Experiences and lessons learned from 29 HPV vaccination programs implemented in 19 low and middle-income countries, 2009-2014

BACKGROUND: Cervical cancer is the greatest cause of age-weighted years of life lost in the developing world. Human papillomavirus (HPV) infection is associated with a high proportion of cervical cancers, and HPV vaccination may help to reduce the incidence of cancer. The aim of the study was to identify barriers, obstacles, and strategies and to analyze key concerns and lessons learned with respect to the implementation of HPV vaccination program in low- and middle-income countries. METHODS: The Gardasil Access Program (GAP) is a donation program established to enable organizations and institutions in eligible low-resource countries to gain operational experience designing and implementing HPV vaccination programs. This study used an online survey to capture the experiences and insights of program managers participating in the GAP. Different factors related to HPV vaccination program management were collected. A mixed-method approach enabled the presentation of both quantitative measurements and qualitative insights. RESULTS: Twenty-nine programs implemented by 23 institutions in 19 low- and middle-income countries were included. Twenty programs managers (97.7 %) reported that their institution implemented sensitization strategies about vaccination prior to the launch of vaccination campaign. The most frequently reported obstacles to HPV vaccination by the program managers were erroneous perceptions of population related to the vaccine’s safety and efficacy. Reaching and maintaining follow-up with target populations were identified as challenges. Insufficient infrastructure and human resources financing and the vaccine delivery method were identified as significant health system barriers. Coupling HPV vaccination with other health interventions for mothers of targeted girls helped to increase vaccination and cervical cancer screening. The majority of program managers reported that their programs had a positive impact on national HPV vaccination policy. The majority of institutions had national and international partners that provided support for human resources, technical assistance, and training and financial support for health professionals. CONCLUSION: Local organizations and institutions can implement successful HPV vaccination campaigns. Adequate and adapted planning and resources that support information sharing, sensitization, and mobilization are essential for such success. These results can inform the development of programs and policies related to HPV vaccination in low- and middle-income countries

Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT 03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT 03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects

Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats

Rationale: Stress elicits functional and structural changes in the hippocampus. Early life stress is one of the major risk factors for stress-related pathologies like depression. Patients suffering from depression show a reduced hippocampal volume, and in women, this occurs more often when depression is preceded by childhood trauma. However, the underlying mechanisms that account for a reduced hippocampal volume are unknown. Objective: We examined the effects of maternal absence on structure and function of the hippocampus in female offspring. Methods: We studied whether 24 h of maternal deprivation (MD) on postnatal day 3 altered adult neurogenesis, individual neuronal morphology and dentate gyrus (DG) structure in young adult female rats. In addition, functional alterations were addressed by studying synaptic plasticity in vitro, and spatial as well as emotional learning was tested. Results: Adult females that were subjected to MD revealed significant reductions in DG granule cell number and density. In addition, DG neurons were altered in their dendritic arrangement. No effects on the rate of adult neurogenesis were found. Furthermore, MD did not alter synaptic plasticity in vitro, neither under normal nor high-stress conditions. In addition, spatial learning and contextual fear conditioning were comparable between control and MD animals. However, MD animals showed an improved amygdala-dependent fear memory. Conclusion: Although early life stress exposure did not impair hippocampus-dependent functioning in female offspring, it irreversibly affected DG structure by reducing cell numbers. This may be relevant for the reduced hippocampal volume observed in depression and the increased vulnerability of women to develop depression

Substantial modification of the gene expression profile following exposure of macrophages to welding-related nanoparticles.

Anthropic nanoparticles (NP) are increasingly produced and emitted, with accompanying concerns for human health. Currently there is no global understanding as to the exact mechanistics of NP toxicity, as the traditional nanotoxicological approaches only provide a restricted overview. To address this issue, we performed an in-depth transcriptomic analysis of human macrophages exposed to a panel of welding-related metal oxide NP that we previously identified in welders lungs (Fe2O3, Fe3O4, MnFe2O4 and CrOOH NP). Utilizing the specified analysis criteria (|fold change| ≥1.5, p ≤ 0.001), a total of 2164 genes were identified to be differentially expressed after THP-1 macrophage exposure to the different NP. Performing Gene Ontology enrichment analysis, for cellular content, biological processes and Swiss-Prot/Protein Information Resource keywords the data show for the first time a profound modification of gene differential expression in response to the different NP, among which MnFe2O4 NP were the most potent to induce THP-1 macrophage activation. The transcriptomic analysis utilized in the study, provides novel insights into mechanisms that could contribute to NP-induced adverse effects and support the need for widened approaches to supplement existing knowledge of the processes underlying NP toxicity which would have not been possible using traditional nanotoxicological studies