The Hepatitis C Cascade of Care: Identifying Priorities to Improve Clinical Outcomes

Background: As highly effective hepatitis C virus (HCV) therapies emerge, data are needed to inform the development of interventions to improve HCV treatment rates. We used simulation modeling to estimate the impact of loss to follow-up on HCV treatment outcomes and to identify intervention strategies likely to provide good value for the resources invested in them. Methods: We used a Monte Carlo state-transition model to simulate a hypothetical cohort of chronically HCV-infected individuals recently screened positive for serum HCV antibody. We simulated four hypothetical intervention strategies (linkage to care; treatment initiation; integrated case management; peer navigator) to improve HCV treatment rates, varying efficacies and costs, and identified strategies that would most likely result in the best value for the resources required for implementation. Main measures Sustained virologic responses (SVRs), life expectancy, quality-adjusted life expectancy (QALE), costs from health system and program implementation perspectives, and incremental cost-effectiveness ratios (ICERs). Results: We estimate that imperfect follow-up reduces the real-world effectiveness of HCV therapies by approximately 75%. In the base case, a modestly effective hypothetical peer navigator program maximized the number of SVRs and QALE, with an ICER compared to the next best intervention of $48,700/quality-adjusted life year. Hypothetical interventions that simultaneously addressed multiple points along the cascade provided better outcomes and more value for money than less costly interventions targeting single steps. The 5-year program cost of the hypothetical peer navigator intervention was$14.5 million per 10,000 newly diagnosed individuals. Conclusions: We estimate that imperfect follow-up during the HCV cascade of care greatly reduces the real-world effectiveness of HCV therapy. Our mathematical model shows that modestly effective interventions to improve follow-up would likely be cost-effective. Priority should be given to developing and evaluating interventions addressing multiple points along the cascade rather than options focusing solely on single points

Evaluation of the contribution of NTFPs gathering: to rural people’s livelihoods around two timber concessions in Gabon

NTFP are often presented as bringing a major contribution to rural livelihoods in terms of food and cash, and this particularly for rural communities. Few data are available in Gabon to confirm this common assertion. An annual monitoring of 127 households was conducted in 14 villages around two timber concessions in the south-east and south-west regions of Gabon. Conventional socio‐economic survey tools such as focus group discussions, census and semi-structured interviews of households were used in gathering data during one year. Results reveal that rural people depend on various sources of livelihoods for food and income generation, but overall, the current contributions of vegetal NTFPs are insignificant compared to other activities. Odika (Irvingiagabonensis), atanga sauvage (Dacryodes buettneri), fungus (Termitomyces spp) and “nut” (Coula edulis) represent the main forest products that are commonly harvested by rural people, primarily for subsistence purposes while the surplus is sold. Although some efforts were made to promote the NTFP sector in the country, the results of this study suggest that: (1) the main components of the decree No.137/PR/MEFP of February 4, 2009, that prohibited the logging of five multiple use tree species over a period of 25 years should be reconsidered for revision; (2) the State authorities and partners should promote projects aiming at increasing the knowledge of the NTFP sector. These projects should contribute to the census of NTFP (for food, medicine and services), characterize their uses, the market chains of target products, and the development potential of NTFP. Such projects may help Gabon and other Congo Basin countries to fix norms/standards for a sustainable natural resource management and for enhancing their contribution to the national economy. This will be particularly relevant in the light of dwindling oil revenues and the need to diversify and promote other revenue sources in the country

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Long COVID and Health Inequities: The Role of Primary Care

An estimated 700,000 people in the United States have "long COVID," that is, symptoms of COVID-19 persisting beyond three weeks. COVID-19 and its long-term sequelae are strongly influenced by social determinants such as poverty and by structural inequalities such as racism and discrimination. Primary care providers are in a unique position to provide and coordinate care for vulnerable patients with long COVID. Policy measures should include strengthening primary care, optimizing data quality, and addressing the multiple nested domains of inequity

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Probing PAC1 receptor activation across species with an engineered sensor

Class-B1 G-protein-coupled receptors (GPCRs) are an important family of clinically relevant drug targets that remain difficult to investigate via high-throughput screening and in animal models. Here, we engineered PAClight1$_{P78A}$, a novel genetically encoded sensor based on a class-B1 GPCR (the human PAC1 receptor, hmPAC1R) endowed with high dynamic range (ΔF/F$_{0}$ = 1100%), excellent ligand selectivity, and rapid activation kinetics (τ$_{ON}$ = 1.15 s). To showcase the utility of this tool for in vitro applications, we thoroughly characterized and compared its expression, brightness and performance between PAClight1$_{P78A}$-transfected and stably expressing cells. Demonstrating its use in animal models, we show robust expression and fluorescence responses upon exogenous ligand application ex vivo and in vivo in mice, as well as in living zebrafish larvae. Thus, the new GPCR-based sensor can be used for a wide range of applications across the life sciences empowering both basic research and drug development efforts

“Community members have more impact on their neighbors than celebrities”: Leveraging community partnerships to build COVID-19 vaccine confidence

Vaccines are a strong public health tool to protect against severe disease, hospitalization, and death from COVID-19. Still, inequities in COVID-19 vaccination rates and health outcomes continue to exist among Black and Latino populations. Boston Medical Center (BMC) has played a significant role in vaccinating medically underserved populations, and organized a series of community-engaged conversations to better understand community concerns regarding the COVID-19 vaccine. We accessed and analyzed nine publicly available recordings of the community-engaged conversations which were held between Mar 2021-Sep 2021 (n=8-122 attendees). We employed a Consolidated Framework for Implementation Research-driven codebook to code our data and utilized a modified version of qualitative rapid analysis methods. Five main themes emerged: (1) Structural factors are important barriers to COVID-19 vaccination; (2) Mistrust exists due to the negative impact of systemic oppression and perceived motivation of the government; (3) There is a desire to learn more about biological and clinical characteristics of the COVID-19 vaccine as well as the practical implications of being vaccinated; (4) Community engagement is important for delivering COVID-19 information and education and; (5) Community leaders believe that the COVID-19 vaccine is a solution to address the pandemic. In highlighting the themes which resulted from these community-engaged conversations, this study illustrates a need for community-engaged COVID-19 vaccine messaging which reflects the nuances of the COVID-19 vaccine and pandemic without oversimplifying information and underscores important considerations for public health and healthcare leadership in the development of initiatives which work to advance health equity