Nucleoprotein reassortment enhanced transmissibility of H3 1990.4.a clade influenza A virus in swine.

The increased detection of H3 C-IVA (1990.4.a) clade influenza A viruses (IAVs) in US swine in 2019 was associated with a reassortment event to acquire an H1N1pdm09 lineage nucleoprotein (pdmNP) gene, replacing a TRIG lineage NP (trigNP). We hypothesized that acquiring the pdmNP conferred a selective advantage over prior circulating H3 viruses with a trigNP. To investigate the role of NP reassortment in transmission, we identified two contemporary 1990.4.a representative strains (NC/19 and MN/18) with different evolutionary origins of the NP gene. A reverse genetics system was used to generate wild-type (wt) strains and swap the pdm and TRIG lineage NP genes, generating four viruses: wtNC/19-pdmNP, NC/19-trigNP, wtMN/18-trigNP, and MN/18-pdmNP. The pathogenicity and transmission of the four viruses were compared in pigs. All four viruses infected 10 primary pigs and transmitted to five indirect contact pigs per group. Pigs infected via contact with MN/18-pdmNP shed virus 2 days earlier than pigs infected with wtMN/18-trigNP. The inverse did not occur for wtNC/19-pdmNP and NC/19-trigNP. This suggests that pdmNP reassortment resulted in a combination of genes that improved transmission efficiency when paired with the 1990.4.a hemagglutinin (HA). This is likely a multigenic trait, as replacing the trigNP gene did not diminish the transmission of a wild-type IAV in swine. This study demonstrates how reassortment and evolutionary change of internal genes can result in more transmissible viruses that influence HA clade detection frequency. Thus, rapidly identifying novel reassortants paired with dominant hemagglutinin/neuraminidase may improve the prediction of strains to include in vaccines.IMPORTANCEInfluenza A viruses (IAVs) are composed of eight non-continuous gene segments that can reassort during coinfection of a host, creating new combinations. Some gene combinations may convey a selective advantage and be paired together preferentially. A reassortment event was detected in swine in the United States that involved the exchange of two lineages of nucleoprotein (NP) genes (trigNP to pdmNP) that became a predominant genotype detected in surveillance. Using a transmission study, we demonstrated that exchanging the trigNP for a pdmNP caused the virus to shed from the nose at higher levels and transmit to other pigs more rapidly. Replacing a pdmNP with a trigNP did not hinder transmission, suggesting that transmission efficiency depends on interactions between multiple genes. This demonstrates how reassortment alters IAV transmission and that reassortment events can provide an explanation for why genetically related viruses with different internal gene combinations experience rapid fluxes in detection frequency.

Reporting of determinants of health inequities and participant characteristics in randomized controlled trials of systemic lupus erythematosus in Canada: A scoping review.

OBJECTIVE: To report participant characteristics relevant to identifying health inequities in systemic lupus erythematosus (SLE) randomized controlled trials conducted in Canada. METHODS: We conducted a scoping review by searching MEDLINE (Ovid) and Embase (1990 to June 2023), and CENTRAL (inception to June 2023). Eligible studies: used an RCT design; evaluated interventions (pharmacologic and non-pharmacologic) among SLE patients aged ≥18 years; and were conducted in Canada. Data extraction was guided by the Campbell and Cochrane Equity Methods Group's PROGRESS-Plus framework on 11 factors leading to health inequities (Place of residence; Race, culture, ethnicity, and language; Occupation; Gender and sex; Religion; Education; Socioeconomic status; Social capital; Plus: Personal characteristics associated with discrimination; Features of relationships; and Time-dependent relationships). RESULTS: Of 1901 unique records, 6 met the inclusion criteria. Sex and age were the only PROGRESS factors that were reported in all studies. The majority of participants were female (84.4% to 100%), and mean ages of participants ranged from 42 to 52.3 years. Place of residence, race, education, and social capital were reported in three studies. Socioeconomic status was reported in two studies, and occupation was reported in one study. Religion, features of relationships, and time-dependent relationships were not reported in any included studies. CONCLUSION: Limited reporting of determinants of health inequities in RCTs for SLE in Canada suggests the need for reporting standards to support equity, diversity, and inclusion practices in research.

Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.

Day-case catheterless and drainless minimal-access pyeloplasty in adults: A single-center experience of 13 years.

OBJECTIVES: To analyze our practice of drainless and catheterless day-case minimal-access pyeloplasty with regard to feasibility, safety and long-term outcomes. METHODS: Patients undergoing minimal-access pyeloplasty (laparoscopic, with or without robotic assistance) in a single center between 2007 and 2020 were included in this retrospective observational study. Patient demographics and the success rate of day-case discharge along with postoperative outcomes were analyzed. RESULTS: A total of 129 patients underwent minimal-access pyeloplasty in this time period, of whom 116 met the inclusion criteria. The mean patient age was 48 years. A total of 65% of the patients (n = 75) were discharged on the same day and 88% (n = 101) were discharged within 23 h of surgery. Of the 14 patients with a hospital stay of >24 h, pain was the most common reason (60%) for delayed discharge. The overall subjective (pain-free status) and objective (unobstructed drainage) success rates were 91% and 86%, respectively. CONCLUSION: This study demonstrates that routine drains or urethral catheters are not necessary in minimal-access pyeloplasty, and their omission could facilitate early recovery and day-case discharge without compromising long-term surgical outcomes. Large randomized controlled studies are required to prospectively evaluate outcomes.

Formalizing the Informal: Lessons Learned from a Competency-Based Mentorship Program for Residents in Psychiatry.

OBJECTIVE: CanMEDS competencies have been established and guide residency education in Canada, yet their inclusion in a formalized mentorship program for competency-based medical education (CBME) has yet to be explored. METHODS: A mixed methods study was conducted to investigate the perceptions of residents and faculty members in psychiatry who participated in a formalized CBME mentorship program. The authors conducted secondary analysis of intake survey data from program participants and collected semi-structured interview data. Chi-square analysis of survey data determined associations between participant demographics and perceptions of mentorship. Thematic analysis techniques were used to analyze interview data. Finally, survey and interview data were triangulated and transformed into broad themes. RESULTS: Survey data from 46 residents and 41 faculty members and semi-structured interview data from 8 residents and 6 faculty members were analyzed. Data analysis revealed support for the informal use of the CanMEDS roles framework in a mentoring context. Factors that influenced participant satisfaction with the program included mentor qualities, the mentor-mentee pairing strategy, informality of mentoring sessions, and the presence of administrators and other program coordinators to maintain and support the program. CONCLUSIONS: The perceptions of participants in this study suggest that formal mentorship programs can be beneficial for residents, in terms of enhancing clinical competencies, advancing overall well-being, ensuring preparedness to undertake professional careers, and the provision of essential psychosocial support. Future work is needed to assess the implementation of formal mentorship programs in other residency training programs.

Clinical and cost effectiveness of a parent mediated intervention to reduce challenging behaviour in pre-schoolers with moderate to severe intellectual disability (EPICC-ID) study protocol: a multi-centre, parallel-group randomised controlled trial.

BACKGROUND: Children with intellectual disabilities are likely to present with challenging behaviour. Parent mediated interventions have shown utility in influencing child behaviour, although there is a paucity of UK research into challenging behaviour interventions in this population. NICE guidelines favour Stepping Stones Triple P (SSTP) as a challenging behaviour intervention and this trial aims to evaluate its clinical and cost effectiveness in preschool children with moderate to severe intellectual disabilities. METHODS: This trial launched in 2017 at four sites across England, with the aim of recruiting 258 participants (aged 30-59 months). The Intervention Group receive nine weeks of SSTP parenting therapy (six group sessions and three individualised face to face or telephone sessions) in addition to Treatment as Usual, whilst the Treatment as Usual only group receive other available services in each location. Both study groups undergo the study measurements at baseline and at four and twelve months. Outcome measures include parent reports and structured observations of behaviour. Service use and health related quality of life data will also be collected to carry out a cost effectiveness and utility evaluation. DISCUSSION: Findings from this study will inform policy regarding interventions for challenging behaviour in young children with moderate to severe intellectual disabilities. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, NCT03086876. Registered 22nd March 2017, https://clinicaltrials.gov/ct2/show/NCT03086876.

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.

Is schizotypic maternal personality linked to sensory gating abilities during infancy?

Schizotypy is a personality dimension within the general population elevated among schizophrenia-spectrum patients and their first-degree relatives. Sensory gating is the pre-attentional habituation of responses distinguishing between important and irrelevant information. This is measured by event-related potentials, which have been found to display abnormalities in schizophrenic disorders. The current study investigated whether 6-month-old infants of mothers with schizotypic traits display sensory gating abnormalities. The paired-tone paradigm: two identical auditory tones (stimulus 1 and stimulus 2) played 500 ms apart, was used to probe the selective activation of the brain during 15-minutes of sleep. Their mothers completed the Oxford and Liverpool Inventory of Feelings and Experiences-Short Form as an index of schizotypy dimensionality, categorized into: infants of control, and infants of schizotypic, mothers. The findings revealed that although the infants' P50 components displayed significant differences between stimulus 1 and stimulus 2 in the paired-tone paradigm, there was no clear difference between infants of schizotypic and infants of control mothers. In contrast, all mothers displayed significant differences between stimulus 1 and stimulus 2, as observed in the infants, but also significant differences between their sensory gating ability correlated with schizotypy dimensionality. These findings are consistent with sensory processes, such as sensory gating, evidencing impairment in schizophrenia-spectrum disorders. The present research supports the idea that first-degree relatives of individuals who identify on this spectrum, within the sub-clinical category, do not display the same deficit at 6 postnatal months of age.

Air-Conducted Vestibular Evoked Myogenic Potential Testing in Children, Adolescents, and Young Adults: Thresholds, Frequency Tuning, and Effects of Sound Exposure.

OBJECTIVES: Pediatric vestibular evaluations incorporate cervical and ocular vestibular evoked myogenic potential (c- and oVEMP, respectively) testing; however, in children, c- and oVEMP thresholds have been minimally investigated and frequency tuning is unknown. Children are also at risk for unsafe sound exposure secondary to VEMP. While it is unknown if VEMP threshold testing leads to cochlear changes, it is possible that this risk increases due to the increased number of trials needed to obtain a threshold. Obtaining VEMP thresholds at various frequencies in children provides further information for pediatric normative VEMP data. Assessing for cochlear changes after VEMP threshold testing would provide information on the safety of threshold VEMP testing in children. The objectives of this study were to (1) characterize c- and oVEMP thresholds in children, adolescents, and young adults with normal hearing using 500 and 750 Hz tone burst (TB) stimuli, (2) compare frequency tuning of 500 and 750 Hz TB, and (3) assess whether cochlear changes exist after VEMP threshold testing. It is hypothesized that children, adolescents, and young adults would not show age-related changes to the vestibular system. Therefore, reliable VEMP thresholds would be seen below maximum acoustical stimulation levels (e.g., <125 dB SPL) and frequency tuning will be similar for 500 and 750 Hz TB stimuli. DESIGN: Ten children (age 4-9), 10 adolescents (age 10-19), and 10 young adults (age 20-29) with normal hearing and tympanometry participated. All subjects received c- and oVEMP testing at maximum stimulation and threshold. To address frequency tuning, but not exceed recommended sound exposure allowance, subjects received a 500 Hz TB stimulus in one ear and a 750 Hz TB stimulus in the other ear. Subjects completed tympanometry pre-VEMP, and audiometric threshold testing, distortion product otoacoustic emission testing, and subjective questionnaire pre- and post-VEMP to study the effect of VEMP exposure on cochlear function for each stimulus frequency. RESULTS: (1) cVEMP thresholds were determined for both stimulus frequencies for children (500 Hz = 106 dB SPL; 750 Hz = 106 dB SPL), adolescents (500 Hz = 107.5 dB SPL; 750 Hz = 109.5 dB SPL), and young adults (500 Hz = 111.5 dB SPL; 750 Hz = 112 dB SPL). oVEMP thresholds were also obtained in response to both stimulus frequencies for children (500 Hz = 111.1 dB SPL; 750 Hz = 112.2 dB SPL), adolescents (500 Hz = 112.5 dB SPL; 750 Hz = 114.5 dB SPL), and young adults (500 Hz = 116 dB SPL; 750 Hz = 117 dB SPL). Similar thresholds were found between groups except for children who had significantly lower thresholds compared with adults for cVEMP (500 Hz: p = 0.002; 750 Hz: p = 0.004) and oVEMP (500 Hz: p = 0.01; 750 Hz: p = 0.02). In addition, equivalent ear-canal volume and VEMP thresholds were linearly correlated. (2) There was no significant effect of stimulus frequency on VEMP response rates, latencies, peak to peak amplitudes, or thresholds, suggesting similar frequency tuning for 500 and 750 Hz. (3) There were no significant effects of VEMP threshold testing on cochlear function for either stimulus frequency. CONCLUSIONS: Children, adolescents, and young adults show VEMP thresholds below high stimulation levels and had similar frequency tuning between 500 and 750 Hz. Use of 750 Hz could be regarded as the safer stimuli due to its shorter duration and thus reduced sound exposure. Children with smaller ear-canal volume had present responses at maximum stimulation and lower thresholds, suggesting that VEMP testing could be initiated at lower acoustic levels to minimize sound exposure and optimize testing.

Oral melatonin for non-respiratory sleep disturbance in children with neurodisabilities: systematic review and meta-analyses.

AIM: To evaluate the effectiveness of pharmacological interventions for managing non-respiratory sleep disturbances in children with neurodisabilities. METHOD: We performed a systematic review and meta-analyses of randomized controlled trials (RCTs). We searched 16 databases, grey literature, and reference lists of included papers up to February 2017. Data were extracted and assessed for quality by two researchers (B.B., C.M., G.S., A.S., A.P.). RESULTS: Thirteen trials were included, all evaluating oral melatonin. All except one were at high or unclear risk of bias. There was a statistically significant increase in diary-reported total sleep time for melatonin compared with placebo (pooled mean difference 29.6min, 95% confidence interval [CI] 6.9-52.4, p=0.01). Statistical heterogeneity was high (97%). For the single RCT with low risk of bias, the unadjusted mean difference in total sleep time was 13.2 minutes (95% CI -13.3 to 39.7) favouring melatonin, while the mean difference adjusted for baseline total sleep time was statistically significant (22.4min, 95% CI 0.5-44.3, p=0.04). Adverse event profile suggested that melatonin was well-tolerated. INTERPRETATION: There is a paucity of evidence on managing sleep disturbances in children with neurodisabilities, and it is mostly of limited scope and poor quality. There is evidence of the benefit and safety of melatonin compared with placebo, although the extent of this benefit is unclear. WHAT THIS PAPER ADDS: Melatonin for the management of non-respiratory sleep disturbances in children with neurodisabilities was well tolerated with minimal adverse effects. The extent of benefit and which children might benefit most from melatonin use is uncertain. Benefit may be greatest in those with autism spectrum disorder; however, this finding should be interpreted with caution.

Melatonina oral para la alteración del sueño no respiratoria en niños con trastornos del neurodesarrollo: revisión sistemática y metaanálisis OBJETIVO: Evaluar la efectividad de las intervenciones farmacológicas para el tratamiento de los trastornos del sueño no respiratorios en niños con trastornos del neurodesarrollo. MÉTODO: Se realizó una revisión sistemática y un metaanálisis de ensayos controlados aleatorios (ECA). Se realizaron búsquedas en 16 bases de datos, literatura gris y listas de referencias de los artículos incluidos hasta febrero de 2.017. Dos investigadores extrajeron y evaluaron la calidad de la calidad. RESULTADOS: Se incluyeron trece ensayos, todos evaluaron la melatonina oral. Todos excepto uno tenía un riesgo alto o incierto de sesgo. Hubo un aumento estadísticamente significativo en el tiempo total de sueño informado por los registros - usando diarios de datos - para la melatonina en comparación con el placebo (diferencia de medias agrupada 29,6 min, intervalo de confianza [IC] del 95% [IC] 6,9-52,4, p = 0,01). La heterogeneidad estadística fue alta (97%). Para el ECA único con bajo riesgo de sesgo, la diferencia media no ajustada en el tiempo total de sueño fue de 13,2 minutos (IC del 95% −13,3 a 39,7) favoreciendo a la melatonina, mientras que la diferencia media ajustada para el tiempo total de sueño basal fue estadísticamente significativa (22,4 min. IC del 95%: 0,5-44,3, p = 0,04). El perfil de eventos adversos sugirió que la melatonina fue bien tolerada. INTERPRETACIÓN: Existe una escasez de evidencia sobre el manejo de los trastornos del sueño en niños con trastornos del neurodesarrollo, los datos actuales son principalmente de alcance limitado y de mala calidad. Existe evidencia del beneficio y la seguridad de la melatonina en comparación con el placebo, aunque el alcance de este beneficio no está claro.

Melatonina oral para distúrbios não-respiratórios do sono em crianças com neuro-incapacidades: revisão sistemática e metanálise OBJETIVO: Avaliar a efetividade de intervenções farmacológicas para o manejo de distúrbios não-respiratórios do sono em crianças com neuro-incapacidades. MÉTODO: Realizamos uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs). Buscamos 16 bases de dados, literatura cinzenta, e listas de referências dos artigos incluídos até fevereiro de 2017. Os dados foram extraídos e avaliados quanto a sua qualidade por dois pesquisadores. RESULTADOS: Treze estudos foram incluídos, todos avaliando a melatonina oral. Todos, com exceção de um, tinham risco de viés alto ou não esclarecido. Houve aumento estatisticamente significativo no tempo total de sono reportado em diário para melatonina comparada com placebo (diferença média agrupada 29,6min, intervalo de confiança [IC] 95% 6,9-52,4, p = 0,01). A heterogeneidade estatística foi alta (97%). Para o único ECR com baixo risco de viés, a diferença média não ajustada no tempo total de sono foi 13,2 minutos (IC 95% −13,3 a 39,7) em favor da melatonina, enquanto a diferença média ajustada para o tempo total de sono na linha de base foi estatisticamente significativa (22,4min, IC 95% 0,5-44,3, p = 0,04). O perfil de eventos adversos sugeriu que a melatonina foi bem tolerada. INTERPRETAÇÃO: Há escassez de evidência sobre o manejo de distúrbios do sono em crianças com neuroincapacidades, e a mesma tem escopo limitado e pouca qualidade. Há evidência do benefício e segurança da melatonina comparada com o placebo, embora e extensão do benefício não esteja clara.

Probiotics to prevent infantile colic.

