The netrin protein family

The netrins are a family of extracellular proteins that direct cell and axon migration during embryogenesis

Mechanisms goevrning netri-1 induced changes in oligodendroglial morphology during central nervous system devlopment and dysfunction

Netrin-l is a bifunctional guidance cue that attracts or repels cell of the developing nervous system. Recent work has shown that netrin-l plays important roles in the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS). In the embryonic spinal cord, netrin-l repels dorsally migrating oligodendrocyte precursor cells (OPCs) by inducing a decrease in process extension. In the adult, netrin-l is expressed by mature, myelinating oligodendrocytes and is required for the maintenance ofaxo-oligodendroglial paranodal junctions. This thesis examines a role for netrin-l in oligodendrocyte maturation and during the demyelinating disorder Multiple Sclerosis (MS). I present data demonstrating that netrin-l, acting through its receptor Deleted in Colorectal Carcinoma (DCC), promotes extension and branching of oligodendrocyte processes, and induces the tonnation of myelin-like membrane sheets. These events require the activation of a signal transduction cascade involving the activation of the src-family kinase Fyn and downreb'lllation of GTPbound RhoA. I also explored a mechanism by which netrin-l ellicits contrasting morphological responses in OPCs and oligodendrocytes. Netrin-l increases RhoA activity in OPCs to induce a decrease in process length, but deactivates RhoA to induce process elaboration in oligodendrocytes.The auto immune disease Multiple Sclerosis (MS) is characterized by sporadic CNS demyelination. The last chapter of the thesis identifies the presence of netrin-l, and a proteolytic fragment of netrin-l, in MS lesions. I also detennined that netrin-l induces distinct morphological changes in humanoligodendroglia, and these changes can influence the ability of adult OPCs to efficiently remyelinate a demyelinated lesion. These results indicate that netrin-l plays distinct roles during the orphological maturation of oligodendrocytes, and continues to influence oligodendroglia in the adult CNS, a factor which has important cLa nétrine-l est une molécule de guidage axonal bifonctionnelle qui attire ou repousse les cellules nerveuses ou les axones pendant le développement du système nerveux. Des études récentes ont démontré que la nétrine-l jouc un rôle dans le développement des oligodendrocytes, les cellules productrices de myéline dans le systeme nerveux central (SNC). Dans la moelle épinière embryonnaire, la nétrine-l repousse les précurseurs d' oligodendrocytcs (OPC) dorsalement enprovoquant une réduction de croissance de leur prolongement. Chez l' adulte, la nétrine-l est exprimée par les oligodendrocytes myélinisants matures, et est requise pour le maintien des jonctions paranodales. La présente thèse étudie la fonction de la nétrine-l dans la maturation des oligodendrocytes et son rôle dans la sclérose en plaques (SP), une pathologie démyélinisante du SN

A Short Message Service (SMS) increases postpartum care-seeking behavior and uptake of family planning of mothers in peri-urban public facilities in Kenya.

BackgroundIt is estimated that one third of maternal deaths in Kenya in 2014 could have been prevented by more timely care-seeking. Mobile health interventions are increasingly being recognized as tools for the delivery of health education and promotion. Many maternal deaths occur in the first few weeks after delivery and mothers who are given adequate care in the postpartum period have better health outcomes. Kiambu County, Kenya has a high level of literacy and phone ownership amongst mothers delivering in public hospitals and was chosen as a site for a postpartum short message service intervention.MethodsWomen were recruited after delivery and randomized to receive a package of mobile messages or standard of care only. Messages covered danger signs, general postpartum topics, and family planning. Endline phone surveys were conducted at 8 weeks postpartum to assess knowledge, care seeking behavior and family planning uptake. Analysis was conducted using Stata and is presented in odds ratios.ResultsWomen who received the danger sign messages were 1.6 times more likely to be able to list at least 1 danger sign and 3.51 times more likely to seek treatment if they experienced postpartum danger signs. There was no significant difference in routine postpartum care seeking or care seeking behaviors concerning newborns. Women who received family planning messages were 1.85 times more likely to uptake family planning services compared to controls and 2.1 times more likely to choose a long-acting method.ConclusionsSimple, low-cost mobile interventions can support women in the early postpartum period when the information is targeted to particular points in the postpartum continuum. Additional research is needed to understand the interplay between healthcare providers and mobile health interventions. Health policy makers should consider direct mobile interventions for women as an option for supporting positive maternal health outcomes in certain populations

A Continual Pre-training Approach to Tele-Triaging Pregnant Women in Kenya

Access to high-quality maternal health care services is limited in Kenya, which resulted in ∼36,000 maternal and neonatal deaths in 2018. To tackle this challenge, Jacaranda Health (a non-profit organization working on maternal health in Kenya) developed PROMPTS, an SMS based tele-triage system for pregnant and puerperal women, which has more than 350,000 active users in Kenya. PROMPTS empowers pregnant women living far away from doctors and hospitals to send SMS messages to get quick answers (through human helpdesk agents) to questions about their medical symptoms and pregnancy status. Unfortunately, ∼1.1 million SMS messages are received by PROMPTS every month, which makes it challenging for helpdesk agents to ensure that these messages can be interpreted correctly and evaluated by their level of emergency to ensure timely responses and/or treatments for women in need. This paper reports on a collaborative effort with Jacaranda Health to develop a state-of-the-art natural language processing (NLP) framework, TRIM-AI (TRIage for Mothers using AI), which can automatically predict the emergency level (or severity of medical condition) of a pregnant mother based on the content of their SMS messages. TRIM-AI leverages recent advances in multi-lingual pre-training and continual pre-training to tackle code-mixed SMS messages (between English and Swahili), and achieves a weighted F1 score of 0.774 on real-world datasets. TRIM-AI has been successfully deployed in the field since June 2022, and is being used by Jacaranda Health to prioritize the provision of services and care to pregnant women with the most critical medical conditions. Our preliminary A/B tests in the field show that TRIM-AI is ∼17% more accurate at predicting high-risk medical conditions from SMS messages sent by pregnant Kenyan mothers, which reduces the helpdesk’s workload by ∼12%

Leveraging tuberculosis case relative locations to enhance case detection and linkage to care in Swaziland

Abstract Background In Swaziland, as in many high HIV/TB burden settings, there is not information available regarding the household location of TB cases for identifying areas of increased TB incidence, limiting the development of targeted interventions. Data from “Butimba”, a TB REACH active case finding project, was re-analyzed to provide insight into the location of TB cases surrounding Mbabane, Swaziland. Objective The project aimed to identify geographical areas with high TB burdens to inform active case finding efforts. Methods Butimba implemented household contact tracing; obtaining landmark based, informal directions, to index case homes, defined here as relative locations. The relative locations were matched to census enumeration areas (known location reference areas) using the Microsoft Excel Fuzzy Lookup function. Of 403 relative locations, an enumeration area reference was detected in 388 (96%). TB cases in each census enumeration area and the active case finders in each Tinkhundla, a local governmental region, were mapped using the geographic information system, QGIS 2.16. Results Urban Tinkhundla predictably accounted for most cases; however, after adjusting for population, the highest density of cases was found in rural Tinkhundla. There was no correlation between the number of active case finders currently assigned to the 7 Tinkhundla surrounding Mbabane and the total number of TB cases (Spearman rho = −0.57, p = 0.17) or the population adjusted TB cases (Spearman rho = 0.14, p = 0.75) per Tinkhundla. Discussion Reducing TB incidence in high-burden settings demands novel analytic approaches to study TB case locations. We demonstrated the feasibility of linking relative locations to more precise geographical areas, enabling data-driven guidance for National Tuberculosis Programs’ resource allocation. In collaboration with the Swazi National Tuberculosis Control Program, this analysis highlighted opportunities to better align the active case finding national strategy with the TB disease burden

Implementation of the INTERGROWTH-21st gestational dating and fetal and newborn growth standards in Nairobi, Kenya: women’s experiences with ultrasound and newborn assessment: Women’s experiences with ultrasound and newborn assessment in peri-urban Kenya

Background In order to make further gains in preventing newborn deaths, effective interventions are needed. Ultrasounds and newborn anthropometry are proven interventions to identify preterm birth complications, the leading cause of newborn deaths. The INTERGROWTH-21st global gestational dating and fetal and newborn growth standards prescribe optimal growth in any population. Jacaranda Health in Kenya was the first low-resource health facility to implement the standards and evaluate their feasibility and acceptability. Objective To capture patients’ perceptions of ultrasound and newborn care before and during implementation of the INTERGROWTH-21st standards. Methods The study was conducted over two years before and during the introduction of the INTERGROWTH-21st standards. Fifty pregnant and/or newly delivered women were selected for in-depth interviews and focus group discussions using convenience and purposive sampling. Interviews were conducted by research assistants using semi-structured guides once in the pre-implementation phase and twice in the implementation phase. Interviews were transcribed, double-coded by two independent researchers and thematically analyzed together. Demographic information was obtained from hospital records. Results Patients reported being generally satisfied with ultrasound care when providers communicated effectively. Women reported a priority for ultrasound was that it allowed them to feel reassured. However, a clear need for better pre-screening information emerged consistently from patients. Women noted that factors facilitating their choosing to have an ultrasound included ensuring the well-being of the fetus and learning the sex. Barriers included wait times and financial constraints. Patients were generally satisfied with care using the newborn standards. Conclusions As the INTERGROWTH-21st standards are implemented worldwide, understanding ways to facilitate implementation is critical. Increased and standardized communication about ultrasound should be provided before the procedure to increase satisfaction and uptake. Considering patient perspectives when integrating new standards or guidelines into routine clinical care will inform effective strategies in care provision, thus improving maternal and newborn health and survival

Implementing the INTERGROWTH-21st gestational dating and fetal and newborn growth standards in peri-urban Nairobi, Kenya: Provider experiences, uptake and clinical decision-making.

BackgroundPerinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and management of high-risk pregnancies and births. The INTERGROWTH-21st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting.MethodsThe study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers' experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making.ResultsFacility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement.ConclusionsThe findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice