findings led us to design and fabricate battery hybrid supercapacitors (BHSC) from CdO-SnO2, and activated carbon (AC), referred to as CdO-SnO2//AC BHSC, attains a high power delivery (5717 W/kg), and a maximum energy density of 42 Wh/kg at low discharge rate. Noteworthy, a stable cycling performance was obtained with only 91.3% retention after 8000 cycling at a large discharge current of 10 A/g, denoting the magnificent durability of the active electrode material.

Development of low-cost bacterial cellulose-pomegranate peel extract-based antibacterial composite for potential biomedical applications.

This study was aimed to develop low-cost bacterial cellulose (BC)-based antibacterial composite with pomegranate (Punica granatum L.) peel extract (PGPE) for potential biomedical applications. BC was cost-effectively produced by utilizing food wastes, and PGPE was ex situ impregnated into its hydrogel. Field-emission scanning electron microscopic (FE-SEM) observation showed a nanofibrous and microporous morphology of pristine BC and confirmed the development of BC-PGPE composite. Fourier transform infrared (FTIR) spectroscopy indicated the chemical interaction of PGPE with BC nanofibers. BC-PGPE composite held 97 % water of its dry weight and retained it for more than 48 h. The BC-PGPE composite exhibited better reswelling capabilities than pristine BC after three consecutive re-wetting cycles. The antibacterial activity of the BC-PGPE composite was determined via minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), disc diffusion, and plate count methods. The PGPE extract showed good antimicrobial activity against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative), both in the form of extract and composite with BC, with relatively better activity against the former. The BC-PGPE composite produced a 17 mm zone of inhibition against S. aureus, while no inhibition zone was formed against E. coli. Furthermore, BC-PGPE composite caused a 100 % and 50 % reduction in the growth of S. aureus and E. coli, respectively. The findings of this study indicate that BC-PGPE composite could be a promising antibacterial wound dressing material.

Detection of Glycosaminoglycans in Biological Specimens.

Proteoglycans (PGs) are macromolecules formed by a protein backbone to which one or more glycosaminoglycan (GAG) side chains are covalently attached. Most PGs are present in connective tissues, cell surfaces, and intracellular compartments. The major biological function of PGs derives from the GAG component of the molecule, which is involved in cell growth and proliferation, embryogenesis, maintenance of tissue hydration, and interactions of the cells via receptors. PGs are categorized into four groups based on their cellular and subcellular localization, including cell surfaces and extracellular, intracellular, and pericellular locations. GAGs are a crucial component of PGs involved in various physiological and pathological processes. GAGs also serve as biomarkers of metabolic diseases such as mucopolysaccharidoses and mucolipidoses. Detection of specific GAGs in various biological fluids helps manage various genetic metabolic disorders before it causes irreversible damage to the patient (Amendum et al., Diagnostics (Basel) 11(9):1563, 2021). There are several methods for detecting GAGs; this chapter focuses on measuring GAGs using enzyme-linked immunosorbent assay, liquid chromatographic tandem mass spectrometry, and automated high-throughput mass spectrometry.

Human papillomavirus testing using existing nucleic acid testing platforms to screen women for cervical cancer: implementation studies from five sub-Saharan African countries.

