A Possible Nocebo Effect in Children Following the Flint Water Crisis: Evidence From Schoolteacher Perceptions and Neuropsychological Evaluations.

OBJECTIVE: Special education enrollment increased in Flint following the 2014-2015 Flint Water Crisis, but lead exposure is not plausibly responsible. Labeling Flint children as lead poisoned and/or brain damaged may have contributed to rising special education needs (ie, nocebo effect). To better document this possibility, we surveyed schoolteachers and reviewed neuropsychological assessments of children for indications of negative labeling. METHODS: A survey of Flint and Detroit (control) public schoolteachers using a modified Illness Perception Questionnaire was conducted 5 years post-crisis. We also examined neuropsychological assessments from a recently settled class lawsuit. RESULTS: Relative to Detroit (n = 24), Flint teachers (n = 11) believed that a higher proportion of their students had harmful lead exposure (91.8% Flint vs 46% Detroit; P = 0.00034), were lead poisoned (51.3% vs 24.3%; P = 0.018), or brain damaged (28.8% vs 12.9%; P = 0.1), even though blood lead of Flint children was always less than half of that of Detroit children. Neuropsychological assessments diagnosed lead poisoning and/or brain damage from water lead exposure in all tested children (n = 8), even though none had evidence of elevated blood lead and a majority had prior learning disability diagnoses. CONCLUSION: Teachers' responses and neuropsychological assessments suggest Flint children were harmed by a nocebo effect.

Analysis of Gout Remission Definitions in a Randomized Controlled Trial of Colchicine Prophylaxis for People With Gout Initiating Allopurinol.

OBJECTIVE: To investigate (1) the effect of colchicine prophylaxis on gout remission when commencing urate-lowering therapy (ULT), and (2) illness perceptions of people in remission using 2 definitions of gout remission. METHODS: Data from a 12-month double-blind placebo-controlled trial of 200 people with gout commencing allopurinol were analyzed. Participants were randomly assigned to prophylaxis with 0.5 mg daily colchicine or placebo for 6 months, followed by 6 months of additional follow-up. Gout remission was assessed using the 2016 preliminary definition or simplified definition without patient-reported outcomes. Illness perceptions were assessed using a gout-specific version of the Brief Illness Perception Questionnaire. RESULTS: In the first 6 months, few participants were in remission according to either the 2016 preliminary definition (3% for colchicine and 4% for placebo) or the simplified definition (7% for colchicine and 12% for placebo). In the second 6 months, after study drug (colchicine or placebo) discontinuation, fewer participants in the colchicine group than in the placebo group were in remission according to the 2016 preliminary definition (4% vs 14%, P = 0.03), and the simplified definition (14% vs 28%, P = 0.02). Participants fulfilling remission using either definition had more favorable perceptions about their gout symptoms and illness concerns, as well as consequences, when using the simplified definition. CONCLUSION: Using either definition, 6 months of colchicine prophylaxis when initiating ULT does not provide an advantage in the fulfillment of gout remission. People fulfilling either definition report fewer symptoms, less concern about their gout, and, when using the simplified definition, are less affected by gout.

Relationship between serum urate and changes in dual-energy CT monosodium urate crystal volume over 1 year in people with gout: an individual participant data analysis.

OBJECTIVES: The dynamics of monosodium urate (MSU) crystal changes across a range of serum urate concentrations in people with gout are unknown. This study aimed to systematically examine the relationship between serum urate and changes in dual-energy CT (DECT) urate volume in people with gout and stable serum urate concentrations. METHODS: Individual participant data were analysed from three studies of people with gout. The time periods for the analysis were selected to identify study participants with serial DECT scans of both feet over a 12-month epoch of stable urate-lowering therapy and serum urate concentrations. Data from 251 study participants were analysed using a mixed models analysis of covariance approach according to mean serum urate cut-points and mean serum urate bands. RESULTS: For all mean serum urate cut-points assessed (0.24, 0.30, 0.36, 0.42 and 0.48 mmol/L), reductions in DECT urate volumes were observed below the cut-point. Increased DECT urate volumes were observed at or above the 0.48 mmol/L mean serum urate cut-point. Differences in the change in DECT volume were observed for the 0.42 mmol/L cut-point (p=0.0044) and the 0.48 mmol/L cut-point (p<0.0001). Significantly reduced DECT urate volumes were observed for the mean serum urate bands<0.24 mmol/L and 0.24-0.29 mmol/L and increased DECT urate volume was observed for the mean serum urate band≥0.48 mmol/L. CONCLUSIONS: Over 1 year, MSU crystal dissolution, as measured by DECT, occurs with mean serum urate bands of<0.24 mmol/L and 0.24-0.29 mmol/L while MSU crystal formation occurs with mean serum urate≥0.48 mmol/L.

