Optimizing the timing of antenatal corticosteroid administration prior to anticipated preterm birth: A retrospective cohort study.

OBJECTIVE: To examine suboptimal antenatal corticosteroid (ACS) administration based on indications and maternal-obstetrical factors. METHODS: Women who prematurely delivered (24 + 0 to 36 + 6 gestational weeks) a viable neonate following ACS treatment between 2012 and 2019 were identified by a retrospective database review. The cohort was divided into patients in whom ACS administration was optimally timed (≥24 h to ≤7 days) or suboptimally timed (>7 days). The groups were compared for ACS indications and maternal, obstetrical, and neonatal parameters. RESULTS: The cohort included 399 women. ACS timing was optimal in 233 patients (58%) and was associated with nulliparity (109 [46.8%] vs. 54 [32.5%], P = 0.004) and preterm premature rupture of membranes (89 [38.2%] vs. 45 [27.1%], P = 0.021). Suboptimal timing was associated with chronic hypertension (22 [9.4%] vs. 36 [21.7%], P < 0.001) and asymptomatic cervical shortening (23 [9.9%] vs. 26 [15.7%], P = 0.020). Optimal ACS timing was associated with higher neonatal intensive care unit admission (135 [58%] vs. 71 [42.8%], P = 0.003). On multivariate analysis, the adjusted odds ratio (aOR) of neonatal intensive care unit admission was 0.69 (95% confidence interval [CI], 0.58-0.83, P < 0.001) and 0.99 (95% CI, 0.99-1, P = 0.003) when adjusted for gestational age and birth weight, respectively. When adjusting for maternal age, the aOR for suboptimal ACS administraion due to chronic hypertension was 2.65 (95% CI, 1.49-4.72; P < 0.001). CONCLUSION: Optimal timing of ACS varies based on different maternal characteristics and clinical indications. In the presence of certain parameters physicians tend to administer ACS suboptimally, diminishing its beneficial effect.

Smartphone-Connected Hearing Aids Enable and Empower Self-Management of Hearing Loss: A Qualitative Interview Study Underpinned by the Behavior Change Wheel.

OBJECTIVES: To identify patient-reported barriers and facilitators to using smartphone-connected hearing aids, using the Behavior Change Wheel (BCW) to understand experiences and how these can be addressed. DESIGN: A single-center, prospective, observational study. Eight hearing aid users (new = 1, existing = 7; mean age = 71.75 years, SD = 5.23, range = 65 to 81 years) were identified through convenience sampling from 44 participants who took part in a 7-week evaluation of smartphone-connected hearing aids controlled by a prototype app. The app allowed users to manually control settings such as gain, noise reduction, and microphone directionality, preset, and customized programmes. Participants were assigned to one of two focus groups following trial of the app. RESULTS: Focus group transcripts were thematically analyzed and underpinned by the COM-B (Capability, Opportunity, Motivation-Behavior) model and Theoretical Domains Framework to identify barriers and facilitators to using smartphone-connected hearing aids (the target behavior). Mapping of themes to the BCW allowed use of the Behavior Change Technique Taxonomy (version 1) to identify behavior change techniques that audiologists could implement in clinical practice to address the barriers and facilitators. Capability: The app increased participants' knowledge of hearing aid controls, encouraging use of the app for improved hearing loss self-management. However, barriers to using the app included perception of insufficient digital literacy skills for smartphone-connected hearing aid use and an increased cognitive load caused by decisions over which controls to use. Opportunity: Perceived smartphone norms (i.e., acceptable occasions to use smartphones) and differing listening contexts acted as both facilitators and barriers. Motivation: The ability to control hearing aid settings in any listening situation (e.g., to reduce noise) empowered users to successfully self-manage their hearing loss, leading to greater confidence and participation in everyday life. The app also reduced hearing aid-related and self-stigma, and the ability to self-adjust hearing aids benefitted both participants and communication partners. It was the adjustability and interaction afforded by the app that empowered users, rather than the hearing aid technology itself. Perceived beliefs and knowledge about digital literacy skills, and specifically abilities to use a smartphone, were perceived to be barriers in this typically older population, particularly when they compared themselves to younger generations. Using the Behavior Change Technique Taxonomy (version 1), behavior change techniques that could be used by audiologists to address these barriers included enablement, goal setting, reframing perceptions toward technology, and addressing patient educational needs. CONCLUSIONS: Smartphone-connected hearing aids, when used in their everyday lives, were viewed positively by participants across a range of domains, empowering them and enabling hearing loss self-management. Audiologists should consider smartphone-connected hearing aid candidacy for all who have access to smartphones and are willing to use one. Use of the BCW has identified that modifiable barriers to using smartphone-connected hearing aids exist. Audiologists could use these evidence-based behavior change techniques to support patients in adopting and using these technologies to successfully self-manage hearing loss. Overall, by reframing smartphone technologies as a tool to remain connected with society, smartphone-connected hearing aids could shift the power of managing hearing loss from clinician to patient.

