A Model for Accelerating Access to Care and Treatment for Children and Adolescents Living with HIV in Nigeria, Tanzania, Uganda, and Zambia: The Faith-Based Action for Scaling-Up Testing and Treatment for the Epidemic Response (FASTER) Initiative.

The number of children newly infected with HIV dropped by 50%, from 320 000 in 2010 to 160 000 in 2021. Despite progress, ongoing gaps persist in diagnosis, continuity of care, and treatment optimization. In response, the United States President's Emergency Plan for AIDS Relief created the Faith-based Action for Scaling-Up Testing and Treatment for Epidemic Response (FASTER). Faith-based Action for Scaling-Up Testing and Treatment for Epidemic Response addressed gaps in countries with the highest unmet need by working with government to operationalize innovative interventions and ensure alignment with national priorities and with communities living with HIV to ensure the change was community-led. Between 2019 and 2021, FASTER's interventions were incorporated into national policies, absorbed by Ministries of Health, and taken up in subsequent awards and country operating plans. Continued effort is needed to sustain gains made during the FASTER initiative and to continue scaling evidence-based interventions to ensure that children and adolescents are not left behind in the global HIV response.

Human papillomavirus testing using existing nucleic acid testing platforms to screen women for cervical cancer: implementation studies from five sub-Saharan African countries.

OBJECTIVES: To demonstrate acceptability and operational feasibility of introducing human papillomavirus (HPV) testing as a principal cervical cancer screening method in public health programmes in sub-Saharan Africa. SETTING: 45 primary and secondary health clinics in Malawi, Nigeria, Senegal, Uganda and Zimbabwe. PARTICIPANTS: 15 766 women aged 25-54 years presenting at outpatient departments (Senegal only, general population) or at antiretroviral therapy clinics (all other countries, HIV-positive women only). Eligibility criteria followed national guidelines for cervical cancer screening. INTERVENTIONS: HPV testing was offered to eligible women as a primary screening for cervical cancer, and HPV-positive women were referred for visual inspection with acetic acid (VIA), and if lesions identified, received treatment or referral. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of HPV-positive women who received results and linked to VIA and the proportion of HPV-positive and VIA-positive women who received treatment. RESULTS: A total of 15 766 women were screened and tested for HPV, among whom 14 564 (92%) had valid results and 4710/14 564 (32%) were HPV positive. 13 837 (95%) of valid results were returned to the clinic and 3376 (72%) of HPV-positive women received results. Of women receiving VIA (n=2735), 715 (26%) were VIA-positive and 622 (87%) received treatment, 75% on the same day as VIA. CONCLUSIONS: HPV testing was found to be feasible across the five study countries in a public health setting, although attrition was seen at several key points in the cascade of care, namely results return to women and linkage to VIA. Once women received VIA, if eligible, the availability of on-site cryotherapy and thermal ablation allowed for same-day treatment. With sufficient resources and supportive infrastructure to ensure linkage to treatment, use of HPV testing for cervical cancer screening as recommended by WHO is a promising model in low-income and middle-income countries.

Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein.

Huntington disease (HD) is a progressive neurodegenerative disorder caused by expression of polyglutamine-expanded mutant huntingtin protein (mhtt). Most evidence indicates that soluble mhtt species, rather than insoluble aggregates, are the important mediators of HD pathogenesis. However, the differential roles of soluble monomeric and oligomeric mhtt species in HD and the mechanisms of oligomer formation are not yet understood. We have shown previously that copper interacts with and oxidizes the polyglutamine-containing N171 fragment of huntingtin. In this study we report that oxidation-dependent oligomers of huntingtin form spontaneously in cell and mouse HD models. Levels of these species are modulated by copper, hydrogen peroxide, and glutathione. Mutagenesis of all cysteine residues within N171 blocks the formation of these oligomers. In cells, levels of oligomerization-blocked mutant N171 were decreased compared with native N171. We further show that a subset of the oligomerization-blocked form of glutamine-expanded N171 huntingtin is rapidly depleted from the soluble pool compared with "native " mutant N171. Taken together, our data indicate that huntingtin is subject to specific oxidations that are involved in the formation of stable oligomers and that also delay removal from the soluble pool. These findings show that inhibiting formation of oxidation-dependent huntingtin oligomers, or promoting their dissolution, may have protective effects in HD by decreasing the burden of soluble mutant huntingtin.

Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease.

Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD.

The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD. RESULTS: Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels. CONCLUSIONS: Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.

Mechanisms of copper ion mediated Huntington's disease progression.

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu(2+)in vitro in a 1:1 copper:protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics.

Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1.

Transcriptional dysregulation has been described as a central mechanism in the pathogenesis of Huntington's disease (HD), in which medium spiny projection neurons (MSN) selectively degenerate whereas neuronal nitric-oxide-synthase-positive interneurons (nNOS-IN) survive. In order to begin to understand this differential vulnerability we compared mRNA levels of selected genes involved in N-methyl-D-aspartate (NMDA) glutamate receptor and calcium (Ca2+) signaling pathways in MSN and nNOS-IN from 12-week-old R6/2 mice, a transgenic mouse model of HD and wild-type littermates. We undertook a laser capture microdissection (LCM) study to examine the contribution of transcriptional dysregulation in candidate genes involved in these two signaling pathways in discrete populations of striatal neurons. The use of LCM in combination with quantitative real-time polymerase chain reaction (Q-PCR) allowed us to quantify the neuronal abundance of candidate mRNAs. We found different transcriptional alterations in R6/2 neurons for both MSN and nNOS-IN, indicating that global transcriptional dysregulation alone does not account for selective vulnerability. Further, we observed a striking enrichment of several mRNAs in the nNOS-IN population, including that for the NMDA receptor subunit NR2D, the postsynaptic density protein 95 (PSD-95) and the huntingtin-associated protein 1 (HAP1) as well as nitric-oxide-synthase (nNOS) mRNA itself. The higher expression levels of these molecules in nNOS-IN when compared with MSN together with an association of nNOS, NR2D and HAP1 in a protein complex with PSD-95 suggest that these proteins may be involved in protective pathways that contribute to the resistance of this interneuron population to neurodegeneration in HD.