OBJECTIVES: To demonstrate acceptability and operational feasibility of introducing human papillomavirus (HPV) testing as a principal cervical cancer screening method in public health programmes in sub-Saharan Africa. SETTING: 45 primary and secondary health clinics in Malawi, Nigeria, Senegal, Uganda and Zimbabwe. PARTICIPANTS: 15 766 women aged 25-54 years presenting at outpatient departments (Senegal only, general population) or at antiretroviral therapy clinics (all other countries, HIV-positive women only). Eligibility criteria followed national guidelines for cervical cancer screening. INTERVENTIONS: HPV testing was offered to eligible women as a primary screening for cervical cancer, and HPV-positive women were referred for visual inspection with acetic acid (VIA), and if lesions identified, received treatment or referral. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of HPV-positive women who received results and linked to VIA and the proportion of HPV-positive and VIA-positive women who received treatment. RESULTS: A total of 15 766 women were screened and tested for HPV, among whom 14 564 (92%) had valid results and 4710/14 564 (32%) were HPV positive. 13 837 (95%) of valid results were returned to the clinic and 3376 (72%) of HPV-positive women received results. Of women receiving VIA (n=2735), 715 (26%) were VIA-positive and 622 (87%) received treatment, 75% on the same day as VIA. CONCLUSIONS: HPV testing was found to be feasible across the five study countries in a public health setting, although attrition was seen at several key points in the cascade of care, namely results return to women and linkage to VIA. Once women received VIA, if eligible, the availability of on-site cryotherapy and thermal ablation allowed for same-day treatment. With sufficient resources and supportive infrastructure to ensure linkage to treatment, use of HPV testing for cervical cancer screening as recommended by WHO is a promising model in low-income and middle-income countries.

Strategies for Using Antigen Rapid Diagnostic Tests to Reduce Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in Low- and Middle-Income Countries: A Mathematical Modelling Study Applied to Zambia.

BACKGROUND: Increasing the availability of antigen rapid diagnostic tests (Ag-RDTs) in low- and middle-income countries (LMICs) is key to alleviating global SARS-CoV-2 testing inequity (median testing rate in December 2021-March 2022 when the Omicron variant was spreading in multiple countries: high-income countries = 600 tests/100 000 people/day; LMICs = 14 tests/100 000 people/day). However, target testing levels and effectiveness of asymptomatic community screening to impact SARS-CoV-2 transmission in LMICs are unclear. METHODS: We used Propelling Action for Testing and Treating (PATAT), an LMIC-focused agent-based model to simulate coronavirus disease 2019 (COVID-19) epidemics, varying the amount of Ag-RDTs available for symptomatic testing at healthcare facilities and asymptomatic community testing in different social settings. We assumed that testing was a function of access to healthcare facilities and availability of Ag-RDTs. We explicitly modelled symptomatic testing demand from individuals without SARS-CoV-2 and measured impact based on the number of infections averted due to test-and-isolate. RESULTS: Testing symptomatic individuals yields greater benefits than any asymptomatic community testing strategy until most symptomatic individuals who sought testing have been tested. Meeting symptomatic testing demand likely requires at least 200-400 tests/100 000 people/day, on average, as symptomatic testing demand is highly influenced by individuals without SARS-CoV-2. After symptomatic testing demand is satisfied, excess tests to proactively screen for asymptomatic infections among household members yield the largest additional infections averted. CONCLUSIONS: Testing strategies aimed at reducing transmission should prioritize symptomatic testing and incentivizing test-positive individuals to adhere to isolation to maximize effectiveness.

Steady-state solutions of split beams in electron storage rings.

Recently, a novel operation method for synchrotron light sources with transversely split beams has been explored to fulfill the rising demand for flexible and high-throughput X-ray sources required in such diverse fields as time-resolved X-ray spectroscopy, molecular chemistry in organic cells, high-resolution medical imaging, quantum materials science or sustainable energy research. Within that novel operation mode, additional stable regions are produced in the horizontal phase space by operating an electron storage ring on a resonance that is driven by the nonlinear sextupole or octupole magnets. In the longitudinal phase space, a similar split can be produced by introducing an oscillation of the synchrotron phase via a modulation of the phase of the radiofrequency resonator. Strong radiation damping in electron storage rings, however, has to be overcome before additional regions in phase space can become populated by particles and form stable islands. This damping mechanism changes the dynamics of the system and causes diffusion between the different islands in phase space, raising the question what kind of equilibrium state exists in the asymptotic temporal limit. In this paper, a finite-differences approximation in rotating action-angle coordinates is used to solve the Vlasov-Fokker-Planck equation and to study the obtained equilibrium states for the longitudinal as well as the transverse case. The number of solution vectors and the magnitude of the corresponding singular values of the matrix of the underlying finite-differences equation are used as abstract indicators to define the required parameter set that provides stable additional beamlets. As a consequence, the beamlets have a stability that is close to that of the main beam in terms of diffusion caused by the radiation damping and quantum excitation.

