Can Genetic Markers Predict the Sporadic Form of Alzheimer's Disease? An Updated Review on Genetic Peripheral Markers.

Alzheimer's disease (AD) is the most common form of dementia that affects millions of individuals worldwide. Although the research over the last decades has provided new insight into AD pathophysiology, there is currently no cure for the disease. AD is often only diagnosed once the symptoms have become prominent, particularly in the late-onset (sporadic) form of AD. Consequently, it is essential to further new avenues for early diagnosis. With recent advances in genomic analysis and a lower cost of use, the exploration of genetic markers alongside RNA molecules can offer a key avenue for early diagnosis. We have here provided a brief overview of potential genetic markers differentially expressed in peripheral tissues in AD cases compared to controls, as well as considering the changes to the dynamics of RNA molecules. By integrating both genotype and RNA changes reported in AD, biomarker profiling can be key for developing reliable AD diagnostic tools.

New Laplace and Helmholtz solvers.

Numerical algorithms based on rational functions are introduced that solve the Laplace and Helmholtz equations on 2D domains with corners quickly and accurately, despite the corner singularities.

A Provider-Focused Intervention to Promote Optimal Care of Pediatric Patients With Suspected Elbow Fracture.

OBJECTIVE: Emergency department (ED) and urgent care (UC) physicians' accurate assessment of the neurovascular and musculoskeletal (NV/MSK) examination in pediatric patients with suspected elbow fracture is crucial to the early recognition of neurovascular compromise. Our objective was to determine the impact of computer-based simulation (CBS) and computerized clinical decision support systems (CCDSS) on ED and UC physicians' assessment of the NV/MSK examination of pediatric patients with elbow fracture as noted in their documentation. METHODS: All ED UC physician participants received CBS training about management of pediatric patients with suspected elbow fracture. Participants were then randomized to receive CCDSS (intervention arm) when an eligible patient was seen or no further intervention (comparison arm.) Participants received feedback on the proportion of patients with discharge diagnosis of elbow fracturewith proper examination elements documented. RESULTS: Twenty-eight ED and UC physicians were enrolled - 14 in each arm. Over the span of 16 weeks, 50 patients with a discharge diagnosis of elbow fracture were seen - 25 in each arm. Twenty-two of 25 (88%) patients seen by intervention arm participants had a complete NV/MSK examination documented. Six of 25 (24%) patients seen by comparison arm participants had a complete NV/MSK examination documented. Elements most commonly missed in the comparison arm included documentation of ulnar pulse as well as radial, median, and ulnar nerve motor functions. CONCLUSIONS: Compared with single CBS training alone, repeated exposure to CCDSS after CBS training resulted in improved documentation of the NV/MSK status of pediatric patients with elbow fracture.

Electronic health record as a research tool: Frequency of exposure to targeted clinical problems and health care providers' clinical proficiency.

OBJECTIVES: The Electronic Health Record (EHR) could provide insight into possible decay in health care providers' (HCP) clinical knowledge and cognitive performance. Analyses of the contributions of variables such as frequency of exposure to targeted clinical problems could inform the development and testing of appropriate individualized interventions to mitigate these threats to quality and safety of care. MATERIALS/METHODS: Nine targeted clinical problems (TCP) were selected for further study, and de-identified, aggregated study data were obtained for one calendar year. Task analysis interviews of subspecialty physicians defined optimal management of each TCP and guided specification of quality of care metrics that could be extracted from the EHR. The Δ-t statistic, days since the provider's prior encounter with a given TCP, quantified frequency of exposure. RESULTS: Frequency of patient encounters ranged from 1566 to 220,774 visits across conditions. Mean Δ-t ranged from 1.72days to 30.79days. Maximum Δ-t ranged from 285 to 497days. The distribution of Δ-t for the TCPs generally fit a Gamma distribution (P<0.001), indicating that Δ-t conforms to a Poisson process. A quality of care metric derived for each TCP declined progressively with increasing Δ-t for 8 of the 9 TCPs, affirming that knowledge decay was detectable from EHR data. DISCUSSION/CONCLUSIONS: This project demonstrates the utility of the EHR as a research tool in studies of health care delivery in association with frequency of exposure of HCPs to TCPs. Subsequent steps in our research include multivariate modeling of clinical knowledge decay and randomized trials of pertinent preventive interventions.

Relationship Between Abdominal Adiposity and Exercise Tolerance in Children With Obesity.

PURPOSE: To determine whether abdominal obesity is associated with lower exercise tolerance in children. METHODS: Waist-to-height ratios (WHtRs) were determined for 50 children aged 8 to 12 years with body mass index greater than the 95th percentile and 6-minute walk distance (6MWD) conducted. RESULTS: Mean 6MWD was found to be 510 (standard deviation = 60) m. Univariate analysis revealed that WHtR was the only significant predictor of 6MWD (P = .01). In modeling using multiple regression analysis, 26% of the variance in 6MWD could be attributed to the participant's age, WHtR, and sex; WHtR was the only significant contributor to 6MWD (P = .001). CONCLUSION: WHtR was the most strongly correlated factor with distance achieved on the 6-minute walk test, a measure of exercise tolerance, and is an important measure to screen for cardiovascular disease risk and to prompt further evaluation of functional exercise capacity.

Reliability of Common Lower Extremity Biomechanical Measures of Children With and Without Obesity.

PURPOSE: To determine intrarater and interrater reliability of common measures of lower extremity alignment among children with obesity. METHODS: The Craig test for femoral anteversion, tibiofemoral angle, Foot Posture Index-6, and sit-and-reach test were performed on 25 children without obesity and 25 children with obesity. RESULTS: Intrarater reliability of all measures in both groups was high. The Craig test demonstrated greatest variability with slight interrater reliability in children who were nonobese [intraclass correlation coefficient [ICC] (95% confidence interval [CI]), 0.372 (-0.051 to 0.6420)] and moderate reliability in children who were obese [ICC (95% CI), 0.527 (0.242 to 0.717)]. Interrater reliability for the tibiofemoral angle and Foot Posture Index-6 was moderate to substantial and for the sit-and-reach test was substantial (ICC >0.99) and highly correlated. Measurement of lower extremity alignment among children with obesity was more reproducible than among children who were not obese. CONCLUSIONS: Measures of lower extremity alignment and general flexibility in children with obesity are both reproducible and reliable.

Hypoxia induced changes in expression of proteins involved in iron uptake and storage in cultured lens epithelial cells.

Hypoxia inducible factor (HIF) regulates expression of over 60 genes by binding to hypoxia response elements (HRE) located upstream of the transcriptional start sites. Many genes encoding proteins involved in iron transport and homeostasis are regulated by HIF. Expression of iron handling proteins can also be translationally regulated by binding of iron regulatory protein (IRP) to iron responsive elements (IREs) on the mRNA of ferritin chains and transferrin receptor (TfR). Lens epithelial cells (LEC) function in a low oxygen environment. This increases the risk of iron catalyzed formation of reactive oxygen species (ROS) and oxidative cell damage. We examined changes in expression of ferritin (iron storage protein) and Tf/TfR1 (iron uptake proteins) in LEC cultured under hypoxic conditions. Ferritin consists of 24 subunits of two types, heavy (H-chain) and light (L-chain) assembled in a cell specific ratio. Real-time PCR showed that 24 h exposure to hypoxia lowered transcription of both ferritin chains by over 50% when compared with normoxic LEC. However it increased the level of ferritin chain proteins (20% average). We previously found that 6 h exposure of LEC to hypoxia increased the concentration of cytosolic iron which would stimulate translation of ferritin chains. This elevated ferritin concentration increased the iron storage capacity of LEC. Hypoxic LEC labeled with 59FeTf incorporated 70% more iron into ferritin after 6 h as compared to normoxic LEC. Exposure of LEC to hypoxia for 24 h reduced the concentration of TfR1 in cell lysates. As a result, hypoxic LEC internalized less Tf at this later time point. Incorporation of 59Fe into ferritin of hypoxic LEC after 24 h did not differ from that of normoxic LEC due to lower 59FeTf uptake. This study showed that hypoxia acutely increased iron storage capacity and lowered iron uptake due to changes in expression of iron handling proteins. These changes may better protect LEC against oxidative stress by limiting iron-catalyzed ROS formation in the low oxygen environment in which the lens resides.

Patient-Reported Outcomes to Describe Global Health and Family Relationships in Pediatric Weight Management.

