APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology.

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants.

loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology.

The ε4 allele of apolipoprotein E () is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of loss-of-function (LoF) on AD pathogenesis is unknown. We searched for LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of LoF variants.

Time-Averaged Wavefront Analysis Demonstrates Preferential Pathways of Atrial Fibrillation, Predicting Pulmonary Vein Isolation Acute Response.

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI).

Anti-infective Waste in a Pediatric Institution: Pinpointing Problems in the Process.

At Children's Hospital Colorado (CHCO), there are approximately 40 000 inpatient anti-infective orders every year resulting over 100 000 dispenses. Significant quantities of anti-infectives are wasted, incurring roughly $100 000 in waste annually. Identifying areas for improvement will result in cost savings and ameliorate the impact of drug shortages.

Evaluation of the reentry vulnerability index to predict ventricular tachycardia circuits using high-density contact mapping.

Background: Identifying arrhythmogenic sites to improve ventricular tachycardia (VT) ablation outcomes remains unresolved. The reentry vulnerability index (RVI) combines activation and repolarization timings to identify sites critical for reentrant arrhythmia initiation without inducing VT.

Objective: The purpose of this study was to provide the first assessment of RVI's capability to identify VT sites of origin using high-density contact mapping and comparison with other activation-repolarization markers of functional substrate.

Managing Paediatric Growth Disorders: Integrating Technology Into a Personalised Approach.

Long-term growth management can be challenging for patients, families and healthcare professionals (HCP). Personalised optimal responses to growth hormone (GH) therapy depend on the creation of a good working relationship between the patient and family and the HCPs responsible for care. Current unmet needs in growth management will be discussed, focusing on the likelihood of a poor growth response and its identification and management with emphasis on the importance of good adherence to GH therapy.

Sustainability of Handshake Stewardship: Extending a Hand Is Effective Years Later.

Background: Children's Hospital Colorado created a unique method of antimicrobial stewardship, called handshake stewardship, that effectively decreased hospital anti-infective use and costs in its pilot year (2013). Handshake stewardship is distinguished by: (1) the lack of prior authorization; (2) a review of all prescribed anti-infectives; (3) a shared review by the physician and the pharmacist; and (4) a daily, rounding-based, in-person approach to supporting providers. We sought to reevaluate the outcomes of the program after 5 years of experience, totaling 8 years of data.

Hospital-wide Description of Clinical Indications for Pediatric Anti-infective Use.

Purpose: This study is the first description of hospital-wide anti-infective use according to clinical indication for a pediatric hospital. Children's Hospital Colorado (CHCO) is uniquely poised to examine its anti-infective use after the implementation of provider-selected order indications (PSOIs), which are distinct from Diagnosis Related Group classifications in that they are used for clinical treatment as opposed to final diagnosis codes for billing and thus are more granular.

Methods: This study used our institution's mandatory PSOIs to describe overall clinical indications for anti-infective use.

Hypoventilation, cardiac dysrhythmia, and cardiac arrest following acute Brunfelsia species (Yesterday, today, tomorrow) intoxication in a dog.

Background: Intoxication following ingestion of the popular garden shrub 'Yesterday, today, tomorrow' (Brunfelsia sp.) is known to result in gastrointestinal and central nervous system clinical signs in dogs.

Case Report: A 2-year-old dog developed acute-onset vomiting, profuse diarrhoea and ptyalism after unsupervised access to an enclosed backyard that contained a Brunfelsia sp.

Pulse Arrival Time and Pulse Interval as Accurate Markers to Detect Mechanical Alternans.

Mechanical alternans (MA) is a powerful predictor of adverse prognosis in patients with heart failure and cardiomyopathy, but its use remains limited due to the need of invasive continuous arterial pressure recordings. This study aims to assess novel cardiovascular correlates of MA in the intact human heart to facilitate affordable and non-invasive detection of MA and advance our understanding of the underlying pathophysiology. Arterial pressure, respiration, and ECG were recorded in 12 subjects with healthy ventricles during voluntarily controlled breathing at different respiratory rate, before and after administration of beta-blockers.

Immunoregulatory Activity of the Natural Product Laminarin Varies Widely as a Result of Its Physical Properties.

