National Immunization Program Decision Making Using the CAPACITI Decision-Support Tool: User Feedback from Indonesia and Ethiopia.

To ensure that limited domestic resources are invested in the most effective interventions, immunization programs in low- and middle-income countries (LMICs) must prioritize a growing number of new vaccines while considering opportunities to optimize the vaccine portfolio, as well as other components of the health system. There is a strong impetus for immunization decision-making to engage and coordinate various stakeholders across the health system in prioritization. To address this, national immunization program decision-makers in LMICs collaborated with WHO to structure deliberation among stakeholders and document an evidence-based, context-specific, and transparent process for prioritization or selection among multiple vaccination products, services, or strategies. The output of this effort is the Country-led Assessment for Prioritization on Immunization (CAPACITI) decision-support tool, which supports using multiple criteria and stakeholder perspectives to evaluate trade-offs affecting health interventions, taking into account variable data quality. Here, we describe the user feedback from Indonesia and Ethiopia, two initial countries that piloted the CAPACITI decision-support tool, highlighting enabling and constraining factors. Potential immunization program benefits and lessons learned are also summarized for consideration in other settings.

Imaging ovarian cancer - from baseline characteristics to high-risk image factors.

BACKGROUND: Imaging ovarian cancer (OC) includes evaluating peritoneal carcinomatosis (PC) and enlarged cardio phrenic lymph nodes (CPLN) by computed tomography (CT), and thorough evaluation is tedious work. A "CT short score" with high-risk CT parameters might be a more pragmatic approach, but it is not known if such a short score associates with aggressive OC subtypes and impaired OC survival. Further, it is not known if certain established OC risk factors are linked to high-risk CT-findings which would be important in image evaluation. Herein, we investigate a CT short score and its relation to baseline characteristics, OC subtypes, and survival. METHODS: The Malmö Diet and Cancer Study is a prospective cohort that included 17,035 women (1991-1996). Baseline characteristics and tumor information on 159 OC and information on OC specific survival (last follow-up, 2017-12-31) was registered. A CT short score (CPLN and PC-index (PCI) in seven regions) was registered and associations with clinical stage [stage I vs. advanced stage (II-IV), histological type/grade (high grade serous and endometrioid vs. other subtypes], and OC-specific survival were analyzed with logistic and Cox regression, respectively. Parity and menopausal status were analyzed in relation to short score and PCI. RESULTS: There was an association between higher short score and advanced clinical stage (adjusted OR 2.76 (1.42-5.38)), adjusted for age at diagnosis and histological type/grade. Higher short score was associated with impaired OC specific survival (adjusted HR 1.17 (1.01-1.35)), adjusted for age at diagnosis, histological type/grade, and clinical stage. There were no significant associations between parity, menopausal status, and short score/PCI. CONCLUSIONS: CT short score was significantly associated with advanced clinical stages and impaired OC survival. A pragmatic approach (based on CT) to evaluate high risk image findings in OC could help reduce radiologists' workload and at the same time provide structured reports to surgeons and oncologists involved in OC care.

COVID-19 vaccine policy development in a sample of 44 countries - Key findings from a December 2021 survey of National Immunization Technical Advisory Groups (NITAGs).

National Immunization Technical Advisory Committees (NITAGs) are tasked with the responsibility of guiding ministries of health and national immunization programmes in their policy development processes. Many NITAGs rely on evidence reviewed by the World Health Organization's (WHO) Strategic Group of Experts(SAGE) on immunization and aim to adapt WHO's recommendations to their respective contexts. This relationship took on exceptional importance since the onset of the COVID-19 pandemic, during which NITAGs have expressed a notable struggle to craft appropriate policies on population prioritization and vaccine utilization in the face of supply constraints and complex programmatic and delivery logistics. This online survey was conducted to assess the usefulness of the SAGE guidance documents for COVID-19 vaccine policies and to examine the persisting needs and challenges facing NITAGs. Results confirmed that SAGE recommendations concerning COVID-19 vaccines are easy to access, understand, and adapt. They have been found to be comprehensive and timely under the data and time constrained circumstances confronting SAGE. The Global NITAG Network (GNN) appears to be the most popular vehicle for addressing questions among high income countries, in contrast to lower income countries who favour WHO Country or Regional Offices. NITAGs place much value on interaction with other NITAGs, which requires facilitation and could benefit from increased opportunities, especially within regions. It is further noted that some NITAGs have had to tackle issues during the pandemic not typically considered by SAGE, such as supply chain logistics and vaccine demand. Learning from the COVID-19 experience offers opportunities to strengthen NITAGs and the pandemic recovery effort through the development of more concrete procedures and consideration of more varied types of data, including implementation effectiveness and uptake data. There is also an opportunity for an increasing involvement of Country Office WHO personnel to support NITAGs, while ensuring information and evidence needs of countries are adequately reflected in SAGE deliberations.

