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Pathological low birth weight due to fetal growth restriction (FGR) is an important predictor of adverse obstetric and neonatal outcomes. It is more common amongst native lowlanders when gestating in the hypoxic environment of high altitude, whilst populations who have resided at high altitude for many generations are relatively protected. Genetic study of pregnant populations at high altitude permits exploration of the role of hypoxia in FGR pathogenesis, and perhaps of FGR pathogenesis more broadly. We studied the umbilical cord blood DNA of 316 neonates born to pregnant women managed at the Sonam Norboo Memorial Hospital, Ladakh (altitude 3540m) between February 2017 and January 2019. Principal component, admixture and genome wide association studies (GWAS) were applied to dense single nucleotide polymorphism (SNP) genetic data, to explore ancestry and genetic predictors of low birth weight. Our findings support Tibetan ancestry in the Ladakhi population, with subsequent admixture with neighboring Indo-Aryan populations. Fetal growth protection was evident in Ladakhi neonates. Although no variants achieved genome wide significance, we observed nominal association of seven variants across genes ( ZBTB38 , ZFP36L2 , HMGA2 , CDKAL1 , PLCG1) previously associated with birthweight.

While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls. We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.

Winkler et al . show that the glucose transporter GLUT1 in brain endothelium is necessary for the maintenance of proper brain capillary networks and blood-brain barrier integrity. The study also shows that loss of GLUT1 in a mouse model of Alzheimer's disease accelerates BBB breakdown, perfusion and metabolic stress resulting in behavioral deficits, elevated amyloid beta levels and neurodegeneration. The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid β-peptide (Aβ) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

The airway epithelial barrier is critical for preventing pathogen invasion and translocation of inhaled particles into the lung. Epithelial cells also serve an important sentinel role after infection and release various pro-inflammatory mediators that recruit and activate immune cells. Airway epithelial barrier disruption has been implicated in a growing number of respiratory diseases including viral infections. It is thought that when a pathogen breaks the barrier and gains access to the host tissue, pro-inflammatory mediators increase, which further disrupts the barrier and initiates a vicious cycle of leak. However, it is difficult to study airway barrier integrity in vivo, and little is known about relationship between epithelial barrier function and airway inflammation. Current assays of pulmonary barrier integrity quantify the leak of macromolecules from the vasculature into the airspaces (or \"inside/out\" leak). However, it is also important to measure the ease with which inhaled particles, allergens, or pathogens can enter the subepithelial tissues (or \"outside/in\" leak). We challenged mice with inhaled double stranded RNA (dsRNA) and explored the relationship between inside/out and outside/in barrier function and airway inflammation. Using wild-type and gene-targeted mice, we studied the roles of the dsRNA sensors Toll Like Receptor 3 (TLR3) and Melanoma Differentiation-Associated protein 5 (MDA5). Here we report that after acute challenge with inhaled dsRNA, airway barrier dysfunction occurs in a TLR3-dependent manner, whereas leukocyte accumulation is largely MDA5-dependent. We conclude that airway barrier dysfunction and inflammation are regulated by different mechanisms at early time points after exposure to inhaled dsRNA.

Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood. Many genetic variants have been associated with body size, but the contribution of copy number of rDNA is unknown. Here, the authors explore the association between rDNA copy number and body size in both rats and humans, finding that lower rDNA CN is associated with higher weight and BMI.

BackgroundStates which reduce foetal oxygen delivery are associated with impaired intrauterine growth. Hypoxia results when barometric pressure falls with ascent to altitude, and with it the partial pressure of inspired oxygen (‘hypobaric hypoxia’). birthweight is reduced when native lowlanders gestate at such high altitude (HA)—an effect mitigated in native (millennia) HA populations. Studying HA populations offer a route to explore the mechanisms by which hypoxia impacts foetal growth.MethodsBetween February 2017 and January 2019, we prospectively studied 316 pregnant women, in Leh, Ladakh (altitude 3524 m, where oxygen partial pressure is reduced by 1/3) and 101 pregnant women living in Delhi (low altitude, 216 m above sea level).ResultsOf Ladakhi HA newborns, 14% were small for gestational age (<10th birthweight centile) vs 19% of newborn at low altitude. At HA, increased maternal body mass index, age, and uterine artery (UtA) diameter were positively associated with growth >10th weight centile.ConclusionsThis study showed that Ladakhi offspring birthweight is relatively spared from the expected adverse HA effects. Furthermore, maternal body composition and greater UtA size may be physiological HA adaptations and warrant further study, as they offer potential mechanisms to overcome hypoxia-related growth issues.ImpactReduced foetal oxygen delivery seen in native lowlanders who gestate at HA causes foetal growth restriction—an effect thought to be mitigated in native HA populations.We found that greater maternal body mass and UtA diameter were associated with increased offspring birthweight in a (Ladakh) HA population.This supports a role for them as physiological mediators of adaptation and provides insights into potential mechanisms that may treat hypoxia-related growth issues.