Ligation of Dectin-1 by fungal glucans elicits a Th17 response that is necessary for clearing many fungal pathogens. Laminarin is a (1→3, 1→6)-β-glucan that is widely reported to be a Dectin-1 antagonist, however, there are reports that laminarin is also a Dectin-1 agonist. To address this controversy, we assessed the physical properties, structure, purity, Dectin-1 binding, and biological activity of five different laminarin preparations from three different commercial sources.

Left Atrial Appendage Thrombus in Transcatheter Aortic Valve Replacement: Incidence, Clinical Impact, and the Role of Cardiac Computed Tomography.

Objectives: The aim of this study was to describe the incidence and clinical impact of left atrial appendage thrombus (LAAT) in a population referred for transcatheter aortic valve replacement (TAVR) and to examine the role of cardiac computed tomography (CCT) in the diagnosis of LAAT.

Background: Atrial fibrillation is common in patients undergoing TAVR. Embolization of LAAT is a potential mechanism of periprocedural stroke.

Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children.

One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules.

Management of paediatric tuberculosis in leading UK centres: unveiling consensus and discrepancies.

Setting: Large specialist paediatric TB clinics in the UK.

Objective: To evaluate clinical practice and compare with national and international guidelines.

Design: A survey based on an electronic questionnaire on the management of latent tuberculous infection (LTBI) and tuberculosis (TB) disease was conducted in 13 specialist paediatric TB clinics.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Background: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.

Methods: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010.

Viability assessment for artificial gametes: the need for biomarkers of functional competency.

Assisted reproductive technology (ART) has resulted in more than 5 million births worldwide. However, mainstream ART techniques are not always successful for an estimated 30% of infertile patients in whom gametes are nonviable. Most patients would clearly prefer genetic parenthood, currently possible only via the use of donated gametes or, in future, via the clinical use of artificial gametes (AGs) incorporating parental DNA.

Usefulness of serum brain natriuretic peptide to predict adverse events in patients with the Eisenmenger syndrome.

The aim of this study was to evaluate the prognostic value of brain natriuretic peptide (BNP) in outpatients with the Eisenmenger syndrome (ES). BNP is often elevated in patients with cyanotic congenital heart disease. The clinical utility of BNP in patients with cyanotic congenital heart disease and the ES has not been clearly delineated.

Patients with single-ventricle physiology: prognostic implications of stress testing.

This study used a retrospective analysis of adults with single-ventricle physiology to ascertain the predictive power of cardiopulmonary stress-testing parameters in determining patients at increased risk of suffering from adverse clinical outcomes. We found that the specific parameters of percent of maximum predicted heart rate achieved and maximum oxygen consumption were significantly correlated with adverse clinical outcomes in patients with single-ventricle congenital heart disease.

Dilated neonatal cisterna magna and Marfan syndrome.

The authors report the incidental finding of a dilated cisterna magna with an abnormal configuration to the falx in a newborn infant with Marfan syndrome who was recruited to a research study involving whole body MRI. To our knowledge, dilation of the cisterna magna has not previously been reported in patients with Marfan syndrome. Potential implications for antenatal diagnosis, the ethics of recruiting healthy volunteers for research and directions for future work are discussed.

Arrhythmia recurrence in adult patients with single ventricle physiology following surgical Fontan conversion.

Objectives: To evaluate the incidence of atrial tachy-arrhythmia (AT) recurrence following conversion from right atrial-pulmonary artery (RA-PA) Fontan to total cavopulmonary connection (TCPC) in adults.

Background: AT is a recognized sequel of Fontan palliation, especially in RA-PA Fontans, and is associated with significant morbidity. While catheter ablation achieves fairly reliable short-term success with low morbidity, conversion to TCPC with arrhythmia surgery is a highly effective treatment option for the classical Fontan patients with incessant AT.

Two-dimensional and Doppler echocardiography reliably predict severe pulmonary regurgitation as quantified by cardiac magnetic resonance.

Background: The grading of pulmonary regurgitation (PR) severity by two-dimensional (2D) and Doppler echocardiography is not standardized. Cardiovascular magnetic resonance imaging is the clinical gold standard for PR quantification. The purpose of this study was to determine the best 2D and Doppler echocardiographic predictors of severe PR.