Association between CNS-active drugs and risk of Alzheimer's and age-related neurodegenerative diseases.

Objective: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated. Research design and methods: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals. Results: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction. Conclusion: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.

Breast cancer therapies reduce risk of Alzheimer's disease and promote estrogenic pathways and action in brain.

Worldwide, an ever-increasing number of women are prescribed estrogen-modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast.

The P2Network-Advancing Pediatric Emergency Care With Point-of-Care Ultrasound.

ABSTRACT: Over the last 2 decades, the use of point-of-care ultrasound (POCUS) in pediatric emergency medicine (PEM) has grown exponentially. In 2014, a group of PEM POCUS leaders met and formed the P2Network. The P2Network provides a platform to build collaborative relationships and share expertise among members from various countries and practice settings. It works with educators and researchers within and outside of the field to advance POCUS practice in PEM. As an organization, the P2Network promotes the evidence-based application of POCUS to facilitate and improve care in the PEM setting and addresses issues related to integration of the PEM POCUS practitioner in this nascent field. The P2Network is building and augmenting its infrastructure for PEM POCUS research and education and has already made some progress in the areas, with published manuscripts and ongoing clinical research studies under its sponsorship. Future goals include developing a PEM POCUS research agenda, formalizing teaching and assessment of PEM POCUS skills, and implementing multicenter research studies on potentially high impact applications.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

BACKGROUND AND AIMS: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. RESULTS: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Point-of-Care Ultrasound for Pediatric Endotracheal Tube Placement Confirmation by Advanced Practice Transport Nurses.

OBJECTIVE: This study aimed to identify which point-of-care ultrasound (POCUS) techniques and sonographic signs were reliably acquired and interpreted by transport nurses for the confirmation of endotracheal tube placement in children. METHODS: We developed and assessed a multimodal POCUS training curriculum for transport nurses that evaluated 5 sonographic signs using 3 scanning techniques. RESULTS: Twenty-one transport nurses were enrolled in the curriculum. The mean scores (95% confidence interval [CI]) of the knowledge test were 82% (95% CI, 63%-93%), 88% (95% CI, 68%-95%), and 74% (95% CI, 53%-87%) for tracheal, lung, and hemidiaphragmatic scans, respectively. For the simulation image evaluation, 94% (95% CI, 77%-99%) of tracheal scan images, 97% (95% CI, 81%-99%) of lung scan images, and 88% (95% CI, 69%-96%) of hemidiaphragmatic scan images were determined clinically useful. For the pediatric intensive care unit image evaluation, 100% (95% CI, 86%-100%) of tracheal scan images, 100% (95% CI, 86%-100%) of lung scan images, and 79% (95% CI, 59%-91%) of hemidiaphragmatic scan images were determined clinically useful. A tracheal dilation sign was rarely captured by POCUS. CONCLUSION: Transport nurses can acquire POCUS skills to confirm endotracheal tube placement in children. A combination of a double trachea sign, a lung sliding sign, and a lung pulse sign could be a feasible POCUS approach.

Pediatric Concussion Management in the Emergency Department: A National Survey of Parents.

OBJECTIVE: To examine parental expectations and beliefs about diagnosis and management of pediatric concussion. STUDY DESIGN: We conducted a cross-sectional web-based survey of a nationally representative panel of US parents in March 2014. Parents of 10- to 17-year-old children responded to questions about their expectations and beliefs about diagnosis and management of pediatric concussion in the emergency department (ED). Weighted percentages for descriptive statistics were calculated, and χ2 statistics were used for bivariate analysis. RESULTS: Survey participation was 53%, and of 912 parent respondents with a child 10-17 years of age who were presented with a scenario of their child having mild symptoms of concussion, 42% would seek immediate ED care. Parents who would seek immediate ED care for this scenario were more likely than parents who would consult their child's usual provider or wait at home to "definitely expect" imaging (65% vs 21%), definitive diagnosis of concussion (77% vs 61%), a timeline for return to activity (80% vs 60%), and a signed return to play form (55% vs 41%). CONCLUSIONS: Many parents who bring children to the ED following a possible concussion are likely to expect comprehensive and definitive care, including imaging, a definitive diagnosis, a timeline for return to activity, and a signed return to play form. To manage these expectations, healthcare providers should continue to educate parents about the evaluation and management of concussion.

Acute vitamin D intoxication in a child.

We present the unique case of a previously healthy, 2-year-old boy with resistant hypercalcemia and hypertension resulting from an unintentional overdose with an imported vitamin D supplement. The patient presented initially to the emergency department with colic and constipation and was discharged after a benign physical examination. The symptoms persisted and, on the second visit, the patient was found to have a serum calcium level of 14.4 mg/dL. Despite therapy with intravenously administered 5% dextrose solution at one-half normal strength, furosemide, calcitonin, and hydrocortisone, the calcium concentration increased to 15.0 mg/dL on the second hospital day and did not decrease until the fourth hospital day, when it fell to 13.9 mg/dL. The vitamin D concentration peaked at 470 ng/mL on hospital day 3. With additional questioning, the mother revealed that she had been giving her son a daily dose of 1 ampule of Raquiferol, an imported vitamin D supplement, instead of the recommended 2 drops per day. Each ampule contained 600,000 IU of vitamin D; therefore, the boy received a total of 2,400,000 IU over 4 days. The patient's hypercalcemia persisted for 14 days and was complicated by persistent hypertension. No renal, cardiac, or neurologic complications were noted. At discharge, the vitamin D concentration was still elevated at 389 ng/mL and the total calcium level had decreased to 11 mg/dL. The boy made a complete clinical recovery. This case highlights the need for caution when using imported and/or unregulated medicines, as well as the dangers of parental dosing errors.