Maternal anaemia prevalence in low‐income countries is unacceptably high. Our research explored the individual‐, family‐ and community‐level factors affecting antenatal care uptake, iron folic acid (IFA) intake and consumption of micronutrient‐rich diets among pregnant women in the plains of Nepal. We discuss how these findings informed the development of a home visit and community mobilisation intervention to reduce anaemia in pregnancy. We used a qualitative methodology informed by the socio‐ecological framework, conducting semi‐structured interviews with recently pregnant women and key informants, and focus group discussions with mothers‐in‐law and fathers. We found that harmful gender norms restricted women's access to nutrient‐rich food, restricted their mobility and access to antenatal care. These norms also restricted fathers' role to that of the provider, as opposed to the caregiver. Pregnant women, mothers‐in‐law and fathers lacked awareness about iron‐rich foods and how to manage the side effects of IFA. Fathers lacked trust in government health facilities affecting access to care and trust in the efficacy of IFA. Our research informed interventions by (1) informing the development of intervention tools and training; (2) informing the intervention focus to engaging mothers‐in‐law and men to enable behaviour change; and (3) demonstrating the need to work in synergy across individual, family and community levels to address power and positionality, gender norms, trust in health services and harmful norms. Participatory groups and home visits will enable the development and implementation of feasible and acceptable strategies to address family and contextual issues generating knowledge and an enabling environment for behaviour change.

Background Reactive hypoglycaemia is a condition where blood glucose drops after a glucose load, and may be associated with adverse pregnancy outcomes. This study aimed to determine the association between gestational reactive hypoglycaemia (GRH) and the risk of adverse pregnancy outcomes including those related to diabetes. Methods We performed a systematic review and meta-analysis by searching 4 databases: Medline, Embase, Web of science, and Maternity & infant care database, from inception to 1 December 2023. The outcomes of interest were any reported adverse pregnancy outcomes including large for gestational age (LGA), macrosomia, small for gestational age (SGA), fetal growth restriction (FGR), low birth weight (LBW), caesarean delivery, neonatal intensive care unit (NICU) admission, neonatal hypoglycaemia, polyhydramnios, 5-min APGAR score < 7 and preterm delivery. Risk of bias assessment was performed with Newcastle Ottawa scale. Subgroup analysis was also performed. Results From 14,746 records, 42 studies were selected for full-text assessment. Thirty studies reporting on 114,148 participants, including 18,878 women with GRH, fulfilled eligibility criteria. Pregnancies with observed GRH had higher risk of SGA (RR = 1.49, 95%CI = 1.33, 1.68), LBW (RR = 1.35, 95%CI = 1.13, 1.60), FGR (RR = 1.21, 95%CI = 1.05, 1.41), and NICU admission (RR = 1.23, 95%CI = 1.02, 1.49) compared to the euglycaemic group. At subgroup analyses, GRH diagnosed at postload glucose < 3 mmol/l was associated with an increased risk of NICU admission (RR = 3.39, 95%CI = 1.56, 7.34); and GRH limited to post glucose tolerance test (GTT) was associated with increased risk of polyhydramnios (RR = 1.93, 95%CI = 1.17, 3.20) and SGA (RR = 1.90, 95%CI = 1.01, 3.58). Conclusions GRH is a condition not routinely diagnosed in pregnancy but associated with adverse fetal-neonatal outcomes as SGA, FGR, and NICU admission. At GTT, GRH is associated with the risk of polyhydramnios. More studies are still necessary to determine the threshold value for diagnosis of GRH and explore associations with other outcomes related to glucose dysmetabolism.

The COVID-19 pandemic affected access to antenatal care in low and middle-income countries where anaemia in pregnancy is prevalent. We analyse how health workers provided antenatal care and the factors affecting access to antenatal care during the COVID-19 pandemic in Kapilvastu district in the western plains of Nepal. We used qualitative and quantitative methodologies, conducting eight semi-structured interviews with health workers who provided antenatal care during the pandemic, and a questionnaire containing open and closed questions with 52 female community health volunteers. Antenatal care was severely disrupted during the pandemic. Health workers had to find ways to provide care with insufficient personal protective equipment and guidance whilst facing extreme levels of stigmatisation which prevented them from providing outreach services. Pregnant women were fearful or unable to visit health institutions during the pandemic because of COVID-19 control measures. Pre-pandemic and during the pandemic health workers tried to contact pregnant and postpartum women and families over the phone, but this was challenging because of limited access to phones, and required pregnant women to make at least one antenatal care visit to give their phone number. The pandemic prevented new pregnancies from being registered, and therefore the possibilities to provide services over the phone for these pregnancies were limited. To reach the most marginalised during a pandemic or other health emergency, health volunteers and households need to exchange phone numbers, enabling proactive monitoring and care-seeking. Strengthening procurement and coordination between the municipal, provincial, and federal levels of government is needed to ensure adequacy of antenatal supplies, such as iron folic acid tablets, in health emergencies. Community engagement is important to ensure women and families are aware of the need to access antenatal care and iron folic acid, and to address stigmatisation of health workers.

Lysophosphatidic acid (LPA) is a pleiotropic lipid signaling molecule associated with asthma pathobiology. LPA elicits its effects by binding to at least six known cell surface G protein-coupled receptors (LPA1-6) that are expressed in the lung in a cell type-specific manner. LPA2 in particular has emerged as an attractive therapeutic target in asthma because it appears to transduce inhibitory or cell-protective signals. We studied a novel and specific small molecule LPA2 agonist (2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid [DBIBB]) in a mouse model of house dust mite-induced allergic airway inflammation. Mice injected with DBIBB developed significantly less airway and lung inflammation compared with vehicle-treated controls. Levels of lung Th2 cytokines were also significantly attenuated by DBIBB. We conclude that pharmacologic activation of LPA2 attenuates Th2-driven allergic airway inflammation in a mouse model of asthma. Targeting LPA receptor signaling holds therapeutic promise in allergic asthma.