The COVID-19 pandemic response is affecting maternal and neonatal health services all over the world. We aimed to assess the number of institutional births, their outcomes (institutional stillbirth ...and neonatal mortality rate), and quality of intrapartum care before and during the national COVID-19 lockdown in Nepal.
In this prospective observational study, we collected participant-level data for pregnant women enrolled in the SUSTAIN and REFINE studies between Jan 1 and May 30, 2020, from nine hospitals in Nepal. This period included 12·5 weeks before the national lockdown and 9·5 weeks during the lockdown. Women were eligible for inclusion if they had a gestational age of 22 weeks or more, a fetal heart sound at time of admission, and consented to inclusion. Women who had multiple births and their babies were excluded. We collected information on demographic and obstetric characteristics via extraction from case notes and health worker performance via direct observation by independent clinical researchers. We used regression analyses to assess changes in the number of institutional births, quality of care, and mortality before lockdown versus during lockdown.
Of 22 907 eligible women, 21 763 women were enrolled and 20 354 gave birth, and health worker performance was recorded for 10 543 births. From the beginning to the end of the study period, the mean weekly number of births decreased from 1261·1 births (SE 66·1) before lockdown to 651·4 births (49·9) during lockdown—a reduction of 52·4%. The institutional stillbirth rate increased from 14 per 1000 total births before lockdown to 21 per 1000 total births during lockdown (p=0·0002), and institutional neonatal mortality increased from 13 per 1000 livebirths to 40 per 1000 livebirths (p=0·0022). In terms of quality of care, intrapartum fetal heart rate monitoring decreased by 13·4% (−15·4 to −11·3; p<0·0001), and breastfeeding within 1 h of birth decreased by 3·5% (−4·6 to −2·6; p=0·0032). The immediate newborn care practice of placing the baby skin-to-skin with their mother increased by 13·2% (12·1 to 14·5; p<0·0001), and health workers' hand hygiene practices during childbirth increased by 12·9% (11·8 to 13·9) during lockdown (p<0·0001).
Institutional childbirth reduced by more than half during lockdown, with increases in institutional stillbirth rate and neonatal mortality, and decreases in quality of care. Some behaviours improved, notably hand hygiene and keeping the baby skin-to-skin with their mother. An urgent need exists to protect access to high quality intrapartum care and prevent excess deaths for the most vulnerable health system users during this pandemic period.
Grand Challenges Canada.
Mitochondrial dysfunction and oxidative stress play a key role in ischemia/reperfusion (I/R) induced brain injury. We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves ...proteostasis and protects brains against oxidative stress and I/R induced brain injury. We demonstrate here that nialamide (NM), a non-selective monoamine oxidase (MAO) inhibitor, upregulated Ublqn1 and protected neurons from oxygen-glucose deprivation- and I/R-caused cell death in in vitro and in vivo, respectively. Post-ischemic administration of the NM in a stroke mouse model even at 3 h following I/R still reduced neuronal injury and improved functional recovery and survival. Treating stroke animals with NM also increased the association of Ubqln1 with mitochondria and decreased the total oxidized and polyubiquitinated protein levels. Intriguingly, NM-enhanced proteostasis was also associated with reduced I/R-caused neuroinflammation, as reflected by attenuated activation of microglia and astrocytes as well as reduced TNF-α level. Thus, our results suggest that MAO inhibition-induced neuroprotection following I/R involves improved proteostasis and reduced neuroinflammation.
Myxobacteria exhibit a variety of complex social behaviors that all depend on coordinated movement of cells on solid surfaces. The cooperative nature of cell movements is known as social ...(S)-motility. This system is powered by cycles of type IV pili (Tfp) extension and retraction. Exopolysaccharide (EPS) also serves as a matrix to hold cells together. Here, we characterized a new S-motility gene in
. This mutant is temperature-sensitive (Ts
) for S-motility; however, Tfp and EPS are made. A 1 bp deletion was mapped to the MXAN_4099 locus and the gene was named
. Null mutations in
exhibit a synthetic enhanced phenotype with a null
mutation, a previously characterized S-motility gene that exhibits a similar Ts
phenotype. Our results suggest that SglS and SglT contribute toward Tfp function at high temperatures in redundant pathways. However, at low temperatures only one pathway is necessary for wild-type S-motility, while in the double mutant, motility is nearly abolished at low temperatures. Interestingly, the few cells that do move do so with a high reversal frequency. We suggest SglS and SglT play conditional roles facilitating Tfp retraction and hence motility in
.
Introduction: Birth defects are structural and functional anomalies that present before, at birth, or later in life. This study aimed to find out total incidence, type of structural birth defects in ...live born babies in Nepal.
Methods: The study was conducted at a tertiary level maternity hospital in Nepal from 14 April 2018 to 13 April 2019. Data was collected on online Newborn Birth Defect data base developed by WHO South- East-Asia Regional Office. All live born babies with external and internal birth defects confirmed by radiographic, ultrasonography and echocardiography until seven days of life were included. Ethical approval was obtained from Institutional Review Committee of hospital.
Results: Total of 21,564 live babies were delivered during one-year study period. Out of these, 220 (1.02%) had one or more birth defects. Number of male babies {130 (59%)} were more than female {89 (40.9%)}. 176 (80%) babies with the malformation were born to mother within age group 20 to 35 years. Of the total 220 babies with birth defects, 197 (89.5%) had isolated malformations and remaining 23 (10.4%) had sequence malformations. The most frequent malformations involved cardiovascular system 125 (56.8%) followed by gastrointestinal system 37 (16.8%), musculoskeletal system 34 (15.4%) and central nervous system 18 (8.1%).
Conclusions: Incidence of overall birth defects in this study was found to be 1.02% in which cardiovascular system anomalies was the most common followed by gastrointestinal, musculoskeletal and central nervous system anomalies.
Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels. Despite having ...advancement in the use of thrombolytic and clot removal medicine, significant numbers of stroke patients are still left out without option for treatment. In this review, we summarize recent research work on the activation of δ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury. Moreover, as activation of δ-opioid receptor by a non-peptidic δ-opioid receptor agonist also modulates the expression, maturation and processing of amyloid precursor protein and β-secretase activity, the potential role of these effects on ischemic stroke caused dementia or Alzheimer's disease are also discussed.
ObjectivesTo evaluate the feasibility of using the NeuroMotion smartphone application for remote General Movements Assessment for screening infants for cerebral palsy in Kathmandu, ...Nepal.MethodThirty-one term-born infants at risk of cerebral palsy due to birth asphyxia or neonatal seizures were recruited for the follow-up at Paropakar Maternity and Women’s Hospital, 1 October 2021 to 7 January 2022. Parents filmed their children at home using the application at 3 months’ age and the videos were assessed for technical quality using a standardised form and for fidgety movements by Prechtl’s General Movements Assessment. The usability of the application was evaluated through a parental survey.ResultsTwenty families sent in altogether 46 videos out of which 35 had approved technical quality. Sixteen children had at least one video with approved technical quality. Three infants lacked fidgety movements. The level of agreement between assessors was acceptable (Krippendorf alpha 0.781). Parental answers to the usability survey were in general positive.InterpretationEngaging parents in screening of cerebral palsy with the help of a smartphone-aided remote General Movements Assessment is possible in the urban area of a South Asian lower middle-income country.
Protein aggregates can be found in peripheral organs, such as the heart, kidney, and pancreas, but little is known about the impact of peripherally misfolded proteins on neuroinflammation and brain ...functional recovery following ischemic stroke.
Here, we studied the ischemia/reperfusion (I/R) induced brain injury in mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryAB
), by examining neuroinflammation and brain functional recovery following I/R in comparison to their non-transgenic (Ntg) littermates. To understand how peripherally misfolded proteins influence brain functionality, exosomes were isolated from CryAB
and Ntg mouse blood and were used to treat wild-type (WT) mice and primary cortical neuron-glia mix cultures. Additionally, isolated protein aggregates from the brain following I/R were isolated and subjected to mass-spectrometric analysis to assess whether the aggregates contained the mutant protein, CryAB
. To determine whether the CryAB
misfolding can self-propagate, a misfolded protein seeding assay was performed in cell cultures.
