Incidence and outcomes for stroke in Ulaanbaatar, Mongolia, during 2019-21: a prospective population-based study.

BACKGROUND: In the absence of reliable data to quantify the burden of stroke, we aimed to determine the incidence and outcome of stroke through the conduct of a prospective population-based study in Ulaanbaatar, Mongolia, during 2019-21. METHODS: All cases of stroke were identified through surveillance of multiple overlapping sources of hospitalised, ambulatory, and deceased individuals, using standardised diagnostic criteria in adult (aged ≥16 years) residents of the six urban districts of Ulaanbaatar, Mongolia (population person-years, N=1 896 965) between Jan 1, 2019, and Dec 31, 2020. Data on sociodemography, medical history, and management were collected. Crude and standardised incidence were calculated for first-ever stroke and its major pathological subtypes, and reported with 95% CIs. Outcomes were 28-day case fatality ratios and functional recovery on the modified Rankin scale at 90 days and 1 year. FINDINGS: 3803 strokes in 3738 patients were identified, of which 2962 were first-ever incident cases (mean age 59 years [SD 13], 1161 [39·2%] females). Annual incidence of first-ever stroke (per 100 000) was 156·1 (95% CI 150·5-161·8) on a crude basis, 171·6 (157·5-185·6) when age-adjusted to the Mongolian population, and 140·3 (136·7-143·9) when age-adjusted to the world population. World-adjusted incidence of pathological subtypes were 66·6 (95% CI 64·8-68·3) for ischaemic stroke, 54·5 (53·0-56·1) for intracerebral haemorrhage, and 18·7 (18·3-19·1) for subarachnoid haemorrhage. Men were twice as likely to suffer ischaemic stroke and intracerebral haemorrhage as women, but the risks were similar for subarachnoid haemorrhage; these patterns were consistent across age-groups. The predominant risk factors were hypertension seen in 1363 (63·1%) of 2161, smoking in 596 (26·8%) of 2220, regular alcohol consumption in 533 (24·0%) of 2220, obesity in 342 (16·1%) of 2125, and diabetes in 282 (12·7%) of 2220. There was little use (0·9%) of thrombolysis for acute ischaemic stroke, partly due to delays in presentation after the onset of symptoms (median 16·0 h [IQR 3·0-48·0]). The 28-day case-fatality rate was 36·1% (95% CI 34·3-37·9) overall, and 14·8% (12·8-16·7) for ischaemic stroke, 52·9% (49·9-55·8) for intracerebral haemorrhage, and 54·3% (49·4-59·1) for subarachnoid haemorrhage. Corresponding figures for poor functional outcome at 1-year, defined by scores of 3-6 for death or dependency on the mRS, were 61·6% (95% CI 59·8-63·4), 47·5% (44·7-50·3), 77·0% (74·5-79·5), and 61·8% (57·0-66·5), respectively. INTERPRETATION: The urban population of Ulaanbaatar, Mongolia, has a high incidence of stroke, particularly for intracerebral haemorrhage and subarachnoid haemorrhage, from which half of patients die within 1 month and more than two-thirds are either dead or dependent at 90 days. Although the overall incidence of stroke is similar to other countries, it occurs at a mean age of 60 years, which is at least 10 years younger than in high-income countries. These epidemiological data can inform the implementation of future programmes and scale-up activities for the primary and secondary prevention of stroke, and in the organisation of systems of care. FUNDING: Science and Technology Foundation of the Ministry of Education, Culture, and Science of Mongolia and The George Institute for Global Health.

Who benefits most from a prenatal HEPA filter air cleaner intervention on childhood cognitive development? The UGAAR randomized controlled trial.

BACKGROUND: Air pollution exposure during pregnancy affects children's brain function. Maternal stress and nutrition, socioeconomic status, and the child's sex may modify this relationship. OBJECTIVE: To identify characteristics of children with the largest increases in full-scale IQ (FSIQ) after their mothers used HEPA filter air cleaners during pregnancy. METHODS: In this randomized controlled trial we randomly assigned women to receive 1-2 air cleaners or no air cleaners during pregnancy. We analyzed maternal hair samples for cortisol and dehydroepiandrosterone (DHEA). When the children were 48 months old, we measured FSIQ with the Wechsler Preschool and Primary Scale of Intelligence. We evaluated ten potential modifiers of the intervention-FSIQ relationship using interaction terms in separate regression models. To account for correlations between modifiers, we also used a single regression model containing main effects and intervention x modifier terms for all potential modifiers. RESULTS: Among 242 mother-child dyads with complete data, the intervention was associated with a 2.3-point increase (95% CI: -1.5, 6.0 points) in mean FSIQ. The intervention improved mean FSIQ among children of mothers in the bottom (5.4 points; 95% CI: -0.8, 11.5) and top (6.1 points; 95% CI: 0.5, 11.8) cortisol tertiles, but not among those whose mothers were in the middle tertile. The largest between-group difference in the intervention's effect was a 7.5-point (95% CI: -0.7, 15.7) larger increase in mean FSIQ among children whose mothers did not take vitamins than among children whose mothers did take vitamins (interaction p-value = 0.07). We also observed larger benefits among children whose mothers did not complete university, and those with lower hair DHEA concentrations, hair cortisol concentrations outside the middle tertile, or more perceived stress. CONCLUSION: The benefits of reducing air pollution during pregnancy on brain development may be greatest for children whose mothers who do not take vitamins, experience more stress, or have less education.

