Globally, the number of people living with diabetes mellitus (DM) increased by 62% between 1990 and 2019, affecting 463 million people in 2019, and is projected to increase further by 51% by 2045. ...The increasing burden of DM that requires chronic care could have a considerable cost implication in the health system, particularly in resource constraint settings like Nepal. In this context, this study attempts to present the burden of DM in terms of prevalence, mortality, and disability adjusted life years (DALYs). The study is based on the Global Burden of Disease Study 2019, a multinational collaborative research, led by the Institute for Health Metrics and Evaluations. In the study, the overall prevalence of DM was estimated using DisMod MR-2.1, a Bayesian metaregression model. DALYs were estimated summing years of life lost due to premature death and years lived with disability. There were a total of 1,412,180 prevalent cases of DM, 3,474 deaths and 189,727 DALYs, due to DM in 2019. All-age prevalence rate and the age-standardized prevalence rate of DM stood at 4,642.83 (95% uncertainty interval (UI): 4,178.58-5,137.74) and 5,735.58 (95% UI: 5,168.74-6327.73) cases per 100,000 population, respectively, in 2019. In 2019, 1.8% (95% UI: 1.54, 2.07) of total deaths were from DM, which is a more than three-fold increase from the proportion of deaths attributed in 1990 (0.43%, 95% UI: 0.36, 0.5) with most of these deaths being from DM type 2. In 2019, a total of 189,727 disability adjusted life years (DALYs) were attributable to DM of which 105,950 DALYs were among males, and the remaining 83,777 DALYs were among females. Overall, between 1990 and 2019, the DALYs, attributable to Type 1 and 2 DM combined and for Type 2 DM only, have increased gradually across both sexes. However, the DALYs per 100,000 attributable to DM have slightly reduced across both sexes in that time. There is a high burden of DM in Nepal in 2019 with a steep increase in the proportion of deaths attributable to DM in Nepal which could pose a serious challenge to the health system. Primary prevention of DM requires collaborative efforts from multiple sectors. Meanwhile, the current federal structure could be an opportunity for integrated, locally tailored public health and clinical interventions for the prevention of the disease and its consequences.
Women's autonomy on sexual and reproductive health issues is critical to women's health and well-being. Women have the right to decide on their fertility and sexuality, be free from coercion and ...violence, and achieve well-being. This study has identified women's autonomy regarding decision and exercise of their sexual reproductive health and rights and its association with determining factors in Nepal. Descriptive and analytical statistics such as bivariate and multivariate regression analysis were performed using data from Nepal Demographic and Health Survey 2016. The survey collected data from 12,862 women of reproductive age groups i.e. 15-49 years. However, for this study, we analyzed the data of only ever-married women and they were 9,875 in total. The analysis showed that women's autonomy in exercising their sexual reproductive health rights is highly associated with media exposure after controlling demographic variables. The frequency of exposure to media (i. less than a week: adjusted odds ratio (AOR):1.383; confidence interval (CI):1.145-1.670, p<0.001, ii. at least once a week: AOR:1.657; CI:1.359-2.021, p<0.001) is positively associated with women's autonomy. Furthermore, factors like women from Janajati (AOR:1.298; CI:1.071-1.576, p<0.01) and other Terai ethnic groups (AOR:1.471; CI:1.160-1.866, p<0.01), higher education attainment (AOR:1.482; CI:1.164-1.888, p<0.01), richest wealth quintile (AOR:1.527; CI:1.151-2.026, p<0.01), paid work (AOR:1.277; CI:1.045-1.561, p<0.05) and living in Lumbini Province (AOR:0.622; CI:0.486-0.797, p<0.001) and Sudur Paschim Province (AOR:0.723; CI:0.554-0.944, p<0.05) were found to be significantly associated with women's autonomy in sexual and reproductive health decision making. Similarly, women's autonomy is also increased with their increased age. In conclusion, women's exposure to media, improved socio-economic status and increased age influence their autonomy to make decisions about sexual and reproductive health rights in Nepal. Therefore, this study underscores the need to address socio-economic barriers and improve women's exposure to the media to enhance their autonomy further.