BACKGROUND: Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three weeks. Infantile colic affects a large number of infants and their families worldwide. Its symptoms are broad and general, and while not indicative of disease, may represent a serious underlying condition in a small percentage of infants who may need a medical assessment. Probiotics are live microorganisms that alter the microflora of the host and provide beneficial health effects. The most common probiotics used are of Lactobacillus, Bifidobacterium and Streptococcus. There is growing evidence to suggest that intestinal flora in colicky infants differ from those in healthy infants, and it is suggested that probiotics can redress this balance and provide a healthier intestinal microbiota landscape. The low cost and easy availability of probiotics makes them a potential prophylactic solution to reduce the incidence and prevalence of infantile colic. OBJECTIVES: To evaluate the efficacy and safety of prophylactic probiotics in preventing or reducing severity of infantile colic. SEARCH METHODS: In January 2018 we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 10 other databases and two trials registers. In addition, we handsearched the abstracts of relevant meetings, searched reference lists, ran citation searches of included studies, and contacted authors and experts in the field, including the manufacturers of probiotics, to identify unpublished trials. SELECTION CRITERIA: Randomised control trials (RCTs) of newborn infants less than one month of age without the diagnosis of infantile colic at recruitment. We included any probiotic, alone or in combination with a prebiotic (also known as synbiotics), versus no intervention, another intervention(s) or placebo, where the focus of the study was the effect of the intervention on infantile colic. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of Cochrane. MAIN RESULTS: Our search yielded 3284 records, and of these, we selected 21 reports for full-text review. Six studies with 1886 participants met our inclusion criteria, comparing probiotics with placebo. Two studies examined Lactobacillus reuteri DSM, two examined multi-strain probiotics, one examined Lactobacillus rhamnosus, and one examined Lactobacillus paracasei and Bifidobacterium animalis. Two studies began probiotics during pregnancy and continued administering them to the baby after birth.We considered the risk of bias for randomisation as low for all six trials; for allocation concealment as low in two studies and unclear in four others. All studies were blinded, and at low risk of attrition and reporting bias.A random-effects meta-analysis of three studies (1148 participants) found no difference between the groups in relation to occurrence of new cases of colic: risk ratio (RR) 0.46, 95% confidence interval (CI) 0.18 to 1.19; low-certainty evidence; I2 = 72%.A random-effects meta-analysis of all six studies (1851 participants) found no difference between the groups in relation to serious adverse effects (RR 1.02, 95% CI 0.14 to 7.21; low-certainty evidence; I2 not calculable (only four serious events for one comparison, two in each group: meconium plug obstruction, patent ductus arteriosus and neonatal hepatitis).A random-effects meta-analysis of three studies (707 participants) found a mean difference (MD) of -32.57 minutes per day (95% CI -55.60 to -9.54; low-certainty evidence; I2 = 93%) in crying time at study end in favour of probiotics.A subgroup analysis of the most studied agent, Lactobacillus reuteri, showed a reduction of 44.26 minutes in daily crying with a random-effects model (95% CI -66.6 to -21.9; I2 = 92%), in favour of probiotics. AUTHORS' CONCLUSIONS: There is no clear evidence that probiotics are more effective than placebo at preventing infantile colic; however, daily crying time appeared to reduce with probiotic use compared to placebo. There were no clear differences in adverse effects.We are limited in our ability to draw conclusions by the certainty of the evidence, which we assessed as being low across all three outcomes, meaning that we are not confident that these results would not change with the addition of further research.

Effects of High Sound Exposure During Air-Conducted Vestibular Evoked Myogenic Potential Testing in Children and Young Adults.

OBJECTIVES: Vestibular evoked myogenic potential (VEMP) testing is increasingly utilized in pediatric vestibular evaluations due to its diagnostic capability to identify otolith dysfunction and feasibility of testing. However, there is evidence demonstrating that the high-intensity stimulation level required to elicit a reliable VEMP response causes acoustic trauma in adults. Despite utility of VEMP testing in children, similar findings are unknown. It is hypothesized that increased sound exposure may exist in children because differences in ear-canal volume (ECV) compared with adults, and the effect of stimulus parameters (e.g., signal duration and intensity) will alter exposure levels delivered to a child's ear. The objectives of this study are to (1) measure peak to peak equivalent sound pressure levels (peSPL) in children with normal hearing (CNH) and young adults with normal hearing (ANH) using high-intensity VEMP stimuli, (2) determine the effect of ECV on peSPL and calculate a safe exposure level for VEMP, and (3) assess whether cochlear changes exist after VEMP exposure. DESIGN: This was a 2-phase approach. Fifteen CNH and 12 ANH participated in phase I. Equivalent ECV was measured. In 1 ear, peSPL was recorded for 5 seconds at 105 to 125 dB SPL, in 5-dB increments for 500- and 750-Hz tone bursts. Recorded peSPL values (accounting for stimulus duration) were then used to calculate safe sound energy exposure values for VEMP testing using the 132-dB recommended energy allowance from the 2003 European Union Guidelines. Fifteen CNH and 10 ANH received cervical and ocular VEMP testing in 1 ear in phase II. Subjects completed tympanometry, pre- and postaudiometric threshold testing, distortion product otoacoustic emissions, and questionnaire addressing subjective otologic symptoms to study the effect of VEMP exposure on cochlear function. RESULTS: (1) In response to high-intensity stimulation levels (e.g., 125 dB SPL), CNH had significantly higher peSPL measurements and smaller ECVs compared with ANH. (2) A significant linear relationship between equivalent ECV (as measured by diagnostic tympanometry) and peSPL exists and has an effect on total sound energy exposure level; based on data from phase I, 120 dB SPL was determined to be an acoustically safe stimulation level for testing in children. (3) Using calculated safe stimulation level for VEMP testing, there were no significant effect of VEMP exposure on cochlear function (as measured by audiometric thresholds, distortion product otoacoustic emission amplitude levels, or subjective symptoms) in CNH and ANH. CONCLUSIONS: peSPL sound recordings in children's ears are significantly higher (~3 dB) than that in adults in response to high-intensity VEMP stimuli that are commonly practiced. Equivalent ECV contributes to peSPL delivered to the ear during VEMP testing and should be considered to determine safe acoustic VEMP stimulus parameters; children with smaller ECVs are at risk for unsafe sound exposure during routine VEMP testing, and stimuli should not exceed 120 dB SPL. Using 120 dB SPL stimulus level for children during VEMP testing yields no change to cochlear function and reliable VEMP responses.

Non-pharmacological interventions for non-respiratory sleep disturbance in children with neurodisabilities: a systematic review.

