Typhoid and Paratyphoid Cost of Illness in Pakistan: Patient and Health Facility Costs from the Surveillance for Enteric Fever in Asia Project II

Background: The objective of this study was to estimate the cost of illness from enteric fever (typhoid and paratyphoid) at selected sites in Pakistan. Methods: We implemented a cost-of-illness study in 4 hospitals as part of the Surveillance for Enteric Fever in Asia Project (SEAP) II in Pakistan. From the patient and caregiver perspective, we collected direct medical, nonmedical, and indirect costs per case of enteric fever incurred since illness onset by phone after enrollment and 6 weeks later. From the health care provider perspective, we collected data on quantities and prices of resources used at 3 of the hospitals, to estimate the direct medical economic costs to treat a case of enteric fever. We collected costs in Pakistani rupees and converted them into 2018 US dollars. We multiplied the unit cost per procedure by the frequency of procedures in the surveillance case cohort to calculate the average cost per case. Results: We collected patient and caregiver information for 1029 patients with blood culture-confirmed enteric fever or with a nontraumatic terminal ileal perforation, with a median cost of illness per case of US $196.37 (IQR, US$72.89-496.40). The median direct medical and nonmedical costs represented 8.2% of the annual labor income. From the health care provider perspective, the estimated average direct medical cost per case was US $50.88 at Hospital A, US$52.24 at Hospital B, and US $11.73 at Hospital C. Conclusions: Enteric fever can impose a considerable economic burden in Pakistan. These new estimates of the cost of illness of enteric fever can improve evaluation and modeling of the costs and benefits of enteric fever prevention and control measures, including typhoid conjugate vaccines

Evidence and Policy in Aid-Dependent Settings

This chapter examines how the political dynamics of aid relationships can affect the use of evidence within health policymaking. Empirical examples from Cambodia, Ethiopia and Ghana illustrate how relationships between national governments and donor agencies influence the ways in which evidence is generated, selected, or utilised to inform policymaking. We particularly consider how relationships with donors influence the underlying systems and processes of evidence use. We find a number of issues affecting which bodies or forms of evidence are taken to be policy relevant, including: levels of local technical capacity to utilise or synthesise evidence; differing stakeholder framing of issues; and the influence of non-state actors on sector-wide systems of agenda setting. The chapter also reflects on some of the key governance implications of these arrangements in which global actors promote forms of evidence use – often under a banner of technical efficiency – with limited consideration for local representation or accountability

The Use of Evidence in Health Policy in Ghana: Implications for Accountability and Democratic Governance

The use of evidence in policymaking is often argued to improve accountability, effectiveness, and stakeholder involvement in policy decisions. The features of this practice, however, remain vague in the discourse of evidence-based policymaking, with the risk of obscuring important governance and legitimacy implications. In programme planning and evaluation especially, the use of evidence can be critical to translate technical measurements of policy achievements into political values for shaping future policy directions. This chapter presents a case study from Ghana to discuss how institutionalized evidentiary practices used in policy review affect aspects of governance. Drawing on interviews, we reflect on how the evidence review process—agreed in collaboration with development partners—links to the evidence advisory system and the accountability systems in place. We find that the uses of evidence promoted by international donors actually creates disconnect with the national accountability system in place, with implications for democratic governance

Comparative analysis among the small RNA populations of source, sink and conductive tissues in two different plant-virus pathosystems

Conclusions: We compare for the first time the sRNA profile of four different tissues, including source, sink and conductive (phloem) tissues, in two plant-virus pathosystems. Our results indicate that antiviral silencing machinery in melon and cucumber acts mainly through DCL4. Upon infection, the total sRNA pattern in phloem remains unchanged in contrast to the rest of the analyzed tissues indicating a certain tissue-tropism to this polulation. Independently of the accumulation level of the vsRNAs both viruses were able to modulate the host sRNA pattern.We thank Dr A. Niehl for critical reading and helpful comments on the manuscript. This work was funded by a supporting program for the research from the Universidad Politecnica de Valencia (PAID-05-10), a grant BIO2011-25018 from the Spanish granting agency Direccion General de Investigacion Cientifica and the PROMETEO program 2011/003 from the Generalitat Valenciana. MCH is the recipient of a contract from JAE-DOC program of the CSIC, JAN is the recipient of a postdoctoral contract from the Ministerio de Educacion y Ciencia of Spain.Herranz Gordo, MDC.; Navarro Bohigues, JA.; Sommen, E.; Pallás Benet, V. (2015). Comparative analysis among the small RNA populations of source, sink and conductive tissues in two different plant-virus pathosystems. BMC Genomics. 16:1-15. https://doi.org/10.1186/s12864-015-1327-5S11516Pumplin N, Voinnet O. RNA silencing suppression by plant pathogens: defence, counter-defence and counter-counter-defence. Nat Rev Microbiol. 2013;11(11):745–60.Brodersen P, Voinnet O. The diversity of RNA silencing pathways in plants. Trends Genet. 2006;22(5):268–80.Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet. 2009;10(2):94–108.Ciaudo C, Jay F, Okamoto I, Chen CJ, Sarazin A, Servant N, et al. RNAi-dependent and independent control of LINE1 accumulation and mobility in mouse embryonic stem cells. PLoS Genet. 2013;9(11):e1003791.Ding SW, Voinnet O. Antiviral immunity directed by small RNAs. Cell. 2007;130(3):413–26.Szittya G, Moxon S, Pantaleo V, Toth G, Rusholme Pilcher RL, Moulton V, et al. Structural and functional analysis of viral siRNAs. PLoS Pathog. 2010;6(4):e1000838.Donaire L, Wang Y, Gonzalez-Ibeas D, Mayer KF, Aranda MA, Llave C. Deep-sequencing of plant viral small RNAs reveals effective and widespread targeting of viral genomes. Virology. 2009;392(2):203–14.Voinnet O. Origin, biogenesis, and activity of plant microRNAs. Cell. 2009;136(4):669–87.Liu Q, Feng Y, Zhu Z. Dicer-like (DCL) proteins in plants. Funct Integr Genomics. 2009;9(3):277–86.Henderson IR, Zhang X, Lu C, Johnson L, Meyers BC, Green PJ, et al. Dissecting Arabidopsis thaliana DICER function in small RNA processing, gene silencing and DNA methylation patterning. Nat Genet. 2006;38(6):721–5.Margis R, Fusaro AF, Smith NA, Curtin SJ, Watson JM, Finnegan EJ, et al. The evolution and diversification of Dicers in plants. FEBS Lett. 2006;580(10):2442–50.Deleris A, Gallego-Bartolome J, Bao J, Kasschau KD, Carrington JC, Voinnet O. Hierarchical action and inhibition of plant Dicer-like proteins in antiviral defense. Science. 2006;313(5783):68–71.Blevins T, Rajeswaran R, Shivaprasad PV, Beknazariants D, Si-Ammour A, Park HS, et al. Four plant Dicers mediate viral small RNA biogenesis and DNA virus induced silencing. Nucleic Acids Res. 2006;34(21):6233–46.Bouche N, Lauressergues D, Gasciolli V, Vaucheret H. An antagonistic function for Arabidopsis DCL2 in development and a new function for DCL4 in generating viral siRNAs. EMBO J. 2006;25(14):3347–56.Moissiard G, Voinnet O. RNA silencing of host transcripts by cauliflower mosaic virus requires coordinated action of the four Arabidopsis Dicer-like proteins. Proc Natl Acad Sci U S A. 2006;103(51):19593–8.Qu F, Ye X, Morris TJ. Arabidopsis DRB4, AGO1, AGO7, and RDR6 participate in a DCL4-initiated antiviral RNA silencing pathway negatively regulated by DCL1. Proc Natl Acad Sci U S A. 2008;105(38):14732–7.Vaucheret H. Plant ARGONAUTES. Trends Plant Sci. 2008;13(7):350–8.Hutvagner G, Simard MJ. Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol. 2008;9(1):22–32.Voinnet O. Use, tolerance and avoidance of amplified RNA silencing by plants. Trends Plant Sci. 2008;13(7):317–28.Palauqui JC, Elmayan T, Pollien JM, Vaucheret H. Systemic acquired silencing: transgene-specific post-transcriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions. EMBO J. 1997;16(15):4738–45.Yoo BC, Kragler F, Varkonyi-Gasic E, Haywood V, Archer-Evans S, Lee YM, et al. A systemic small RNA signaling system in plants. Plant Cell. 2004;16(8):1979–2000.Buhtz A, Pieritz J, Springer F, Kehr J. Phloem small RNAs, nutrient stress responses, and systemic mobility. BMC Plant Biol. 2010;10:64.Buhtz A, Springer F, Chappell L, Baulcombe DC, Kehr J. Identification and characterization of small RNAs from the phloem of Brassica napus. Plant J. 2008;53(5):739–49.Rodriguez-Medina C, Atkins CA, Mann AJ, Jordan ME, Smith PM. Macromolecular composition of phloem exudate from white lupin (Lupinus albus L.). BMC Plant Biol. 2011;11:36.Pallas V, Gomez G. Phloem RNA-binding proteins as potential components of the long-distance RNA transport system. Frontiers in Plant Science. 2013;4:130.Tournier B, Tabler M, Kalantidis K. Phloem flow strongly influences the systemic spread of silencing in GFP Nicotiana benthamiana plants. Plant J. 2006;47(3):383–94.Hamilton A, Voinnet O, Chappell L, Baulcombe D. Two classes of short interfering RNA in RNA silencing. EMBO J. 2002;21(17):4671–9.Voinnet O. MicroRNA and autophagy--C. elegans joins the crew. EMBO Rep. 2013;14(6):485–7.Dunoyer P, Schott G, Himber C, Meyer D, Takeda A, Carrington JC, et al. Small RNA duplexes function as mobile silencing signals between plant cells. Science. 2010;328(5980):912–6.Brosnan CA, Mitter N, Christie M, Smith NA, Waterhouse PM, Carroll BJ. Nuclear gene silencing directs reception of long-distance mRNA silencing in Arabidopsis. Proc Natl Acad Sci U S A. 2007;104(37):14741–6.Silva TF, Romanel EA, Andrade RR, Farinelli L, Osteras M, Deluen C, et al. Profile of small interfering RNAs from cotton plants infected with the polerovirus Cotton leafroll dwarf virus. BMC Mol Biol. 2011;12:40.Martinez G, Donaire L, Llave C, Pallas V, Gomez G. High-throughput sequencing of Hop stunt viroid-derived small RNAs from cucumber leaves and phloem. Mol Plant Pathol. 2010;11(3):347–59.Donaire L, Barajas D, Martinez-Garcia B, Martinez-Priego L, Pagan I, Llave C. Structural and genetic requirements for the biogenesis of tobacco rattle virus-derived small interfering RNAs. J Virol. 2008;82(11):5167–77.Qi X, Bao FS, Xie Z. Small RNA deep sequencing reveals role for Arabidopsis thaliana RNA-dependent RNA polymerases in viral siRNA biogenesis. PLoS One. 2009;4(3):e4971.Pantaleo V, Saldarelli P, Miozzi L, Giampetruzzi A, Gisel A, Moxon S, et al. Deep sequencing analysis of viral short RNAs from an infected Pinot Noir grapevine. Virology. 2010;408(1):49–56.Lin KY, Cheng CP, Chang BC, Wang WC, Huang YW, Lee YS, et al. Global analyses of small interfering RNAs derived from Bamboo mosaic virus and its associated satellite RNAs in different plants. PLoS One. 2010;5(8):e11928.Navarro B, Pantaleo V, Gisel A, Moxon S, Dalmay T, Bisztray G, et al. Deep sequencing of viroid-derived small RNAs from grapevine provides new insights on the role of RNA silencing in plant-viroid interaction. PLoS One. 2009;4(11):e7686.Martin R, Arenas C, Daros JA, Covarrubias A, Reyes JL, Chua NH. Characterization of small RNAs derived from Citrus exocortis viroid (CEVd) in infected tomato plants. Virology. 2007;367(1):135–46.St-Pierre P, Hassen IF, Thompson D, Perreault JP. Characterization of the siRNAs associated with peach latent mosaic viroid infection. Virology. 2009;383(2):178–82.Di Serio F, Gisel A, Navarro B, Delgado S, de Alba AE M, Donvito G, et al. Deep sequencing of the small RNAs derived from two symptomatic variants of a chloroplastic viroid: implications for their genesis and for pathogenesis. PLoS One. 2009;4(10):e7539.Li R, Gao S, Hernandez AG, Wechter WP, Fei Z, Ling KS. Deep sequencing of small RNAs in tomato for virus and viroid identification and strain differentiation. PLoS One. 2012;7(5):e37127.Hu Q, Hollunder J, Niehl A, Korner CJ, Gereige D, Windels D, et al. Specific impact of tobamovirus infection on the Arabidopsis small RNA profile. PLoS One. 2011;6(5):e19549.Hibi T, Furuki I. Melon Necrotic Spot Virus. In: CMI: AAB Descriptions of Plants Viruses N° 302. Kew, UK: Commonwealth Mycological Institute; 1985.Riviere CJ, Rochon DM. Nucleotide sequence and genomic organization of melon necrotic spot virus. J Gen Virol. 1990;71(Pt 9):1887–96.Diaz JA, Nieto C, Moriones E, Truniger V, Aranda MA. Molecular characterization of a Melon necrotic spot virus strain that overcomes the resistance in melon and nonhost plants. Mol Plant Microbe Interact. 2004;17(6):668–75.Navarro JA, Genoves A, Climent J, Sauri A, Martinez-Gil L, Mingarro I, et al. RNA-binding properties and membrane insertion of Melon necrotic spot virus (MNSV) double gene block movement proteins. Virology. 2006;356(1–2):57–67.Genoves A, Navarro JA, Pallas V. A self-interacting carmovirus movement protein plays a role in binding of viral RNA during the cell-to-cell movement and shows an actin cytoskeleton dependent location in cell periphery. Virology. 2009;395(1):133–42.Genoves A, Navarro JA, Pallas V. The Intra- and intercellular movement of Melon necrotic spot virus (MNSV) depends on an active secretory pathway. Mol Plant Microbe Interact. 2010;23(3):263–72.Serra-Soriano M, Pallas V, Navarro JA. A model for transport of a viral membrane protein through the early secretory pathway: minimal sequence and endoplasmic reticulum lateral mobility requirements. Plant J. 2014;77(6):863–79.Genoves A, Navarro JA, Pallas V. Functional analysis of the five melon necrotic spot virus genome-encoded proteins. J Gen Virol. 2006;87(Pt 8):2371–80.Pallas V, Aparicio F, Herranz MC, Amari K, Sanchez-Pina MA, Myrta A, et al. Ilarviruses of Prunus spp.: a continued concern for fruit trees. Phytopathology. 2012;102(12):1108–20.Pallas V, Aparicio F, Herranz MC, Sanchez-Navarro JA, Scott SW. The molecular biology of ilarviruses. Adv Virus Res. 2013;87:139–81.Varkonyi-Gasic E, Wu R, Wood M, Walton EF, Hellens RP. Protocol: a highly sensitive RT-PCR method for detection and quantification of microRNAs. Plant Methods. 2007;3:12.Blevins T, Rajeswaran R, Aregger M, Borah BK, Schepetilnikov M, Baerlocher L, et al. Massive production of small RNAs from a non-coding region of Cauliflower mosaic virus in plant defense and viral counter-defense. Nucleic Acids Res. 2011;39(12):5003–14.Takeda A, Tsukuda M, Mizumoto H, Okamoto K, Kaido M, Mise K, et al. A plant RNA virus suppresses RNA silencing through viral RNA replication. EMBO J. 2005;24(17):3147–57.Andersson MG, Haasnoot PC, Xu N, Berenjian S, Berkhout B, Akusjarvi G. Suppression of RNA interference by adenovirus virus-associated RNA. J Virol. 2005;79(15):9556–65.Himeno M, Maejima K, Komatsu K, Ozeki J, Hashimoto M, Kagiwada S, et al. Significantly low level of small RNA accumulation derived from an encapsidated mycovirus with dsRNA genome. Virology. 2010;396(1):69–75.Aparicio F, Vilar M, Perez-Paya E, Pallas V. The coat protein of prunus necrotic ringspot virus specifically binds to and regulates the conformation of its genomic RNA. Virology. 2003;313(1):213–23.Ruiz-Ruiz S, Navarro B, Gisel A, Pena L, Navarro L, Moreno P, et al. Citrus tristeza virus infection induces the accumulation of viral small RNAs (21-24-nt) mapping preferentially at the 3′-terminal region of the genomic RNA and affects the host small RNA profile. Plant Mol Biol. 2011;75(6):607–19.Folimonova SY, Folimonov AS, Tatineni S, Dawson WO. Citrus tristeza virus: survival at the edge of the movement continuum. J Virol. 2008;82(13):6546–56.Kreuze JF, Perez A, Untiveros M, Quispe D, Fuentes S, Barker I, et al. Complete viral genome sequence and discovery of novel viruses by deep sequencing of small RNAs: a generic method for diagnosis, discovery and sequencing of viruses. Virology. 2009;388(1):1–7.Karyeija RF, Kreuze JF, Gibson RW, Valkonen JP. Synergistic interactions of a potyvirus and a phloem-limited crinivirus in sweet potato plants. Virology. 2000;269(1):26–36.Melnyk CW, Molnar A, Bassett A, Baulcombe DC. Mobile 24 nt small RNAs direct transcriptional gene silencing in the root meristems of Arabidopsis thaliana. Curr Biol. 2011;21(19):1678–83.Gosalvez-Bernal B, Genoves A, Navarro JA, Pallas V, Sanchez-Pina MA. Distribution and pathway for phloem-dependent movement of Melon necrotic spot virus in melon plants. Mol Plant Pathol. 2008;9(4):447–61.Harper SJ, Cowell SJ, Robertson CJ, Dawson WO. Differential tropism in roots and shoots infected by Citrus tristeza virus. Virology. 2014;460–461:91–9.Andika IB, Kondo H, Tamada T. Evidence that RNA silencing-mediated resistance to beet necrotic yellow vein virus is less effective in roots than in leaves. Mol Plant Microbe Interact. 2005;18(3):194–204.Mi S, Cai T, Hu Y, Chen Y, Hodges E, Ni F, et al. Sorting of small RNAs into Arabidopsis argonaute complexes is directed by the 5' terminal nucleotide. Cell. 2008;133(1):116–27.Takeda A, Iwasaki S, Watanabe T, Utsumi M, Watanabe Y. The mechanism selecting the guide strand from small RNA duplexes is different among argonaute proteins. Plant Cell Physiol. 2008;49(4):493–500.Wu L, Zhang Q, Zhou H, Ni F, Wu X, Qi Y. Rice MicroRNA effector complexes and targets. Plant Cell. 2009;21(11):3421–35.Xu Y, Huang L, Fu S, Wu J, Zhou X. Population diversity of rice stripe virus-derived siRNAs in three different hosts and RNAi-based antiviral immunity in Laodelphgax striatellus. PLoS One. 2012;7(9):e46238

Leadership and governance of community health worker programmes at scale: a cross case analysis of provincial implementation in South Africa

BACKGROUND: National community health worker (CHW) programmes are returning to favour as an integral part of primary health care systems, often on the back of pre-existing community based initiatives. There are significant challenges to the integration and support of such programmes, and they require coordination and stewardship at all levels of the health system. This paper explores the leadership and governance tasks of large-scale CHW programmes at sub-national level, through the case of national reforms to South Africa’s community based sector, referred to as the Ward Based Outreach Team (WBOT) strategy. METHODS: A cross case analysis of leadership and governance roles, drawing on three case studies of adoption and implementation of the WBOTs strategy at provincial level (Western Cape, North West and Gauteng) was conducted. The primary case studies mapped system components and assessed implementation processes and contexts. They involved teams of researchers and over 200 interviews with stakeholders from senior to frontline, document reviews and analyses of routine data. The secondary, cross case analysis specifically focused on the issues and challenges facing, and strategies adopted by provincial and district policy makers and managers, as they engaged with the new national mandate. From this key sub-national leadership and governance roles were formulated. RESULTS: Four key roles are identified and discussed: 1. Negotiating a fit between national mandates and provincial and district histories and strategies of community based services 2. Defining new organisational and accountability relationships between CHWs, local health services, communities and NGOs 3. Revising and developing new aligned and integrated planning, human resource, financing and information systems 4. Leading change by building new collective visions, mobilising political, including budgetary, support and designing implementation strategies. CONCLUSION: This analysis, from real-life systems, adds to understanding of the processes involved in developing CHW programmes at scale, and specifically the negotiated and multilevel nature of leadership and governance in such programmes, spanning analytic, managerial, technical and political roles.IS

Integrating community health assistant- driven sexual and reproductive health services in the community health system in Nyimba district in Zambia: Mapping key actors, points of integration, and conditions shaping the process

Introduction: Although large scale public sector community health worker programs have been key in providing sexual and reproductive health (SRH) services in low- and middle-income countries, their integration process into community health systems is not well understood. This study aimed to identify the conditions and strategies through which Community Health Assistants (CHAs) gained entry and acceptability into community health systems to provide SRH services to youth in Zambia. The country’s CHA program was launched in 2010. Methodology: A phenomenological design was conducted in Nyimba district. All nine CHAs deployed in Nyimba district were interviewed in-depth on their experiences of navigating the introduction of SRH services for youth in community settings, and the data obtained analyzed thematically. Results: In delivering SRH services targeting youth, CHAs worked with a range of community actors, including other health workers, safe motherhood action groups, community health workers, neighborhood health committees, teachers, as well as political, traditional and religious leaders. CHAs delivered SRH education and services in health facilities, schools, police stations, home settings, and community spaces. They used their health facility service delivery role to gain trust and entry into the community, and they also worked to build relationships with other community level actors by holding regular joint meetings, and acting as brokers between the volunteer health workers and the Ministry of Health. CHAs used their existing social networks to deliver SRH services to adolescents. By embedding the provision of information about SRH into general life skills at community level, the topic’s sensitivity was reduced and its acceptability was enhanced. Further, support from community leaders towards CHA-driven services promoted the legitimacy of providing SRH for youth. Factors limiting the acceptability of CHA services included the taboo of discussing sexuality issues, a gender discriminatory environment, competition with other providers, and challenges in conducting household visits

Taking stock of 10 years of published research on the ASHA programme: Examining India’s national community health worker programme from a health systems perspective

Background: As India’s accredited social health activist (ASHA) community health worker (CHW) programme enters its second decade, we take stock of the research undertaken and whether it examines the health systems interfaces required to sustain the programme at scale. Methods: We systematically searched three databases for articles on ASHAs published between 2005 and 2016. Articles that met the inclusion criteria underwent analysis using an inductive CHW–health systems interface framework. Results: A total of 122 academic articles were identified (56 quantitative, 29 mixed methods, 28 qualitative, and 9 commentary or synthesis); 44 articles reported on special interventions and 78 on the routine ASHA program. Findings on special interventions were overwhelmingly positive, with few negative or mixed results. In contrast, 55% of articles on the routine ASHA programme showed mixed findings and 23% negative, with few indicating overall positive findings, reflecting broader system constraints. Over half the articles had a health system perspective, including almost all those on general ASHA work, but only a third of those with a health condition focus. The most extensively researched health systems topics were ASHA performance, training and capacity-building, with very little research done on programme financing and reporting, ASHA grievance redressal or peer communication. Research tended to be descriptive, with fewer influence, explanatory or exploratory articles, and no predictive or emancipatory studies. Indian institutions and authors led and partnered on most of the research, wrote all the critical commentaries, and published more studies with negative results. Conclusion: Published work on ASHAs highlights a range of small-scale innovations, but also showcases the challenges faced by a programme at massive scale, situated in the broader health system. As the programme continues to evolve, critical comparative research that constructively feeds back into programme reforms is needed, particularly related to governance, intersectoral linkages, ASHA solidarity, and community capacity to provide support and oversight