BackgroundDespite the success of CAR-T therapy in treating relapsed/refractory B-cell malignancies, >40% of patients experience relapse in part due to reduction of CAR-T function and poor ...persistence. Traditional αCD3/αCD28-based activation of T-cells prior to CAR transduction is associated with production of more differentiated CAR-Ts, corresponding to reduced functional persistence. This may be overcome by targeting early memory T-cells. TSCM-cells are the least differentiated T-cell population with self-renewal capacity and a crucial role in the diversification of immune memory.1 We hypothesize that treatment of T-cells with specific cytokines will drive cell-cycle transitioning to enable lentiviral transduction and expansion of CAR-Ts displaying the TSCM phenotype. Using cytokine/protein scaffolds, we evaluated the impact that IL-7, IL-15, IL-21 and the TGF-β sink (TGFβRII) had on the generation of TSCM-like CAR-Ts.MethodsHCW Biologics has developed a bifunctional fusion molecule (HCW9218), which incorporates the extracellular domain of TGFβRII and an IL-15/IL-15 receptor α complex into a tissue factor-based scaffold.2 A similar scaffold comprised of IL-7, IL-15 and IL-21 (HCW9206) was also produced (figure 1). To generate CAR-Ts, primary T-cells isolated from donor-derived PBMCs are treated with HCW scaffolds prior to transduction with a lentivirus expressing an αCD19-CAR and a GFP reporter. 6-days post transduction we compared T-memory differentiation of HCW-treated CAR-T cells to αCD3/αCD28-activated cells by flow cytometry (figure 2). The functional activity of HCW-treated CAR-Ts was determined by a B-cell leukemia cytotoxicity assay.ResultsAfter stimulation with HCW scaffolds for 3-days prior to transduction, the population of T-cells were enriched with a TSCM-like phenotype, which mediated the generation of CAR-TSCMs (figure 3). HCW-stimulated CAR-Ts also displayed more potent dose-responsive cytotoxic function towards a B-cell leukemia cell line than CAR-T cells generated using traditional aCD3/aCD28 activation (figure 4). Finally, these TSCM-like CAR-Ts will be assessed in future experiments for their longevity in vivo and their functional persistence to a relapse event in a humanized mouse model.ConclusionsHCW scaffolds are a novel class of immunotherapeutic that are currently being evaluated in Phase I clinical trials. We have demonstrated that activation with cytokine scaffolds significantly increases the number of TSCM-like CAR-Ts, while also retaining cytotoxic function. Our results indicated that treatment with cytokine scaffolds generate a large population of CD19 CAR-Ts with an early memory T-cell phenotype which should enhance the persistence of CAR-Ts in patients. This strategy will likely enhance long-term in vivo survival of CAR-T therapy and enable sustained suppression of relapsed/refractory B-cell malignancies.ReferencesArcangeli S, et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. JCI. 2022;132(12).Liu B, et al. Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors. Molecular Therapy. 2021;29(10):2949–2962.Ethics ApprovalThis study was approved by Albert Einstein College of Medicine institution’s IRB Ethics Board; approval number 2017–8116.Abstract 243 Figure 12nd generation CD19 CAR and HCW heterodimeric protein constructs. (A) Schematic of the 2nd generation CD19 CAR construct including CDɀ, CD28 and 4–1BB stimulatory domains under the control of an SFFV promoter. A GFP reporter gene is used to assess transduction efficiency. (B) Schematic of the HCW heterodimeric fusion molecules. We will evaluate scaffolds consisting of a TGFßRII extracellular domain linked to a human IL-15Rα sushi domain (HCW9218), a scaffold with the same TGFßRII domain but carrying a D8N nonfunctional mutation in the IL-15 domain (HCW9228), as well as a molecule consisting of IL-15, IL-7 and IL-21 cytokine domains (HCW9206).Abstract 243 Figure 2Enhanced transduction of CD8+ T-cells following stimulation with HCW protein scaffolds. (A) Schematic timeline of HCW activation and CD19 CAR transduction of donor-derived T-cells. (B) Donor-derived (HGLK0086) CD4/8 T-cell activation with 100nM HCW protein scaffolds prior to CAR LV transduction, which mediated increased transduction of the CD8+ T-cell subtype.Abstract 243 Figure 3Stimulation and expansion of TSCM CD19 specific CAR-T cells. (A) Donor-derived (HGLK0086) CD4/8 T-cell activation with HCW protein scaffolds prior to CAR LV transduction mediates larger expansion of TSCM-like (CD45RO-CCR7+) CAR-Ts compared to αCD3/28 activated CD19 CAR-T cells 6-days post transduction. Gating Strategy: Lymphocytes, Single Cells, CD4-, CD8+, GFP+, CD45RO- CCR7+, CD45RA+ CD95+. (B) Flow cytometric analysis of CD19 CAR-Ts showed that approximately 100% of the CD45RO-CCR7+ CAR-Ts express CD27 and CD95/Fas, which are commonly associated with TSCM memory. Gating Strategy: Lymphocytes, Single Cells, CD4-, CD8+, GFP+, CD45RO- CCR7+, CD95+ CD27+. (C) Percentage of TSCM-like (CD45RO-CCR7+) CD19 CAR-T cells. (D) Average cell count of CD45RO-CCR7+CD45RA+CD95+ TSCM-like CAR-Ts per sample. Data from one donor tested in duplicate are represented as mean ± SEM and statistical significance is calculated by 1-way ANOVA.Abstract 243 Figure 4HCW-stimuIated CAR-T cells demonstrated potent cytotoxic function against B-cell leukemic cell line. Through a fluorescence-based PKH26 cytotoxicity assay we compared the cytoxic function of cytokine activated CAR-T cells to αCD3/αCD28 activated CAR-T cells. In this assay, cytotoxic function of CD19 CAR-Ts was measured through fluorescence expression triggered by lysis of a stained CD19 expressing ALL cell line (NALM6) at effector:target ratios of 1:1 (A) and 0.5:1 (B). Data from one donor tested in triplicate are represented as mean ± SEM and statistical significance is calculated by 1-way ANOVA.
Management of COVID-19 in Nepal will certainly benefit from the experiences of other countries. However, they are less likely to be suitable for Nepal both in terms of context and resource ...availability. Social contact pattern studies have shown that understanding the nature of human-to-human contacts can help describe the dynamics of infectious disease transmission. The findings of such studies will help the country prepare itself for future outbreaks, inform mathematically modelling and public health interventions that match domestic capabilities. Methods such as self-reported contact diary can be used to conduct such studies following a feasibility study. Keywords: Contact diary;COVID-19; disease transmission; social contact pattern.
The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within ...membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2(-/-)mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2(-/-)cells that the vacuole-to-cytosol transitioning of L. monocytogenesis greatly accelerated. Unexpectedly, we found that in Perforin-2(-/-)macrophages,Listeria-containing vacuoles quickly (≤ 15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that aL. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2(+/+)and Perforin-2(-/-)macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.
Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid ...cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4
effector T cells. In an
mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases.
Models of infectious disease are increasingly utilising empirical contact data to quantify the number of potentially infectious contacts between age groups. While a growing body of data is being ...collected on contact patterns across many populations, less attention has been paid to the social contacts of young infants. We collected information on the social contacts of primary carers of young infants and investigated their potential for use as a proxy for contacts made by their infant.
We recruited primary carers of infants under one year of age residing in two geographically, demographically and socioeconomically distinct local government areas of Melbourne, Australia - Boroondara and Hume - including a sub-group of Turkish-speaking participants. Participants recorded their own contacts in a paper diary and noted whether their infant was present or absent. Information collected included times at an address; description of location; and details on people contacted at the location. Descriptive summary measures and distributions of contacts by location type, intensity, day of contact and by age are reported.