AIM: To describe existing evidence on non-pharmacological interventions to manage sleep disturbance in children with neurodisabilities. METHOD: We systematically reviewed non-pharmacological interventions aimed at improving non-respiratory sleep disturbance in children with neurodisability. Sixteen databases, grey literature, and reference lists of included papers were searched up to February 2017. Two researchers (B.B., C.M., G.S., A.S., A.P.) undertook screening, data extraction, and quality appraisal. RESULTS: Twenty-five studies were included: 11 randomized controlled trials and 14 before-and-after studies. All studies were at high or unclear risk of bias. Parent-directed interventions were categorized as comprehensive tailored interventions (n=9), comprehensive non-tailored interventions (n=8), and non-comprehensive interventions (n=2). Six 'other' non-pharmacological interventions were included. Seventy-one child and parent sleep-related outcomes were measured across the included studies. We report the two most commonly measured outcomes: the Child Sleep Habits Questionnaire and sleep onset latency. Five studies reported significant improvements on at least one of these outcomes. INTERPRETATION: Various types of non-pharmacological intervention for managing sleep disturbance have been evaluated. Clinical heterogeneity and poor study quality meant we could not draw definitive conclusions on the effectiveness of these interventions. Current clinical guidance recommends parent-directed interventions as the first approach to managing sleep disturbance; prioritizing research in this area is recommended. WHAT THIS PAPER ADDS: Existing evidence on non-pharmacological interventions to manage sleep disturbance in children with neurodisabilities is predominately of poor quality. Most included studies evaluated parent-directed interventions of varying content and intensity. There was very little consistency between studies in the outcome measures used. There is some evidence that parent-directed interventions may improve child outcomes.

Predicting the location of missing outer hair cells using the electrical signal recorded at the round window.

The electrical signal recorded at the round window was used to estimate the location of missing outer hair cells. The cochlear response was recorded to a low frequency tone embedded in high-pass filtered noise conditions. Cochlear damage was created by either overexposure to frequency-specific tones or laser light. In animals with continuous damage along the partition, the amplitude of the cochlear response increased as the high-pass cutoff frequency increased, eventually reaching a plateau. The cochlear distance at the onset of the plateau correlated with the anatomical onset of outer hair cell loss. A mathematical model replicated the physiologic data but was limited to cases with continuous hair cell loss in the middle and basal turns. The neural contribution to the cochlear response was determined by recording the response before and after application of Ouabain. Application of Ouabain eliminated or reduced auditory neural activity from approximately two turns of the cochlea. The amplitude of the cochlear response was reduced for moderate signal levels with a limited effect at higher levels, indicating that the cochlear response was dominated by outer hair cell currents at high signal levels and neural potentials at low to moderate signal levels.

Prioritizing Maternal Mental Health in Addressing Morbidity and Mortality.

Importance: The rate of maternal mortality in the United States is 2-fold to 3-fold greater than that in other high-income countries. While many national initiatives have been developed to combat maternal mortality, these efforts often fail to include mental illness. Objective: To highlight the underrecognized contribution of mental illness to maternal mortality, which is nearly double that of postpartum hemorrhage. Evidence Review: A topic outline was developed to include challenges in measuring perinatal mental conditions and mortality rates; contributions of social determinants of health to mental conditions and mortality; perinatal psychiatric disorder characterization; mechanisms by which maternal mental illness increases mortality, specifically, suicide and addictive disorders; access limitations and care "deserts"; prenatal stress and its impact on reproductive outcomes; increasing clinician expertise through cross-disciplinary education; intervention sites and models; and asserting that mental health is fundamental to maternal health. Publications in the last 3 years were prioritized, particularly those relating to policy. References were selected through consensus. Sources were PubMed, Ovid, direct data published on government websites, and health policy sources such as the Policy Center for Maternal Mental Health. Findings: Priority was given to recent sources. Citations from 2022-2023 numbered 26; within the last 5 years, 14; and historical references, 15. Recommendations to address each topic area serve as concluding statements for each section. To mitigate the contributions of mental illness to the maternal mortality risk, a coordinated effort is required across professional and governmental organizations. Conclusions and Relevance: Concrete programmatic and policy changes are needed to reduce perinatal stress and address trauma, standardize the collection of social determinant of health data among perinatal patients, increase access to reproductive psychiatry curricula among prescribers, reduce perinatal mental health and obstetrical deserts, institute paid parental leave, and support seamless integration of perinatal and behavioral health care. Moreover, instead of focusing on a relatively minor portion of the contributors to health that current medical practice targets, fortifying the social foundation strengthens the prospects for the health of families for our current and future generations.

Rheumatoid Arthritis Care Experiences of Black People Living in Canada: A Qualitative Study to Inform Health Service Improvements.

OBJECTIVE: To understand experiences related to rheumatoid arthritis (RA) care and propose service-level strategies to reduce and mitigate inequities for Black people living in Canada. METHODS: Purposive and respondent driven sampling was used to recruit participants for qualitative interviews to explore population factors relevant to RA care and challenges and facilitators for access to health care services, medications, and enacting preferred treatment plans. Thematic analysis was conducted using the Braun and Clarke method with inductive and deductive coding and critical race theory guiding analysis. RESULTS: Six women and two men with RA, and two women health care professionals, expressed how their racial identity contributed to their understanding of RA, preferences for treatment, and outcome goals. Health care access was influenced by financial limitations and racism, by exclusion, and discrimination, and also by cultural norms in seeking health care and awareness about RA within the Black community. Participants experienced health system fragmentation and were not connected to ancillary supports. Treatment decision-making was influenced by the legacy of oppression and medical experimentation on Black people and the predominance of biomedical approaches emphasized by health care providers. Holistic and cultural approaches, provided in safe, trauma-informed care environments, with flexibility in service models, are desired. Partnerships between arthritis care services and Black community organizations are proposed to promote community awareness and knowledge about arthritis and provide support mechanisms for patients within their community. CONCLUSION: Our study highlights unique considerations based on race and ethnicity and provides suggestions for arthritis care to mitigate inequities for Black people living with arthritis.

Clinical and cost-effectiveness of an adapted intervention for preschoolers with moderate to severe intellectual disabilities displaying behaviours that challenge: the EPICC-ID RCT.

Background: Stepping Stones Triple P is an adapted intervention for parents of young children with developmental disabilities who display behaviours that challenge, aiming at teaching positive parenting techniques and promoting a positive parent-child relationship. Objective: To evaluate the clinical and cost-effectiveness of level 4 Stepping Stones Triple P in reducing behaviours that challenge in children with moderate to severe intellectual disabilities. Design, setting, participants: A parallel two-arm pragmatic multisite single-blind randomised controlled trial recruited a total of 261 dyads (parent and child). The children were aged 30-59 months and had moderate to severe intellectual disabilities. Participants were randomised, using a 3 : 2 allocation ratio, into the intervention arm (Stepping Stones Triple P; n = 155) or treatment as usual arm (n = 106). Participants were recruited from four study sites in Blackpool, North and South London and Newcastle. Intervention: Level 4 Stepping Stones Triple P consists of six group sessions and three individual phone or face-to-face contacts over 9 weeks. These were changed to remote sessions after 16 March 2020 due to the coronavirus disease 2019 pandemic. Main outcome measure: The primary outcome measure was the parent-reported Child Behaviour Checklist, which assesses the severity of behaviours that challenge. Results: We found a small non-significant difference in the mean Child Behaviour Checklist scores (-4.23, 95% CI -9.98 to 1.52, p = 0.146) in the intervention arm compared to treatment as usual at 12 months. Per protocol and complier average causal effect sensitivity analyses, which took into consideration the number of sessions attended, showed the Child Behaviour Checklist mean score difference at 12 months was lower in the intervention arm by -10.77 (95% CI -19.12 to -2.42, p = 0.014) and -11.53 (95% CI -26.97 to 3.91, p = 0.143), respectively. The Child Behaviour Checklist mean score difference between participants who were recruited before and after the coronavirus disease 2019 pandemic was estimated as -7.12 (95% CI -13.44 to -0.81) and 7.61 (95% CI -5.43 to 20.64), respectively (p = 0.046), suggesting that any effect pre-pandemic may have reversed during the pandemic. There were no differences in all secondary measures. Stepping Stones Triple P is probably value for money to deliver (-£1057.88; 95% CI -£3218.6 to -£46.67), but decisions to roll this out as an alternative to existing parenting interventions or treatment as usual may be dependent on policymaker willingness to invest in early interventions to reduce behaviours that challenge. Parents reported the intervention boosted their confidence and skills, and the group format enabled them to learn from others and benefit from peer support. There were 20 serious adverse events reported during the study, but none were associated with the intervention. Limitations: There were low attendance rates in the Stepping Stones Triple P arm, as well as the coronavirus disease 2019-related challenges with recruitment and delivery of the intervention. Conclusions: Level 4 Stepping Stones Triple P did not reduce early onset behaviours that challenge in very young children with moderate to severe intellectual disabilities. However, there was an effect on child behaviours for those who received a sufficient dose of the intervention. There is a high probability of Stepping Stones Triple P being at least cost neutral and therefore worth considering as an early therapeutic option given the long-term consequences of behaviours that challenge on people and their social networks. Future work: Further research should investigate the implementation of parenting groups for behaviours that challenge in this population, as well as the optimal mode of delivery to maximise engagement and subsequent outcomes. Study registration: This study is registered as NCT03086876 (https://www.clinicaltrials.gov/ct2/show/NCT03086876?term=Hassiotis±Angela&draw=1&rank=1). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: HTA 15/162/02) and is published in full in Health Technology Assessment; Vol. 28, No. 6. See the NIHR Funding and Awards website for further award information.

Research shows that in children without learning disabilities, parenting groups which support parents to develop skills to manage behaviours that challenge in their child can be helpful. The National Institute of Health and Care Excellence recommended that more research was needed to strengthen the evidence for such interventions for children with moderate to severe learning disability who are more likely to display behaviours that challenge in England. In this study, we tested in real-world conditions a programme called level 4 Stepping Stones Triple P, which has shown positive results in trials outside of the United Kingdom. Trained therapists delivered six groups and three individual sessions over 9 weeks to parents of children aged 30­59 months with moderate to severe learning disabilities. Two hundred and sixty-one parents were allocated to one of two arms by chance (randomisation): one received Stepping Stones Triple P and treatment as usual and the other treatment as usual only. Treatment as usual included support and advice by general practitioners or community child development teams. Our primary outcome was parent-reported child behaviour at 12 months after randomisation. We also collected data on other outcomes and carried out interviews with parents, service managers and therapists to find out their views about Stepping Stones Triple P. We did not find that Stepping Stones Triple P reduces behaviours that challenge in the child more than treatment as usual at 12 months. However, when we looked at people who received more than half of the sessions, there was a larger reduction in behaviours which suggests that Stepping Stones Triple P works for families if they attend the full programme. Stepping Stones Triple P seems to be good value for money, as we found that at 12 months (covering 10 months of costs), the Stepping Stones Triple P cost £1058 less than treatment as usual from a health and social care perspective. As such, Stepping Stones Triple P is fairly cheap to deliver and a suitable early intervention for behaviours that challenge especially because of positive feedback from parents. Throughout the trial, we included a Parent Advisory Group that oversaw study materials, interview topic guides and promotion of the study.

Spontaneous Hemoperitoneum in Pregnancy: Masquerading as Acute Appendicitis.

Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare obstetric emergency that may have an adverse outcome for the mother and baby. This case report describes a unique SHiP case initially diagnosed as acute appendicitis in a patient with severe endometriosis before conception. A woman in her 30s, a primigravida, was admitted with abdominal pain at 32+5 weeks gestational age. Following a surgical review, she was initially diagnosed with acute appendicitis and commenced on intravenous antibiotics. She experienced a dramatic deterioration in her health in the form of clinical shock and fetal distress. She had an emergency laparotomy, a hysterectomy, and a left salpingo-oophorectomy for uncontrollable bleeding. The baby was born in good health, and the mother had an uneventful recovery.

Reporting of Determinants of Health Inequities in Rheumatoid Arthritis Randomized Controlled Trials in Canada: A Scoping Review.

OBJECTIVE: More than ever, it is important to consider inclusion and diversity in rheumatology research. We reviewed and synthesized randomized controlled trials (RCTs) for rheumatoid arthritis (RA) in Canada with the aim of characterizing participants and identifying how determinants of health inequities are reported. METHODS: We conducted a scoping review following the Arksey and O'Malley framework. We searched Medline (1990 to December 2021), Embase (1990 to December 2021), and CENTRAL (inception to December 2021) for articles meeting inclusion criteria of: 1) used an RCT design; 2) evaluated pharmacologic or nonpharmacologic interventions; 3) included participants with RA; and 4) conducted in Canada. Data extraction was guided by the Campbell and Cochrane Equity Methods Group's PROGRESS-Plus framework on determinants that lead to health inequities (e.g., place of residence; race; occupation; gender/sex; religion; education; socioeconomic status; and social capital). RESULTS: Of 6,290 unique records, 42 were eligible for inclusion. We grouped studies according to 3 time periods: before 2000; 2000-2010; and 2011 to present. Participants of included studies were mostly middle-aged, female, and White. Sex and age were the most widely reported determinants in 41 studies. Other determinants reported were race (15 studies), education (11 studies), socioeconomic status (7 studies), and occupation (6 studies). Religion, features of relationships, and time-dependent relationships were not reported in any study. CONCLUSION: This scoping review suggests limited reporting on determinants of health inequities in RCTs for RA in Canada. Establishing reporting standards for equity factors in RCTs is important for addressing health inequities and informing accessible research and care for patients with RA.

Exploring the construct of anticipatory stress in finding a job after residency training through cognitive interviewing: Implications for learner well-being and health workforce planning.

Background: Anticipatory stress (AS) is denoted by concern about future events for which there is little control. Most AS research has been physiological studies such as measuring salivary cortisol levels. Medical learners may experience AS regarding employment after residency, however AS a psychological construct across career stages has not previously been studied. The objective of this study is to explore the psychological construct of employment AS in medical students, residents, and former Program Directors (PDs). Methods: Participants were recruited from a large Canadian medical school via purposive sampling. Semi-structured interviews with n=21 participants (six medical students, nine residents, and six PDs) were transcribed verbatim, and coded by two independent reviewers using thematic analysis. Results: Participants agreed that financial, family, and geographical factors exacerbate AS, and it is mitigated by flexibility, social support, and being proactive. External support, job market saturation, and differences between medical specialities also influence AS. Perspectives unique to participant groups included: medical students reflecting on a hidden curriculum and preoccupation with proximal issues over distal concerns of employment; residents experiencing competing residency program demands; former PDs finding that resident competency, yearly hiring fluctuations, and existing stress impact AS. Consequences of AS include physical and psychological manifestations, performance anxiety, and pursuing additional training. Conclusions: Perceptions of AS vary by medical career stage. Individual, program and systems-level changes can help manage and address the underlying cause of AS: an unreliable job market for physicians. Correcting the mismatch between residency positions and job openings may be a proactive, preventative approach.