Maternal and perinatal health research during emerging and ongoing epidemic threats: a landscape analysis and expert consultation.

INTRODUCTION: Pregnant women and their offspring are often at increased direct and indirect risks of adverse outcomes during epidemics and pandemics. A coordinated research response is paramount to ensure that this group is offered at least the same level of disease prevention, diagnosis, and care as the general population. We conducted a landscape analysis and held expert consultations to identify research efforts relevant to pregnant women affected by disease outbreaks, highlight gaps and challenges, and propose solutions to addressing them in a coordinated manner. METHODS: Literature searches were conducted from 1 January 2015 to 22 March 2022 using Web of Science, Google Scholar and PubMed augmented by key informant interviews. Findings were reviewed and Quid analysis was performed to identify clusters and connectors across research networks followed by two expert consultations. These formed the basis for the development of an operational framework for maternal and perinatal research during epidemics. RESULTS: Ninety-four relevant research efforts were identified. Although well suited to generating epidemiological data, the entire infrastructure to support a robust research response remains insufficient, particularly for use of medical products in pregnancy. Limitations in global governance, coordination, funding and data-gathering systems have slowed down research responses. CONCLUSION: Leveraging current research efforts while engaging multinational and regional networks may be the most effective way to scale up maternal and perinatal research preparedness and response. The findings of this landscape analysis and proposed operational framework will pave the way for developing a roadmap to guide coordination efforts, facilitate collaboration and ultimately promote rapid access to countermeasures and clinical care for pregnant women and their offspring in future epidemics.

A social media intervention for communicating vaccine safety in low- and middle-income countries: protocol for a pilot study.

Vaccine safety is a concern that continues to drive hesitancy and refusal in populations in low-and-middle income countries (LMICs). Communicating about vaccine safety is a strategy that can successfully change personal and community perceptions and behaviors toward vaccination. The COVID-19 infodemic emergency with the rapid rollout of new vaccines and new technology, demonstrated the need for good and effective vaccine safety communication. The Vaccine Safety Net (VSN), a WHO-led global network of websites that provide reliable information on vaccine safety offers the ideal environment for gathering web and social media analytics for measuring impact of vaccine safety messages. Its members work with a wide range of populations, in different geographic locations and at many levels including national, regional, and local. We propose to undertake a pilot study to evaluate the feasibility of implementing COVID-19 vaccine safety communications with VSN members working in LMICs and to assess the impact of communications on public knowledge, attitudes, and perceptions.

Mapping the landscape of global programmes to evaluate health interventions in pregnancy: the need for harmonised approaches, standards and tools.

Pregnant women and their babies are among the populations most vulnerable to untoward health outcomes. Yet current standards for evaluating health interventions cannot be met during pregnancy because of lack of adequate evidence. The situation is even more concerning in low-income and middle-income countries, where the need for effective interventions is the greatest. Meeting the Sustainable Development Goals for health will require strengthened attention to maternal and child health. In this paper we examine ongoing initiatives aimed at improving the assessment of maternal interventions. We review current methodologies to monitor outcomes of maternal interventions and identify where harmonisation is needed. Based on this analysis we identify settings where different minimal data sets should be considered taking into consideration the clinical realities. Stronger coordination mechanisms and a roadmap to support harmonised monitoring of maternal interventions across programmes and partners, working on improving pregnancy and early childhood health events, will greatly enhance ability to generate evidence-based policies.

Vaccine safety surveillance in pregnancy in low- and middle-income countries using GAIA case definitions: A feasibility assessment.

BACKGROUND: Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. METHODS: Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. RESULTS: Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. DISCUSSION: GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy.

Cluster anxiety-related adverse events following immunization (AEFI): An assessment of reports detected in social media and those identified using an online search engine.

BACKGROUND: Adverse events following immunization (AEFI) arising from anxiety have rarely been reported as a cluster(s) in the setting of a mass vaccination program. Reports of clusters of anxiety-related AEFIs are understudied. Social media and the web may be a resource for public health investigators. METHODS: We searched Google and Facebook separately from Atlanta and Geneva to identify reports of cluster anxiety-related AEFIs. We reviewed a sample of reports summarizing year, country/setting, vaccine involved, patient symptoms, clinical management, and impact to vaccination programs. RESULTS: We found 39 reports referring to 18 unique cluster events. Some reports were only found based on the geographic location from where the search was performed. The most common vaccine implicated in reports was human papillomavirus (HPV) vaccine (48.7%). The majority of reports (97.4%) involved children and vaccination programs in school settings or as part of national vaccination campaigns. Five vaccination programs were reportedly halted because of these cluster events. In this study, we identified 18 cluster events that were not published in traditional scientific peer-reviewed literature. CONCLUSIONS: Social media and online search engines are useful resources for identifying reports of cluster anxiety-related AEFIs and the geographic location of the researcher is an important factor to consider when conducting these studies. Solely relying upon traditional peer-reviewed journals may seriously underestimate the occurrence of such cluster events.

Anxiety-related adverse events following immunization (AEFI): A systematic review of published clusters of illness.

BACKGROUND: Clusters of anxiety-related adverse events following immunization (AEFI) have been observed in several countries and have disrupted country immunization programs. We conducted a systematic literature review to characterize these clusters, to generate prevention and management guidance for countries. METHODS: We searched seven peer-reviewed databases for English language reports of anxiety-related AEFI clusters (≥2 persons) with pre-specified keywords across 4 categories: symptom term, cluster term, vaccine term, and cluster AEFI phenomenon term/phrase. All relevant reports were included regardless of publication date, case-patient age, or vaccine. Two investigators independently reviewed abstracts and identified articles for full review. Data on epidemiologic/clinical information were extracted from full text review including setting, vaccine implicated, predominant case-patient symptoms, clinical management, community and media response, and outcome/impact on the vaccination program. RESULTS: Of 1472 abstracts reviewed, we identified eight published clusters, from all six World Health Organization (WHO) regions except the African Region. Seven clusters occurred among children in school settings, and one was among adult military reservists. The size and nature of these clusters ranged from 7 patients in one school to 806 patients in multiple schools. Patients' symptoms included dizziness, headache, and fainting with rapid onset after vaccination. Implicated vaccines included tetanus (2), tetanus-diphtheria (1), hepatitis B (1), oral cholera (1), human papillomavirus (1), and influenza A (H1N1)pdm09 (2). In each report, all affected individuals recovered rapidly; however, vaccination program disruption was noted in some instances, sometimes for up to one year. CONCLUSIONS: Anxiety-related AEFI clusters can be disruptive to vaccination programs, reducing public trust in immunizations and impacting vaccination coverage; response efforts to restore public confidence can be resource intensive. Health care providers should have training on recognition and clinical management of anxiety-related AEFI; public health authorities should have plans to prevent and effectively manage anxiety-related AEFI clusters. Prompt management of these occurrences can be even more important in an era of social media, in which information is rapidly spread.

Glibenclamide Prevents Diabetes in NOD Mice.

Previous work has revealed that Cx36, the sole connexin expressed in the insulin-producing beta cells, enhances the secretion of insulin, and promotes the resistance of beta cells against pro-inflammatory cytokines. In parallel, the anti-diabetic sulphonylurea glibenclamide was shown to promote the assembly and function of Cx36 channels. Here, we assessed whether glibenclamide could protect the insulin-producing cells against conditions mimicking those expected at the onset of type 1 diabetes. We found that the drug 1) protected in vitro the mouse MIN6 cells from the apoptosis and loss of Cx36, which are induced by Th1 cytokines; 2) prevented the development of hyperglycemia as well as the loss of beta cells and Cx36, which rapidly develop with aging in untreated NOD mice; 3) modified the proportion of effector CD4+ and CD8+ T cells in pancreatic draining lymph nodes. The data imply that an early glibenclamide treatment may help protecting beta cells against the autoimmune attack, which triggers the development of type 1 diabetes.

Multivalent glibenclamide to generate islet specific imaging probes.

The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo. The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics.

Role of Connexins and Pannexins in the Pancreas.

The pancreas produces enzymes with a digestive function and hormones with a metabolic function, which are produced by distinct cell types of acini and islets, respectively. Within these units, secretory cells coordinate their functioning by exchanging information via signals that flow in the intercellular spaces and are generated either at distance (several neural and hormonal inputs) or nearby the pancreatic cells themselves (inputs mediated by membrane ionic-specific channels and by ionic- and metabolite-permeant pannexin channels and connexin "hemichannels"). Pancreatic secretory cells further interact via the extracellular matrix of the pancreas (inputs mediated by integrins) and directly with neighboring cells, by mechanisms that do not require extracellular mediators (inputs mediated by gap and tight junction channels). Here, we review the expression and function of the connexins and pannexins that are expressed by the main secretory cells of the exocrine and endocrine pancreatic cells. Available data show that the patterns of expression of these proteins differ in acini and islets, supporting distinct functions in the physiological secretion of pancreatic enzymes and hormones. Circumstantial evidence further suggests that alterations in the signaling provided by these proteins are involved in pancreatic diseases.

Targeting GLP-1 receptors for repeated magnetic resonance imaging differentiates graded losses of pancreatic beta cells in mice.

AIMS/HYPOTHESIS: Non-invasive imaging of beta cells is a much-needed development but is one that faces significant biological and technological hurdles. A relevant imaging method should at least allow for an evaluation over time of the mass of beta cells under physiological and pathological conditions, and for an assessment of novel therapies. We, therefore, investigated the ability of a new MRI probe to repeatedly measure the loss of beta cells in a rodent model. METHODS: We developed an innovative nanoparticle probe that targets the glucagon-like peptide 1 receptor, and can be used for both fluorescence imaging and MRI. Using fluorescence, we characterised the specificity and biodistribution of the probe. Using 1.5 T MRI, we longitudinally imaged the changes in insulin content in male and female mice of the RIP-DTr strain, which mimic the changes expected in type 1 and type 2 diabetes, respectively. RESULTS: We showed that this probe selectively labelled beta cells in situ, imaged in vivo native pancreatic islets and evaluated their loss after diphtheria toxin administration, in a model of graded beta cell deletion. Thus, using clinical MRI, the probe quantitatively differentiates, in the same mouse strain, between female animals featuring a 50% loss of beta cells and the males featuring an almost complete loss of beta cells. CONCLUSIONS/INTERPRETATION: The approach addresses several of the hurdles that have so far limited the non-invasive imaging of beta cells, including the potential to repeatedly monitor the very same animals using clinically available equipment, and to differentiate graded losses of beta cells.

Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients.

A non-invasive method to image the mass and/or function of human pancreatic islets is needed to monitor the progression of diabetes, and the effect of therapeutic interventions. As yet, no method is available for this purpose, which could be applied to in situ human islets. Animal and in vitro studies have documented that manganese infusion could improve the magnetic resonance imaging (MRI) of the endocrine pancreas. Here, we have tested whether a similar approach could discriminate diabetic and non-diabetic patients. In vitro, human isolated islets readily incorporated manganese. In vivo, 243 manganese-enhanced magnetic resonance imaging (MEMRI) examinations were reviewed, including 41 examinations which were run on 24 patients with type 2 diabetes and 202 examinations which were run on 119 normoglycemic patients. The results show that MEMRI discriminates type 2 diabetics from non-diabetic patients, based on the signal enhancement of pancreas.

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands.

We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]FP-DTBZ), [(18)F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ((18)F-AV-266), and (2S,3R,11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.

A complex between contactin-1 and the protein tyrosine phosphatase PTPRZ controls the development of oligodendrocyte precursor cells.

The six members of the contactin (CNTN) family of neural cell adhesion molecules are involved in the formation and maintenance of the central nervous system (CNS) and have been linked to mental retardation and neuropsychiatric disorders such as autism. Five of the six CNTNs bind to the homologous receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ), but the biological roles of these interactions remain unclear. We report here the cocrystal structure of the carbonic anhydrase-like domain of PTPRZ bound to tandem Ig repeats of CNTN1 and combine these structural data with binding assays to show that PTPRZ binds specifically to CNTN1 expressed at the surface of oligodendrocyte precursor cells. Furthermore, analyses of glial cell populations in wild-type and PTPRZ-deficient mice show that the binding of PTPRZ to CNTN1 expressed at the surface of oligodendrocyte precursor cells inhibits their proliferation and promotes their development into mature oligodendrocytes. Overall, these results implicate the PTPRZ/CNTN1 complex as a previously unknown modulator of oligodendrogenesis.

High-resolution magnetic resonance imaging quantitatively detects individual pancreatic islets.

OBJECTIVE: We studied whether manganese-enhanced high-field magnetic resonance (MR) imaging (MEHFMRI) could quantitatively detect individual islets in situ and in vivo and evaluate changes in a model of experimental diabetes. RESEARCH DESIGN AND METHODS: Whole pancreata from untreated (n = 3), MnCl(2) and glucose-injected mice (n = 6), and mice injected with either streptozotocin (STZ; n = 4) or citrate buffer (n = 4) were imaged ex vivo for unambiguous evaluation of islets. Exteriorized pancreata of MnCl(2) and glucose-injected mice (n = 6) were imaged in vivo to directly visualize the gland and minimize movements. In all cases, MR images were acquired in a 14.1 Tesla scanner and correlated with the corresponding (immuno)histological sections. RESULTS: In ex vivo experiments, MEHFMRI distinguished different pancreatic tissues and evaluated the relative abundance of islets in the pancreata of normoglycemic mice. MEHFMRI also detected a significant decrease in the numerical and volume density of islets in STZ-injected mice. However, in the latter measurements the loss of ß-cells was undervalued under the conditions tested. The experiments on the externalized pancreata confirmed that MEHFMRI could visualize native individual islets in living, anesthetized mice. CONCLUSIONS: Data show that MEHFMRI quantitatively visualizes individual islets in the intact mouse pancreas, both ex vivo and in vivo.

Connexin implication in the control of the murine beta-cell mass.

Diabetes develops when the insulin needs of peripheral cells exceed the availability or action of the hormone. This situation results from the death of most beta-cells in type 1 diabetes, and from an inability of the beta-cell mass to adapt to increasing insulin needs in type 2 and gestational diabetes. We analyzed several lines of transgenic mice and showed that connexins (Cxs), the transmembrane proteins that form gap junctions, are implicated in the modulation of the beta-cell mass. Specifically, we found that the native Cx36 does not alter islet size or insulin content, whereas the Cx43 isoform increases both parameters, and Cx32 has a similar effect only when combined with GH. These findings open interesting perspectives for the in vitro and in vivo regulation of the beta-cell mass.

Receptor protein tyrosine phosphatase from stem cells to mature glial cells of the central nervous system.

The cornerstone of cell signaling is largely based on the phosphorylation state that is defined by the equilibrium of the activity of protein kinases and protein phosphatases. The role of protein tyrosine kinases in brain development, brain tumors, and neurodegenerative diseases was studied extensively, yet, the importance of protein tyrosine phosphatases (PTPs) in the development of glial cells was somewhat neglected. In this review, we have summarized recent findings of PTP expression during development of the central nervous system and the different cell types of the brain, from stem cells to mature glial cells, and highlighted the potential role of these enzymes in neuronal stem cell development, glioblastomas, and myelination.

Receptor protein tyrosine phosphatase gamma is a marker for pyramidal cells and sensory neurons in the nervous system and is not necessary for normal development.

In order to gain insight into the biological role of receptor protein tyrosine phosphatase gamma (RPTPgamma), we have generated RPTPgamma-null mice. RPTPgamma was disrupted by insertion of the beta-galactosidase gene under the control of the RPTPgamma promoter. As the RPTPgamma-null mice did not exhibit any obvious phenotype, we made use of these mice to study RPTPgamma expression and thus shed light on potential biological functions of this phosphatase. Inspection of mouse embryos shows that RPTPgamma is expressed in a variety of tissues during embryogenesis. RPTPgamma is expressed in both embryonic and adult brains. Specifically, we detected RPTPgamma expression in cortical layers II and V and in the stratum pyramidale of the hippocampus, indicating that RPTPgamma is a marker for pyramidal neurons. Mixed primary culture of glial cells showed a lack of expression of RPTPgamma in astrocytes and a low expression of RPTPgamma in oligodendrocytes and in microglia. Interestingly, RPTPgamma expression was detected in all sensory organs, including the ear, nose, tongue, eye, and vibrissa follicles, suggesting a potential role of RPTPgamma in sensory neurons. An initial behavioral analysis showed minor changes in the RPTPgamma-null mice.