Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda

Abstract Background To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. Methods The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. Results Thirty of 33 doctors (91%), 24 of 40 clinical officers (60%), 16 of 114 nurses (14%) and 13 of 54 midwives (24%) who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p Conclusion Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.</p

Retention in care among HIV-infected pregnant and breastfeeding women on lifelong antiretroviral therapy in Uganda: A retrospective cohort study.

The study conducted a retrospective cohort analysis of data abstracted from records of 2,169 women enrolled on Option B+ between January and March 2013 from a representative sample of 145 health facilities in all 24 districts of the Central region of Uganda.Background: In 2013, Uganda updated its prevention of maternal-to-child transmission of HIV program to Option B+, which requires that all HIV-infected pregnant and breastfeeding women be started on lifelong antiretroviral therapy (ART) regardless of CD4 count. We describe retention in care and factors associated with loss to follow-up (LTFU) among women initiated on Option B+ as part of an evaluation of the effectiveness of the national program. Methods: We conducted a retrospective cohort analysis of data abstracted from records of 2,169 women enrolled on Option B+ between January and March 2013 from a representative sample of 145 health facilities in all 24 districts of the Central region of Uganda. We defined retention as ªbeing alive and receiving ART at the last clinic visitº. We used Kaplan-Meier analysis to estimate retention in care and compared differences between women retained in care and those LTFU using the chi-squared test for dichotomized or categorical variables. Results: The median follow-up time was 20.2 months (IQR 4.2±22.5). The proportion of women retained in HIV care at 6, 12 and 18 months post-ART initiation was 74.2%, 66.7% and 62.0%, respectively. Retention at 18 months varied significantly by level of health facility and ranged from 70.0% among those seen at hospitals to 56.6% among those seen at lower level health facilities. LTFU was higher among women aged less than 25 years, 59.3% compared to those aged 25 years and above, 40.7% (p = 0.02); among those attending care at lower level facilities, 44.0% compared to those attending care at hospitals, 34.1% (p = 0.01), and among those who were not tested for CD4 cell count at ART initiation, 69.4% compared to those who were tested, 30.9% (p = 0.002). Conclusion: Retention of women who were initiated on Option B+ during the early phases of roll-out was only moderate, and could undermine the effectiveness of the program. Identifying reasons why women drop out and designing targeted interventions for improved retention should be a priority

Proportion of women on Option B+ retained in care at 6, 12 and 18 months, over time, by level of health facility.

<p>Proportion of women on Option B+ retained in care at 6, 12 and 18 months, over time, by level of health facility.</p

Baseline characteristics of women enrolled on Option B+ between January and March 2013.

<p>Baseline characteristics of women enrolled on Option B+ between January and March 2013.</p

Retention in care over time among women initiated on Option B+ between January and March 2013 in Uganda, stratified by level of health facility.

<p>Retention in care over time among women initiated on Option B+ between January and March 2013 in Uganda, stratified by level of health facility.</p