Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

How to measure human leukocyte antigen-specific B cells.

PURPOSE OF REVIEW: The implementation of highly sensitive immune assays measuring anti-human leukocyte antigen (HLA) antibodies has modified alloimmune risk stratification and diagnosis of rejection. Nonetheless, anti-HLA antibodies represent the downstream effector mechanism of the B-cell response. Better characterizing the cellular components of the humoral immune response (including memory B cells (mBCs) and long-lived plasma cells) could help to further stratify the alloimmune risk stratification and enable discovery of new therapeutic targets. Several tests that characterize HLA-specific mBCs, either functionally or phenotypically, have been developed in the last years, showing promising applications as well as some limitations. RECENT FINDINGS: Functional assays involving ex vivo polyclonal activation of mBC have been refined to allow the detection of HLA-specific mBC capable of producing anti-HLA Abs, using different and complementary detection platforms such as multiplex Fluorospot and single antigen bead assay on culture supernatants. Detection of circulating HLA-specific B cells by flow cytometry remains hindered by the very low frequency of HLA-specific mBC. SUMMARY: Technological refinements have allowed the development of tests detecting HLA-specific mBC. Further evaluation of these assays in clinical trials, both for immune risk stratification and to assess treatment efficacy (desensitization strategies, rescue therapies for ABMR) are now urgently needed.

Multi-Phase Interleaved AC-DC Step-Down Converter with Power Factor Improvement.

This paper presents the converter design of a single-phase non-isolated step-down controlled rectifier for power factor improvement and output voltage regulation. The converter consists of a full-bridge diode rectifier and a DC-DC interleaved buck converter of two or more switching cells that has an LC filter in its input. It is proposed that the interleaved switching cells operate in discontinuous conduction mode and the current through the input LC filter be continuous, avoiding switching frequency components to be injected into the grid. The controller, which has a simple structure and a small number of sensors, allows the system to achieve a high power factor. It also regulates the output voltage to a constant reference. An experimental prototype is built and tested to validate the analysis and proposed design. The closed-loop converter is evaluated both in a steady state and in transient conditions. At steady state, the converter achieves a power factor above 0.9 with a maximum of 45.4% THD at 110.1W. The main contributions of this paper are guidelines for the design of the converter, open-loop analysis, and converter control.

A global public health convention for the 21st century.

As shown by COVID-19, infectious diseases with a pandemic potential present a grave threat to health and wellbeing. Although the International Health Regulations provide a framework of binding legal obligations for pandemic prevention, preparedness, and response, many countries do not comply with these regulations. There is a need for a renewed framework for global collective action that ensures conformity with international regulations and promotes effective prevention and response to pandemic infectious diseases. This Health Policy identifies the necessary characteristics for a new global public health security convention designed to optimise prevention, preparedness, and response to pandemic infectious diseases. We propose ten recommendations to strengthen global public health governance and promote compliance with global health security regulations. Recommendations for a new global public health security convention include greater authority for a global governing body, an improved ability to respond to pandemics, an objective evaluation system for national core public health capacities, more effective enforcement mechanisms, independent and sustainable funding, representativeness, and investment from multiple sectors, among others. The next steps to achieve these recommendations include assembling an invested alliance, specifying the operational structures of a global public health security system, and overcoming barriers such as insufficient political will, scarcity of resources, and individual national interests.

Hybrid PWM Techniques for a DCM-232 Three-Phase Transformerless Inverter with Reduced Leakage Ground Current.

Pulse Width Modulation (PWM) strategies are crucial for controlling DC-AC power converters. In particular, transformerless inverters require specific PWM techniques to improve efficiency and to deal with leakage ground current issues. In this paper, three hybrid PWM methods are proposed for a DCM-232 three-phase topology. These methods are based on the concepts of carrier-based PWM and space vector modulation. Calculations of time intervals for active and null vectors are performed in a conventional way, and the resulting waveforms are compared with a carrier signal. The digital signals obtained are processed using Boolean functions, generating ten signals to control the DCM-232 three-phase inverter. The performance of the three proposed PWM methods is evaluated considering the reduction in leakage ground current and efficiency. The proposed modulation techniques have relevant performances complying with international standards, which make them suitable for transformerless three-phase photovoltaic (PV) inverter markets. To validate the proposed hybrid PWM strategies, numerical simulations and experimental tests were performed.

Fast-Track Cities: striving to end urban HIV epidemics by 2030.

PURPOSE OF REVIEW: To provide a summary of progress achieved, lessons learned, and best practices employed in select Fast-Track Cities striving to attain and surpass the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets. RECENT FINDINGS: The 90-90-90 targets have served as a catalyst to galvanize political, programmatic, and funding support for urban HIV responses, while prompting increased community engagement. More than 300 cities and municipalities have joined the Fast-Track Cities network, pledging to attain and surpass the UNAIDS 90-90-90 targets. One city has officially surpassed the 95-95-95 targets; four cities have surpassed the 90-90-90 targets; and 34 cities have achieved one or more of the 90 targets. Across the Fast-Track Cities network, upward trends have been recorded in numerous cities and municipalities using data-driven approaches to close HIV care continuum gaps through data-driven implementation planning. SUMMARY: The Fast-Track Cities initiative has served as a catalyst for leveraging accelerated and optimized urban HIV responses to scale up HIV diagnosis, treatment, and viral suppression. Key to attaining and surpassing the 90-90-90 targets is a 'calculus for success' that includes political will, public health leadership, data-driven implementation planning, and equity-based interventions facilitated by active engagement with affected communities, notably people living with HIV.

Pattern, Determinants, and Impact of HIV Spending on Care and Treatment in 38 High-Burden Low- and Middle-Income Countries.

UNLABELLED: : Achieving the 90-90-90 targets by 2020 requires increased focus, resources, and efficiency to provide earlier access to antiretroviral therapy (ART). METHODS: We used 2009 to 2013 National AIDS Spending Assessment data to assess HIV care and treatment spending in 38 high-burden, low- and middle-income countries (LMICs). RESULTS: In 2013, 23 of the 38 high-burden countries spent less than 50% of total HIV spending on care and treatment. HIV spending on ART per people living with HIV (PLHIV; adjusted) averaged US$299 (US$32-US$2463). During 2009 to 2013, a 10% increase in average spending on care and treatment per PLHIV was associated with an increase in ART coverage of 2.4% and a decrease in estimated AIDS-related death rate of 2.4 per 1000 PLHIV. DISCUSSION: HIV spending in high-burden LMICs does not consistently reflect the new science around the preventative and clinical benefits of earlier HIV diagnosis and ART initiation.

Trends in AIDS Deaths, New Infections and ART Coverage in the Top 30 Countries with the Highest AIDS Mortality Burden; 1990-2013.

BACKGROUND: Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV) disease progression, mortality and transmission. We assess the impact of expanded HIV treatment for the prevention of Acquired Immunodeficiency Syndrome (AIDS)-related deaths and simulate four treatment scenarios for Nigeria and South Africa. METHODS: For 1990-2013, we used the Joint United Nations Programme on HIV/AIDS (UNAIDS) database to examine trends in AIDS deaths, HIV incidence and prevalence, ART coverage, annual AIDS death rate, AIDS death-to-treatment and HIV infections to treatment ratios for the top 30 countries with the highest AIDS mortality burden and compare them with data from high-income countries. We projected the 1990-2020 AIDS deaths for Nigeria and South Africa using four treatment scenarios: 1) no ART; 2) maintaining current ART coverage; 3) 90% ART coverage based on 2013 World Health Organization (WHO) ART guidelines by 2020; and 4) reaching the United Nations 90-90-90 Target by 2020. FINDINGS: In 2013, there were 1.3 million (1.1 million-1.6 million) AIDS deaths in the top 30 countries representing 87% of global AIDS deaths. Eight countries accounted for 58% of the global AIDS deaths; Nigeria and South Africa accounted for 27% of global AIDS deaths. The highest death rates per 1000 people living with HIV were in Central African Republic (91), South Sudan (82), Côte d'Ivoire (75), Cameroon (72) and Chad (71), nearly 8-10 times higher than the high-income countries. ART access in 2013 has averted as estimated 1,051,354 and 422,448 deaths in South Africa and Nigeria, respectively. Increasing ART coverage in these two countries to meet the proposed UN 90-90-90 Target by 2020 could avert 2.2 and 1.2 million deaths, respectively. INTERPRETATION: Over the past decade the expansion of access to ART averted millions of deaths. Reaching the proposed UN 90-90-90 Target by 2020 will prevent additional morbidity, mortality and HIV transmission. Despite progress, high-burden countries will need to accelerate access to ART treatment to avert millions of premature AIDS deaths and new HIV infections.