Portable HEPA filter air cleaner use during pregnancy and children's autistic behaviors at four years of age: The UGAAR randomized controlled trial.

BACKGROUND: Developmental exposure to airborne particulate matter (PM) may increase children's risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM2.5) concentrations during pregnancy and autistic traits. METHODS: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM2.5 concentrations and T-scores. RESULTS: We enrolled participants at a median of 11 weeks' gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: -2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m3) increase in indoor PM2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM2.5 concentrations by trimester were smaller and confidence intervals spanned no effect. CONCLUSION: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01741051.

Portable HEPA Filter Air Cleaner Use during Pregnancy and Children's Cognitive Performance at Four Years of Age: The UGAAR Randomized Controlled Trial.

BACKGROUND: Developmental exposure to air pollution is associated with diminished cognitive abilities in observational studies, but no randomized controlled trial has examined the effect of reducing air pollution on cognition in children. OBJECTIVES: We sought to quantify the impact of reducing exposure to particulate matter (PM) during pregnancy on children's cognitive performance at 4 y of age. METHODS: In this single-blind, parallel-group, randomized controlled trial in Ulaanbaatar, Mongolia, we randomly assigned 540 nonsmoking pregnant women (268 intervention and 272 control) to receive 1-2 portable high-efficiency particulate air (HEPA) filter air cleaners or no air cleaners. The air cleaners were used from a median of 11 wk gestation until the end of pregnancy. The primary outcome was full-scale intelligence quotient (FSIQ) assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when children were a median of 48 months old. We imputed missing outcome data using multiple imputation with chained equations, and our primary analysis was by intention to treat. RESULTS: After excluding known miscarriages, stillbirths, neonatal deaths, and medical conditions that impeded cognitive testing and imputation, 475 (233 control and 242 intervention) children were included in our analyses. In an unadjusted analysis, the mean FSIQ of children who were randomly assigned to the intervention group was 2.5 points [95% confidence interval (CI): -0.4, 5.4 points] higher than that of children in the control group. After adjustment to account for an imbalance in preterm birth between groups, the effect estimate increased to 2.8 points (95% CI: -0.1, 5.7). CONCLUSIONS: Reducing PM air pollution during pregnancy may improve cognitive performance in childhood. https://doi.org/10.1289/EHP10302.

Portable HEPA filter air cleaner use during pregnancy and children's behavior problem scores: a secondary analysis of the UGAAR randomized controlled trial.

BACKGROUND: Developmental exposure to particulate matter (PM) air pollution may impair children's behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children's behavior. METHODS: This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. RESULTS: We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. CONCLUSION: We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01741051.

Portable HEPA filter air cleaner use during pregnancy and children's body mass index at two years of age: The UGAAR randomized controlled trial.

IMPORTANCE: Gestational exposure to particulate matter (PM) air pollution may increase the risk of childhood obesity, but the impact of reducing air pollution during pregnancy on obesity-related outcomes in childhood has not been examined. OBJECTIVE: To assess the impact of reducing gestational PM exposure on body mass index (BMI) at two years of age. METHODS: In this single-blind, parallel group randomized controlled trial in Ulaanbaatar Mongolia, we randomly assigned 540 pregnant women to receive 1-2 portable high efficiency particulate air (HEPA) filter air cleaners or no air cleaners. We measured height and weight when children were a mean age of 23.8 months. Our primary outcome was age- and sex-specific BMI z-score based on the World Health Organization 2007 Growth Charts. Secondary outcomes included age- and sex-specific weight z score, overweight/obesity (defined as BMI z-score > 2.00), and catch-up growth (defined using various cut-offs to identify children with relatively low birth weight for sex and gestational age and relatively high age- and sex-specific weight in childhood). We imputed missing outcome data using multiple imputation with chained equations and our primary analysis was by intention to treat (ITT). We estimated intervention effects on continuous and binary outcomes using linear and logistic regression, respectively. RESULTS: After excluding known miscarriages, still births, and neonatal deaths our analysis included 480 children (235 control and 245 intervention). The mean (SD) child BMI z score was 0.79 (1.0); 9.8% of children were overweight or obese. The mean BMI z score of children who were randomly assigned to the intervention group was 0.16-units lower (95% CI: -0.35, 0.04) than children in the control group. The intervention was also associated with reductions in overweight/obesity (odds ratio = 0.59; 95% CI: 0.31, 1.12). Catch-up growth occurred less frequently in the intervention group, but effect estimates varied depending on the specific definition of catch-up growth and confidence intervals consistently spanned no effect. CONCLUSIONS: We found that the use of portable air cleaners during pregnancy was associated with improvements in obesity-related outcomes, although some effect estimates lacked precision. Reducing PM exposure during pregnancy may lead to improvements in cardiometabolic health in childhood.

