Prevalence of chronic respiratory diseases in Aboriginal children: A whole population study.

BACKGROUND: The burden of bronchiectasis is disproportionately high in Aboriginal adults, with early mortality. Bronchiectasis precursors, that is, protracted bacterial bronchitis (PBB) and chronic suppurative lung disease (CSLD), often commence in early childhood. We previously reported a 10% prevalence of PBB in Aboriginal children aged 0 to 7 years, however there are no data on prevalence of chronic lung diseases in older children. Our study aimed to determine the prevalence of PBB, CSLD, bronchiectasis, and asthma in Aboriginal children living in four communities. METHODS: A whole-population cross-sectional community co-designed study of Aboriginal children aged <18-years in four remote communities in Western Australia across two-time points, a month apart. Children were assessed by pediatric respiratory clinicians with spirometry undertaken (when possible) between March-September 2021. Children with respiratory symptoms were followed up via medical record audit from either the local medical clinic or via a respiratory specialist clinic through to March 2022 to establish a final diagnosis. FINDINGS: We recruited 392 (91.6%) of those in the selected communities; median age = 8.4 years (interquartile range [IQR] 5.1-11.5). Seventy children (17.9%) had a chronic respiratory pathology or abnormal spirometry results. PBB was confirmed in 30 (7.7%), CSLD = 13 (3.3%), bronchiectasis = 5 (1.3%) and asthma = 17 (4.3%). The prevalence of chronic wet cough significantly increased with increasing age. INTERPRETATION: The prevalence of PBB, CSLD and bronchiectasis is high in Aboriginal children and chronic wet cough increases with age. This study highlights the high disease burden in Aboriginal children and the urgent need for strategies to address these conditions.

Periprosthetic joint infection with Ureaplasma parvum detected by 16S rRNA PCR.

Usual culture methods to identify pathogenic bacteria can be unsuccessful, particularly when working with fastidious organisms. We present a case of early periprosthetic knee joint infection with Ureaplasma parvum only identified using 16S ribosomal RNA PCR. This case represents the impact molecular methods of bacterial identification can have on clinical care allowing for more targeted antimicrobial therapy; something which is imperative in an era of increasing antimicrobial resistance.

Pilot trial of home-administered transcranial direct current stimulation for the treatment of depression.

BACKGROUND: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, neuromodulation approach with promising efficacy for treating depression. To date, tDCS has been limited to clinical or research centre settings with treatment administered by staff. The aim of this study is to examine the efficacy, tolerability and feasibility of home-administered, remotely-supervised tDCS for depression. METHODS: In an open label trial, 34 participants used a Soterix 1 × 1 mini-CT device to self-administer 20-28 tDCS sessions (2 mA, 30 min, F3-anode and F8-cathode montage according to 10-20 EEG placement) over 4 weeks followed by a taper phase of 4 sessions 1 week apart. Participants were initially monitored via video link and then through completion of an online treatment diary. Mixed effects repeated measures analyses assessed change in mood scores. RESULTS: Mood improved significantly from baseline (27.47 on Montgomery-Asberg Depression Rating Scale) to 1 month after the end of acute treatment (15.48) (p < 0.001). Side effects were largely transient and minor. Outcomes were comparable to those reported in clinic-based trials. Protocol adherence was excellent with a drop-out rate of 6% and 93% of scheduled sessions completed. LIMITATIONS: The tDCS and remote monitoring procedures employed in this study require a level of manual dexterity and computer literacy, which may be challenging for some patients. This study did not have a control condition. CONCLUSIONS: This study provides initial evidence that home-based, remotely-supervised tDCS treatment may be efficacious and feasible for depressed patients and has high translational potential.

Choice of Moisturiser for Eczema Treatment (COMET): feasibility study of a randomised controlled parallel group trial in children recruited from primary care.

OBJECTIVES: To determine the feasibility of a randomised controlled trial of 'leave on' emollients for children with eczema. DESIGN: Single-centre, pragmatic, 4-arm, observer-blinded, parallel, randomised feasibility trial. SETTING: General practices in the UK. PARTICIPANTS: Children with eczema aged 1 month to <5 years. OUTCOME MEASURES: Primary outcome-proportion of parents who reported use of the allocated study emollient every day for the duration of follow-up (12 weeks). Other feasibility outcomes-participant recruitment and retention, data collection and completeness and blinding of observers to allocation. INTERVENTIONS: Aveeno lotion, Diprobase cream, Doublebase gel, Hydromol ointment. RESULTS: 197 children were recruited-107 by self-referral (mainly via practice mail-outs) and 90 by inconsultation (clinician consenting and randomising) pathways. Participants recruited inconsultation were younger, had more severe Patient-Oriented Eczema Measure scores and were more likely to withdraw than self-referrals. Parents of 20 (10%) of all the randomised participants reported using the allocated emollient daily for 84 days. The use of other non-study emollients was common. Completeness of data collected by parent-held daily diaries and at monthly study visits was good. Daily diaries were liked (81%) but mainly completed on paper rather than via electronic ('app') form. Major costs drivers were general practitioner consultations and eczema-related prescriptions. Observer unblinding was infrequent, and occurred at the baseline or first follow-up visit through accidental disclosure. CONCLUSIONS: It is feasible in a primary care setting to recruit and randomise young children with eczema to emollients, follow them up and collect relevant trial data, while keeping observers blinded to their allocation. However, reported use of emollients (study and others) has design implications for future trials. TRIAL REGISTRATION NUMBER: ISRCTN21828118/EudraCT2013-003001-26.

Choice of Moisturiser for Eczema Treatment (COMET): study protocol for a randomized controlled trial.

BACKGROUND: Eczema is common in children and in the UK most cases are managed in primary care. The foundation of all treatment is the regular use of leave-on emollients to preserve and restore moisture to the skin. This not only improves comfort but may also reduce the need for rescue treatment for 'flares', such as topical corticosteroids. However, clinicians can prescribe many different types of emollient and there is a paucity of evidence to guide this choice. One reason for this may be the challenges of conducting a clinical trial: are parents or carers of young children willing to be randomly allocated an emollient and followed up for a meaningful amount of time? DESIGN: This is a single-centre feasibility study of a pragmatic, four-arm, single-masked, randomized trial. Children with eczema who are eligible (from 1 month to less than 5 years of age, not known to be sensitive or allergic to any of study emollients or their constituents) are recruited via their general practices. Participants are allocated Aveeno® lotion, Diprobase® cream, Doublebase® gel or Hydromol® ointment via a web-based system, using a simple randomization process in a 1:1:1:1 fashion. Researchers are masked to the study emollient. Participants are assessed at baseline and followed up for 3 months. Data are collected by daily diaries, monthly researcher visits and review of electronic medical records. Because this is a feasibility study, a formal sample size calculation for the estimation of treatment effectiveness has not be made but we aim to recruit 160 participants. DISCUSSION: Recruitment is on-going. At the end of the study, as well as being able to answer the question, 'Is it is possible to recruit and retain children with eczema from primary care into a four-arm randomized trial of emollients?', we will also have collected important data on the acceptability and effectiveness of four commonly used emollients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21828118 and Clinical Trials Register EudraCT2013-003001-26.

Induction of Krox-24 by endogenous cannabinoid type 1 receptors in Neuro2A cells is mediated by the MEK-ERK MAPK pathway and is suppressed by the phosphatidylinositol 3-kinase pathway.

Neuro2a cells endogenously express cannabinoid type 1 (CB1) receptors. CB1 stimulation with HU210 activated ERK and induced the transcription factor Krox-24. A functional MEK-ERK pathway is an important requirement for CB1-mediated Krox-24 induction as blockade of MEK signaling by UO126 reduces both basal and CB1-mediated activation of Krox-24. CB1 receptor stimulation did not activate either JNK or p38 MAPK pathways or the pro-proliferation phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, serum removal or blockade of PI3K signaling by LY294002 transiently stimulated basal Krox-24 expression and increased CB1-mediated induction of Krox-24. This was consistent with a transient increase in pMEK, pERK, and pCREB levels following PI3K blockade. These data demonstrate that CB1-mediated activation of the Krox-24 transcription factor is negatively regulated through the PI3K-Akt pathway and reveals several points of signaling cross-talk between these two important kinase pathways.

Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population.

We have developed a mutation-scanning approach suitable for whole population screening for unknown mutations. The method, meltMADGE, combines thermal ramp electrophoresis with MADGE to achieve suitable cost efficiency and throughput. The sensitivity was tested in blind trials using 54 amplicons representing the BRCA1 coding region and a panel of 94 unrelated family breast cancer risk consultands previously screened in a clinical diagnostic laboratory. All 10 common polymorphisms, 15/15 previously identified disease-causing mutations, and three previously untested single base changes were identified. Assays of LDLR exons 3 and 8 were validated in 460 familial hypercholesteremics and detected 8/9 known variants. We then applied the exon 3 assay in several DNA banks representing approximately 8000 subjects with known cholesterol values and applied both assays in one DNA bank (n = 3600). In exon 3 we identified one previously reported moderate mutation, P84S (n = 1), also associated with moderate hypercholesteremia in this subject; an unreported silent variant, N76N (n = 1); and known severe hypercholesteremia splice mutation 313+1G-->A (n = 2). Around exon 8 we identified a paucimorphism (n = 35) at the splice site 1061-8T-->C (known to be in complete linkage disequilibrium with T705I) and unreported sequence variants 1186+11G-->A (n = 1) and D335N G-->A (n = 1). The cholesterol value for D335N was on the 96.2 percentile and for T705I, 2/35 carriers were above the 99th percentile. Thus, variants with predicted severe, moderate, and no effect were identified at the population level. In contrast with case collections, CpG mutations predominated. MeltMADGE will enable definition of the full population spectrum of rare, paucimorphic, severe, moderate (forme fruste), and silent mutations and effects.