Background: Patient-reported outcomes (PROs) can assess chronic health. The study aims were to pilot a survey through the PEDSnet Healthy Weight Network (HWN), collecting PROs in tertiary care pediatric weight management programs (PWMP) in the United States, and demonstrate that a 50% enrollment rate was feasible; describe PROs in this population; and explore the relationship between child/family characteristics and PROs. Methods: Participants included 12- to 18-year-old patients and parents of 5- to 18-year-olds receiving care at PWMP in eight HWN sites. Patient-Reported Outcomes Measurement Information System (PROMIS®) measures assessed global health (GH), fatigue, stress, and family relationships (FR). T-score cut points defined poor GH or FR or severe fatigue or stress. Generalized estimating equations explored relationships between patient/family characteristics and PROMIS measures. Results: Overall, 63% of eligible parents and 52% of eligible children enrolled. Seven sites achieved the goal enrollment for parents and four for children. Participants included 1447 children. By self-report, 44.6% reported poor GH, 8.6% poor FR, 9.3% severe fatigue, and 7.6% severe stress. Multiple-parent household was associated with lower odds of poor GH by parent proxy report [adjusted odds ratio (aOR) 0.69, 95% confidence interval (CI) 0.55-0.88] and poor FR by self-report (aOR 0.36, 95% CI 0.17-0.74). Parents were significantly more likely to report that the child had poor GH and poor FR when a child had multiple households. Conclusions: PROs were feasibly assessed across the HWN, although implementation varied by site. Nearly half of the children seeking care in PWMP reported poor GH, and family context may play a role. Future work may build on this pilot to show how PROs can inform clinical care in PWMP.

Whole systems approach to diet and healthy weight: a longitudinal process evaluation in East Scotland.

AIMS: Obesity contributes to morbidity and early mortality, affecting people of all ages and sociodemographic backgrounds. Despite attempts to address obesity, efforts to date have only had limited success. Adopting a whole systems approach (WSA) may potentially address obesity and emphasise complex inter-relating factors beyond individual choice. This study aimed to assess implementation of WSA to diet and healthy weight in two council areas of Scotland, longitudinally exploring enablers and barriers. One area followed a Leeds Beckett WSA model (LBM) of implementation, while the other used a hybrid model incorporating existing working systems. METHODS: To assess the process of implementing a WSA, interviews and focus groups were conducted after initiation and 1 year later. RESULTS: Main enablers included: belief in WSA effectiveness; positive relationships between key personnel; buy-in at community and national levels; funding availability; the working group responsible for coordinating the system development comprising individuals with diverse expertise; good communication; and existing governance structures. Barriers included: insufficient funding; high staff turnover; inadequate training in WSA methodology; engaging all relevant stakeholders and reverting to 'old ways' of non-WSA working. The LBM provided a framework for system setup and generating an action plan. CONCLUSION: This study provides the first independent longitudinal process evaluation of WSAs that have incorporated Leeds Beckett methodology, and offers insights into how a WSA can be implemented to address diet and healthy weight.

Infants with Congenital Adrenal Hyperplasia Exhibit Thalamic Discrepancies in Early Brain Structure.

INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study the brain structure in infants with CAH compared to healthy controls. METHODS: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency (8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age [PCA] 42.2 ± 3.0 weeks) and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses (mean, 95% confidence interval [CI]). The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex. RESULTS: Infants with CAH had significantly smaller thalamic volumes (8,606 mm3, 95% CI [8,209, 9,002]) compared to age-matched control infants (9,215 mm3, 95% CI [8,783, 9,647]; ß = -609; p = 0.02) which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH (66,817 mm3, CI [65,957, 67,677]) compared to controls (65,616 mm3, CI [64,680, 66,551]; ß = 1,202, p = 0.03). The brain regions most differentiated between CAH versus controls were the thalamus (22%) and parietal lobe (10%). CONCLUSIONS: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8-14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.

Parent perceptions to promote a healthier lifestyle for their obese child.

