Acting on the call for cervical cancer elimination: Planning tools for low- and middle- income countries to increase the coverage and effectiveness of screening and treatment.

INTRODUCTION: Accessible planning tools tailored for low-and middle-income countries can assist decision makers in comparing implementation of different cervical cancer screening approaches and treatment delivery scenarios in settings with high cervical cancer burden. METHODS: The Cervical Precancer Planning Tool (CPPT) was developed by PATH for users to explore and compare the accuracy of screening approaches, what treatment equipment to procure, and how best to deploy treatment equipment in a given country. The CPPT compares four screening approaches: 1) visual inspection with acetic acid (VIA), 2) HPV testing, 3) HPV testing followed by a VIA triage, and 4) HPV testing followed by an enhanced triage test. Accuracy of screening outcomes (e.g., true positives, false positives) is based on published sensitivity and specificity of tests to detect cervical precancerous lesions. The CPPT compares five scenarios for deploying ablative treatment equipment: 1) cervical precancer equipment at every location a woman is screened (single visit approach), 2) equipment only at a hospital level, 3) a single unit of equipment in each district, 4) allowing two districts to share a single unit of equipment, and 5) equipment placed at select district hospitals paired with mobile outreach. Users can customize the CPPT by adjusting pre-populated baseline values and assumptions, including population estimates, screening age range, screening frequency, HPV and HIV prevalence, supply costs, and health facility details. RESULTS: The CPPT generates data tables and graphs that compare the results of implementing each of the four screening and five treatment scenarios disaggregated by HIV status. Outputs include the number and outcomes of women screened, cost of each screening approach, provider time and cost saved by implementing self-sampling for HPV testing, number of women treated, treatment equipment needed by type, and the financial and economic costs for each equipment deployment scenario. CONCLUSION: The CPPT provides practical information and data to compare tradeoffs of patient access and screening accuracy as well as efficient utilization of equipment, skilled personnel, and financial resources. Country decision makers can use outputs from the CPPT to guide the scale-up of cervical cancer screening and treatment while optimizing limited resources.

Syringes must be prioritized globally to ensure equitable access to COVID-19 and other essential vaccines and to sustain safe injection practices.

Supply of autodisable (AD) syringes has been a key component of global COVID-19 vaccination campaigns, and it is critical to maintaining safe injection practices for routine immunization as well as pandemic response. AD syringe production increased significantly in response to demand, but distribution challenges have included the need to coordinate syringes to meet the specific delivery requirements of various COVID-19 vaccines, shipping bottlenecks, and syringe export restrictions. Stockpiling syringes, ensuring standardization of future vaccine dose volumes, and geographical diversification of syringe production would improve syringe logistics in the future. Balancing syringe supply and demand and stabilizing the market over the long term is essential to ensure that the world is prepared for possible new variants of COVID-19 or a new global outbreak. This will require concerted action on the part of public, nonprofit, and private partners.

Estimation of health impact from digitalizing last-mile Logistics Management Information Systems (LMIS) in Ethiopia, Tanzania, and Mozambique: A Lives Saved Tool (LiST) model analysis.

BACKGROUND: Digital health has become a widely recognized approach to addressing a range of health needs, including advancing universal health coverage and achieving the Sustainable Development Goals. At present there is limited evidence on the impact of digital interventions on health outcomes. A growing body of peer-reviewed evidence on digitalizing last-mile electronic logistics management information systems (LMIS) presents an opportunity to estimate health impact. METHODS: The impact of LMIS on reductions in stockouts was estimated from primary data and peer-reviewed literature, with three scenarios of impact: 5% stockout reduction (conservative), 10% stockout reduction (base), and 15% stockout reduction (optimistic). Stockout reduction data was inverted to stock availability and improved coverage for vaccines and essential medicines using a 1:1 conversion factor. The Lives Saved Tool (LiST) model was used to estimate health impact from lives saved in newborns and children in Mozambique, Tanzania, and Ethiopia between 2022 and 2026 across the three scenarios. RESULTS: Improving coverage of vaccines with a digital LMIS intervention in the base scenario (conservative, optimistic) could prevent 4,924 (2,578-6,094), 3,998 (1,621-4,915), and 17,648 (12,656-22,776) deaths in Mozambique, Tanzania, and Ethiopia, respectively over the forecast timeframe. In addition, scaling up coverage of non-vaccine medications could prevent 17,044 (8,561-25,392), 21,772 (10,976-32,401), and 34,981 (17,543-52,194) deaths in Mozambique, Tanzania, and Ethiopia, respectively. In the base model scenario, the maximum percent reduction in deaths across all geographies was 1.6% for vaccines and 4.1% for non-vaccine medications. INTERPRETATION: This study projects that digitalization of last-mile LMIS would reduce child mortality by improving coverage of lifesaving health commodities. This analysis helps to build the evidence base around the benefits of deploying digital solutions to address health challenges. Findings should be interpreted carefully as stockout reduction estimates are derived from a small number of studies.

Formative research to inform development of a new diagnostic for soil-transmitted helminths: Going beyond the laboratory to ensure access to a needed product.

Soil-transmitted helminths (STHs) affect more than 1.5 billion people. The global strategy to control STH infections requires periodic mass drug administration (MDA) based on prevalence among populations at risk determined by diagnostic testing. Widely used copromicroscopy methods to detect infection, however, have low sensitivity as the prevalence and intensity of STH infections decline with repeated MDA. More sensitive diagnostic tools are needed to inform program decision-making. Using an integrated product development process, PATH conducted qualitative and quantitative formative research to inform the design and development of a more sensitive test for STH infections. The research, grounded in a conceptual framework for ensuring access to health products, involved stakeholder analysis, key opinion leader interviews, observational site visits of ongoing STH surveillance programs, and market research including market sizing, costing and willingness-to-pay analyses. Stakeholder analysis identified key groups and proposed strategic engagement of stakeholders during product development. Interviews highlighted features, motivations and concerns that are important for guiding design and implementation of new STH diagnostics. Process mapping outlined current STH surveillance workflows in Kenya and the Philippines. Market sizing in 2016 was estimated around half a million tests for lower STH burden countries, and 1-2 million tests for higher STH burden countries. The cost of commodities per patient for a molecular STH diagnostic may be around $10, 3-4 times higher than copromicroscopy methods, though savings may be possible in time and staffing requirements. The market is highly price sensitive as even at $5 per test, only 27% of respondents thought the test would be used by surveillance programs. A largely subsidized STH control strategy and a semi-functional Kato-Katz test may have created few incentives for manufacturers to innovate in STH diagnostics. Diverse partnerships, as well as balancing needs and expectations for new STH diagnostics are necessary to ensure access to needed products.

A low-cost uterine balloon tamponade for management of postpartum hemorrhage: modeling the potential impact on maternal mortality and morbidity in sub-Saharan Africa.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal deaths worldwide. This study sought to quantify the potential health impact (morbidity and mortality reductions) that a low-cost uterine balloon tamponade (UBT) could have on women suffering from uncontrolled PPH due to uterine atony in sub-Saharan Africa. METHODS: The Maternal and Neonatal Directed Assessment of Technology (MANDATE) model was used to estimate maternal deaths, surgeries averted, and cases of severe anemia prevented through UBT use among women with PPH who receive a uterotonic drug but fail this therapy in a health facility. Estimates were generated for the year 2018. The main outcome measures were lives saved, surgeries averted, and severe anemia prevented. RESULTS: The base case model estimated that widespread use of a low-cost UBT in clinics and hospitals could save 6547 lives (an 11% reduction in maternal deaths), avert 10,823 surgeries, and prevent 634 severe anemia cases in sub-Saharan Africa annually. CONCLUSIONS: A low-cost UBT has a strong potential to save lives and reduce morbidity. It can also potentially reduce costly downstream interventions for women who give birth in a health care facility. This technology may be especially useful for meeting global targets for reducing maternal mortality as identified in Sustainable Development Goal 3.

Modeling the potential impact of emerging innovations on achievement of Sustainable Development Goals related to maternal, newborn, and child health.

BACKGROUND: Innovations that improve the affordability, accessibility, or effectiveness of health care played a major role in the Millennium Development Goal achievements and will be critical for reaching the ambitious new Sustainable Development Goal (SDG) health targets. Mechanisms to identify and prioritize innovations are essential to inform future investment decisions. METHODS: Innovation Countdown 2030 crowdsourced health innovations from around the world and engaged recognized experts to systematically assess their lifesaving potential by 2030. A health impact modeling approach was developed and used to quantify the costs and lives saved for select innovations identified as having great promise for improving maternal, newborn, and child health. RESULTS: Preventive innovations targeting health conditions with a high mortality burden had the greatest impact in regard to the absolute number of estimated lives saved. The largest projected health impact was for a new tool for small-scale water treatment that automatically chlorinates water to a safe concentration without using electricity or moving parts. An estimated 1.5 million deaths from diarrheal disease among children under five could be prevented by 2030 by scaling up use of this technology. Use of chlorhexidine for umbilical cord care was associated with the second highest number of lives saved. CONCLUSIONS: The results show why a systematic modeling approach that can compare and contrast investment opportunities is important for prioritizing global health innovations. Rigorous impact estimates are needed to allocate limited resources toward the innovations with great potential to advance the SDGs.

Cost-effectiveness of condom uterine balloon tamponade to control severe postpartum hemorrhage in Kenya.

OBJECTIVE: To evaluate the cost-effectiveness of condom uterine balloon tamponade (UBT) for control of severe postpartum hemorrhage (PPH) due to uterine atony versus standard PPH care in Kenya. METHODS: A cross-sectional analysis was conducted using cost data collected from 30 facilities in Western Kenya from April 15 to July 16, 2015. Effectiveness data were derived from the published literature. The modeling analysis was performed from the health-system perspective for a cohort of women who gave birth in 2015. Sensitivity analyses tested the robustness of model estimates. Costs were in 2015 US dollars. RESULTS: Compared with standard care with no uterine packing, condom UBT could prevent 1255 hospital transfers, 430 hysterectomies, and 44 maternal deaths. At $5 or $15 per UBT device, the incremental cost per disability-adjusted life year (DALY) averted was $26 or $40, respectively. If uterine packing was assumed to be done with standard care, the cost per DALY averted was $164 when the UBT price was $5 and $199 when the price was $15. CONCLUSION: Condom UBT was a highly cost-effective intervention for controlling severe PPH. This finding remained robust even when key model inputs were varied by wide margins.

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings.

In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS). The importance of quantifying maternal and perinatal risks and identifying which pregnancies can be safely prolonged is also much greater in LRS, where intensive care facilities that can rapidly respond to PE-related health threats for women and infants are limited. For these reasons, simple, low cost, sensitive, and specific point-of-care (POC) tests are needed that can be performed by antenatal health care providers in LRS and that can facilitate decisions about detection and management of PE. Our study aims to provide a comprehensive systematic review of current and emerging blood and urine biomarkers for PE, not only on the basis of their clinical performance, but also of their suitability to be used in LRS-compatible test formats, such as lateral flow and other variants of POC rapid assays.

Prioritizing investments in innovations to protect women from the leading causes of maternal death.

PATH, an international nonprofit organization, assessed nearly 40 technologies for their potential to reduce maternal mortality from postpartum hemorrhage and preeclampsia and eclampsia in low-resource settings. The evaluation used a new Excel-based prioritization tool covering 22 criteria developed by PATH, the Maternal and Neonatal Directed Assessment of Technology (MANDATE) model, and consultations with experts. It identified five innovations with especially high potential: technologies to improve use of oxytocin, a uterine balloon tamponade, simplified dosing of magnesium sulfate, an improved proteinuria test, and better blood pressure measurement devices. Investments are needed to realize the potential of these technologies to reduce mortality.

High affinity binding of Dab1 to Reelin receptors promotes normal positioning of upper layer cortical plate neurons.

The positions of neurons in the neocortex, hippocampus, cerebellum and various other laminated brain regions are regulated by a signaling pathway initiated by the secreted protein Reelin and requiring the intracellular adaptor protein Dab1. Dab1 and the Reelin receptors VLDLR and ApoER2 are expressed by neurons whose migrations are coordinated by Reelin. In vitro, Dab1 binds with high affinity to the cytoplasmic tails of VLDLR and ApoER2 via its PTB domain. To test the importance of Dab1 binding to VLDLR and ApoER2, we replaced the Dab1 gene with a cDNA cassette encoding a point mutant allele, Dab1(F158V). This mutation strongly decreases Dab1 binding in vitro to peptides containing the ApoER2 or VLDLR cytoplasmic regions. Surprisingly, Dab1(F158V/F158V) homozygotes have no discernable phenotype. However, Dab1(F158V/-) hemizygous animals have a subtle phenotype in which late-generated cortical plate neurons migrate excessively into the marginal zone. Early cortical plate neurons, subplate neurons, hippocampal pyramidal cells and cerebellar Purkinje cells are positioned normally. Thus Dab(F158V) is a weak loss-of-function (hypomorphic) allele that has no detectable effect when homozygous. The phenotype of Dab1(F158V/-) hemizygotes shows that late cortical plate neurons of layers 2-3 require efficient Reelin-Dab1 signaling to prevent them entering the marginal zone. The Dab1(F158V) allele adds to a series of Dab1 alleles that demonstrates cell type-specific variation in the Reelin-Dab1 pathway.

A hypomorphic allele of dab1 reveals regional differences in reelin-Dab1 signaling during brain development.

The disabled 1 (Dab1) p80 protein is essential for reelin signaling during brain development. p80 has an N-terminal domain for association with reelin receptors, followed by reelin-dependent tyrosine phosphorylation sites and about 310 C-terminal residues of unknown function. We have generated mutant mice that express only a natural splice form of Dab1, p45, that lacks the C-terminal region of p80. The normal development of these mice implies that the receptor-binding region and tyrosine phosphorylation sites of p80 are sufficient for reelin signaling. However, a single copy of the truncated gene does not support normal development of the neocortex and hippocampus. The CA1 region of the hippocampus is split into two well-organized layers, while the marginal zone of the neocortex is invaded by late-born cortical plate neurons. The haploinsufficiency of the p45 allele of Dab1 implies that the C terminus of p80 affects the strength of reelin-Dab1 signaling, yet there is no apparent change in reelin-dependent tyrosine phosphorylation of p45 relative to p80. Therefore, we suggest that the C-terminal region of Dab1 p80 is involved in signaling to downstream effector molecules. Furthermore, the presence of late-born cortical plate neurons in the marginal zone reveals a requirement for reelin-Dab1 signaling in late-born cortical plate neurons, and helps distinguish models for the cortical inversion in the reeler mutant mouse.