Of the 226 participants recruited, 220 completed diaries were returned. Participant contact patterns were similar across all groups, with respect to the types of locations, intensity and day of contact, with some variation in the number of unique daily contacts. The infant was present at around 85% of locations at which the primary carer contacted other individuals. The majority of contacts occurring when the infant was present were in Own Home (32%), Retail and Hospitality (18%) and Transport (18%) settings. The mean daily number of unique contacts by infants was estimated as 9.1, 8.7 and 6.5 in Boroondara, Hume (English) and Hume (Turkish), respectively, with a similar age distribution across each of our surveyed groups.
Our demonstration that contact patterns of mothers with infants are reasonably robust to socioeconomic and cultural differences is a step forward in modelling infectious disease transmission. With infants spending most of their time in the company of their mother, contact patterns of mothers are a useful proxy measure of infant contact patterns. The age distribution of contacts made by infants estimated in this study may be used to supplement population-wide contact information commonly used in infectious disease transmission models.
The replacement of traditional CdS with zinc magnesium oxide (ZMO) has been demonstrated as being helpful to boost power conversion efficiency of cadmium telluride (CdTe) solar cells to over 18%, due ...to the reduced interface recombination and parasitic light absorption by the buffer layer. However, due to the atmosphere sensitivity of ZMO film, the post treatments of ZMO/CdTe stacks, including CdCl
treatment, back contact deposition, etc., which are critical for high-performance CdTe solar cells became crucial challenges. To realize the full potential of the ZMO buffer layer, plenty of investigations need to be accomplished. Here, copper thiocyanate (CuSCN) is demonstrated to be a suitable back-contact material with multi-advantages for ZMO/CdTe solar cells. Particularly, ammonium hydroxide as the solvent for CuSCN deposition shows no detrimental impact on the ZMO layer during the post heat treatment. The post annealing temperature as well as the thickness of CuSCN films are investigated. Finally, a champion power conversion efficiency of 16.7% is achieved with an open-circuit voltage of 0.857 V, a short-circuit current density of 26.2 mA/cm
, and a fill factor of 74.0%.
Cardiovascular diseases (CVDs) have emerged as the leading cause of deaths worldwide in 2019. Globally, more than three-quarters of the total deaths due to CVDs occur in low- and middle-income ...countries like Nepal. Although increasing number of studies is available on the prevalence of CVDs, there is limited evidence presenting a complete picture on the burden of CVDs in Nepal. In this context, this study aims to provide comprehensive picture on the burden of CVDs in the country. This study is based on the Global Burden of Disease (GBD) study 2019, which is a multinational collaborative research covering 204 countries and territories across the world. The estimations made from the study are publicly available in the GBD Compare webpage operated by the Institute for Health Metrics and Evaluation (IHME), University of Washington. This article makes use of those data available on the GBD Compare page of IHME website to present the comprehensive picture of the burden of CVDs in Nepal. Overall, in 2019, there were an estimated 1,214,607 cases, 46,501 deaths, and 1,104,474 disability-adjusted life years (DALYs) due to CVDs in Nepal. The age-standardized mortality rates for CVDs witnessed a marginal reduction from 267.60 per 100,000 population in 1990 to 245.38 per 100,000 population in 2019. The proportion of deaths and DALYs attributable to CVDs increased from 9.77% to 24.04% and from 4.82% to 11.89%, respectively, between 1990 and 2019. Even though there are relatively stable rates of age-standardized prevalence, and mortality, the proportion of deaths and DALYs attributed to CVDs have risen sharply between 1990 and 2019. Besides implementing the preventive measures, the health system also needs to prepare itself for the delivery of long-term care of patients with CVDs which could have significant implications on resources and operations.
PDF