Modification of multiple ion channel functions in vivo by pharmacological inhibition: observation by threshold tracking and modeling.

Maintenance of axonal excitability relies on complex balance by multiple ion currents, but its evaluation is limited by in vitro single channel neurophysiological study on overall behavior. We sought to evaluate behaviors of multiple ion currents by pharmacological blockade. The threshold tracking technique was used to measure multiple excitability indices on tail sensory nerve of normal male mice before and after administration of either BaCl2 or ivabradine. Mathematical modeling was used to identify the interval changes of the channel parameters. After administration of BaCl2 and ivabradine, the following changes were present: greater threshold changes of both depolarizing and hyperpolarizing threshold electrotonus by both; additionally, reduced S2 accommodation, reduced late subexcitability and increased superexcitability by BaCl2, increased S3 accommodation by ivabradine. Mathematical modelling implied reduction of slow K+ conductance, along with reduction of H conductance (Ih) by BaCl2; and reduction of Ih while augmentation of K+ conductances by ivabradine. Pharmacological blockade of a selective ion channel may be compensated by other ion channels. Unintended effects by ion channel modification could be caused by secondary current alteration by multiple ion channels. J. Med. Invest. 64: 30-38, February, 2017.

Impaired Axonal Na(+) Current by Hindlimb Unloading: Implication for Disuse Neuromuscular Atrophy.

This study aimed to characterize the excitability changes in peripheral motor axons caused by hindlimb unloading (HLU), which is a model of disuse neuromuscular atrophy. HLU was performed in normal 8-week-old male mice by fixing the proximal tail by a clip connected to the top of the animal's cage for 3 weeks. Axonal excitability studies were performed by stimulating the sciatic nerve at the ankle and recording the compound muscle action potential (CMAP) from the foot. The amplitudes of the motor responses of the unloading group were 51% of the control amplitudes [2.2 ± 1.3 mV (HLU) vs. 4.3 ± 1.2 mV (Control), P = 0.03]. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls [0.075 ± 0.01 (HLU) vs. 0.12 ± 0.01 (Control), P < 0.01; 5.4 ± 1.0 (HLU) vs. 10.0 ± 1.3 % (Control), P = 0.01, respectively]. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent Na(+) currents along with parameters related to current leakage. Quantification of RNA of a SCA1A gene coding a voltage-gated Na(+) channel tended to be decreased in the sciatic nerve in HLU. The present study suggested that axonal ion currents are altered in vivo by HLU. It is still undetermined whether the dysfunctional axonal ion currents have any pathogenicity on neuromuscular atrophy or are the results of neural plasticity by atrophy.

Age-dependent effects on sensory axonal excitability in normal mice.

Serial recordings were performed to measure sensory excitability in peripheral nerves and elucidate age-dependent changes in neuronal ion currents in the peripheral sensory nervous system. The threshold tracking technique was used to measure multiple excitability indices in the tail sensory nerves of five normal male mice at four time points (6, 10, 14, and 19 weeks of age). A separate group of four mice was also measured at 43 weeks and at 60 weeks of age. Maturation was accompanied by an increase in early hyperpolarization and superexcitability at 10 weeks. At 60 weeks, the hyperpolarizing electrotonus shifted downward, while superexcitability became greater and subexcitability (double stimuli) decreased. Computer modeling showed that the most notable age-related interval changes in excitability parameters were Barrett-Barrett, H, and slow K(+) conductances. Understanding age-related changes in the excitability of sensory axons may provide a platform for understanding age-dependent sensory symptoms and developing age-specific channel-targeting therapies.

Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy.

OBJECTIVE: To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy. METHODS: (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling. RESULTS: In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes. CONCLUSION: Ih was upregulated after MGO administration in normal mice. SIGNIFICANCE: MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.

Effects of anesthetic agents on in vivo axonal HCN current in normal mice.

OBJECTIVE: The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. METHODS: Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. RESULTS: Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. CONCLUSIONS: Anesthetic agents affected responses to long hyperpolarizing currents. SIGNIFICANCE: Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents.