G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.

Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials.

Bushfires and Mothers' Mental Health in Pregnancy and Recent Post-Partum.

Background: The compounding effects of climate change catastrophes such as bushfires and pandemics impose significant burden on individuals, societies, and their economies. The enduring effects of such syndemics on mental health remain poorly understood, particularly for at-risk populations (e.g.

Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity.

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain.

Heatwaves and wildfires suffocate our healthy start to life: time to assess impact and take action.

Adverse environmental exposures in utero and early childhood are known to programme long-term health. Climate change, by contributing to severe heatwaves, wildfires, and other natural disasters, is plausibly associated with adverse pregnancy outcomes and an increase in the future burden of chronic diseases in both mothers and their babies. In this Personal View, we highlight the limitations of existing evidence, specifically on the effects of severe heatwave and wildfire events, and compounding syndemic events such as the COVID-19 pandemic, on the short-term and long-term physical and mental health of pregnant women and their babies, taking into account the interactions with individual and community vulnerabilities.

Parental perceptions on the impact of visiting restrictions during COVID-19 in a tertiary neonatal intensive care unit.

Aim: During the first wave of coronavirus disease 2019 (COVID-19), visiting guidelines in neonatal units changed to maintain the health and safety of staff, neonates, and families. In the neonatal intensive care unit/special care nursery (NICU/SCN), restrictions were placed on parental contact and extended family excluded. Our team was interested in evaluating the effect of these restrictions on parental stress and discharge confidence.

Extubation generates lung volume inhomogeneity in preterm infants.

Objective: To evaluate the feasibility of electrical impedance tomography (EIT) to describe the regional tidal ventilation (V) and change in end-expiratory lung volume (EELV) patterns in preterm infants during the process of extubation from invasive to non-invasive respiratory support.

Design: Prospective observational study.

Setting: Single-centre tertiary neonatal intensive care unit.

Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor.

Background: A common genetic mutation that causes Parkinson's disease (PD) is the G2019S LRRK2 mutation. A precision medicine approach that selectively blocks only excess kinase activity of the mutant allele could yield a safe and effective treatment for G2019S LRRK2 PD.

Objective: To determine the activity of a G2019S mutant selective leucine-rich repeat kinase 2 (LRRK2) kinase inhibitor as compared to a nonselective inhibitor in blood of subjects with genetic and idiopathic PD on two LRRK2 biomarkers, pSer935 LRRK2 and pThr73 Rab10.

Selective Inhibitors of G2019S-LRRK2 Kinase Activity.

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers.

American Society for Pain Management Nursing Guidelines on Monitoring for Opioid-Induced Advancing Sedation and Respiratory Depression: Revisions.

Objectives: This report presents up-to-date evidence and expert consensus-based revisions to the ASPMN 2011 guidelines that inform interprofessional clinical decision-making for hospitalized adults receiving opioid analgesics.

Design: Systematic review of the literature.

Methods: A 14-member expert panel was charged with reviewing and grading the strength of scientific evidence published in peer reviewed journals and revising the ASPMN 2011 existing guidelines.

Impact of inhaled nitric oxide stewardship programme in a neonatal intensive care unit.

Aim: Inhaled nitric oxide (iNO) is the most common, although expensive, therapy for persistent pulmonary hypertension of the newborn and hypoxaemic respiratory failure. With significant variation in iNO delivery practices amongst clinicians, this study aimed to assess the effectiveness of a stewardship programme in increasing clinician compliance with revised, standardised protocols and to measure the impact of compliance on iNO therapy use.

Methods: Initiation and weaning protocols for iNO were introduced to the neonatal intensive care unit at The Centenary Hospital on 01 March 2016.

Correction: A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

In the published version of this paper the author Yan Chen was missed out of the author list. This has now been corrected in the HTML and PDF versions of the paper.

A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

Objective: To explore the efficacy and risks of oral paracetamol in later (>2 weeks old) treatment of patent ductus arteriosus (PDA).

Study Design: A multicentre double-blind placebo-controlled randomised pilot trial in three neonatal intensive care units in Australia. Infants born <33 weeks with haemodynamically significant PDA were treated with a 5-day course of oral paracetamol or placebo.

Exploring Parental and Staff Perceptions of the Family-Integrated Care Model: A Qualitative Focus Group Study.

Background: Family-integrated care (FICare) is an innovative model of care developed at Mount Sinai Hospital, Canada, to better integrate parents into the team caring for their infant in the neonatal intensive care unit (NICU). The effects of FICare on neonatal outcomes and parental anxiety were assessed in an international multicenter randomized trial. As an Australian regional level 3 NICU that was randomized to the intervention group, we aimed to explore parent and staff perceptions of the FICare program in our dual occupancy NICU.

Identification of modulators of autophagic flux in an image-based high content siRNA screen.

Autophagy is the primary process for recycling cellular constituents through lysosomal degradation. In addition to nonselective autophagic engulfment of cytoplasm, autophagosomes can recognize specific cargo by interacting with ubiquitin-binding autophagy receptors such as SQSTM1/p62 (sequestosome 1). This selective form of autophagy is important for degrading aggregation-prone proteins prominent in many neurodegenerative diseases.

Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?

A common pathological hallmark of age-related neurodegenerative diseases is the intracellular accumulation of protein aggregates such as α-synuclein in Parkinson's disease, TDP-43 in ALS, and tau in Alzheimer's disease. Enhancing intracellular clearance of aggregation-prone proteins is a plausible strategy for slowing progression of neurodegenerative diseases and there is great interest in identifying molecular targets that control protein turnover. One of the main routes for protein degradation is through the proteasome, a multisubunit protease that degrades proteins that have been tagged with a polyubiquitin chain by ubiquitin activating and conjugating enzymes.

Promoting the use of capnography in acute care settings: an evidence-based practice project.

Opioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid analgesia. End-tidal carbon dioxide monitoring (capnography) has been shown to detect early signs of OIRD earlier than other commonly used monitoring methods. The goal of this evidence-based practice project was to promote the standardized use of capnography to reduce the incidence of OIRD.

Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases.

synGAP is a neuron-specific Ras and Rap GTPase-activating protein (GAP) found in high concentrations in the postsynaptic density (PSD) fraction from the mammalian forebrain. We have previously shown that, in situ in the PSD fraction or in recombinant form in Sf9 cell membranes, synGAP is phosphorylated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), another prominent component of the PSD. Here, we show that recombinant synGAP (r-synGAP), lacking 102 residues at the N terminus, can be purified in soluble form and is phosphorylated by cyclin-dependent kinase 5 (CDK5) as well as by CaMKII.

Reference interval determination for anabasine: a biomarker of active tobacco use.

Laboratory detection of nicotine exposure is important for establishing eligibility for organ transplant and elective surgery. Nicotine testing is also used to verify compliance with nicotine replacement therapies (NRT), smoking cessation programs and for life insurance purposes. Nicotine metabolites, such as cotinine and trans-3'-hydroxycotinine, are used as biomarkers of nicotine exposure.

Breech preterm infants are at risk of developmental dysplasia of the hip.

Aim: There is uncertainty about the risk of developmental dysplasia of the hip (DDH) in breech preterm infants and therefore uncertainty about the benefits of using ultrasound screening in this population. The aim of this study was to determine if preterm infants born in the breech position are at risk of DDH.

Methods: A retrospective audit of preterm and term infants born in the breech position was performed to determine the incidence of DDH.

The darker side of randomized trials: recruitment challenges.

Randomized trials are thought to provide optimal evidence if carried out correctly. Their application to important questions is the best guide to clinical decision-making. However, these trials are expensive to complete and have a variety of challenges in design and application.

Patterns of free (unconjugated) buprenorphine, norbuprenorphine, and their glucuronides in urine using liquid chromatography-tandem mass spectrometry.

Patterns of buprenorphine and metabolites were examined in 1946 positive urine samples analyzed by liquid chromatography-tandem mass spectrometry for free (unconjugated) buprenorphine and norbuprenorphine (quantitative, 2 to 1000 ng/mL) and buprenorphine-glucuronide (B3G) and norbuprenorphine-glucuronide (N3G) (semi-quantitative, 5 to 1000 ng/mL). Two distribution patterns predominated with 49.1% positive for norbuprenorphine, B3G, and N3G and 41.

A natural deletion of the HoxC cluster in elasmobranch fishes.

Hox proteins are a metazoan-specific family of transcription factors that are required for developmental patterning. The genomic arrangement of Hox genes into four paralogous clusters is a primitive feature of jawed vertebrates. By using high-throughput sequencing, we demonstrate the absence of all HoxC transcripts from embryos of the shark Scyliorhinus canicula and the skate Leucoraja erinacea and the absence of all HoxC genes and two HoxC-associated microRNAs from the genome of L.

Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.

Densin is an abundant scaffold protein in the postsynaptic density (PSD) that forms a high-affinity complex with αCaMKII and α-actinin. To assess the function of densin, we created a mouse line with a null mutation in the gene encoding it (LRRC7). Homozygous knock-out mice display a wide variety of abnormal behaviors that are often considered endophenotypes of schizophrenia and autism spectrum disorders.

Assessment of motor balance and coordination in mice using the balance beam.

Brain injury, genetic manipulations, and pharmacological treatments can result in alterations of motor skills in mice. Fine motor coordination and balance can be assessed by the beam walking assay. The goal of this test is for the mouse to stay upright and walk across an elevated narrow beam to a safe platform.

Distribution of tidal ventilation during volume-targeted ventilation is variable and influenced by age in the preterm lung.

Purpose: Synchronised volume-targeted ventilation (SIPPV + VTV) attempts to reduce lung injury by standardising volume delivery to the preterm lung. The aim of this study is to describe the regional distribution and variability of ventilation within the preterm lung during SIPPV + VTV.

Methods: Twenty-seven stable, supine, preterm infants with <32 weeks gestation receiving SIPPV + VTV were studied.