Parents of children referred to a pediatric multidisciplinary weight-management clinic were queried regarding the importance of and their readiness to promote healthy lifestyle behaviors with their children and also regarding their confidence in their ability to adopt those changes. Among the 193 children's parents who completed a questionnaire (93.7% response), greater than 75% of respondents recognized the importance of healthy eating and physical activity, and many indicated feeling both confident and ready to make changes. Surprisingly, even among those not confident, parents also indicated they were ready to change their child's eating (p < .001). This study explores the discrepancy between parents indicating a high level of importance and readiness to promote healthy lifestyle behaviors but having less confidence that they would actually be able to enact change.

Upskilling the surgical workforce for vascular access provision during the COVID-19 pandemic - The Salisbury experience.

A vascular access device is defined as a catheter inserted into veins allowing fluids and medicines to be delivered intravenously1. The need for such devices in acutely unwell patients has remained steady throughout the COVID-19 pandemic. We describe here our experience of up-skilling the resident plastic surgery and maxillofacial surgical registrars to provide a vascular access service to reduce the workload on our intensive care colleagues. We hope that our practice and an 'all hands on deck' approach to the utilisation of baseline skills within the existing workforce will inform other departments to help ease the burden on critical care departments as we progress through the next stages of the COVID-19 pandemic.

Exponential node clustering at singularities for rational approximation, quadrature, and PDEs.

Rational approximations of functions with singularities can converge at a root-exponential rate if the poles are exponentially clustered. We begin by reviewing this effect in minimax, least-squares, and AAA approximations on intervals and complex domains, conformal mapping, and the numerical solution of Laplace, Helmholtz, and biharmonic equations by the "lightning" method. Extensive and wide-ranging numerical experiments are involved. We then present further experiments giving evidence that in all of these applications, it is advantageous to use exponential clustering whose density on a logarithmic scale is not uniform but tapers off linearly to zero near the singularity. We propose a theoretical model of the tapering effect based on the Hermite contour integral and potential theory, which suggests that tapering doubles the rate of convergence. Finally we show that related mathematics applies to the relationship between exponential (not tapered) and doubly exponential (tapered) quadrature formulas. Here it is the Gauss-Takahasi-Mori contour integral that comes into play.

Epigenetic Regulation of miR-92a and TET2 and Their Association in Non-Hodgkin Lymphoma.

MicroRNAs (miRNAs) are well known for their ability to regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. In various cancers, miRNAs regulate gene expression by altering the epigenetic status of candidate genes that are implicated in various difficult to treat haematological malignancies such as non-Hodgkin lymphoma by acting as either oncogenes or tumour suppressor genes. Cellular and circulating miRNA biomarkers could also be directly utilised as disease markers for diagnosis and monitoring of non-Hodgkin lymphoma (NHL); however, the role of DNA methylation in miRNA expression regulation in NHL requires further scientific inquiry. In this study, we investigated the methylation levels of CpGs in CpG islands spanning the promoter regions of the miR-17-92 cluster host gene and the TET2 gene and correlated them with the expression levels of TET2 mRNA and miR-92a-3p and miR-92a-5p mature miRNAs in NHL cell lines, tumour samples, and the whole blood gDNA of an NHL case control cohort. Increased expression of both miR-92a-3p and miR-92a-5p and aberrant expression of TET2 was observed in NHL cell lines and tumour tissues, as well as disparate levels of dysfunctional promoter CGI methylation. Both miR-92a and TET2 may play a concerted role in NHL malignancy and disease pathogenesis.

Testing the Use of Data Drawn from the Electronic Health Record to Compare Quality.

INTRODUCTION: Health systems spend $1.5 billion annually reporting data on quality, but efficacy and utility for benchmarking are limited due, in part, to limitations of data sources. Our objective was to implement and evaluate measures of pediatric quality for three conditions using electronic health record (EHR)-derived data. METHODS: PCORnet networks standardized EHR-derived data to a common data model. In 13 health systems from 2 networks for 2015, we implemented the National Quality Forum measures: % children with sickle cell anemia who received a transcranial Doppler; % children on antipsychotics who had metabolic screening; and % pediatric acute otitis media with amoxicillin prescribed. Manual chart review assessed measure accuracy. RESULTS: Only 39% (N = 2,923) of 7,278 children on antipsychotics received metabolic screening (range: 20%-54%). If the measure indicated screening was performed, the chart agreed 88% of the time [95% confidence interval (CI): 81%-94%]; if it indicated screening was not done, the chart agreed 86% (95% CI: 78%-93%). Only 69% (N = 793) of 1,144 children received transcranial Doppler screening (range across sites: 49%-88%). If the measure indicated screening was performed, the chart agreed 98% of the time (95% CI: 94%-100%); if it indicated screening was not performed, the chart agreed 89% (95% CI: 82%-95%). For acute otitis media, chart review identified many qualifying cases missed by the National Quality Forum measure, which excluded a common diagnostic code. CONCLUSIONS: Measures of healthcare quality developed using EHR-derived data were valid and identified wide variation among network sites. This data can facilitate the identification and spread of best practices.

Quality Improvement Project to Promote Identification and Treatment of Children With Obesity Admitted to Hospital.

Among children hospitalized for acute problems, comorbid obesity is commonly unaddressed. The objective was to improve identification and initial management of obesity among hospitalized children. In collaboration with nurses and dietitians, pediatric hospitalists of 2 children's hospitals conducted a quality improvement project to improve body mass index (BMI) documentation, obesity diagnosis, diet, and nutrition consultation through clinician education, development of computerized clinical decision-support system tools, and workflow modifications. Participants received monthly performance feedback. Among those with elevated BMI, diagnosis rose to 70.2%; a documented obesity diagnosis was associated with being 35 times more likely (P < .001) to receive at least 1 intervention while hospitalized. Participants reported an increase in skill in (27%), comfort with (27%), and knowledge of (33%) obesity management. Improvement in health care provider recognition and management of obesity in the inpatient setting is achievable. Additional work is needed to identify how best to sustain desired practice patterns.

Impact of a Personalized Audit and Feedback Intervention on Antibiotic Prescribing Practices for Outpatient Pediatric Community-Acquired Pneumonia.

Antibiotic choice for pediatric community-acquired pneumonia (CAP) varies widely. We aimed to determine the impact of a 6-month personalized audit and feedback program on primary care providers' antibiotic prescribing practices for CAP. Participants in the intervention group received monthly personalized feedback. We then analyzed enrolled providers' CAP antibiotic prescribing practices. Participants diagnosed 316 distinct cases of CAP (214 control, 102 intervention); among these 316 participants, 301 received antibiotics (207 control, 94 intervention). In patients ≥5 years, the intervention group had fewer non-guideline-concordant antibiotics prescribed (22/103 [21.4%] control; 3/51 [5.9%] intervention, P < .05) and received more of the guideline-concordant antibiotics (amoxicillin and azithromycin). Personalized, scheduled audit and feedback in the outpatient setting was feasible and had a positive impact on clinician's selection of guideline-recommended antibiotics. Audit and feedback should be combined with other antimicrobial stewardship interventions to improve guideline adherence in the management of outpatient CAP.

Use of EHR-Based Pediatric Quality Measures: Views of Health System Leaders and Parents.

Measures of health care quality are produced from a variety of data sources, but often, physicians do not believe these measures reflect the quality of provided care. The aim was to assess the value to health system leaders (HSLs) and parents of benchmarking on health care quality measures using data mined from the electronic health record (EHR). Using in-context interviews with HSLs and parents, the authors investigated what new decisions and actions benchmarking using data mined from the EHR may enable and how benchmarking information should be presented to be most informative. Results demonstrate that although parents may have little experience using data on health care quality for decision making, they affirmed its potential value. HSLs expressed the need for high-confidence, validated metrics. They also perceived barriers to achieving meaningful metrics but recognized that mining data directly from the EHR could overcome those barriers. Parents and HSLs need high-confidence health care quality data to support decision making.

Tuberculosis and Biologic Therapies: Anti-Tumor Necrosis Factor-α and Beyond.

Biologic drugs have revolutionized the treatment of certain hematologic, autoimmune, and malignant diseases, but they may place patients at risk for reactivation or acquisition of tuberculosis. This risk is highest with the tumor necrosis factor-alpha (TNF-α) inhibitors. Amongst this class of drugs, the monoclonal antibodies (infliximab, adalimumab, golimumab) and antibody fragment (certolizumab) carry an increased risk compared to the soluble receptor fusion molecule, etanercept. Treatment of latent TB is critical to decrease the risk of reactivation. Data continues to emerge regarding tuberculosis risk associated with novel biologics targeting cytokines involved in tuberculosis control.