Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161∗). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

Addressing smoking among people living with HIV: a cross-sectional survey of Australian HIV health practitioners' practices and attitudes.

People living with HIV (PLHIV) have high rates of tobacco smoking, and smoking is a leading cause of premature mortality and morbidity. It is important to understand HIV healthcare providers' practices and attitudes towards addressing smoking with their patients. An online survey that measured: (i) use of the 5A framework for addressing smoking (Ask, Assess, Advise, Assist, Arrange) and (ii) attitudes and barriers to addressing smoking cessation was distributed by relevant professional bodies. Eligible participants were Australian health practitioners providing healthcare to PLHIV. Of the 179 respondents, most reported practising at least one of the 5As: Ask (94%); Assess (78%); Advise (82%); Assist (89%); and Arrange (73%). Practising the full 5A framework (completing at least one activity from each A) was less common (62%) and associated with having undertaken smoking cessation training (OR 2.1, CI 1.1-3.9), being a medical practitioner (OR 6.0, CI 3.1-11.6), having greater perceived knowledge and resources (OR 1.7, CI 1.3-2.4) and more positive attitudes (OR 1.5, CI 1.1-2.0). Common barriers to delivering cessation assistance related to knowledge and availability of resources. Development and greater dissemination of effective smoking cessation training and resources may be required to ensure healthcare practitioners have the capacity to complete all aspects of the 5A framework for smoking cessation and support their patients with HIV who smoke.

Lumbosacral ventral spinal nerve root atrophy identified on MRI in a case of spinal muscular atrophy type II.

Spinal muscular atrophies are rare genetic disorders most often caused by homozygous deletion mutations in SMN1 that lead to progressive neurodegeneration of anterior horn cells. Ventral spinal root atrophy is a consistent pathological finding in post-mortem examinations of patients who suffered from various subtypes of spinal muscular atrophy; however, corresponding radiographic findings have not been previously reported. We present a patient with hypotonia and weakness who was found to have ventral spinal root atrophy in the lumbosacral region on MRI and was subsequently diagnosed with spinal muscular atrophy. More systematic analyses of imaging studies in spinal muscular atrophy will help determine whether such findings have the potential to serve as reliable diagnostic markers for clinical evaluations or as outcome measure for clinical trials.

Vaporised nicotine and tobacco harm reduction for addressing smoking among people living with HIV: A cross-sectional survey of Australian HIV health practitioners' attitudes.

BACKGROUND: Tobacco smoking is a major cause of morbidity and mortality among people living with HIV (PLHIV). Due to the limited success of standard abstinence-focused smoking cessation strategies in this population, there is growing interest in tobacco harm reduction (THR) approaches as an additional strategy to address these high smoking rates. This study explored the attitudes of health practitioners who provide healthcare to PLHIV towards THR. METHODS: 179 Australian health practitioners who provide healthcare to PLHIV completed an online survey that measured their attitudes towards THR approaches, including switching from cigarettes to e-cigarettes or vaporised nicotine products (VNPs). RESULTS: Respondents supported the concept of THR but were undecided on the role of VNPs. Respondents most commonly reported 'don't know' or 'undecided' responses to statements regarding VNPs. More respondents, however, agreed than disagreed that switching from smoking to long-term vaping could reduce risk (36% and 22% respectively) and be an effective strategy to help PLHIV to quit smoking (37% agree and 17% disagree). Only a minority of respondents (20%) agreed that VNPs are too harmful to recommend to patients, however around half (53%) were undecided. CONCLUSIONS: Despite supporting the principle of THR, health practitioners may require more evidence and knowledge about VNPs before being willing to consider them as a suitable intervention strategy.

Smart drugs "as common as coffee": media hype about neuroenhancement.

BACKGROUND: The use of prescription drugs to improve cognitive functioning in normal persons--neuroenhancement"--has gained recent attention from bioethicists and neuroscientists. Enthusiasts claim that the practice is widespread and increasing, and has many potential benefits; however recent evidence provides weak support for these claims. In this study we explored how the newsprint media portrays neuroenhancement. AIMS: We conducted an empirical study of media reporting of neuroenhancement to explore: media portrayals of the prevalence of neuroenhancement; the types of evidence used by the media to support claims about its prevalence; and, the possible benefits and risks of neuroenhancement mentioned in these media articles. METHODS: Using the Factiva database, we found 142 newspaper articles about the non-medical use prescription drugs for neuroenhancement for the period 2008-2010. We conducted a thematic content analysis of how articles portrayed the prevalence of neuroenhancement; what type of evidence they used in support; and, the potential benefits and risks/side-effects of neuroenhancement that were mentioned. RESULTS: 87% of media articles mentioned the prevalence of neuroenhancement, and 94% portrayed it as common, increasing or both. 66% referred to the academic literature to support these claims and 44% either named an author or a journal. 95% of articles mentioned at least one possible benefit of using prescription drugs for neuroenhancement, but only 58% mentioned any risks/side effects. 15% questioned the evidence for efficacy of prescription drugs to produce benefits to users. CONCLUSIONS: News media articles mentioned the possible benefits of using drugs for neuroenhancement more than the potential risks/side effects, and the main source for media claims that neuroenhancement is common and increasingly widespread has been reports from the academic literature that provide weak support for this claim. We urge journalists and researchers to be cautious in their portrayal of the non-medical use of drugs for neuroenhancement.

Assessment of silicone polymer composites for environmental forensic applications: a proof of concept study.

This study evaluates the use of polydimethylsiloxane polymer composites (PDMS, Fe-PDMS) as a passive sampling media to preconcentrate analytes found in environmental settings. Samplers were made using commercially available silicone products. The composite samplers were assessed for their sorption properties using Atrazine and Irgarol 1051 as model compounds. The initial study assessed the utility of PDMS sheets as adsorption material by following analyte depletion from spiked water samples by solid-phase microextraction gas chromatography/mass spectrometry (GC/MS). Follow-up studies conducted at high and low concentrations using lab manufactured iron- PDMS rods (Fe-PDMS) showed effective uptake at differential rates from concentrations ranging between 1 µg/L and 10 µg/L. Adsorption mechanism was reversible, and compounds were recovered from the exposed materials and analyzed by liquid-liquid extraction-GC/MS. Both composites showed better affinity for Irgarol 1051, 100% removal, than for Atrazine, 30% removal, likely representing their K(OW) differences, 3.6 and 2.6, respectively. This "proof of concept" study demonstrates the positive implications for the use of silicon polymer composites as a monitoring tool for environmental forensic purposes.