Premature Deaths Due To Heat Exposure: The Potential Effects of Neighborhood-Level Versus City-Level Acclimatization Within US Cities.

For the population of a given US city, the risk of premature death associated with heat exposure increases as temperatures rise, but risks in hotter cities are generally lower than in cooler cities at equivalent temperatures due to factors such as acclimatization. Those living in especially hot neighborhoods within cities might therefore suffer much more than average if such adaptation is only at the city-wide level, whereas they might not experience greatly increased risk if adjustment is at the neighborhood level. To compare these possibilities, we use high spatial resolution temperature data to evaluated heat-related deaths assuming either adjustment at the city-wide or at the neighborhood scale in 10 large US cities. On average, we find that if inhabitants are adjusted to their local conditions, a neighborhood that was 10°C hotter than a cooler one would experience only about 1.0-1.5 excess heat deaths per year per 100,000 persons. By contrast, if inhabitants are acclimatized to city-wide temperatures, the hotter neighborhood would experience about 15 excess deaths per year per 100,000 persons. Using idealized analyses, we demonstrate that current city-wide epidemiological data do not differentiate between these differing adjustments. Given the very large effects of assumptions about neighborhood-level acclimatization found here, as well as the fact that current literature is conflicting on the spatial scale of acclimatization, more neighborhood-level epidemiological data are urgently needed to determine the health impacts of variations in heat exposure within urban areas, better constrain projected changes, and inform mitigation efforts.

Higher Temperatures in Socially Vulnerable US Communities Increasingly Limit Safe Use of Electric Fans for Cooling.

As the globe warms, people will increasingly need affordable, safe methods to stay cool and minimize the worst health impacts of heat exposure. One of the cheapest cooling methods is electric fans. Recent research has recommended ambient air temperature thresholds for safe fan use in adults. Here we use hourly weather reanalysis data (1950-2021) to examine the temporal and spatial evolution of ambient climate conditions in the continental United States (CONUS) considered safe for fan use, focusing on high social vulnerability index (SVI) regions. We find that although most hours in the day are safe for fan use, there are regions that experience hundreds to thousands of hours per year that are too hot for safe fan use. Over the last several decades, the number of hours considered unsafe for fan use has increased across most of the CONUS (on average by ∼70%), with hotspots across the US West and South, suggesting that many individuals will increasingly need alternative cooling strategies. People living in high-SVI locations are 1.5-2 times more likely to experience hotter climate conditions than the overall US population. High-SVI locations also experience higher rates of warming that are approaching and exceeding important safety thresholds that relate to climate adaptation. These results highlight the need to direct additional resources to these communities for heat adaptive strategies.

Premature Deaths in Africa Due To Particulate Matter Under High and Low Warming Scenarios.

Sustainable development and climate change mitigation can provide enormous public health benefits via improved air quality, especially in polluted areas. We use the latest state-of-the-art composition-climate model simulations to contrast human exposure to fine particulate matter in Africa under a "baseline" scenario with high material consumption, population growth, and warming to that projected under a sustainability scenario with lower consumption, population growth, and warming. Evaluating the mortality impacts of these exposures, we find that under the low warming scenario annual premature deaths due to PM2.5 are reduced by roughly 515,000 by 2050 relative to the high warming scenario (100,000, 175,000, 55,000, 140,000, and 45,000 in Northern, West, Central, East, and Southern Africa, respectively). This reduction rises to ∼800,000 by the 2090s, though by that time much of the difference is attributable to the projected differences in population. By contrast, during the first half of the century benefits are driven predominantly by emissions changes. Depending on the region, we find large intermodel spreads of ∼25%-50% in projected future exposures owing to different physics across the ensemble of 6 global models. The spread of projected deaths attributable to exposure to fine particulate matter, including uncertainty in the exposure-response function, are reduced in every region to ∼20%-35% by the non-linear exposure-response function. Differences between the scenarios have an even narrower spread of ∼5%-25% and are highly statistically significant in all regions for all models. These results provide valuable information for policy-makers to consider when working toward climate change mitigation and sustainable development goals.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register.

BACKGROUND: Animal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. OBJECTIVE: To calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. METHODS AND MATERIALS: Data were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. RESULTS: From December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). CONCLUSION: These data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Bisexuality and Health Care.

Using data from the fourth wave of the National Study of Adolescent Health, this paper offers a preliminary investigation of factors implicated in the physical and mental health of bisexual individuals. The roles of sleep, socioeconomic status, feelings of disrespect, and reported lack of health insurance are considered. Further, this study examines depression as a psychological stress response and systemic inflammation as a physiological stress response. Systemic inflammation in this population was estimated using the biomarker C-reactive protein (CRP). Reported acute illness in the past month and blood pressure serve as measures of physical health outcomes. Analyses revealed a pattern of elevated CRP (>3mg/L) among participants who reported no health insurance coverage. For participants who reported no health insurance coverage and identified as mostly homosexual, bisexual, or mostly heterosexual, feelings of disrespect were associated both with their sleep outcomes as well as their total household income. Moreover, linear regression showed that CRP significantly predicted blood pressure values. These analyses serve to bring health disparities and specific considerations for individuals attracted to more than one gender further into scientific conversation. Suggestions for further study of bisexual minority stress and bisexual health are offered.

Smoking cessation in elective surgical patients offered free nicotine patches at listing: a pilot study.

Free nicotine patches may promote pre-operative smoking cessation. Smokers (≥ 10 cigarettes.day-1 ) awaiting non-urgent surgery were randomly assigned (3:1) to an offer of free nicotine patches or a control group who were not offered free nicotine patches. The suggested regimen lasted 5 weeks, with patch strength decreasing incrementally after 3 and 4 weeks. The primary outcome was smoking abstinence for ≥ 4 weeks, as self-reported by participants on the day of surgery, including, where possible, corroboration using exhaled carbon monoxide testing. Out of 600 included smokers, 447 (74.5%) were randomly assigned to an offer of pre-operative nicotine patches, with 175 (39.1%) of these accepting the offer and 56 (12.5%) using patches for ≥ 3 weeks. Out of 396 participants offered nicotine patches who were included for analysis, 36 (9.1%) quit smoking for ≥ 4 weeks before surgery as compared with 8 (5.9%) controls, OR 1.5 [95%CI 0.7-3.2], p = 0.300. Sixty-three (15.9%) quit smoking for 24 h before surgery as compared with 15 (11.1%) controls, OR 1.4 [95%CI 0.8-2.4], p = 0.200. Participants offered nicotine patches were more likely to engage in a cessation attempt lasting more than 24 h, 46 (11.6%) vs. 5 (3.7%), OR 3.4 [95%CI 1.8-8.8], p = 0.010. Out of 78 participants who quit smoking by the day of surgery and were followed up at 6 months, 46 (59%) had relapsed. Offering free nicotine patches stimulated interest in quitting compared with controls, but our protocol had limited effectiveness.

An Evidence-based Recommendation for a Standardized Approach to Detecting Metastatic Neuroblastoma in Staging Bone Marrow Biopsies.

Neuroblastoma is a common malignant tumor of childhood. Accurate bone marrow (BM) evaluation for metastatic tumor is essential; however, no standardized pathologic workup exists for staging BMs. We examined the diagnostic yield of various BM components and optimal core biopsy (CB) length as part of developing evidence-based recommendations for BM evaluation. After obtaining institutional review board approval, 160 BM biopsies from 50 neuroblastoma patients were retrospectively selected. Hematoxylin and eosin-stained CB and Wright-stained aspirates were scored as positive, negative, or indeterminate. Total/trabecular CB lengths were measured using cellSens software and a DP71 camera (Olympus). Of the 160 BMs, 72 were positive for tumor in any component. Of these, 33 (45.8%) were positive in a single portion of the specimen: 19 CBs and 14 aspirates. Compared with overall diagnosis, sensitivities were as follows: CB 76.3%; aspirate 67.1%; core/aspirate combined 94.7%. Diagnostic CBs had significantly longer trabecular length than nondiagnostic CBs (6.74 mm vs 4.03 mm, P = .006). Positive CBs had longer trabecular space than negative marrows (7.91 mm vs 6.25 mm, P = .002). Nearly 50% of our positive specimens showed diagnostic discordance among the various components examined. However, combining CB and aspirate examination improved sensitivity for tumor detection. We therefore recommend bilateral CBs (>1 cm each) and aspirates for the optimal evaluation of BM for metastatic neuroblastoma.

Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid.

The synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)-indole (JWH-018) has been detected in about 140 samples of a smokable herbal mixture termed "Spice". JWH-018 is a CB1 and CB2 agonist with a higher affinity than Δ9-THC. In order to investigate the neurobiological substrates of JWH-018 actions, we studied by microdialysis in freely moving rats the effect of JWH-018 on extracellular dopamine (DA) levels in the nucleus accumbens (NAc) shell and core and in the medial prefrontal cortex (mPFC). JWH-018, at the dose of 0.25 mg/kg i.p., increased DA release in the NAc shell but not in the NAc core and mPFC. Lower (0.125 mg/kg) and higher doses (0.50 mg/kg) were ineffective. These effects were blocked by CB1 receptor antagonists (SR-141716A and AM 251) and were absent in mice lacking the CB1 receptor. Ex vivo whole cell patch clamp recordings from rat ventral tegmental area (VTA) DA neurons showed that JWH-018 decreases GABAA-mediated post-synaptic currents in a dose-dependent fashion suggesting that the stimulation of DA release observed in vivo might result from disinhibition of DA neurons. In addition, on the "tetrad" paradigm for screening cannabinoid-like effects (i.e., hypothermia, analgesia, catalepsy, hypomotility), JWH-018, at doses of 1 and 3 mg/kg i.p., produced CB1 receptor-dependent behavioural effects in rats. Finally, under appropriate experimental conditions, rats (20 µg/kg/inf i.v., FR3; nose-poking) and mice (30 µg/kg/inf i.v., FR1; lever-pressing) self-administer intravenously JWH-018. In conclusion, JWH-018 shares with the active ingredient of Marijuana, Δ9-THC, CB1-dependent reinforcing and DA stimulant actions.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.

OBJECTIVES: Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. METHODS: Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. RESULTS: Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). CONCLUSIONS: In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland.

Compared to the background population, people with epilepsy tend to have lower rates of education and employment, lower rates of marriage and childbearing, and lower overall socioeconomic status (SES). Disparities in epilepsy care based on sociodemographic factors have been observed in the literature, but it is not known whether any such disparities exist in the UK. The UK Epilepsy and Pregnancy Register is a prospective, observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. Here, we report outcomes of registered pregnancies to women with epilepsy living in Scotland from December 1996 to June 2012, based on the degree of socioeconomic deprivation of their postcode area. The Scottish Index of Multiple Deprivation (SIMD) quintile scores from 2006 were used to determine degree of socioeconomic deprivation, and group 1 (most deprived) and group 5 (least deprived) were compared. There were 1526 pregnancies with complete outcome data to women living in Scotland. Of these, 1453 (95.1%) resulted in a live birth and 68 (4.7%) had a major congenital malformation (MCM). Postcodes could not be reliably identified or verified for an additional three women, who have been excluded from SIMD group analysis. Of all women included in this study, 32.4% were in group 1 and 13.2% in group 5. No difference in MCM rate was observed between the two groups (4.4% in group 1 compared to 4.7% in group 5, p=0.84). Women in group 5 were more likely to take preconceptual folic acid (56.8% compared to 14.0%, relative risk: 4.1; 95% CI: 3.1-5.2) and less likely to have generalized tonic-clonic seizures in pregnancy (13.0% compared to 29.2%, relative risk: 0.4; 95% CI: 0.3-0.7) than those in group 1. Women in group 5 were more likely to be on monotherapy regimens (80.2% compared to 65.9%, relative risk: 1.2; 95% CI: 1.1-1.3), less likely to be on valproate (19.5% compared to 28.0%, p=0.05), and more likely to be on lower doses of the drug (825.9mg/day compared to 1012.0mg/day, p=0.05) compared to those in group 1. Although no change in MCM rate was seen based on SES, differences in treatment between socioeconomic groups do exist, particularly for preconceptual folic acid consumption, AED regimen, and seizure frequency. Greater emphasis on the importance of preconceptual counseling, both to discuss AED choice and folic acid intake, would be of benefit, particularly to those living in areas of high socioeconomic deprivation, to improve equity of healthcare delivery for women with epilepsy in Scotland.

Taurine transport in human placental trophoblast is important for regulation of cell differentiation and survival.

The outer epithelial cell layer of human placenta, the syncytiotrophoblast, is a specialised terminally differentiated multinucleate tissue. It is generated and renewed from underlying cytotrophoblast cells that undergo proliferation, differentiation and fusion with syncytiotrophoblast. Acquisition of fresh cellular components is thought to be balanced by apoptosis and shedding of aged nuclei. This process of trophoblast cell turnover maintains a functional syncytiotrophoblast, capable of sufficient nutrient transfer from mother to foetus. Foetal growth restriction (FGR) is a pregnancy complication associated with aberrant trophoblast turnover and reduced activity of certain amino acid transporters, including the taurine transporter (TauT). Taurine is the most abundant amino acid in human placenta implying an important physiological role within this tissue. Unlike other amino acids, taurine is not incorporated into proteins and in non-placental cell types represents an important osmolyte involved in cell volume regulation, and is also cytoprotective. Here, we investigated the role of taurine in trophoblast turnover using RNA interference to deplete primary human trophoblast cells of TauT and reduce intracellular taurine content. Trophoblast differentiation was compromised in TauT-deficient cells, and susceptibility of these cells to an inflammatory cytokine that is elevated in FGR was increased, evidenced by elevated levels of apoptosis. These data suggest an important role for taurine in trophoblast turnover and cytoprotection.

Δ(9)Tetrahydrocannabinol impairs reversal learning but not extra-dimensional shifts in rhesus macaques.

Expansion of medical marijuana use in the US and the recently successful decriminalization of recreational marijuana in two States elevates interest in the specific cognitive effects of Δ(9)tetrahydrocannabinol (Δ(9)THC), the major psychoactive constituent of marijuana. Controlled laboratory studies in nonhuman primates provide mixed evidence for specific effects of Δ(9)THC in learning and memory tasks, with a suggestion that frontal-mediated tasks may be the most sensitive. In this study, adult male rhesus monkeys were trained on tasks which assess reversal learning, extradimensional attentional shift learning and spatial delayed-response. Subjects were challenged with 0.1-0.5mg/kg Δ(9)THC, i.m., in randomized order and evaluated on the behavioral measures. Peak plasma levels of Δ(9)THC were observed 30min after 0.2mg/kg (69±29ng/ml) and 60min after 0.5mg/kg (121±23ng/ml) was administered and behavioral effects on a bimanual motor task persisted for up to 2h after injection. An increase in errors-to-criterion (ETC) associated with reversal learning was further increased by Δ(9)THC in a dose-dependent manner. The increase in ETC associated with extradimensional shifts was not affected by Δ(9)THC. Spatial delayed-response performance was impaired by Δ(9)THC in a retention-interval-dependent manner. Overall the pattern of results suggests a more profound effect of Δ(9)THC on tasks mediated by orbitofrontal (reversal learning) versus dorsolateral (extradimensional shifts) prefrontal mechanisms.

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BACKGROUND: Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. METHODS: The UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. RESULTS: Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1-2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67-1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58-1.70). CONCLUSION: Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

A genetic determinant of the striatal dopamine response to alcohol in men.

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Endocannabinoid signaling in neurotoxicity and neuroprotection.

The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Delta(9)-tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways.