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Background: Free thyroxine (fT4) is often ordered when not indicated. The goal of the current study was to use quality improvement tools to identify and implement an optimal approach to reduce inappropriate fT4 testing throughout a large pediatric hospital system., Methods: After reviewing evidence-based guidelines and best practices, a thyroid-stimulating hormone with reflex to fT4 test and an outpatient thyroid order panel with clinical decision support at order entry, along with several rounds of provider education and feedback, were implemented. Outpatient and inpatient order sets and system preference lists were reviewed with subject matter experts and revised when appropriate. Tracking metrics were identified. Automated monthly run charts and statistical process control charts were created using data retrieved from the electronic health record. Charts established baseline data, balancing measure data, monitored the impact of interventions, and identified future interventions., Results: Over a 44-month period, among nonendocrinology providers, a reduction in fT4 and thyroid-stimulating hormone co-orders from 67% to 15% and an increase in reflex fT4 tests from 0% to 77% was obtained in inpatient and outpatient settings. Direct cost savings as a result of performing 5179 fewer fT4 tests over 3 years was determined to be $45 800., Conclusions: After implementation of a reflex fT4 test, a novel order panel with clinical decision support, provider education, and changes to ordering modes, a large and sustainable reduction in fT4 tests that was associated with significant cost savings was achieved among nonendocrinology providers., (Copyright © 2024 by the American Academy of Pediatrics.)

Biodegradable polyesters are a popular choice for both packaging and medical device manufacture owing to their ability to break down into harmless components once they have completed their function. However, commonly used polyesters such as poly(hydroxybutyrate) (PHB), poly(lactic acid) (PLA), and polycaprolactone (PCL), while readily available and have a relatively low price compared to other biodegradable polyesters, do not meet the degradation profiles required for many applications. As such, this study aimed to determine if the mechanical and degradation properties of biodegradable polymers could be tailored by blending different polymers. The seawater degradation mechanisms were evaluated, revealing surface erosion and bulk degradation in the blends. The extent of degradation was found to be dependent on the specific chemical composition of the polymer and the blend ratio, with degradation occurring via hydrolytic, enzymatic, oxidative, or physical pathways. PLA presents the highest tensile strength (67 MPa); the addition of PHB and PCL increased the flexibility of the samples; however, the tensile strength reduced to 25.5 and 18 MPa for the blends 30/50/20 and 50/25/25, respectively. Additionally, PCL presented weight loss of up to 10 wt.% and PHB of up to 6 wt.%; the seawater degradation in the blends occurs by bulk and surface erosion. The blending process facilitated the flexibility of the blends, enabling their use in diverse industrial applications such as medical devices and packaging. The proposed methodology produced biodegradable blends with tailored properties within a seawater environment. Additionally, further tests that fully track the biodegradation process should be put in place; incorporating compatibilizers might promote the miscibility of different polymers, improving their mechanical properties and biodegradability.

Objectives: Our goal with this initiative was to reduce discharge opioid prescriptions while maintaining optimal pain management through the use of standardized pain prescribing guidelines for pediatric patients after orthopedic surgical procedures., Methods: Through analysis of established yet inconsistent prescribing practices, we created a 4-tiered guideline for pediatric orthopedic postoperative pain management prescription ordering. Following the Model for Improvement methodology including iterative plan-do-study-act cycles, the team created an electronic medical record order set to be used at discharge from the hospital. The provider compliance with this order set was monitored and analyzed over time by using provider-level and aggregate control charts. A secondary measure of opioid prescriptions (morphine milligram Eq [MME] dosage per patient) was tracked over time. The balancing measure was the analysis of unanticipated opioid prescription refills., Results: Greater than 90% compliance with the guidelines was achieved and sustained for 20 months. This resulted in a 54% reduction in opioids prescribed during the improvement period (baseline = 71 MME per patient; postintervention = 33 MME per patient) and has been sustained for 12 months. The percentage of unanticipated opioid prescription refills did not significantly change from the period before the institution of the guidelines and after institution of the guidelines (2017 = 3%; 2019 = 3%)., Conclusions: The creation of these guidelines has led to a significant reduction in the number of opioids prescribed while maintaining effective postoperative pain management., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

The mineralocorticoid receptor (MR)/glucocorticoid receptor balance plays an important role in the pathophysiology of anxiety and depression. Aldosterone, a primary MR ligand, seems to be related to the pathophysiology of anxiety and depressive symptoms. The objective of this study was to investigate effects of aldosterone excess on sleep EEG, as sleep EEG is a tool to gain insight into psychoneuroendocrine function. Here, 19 untreated patients (9 males, 10 females) suffering from primary aldosteronism were investigated using sleep EEG and several rating scales for anxiety, depression, quality of life and sleep before starting specific treatment. Parameters were compared to age and sex matched healthy controls and patients with depression and correlated with laboratory findings and blood pressure. Patients had higher values for anxiety and depression compared to the general population, although a psychiatric disorder in their history was ruled out. Although sleep disturbances were reported in the Pittsburgh sleep quality index, sleep EEG did not show significant changes between patients and healthy controls. No depression specific pattern in sleep EEG was found. But in contrast to females, several sleep-EEG parameters of male PA patients differed significantly from patients with depression. There was a significant correlation between blood pressure and the severity of depression and anxiety in females. Correlation analysis between blood pressure and rating scales indicate a relationship between blood pressure and anxiety in women. In conclusion, these data suggest gender related effects of aldosterone excess in males and females., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.

Cardiovascular disease often develops during childhood, but the determinants of vascular health and disease in young children remain unclear. The study aimed to investigate the association of obesity and hypertension, as well as physical fitness with retinal microvascular health and large artery stiffness, in children. In this cross-sectional study, 1171 primary school children (aged 7.2±0.4 years) were screened for central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) diameters, pulse wave velocity (PWV), body mass index, blood pressure (BP), and cardiorespiratory fitness by standardized procedures for children. BP was categorized according to the reference values of the population-based German KiGGS study (Kinder- und Jugendgesundheitssurvey [Children- and Adolescents Health Survey]) and the American Academy of Pediatrics guidelines. Overweight (mean [95% CI]: CRAE, 200.5 [197.9-203.2] µm; CRVE, 231.4 [228.6-234.2] µm; PWV, 4.46 [4.41-4.52] m/s) and obese children (CRAE, 200.5 [196.4-204.7] µm; CRVE, 233.3 [229.0-237.7] µm; PWV, 4.51 [4.43-4.60] m/s) had narrower CRAE, wider CRVE, and higher PWV compared with normal-weight children (CRAE: 203.3 [202.5-204.1] µm, P<0.001; CRVE: 230.1 [229.1-230.9] µm, P=0.07; PWV: 4.33 [4.31-4.35] m/s, P<0.001). Children with high-normal BP (CRAE, 202.5 [200.0-205.0] µm; PWV, 4.44 [4.39-4.49] m/s) and BP in the hypertensive range (CRAE, 198.8 [196.7-201.0] µm; PWV, 4.56 [4.51-4.60] m/s) showed narrower CRAE, as well as higher PWV, compared with normotensive peers (CRAE: 203.7 [202.9-204.6] µm, P<0.001; PWV: 4.30 [4.28-4.32] m/s, P<0.001). With each unit increase of body mass index and systolic BP, CRAE decreased and PWV increased significantly. Children with the highest cardiorespiratory fitness had wider CRAE, narrower CRVE, and lower PWV compared with least fit children. Childhood obesity and hypertension, even at preclinical stages, are associated with microvascular and macrovascular impairments in young children. Primary prevention programs targeting physical activity behavior may have the potential to counteract development of small and large vessel disease early in life. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02853747.

Humans have circulating antibodies against diverse glycans containing N -glycolylneuraminic acid (Neu5Gc) due to function-loss mutation of the CMAH gene. This xenogenic non-human carbohydrate is abundant in red meat, xenografts and biotherapeutics. Low levels of diet-derived Neu5Gc is also present on normal human endothelial cells, and together with anti-Neu5Gc antibodies could potentially mediate "xenosialitis" chronic-inflammation. Rabbit anti-human thymocyte globulin (ATG) is a drug containing polyclonal IgG glycoproteins commonly used as an immunosuppressant in human transplantation and autoimmune diseases. In type-1 diabetes patients, infusion of Neu5Gc-glycosylated ATG caused increased global anti-Neu5Gc response. Here, for the first time we explore changes in anti-Neu5Gc IgG repertoire following the immunization elicited by ATG, compared with the basal antibodies repertoire that reflect exposure to dietary-Neu5Gc. We used glycan microarrays with multiple Neu5Gc-glycans and controls to elucidate eventual differences in ATG-elicited repertoire, before/after ATG administration and track their kinetics (0, 1, 18 and 24 months). Response of all basal-pre-existing Neu5Gc-specific antibodies rapidly increased. This response peaked at one month post-ATG, with enhanced affinity, then resolved at 18-24 months. Induced-antibodies showed expanded diversity and de-novo recognition of different Neu5Gc-glycans, including endogenous glycolipids, that was further validated by affinity-purified anti-Neu5Gc antibodies from patients' sera. These findings strongly suggest that ATG-induced anti-Neu5Gc IgGs represent a secondary exposure to this dietary carbohydrate-antigen in humans, with immune memory. Given their modified recognition patterns, ATG-evoked anti-Neu5Gc antibodies could potentially mediate biological effects different from pre-existing antibodies., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

The interaction of BamHI endonuclease with DNA has been studied crystallographically, but has not been characterized rigorously in solution. The enzyme binds in solution as a homodimer to its recognition site GGATCC. Only six base-pairs are directly recognized, but binding affinity (in the absence of the catalytic cofactor Mg(2+)) increases 5400-fold as oligonucleotide length increases from 10 to 14 bp. Binding is modulated by sequence context outside the recognition site, varying about 30-fold from the bes t (GTG or TAT) to the worst (CGG) flanking triplets. BamHI, EcoRI and EcoRV endonucleases all have different context preferences, suggesting that context affects binding by influencing the free energy levels of the complexes rather than that of the free DNA. Ethylation interference footprinting in the absence of divalent metal shows a localized and symmetrical pattern of phosphate contacts, with strong contacts at NpNpNpGGApTCC. In the presence of Mg(2+), first-order cleavage rate constants are identical in the two GGA half-sites, are the same for the two nicked intermediates and are unaffected by substrate length in the range 10-24 bp. DNA binding is strongly enhanced by mutations D94N, E111A or E113K, by binding of Ca(2+) at the active site, or by deletion of the scissile phosphate GpGATCC, indicating that a cluster of negative charges at the catalytic site contributes at least 3-4 kcal/mol of unfavorable binding free energy. This electrostatic repulsion destabilizes the enzyme-DNA complex and favors metal ion binding and progression to the transition state for cleavage., (Copyright 2001 Academic Press.)

Background: Site-specific protein-DNA complexes vary greatly in structural properties and in the thermodynamic strategy for achieving an appropriate binding free energy. A better understanding of the structural and energetic engineering principles might lead to rational methods for modification or design of such proteins., Results: A novel analysis of ten site-specific protein-DNA complexes reveals a striking correspondence between the degree of imposed DNA distortion and the thermodynamic parameters of each system. For complexes with relatively undistorted DNA, favorable enthalpy change drives unfavorable entropy change, whereas for complexes with highly distorted DNA, unfavorable DeltaH degrees is driven by favorable DeltaS degrees. We show for the first time that protein-DNA associations have isothermal enthalpy-entropy compensation, distinct from temperature-dependent compensation, so DeltaH degrees and DeltaS degrees do not vary independently. All complexes have favorable DeltaH degrees from direct protein-DNA recognition interactions and favorable DeltaS degrees from water release. Systems that strongly distort the DNA nevertheless have net unfavorable DeltaH degrees as the result of molecular strain, primarily associated with the base pair destacking. These systems have little coupled protein folding and the strained interface suffers less immobilization, so DeltaS degrees is net favorable. By contrast, systems with little DNA distortion have net favorable DeltaH degrees, which must be counterbalanced by net unfavorable DeltaS degrees, derived from loss of vibrational entropy (a result of isothermal enthalpy-entropy compensation) and from coupling between DNA binding and protein folding., Conclusions: Isothermal enthalpy-entropy compensation implies that a structurally optimal, unstrained fit is achieved only at the cost of entropically unfavorable immobilization, whereas an enthalpically weaker, strained interface entails smaller entropic penalties.

