Peptide-based approaches to directly target alpha-synuclein in Parkinson's disease.

Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson's disease and related synucleinopathies. The subsequent formation of toxic, intracellular, Lewy body deposits, in which alpha-synuclein is a major component, is a key diagnostic hallmark of the disease. To reach their therapeutic site of action, peptides must both cross the blood-brain barrier and enter dopaminergic neurons to prevent the formation of these intracellular inclusions. In this review, we describe and summarise the current efforts made in the development of peptides and their mimetics to directly engage with alpha-synuclein with the intention of modulating aggregation, and importantly, toxicity. This is a rapidly expanding field with great socioeconomic impact; these molecules harbour significant promise as therapeutics, or as early biomarkers during prodromal disease stages, or both. As these are age-dependent conditions, an increasing global life expectancy means disease prevalence is rising. No current treatments exist to either prevent or slow disease progression. It is therefore crucial that drugs are developed for these conditions before health care and social care capacities become overrun.

A Turbine-Driven Ventilator Improves Adherence to Advanced Cardiac Life Support Guidelines During a Cardiopulmonary Resuscitation Simulation.

BACKGROUND: Research has shown that increased breathing frequency during cardiopulmonary resuscitation is inversely correlated with systolic blood pressure. Rescuers often hyperventilate during cardiopulmonary resuscitation (CPR). Current American Heart Association advanced cardiac life support recommends a ventilation rate of 8-10 breaths/min. We hypothesized that a small, turbine-driven ventilator would allow rescuers to adhere more closely to advanced cardiac life support (ACLS) guidelines. METHODS: Twenty-four ACLS-certified health-care professionals were paired into groups of 2. Each team performed 4 randomized rounds of 2-min cycles of CPR on an intubated mannikin, with individuals altering between compressions and breaths. Two rounds of CPR were performed with a self-inflating bag, and 2 rounds were with the ventilator. The ventilator was set to deliver 8 breaths/min, pressure limit 22 cm H2O. Frequency, tidal volume (VT), peak inspiratory pressure, and compression interruptions (hands-off time) were recorded. Data were analyzed with a linear mixed model and Welch 2-sample t test. RESULTS: The median (interquartile range [IQR]) frequency with the ventilator was 7.98 (7.98-7.99) breaths/min. Median (IQR) frequency with the self-inflating bag was 9.5 (8.2-10.7) breaths/min. Median (IQR) ventilator VT was 0.5 (0.5-0.5) L. Median (IQR) self-inflating bag VT was 0.6 (0.5-0.7) L. Median (IQR) ventilator peak inspiratory pressure was 22 (22-22) cm H2O. Median (IQR) self-inflating bag peak inspiratory pressure was 30 (27-35) cm H2O. Mean ± SD hands-off times for ventilator and self-inflating bag were 5.25 ± 2.11 and 6.41 ± 1.45 s, respectively. CONCLUSIONS: When compared with a ventilator, volunteers ventilated with a self-inflating bag within ACLS guidelines. However, volunteers ventilated with increased variation, at higher VT levels, and at higher peak pressures with the self-inflating bag. Hands-off time was also significantly lower with the ventilator. (ClinicalTrials.gov registration NCT02743299.).

Enhancing developmentally oriented primary care: an Illinois initiative to increase developmental screening in medical homes.

In 2005, the Enhancing Developmentally Oriented Primary Care (EDOPC) project of the Illinois chapter of the American Academy of Pediatrics and the Illinois Department of Healthcare and Family Services began a project to improve the delivery and financing of preventive health and developmental services for children in Illinois. The leaders of this initiative sought to increase primary care providers' use of validated tools for developmental, social/emotional, maternal depression, and domestic violence screening and to increase early awareness of autism symptoms during pediatric well-child visits in children aged 0 to 3 years. These screenings facilitate identification of children at risk and those who need referral for further evaluation. Primary barriers to such screenings include lack of practitioner confidence in using validated screening tools. In this article we describe the accomplishments of the EDOPC project, which created training programs to address these barriers. This training is delivered by EDOPC staff and peer educators (physicians and nurse practitioners) in medical practices. The EDOPC project enhanced confidence and intent to screen among a large group of Illinois primary health care providers. Among a sample of primary care sites at which chart reviews were conducted, the EDOPC project increased developmental screening rates to the target of 85% of patients at most sites and increased social/emotional screening rates to the same target rate in nearly half of the participating practices.