Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Usability and acceptability of a multimodal respiratory rate and pulse oximeter device in case management of children with symptoms of pneumonia: A cross-sectional study in Ethiopia.

AIM: Pneumonia is the leading infectious cause of death among children under five globally. Many pneumonia deaths result from inappropriate treatment due to misdiagnosis of signs and symptoms. This study aims to identify whether health extension workers (HEWs) in Ethiopia, using an automated multimodal device (Masimo Rad-G), adhere to required guidelines while assessing and classifying under five children with cough or difficulty breathing and to understand device acceptability. METHODS: A cross-sectional study was conducted in three districts of Southern Nations, Nationalities, and Peoples' Region, Ethiopia. Between September and December 2018, 133 HEWs were directly observed using Rad-G while conducting 599 sick child consultations. Usability was measured as adherence to the World Health Organization requirements to assess fast breathing and device manufacturer instructions for use. Acceptability was assessed using semi-structured interviews with HEWs, first-level health facility workers and caregivers. RESULTS: Adherence using the Rad-G routinely for 2 months was 85.3% (95% CI 80.2, 89.3). Health workers and caregivers stated a preference for Rad-G. Users highlighted a number of device design issues. CONCLUSION: While demonstrating high levels of acceptability and usability, the device modifications to consider include better probe fit, improved user interface with exclusive age categories and simplified classification outcomes.

Evaluating the Interrater Agreement and Acceptability of a New Reference Tool for Assessing Respiratory Rate in Children under Five with Cough and/or Difficulty Breathing.

BACKGROUND: Manual assessment of respiratory rate (RR) in children is unreliable, but remains the main method to diagnose pneumonia in low-resource settings. While automated RR counters offer a potential solution, there is currently no gold standard to validate these diagnostic aids. A video-based reference tool is proposed that allows users to annotate breaths and distortions including movement periods, allowing the exclusion of distortions from the computation of RR measures similar to how new diagnostic aids account for distortions automatically. This study evaluated the interrater agreement and acceptability of the new reference tool. METHODS: Annotations were based on previously recorded reference videos of children under five years old with cough and/or difficulty breathing (n = 50). Five randomly selected medical experts from a panel of ten annotated each video. RR measures (breaths per minute, bpm) were computed as the number of annotated certain breaths divided by the length of calm periods after removing annotated distorted periods. RESULTS: Reviewers showed good interrater agreement on continuous RR {standard error of measurement (SEM) [4.8 (95%CI 4.4-5.3)]} and substantial agreement on classification of fast breathing (Fleiss kappa, κ 0.71). Agreement was lowest in the youngest age group [< 2 months: SEM 6.2 (5.4-7.4) bpm, κ 0.48; 2-11 months: 4.7 (4.0-5.8) bpm, κ 0.84; 12-59 months: 2.6 (2.2-3.1) bpm, κ 0.8]. Reviewers found the functionalities of the tool helpful in annotating breaths, but remained uncertain about the validity of their annotations. CONCLUSIONS: Before the new tool can be considered a reference standard for RR assessments, interrater agreement in children younger than 2 months must be improved.

Usability and acceptability of an automated respiratory rate counter to assess childhood pneumonia in Nepal.

AIM: Pneumonia is the leading cause of child death after the neonatal period, resulting from late care seeking and inappropriate treatment. Diagnosis involves counting respiratory rate (RR); however, RR counting remains challenging for health workers and miscounting, and misclassification of RR is common. We evaluated the usability of a new automated RR counter, the Philips Children's Respiratory Monitor (ChARM), to Female Community Health Volunteers (FCHVs), and its acceptability to FCHVs and caregivers in Nepal. METHODS: A cross-sectional study was conducted in Jumla district, Nepal. About 133 FCHVs were observed between September and December 2018 when using ChARM during 517 sick child consultations, 264 after training and 253 after 2 months of routine use of ChARM. Acceptability of the ChARM was explored using semi-structured interviews. RESULTS: FCHV adherence to guidelines after 2 months of using ChARM routinely was 52.8% (95% CI 46.6-58.9). The qualitative findings suggest that ChARM is acceptable to FCHVs and caregivers; however, capacity constraints such as older age and low literacy and impacted device usability were mentioned. CONCLUSION: Further research on the performance, cost-effectiveness and implementation feasibility of this device is recommended, especially among low-literate CHWs.

Usability and acceptability of an automated respiratory rate counter to assess children for symptoms of pneumonia: A cross-sectional study in Ethiopia.

AIM: Manually counting respiratory rate (RR) is commonly practiced by community health workers to detect fast breathing, an important sign of childhood pneumonia. Correctly counting and classifying breaths manually is challenging, often leading to inappropriate treatment. This study aimed to determine the usability of a new automated RR counter (ChARM) by health extension workers (HEWs), and its acceptability to HEWs, first-level health facility workers (FLHFWs) and caregivers in Ethiopia. METHODS: A cross-sectional study was conducted in one region of Ethiopia between May and August 2018. A total of 131 HEWs were directly observed conducting 262 sick child consultations after training and 337 after 2 months. Usability was measured as adherence to the WHO requirements to assess fast breathing and device manufacturer instructions for use (IFU). Acceptability was measured through semi-structured interviews. RESULTS: After 2 months, HEWs were shown to adhere to the requirements in 74.6% consultations; an increase of 18.6% after training (P < .001). ChARM is acceptable to users and caregivers, with HEWs suggesting that ChARM increased client flow and stating a willingness to use ChARM in future. CONCLUSION: Further research on the performance, cost-effectiveness and implementation of this device is warranted to inform policy decisions in countries with a high childhood pneumonia burden.

Automated Respiratory Rate Counter to Assess Children for Symptoms of Pneumonia: Protocol for Cross-Sectional Usability and Acceptability Studies in Ethiopia and Nepal.

BACKGROUND: Manually counting a child's respiratory rate (RR) for 60 seconds using an acute respiratory infection timer is the World Health Organization (WHO) recommended method for detecting fast breathing as a sign of pneumonia. However, counting the RR is challenging and misclassification of an observed rate is common, often leading to inappropriate treatment. To address this gap, the acute respiratory infection diagnostic aid (ARIDA) project was initiated in response to a call for better pneumonia diagnostic aids and aimed to identify and assess automated RR counters for classifying fast breathing pneumonia when used by front-line health workers in resource-limited community settings and health facilities. The Children's Automated Respiration Monitor (ChARM), an automated RR diagnostic aid using accelerometer technology developed by Koninklijke Philips NV, and the Rad-G, a multimodal RR diagnostic and pulse oximeter developed by Masimo, were the two devices tested in these studies conducted in the Southern Nations, Nationalities, and Peoples' Region in Ethiopia and in the Karnali region in Nepal. OBJECTIVE: In these studies, we aimed to understand the usability of two new automated RR diagnostic aids for community health workers (CHWs; health extension workers [Ethiopia] and female community health volunteers [Nepal]) and their acceptability to CHWs in Ethiopia and Nepal, first-level health facility workers (FLHFWs) in Ethiopia only, and caregivers in both Ethiopia and Nepal. METHODS: This was a prospective, cross-sectional study with a mixed methods design. CHWs and FLHFWs were trained to use both devices and provided with refresher training on all WHO requirements to assess fast breathing. Immediately after training, CHWs were observed using ARIDA on two children. Routine pneumonia case management consultations for children aged 5 years and younger and the device used for these consultations between the first and second consultations were recorded by CHWs in their patient log books. CHWs were observed a second time after 2 months. Semistructured interviews were also conducted with CHWs, FLHFWs, and caregivers. The proportion of consultations with children aged 5 years and younger where CHWs using an ARIDA and adhered to all WHO requirements to assess fast breathing and device manufacturer instructions for use after 2 months will be calculated. Qualitative data from semistructured interviews will be analyzed using a thematic framework approach. RESULTS: The ARIDA project was funded in November 2015, and data collection was conducted between April and December 2018. Data analysis is currently under way and the first results are expected to be submitted for publication in 2020. CONCLUSIONS: This is the first time the usability and acceptability of automated RR counters in low-resource settings have been evaluated. Outcomes will be relevant for policy makers and are important for future research of this new class of diagnostic aids for the management of children with suspected pneumonia. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14405.