Pediatric pharmacodynamics of midazolam oral syrup. Pediatric Pharmacology Research Unit Network

In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.     

Testosterone : testosterone estradiol binding globulin ratio in evaluating hirsute women

Testosterone : testosterone estradiol binding globulin (TEBG) ratio is evaluated in 35 hirsute women (age 12 to 38 years), and 14 healthy nonhirsute normal controls (age 21 to 40 years). This is an attempt to emphasize the significance of TEBG in evaluating hirsute women. This is a significant negative linear correlation between the weight of the patients and TEBG concentrations (r = 0.414, P less than 0.05). There is negative linear correlation between TEBG and serum free testosterone concentration that reached significance only in the hirsute nonobese. T:TEBG ratio is significantly high in hirsute women compared to the controls. T:TEBG ratio shows a significant positive linear correlation with free testosterone concentration. In addition, T:TEBG ratio is a direct simple method of evaluating hirsute women. Demulen and Dexamethazone treatment produced a significant fall in T:TEBG ratio in hirsute women.     

Hypothalamic-pituitary function following bromocriptine therapy in patients with prolactinomas

Bromocriptine in a dose of 5 mg daily was given to 18 patients with prolactinomas to promote resumption of menses, to overcome infertility and as a primary treatment for the tumor. Serum prolactin levels fell to within the normal range in 95% of the patients by 12 weeks of therapy. The prolactin response to TRH stimulation was significantly less than before treatment; however, the percent maximum increment was significantly higher. There was no significant change in pituitary reserve of the other hormones. Seven pregnancies occurred during treatment. All the pregnancies have been progressing normally. All patients have already been delivered of healthy babies, including one set of twins. It is suggested that follow-up studies of the various pituitary hormones be conducted on patients on maintenance bromocriptine treatment. In addition, bromocriptine treatment might be used to promote fertility in patients with prolactin-secreting microadenomas.     

An assessment of grafts in the posterior cricoid lamina

Subglottic stenosis is a recognized complication of prolonged intubation. To date, there is no uniformly successful operative procedure for severe subglottic stenosis, fulfilling the criteria of decannulation and a serviceable voice. The surgical ideals for such a procedure should include the use of autogenous grafting material, avoidance of internal stenting, and limited manipulation of the mucosa. This study was intended to assess the fate of isolated hyoid and thyroid alar grafts interposed in the posterior cricoid lamina. Additionally, anterior/posterior splits with and without anterior grafting were evaluated. Seventeen dogs were used in the determinate animal model. Vocal cord mobility was evaluated by direct laryngoscopy prior to sacrifice. Graphic gross anatomical specimens depict the effects of anterior/posterior splitting on the cricoid cartilage. Clinical correlations are suggested.     

Confocal imaging of the fundus using a scanning laser ophthalmoscope.

A confocal scanning laser ophthalmoscope (cSLO) was used to examine the effects of confocal optics on the image of the human fundus in vivo. Patients from a retinal clinic and a glaucoma clinic were examined using the cSLO in the confocal mode. A degree of optical sectioning could be achieved, and the results agree with a best axial resolution of 300 microns measured in a model eye. The main advantage of using a confocal system was found to be the improved contrast of the images. This improved the resolution of structures such as the lamina cribrosa and optic disc drusen which are seen in low contrast in conventional images. The improved contrast of the confocal images is partly achieved by excluding light which has been scattered within the plane of focus. Structures which multiply scatter light will become less visible with confocal optics and hard exudates were found to be an example of such a structure. The cSLO and the fundus camera are seen as complementary instruments rather than as alternatives for imaging the fundus. It is envisaged that confocal imaging will enable details of the fundus to be revealed which are at present not seen in conventional images.     

The Role of Parental ADHD in Sustaining the Effects of a Family-School Intervention for ADHD

This study investigated the extent to which parental Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms impact child and parent outcomes following a multimodal family–school intervention, the Family School Success (FSS) program, when compared to an active-control condition (CARE). Participants were 139 children with ADHD (67% male; 91% non-Hispanic; 77% Caucasian; Grades 2–6) and their primary caretaker (91% female; ages 26–59) who participated in a randomized clinical trial evaluating the efficacy of FSS. Associations were examined between parent-reported ADHD symptoms at baseline and intervention outcomes reported by parents and teachers after treatment and at a 3-month follow-up, including child homework and classroom impairments, child ADHD and oppositional defiant disorder symptoms, parenting behaviors, and parent–teacher relationship quality. Across both treatment conditions, parental ADHD was not associated with parent or child outcomes at postassessment. However, differences emerged between the two treatment groups at follow-up for parents with ADHD, particularly when an empirically supported symptom cutoff was used to identify parents at risk for having ADHD. In FSS, but not in CARE, parental ADHD was associated with declines in treatment gains in the quality of the parent–teacher relationship and the child's homework performance. Parents at risk for ADHD had difficulty maintaining treatment effects for themselves and their child in the FSS intervention but not in CARE. The supportive and educational components central to the CARE intervention may be helpful in promoting the sustainability of psychosocial interventions for children with ADHD who have parents with elevated ADHD symptoms.     