Factors associated with men's health facility attendance as clients and caregivers in Malawi: a community-representative survey.

INTRODUCTION: Men have higher rates of morbidity and mortality across nearly all top ten causes of mortality worldwide. Much of this disparity is attributed to men's lower utilization of routine health services; however, little is known about men's general healthcare utilization in sub-Saharan Africa. METHODS: We analyze the responses of 1,116 men in a community-representative survey of men drawn from a multi-staged sample of residents of 36 villages in Malawi to identify factors associated with men's facility attendance in the last 12 months, either for men's own health (client visit) or to support the health care of someone else (caregiver visit). We conducted single-variable tests of association and multivariable logistic regression with random effects to account for clustering at the village level. RESULTS: Median age of participants was 34, 74% were married, and 82% attended a health facility in the last year (63% as client, 47% as caregiver). Neither gender norm beliefs nor socioeconomic factors were independently associated with attending a client visit. Only problems with quality of health services (adjusted odds ratio [aOR] 0.294, 95% confidence interval [CI] 0.10-0.823) and good health (aOR 0.668, 95% CI 0.462-0.967) were independently associated with client visit attendance. Stronger beliefs in gender norms were associated with caregiver visits (beliefs about acceptability of violence [aOR = 0.661, 95% CI 0.488-0.896], male sexual dominance [aOR = 0.703, 95% CI 0.505-0.978], and traditional women's roles [aOR = 0.718, 95% CI 0.533-0.966]). Older age (aOR 0.542, 95% CI 0.401-0.731) and being married (aOR 2.380, 95% CI 1.196-4.737) were also independently associated with caregiver visits. CONCLUSION: Quality of services offered at local health facilities and men's health status were the only variables associated with client facility visits among men, while harmful gender norms, not being married, and being younger were negatively associated with caregiver visits.

Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy.

Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA.

Facility-based HIV self-testing strategies may substantially and cost-effectively increase the number of men and youth tested for HIV in Malawi: results from an individual-based mathematical model.

INTRODUCTION: Malawi is rapidly closing the gap in achieving the UNAIDS 95-95-95 targets, with 90% of people living with HIV in Malawi aware of their status. As we approach epidemic control, interventions to improve coverage will become more costly. There is, therefore, an urgent need to identify innovative and low-cost strategies to maintain and increase testing coverage without diverting resources from other HIV services. The objective of this study is to model different combinations of facility-based HIV testing modalities and determine the most cost-effective strategy to increase the proportion of men and youth testing for HIV. METHODS: A data-driven individual-based model was parameterized with data from a community-representative survey (socio-demographic, health service utilization and HIV testing history) of men and youth in Malawi (data collected August 2019). In total, 79 different strategies for the implementation of HIV self-testing (HIVST) and provider-initiated-testing-and-counselling at the outpatient department (OPD) were evaluated. Outcomes included percent of men/youth tested for HIV in a 12-month period, cost-effectiveness and human resource requirements. The testing yield was assumed to be constant across the scenarios. RESULTS: Facility-based HIVST offered year-round resulted in the greatest increase in the proportion of men and youth tested in the OPD (from 45% to 72%-83%), was considered cost-saving for HIVST kit priced at $1.00, and generally reduced required personnel as compared to the status quo. At higher HIVST kit prices, and more relaxed eligibility criteria, all scenarios that considered year-round HIVST in the OPD remained on the cost-effectiveness frontier. CONCLUSIONS: Facility-based HIVST is a cost-effective strategy to increase the proportion of men/youth tested for HIV in Malawi and decreases the human resource requirements for HIV testing in the OPD-providing additional healthcare worker time for other priority healthcare activities.