HIV provider-patient communication regarding cardiovascular risk: results from the AIDS Treatment for Life International Survey.

DESIGN: Few global studies have assessed HIV clinician-patient communication regarding cardiovascular disease (CVD) risks. METHODS: We conducted a multicountry, comparative, cross-sectional survey of HIV-infected individuals in 12 countries on 5 continents in 2010, with 100 to 200 enrollees per country. HIV-infected adults >17 years and on antiretroviral therapy were recruited in clinics and community organizations and surveyed via direct interview, telephone encounter, or online. Chi-square analyses were performed with an 80% power to detect a difference of >20%. RESULTS: Of 2035 participants, 37% were women. Prevalence of self-reported CVD risk factors was 28% overall, and greater CVD risk was present in 55% of patients in North America, 12% in Africa, and 26% to 28% on other continents. Only 19% of patients ever discussed CVD with their physician, and 31% had ever discussed hypertension, hypercholesterolemia, family history of CVD, or smoking; these findings were true for HIV clinicians in all regions of the world. Forty-four percent of smokers reported never discussing smoking with their HIV clinician. CONCLUSION: We found that HIV clinicians worldwide are not sufficiently addressing CVD risk factors with their patients. Expanded training and education for HIV clinicians should include effective approaches to the mitigation of CV risk factors.

Controlling the HIV epidemic with antiretrovirals: moving from consensus to implementation.

The second Controlling the HIV With Antiretrovirals evidence summit was held 22-24 September 2013, in London, England. This preface summarizes the summit's background and key themes, and is an introduction to a series of articles written by select summit faculty and featured in this supplement. In many respects, the supplement can serve as a roadmap for how to move from general consensus around to wider scale implementation of a comprehensive menu of interventions to control the HIV epidemic.

Leveraging HIV treatment to end AIDS, stop new HIV infections, and avoid the cost of inaction.

We have the tools at our disposal to significantly bend AIDS-related morbidity and mortality curves and reduce human immunodeficiency virus (HIV) incidence. It is thus essential to redouble our efforts to reach the goal of placing 15 million people on life-saving and -enhancing antiretroviral therapy (ART) by 2015. In reaching this milestone, we can write a new chapter in the history of global health, demonstrating that a robust, multidimensional response can succeed against a complex pandemic that presents as many social and political challenges as it does medical ones. This milestone is also critical to advance our ultimate goal of ending AIDS by maximizing the therapeutic and preventive effects of ART, which translates into a world in which AIDS-related deaths and new HIV infections are exceedingly rare.

HIV provider-patient communication regarding cardiovascular risk: results from the AIDS Treatment for Life International Survey.

DESIGN: Few global studies have assessed HIV clinician-patient communication regarding cardiovascular disease (CVD) risks. METHODS: We conducted a multicountry, comparative, cross-sectional survey of HIV-infected individuals in 12 countries on 5 continents in 2010, with 100 to 200 enrollees per country. HIV-infected adults >17 years and on antiretroviral therapy were recruited in clinics and community organizations and surveyed via direct interview, telephone encounter, or online. Chi-square analyses were performed with an 80% power to detect a difference of >20%. RESULTS: Of 2035 participants, 37% were women. Prevalence of self-reported CVD risk factors was 28% overall, and greater CVD risk was present in 55% of patients in North America, 12% in Africa, and 26% to 28% on other continents. Only 19% of patients ever discussed CVD with their physician, and 31% had ever discussed hypertension, hypercholesterolemia, family history of CVD, or smoking; these findings were true for HIV clinicians in all regions of the world. Forty-four percent of smokers reported never discussing smoking with their HIV clinician. CONCLUSION: We found that HIV clinicians worldwide are not sufficiently addressing CVD risk factors with their patients. Expanded training and education for HIV clinicians should include effective approaches to the mitigation of CV risk factors.