Crosslinking-induced endocytosis of acetylcholine receptors by quantum dots

In a majority of patients with myasthenia gravis (MG), anti-acetylcholine receptor (AChR) antibodies target postsynaptic AChR clusters and thus compromise the membrane integrity of neuromuscular junctions (NMJs) and lead to muscle weakness. Antibody-induced endocytosis of AChRs in the postsynaptic membrane represents the initial step in the pathogenesis of MG; however, the molecular mechanisms underlying AChR endocytosis remain largely unknown. Here, we developed an approach to mimic the pathogenic antibodies for inducing the crosslinking and internalization of AChRs from the postsynaptic membrane. Using biotin-α-bungarotoxin and quantum dot (QD)-streptavidin, cell-surface and internalized AChRs could be readily distinguished by comparing the size, fluorescence intensity, trajectory, and subcellular localization of the QD signals. QD-induced AChR endocytosis was mediated by clathrin-dependent and caveolin-independent mechanisms, and the trafficking of internalized AChRs in the early endosomes required the integrity of microtubule structures. Furthermore, activation of the agrin/MuSK (muscle-specific kinase) signaling pathway strongly suppressed QD-induced internalization of AChRs. Lastly, QD-induced AChR crosslinking potentiated the dispersal of aneural AChR clusters upon synaptic induction. Taken together, our results identify a novel approach to study the mechanisms of AChR trafficking upon receptor crosslinking and endocytosis, and demonstrate that agrin-MuSK signaling pathways protect against crosslinking-induced endocytosis of AChRs. © 2014 Lee et al.published_or_final_versio

Strengthening Mentoring in Low- and Middle-Income Countries to Advance Global Health Research: An Overview.

Mentoring is a proven path to scientific progress, but it is not a common practice in low- and middle-income countries (LMICs). Existing mentoring approaches and guidelines are geared toward high-income country settings, without considering in detail the differences in resources, culture, and structure of research systems of LMICs. To address this gap, we conducted five Mentoring-the-Mentor workshops in Africa, South America, and Asia, which aimed at strengthening the capacity for evidence-based, LMIC-specific institutional mentoring programs globally. The outcomes of the workshops and two follow-up working meetings are presented in this special edition of the American Journal of Tropical Medicine and Hygiene. Seven articles offer recommendations on how to tailor mentoring to the context and culture of LMICs, and provide guidance on how to implement mentoring programs. This introductory article provides both a prelude and executive summary to the seven articles, describing the motivation, cultural context and relevant background, and presenting key findings, conclusions, and recommendations

Chronic Hepatitis B Virus Coinfection Is Associated With Renal Impairment Among Zambian HIV-Infected Adults

Among 6789 HIV-infected Zambian adults screened for hepatitis B virus (HBV) coinfection, estimated glomerular filtration rate (eGFR) was 50-90 mL/minute/1.73 m2 in 17.6% and <50 mL/minute/1.73 m2 in 2.5%. Human immunodeficiency virus/HBV coinfection was associated with eGFR <50 mL/minute/1.73 m2 (adjusted odds ratio, 1.96 [95% confidence interval, 1.34-2.86]), adjusted for age, sex, CD4+ count, and World Health Organization disease stag

Dosage of Sulfadoxine–Pyrimethamine and Risk of Low Birth Weight in a Cohort of Zambian Pregnant Women in a Low Malaria Prevalence Region

In Lusaka, Zambia, where malaria prevalence is low, national guidelines continue to recommend that all pregnant women receive sulfadoxine–pyrimethamine (SP) for malaria prophylaxis monthly at every scheduled antenatal care visit after 16 weeks of gestation. Human immunodeficiency virus (HIV)–positive women should receive co-trimoxazole prophylaxis for HIV and not SP, but many still receive SP. We sought to determine whether increased dosage of SP is still associated with a reduced risk of low birth weight (LBW) in an area where malaria transmission is low. Our secondary objective was to determine whether any association between SP and LBW is modified by receipt of antiretroviral therapy (ART). We analyzed data routinely collected from a cohort of HIV-positive pregnant women with singleton births in Lusaka, Zambia, between February 2006 and December 2012. We used a log-Poisson model to estimate the risk of LBW by dosage of SP and to determine whether the association between SP and LBW varied by receipt of ART. Risk of LBW declined as the number of doses increased and appeared lowest among women who received three doses (adjusted risk ratio [ARR] = 0.78; 95% confidence interval [CI] = 0.64–0.95). In addition, women receiving combination ART had a higher risk of delivering an LBW infant compared with women receiving no treatment or prophylaxis (ARR = 1.18; 95% CI = 1.09–1.28), but this risk was attenuated among women who were receiving SP (risk ratio = 1.09; 95% CI = 0.99–1.21). SP was associated with a reduced risk of LBW in HIV-positive women, including those receiving ART, in a low malaria prevalence region

Unified Embedding: Battle-Tested Feature Representations for Web-Scale ML Systems

Learning high-quality feature embeddings efficiently and effectively is critical for the performance of web-scale machine learning systems. A typical model ingests hundreds of features with vocabularies on the order of millions to billions of tokens. The standard approach is to represent each feature value as a d-dimensional embedding, introducing hundreds of billions of parameters for extremely high-cardinality features. This bottleneck has led to substantial progress in alternative embedding algorithms. Many of these methods, however, make the assumption that each feature uses an independent embedding table. This work introduces a simple yet highly effective framework, Feature Multiplexing, where one single representation space is used across many different categorical features. Our theoretical and empirical analysis reveals that multiplexed embeddings can be decomposed into components from each constituent feature, allowing models to distinguish between features. We show that multiplexed representations lead to Pareto-optimal parameter-accuracy tradeoffs for three public benchmark datasets. Further, we propose a highly practical approach called Unified Embedding with three major benefits: simplified feature configuration, strong adaptation to dynamic data distributions, and compatibility with modern hardware. Unified embedding gives significant improvements in offline and online metrics compared to highly competitive baselines across five web-scale search, ads, and recommender systems, where it serves billions of users across the world in industry-leading products.Comment: NeurIPS'23 Spotligh

Prevention of mother-to-child HIV transmission within the continuum of maternal, newborn, and child health services

To reach virtual elimination of pediatric HIV, programs for the prevention of mother-to-child HIV transmission (PMTCT) must expand coverage and achieve long-term retention of mothers and infants. While PMTCT have been traditionally aligned with maternal, newborn, and child health (MNCH) services, novel approaches are needed to address the increasing demands of evolving global PMTCT policies

Antiretroviral drug regimens to prevent mother-to-child transmission of HIV : a review of scientific, program, and policy advances for sub-Saharan Africa.

CAPRISA 2013.Considerable advances have been made in the effort to prevent mother-to-child HIV transmission (PMTCT) in sub-Saharan Africa. Clinical trials have demonstrated the efficacy of antiretroviral regimens to interrupt HIV transmission through the antenatal, intrapartum, and postnatal periods. Scientific discoveries have been rapidly translated into health policy, bolstered by substantial investment in health infrastructure capable of delivering increasingly complex services. A new scientific agenda is also emerging, one that is focused on the challenges of effective and sustainable program implementation. Finally, global campaigns to “virtually eliminate” pediatric HIV and dramatically reduce HIV-related maternal mortality have mobilized new resources and renewed political will. Each of these developments marks a major step in regional PMTCT efforts; their convergence signals a time of rapid progress in the field, characterized by an increased interdependency between clinical research, program implementation, and policy. In this review, we take stock of recent advances across each of these areas, highlighting the challenges – and opportunities – of improving health services for HIV-infected mothers and their children across the region

Trends in all-cause mortality during the scale-up of an antiretroviral therapy programme: a cross-sectional study in Lusaka, Zambia.

OBJECTIVE: To follow the trends in all-cause mortality in Lusaka, Zambia, during the scale-up of a national programme of antiretroviral therapy (ART). METHODS: Between November 2004 and September 2011, we conducted 12 survey rounds as part of a cross-sectional study in Lusaka, with independent sampling in each round. In each survey, we asked the heads of 3600 households to state the number of deaths in their households in the previous 12 months and the number of orphans aged less than 16 years in their households and investigated the heads' knowledge, attitudes and practices related to human immunodeficiency virus (HIV). FINDINGS: The number of deaths we recorded - per 100 person-years - in each survey ranged from 0.92 (95% confidence interval, CI: 0.78-1.09) in September 2011, to 1.94 (95% CI: 1.60-2.35) in March 2007. We found that mortality decreased only modestly each year (mortality rate ratio: 0.98; 95% CI: 0.95-1.00; P = 0.093). The proportion of households with orphans under the age of 16 years decreased from 17% in 2004 to 7% in 2011. The proportions of respondents who had ever been tested for HIV, had a comprehensive knowledge of HIV, knew where to obtain free ART and reported that a non-pregnant household member was receiving ART gradually increased. CONCLUSION: The expansion of ART services in Lusaka was not associated with a reduction in all-cause mortality. Coverage, patient adherence and retention may all have to be increased if ART is to have a robust and lasting impact at population level in Lusaka

The Transmission Dynamics of Tuberculosis in a Recently Developed Chinese City

BACKGROUND: Hong Kong is an affluent subtropical city with a well-developed healthcare infrastructure but an intermediate TB burden. Declines in notification rates through the 1960s and 1970s have slowed since the 1980s to the current level of around 82 cases per 100 000 population. We studied the transmission dynamics of TB in Hong Kong to explore the factors underlying recent trends in incidence. METHODOLOGY/PRINCIPAL FINDINGS: We fitted an age-structured compartmental model to TB notifications in Hong Kong between 1968 and 2008. We used the model to quantify the proportion of annual cases due to recent transmission versus endogenous reactivation of latent infection, and to project trends in incidence rates to 2018. The proportion of annual TB notifications attributed to endogenous reactivation increased from 46% to 70% between 1968 and 2008. Age-standardized notification rates were projected to decline to approximately 56 per 100 000 in 2018. CONCLUSIONS/SIGNIFICANCE: Continued intermediate incidence of TB in Hong Kong is driven primarily by endogenous reactivation of latent infections. Public health interventions which focus on reducing transmission may not lead to substantial reductions in disease burden associated with endogenous reactivation of latent infections in the short- to medium-term. While reductions in transmission with socio-economic development and public health interventions will lead to declines in TB incidence in these regions, a high prevalence of latent infections may hinder substantial declines in burden in the longer term. These findings may therefore have important implications for the burden of TB in developing regions with higher levels of transmission currently.published_or_final_versio

Implementation Research for the Prevention of Mother-to-Child HIV Transmission in Sub-Saharan Africa: Existing Evidence, Current Gaps, and New Opportunities

Tremendous gains have been made in the prevention of mother-to-child HIV transmission (PMTCT) in sub-Saharan Africa. Ambitious goals for the “virtual elimination” of pediatric HIV appear increasingly feasible, driven by new scientific advances, forward-thinking health policy, and substantial donor investment. To fulfill this promise, however, rapid and effective implementation of evidence-based practices must be brought to scale across a diversity of settings. The discipline of implementation research can facilitate this translation from policy into practice; however, to date, its core principles and frameworks have been inconsistently applied in the field. We reviewed the recent developments in implementation research across each of the four “prongs” of a comprehensive PMTCT approach. While significant progress continues to be made, a greater emphasis on context, fidelity, and scalability – in the design and dissemination of study results – would greatly enhance current efforts and provide the necessary foundation for future evidence-based programs