Restriction endonuclease EcoRV has been reported to be unable to distinguish its specific DNA site, GATATC, from non-specific DNA sites in the absence of the catalytic cofactor Mg2+, and thus to exercise sequence specificity solely in the catalytic step. In contrast, we show here that under appropriate conditions of pH and salt concentration, specific complexes with oligonucleotides containing the GATATC site can be detected by either filter-binding or gel-retardation. Equilibrium binding constants (K(A)) are easily measured by both direct equilibrium and equilibrium-competition methods. The preference for "specific" over "non-specific" binding at pH 7 in the absence of divalent cations is about 1000-fold (per mole of oligonucleotide) or 12,000-fold (per mole of binding sites). Ethylation-interference footprinting shows that the "specific" complex includes strong contacts to the phosphate groups GpApTpApTC. Specific DNA binding is strongly pH-dependent, decreasing about 15-fold for each increase of one pH unit above pH 6, but non-specific binding is not; thus, binding specificity decreases with increasing pH. Gel retardation and filter-binding at pH < or = 7 yield essentially identical values of K(A) for specific-site binding, but at pH > 7 gel retardation significantly underestimates K(A). Specific-site binding is stimulated about 700-fold by Ca2+ (not a cofactor for cleavage), but with non-cleavable 3'-phosphorothiolate and 4'-thiodeoxyribose derivatives whose response to Ca2+ is similar to that of the parent oligonucleotide, Mg2+ stimulates binding only fourfold and twofold, respectively. Thus, binding specificity is not dramatically enhanced by Mg2+. Taking into account discrimination in binding and in the first-order rate constant for phosphodiester bond scission, the overall discrimination exercised against the incorrect site GTTATC is about 10(7)-fold. EcoRV endonuclease is thus not a "new paradigm" for site-specific interaction without binding specificity, but like other type II restriction endonucleases achieves sequence specificity by discriminating both in DNA binding and in catalysis.

We investigated the influence of nutrition and exercise interventions within cognitive/behavioral and public health formats on weight and blood lipid profiles in obese children. Compliance was also examined as well as the relationship of the compliance measures with clinical outcome variables. Three conditions were compared over 16 sessions: nutrition and eating-habit change followed by exercise (NE), exercise followed by nutrition and eating-habit change (EN), and an information control (INFO). NE and EN were presented in a cognitive/ behavioral framework which focused on the development of self-regulation whereas the INFO condition received the same material in a public health/educational model. NE and EN participants evidenced modest, yet significant, reductions in weight and blood lipids, and the impact of these two interventions endured at a five-year follow-up. In contrast, INFO participants displayed stable weight and blood lipids during the course of the program, and most remained morbidly obese at follow-up. Improved nutrition, increased physical activity and fitness were significantly correlated with weight and lipid reductions.

Proposed binge eating disorder (BED) diagnostic criteria were investigated to provide necessary psychometric characteristics and explore their utility in assessment. One hundred four subjects (52 self-referred bingers, 52 comparison subjects) completed an initial administration of the Questionnaire of Eating and Weight Patterns (QEWP). The results supported the ability of the two core BED criteria (i.e., episodic overeating, loss of control) to discriminate between clinical and nonclinical binge eaters. Thirty-nine of the self-referred and 40 of the comparison subjects completed a second QEWP administration 3 weeks later. Results indicated that the BED diagnosis was moderately stable over the 3-week interval (kappa = .58, combined sample). Using self-monitoring data completed by the self-referred subjects, predictive efficiency analyses indicated that the QEWP was able to identify both high and low probability binge eaters. Implications of the findings for the definition, assessment, and utility of the BED diagnosis are discussed.