Location-specific strategies for eliminating US national racial-ethnic [... formula ...] exposure inequality

Air pollution levels in the United States have decreased dramatically over the past decades, yet national racial-ethnic exposure disparities persist. For ambient fine particulate matter (PM2.5), we investigate three emission-reduction approaches and compare their optimal ability to address two goals: 1) reduce the overall population average exposure (“overall average”) and 2) reduce the difference in the average exposure for the most exposed racial-ethnic group versus for the overall population (“national inequalities”). We show that national inequalities in exposure can be eliminated with minor emission reductions (optimal: ~1% of total emissions) if they target specific locations. In contrast, achieving that outcome using existing regulatory strategies would require eliminating essentially all emissions (if targeting specific economic sectors) or is not possible (if requiring urban regions to meet concentration standards). Lastly, we do not find a trade-off between the two goals (i.e., reducing overall average and reducing national inequalities); rather, the approach that does the best for reducing national inequalities (i.e., location-specific strategies) also does as well as or better than the other two approaches (i.e., sector-specific and meeting concentration standards) for reducing overall averages. Overall, our findings suggest that incorporating location-specific emissions reductions into the US air quality regulatory framework 1) is crucial for eliminating long-standing national average exposure disparities by race-ethnicity and 2) can benefit overall average exposures as much as or more than the sector-specific and concentration-standards approaches.

The Clean Air Act has dramatically reduced outdoor air pollution levels in the United States, with (during 1990 through 2020) aggregate benefits exceeding costs 30-to-1 ($2 trillion versus $65 billion) (1). Important regulatory strategies include the National Ambient Air Quality Standards (NAAQS) and sector-specific emission-reduction technology requirements (e.g., Best Achievable Control Technology [BACT] standards). However, exposure inequalities persist (2–7). Disparities by race-ethnicity are larger than, and distinct from, those by income (4–6, 8, 9). Racial-ethnic inequalities in US ambient air pollution and subsequent exposures are attributable in part to racist planning, including historical, race-based housing segregation and land-use practices (10–18). Environmental racism scholars have suggested that strategies and policies for eliminating disparities will be most effective when racial-ethnic injustices are centered and directly addressed (19–22).The existing literature documents exposure inequities (3–7, 9, 23–26) and investigates the impacts on inequities of emission changes for specific sources (e.g., refs. 27–36) or locations (37–43). However, the scientific literature has not investigated how to eliminate national racial-ethnic inequalities in air pollution or what level of emission reduction would be required to do so (44).We examine three potential approaches to reduce or eliminate national exposure inequalities: 1) location-specific emission reductions (hereafter, “location”), 2) sector-specific emission reductions (“sector”; analogous to BACT-type approaches), and 3) requiring regions to meet a concentration standard (“NAAQS-like”). Approaches 2 and 3 mirror aspects of current regulations; approach 1 would be a new regulatory approach. We find that the location approach is by far the most effective (can eliminate national disparities with only small absolute emission reductions); the sector approach is poor (can reduce disparities, but requires substantially larger emission reductions; cannot eliminate disparities except by eliminating nearly all emissions); and NAAQS-like is the least effective (does not eliminate disparities). The location approach is also the strongest of the three for reducing population-average exposures.To quantitatively compare the three approaches, we use the publicly available InMAP (Intervention Model for Air Pollution) source-receptor matrix (ISRM) (45) to estimate long-term average ambient fine particulate matter (PM2.5) concentrations across the contiguous United States caused by anthropogenic emissions in 2014. Disparity here refers to the difference between population-weighted average PM2.5 concentrations for the most exposed racial-ethnic group minus the overall population (in sensitivity analyses, we instead investigate government-designated “high vulnerability” [HV] locations; Materials and Methods). ISRM predicts the concentration of primary PM2.5 and secondary PM2.5 formed from nitrogen oxides (NOx), sulfur oxides (SOx), ammonia (NH3), and volatile organic compounds (VOCs). We employ the 2014 US Environmental Protection Agency (EPA) National Emission Inventory, grouped into 14 source sectors (see Fig. 2B, SI Appendix, and below). ISRM contains 52,411 grid cells (locations) with size (i.e., spatial resolution) ranging from 1 km in densely populated urban centers to 48 km in sparsely populated rural areas; the average spatial resolution is 2.6 km in Urban Areas and 22.6 km in non-Urban Areas (13.2 km overall). Emissions reductions for location and sector are an optimization to maximally reduce disparities for the most exposed group relative to the overall population average. They use the spatial resolution of the simulation grid and the 14 source sectors, respectively. Thus, our results inform what that method could optimally do to reduce or eliminate racial-ethnic exposure disparities. The NAAQS-like approach simulates successive, proportional emission reductions in each region violating the hypothetical NAAQS (e.g., 6 µg/m3), until the NAAQS-like standard is met.Open in a separate windowFig. 2.Emission reductions for the three approaches: by location (i.e., corresponding to the green lines, Fig. 1) (A), by sector (corresponding to blue lines, Fig. 1) (B), and NAAQS-like (orange lines, Fig. 1) (C). A displays national results (Left) and zoomed-in results for 10 large areas (Right). Spatial units displayed in C are CBSAs, the geographic unit for NAAQS evaluation. The three approaches offer fundamentally different ways of formulating and prioritizing emission reductions. Ag., agriculture; Const., construction; Elec., electricity; HD, heavy duty; LD, light duty; Misc., miscellaneous; Res., residential; Veh., vehicle.