Effect of utilizing either a self-reported questionnaire or administrative data alone or in combination on the findings of a randomized controlled trial of the long-term effects of antenatal corticosteroids.

INTRODUCTION: A combination of self-reported questionnaire and administrative data could potentially enhance ascertainment of outcomes and alleviate the limitations of both in follow up studies. However, it is uncertain how access to only one of these data sources to assess outcomes impact study findings. Therefore, this study aimed to determine whether the study findings would be altered if the outcomes were assessed by different data sources alone or in combination. METHODS: At 50-year follow-up of participants in a randomized trial, we assessed the effect of antenatal betamethasone exposure on the diagnosis of diabetes, pre-diabetes, hyperlipidemia, hypertension, mental health disorders, and asthma using a self-reported questionnaire, administrative data, a combination of both, or any data source, with or without adjudication by an expert panel of five clinicians. Differences between relative risks derived from each data source were calculated using the Bland-Altman approach. RESULTS: There were 424 participants (46% of those eligible, aged 49 years, SD 1, 50% male). There were no differences in study outcomes between participants exposed to betamethasone and those exposed to placebo when the outcomes were assessed using different data sources. When compared to the study findings determined using adjudicated outcomes, the mean difference (limits of agreement) in relative risks derived from other data sources were: self-reported questionnaires 0.02 (-0.35 to 0.40), administrative data 0.06 (-0.32 to 0.44), both questionnaire and administrative data 0.01 (-0.41 to 0.43), and any data source, 0.01 (-0.08 to 0.10). CONCLUSION: Utilizing a self-reported questionnaire, administrative data, both questionnaire and administrative data, or any of these sources for assessing study outcomes had no impact on the study findings compared with when study outcomes were assessed using adjudicated outcomes.

Baseline Dual-Energy Computed Tomography Urate Volume Predicts Fulfillment of Gout Remission After Two Years of Urate-Lowering Therapy.

OBJECTIVE: This study aimed to identify variables that predict gout remission in people with erosive gout receiving urate-lowering therapy. METHODS: We analyzed data from a two-year, double-masked randomized-controlled trial of people with erosive gout, randomized to a serum urate target of <0.20 mmol/L or <0.30 mmol/L using oral urate-lowering therapies. All participants had dual-energy computed tomography (DECT) scans of the feet and ankles at baseline. The proportion of participants achieving gout remission according to the 2016 preliminary gout remission criteria and simplified gout remission criteria (without the patient reported outcomes) was analyzed. Logistic regression models were used to evaluate predictors of gout remission in year 2. RESULTS: The preliminary gout remission criteria were fulfilled in 11 of 97 participants (11%) at year 1 and 21 of 92 participants (23%) at year 2. The simplified criteria were fulfilled in 26 of 97 participants (27%) in year 1 and 40 of 92 participants (44%) in year 2. In multivariable regression models, baseline DECT monosodium urate crystal volume was the only significant independent predictor of gout remission at year 2, using either criteria. Each 1-cm3 increase in the baseline DECT monosodium urate crystal volume decreased the odds of fulfilling the 2016 preliminary gout remission criteria (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.46-0.93; P = 0.02) and the simplified gout remission criteria (OR 0.57, 95% CI 0.41-0.78; P < 0.001). CONCLUSION: In people with erosive gout on urate-lowering therapy, higher baseline DECT monosodium urate crystal volume is associated with lower odds of gout remission after two years of treatment, defined by either the preliminary gout remission criteria or simplified gout remission criteria.

Comparison of outcomes of the 50-year follow-up of a randomized trial assessed by study questionnaire and by data linkage: The CONCUR study.

BACKGROUND/AIMS: Self-reported questionnaires on health status after randomized trials can be time-consuming, costly, and potentially unreliable. Administrative data sets may provide cost-effective, less biased information, but it is uncertain how administrative and self-reported data compare to identify chronic conditions in a New Zealand cohort. This study aimed to determine whether record linkage could replace self-reported questionnaires to identify chronic conditions that were the outcomes of interest for trial follow-up. METHODS: Participants in 50-year follow-up of a randomized trial were asked to complete a questionnaire and to consent to accessing administrative data. The proportion of participants with diabetes, pre-diabetes, hyperlipidaemia, hypertension, mental health disorders, and asthma was calculated using each data source and agreement between data sources assessed. RESULTS: Participants were aged 49 years (SD = 1, n = 424, 50% male). Agreement between questionnaire and administrative data was slight for pre-diabetes (kappa = 0.10), fair for hyperlipidaemia (kappa = 0.27), substantial for diabetes (kappa = 0.65), and moderate for other conditions (all kappa >0.42). Administrative data alone identified two to three times more cases than the questionnaire for all outcomes except hypertension and mental health disorders, where the questionnaire alone identified one to two times more cases than administrative data. Combining all sources increased case detection for all outcomes. CONCLUSIONS: A combination of questionnaire, pharmaceutical, and laboratory data with expert panel review were required to identify participants with chronic conditions of interest in this follow-up of a clinical trial.

Are toddlers with neurosensory impairment more difficult to follow up? A secondary analysis of the hPOD follow-up study.

OBJECTIVE: To describe strategies used to maximise follow-up after a neonatal randomised trial, how these differed for families of different ethnicity, socioeconomic status and urban versus rural residence and investigate relationships between the difficulty of follow-up and rate of neurosensory impairment. METHOD: hPOD was a multicentre randomised trial assessing oral dextrose gel prophylaxis for neonatal hypoglycaemia. Follow-up at 2 years was conducted from 2017 to 2021. We analysed all recorded contacts between the research team and participants' families. Neurosensory impairment was defined as blindness, deafness, cerebral palsy, developmental delay or executive function impairment. RESULTS: Of 1321 eligible participants, 1197 were assessed (91%) and 236/1194 (19.8%) had neurosensory impairment. Participants received a median of five contacts from the research team (range 1-23). Those from more deprived areas and specific ethnicities received more contacts, particularly home tracking visits and home assessments. Impairment was more common among participants receiving more contacts (relative risk 1.81, 95% CI 1.34 to 2.44 for ≥7 contacts vs <7 contacts), and among those assessed after the intended age (76/318, 23.9% if >25 months vs 160/876, 18.3% if ≤25 months). CONCLUSIONS: Varied contact strategies and long timeframes are required to achieve a high follow-up rate. Without these, the sociodemographics of children assessed would not have been representative of the entire cohort, and the rate of neurosensory impairment would have been underestimated. To maximise follow-up after randomised trials, substantial effort and resources are needed to ensure that data are useful for clinical decision-making.

Relationship between Neonatal Cerebral Fuels and Neurosensory Outcomes at 3 Years in Well Babies: Follow-Up of the Glucose in Well Babies (GLOW) Study.

INTRODUCTION: We sought to investigate if the availability of cerebral fuels soon after birth in healthy term babies was associated with developmental progress at 3 years of age. METHODS: Healthy term babies had plasma glucose, lactate, and beta-hydroxybutyrate concentrations measured over the first 5 days. At 3 years, parents completed Ages and Stages (ASQ-3) questionnaires between December 2018 and August 2022. Developmental progress, analysed using structural equation modelling, was compared between children whose median fuel concentrations were above and below the mean neonatal concentrations of glucose (3.3 mmol/L) and total ATP-equivalents (140 mmol/L) in the first 48 h and over the first 5 days. RESULTS: Sixty-four (96%) families returned completed questionnaires. We found no differences between developmental progress in children who had median neonatal plasma glucose concentrations <3.3 or ≥3.3 mmol/L in the first 48 h (estimated mean difference in ASQ scores -1.0, 95% confidence interval: -5.8, 3.7, p = 0.66) or 120 h (-3.7, -12.0, 4.6, p = 0.39]). There were also no differences for any other measures of cerebral fuels including total ATP above and below the median over 48 and 120 h, any plasma or interstitial glucose concentration <2.6 mmol/L, or cumulative duration of interstitial glucose concentration <2.6 mmol/L. CONCLUSIONS: There was no detectable relationship between plasma concentrations of glucose, lactate, and beta-hydroxybutyrate soon after birth in healthy term babies and developmental progress at 3 years of age.

Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. METHODS AND FINDINGS: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. CONCLUSIONS: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

Associations between neonatal nutrition and visual outcomes in 7-year-old children born very preterm.

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm. METHODS: The study cohort comprised children (n = 128) with birthweight <1500 g or gestational age < 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years' corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models. RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02). CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.

Prevalence and determinants of perinatal mental disorders in women with gestational diabetes in New Zealand: Findings from a national longitudinal study.

INTRODUCTION: Concurrent diagnosis of gestational diabetes mellitus and mental disorders is associated with adverse outcomes for mother and child, but there is limited information about prevalence or which women are at risk. MATERIAL AND METHODS: This study was a prospective cohort study of women with gestational diabetes from 10 hospitals in New Zealand who reported anxiety (6-item Spielberger State-Trait Anxiety Inventory), depression (Edinburgh Postnatal Depression Scale) and health-related quality of life (36-Item Short-Form General Health Survey) at time of gestational diabetes diagnosis (baseline), 36 weeks' gestation, and 6 months postpartum. Potential predictors were assessed using multivariable logistic regression. RESULTS: Among 414 respondents, 17% reported anxiety, 16% vulnerability to depression and 27% poor mental health-related quality of life at time of gestational diabetes diagnosis. At 36 weeks' gestation, prevalence decreased for vulnerability to depression (8%) and poor mental health-related quality of life (20%). Younger maternal age, Pacific ethnicity, previous history of gestational diabetes, and older gestational age at time of gestational diabetes diagnosis were associated with poorer mental health outcomes. At 6 months postpartum the prevalence of mental disorders did not differ from in late pregnancy and they were associated with later gestational age at time of gestational diabetes diagnosis and elevated 2-hour postprandial glucose concentrations. CONCLUSIONS: Perinatal mental disorders are common at time of diagnosis among women with gestational diabetes in New Zealand and had decreased by late pregnancy and at 6 months after birth. These disorders are more common among women with specific risk factors who may therefore benefit from additional support.

Maternal ethnicity and gestational age at birth predict hypoglycaemia among neonates of mothers with gestational diabetes.

AIM: Hypoglycaemia is common in neonates born to mothers with gestational diabetes mellitus (GDM). We aimed to determine predictors of hypoglycaemia among neonates of women with GDM and association with short-term outcomes. METHODS: We conducted a secondary cohort analysis of data from a multi-centre randomised trial (the TARGET trial) conducted across ten maternity hospitals in New Zealand between May 2015 and November 2017. Data were analysed using univariate analysis and multivariable forward stepwise logistic regression. RESULTS: Among 1085 neonates, those born to Asian mothers had reduced odds of hypoglycaemia (OR [95% CI]: 0.54 [0.38, 0.75], p = 0.001), as did those born at higher gestational ages (0.76 [0.68, 0.85], p < 0.001). Neonates born to Pacific mothers had increased odds of hypoglycaemia (OR [95% CI]: 1.57 [1.04, 2.39], p = 0.034). Neonates who experienced hypoglycaemia were more likely to experience neonatal intensive care unit admission (8.3% vs. 2.1%; p ≤ 0.001), hyperbilirubinaemia (8.6% vs. 3.3%; p ≤ 0.001) and receive respiratory support (11.4% vs. 4.8%; p ≤ 0.001) and less likely to be breastfed at discharge (92.4% vs. 96.2%; p = 0.009). CONCLUSION: Among neonates of women with GDM, maternal ethnicity and gestation at birth are independent predictors of hypoglycaemia, and hypoglycaemia is associated with short-term comorbidities. Additional surveillance may be appropriate for neonates in these high-risk groups.

The statistical challenge of analysing changes in dual energy computed tomography (DECT) urate volumes in people with gout.

BACKGROUND: Dual energy computed tomography (DECT) allows direct visualization of monosodium urate crystal deposition in gout. However, DECT urate volume data are often highly skewed (mostly small volumes with the remainder considerably larger), making statistical analyses challenging in longitudinal research. The aim of this study was to explore the ability of various analysis methods to normalise DECT urate volume data and determine change in DECT urate volumes over time. METHODS: Simulated datasets containing baseline and year 1 DECT urate volumes for 100 people with gout were created from two randomised controlled trials. Five methods were used to transform the DECT urate volume data prior to analysis: log-transformation, Box-Cox transformation, log(X-(min(X)-1)) transformation; inverse hyperbolic sine transformation, and rank order. Linear regression analyses were undertaken to determine the change in DECT urate volume between baseline and year 1. Cohen's d were calculated as a measure of effect size for each data treatment method. These analyses were then tested in a validation clinical trial dataset containing baseline and year 1 DECT urate volumes from 91 people with gout. RESULTS: No data treatment method successfully normalised the distribution of DECT urate volumes. For both simulated and validation data sets, significant reductions in DECT urate volumes were observed between baseline and Year 1 across all data treatment methods and there were no significant differences in Cohen's d effect sizes. CONCLUSIONS: Normalising highly skewed DECT urate volume data is challenging. Adopting commonly used transformation techniques may not significantly improve the ability to determine differences in measures of central tendency when comparing the change in DECT urate volumes over time.

The Tophus Impact Questionnaire (TIQ-20): responsiveness to change during urate-lowering therapy.

OBJECTIVES: In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy. METHODS: We analysed data from a two-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured using Vernier calipers and the TIQ-20 was recorded at study visits. Participants at the one site were invited into a dual energy CT (DECT) sub-study. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1, and Year 2 (n = 58, 39 with DECT data). Data were analysed using mixed model approach to repeated measures. RESULTS: Improvements were observed in all tophus measures over the two-year period. The mean (SD) TIQ-20 scores reduced over two years from 3.59 (1.77)-2.46 (1.73), P< 0.0001, and the mean (95%CI) TIQ-20 change over the two years was -1.13 (-1.54, -0.71). Effect size (Cohen's d) for the change in the sum of the index tophi diameter over two years was 0.68, for DECT urate volume was 0.50, and for the TIQ-20 was 0.71. CONCLUSION: For people with tophaceous gout treated with allopurinol using a treat to target serum urate approach, improvements in TIQ-20 occur, as well as improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact.

Associations Between Autism Spectrum Quotient and Integration of Visual Stimuli in 9-year-old Children: Preliminary Evidence of Sex Differences.

PURPOSE: The dorsal stream vulnerability hypothesis posits that the dorsal stream, responsible for visual motion and visuo-motor processing, may be particularly vulnerable during neurodevelopment. Consistent with this, autism spectrum disorder (ASD) has been associated with deficits in global motion integration, though deficits in ventral stream tasks, such as form identification, have also been reported. In the current study, we examined whether a similar pattern of results is found in a cohort of 381 children born with neurodevelopmental risk factors and exhibiting a wide spectrum of caregiver-reported autistic traits. METHODS: We examined the associations between global motion perception, global form perception, fine motor function, visual-motor integration, and autistic traits (autism spectrum quotient, AQ) using linear regression, accounting for possible interactions with sex and other factors relevant to neurodevelopment. RESULTS: All assessments of dorsal stream function were significantly associated with AQ such that worse performance predicted higher AQ scores. We also observed a significant sex interaction, with worse global form perception associated with higher AQ in boys (n = 202) but not girls (n = 179). CONCLUSION: We found widespread associations between dorsal stream functions and autistic traits. These associations were observed in a large group of children with a range of AQ scores, demonstrating a range of visual function across the full spectrum of autistic traits. In addition, ventral function was associated with AQ in boys but not girls. Sex differences in the associations between visual processing and neurodevelopment should be considered in the designs of future studies.

Did a Nocebo Effect Contribute to the Rise in Special Education Enrollment Following the Flint, Michigan Water Crisis?

Background: Exposure to waterborne lead during the Flint Water Crisis during April 2014-October 2015 is believed to have caused increased special education enrollment in Flint children. Method: This retrospective population-based cohort study utilized de-identified data for children under six years of age who had their blood lead tested during 2011 to 2019, and special education outcomes data for children enrolled in public schools for corresponding academic years (2011-12 to 2019-20) in Flint, Detroit (control city) and the State of Michigan. Trends in the following crisis-related covariates were also evaluated: waterborne contaminants, poverty, nutrition, city governance, school district policies, negative community expectations, media coverage and social media interactions. Results: Between 2011 and 2019, including the 2014-15 crisis period, the incidence of elevated blood lead in Flint children (≥ 5µg/dL) was always at least 47% lower than in the control city of Detroit (p < .0001) and was also never significantly higher than that for all children tested in Michigan (p = 0.33). Nonetheless, special education enrollment in Flint spiked relative to Detroit and Michigan (p < .0001). There is actually an inverse relationship between childhood blood lead and special education enrollment in Flint. Conclusion: This study failed to confirm any positive association between actual childhood blood lead levels and special education enrollment in Flint. Negative psychological effects associated with media predictions of brain damage could have created a self-fulfilling prophecy via a nocebo effect. The findings demonstrate a need for improved media coverage of complex events like the Flint Water Crisis.

Titration of medications and outcomes in multi-ethnic heart failure cohorts (with reduced ejection fraction) from Singapore and New Zealand.

AIMS: We investigated titration patterns of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta-blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all-cause mortality/heart failure (HF) hospitalization] in a real-world population with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi-centre study were examined for use and dose [relative to guideline-recommended maintenance dose (GRD)] of ACEis/ARBs and beta-blockers at baseline and 6 months. 'Stay low' was defined as <50% GRD at both time points, 'stay high' as ≥50% GRD, and 'up-titrate' and 'down-titrate' as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi-ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta-blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta-blockers. At 6 months, a large majority remained in the 'stay low' category, one third remained in 'stay high', whereas 10-16% up-titrated and 4-6% down-titrated. Patients with lower (vs. higher) N-terminal pro-beta-type natriuretic peptide levels were more likely to be up-titrated or be in 'stay high' for ACEis/ARBs and beta-blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of 'staying low' (all P < 0.005) for prescribed doses of ACEis/ARBs and beta-blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24-0.73] and ≥50% GRD for beta-blockers (HR = 0.58; 95% CI 0.37-0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. CONCLUSIONS: Although HF medication use at baseline was high, most patients did not have these medications up-titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up-titration of HF therapy (and its frequency), which could inform strategies for timely up-titration of HF therapy based on clinical and biochemical parameters.

Nitrate contamination in drinking water and adverse reproductive and birth outcomes: a systematic review and meta-analysis.

Exposure to low levels of nitrate in drinking water may have adverse reproductive effects. We reviewed evidence about the association between nitrate in drinking water and adverse reproductive outcomes published to November 2022. Randomized trials, cohort or case-control studies published in English that reported the relationship between nitrate intake from drinking water and the risk of perinatal outcomes were included. Random-effect models were used to pool data. Three cohort studies showed nitrate in drinking water is associated with an increased risk of preterm birth (odds ratio for 1 mg/L NO3-N increased (OR1) = 1.01, 95% CI 1.00, 1.01, I2 = 23.9%, 5,014,487 participants; comparing the highest versus the lowest nitrate exposure groups pooled OR (ORp) = 1.05, 95% CI 1.01, 1.10, I2 = 0%, 4,152,348 participants). Case-control studies showed nitrate in drinking water may be associated with the increased risk of neural tube defects OR1 = 1.06, 95% CI 1.02, 1.10; 2 studies, 2196 participants; I2 = 0%; and ORp = 1.51, 95% CI 1.12, 2.05; 3 studies, 1501 participants; I2 = 0%). The evidence for an association between nitrate in drinking water and risk of small for gestational age infants, any birth defects, or any congenital heart defects was inconsistent. Increased nitrate in drinking water may be associated with an increased risk of preterm birth and some specific congenital anomalies. These findings warrant regular review as new evidence becomes available.