Our results showed that CryAB
mice exhibited dramatically increased infarct volume, delayed brain functional recovery, and enhanced neuroinflammation and protein aggregation in the brain following I/R when compared to the Ntg mice. Intriguingly, mass-spectrometric analysis of the protein aggregates isolated from CryAB
mouse brains confirmed presence of the mutant CryAB
protein in the brain. Importantly, intravenous administration of WT mice with the exosomes isolated from CryAB
mouse blood exacerbated I/R-induced cerebral injury in WT mice. Moreover, incubation of the CryAB
mouse exosomes with primary neuronal cultures induced pronounced protein aggregation. Transduction of CryAB
aggregate seeds into cell cultures caused normal CryAB proteins to undergo dramatic aggregation and form large aggregates, suggesting self-propagation of CryAB
misfolding in cells.
These results suggest that peripherally misfolded proteins in the heart remotely enhance neuroinflammation and exacerbate brain injury following I/R likely through exosomes, which may represent an underappreciated mechanism underlying heart-brain crosstalk.
LIM domain-binding 3 (LDB3) is a member of the Enigma family of PDZ-LIM proteins. LDB3 has been reported as a striated muscle-specific Z-band alternatively spliced protein that plays an important ...role in mechanosensory actin cytoskeleton remodeling. This study shows that LDB3 is broadly expressed in the central and peripheral nervous system of human and mouse. LDB3 is predominantly expressed in the adult stages compared to early development and at a significantly higher level in the spinal cord than in the brain. As in skeletal muscle and heart, LDB3 is extensively alternatively spliced in the neurons. Three novel splice isoforms were identified suggesting splicing-dependent regulation of LDB3 expression in the nervous system. Expression of LDB3 in the motor cortex, cerebellum, spinal motor neuron, peripheral nerve, and neuromuscular junction in addition to skeletal muscle indicates important roles for this PDZ-LIM family protein in motor planning and execution. Moreover, expression in the hippocampal neurons suggests roles for LDB3 in learning and memory. LDB3 interactors filamin C and myotilin are also expressed in the spinal motor neuron, nerve, and neuromuscular junction, thereby providing the basis for neurogenic manifestations in myopathies associated with mutations in these so-called muscle proteins.
Transition from resting to cell cycle in response to antigenic stimulation is an essential step for naïve CD8
T cells to differentiate to effector and memory cells. Leaving the resting state requires ...dramatic changes of chromatin status in the key cell cycle inhibitors but the details of these concerted events are not fully elucidated. Here, we showed that Ezh2, an enzymatic component of polycomb repressive complex 2 (PRC2) catalyzing the trimethylation of lysine 27 on histone 3 (H3K27me3), regulates activation induced naïve CD8
T cells proliferation and apoptosis. Upon deletion of Ezh2 during thymocyte development (Ezh2
Cd4Cre
mice), naive CD8
T cells displayed impaired proliferation and increased apoptosis in response to antigen stimulation. However, naive CD8
T cells only had impaired proliferation but no increase in apoptosis when Ezh2 was deleted after activation (Ezh2
GzmBCre
mice), suggesting cell cycle and apoptosis are temporally separable events controlled by Ezh2. We then showed that deletion of Ezh2 resulted in the increase in expression of cyclin-dependent kinase inhibitors Cdkn2a (p16 and Arf) and Cdkn1c (p57) in activated naïve CD8
T cells as the consequence of reduced levels of H3K27me3 at these two gene loci. Finally, with real time imaging, we observed prolonged cell division times of naïve CD8
T cells in the absence of Ezh2 post
stimulation. Together, these findings reveal that repression of
and
by Ezh2 plays a critical role in execution of activation-induced CD8
T cell proliferation.
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to ...function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle. Studies of Ldb3
mice indicate that the myopathy-associated LDB3 p.Ala165Val mutation triggers early aggregation of filamin C and its chaperones at muscle Z-disc before aggregation of the mutant protein. The mutation causes protein aggregation and eventually Z-disc myofibrillar disruption by impairing PKCα and TSC2-mTOR, two important signaling pathways regulating protein stability and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.
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