Controlled temperature chain for vaccination in low- and middle-income countries: a realist evidence synthesis.

Objective: To evaluate the evidence describing how the controlled temperature chain approach for vaccination could lead to improved equitable immunization coverage in low- and middle-income countries. Methods: We created a theory of change construct from the Controlled temperature chain: strategic roadmap for priority vaccines 2017-2020, containing four domains: (i) uptake and demand for the approach; (ii) compliance and safe use of the approach; (iii) programmatic efficiency gains from the approach; and (iv) improved equitable immunization coverage. To verify and improve the theory of change, we applied a realist review method to analyse published descriptions of controlled temperature chain or closely related experiences. Findings: We evaluated 34 articles, describing 22 unique controlled temperature chain or closely related experiences across four World Health Organization regions. We identified a strong demand for this approach among service delivery providers; however, generating an equal level of demand among policy-makers requires greater evidence on economic benefits and on vaccination coverage gains, and use case definitions. Consistent evidence supported safety of the approach when integrated into special vaccination programmes. Feasible training and supervision supported providers in complying with protocols. Time-savings were the main evidence for efficiency gains, while cost-saving data were minimal. Improved equitable coverage was reported where vaccine storage beyond the cold chain enabled access to hard-to-reach populations. No evidence indicated an inferior vaccine effectiveness nor increased adverse event rates for vaccines delivered under the approach. Conclusion: Synthesized evidence broadly supported the initial theory of change. Addressing evidence gaps on economic benefits and coverage gains may increase future uptake.

An E-Textile Respiration Sensing System for NICU Monitoring: Design and Validation.

The world is witnessing a rising number of preterm infants who are at significant risk of medical conditions. These infants require continuous care in Neonatal Intensive Care Units (NICU). Medical parameters are continuously monitored in premature infants in the NICU using a set of wired, sticky electrodes attached to the body. Medical adhesives used on the electrodes can be harmful to the baby, causing skin injuries, discomfort, and irritation. In addition, respiration rate (RR) monitoring in the NICU faces challenges of accuracy and clinical quality because RR is extracted from electrocardiogram (ECG). This research paper presents a design and validation of a smart textile pressure sensor system that addresses the existing challenges of medical monitoring in NICU. We designed two e-textile, piezoresistive pressure sensors made of Velostat for noninvasive RR monitoring; one was hand-stitched on a mattress topper material, and the other was embroidered on a denim fabric using an industrial embroidery machine. We developed a data acquisition system for validation experiments conducted on a high-fidelity, programmable NICU baby mannequin. We designed a signal processing pipeline to convert raw time-series signals into parameters including RR, rise and fall time, and comparison metrics. The results of the experiments showed that the relative accuracies of hand-stitched sensors were 98.68 (top sensor) and 98.07 (bottom sensor), while the accuracies of embroidered sensors were 99.37 (left sensor) and 99.39 (right sensor) for the 60 BrPM test case. The presented prototype system shows promising results and demands more research on textile design, human factors, and human experimentation.

Textile Knitted Stretch Sensors for Wearable Health Monitoring: Design and Performance Evaluation.

The advancement of smart textiles has led to significant interest in developing wearable textile sensors (WTS) and offering new modalities to sense vital signs and activity monitoring in daily life settings. For this, textile fabrication methods such as knitting, weaving, embroidery, and braiding offer promising pathways toward unobtrusive and seamless sensing for WTS applications. Specifically, the knitted sensor has a unique intermeshing loop structure which is currently used to monitor repetitive body movements such as breathing (microscale motion) and walking (macroscale motion). However, the practical sensing application of knit structure demands a comprehensive study of knit structures as a sensor. In this work, we present a detailed performance evaluation of six knitted sensors and sensing variation caused by design, sensor size, stretching percentages % (10, 15, 20, 25), cyclic stretching (1000), and external factors such as sweat (salt-fog test). We also present regulated respiration (inhale-exhale) testing data from 15 healthy human participants; the testing protocol includes three respiration rates; slow (10 breaths/min), normal (15 breaths/min), and fast (30 breaths/min). The test carried out with statistical analysis includes the breathing time and breathing rate variability. These testing results offer an empirically derived guideline for future WTS research, present aggregated information to understand the sensor behavior when it experiences a different range of motion, and highlight the constraints of the silver-based conductive yarn when exposed to the real environment.

Strategies for vaccine-product innovation: Creating an enabling environment for product development to uptake in low- and middle-income countries.

Vaccine-product innovations that address barriers to immunization are urgently needed to achieve equitable vaccine coverage, as articulated in the new Immunization Agenda 2030 and the Gavi 5.0 strategy. In 2020, the Vaccine Innovation Prioritisation Strategy (VIPS) prioritized three innovations, namely microarray patches (MAPs), heat-stable and controlled-temperature chain (CTC) enabled liquid vaccine formulations and barcodes on primary packaging. These innovations were prioritized based on the priority immunization barriers that they may help overcome in resource constrained contexts, as well as by considering their potential impact on health, coverage and equity, safety, economic costs and their technical readiness and commercial feasibility. VIPS is now working to accelerate the development and lay the foundation for future uptake of the three priority vaccine-product innovations, with the long term-goal to ensure equitable vaccine coverage and increased impact of vaccines in low- and middle- income countries. To inform our strategic planning, we analyzed four commercially available vaccine product-innovations and conducted interviews with individuals from 17 immunization organizations, and/or independent immunization experts. The findings are synthesized into an 'innovation conundrum' that describes the challenges encountered in developing vaccine-product innovations and a vaccine-product innovation 'theory of change', which highlights actions that should be undertaken in parallel to product development to incentivize sustainable investment and prepare the pathway for uptake and impact.

Vaccine innovation prioritisation strategy: Findings from three country-stakeholder consultations on vaccine product innovations.

As part of the Vaccine Innovation Prioritisation Strategy (VIPS), three immunization-stakeholder consultations were conducted between September 2018 and February 2020 to ensure that countries' needs drove the prioritization of vaccine product innovations. All consultations targeted respondents with immunization program experience. They included: (1) an online survey to identify immunization implementation barriers and desired vaccine attributes in three use settings, (2) an online survey to identify and evaluate the most important immunization challenges for ten exemplar vaccines, and (3) in-depth interviews to better understand the perceived programmatic benefits and challenges that could be addressed by nine innovations and to rank the innovations that could best address current challenges. The first consultation included responses from 442 participants in 61 countries, representing 89% of the 496 respondents who correctly completed at least one section of the online survey. For facility-based settings, missed opportunities for vaccination due to reluctance to open multidose vaccine vials was the barrier most frequently selected by respondents. In community-based (outreach) and campaign settings, limited access to immunization services due to geographic barriers was most frequently selected. Multidose presentations with preservative or single-dose presentations were most frequently selected as desired vaccine attributes for facility-based settings while improved thermostability was most frequently selected for outreach and campaign settings. The second online survey was completed by 220 respondents in 54 countries. For the exemplar vaccines, vaccine ineffectiveness or wastage due to heat or freeze exposure and missed opportunities due to multidose vial presentations were identified as the greatest vaccine-specific challenges. In-depth interviews with 84 respondents in six countries ranked microarray patches, dual-chamber delivery devices, and heat-stable/controlled temperature chain qualified liquid vaccines as the three innovations that could have the greatest impact in helping address current immunization program challenges. These findings informed the VIPS prioritization and provided broader application to designing immunization interventions to better meet country needs.

The CAPACITI Decision-Support Tool for National Immunization Programs.

OBJECTIVES: Immunization programs in low-income and middle-income countries (LMICs) are faced with an ever-growing number of vaccines of public health importance recommended by the World Health Organization, while also financing a greater proportion of the program through domestic resources. More than ever, national immunization programs must be equipped to contextualize global guidance and make choices that are best suited to their setting. The CAPACITI decision-support tool has been developed in collaboration with national immunization program decision makers in LMICs to structure and document an evidence-based, context-specific process for prioritizing or selecting among multiple vaccination products, services, or strategies. METHODS: The CAPACITI decision-support tool is based on multi-criteria decision analysis, as a structured way to incorporate multiple sources of evidence and stakeholder perspectives. The tool has been developed iteratively in consultation with 12 countries across Africa, Asia, and the Americas. RESULTS: The tool is flexible to existing country processes and can follow any type of multi-criteria decision analysis or a hybrid approach. It is structured into 5 sections: decision question, criteria for decision making, evidence assessment, appraisal, and recommendation. The Excel-based tool guides the user through the steps and document discussions in a transparent manner, with an emphasis on stakeholder engagement and country ownership. CONCLUSIONS: Pilot countries valued the CAPACITI decision-support tool as a means to consider multiple criteria and stakeholder perspectives and to evaluate trade-offs and the impact of data quality. With use, it is expected that LMICs will tailor steps to their context and streamline the tool for decision making.

Digital electronics in fibres enable fabric-based machine-learning inference.

Digital devices are the essential building blocks of any modern electronic system. Fibres containing digital devices could enable fabrics with digital system capabilities for applications in physiological monitoring, human-computer interfaces, and on-body machine-learning. Here, a scalable preform-to-fibre approach is used to produce tens of metres of flexible fibre containing hundreds of interspersed, digital temperature sensors and memory devices with a memory density of ~7.6 × 105 bits per metre. The entire ensemble of devices are individually addressable and independently operated through a single connection at the fibre edge, overcoming the perennial single-fibre single-device limitation and increasing system reliability. The digital fibre, when incorporated within a shirt, collects and stores body temperature data over multiple days, and enables real-time inference of wearer activity with an accuracy of 96% through a trained neural network with 1650 neuronal connections stored within the fibre. The ability to realise digital devices within a fibre strand which can not only measure and store physiological parameters, but also harbour the neural networks required to infer sensory data, presents intriguing opportunities for worn fabrics that sense, memorise, learn, and infer situational context.

How can we evaluate the potential of innovative vaccine products and technologies in resource constrained settings? A total systems effectiveness (TSE) approach to decision-making.

Innovations in vaccine product attributes could play an important role in addressing coverage and equity (C&E) gaps, but there is currently a poor understanding of the full system impact and trade-offs associated with investing in such technologies, both from the perspective of national immunisation programmes (NIPs) and vaccine developers. Total Systems Effectiveness (TSE) was developed as an approach to evaluate vaccines with different product attributes from a systems perspective, in order to analyse and compare the value of innovative vaccine products in different settings. The TSE approach has been advanced over the years by various stakeholders including the Bill and Melinda Gates Foundation (BMGF), Gavi, PATH, UNICEF and WHO. WHO further developed the TSE approach to incorporate the country perspective into immunisation decision-making, in order for countries to evaluate innovative products for introduction and product switch decisions, and for vaccine development stakeholders to conduct their assessments of product value in line with country preferences. This paper describes the original TSE approach, development of the tool and processes for NIPs to apply the WHO TSE approach, and results from piloting in 12 countries across Africa, Asia and the Americas. The WHO TSE framework emerged from this piloting effort. The WHO TSE approach has been welcomed by NIP and vaccine development stakeholders as a useful tool to evaluate trade-offs between different products. It was emphasised that the concept of "total systems effectiveness" is likely to be context-specific and that TSE is valuable in facilitating a deliberative process to articulate NIP priorities, for decisions around product choice, and for prioritising the development of future vaccine innovations.

Ovarian cancer subtypes and survival in relation to three comprehensive imaging parameters.

BACKGROUND: Ovarian cancer (OC) is usually detected in late clinical stages, and imaging at diagnosis is crucial. Peritoneal carcinomatosis (PC) and cardio phrenic lymph nodes (CPLN) are pathological findings of computed tomography (CT) and are relevant for surgical planning. Furthermore, mammographic breast density (BD) has shown an association with OC risk and might be prognostically relevant. However, it is not known if PC, CPLN, and BD are associated with aggressive OC subtypes and impaired OC survival. Herein, we investigated associations between three comprehensive image parameters and OC subtypes and survival. METHODS: The Malmö Diet and Cancer Study is a prospective study that included 17,035 women (1991-1996). Tumor information on 159 OC and information on OC specific survival (last follow-up, 2017-12-31) was registered. The CT and mammography closest to diagnosis were evaluated (Peritoneal Carcinomatosis Index PCI, CPLN, and BD). Associations between CT-PCI, CPLN, and BD vs. clinical stage [stage I vs. advanced stage (II-IV), histological type/grade (high grade serous and endometrioid vs. other subtypes], and OC-specific survival were analyzed by logistic and Cox regression. RESULTS: There was a significant association between higher CT-PCI score and advanced clinical stage (adjusted OR 1.26 (1.07-1.49)), adjusted for age at diagnosis and histological type/grade. Increasing CT-PCI was significantly associated with impaired OC specific survival (adjusted HR 1.04 (1.01-1.07)), adjusted for age at diagnosis, histological type/grade, and clinical stage. There was no significant association between PCI and histological type/grade, nor between BD or CPLN vs. the studied outcomes. CONCLUSIONS: Image PCI score was significantly associated with advanced clinical stages and impaired OC survival. An objective approach (based on imaging) to scoring peritoneal carcinomatosis in ovarian cancer could help surgeons and oncologists to optimize surgical planning, treatment, and care.

Brain Volumes and Developmental Outcome in Childhood Following Fetal Growth Restriction Leading to Very Preterm Birth.

Background: Children born very preterm (PT) after fetal growth restriction (FGR) exhibit cognitive impairment at early school age. The relationship between neurodevelopmental impairment and attained regional brain volumes is unknown. Methods: We studied 23 preterm children with FGR (PT-FGR), 24 matched preterm children AGA (PT-AGA), and 27 matched term AGA children (T-AGA) by measuring brain volumes with magnetic resonance imaging at early school age. Cognitive and motor functions were assessed by the Wechsler Intelligence Scales for Children and the ABC-Movement score. Results: The mean (SD) full-scale IQ was 80 (17) in the PT-FGR group and 103 (12) in the PT-AGA group (p < 0.001). The PT-FGR group had lower mean total, gray matter, white matter, thalamic, cerebellar white matter, and hippocampal volumes as compared to the T-AGA group (p = 0.01, 0.04, 0.003, 0.002, 0.001, and 0.009, respectively). Brain volumes did not differ significantly between the PT groups. Reduction of hippocampal volume correlated with degree of growth restriction at birth (r = 0.46, p = 0.05). Neither the full-scale IQ nor the ABC movement score <5th percentile were related to brain volumes. Conclusion: Brain volumes as determined by MRI at early school age were primarily associated with degree of prematurity at birth and less with FGR. Regional brain volumes did not discriminate cognitive and motor function beyond that predicted by gestational age at birth.

Countries' interest in a hepatitis B vaccine licensed for the controlled temperature chain; survey results from African and Western Pacific regions.

Chronic hepatitis B infection can be prevented by hepatitis B vaccine birth dose (hepB-BD) given within 24 h after birth, followed by two hepatitis B vaccinations within the first year of life. Yet nearly half of World Health Organization (WHO) Member States do not provide a hepB-BD. Barriers are primarily attributed to vaccine storage and transportation, as well as high rates of home births. Delivering the vaccine outside the cold chain could potentially increase coverage. To do this, WHO recommends vaccines be licensed for use in a "controlled temperature chain" (CTC), which requires a given product to tolerate temperature excursions up to at least 40 °C for a minimum of three days. To date, no hepB vaccine is labelled for CTC. To inform dialogue with manufacturers, WHO conducted a survey among countries in the African and Western Pacific Regions (AFR and WPR) to assess demand for a hepatitis B product licensed for use in a CTC. Twenty-five (44%) countries responded, with 8 of 11 (73%) from the WPR and 17 of 46 (37%) from the AFR. Of these responding countries, 5 in AFR and all 8 in WPR have introduced universal hepB-BD. Seventy-two percent indicated that CTC would facilitate the provision of hepB-BD. While no overall difference in responses was detected between countries either providing or not providing hepB-BD, countries that already introduced hepB-BD but had low hepB-BD coverage were particularly interested in CTC. Irrespective of hepB-BD policy, responding countries suggested that a CTC-licenced product would be beneficial, though the price of such a vaccine would influence procurement decisions. This survey was beneficial to inform the CTC agenda. However, countries' lack of experience with HepB-BD as well as with CTC and the fact that countries were commenting on a product that is not yet on the market should be acknowledged.

[Impact of Controlled Temperature Chain (CTC) approach on immunization coverage achieved during the preventive vaccination campaign against meningitis A using MenAfriVac in Togo in 2014]. / L'utilisation de l'approche CTC: quel impact sur la couverture vaccinale lors de la campagne préventive de vaccination contre la méningite A avec le MenAfriVac au Togo en 2014?

METHOD: We conducted a survey from 9 to 14 March 2015 (for approximately 3 months) after the end of the vaccination campaign in these four regions. Interviewees were selected using two stages cluster sampling stratified according to the regions. MenAfriVac vaccine in Controlled Temperature Chain (CTC) was used in 10 districts, in Togo. RESULTS: A total of 2707 households were surveyed and 9082 people aged 1-29 years were interviewed. The average age of the individuals surveyed was 11.8±7.7 years and sex-ratio (H/F) was 1.01. The average number of individuals per household was 5.7 and that of persons aged 1-29 years targeted in the campaign was 3.4. Out of 9082 people surveyed 8889 (98%) were vaccinated. Multivariate analysis showed that the factors associated with immunization coverage using MenAfrivac vaccine were: habitual residence in the area at the time of the campaign (AOR = 4.52; 95%CI = [4.07 - 4.97]) and level of information about the campaign before it starts (AOR=2.42; 95%CI = [2.05 - 2.80]). By contrast, there were no differences in vaccination coverage between the areas based on whether the CTC approach was used or not (AOR=0.09; 95%CI = [-0.27 - 0.45]). Two hundred and seven respondents (2.3%) reported that they had Adverse Event Following Immunisation (AEFI) after the administration of the vaccine. These were usually minor AEFI involving fever, abscesses and swelling at the injection site. CONCLUSION: Survey results show that the use of CTC in a country with limited resources such as Togo doesn't have a negative impact on immunization coverage. Indeed, there was no difference between immunization coverage in CTC and non-CTC areas. It is important to capitalize on the experience gained in order to use vaccines by Expanded Program of Immunization in CTC approach especially in countries with limited resources in terms of cold chain availability.

Challenges of vaccine presentation and delivery: How can we design vaccines to have optimal programmatic impact?

Immunization program delivery strategies that enable high vaccine coverage, particularly in inaccessible and remote areas, are critical to achieving optimal vaccine impact. In addition to demonstration of safety and efficacy, there are many factors that influence whether a newly licensed vaccine will be introduced into a country's national immunization program, particularly in resource-constrained environments. This paper describes three case studies of novel approaches that represent the potential for improved programmatic impact by increasing vaccine accessibility in different ways. However, the pathway to regulatory approval, policy recommendation, and program introduction in low- and middle-income countries is complex, requiring engagement with multiple, diverse stakeholders. Consideration of aspects that affect uptake in low- and middle-income countries, during the product development stage, will help better position new or second-generation vaccine products for successful implementation to achieve public health impact.