Immune Function Effects of Dental Amalgam in Children: A Randomized Clinical Trial

Background Dental amalgam is a widely used restorative material containing 50% elemental mercury that emits mercury vapor. No randomized clinical trials have determined whether there are adverse immunologic effects associated with this low-level mercury exposure in children. The objective of this study was to evaluate a sub-population of the New England Children’s Amalgam Trial (NECAT) for in vitro manifestations of immunotoxic effects of dental amalgam. Methods A randomized clinical trial in which children requiring dental restorative treatment were randomized to either amalgam for posterior restorations or resin composite. A total of 66 children, aged 6–10 years, were assessed for total white cell numbers, T-cell, B-cell, neutrophil and monocyte responsiveness over a five-year period. Owing to the small number of participants, the study is exploratory in nature with limited statistical power. Results The mean number of tooth surfaces restored during the five-year period was 7.8 for the amalgam group and 10.1 for composite group. In the amalgam group there was a slight, but not statistically significant, decline in responsiveness of T-cells and monocytes at 5–7 days post treatment; no differences were consistently observed at 6, 12 or 60 months. Conclusions This study confirms that treatment of children with dental amalgams leads to increased, albeit low level, exposure to mercury. In this exploratory analysis of immune function, amalgam exposure did not cause overt immune deficits, although small transient effects were observed 5–7 days post restoration. Clinical implications These findings suggest that immunotoxic effects of amalgam restorations in children need not be a concern when choosing this restorative dental material

Dental Amalgam Restorations and Children’s Neuropsychological Function: The New England Children’s Amalgam Trial

BACKGROUND: A concern persists that children’s exposure to mercury vapor from dental amalgams produces neurotoxicity. OBJECTIVE: Our goal was to compare the neuropsychological function of children, without prior exposure to dental amalgam, whose caries were repaired using either dental amalgam or mercury-free composite materials. METHODS: We conducted a randomized controlled trial involving 534 6- to 10-year-old urban and rural children who were assessed yearly for 5 years using a battery of tests of intelligence, achievement, language, memory, learning, visual–spatial skills, verbal fluency, fine motor function, problem solving, attention, and executive function. RESULTS: Although the mean urinary mercury concentration was greater among children in the amalgam group than the composite group (0.9 vs. 0.6 μg/g creatinine), few significant differences were found between the test scores of children in the two groups. The differences found were inconsistent in direction. Analyses using two cumulative exposure indices—surface years of amalgam and urinary mercury concentration—produced similar results. CONCLUSIONS: Exposure to elemental mercury in amalgam at the levels experienced by the children who participated in the trial did not result in significant effects on neuropsychological function within the 5-year follow-up period

Blood lead level and dental caries in school-age children.

The association between blood lead level and dental caries was evaluated in cross-sectional analyses of baseline data for 543 children 6-10 years old screened for enrollment in the Children's Amalgam Trial, a study designed to assess potential health effects of mercury in silver fillings. Approximately half of the children were recruited from an urban setting (Boston/Cambridge, MA, USA) and approximately half from a rural setting (Farmington, ME, USA). Mean blood lead level was significantly greater among the urban subgroup, as was the mean number of carious tooth surfaces. Blood lead level was positively associated with number of caries among urban children, even with adjustment for demographic and maternal factors and child dental practices. This association was stronger in primary than in permanent dentition and stronger for occlusal, lingual, and buccal tooth surfaces than for mesial or distal surfaces. In general, blood lead was not associated with caries in the rural subgroup. The difference between the strength of the associations in the urban and rural settings might reflect the presence of residual confounding in the former setting, the presence of greater variability in the latter setting in terms of important caries risk factors (e.g., fluoride exposure), or greater exposure misclassification in the rural setting. These findings add to the evidence supporting a weak association between children's lead exposure and caries prevalence. A biologic mechanism for lead cariogenicity has not been identified, however. Our data are also consistent with residual confounding by factors associated with both elevated lead exposure and dental caries

Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function

BACKGROUND Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood. OBJECTIVES The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF. METHODS In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term. RESULTS WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF. CONCLUSIONS Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF. (c) 2021 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved

Spironolactone for heart failure with preserved ejection fraction

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure

Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans

IMPROVE trial: A randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies

BACKGROUND: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. PURPOSE: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. METHODS: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. RESULTS: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. LIMITATIONS: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. LESSONS LEARNED: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. CONCLUSIONS: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials

The menopausal syndrome

Results of a postal questionnaire survey of 638 women aged 45 to 54, living in the London area in 1964-65, indicate (consistently with other recent surveys) that hot flushes and night sweats are clearly associated with the onset of a natural menopause and that they occur in the majority of women. Hot flushes were reported to occur more frequently (usually daily) and over more of the body by women whose menstrual flow showed evidence of change or cessation, and for 25% of those women whose menses had ceased for at least one year, hot flushes persisted for five years or more. The other six symptoms specified, namely, headaches, dizzy spells, palpitations, sleeplessness, depression, and weight increase, showed no direct relationship to the menopause but tended to occur together, each being reported by approximately 30 to 50% of the respondents with little variation according to menopausal status. None of the six sociodemographic variables investigated, i.e., employment status, school leaving age, social class, domestic workload, marital status, and parity, had any marked association with the reported frequency of symptoms. The majority of respondents did not anticipate or experience any difficulties and only about 10% expressed regret at the cessation of menses. Despite embarrassment and/or discomfort from hot flushes, reported by nearly three-quarters of those experiencing this symptom, only one-fifth had apparently sought medical treatment