Prolonged exposure to meconium in cases of spontaneous premature rupture of membranes at term and pregnancy outcome.

OBJECTIVE: To evaluate the impact of prolonged exposure to meconium-stained amniotic fluid (MSAF), in women with term pre-labor spontaneous rupture of membranes (PROM), on pregnancy outcome. METHODS: A retrospective cohort study of women who gave birth in a single university-affiliated tertiary medical center (2011-2019). Eligibility was limited to singleton pregnancies at term who presented with PROM. Women with MSAF were immediately induced and were compared to low-risk pregnant women with clear amniotic fluid (CAF) at admission who underwent induction of labor 24 h after rupture of membranes. All women were stratified into 4-time frame groups from rupture of membranes to delivery: T0: 0-7 h, T1: 8-13 h, T2: 14-18 h, and T3: > 18 h for the MSAF group. The time frames for the CAF were: T0 - 24-31 h, T1: 32-38 h, T2: 40-44 h, and T3: > 44 h. The maternal adverse composite outcome included any of the following: intrapartum fever (IPF), prolonged second stage (PSS), need for manual removal of suspected retained placenta, postpartum hemorrhage, and readmission within 45 days after delivery. The adverse composite neonatal outcome included one or more of the following: meconium aspiration syndrome, neonatal asphyxia, need for respiratory support, and intracranial hemorrhage. RESULTS: Overall, 1631 women met the inclusion criteria (536 in the MSAF and 1095 in the CAF group). Both groups showed a gradual decrease in the rate of vaginal delivery over time, the vaginal delivery rate in the MSAF group was 75.7% at T0 in comparison to 61.6% at T3 (p < .001). In the CAF group, the vaginal delivery rate was 84.5% at T0 in comparison to 68.8% at T3 (p < .001). This decrease was in concomitance with an increase in the rates of prolonged second-stage and intrapartum fever. There were no significant differences in the rates of postpartum hemorrhage, suspected retained placenta, or readmission within 45 days between women with either MSAF or CAF. There was a significant gradual increase in the adverse composite neonatal outcome in the MSAF group (1.9% at T0, 5.2% at T1, 6.0% at T2, and 8.2% at T3. p = .038). No similar increase was found in the CAF group (2.5% at T0, 4.1% at T1, 2.6% at T2, and 4.1% at T3. p = .449). CONCLUSION: Prolonged rupture of membranes in the presence of meconium does not affect maternal outcomes, however, prolonged exposure to meconium lead to an increased adverse neonatal outcome.

Rab29 Fast Exchange Mutants: Characterization of a Challenging Rab GTPase.

Rab29 has been implicated in multiple membrane trafficking processes with no described effectors or regulating proteins. Its fast nucleotide exchange rate and inability to bind GDI in cytosol make it a unique and poorly understood Rab. Because the conventional, "GTP-locked" Rab mutation does not have the desired effect in Rab29, we present here the use of a fluorescence-based assay to characterize novel Rab29 mutants (I64T and V156G) that display faster nucleotide exchange rates, allowing for GEF-independent Rab29 activation.

The feasibility of an m-health educational programme (m2Hear) to improve outcomes in first-time hearing aid users.

OBJECTIVE: To (i) assess the delivery, accessibility, usability, acceptability, and adherence, and (ii) identify suitable outcome measures, for a mobile-enhanced multimedia educational programme (m2Hear) in first-time hearing aid users. DESIGN: A prospective, single-centre feasibility study. STUDY SAMPLE: First-time hearing aid users (n = 59), recruited at their initial hearing assessment. Evaluations were made at 1-week and at 10-12 weeks post-hearing aid fitting. RESULTS: m2Hear was most commonly accessed via tablets (42.3%). Usability was high for the System Usability Scale (88.5%), and the uMARS, particularly for the Information (M = 4.7), Functionality (M = 4.5) and Aesthetics (M = 4.2) subscales (maximum score = 5). Participant feedback was positive, with a high percent agreeing that m2Hear aided understanding of hearing aids (98%), held their interest (86%), improved confidence to use hearing aids and communicate (84%), and provided additional information to audiologist's advice (82%). Learnings about practical hearing aid handling/maintenance skills and how to communicate with others were reportedly used equally in participant's everyday lives. m2Hear was convenient to use, clear, concise and comprehensive. Outcome measures of social participation resulted in large effect sizes (Cohen's d > 1.6). CONCLUSIONS: A theoretically-driven, personalised and co-designed educational m-health intervention is feasible and beneficial for use in the self-management of hearing loss and hearing aids.

Qualitative and quantitative assessment of magnetic vestibular stimulation in humans.

The sensation of phantom motion or exhibition of bodily sway is often reported in the proximity of an MR scanner. It is proposed that the magnetic field stimulates the vestibular system. There are a number of possible mechanisms responsible, and the relative contributions of susceptibility on the otolithic receptors and the Lorentz force on the cupulae have not yet been explored. This exploratory study aims to investigate the impact of being in the proximity of a 7.0 T MR scanner.The modified clinical test of sensory interaction on balance (mCTSIB) was used to qualitatively ascertain whether or not healthy control subjects who passed the mCTSIB in normal conditions 1) experienced subjective sensations of dizziness, vertigo or of leaning or shifting in gravity when in the magnetic field and 2) exhibited visibly increased bodily sway whilst in the magnetic field compared to outside the magnetic field. Condition IV of the mCTSIB was video recorded outside and inside the magnetic field, providing a semi-quantitative measure of sway.For condition IV of the mCTSIB (visual and proprioceptive cues compromised), all seven locations/orientations around the scanner yielded significantly more sway than at baseline (p < 0.01 FDR). A Student's t-test comparing the RMS velocity of a motion marker on the upper arm during mCTSIB condition IV showed a significant increase in the amount of motion exhibited in the field (T = 2.59; d.f. = 9; p = 0.029) compared to outside the field.This initial study using qualitative measures of sway demonstrates that there is evidence for MR-naïve individuals exhibiting greater sway while performing the mCTSIB in the magnetic field compared to outside the field. Directional polarity of sway was not significant. Future studies of vestibular stimulation by magnetic fields would benefit from the development of a sensitive, objective measure of balance function, which can be performed inside a magnetic field.

Evaluating a Theoretically Informed and Cocreated Mobile Health Educational Intervention for First-Time Hearing Aid Users: Qualitative Interview Study.

BACKGROUND: Adults living with hearing loss have highly variable knowledge of hearing aids, resulting in suboptimal use or nonuse. This issue can be addressed by the provision of high-quality educational resources. OBJECTIVE: This study aims to assess the everyday experiences of first-time hearing aid users when using a newly developed, theoretically informed cocreated mobile health (mHealth) educational intervention called m2Hear. This intervention aims to deliver greater opportunities for individualization and interactivity compared with our previously developed multimedia intervention, C2Hear. METHODS: A total of 16 first-time hearing aid users trialed m2Hear for a period of 10-weeks in their everyday lives, after which individual semistructured interviews were completed. The data were analyzed using an established deductive thematic analysis procedure underpinned by the Capability, Opportunity, Motivation-Behavior model. The model stipulates that to engage in a target behavior, an individual must have physical and psychological capability, physical and social opportunity, and automatic and reflective motivation. RESULTS: Capability-m2Hear was viewed as a concise and comprehensive resource, suitable for a range of digital literacy skills. It was stated that m2Hear could be conveniently reused to provide useful reminders that facilitate knowledge of hearing aids and communication. Opportunity-m2Hear was simple and straightforward to use, enabling greater individualization and independence. The availability of m2Hear via mobile technologies also improved accessibility. Motivation-m2Hear provided greater support and reassurance, improving confidence and empowering users to self-manage their hearing loss. CONCLUSIONS: Overall, this qualitative study suggests that m2Hear supports first-time hearing aid users to successfully self-manage their hearing loss postfitting. Furthermore, this study demonstrates the utility of employing a combined theoretical and ecologically valid approach in the development of mHealth educational resources to meet the individual self-management needs of adults living with hearing loss. TRIAL REGISTRATION: ClinicalTrials.gov NCT03136718; https://clinicaltrials.gov/ct2/show/NCT03136718.

Improving self-efficacy for hearing aid self-management: the early delivery of a multimedia-based education programme in first-time hearing aid users.

Objectives: This study examined the effect of a multimedia educational programme for first-time hearing aid users (C2Hear reusable learning objects, RLOs), delivered at the hearing assessment on (1) self-efficacy for hearing aids (primary outcome), and (2) readiness for hearing rehabilitation and hearing aid knowledge (secondary outcomes).Design: A single-centre, prospective, pre-post, randomised controlled trial with two arms. The intervention group (n = 24) received RLOs, and the waitlist control group (n = 23) received a printed booklet on hearing aids. Outcomes were measured at the hearing assessment and hearing aid fitting appointments.Study sample: Fifty-six adult first-time hearing aid users attending a publicly funded audiology service.Results: The RLO group showed significantly greater improvement in self-efficacy and knowledge of hearing aids than the control group. A borderline effect of readiness for hearing rehabilitation was also found. Potential links between hearing aid self-efficacy and knowledge were identified.Conclusions: Early delivery of the RLOs results in greater hearing aid self-efficacy and knowledge at the hearing aid fitting appointment, with indications that RLOs increase readiness for hearing rehabilitation. As knowledge, self-efficacy and readiness are cornerstones of self-management, the C2Hear RLOs can prime first-time hearing aid users to better self-manage their hearing aids before they receive them.

Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases.

LRRK2 kinase mutations cause familial Parkinson's disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2's major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation. Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in the cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane bound and GTP bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phosphorylated Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane-anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them.

A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.

Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review.

Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer. Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized. Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin. Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed.

Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.

Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector-binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans-Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild-type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29-mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2-mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation.

Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling.

Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic ß-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote ß-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat ß cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation.

Converting evidence to practice: a guide for the clinical application of MRI for the screening and management of breast cancer.

INTRODUCTION: Magnetic resonance imaging (MRI) has been increasingly utilized to screen and manage breast care. As the literature demonstrating its benefit expands, so do the potential clinical indications. However, routine review of the literature is merited to re-evaluate the appropriate and cost-effective use of MRI and guide clinicians in the areas of controversy. METHODS: A literature review was performed to evaluate the current evidence for the use of MRI. RESULTS: Evidence supports MRI screening for genetic mutation carriers and for those with an equivalent lifetime risk (>50%). Regarding staging and management, MRI is indicated for monitoring tumour response to neoadjuvant therapy. MRI should also be considered for patients with invasive lobular carcinoma, mammographically occult breast cancer and Paget's disease. DISCUSSION: Though MRI is limited by moderate specificity and high cost, it can be a valuable, sensitive and cost-effective tool with thoughtful and judicious patient selection.