Deficient O-GlcNAc Glycosylation Impairs Regulatory T Cell Differentiation and Notch Signaling in Autoimmune Hepatitis

Post-translational modifications such as glycosylation play an important role in the functions of homeostatic proteins, and are critical driving factors of several diseases; however, the role of glycosylation in autoimmune hepatitis is poorly understood. Here, we established an O-GlcNAc glycosylation-deficient rat model by knocking out the Eogt gene by TALEN-mediated gene targeting. O-GlcNAc glycosylation deficiency overtly aggravated liver injury in concanavalin-A induced autoimmune hepatitis, and delayed self-recovery of the liver. Furthermore, flow cytometry analysis revealed increased CD4+ T cell infiltration in the liver of rats with O-GlcNAc glycosylation deficiency, and normal differentiation of regulatory T cells (Tregs) in the liver to inhibit T cell infiltration could not be activated. Moreover, in vitro experiments showed that O-GlcNAc glycosylation deficiency impaired Treg differentiation to inhibit the Notch signaling pathway in CD4+ T cells. These finding indicate that O-GlcNAc glycosylation plays a critical role in the activation of Notch signaling, which could promote Treg differentiation in the liver to inhibit T cell infiltration and control disease development in autoimmune hepatitis. Therefore, this study reveals a regulatory role for glycosylation in the pathogenesis of autoimmune hepatitis, and highlights glycosylation as a potential treatment target

Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy : a systematic analysis for the Global Burden of Disease Study 2021

Background: Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020. Methods: We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990–2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data. Findings: We estimated 9·40 million (95% uncertainty interval [UI] 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5–14 years, 6·29% (5·05 to 7·70) in those aged 15–49 years, 5·72% (4·02 to 7·39) in those aged 50–69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5–14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15–49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50–69 years, and a 3·29% (–5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis fo 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (–713 to 2180) fewer deaths. Interpretation: Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups. Funding: Bill & Melinda Gates Foundation. © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Biswajit Banik and Muhammad Aziz Rahman” are provided in this record*

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Fabrication of carboxymethyl chitosan-strontium chondroitin sulfate composites for potential bone regeneration

Large bone defects have been a major healthcare concern. These defects are difficult to heal because of the chronic inflammatory environment surrounding the injury area. Osteoconductive composites with anti-inflammatory effects could provide a substrate to support cell growth and guide bone defect repair. Here, we synthesized a biofunctional composite that combined carboxymethyl-chitosan (CMCS) and strontium chondroitin sulfate (SrCS), for potential use in bone regeneration. We hypothesized that the as-prepared CMCS-SrCS composites could stimulate osteogenic activity and suppress inflammatory responses. The resultant composites displayed uniformly porous structures and good swelling capacity. The effect of the composites on MC3T3-E1 cells was investigated in vitro and the live cells showed favorable viability. Moreover, the RT-PCR results indicated that the CMCS-SrCS composites could suppress inflammatory responses and promote the osteogenic differentiation of MC3T3-E1 cells. These results suggested the CMCS-SrCS composites should have osteoconductive characteristics. Thus, we believe that the developed CMCS-SrCS composites should be a promising skeletal candidate for regenerative engineering applications

An autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer

Abstract Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca2+ under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca2+ to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca2+ homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation

Clinical outcomes of guider-assisted osteotomy compared to conventional pendulum-saw osteotomy in open wedge high tibial osteotomy: a propensity score-matched cohort study

Abstract Purpose We developed a novel guider-assisted osteotomy (GAO) procedure to improve the safety of open wedge high tibial osteotomy (OWHTO) and aimed to compare its efficacy and complications with the conventional pendulum-saw osteotomy (PSO). Methods This is a retrospective cohort study of patients undergoing either GAO or PSO procedure in the OWHTO to treat varus knee osteoarthritis, who had a minimum of 2 years of follow-up. Patients were propensity score matched (PSM) in a 1:1 ratio based on demographic and clinical data with a caliper width of 0.02. The outcomes assessed involved the hospital for special surgery (HSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and the Intraoperative and postoperative complications. Results 199 patients were included in each group after PSM. The mean duration of follow-up was 38.3 ± 8.9 months. The GAO group had a shorter operation duration (104.5 ± 35.7 vs. 112.1 ± 36.0 min, p = 0.027) and fewer times of intraoperative fluoroscopy (4.2 ± 1.4 vs. 6.0 ± 1.4, p  0.05). In addition, the intraoperative complications (0.5% vs. 3.5%, p = 0.068) and the postoperative bone delayed union and nonunion (1.0% vs. 4.5%, p = 0.032) were marginally or significantly reduced in the GAO versus PSO group. Conclusion GAO demonstrates improvements in intraoperative radiation exposure and complications, with comparable short-term efficacy to PSO, and could be considered a viable alternative in clinical practice

Development of Aptamer-DNAzyme Based Metal-Nucleic Acid Frameworks for Gastric Cancer therapy

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Global-, Regional-, and National-Level Impacts of the COVID-19 Pandemic on Tuberculosis Diagnoses, 2020–2021

Evaluating cross-country variability on the impact of the COVID-19 pandemic on tuberculosis (TB) may provide urgent inputs to control programs as countries recover from the pandemic. We compared expected TB notifications, modeled using trends in annual TB notifications from 2013–2019, with observed TB notifications to compute the observed to expected (OE) ratios for 170 countries. We applied the least absolute shrinkage and selection operator (LASSO) method to identify the covariates, out of 27 pandemic- and tuberculosis-relevant variables, that had the strongest explanatory power for log OE ratios. The COVID-19 pandemic was associated with a 1.55 million (95% CI: 1.26–1.85, 21.0% [17.5–24.6%]) decrease in TB diagnoses in 2020 and a 1.28 million (0.90–1.76, 16.6% [12.1–21.2%]) decrease in 2021 at a global level. India, Indonesia, the Philippines, and China contributed the most to the global declines for both years, while sub-Saharan Africa achieved pre-pandemic levels by 2021 (OE ratio = 1.02 [0.99–1.05]). Age-stratified analyses revealed that the ≥ 65-year-old age group experienced greater relative declines in TB diagnoses compared with the under 65-year-old age group in 2020 (RR = 0.88 [0.81–0.96]) and 2021 (RR = 0.88 [0.79–0.98]) globally. Covariates found to be associated with all-age OE ratios in 2020 were age-standardized smoking prevalence in 2019 (β = 0.973 [0.957–990]), school closures (β = 0.988 [0.977–0.998]), stay-at-home orders (β = 0.993 [0.985–1.00]), SARS-CoV-2 infection rate (β = 0.991 [0.987–0.996]), and proportion of population ≥65 years (β = 0.971 [0.944–0.999]). Further research is needed to clarify the extent to which the observed declines in TB diagnoses were attributable to disruptions in health services, decreases in TB transmission, and COVID-19 mortality among TB patients

Automatic segmentation of hemispheric CSF on MRI using deep learning: Quantifying cerebral edema following large hemispheric infarction

Background and objective: Cerebral edema (CED) is a serious complication of acute ischemic stroke (AIS), especially in patients with large hemispheric infarction (LHI). Herein, a deep learning-based approach is implemented to extract CSF from T2-Weighted Imaging (T2WI) and evaluate the relationship between quantified cerebrospinal fluid and outcomes. Methods: Patients with acute LHI who underwent magnetic resonance imaging (MRI) were included. We used a deep learning algorithm to segment the CSF from T2WI. The hemispheric CSF ratio was calculated to evaluate its relationship with the degree of brain edema and prognosis in patients with LHI. Results: For the 93 included patients, the left and right cerebrospinal fluid regions were automatically extracted with a mean Dice similarity coefficient of 0.830. Receiver operating characteristic analysis indicated that hemispheric CSF ratio was an accurate marker for qualitative severe cerebral edema (area under receiver-operating-characteristic curve 0.867 [95% CI, 0.781–0.929]). Multivariate logistic regression analysis of functional prognosis showed that previous stroke (OR = 5.229, 95% CI 1.013–26.984), ASPECT≤6 (OR = 13.208, 95% CI 1.136–153.540) and low hemispheric CSF ratio (OR = 0.966, 95% CI 0.937–0.997) were significantly associated with higher chances for unfavorable functional outcome in patients with LHI. Conclusions: Automated assessment of CSF volume provides an objective biomarker of cerebral edema that can be leveraged to quantify the degree of cerebral edema and confirm its predictive effect on outcomes after LHI

Governing Migration for Development from the Global Souths

The 14th thematic volume of International Development Policy provides perspectives through case studies from the global South(s) focusing on the challenges and opportunities of governing migration on multiple levels: the subnational, national, regional and international. It explores existing and new policies and frameworks in terms of their successes and best practices, and looks at them through the lens of additional challenges, such as those brought on by the COVID-19 pandemic, the rise of nationalisms and an increase in xenophobia. The chapters also take the ‘5 Ps’ approach to sustainable development (people, planet, prosperity, peace and partnerships) and assess how migration policies serve sustainable development in a rapidly evolving context. Guest Editors: Dêlidji Eric Degila and Valeria Marina Valle. ‘A powerful and challenging collection that offers a depth of empirical and conceptual insight in order to demonstrate the need both to think about and understand international migration from perspectives of the ‘global south’.’ Andrew Geddes Professor of Migration Studies/Director of the Migration Policy Centre, Migration Policy Centre / Robert Schuman Centre ‘Governing Migration for Development from the Global Souths is an excellent volume that addresses and unpacks the governance-migration-sustainable development nexus in the global Souths. It maps distinct ways in which global South states are involved in and create new forms of migration governance that tend to be overlooked in analyses of multilevel governance that primarily reflect the concerns of the global North. The present volume is a must read for anyone interested in the role of the global Souths in migration governance.’ Marianne H. Marchand Research Chair in International Relations, Universidad de las Américas Puebla Cite the volume: Dêlidji Eric Degila and Valeria Marina Valle (eds.) (2022) Governing Migration for Development from the Global Souths, International Development Policy | Revue internationale de politique de développement, 14 (Geneva, Boston: Graduate Institute Publications, Brill-Nijhoff). DOI: 10.4000/poldev.4544 (paperback version: forthcoming, Autumn 2022 - https://brill.com/view/title/63268). Watch the videos of the authors explaining their chapter