Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Use of Telemedicine in Pediatric Services for 4 Representative Clinical Conditions: Scoping Review

BackgroundTelemedicine is becoming routine in health care. Postpandemic, a universal return to face-to-face consultations may risk a loss of some of the advantages of telemedicine. However, rapid implementation and adoption without robust evaluation of usability, efficacy, and effectiveness could potentially lead to suboptimal health outcomes and downstream challenges to providers. ObjectiveThis review assesses telemedicine interventions against international guidance and sufficiency of evidence to support postpandemic utilization in pediatric settings. MethodsThis scoping review was performed following searches on PubMed, Embase, and CINAHL databases on April 15, 2021, and May 31, 2022, and examined studies focused on telemedicine, remote consultation, video call, or remote patient monitoring in children (0-18 years) receiving outpatient care for diabetes, asthma, epilepsy, or renal disease. Exclusion criteria included studies published before 2011 as the technologies used have likely been improved or replaced, studies in adult populations or where it was not possible to disaggregate data for participants younger than 18 years as the focus of the review was on pediatric care, and studies not published in English. Data were extracted by 4 authors, and the data were corroborated by a second reviewer. Studies were examined for feasibility and usability, clinical and process outcomes, and cost-effectiveness. ResultsOf the 3158 studies identified, 56 were suitable for final inclusion and analysis. Data on feasibility or usability of interventions (48 studies) were overwhelmingly positive in support of telemedicine interventions, with common themes including convenience, perceived cost savings, and ease of use. However, use in preference to usual care was rarely explored. Clinical and process outcome data (31 studies) were mostly positive. Across all studies, there was limited measurement of standardized clinical outcomes, although these were more commonly reported in asthma (peak flow) and diabetes (glycated hemoglobin [HbA1c]). Implementation science data generally supported cost-effectiveness of telemedicine with a reduction of health care costs. ConclusionsThere is promising evidence supporting telemedicine in pediatric settings. However, there is a lack of evaluation of telemedicine in comparison with usual outpatient care for noninferiority of clinical outcomes, and this review highlights the need for a more standardized approach to evaluation of digital interventions

Acute kidney injury and short-term renal support in the post-operative management of neonates following repair of transposition of the great arteries

Neonates requiring congenital cardiac surgery are at risk of acute kidney injury, associated with significant morbidity, mortality, and increased hospital length of stay; treatment may require renal replacement therapy. Data for single cardiac defect cohorts is important to stratify risk, but is lacking for transposition of the great arteries. Our study aimed at collecting data for this single lesion. A single-centre, retrospective analysis of 71 cases of arterial switch operation in neonates with isolated transposition of the great arteries, or transposition of the great arteries with ventricular septal defect, including length of stay, renal function and need for renal replacement therapy was performed. Acute kidney injury developed in 50.7%, and was associated with longer paediatric intensive care and hospital stays (p < 0.05). Paediatric intensive care unit length of stay correlated with higher peak creatinine and urea (p < 0.05) and also with higher lactate levels at paediatric intensive care unit admission and 1 and 6 h post-admission (p < 0.05). Renal replacement therapy via peritoneal dialysis was delivered to 11.1%, but this was not found to prolong paediatric intensive care unit length of stay. Initiation of renal replacement therapy was associated with a positive fluid balance at 1 and 6 h (p < 0.05). This study analyses renal outcomes in a cohort of neonates with transposition of the great arteries undergoing an arterial switch operation. Acute kidney injury is a significant complication, with accompanying need for renal replacement therapy. Development of acute kidney injury and a positive fluid balance were associated with increased length of stay. Initiation of renal replacement therapy was not associated with increased length of stay, and with some evidence from the literature that early or prophylactic peritoneal dialysis catheter insertion improves outcomes, these data report minimal complication rates which may be important when deciding to utilise peritoneal dialysis

Registry Data Show Complication Rates and Cost in Revision Hip Arthroplasty.

BACKGROUND: Revision total hip arthroplaty (rTHA) places a burden on patients, surgeons, and health care systems because outcomes and costs are less predictable than primary THA. The purpose of this study was to define indications and treatments for rTHA, quantify risk for readmissions, and evaluate the economic impacts of rTHA in a hospital system. METHODS: The arthroplasty database of a hospital system was queried to generate a retrospective cohort of 793 rTHA procedures, performed on 518 patients, from 2017 to 2019 at 27 hospitals. Surgeons performed chart reviews to classify indication and revision procedure. Demographics, lengths of stay, discharge dispositions, and readmission data were collected. Analyses of direct costs were performed and categorized by revision type. RESULTS: Totally, 46.3% of patients presented for infection. Patients presenting for infection were 5.6 times more likely to have repeat rTHA than aseptic patients. Septic cases (4.3 days) had longer length of stay than aseptic ones (2.4) (P \u3c .0001). However, 31% of patients discharged to a skilled nursing facility. Direct costs were greatest for a two-stage exchange ($37,642) and lowest for liner revision ($8,979). Septic revisions ($17,696) cost more than aseptic revisions ($11,204) (P \u3c .0001). The 90-day readmission rate was 21.8%. Septic revisions had more readmissions (13.5%) than aseptic revisions (8.3%). CONCLUSIONS: Hip revisions, especially for infection, have an increased risk profile and create a major economic impact on hospital systems. Surgeons may use these data to counsel patients on risks of rTHA and advocate for improved reimbursement for the care of revision patients

Whole-genome sequencing of patients with rare diseases in a national health system

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare