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Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

BackgroundEvaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA).MethodsUsing previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus.ResultsThe ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated.ConclusionThis review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Abstract Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12–73%), 33% (6–86%) in cohorts with prior genetic testing, and 33% (9–60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24–100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

Background: This was the first Phase III randomized study comparing an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, to standard-of-care chemotherapy (pemetrexed + carboplatin followed by pemetrexed maintenance) in advanced EGFR-mutated lung cancer. The initial interim analysis showed the superiority of gefitinib over chemotherapy in terms of progression-free survival (PFS), objective response rate (ORR), and safety. Objectives: We aimed to evaluate the long-term outcomes. Our primary endpoint was to evaluate the overall survival (OS) and the secondary endpoints were progression-free survival 2 (PFS2) and duration of response (DOR). Materials and Methods: This was a Phase III open-label, randomized, parallel-group study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, in patients with EGFR mutation-positive treatment-naïve Stage IIIB or IV lung adenocarcinoma. Patients were randomized to gefitinib (250 mg orally daily) or carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) chemotherapy, followed by maintenance pemetrexed (500 mg/m2). Results: Between February 2012 and April 2016, 290 patients were randomized:145 to each arm. At a median follow-up of 104 months, all 290 (100%) patients had progressed, and 287 (99%) deaths had occurred. The median OS in the gefitinib arm was 19.5 months (95% confidence interval [CI], 16.7-24.8) compared to 22.6 months (95% CI, 19.2-25.2) in the chemotherapy arm; hazard ratio [HR], 1.11; 95% CI, 0.87-1.39; P, 0.423. The median PFS2 in the gefitinib arm was 15.5 months (95% CI, 13.5-18.1) compared to 12.5 months (95% CI, 11.1-14.5) in the chemotherapy arm; HR, 0.86 (95% CI, 0.66-1.13); P, 0.270. The median DOR was improved in the gefitinib arm (7.6 months; 95% CI, 5.45-9.88) compared to 3.9 months (95% CI, 3.49-6.35) in the chemotherapy arm; HR, 0.59; 95% CI, 0.42-0.82; P, 0.002. The 5-year survival was 4.1% in the gefitinib arm versus 6.8% in the chemotherapy arm. Conclusions: This study establishes the advantages of first-line EGFR TKI therapy over chemotherapy in terms of a durable response and numerically superior PFS2. Due to crossover post-progression, there was is no significant difference in OS (Clinical Trials Registry of India number: CTRI/2015/08/006113).

The co-occurrence of Mega Cisterna Magna and Periventricular Nodular Heterotopia in an adult female patient is an uncommon and intriguing observation. Most instances are X-linked, typically with the Xq28-localized filamin A gene FLNA as the culprit. In this case study, we present a 52-year-old female patient who sought medical care for recurring headaches and epilepsy. The present case emphasizes the necessity for ongoing study and exploration into the clinical trajectory and imaging of uncommon correlations between nodular heterotopia and mega cisterna magna.

Introduction: The outcomes in advanced NSCLC have improved owing to the availability of more effective systemic and improved supportive care. This has increased the number of patients who seek treatment in the third line and beyond setting. We conducted this study to compare the quality of life (QoL), toxicity, and outcomes in patients receiving chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) in this setting. Methods: In this phase 3, randomized, open-label study, patients with stage III or IV NSCLC with disease progression on at least two prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior EGFR TKI exposure, and stable brain metastases (if any) were included. Patients were randomized to receive chemotherapy (gemcitabine or docetaxel or paclitaxel or vinorelbine) or an EGFR TKI (erlotinib or gefitinib). The primary end point was the change in QoL at 8 to 10 weeks; the secondary outcomes were safety and overall survival (OS). Patients underwent clinical evaluation at every visit, and toxicity was assessed as per Common Terminology Criteria for Adverse Events version 4.03. A radiological tumor response assessment was done every 8 to 12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C30 and LC13 questionnaires. The change in QoL scores was calculated as the difference between scores at baseline and scores at 8 to 10 weeks (Δ) for each QoL domain. The Mann-Whitney U test was used to compare the mean difference (Δ) for each domain. OS and progression-free survival (PFS) were determined using the Kaplan-Meier method and Cox proportional regression analysis. Results: A total of 246 patients were enrolled in the study, with 123 in each arm. There was a male predominance with 69.1% male patients in the chemotherapy arm and 70.7% in the EGFR TKI arm. The median age of patients in the chemotherapy arm was 54 years and 55 years in the chemotherapy and EGFR TKI arms, respectively. There was no significant difference in the change in QoL at baseline and the second visit (Δ) in both arms in all domains of EORTC QLQ C30 except cognitive function (p = 0.0045) and LC13 except alopecia (0.01249). The mean Δ Global Health Status was −28 in the chemotherapy arm and −26.8 in the EGFR TKI arm; this was not statistically significant (p = 0.973). The median follow-up was 88.1 months (95% confidence interval [CI]: 39.04–137.15). On the intention-to-treat analysis, the median PFS was 3.13 months (95% CI: 2.15–4.11) in the chemotherapy arm and 2.26 months (95% CI: 2.1–2.43) in the EGFR TKI arm, with hazard ratio at 1.074 (95% CI: 0.83–1.38) (p = 0.58). There were 120 deaths in each arm. The median OS was 7.63 months (95% CI: 5.96–9.30) in the chemotherapy arm and 7.5 months in the EGFR TKI arm (95% CI: 5.85–9.14); hazard ratio at 1.033 (95% CI: 0.80–1.33) (p = 0.805). The toxicity profile was similar in both arms except for a significantly higher incidence of fatigue (p = 0.043), peripheral neuropathy (0.000), alopecia, hypokalemia (0.037), and pedal edema (0.007) in the chemotherapy arm and dry skin (p = 0.000) and skin rash (p = 0.019) in the EGFR TKI arm. Conclusions: There was no significant difference in most QoL scales (except cognitive function and alopecia), OS, and PFS of patients with advanced NSCLC receiving an EGFR TKI as compared with chemotherapy TKI in the third-line setting. The toxicity profile is consistent with the known toxicities of the agents.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Abstract Background The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. Methods We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. Discussion The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.

Aim: The objective of this study was to evaluate and compare canal transportation (CT) and centering ability (CA) in the curved canals prepared using HyFlex CM (HCM) and TruNatomy (TN) rotary file systems with the help of cone-beam computed tomography (CBCT). Materials and Methods: Forty extracted single-rooted mandibular premolars with 10°–30° of curvature were selected and divided into two groups. In Group 1, the canals were prepared with HCM files (Coltene Whaledent) and in Group 2 the canals were prepared with TN Prime rotary files (Dentsply Sirona). Pre- and postinstrumentation scans were performed at the same position using CBCT to evaluate CT and CA at three levels 3 mm, 6 mm, and 9 mm from the apex and were compared using CBCT software (On Demand 3D software). Statistical Analysis Used: The two groups were statistically analyzed with Mann–Whitney U-test. Results: There was no significant difference among the tested groups regarding the canal centering ratio (P > 0.05). At 6- and 9-mm levels, there was no significant difference in CT among the two groups (P > 0.05). However, at 3 mm from apex, there was a statistically significant difference (P = 0.006) with TN files exhibiting lesser CT. Conclusion: Both the file systems respected the canal anatomy, although in the apical third, TN files exhibited better results. Hence, this file system can be considered for instrumentation of canals with moderate apical curvatures. In regard to CA, no significant differences were found among the file systems.

System islanding, relay tripping, and reverse power flow-like issues in the distribution network are all caused by randomly placed distributed energy resources. To minimize such problems, distributed energy resource (DER) optimal placement in the radial distribution network (RDN) is essential to reduce power loss and enhance the voltage profile. When placing DERs, consideration of constraints like size, location, number, type, and power factor (PF) should be considered. For optimal placement, renewable and nonrenewable DERs are considered. The effects of different types and PFs of DER placements have been tested on the IEEE 33 bus RDN to satisfy all limitations. Using various intelligent techniques, distributed energy resource units of optimal type, PF, size, quantity, and position were placed in the IEEE 33 bus RDN. These intelligent strategies for minimizing power loss, enhancing the voltage profile, and increasing the convergence rate are based on an adaptive neuro-fuzzy inference system, a genetic algorithm, and enhanced particle swarm optimization.

Abstract Inherited retinal degenerations are clinically and genetically heterogeneous diseases characterized by progressive deterioration of vision. This study aimed at assessing the diagnostic yield of exome sequencing (ES) for an unselected cohort of individuals with hereditary retinal disorders. It is a retrospective study of 357 unrelated affected individuals, diagnosed with retinal disorders who underwent clinical ES. Variants from ES were filtered, prioritized, and classified using the ACMG recommendations. Clinical diagnosis of the individuals included rod-cone dystrophy (60%), macular dystrophy (20%), cone-rod dystrophy (9%), cone dystrophy (4%) and other phenotypes (7%). Majority of the cases (74%) were singletons and 6% were trios. A confirmed molecular diagnosis was obtained in 24% of cases. In 6% of cases, two pathogenic variants were identified with phase unknown, bringing the potential molecular diagnostic rate to ~ 30%. Including the variants of uncertain significance (VUS), potentially significant findings were reported in 57% of cases. Among cases with a confirmed molecular diagnosis, variants in EYS, ABCA4, USH2A, KIZ, CERKL, DHDDS, PROM1, NR2E3, CNGB1, ABCC6, PRPH2, RHO, PRPF31, PRPF8, SNRNP200, RP1, CHM, RPGR were identified in more than one affected individual. Our results support the utility of clinical ES in the diagnosis of genetically heterogeneous retinal disorders.

Abstract Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.

Abstract Background Overlapping microdeletions of chromosome 3q26-3q28 have been reported in eight individuals. The common phenotype observed in these individuals include intrauterine growth restriction, short stature, microcephaly, feeding difficulties, facial dysmorphisms, limb abnormalities and developmental delay. The most striking clinical features shared among all reported cases is prenatal and postnatal growth restriction and neurodevelopmental abnormalities. Case presentation We identified two additional individuals with overlapping deletions and shared clinical features by high-resolution SNP oligonucleotide microarray, and refined the smallest region of overlap (SRO) to a 1.2 Mb genomic location in chromosome 3q27.1 by reviewing and comparing all published cases. We evaluated the SRO using ACMG/ClinGen current recommendations for classifying copy number variants (CNVs), and discussed the contribution of the genes deleted in the SRO to the abnormal phenotype observed in these individuals. Conclusions This study provides further evidence supporting the existence of a novel 3q27.1 microdeletion syndrome and suggests that haploinsufficiency of potential candidate genes, DVL3, AP2M1, and PARL in the SRO in 3q27.1 is responsible for the phenotype.

Abstract Objectives We evaluated routine healthcare management, clinical status and patient‐ and carer‐reported outcomes in UK paediatric and adult patients with transfusion‐dependent β‐thalassaemia (TDT). Methods A multi‐centre, observational mixed‐methodology study evaluated 165 patients (50% male; median age 24.1 [interquartile range (IQR)] 11.8–37.2] years) from nine UK centres. Results Patients had a mean of 13.7 (standard deviation [SD] ±3.2) transfusion episodes/year (mean retrospective observation period 4.7 [±0.7] years). The median (IQR) for iron overload parameters at the last assessment during the observation period were: serum ferritin (n = 165) 1961.0 (1090.0–3003.0) μg/L (38% > 2500 μg/L); R2 liver iron (n = 119) 5.4 (2.9–11.6) mg/g (16% ≥15 mg/g); T2* cardiac iron (n = 132) 30.3 (22.0–37.1) ms (10%

Abstract The use of close-fitting PPE is essential to prevent exposure to dispersed airborne matter, including the COVID-19 virus. The current pandemic has increased pressure on healthcare systems around the world, leading to medical professionals using high-grade PPE for prolonged durations, resulting in device-induced skin injuries. This study focuses on computationally improving the interaction between skin and PPE to reduce the likelihood of discomfort and tissue damage. A finite element model is developed to simulate the movement of PPE against the face during day-to-day tasks. Due to limited available data on skin characteristics and how these vary interpersonally between sexes, races and ages, the main objective of this study was to establish the effects and trends that mask modifications have on the resulting subsurface strain energy density distribution in the skin. These modifications include the material, geometric and interfacial properties. Overall, the results show that skin injury can be reduced by using softer mask materials, whilst friction against the skin should be minimised, e.g. through use of micro-textures, humidity control and topical creams. Furthermore, the contact area between the mask and skin should be maximised, whilst the use of soft materials with incompressible behaviour (e.g. many elastomers) should be avoided.

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.

Abstract Background In response to the rising global NCD burden, humanitarian actors have rapidly scaled-up NCD services in crisis-affected low-and-middle income countries. Using the RE-AIM implementation framework, we evaluated a multidisciplinary, primary level model of NCD care for Syrian refugees and vulnerable Jordanians delivered by MSF in Irbid, Jordan. We examined the programme’s Reach, Effectiveness, Adoption and acceptance, Implementation and Maintenance over time. Methods This mixed methods retrospective evaluation, undertaken in 2017, comprised secondary analysis of pre-existing cross-sectional household survey data; analysis of routine cohort data from 2014 to 2017; descriptive costing analysis of total annual, per-patient and per-consultation costs for 2015–2017 from the provider-perspective; a clinical audit; a medication adherence survey; and qualitative research involving thematic analysis of individual interviews and focus group discussions. Results The programme enrolled 23% of Syrian adult refugees with NCDs in Irbid governorate. The cohort mean age was 54.7 years; 71% had multi-morbidity and 9.9% self-reported a disability. The programme was acceptable to patients, staff and stakeholders. Blood pressure and glycaemic control improved as the programme matured and by 6.6 mmHg and 1.12 mmol/l respectively within 6 months of patient enrolment. Per patient per year cost increased 23% from INT$ 1424 (2015) to 1751 (2016), and by 9% to 1904 (2017). Cost per consultation increased from INT$ 209 to 253 (2015–2017). Staff reported that clinical guidelines were usable and patients’ self-reported medication adherence was high. Individual, programmatic and organisational challenges to programme implementation and maintenance included the impact of war and the refugee experience on Syrian refugees’ ability to engage; inadequate low-cost referral options; and challenges for MSF to rapidly adapt to operating in a highly regulated and complex health system. Essential programme adaptations included refinement of health education, development of mental health and psychosocial services and addition of essential referral pathways, home visit, physiotherapy and social worker services. Conclusion RE-AIM proved a valuable tool in evaluating a complex intervention in a protracted humanitarian crisis setting. This multidisciplinary programme was largely acceptable, achieving good clinical outcomes, but for a limited number of patients and at relatively high cost. We propose that model simplification, adapted procurement practices and use of technology could improve cost effectiveness without reducing acceptability, and may facilitate replication.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

Introduction: South Africa has the world's largest antiretroviral treatment programme, which may contribute to the adverse drug reaction (ADR) burden. We aimed to determine the proportion of adult non-trauma emergency unit (EU) presentations attributable to ADRs and to characterise ADR-related EU presentations, stratified according to HIV status, to determine the contribution of drugs used in management of HIV and its complications to ADR-related EU presentations, and identify factors associated with ADR-related EU presentation. Methods: We conducted a retrospective folder review on a random 1.7% sample of presentations over a 12-month period in 2014/2015 to the EUs of two hospitals in Cape Town, South Africa. We identified potential ADRs with the help of a trigger tool. A multidisciplinary panel assessed potential ADRs for causality, severity, and preventability. Results: We included 1010 EU presentations and assessed 80/1010 (7.9%) as ADR-related, including 20/239 (8.4%) presentations among HIV-positive attendees. Among HIV-positive EU attendees with ADRs 17/20 (85%) were admitted, versus 22/60 (37%) of HIV-negative/unknown EU attendees. Only 5/21 (24%) ADRs in HIV-positive EU attendees were preventable, versus 24/63 (38%) in HIV-negative/unknown EU attendees. On multivariate analysis, only increasing drug count was associated with ADR-related EU presentation (adjusted odds ratio 1.10 per additional drug, 95% confidence interval 1.03 to 1.18), adjusted for age, sex, HIV status, comorbidity, and hospital. Conclusions: ADRs caused a significant proportion of EU presentations, similar to findings from other resource-limited settings. The spectrum of ADR manifestations in our EUs reflects South Africa's colliding epidemics of infectious and non-communicable diseases. ADRs among HIV-positive EU attendees were more severe and less likely to be preventable.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing. Methods The NYCKidSeq project is a randomized controlled trial recruiting 1130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo, or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost, and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits: baseline (0 months), result disclosure visit (ROR1, + 3 months), and follow-up visit (ROR2, + 9 months). Outcomes will assess parental understanding of and attitudes toward receiving genomic results for their child and behavioral, psychological, and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver’s ability to increase the diagnostic yield compared to standard practices, improve clinician’s ability to perform targeted reverse phenotyping, and increase the efficiency of genetic testing lab personnel. Discussion The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound. Trial registration ClinicalTrials.gov NCT03738098 . Registered on November 13, 2018 Trial Sponsor: Icahn School of Medicine at Mount Sinai Contact Name: Eimear Kenny, PhD (Principal Investigator) Address: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., Box 1003, New York, NY 10029 Email: eimear.kenny@mssm.edu

Abstract Whole-genome sequencing (WGS) is positioned to become one of the most robust strategies for achieving timely diagnosis of rare genomic diseases. Despite its favorable diagnostic performance compared to conventional testing strategies, routine use and reimbursement of WGS are hampered by inconsistencies in the definition and measurement of clinical utility. For example, what constitutes clinical utility for WGS varies by stakeholder’s perspective (physicians, patients, families, insurance companies, health-care organizations, and society), clinical context (prenatal, pediatric, critical care, adult medicine), and test purpose (diagnosis, screening, treatment selection). A rapidly evolving technology landscape and challenges associated with robust comparative study design in the context of rare disease further impede progress in this area of empiric research. To address this challenge, an expert working group of the Medical Genome Initiative was formed. Following a consensus-based process, we align with a broad definition of clinical utility and propose a conceptually-grounded and empirically-guided measurement toolkit focused on four domains of utility: diagnostic thinking efficacy, therapeutic efficacy, patient outcome efficacy, and societal efficacy. For each domain of utility, we offer specific indicators and measurement strategies. While we focus on diagnostic applications of WGS for rare germline diseases, this toolkit offers a flexible framework for best practices around measuring clinical utility for a range of WGS applications. While we expect this toolkit to evolve over time, it provides a resource for laboratories, clinicians, and researchers looking to characterize the value of WGS beyond the laboratory.

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Background: There are an estimated 55 million internally displaced persons (IDPs) globally. IDPs commonly have worse health outcomes than host populations and other forcibly displaced populations such as refugees. Official development assistance (ODA) is a major source of the global financial response for health in low- and middle-income countries (LMICs), including for populations affected by armed conflict and forced displacement. Analysis of ODA supports efforts to improve donor accountability, transparency and the equitable use of ODA. The aim of this study is to examine international donor support and responsiveness to IDP health needs through analysis of ODA disbursements to LMICs between 2010 and 2019. Methods: ODA disbursement data to LMICs from 2010 to 2019 were extracted from the Creditor Reporting System (CRS) database and analysed with Stata software using a combination of: (i) text searching for IDP and refugee related terms; and (ii) relevant health and humanitarian CRS purpose codes. Descriptive analysis was used to examine patterns of ODA disbursement, and nonlinear least squared regression analysis was used to examine responsiveness of ODA disbursement to recipient country IDP population size and health system capacity and health characteristics. Findings: The study highlighted declining per IDP capita health ODA from USD 5.34 in 2010 to USD 3.72 in 2019 (with annual average decline of -38% from the 2010 baseline). In contrast, health ODA for refugees in LMICs increased from USD 18.55 in 2010 to USD 23.31 in 2019 (with an annual average increase of +14%). Certain health topics for IDPs received very low ODA, with only 0.44% of IDP health ODA disbursed for non-communicable diseases (including mental health). There was also weak evidence of IDP health ODA being related to recipient country IDP population size, and health system capacity and health characteristics. The paper highlights the need for increased investment by donors in IDP health ODA and to ensure that it is responsive to their health needs.

Abstract Background The conflict in Syria has required humanitarian agencies to implement primary-level services for non-communicable diseases (NCDs) in Jordan, given the high NCD burden amongst Syrian refugees; and to integrate mental health and psychosocial support into NCD services given their comorbidity and treatment interactions. However, no studies have explored the mental health needs of Syrian NCD patients. This paper aims to examine the interaction between physical and mental health of patients with NCDs at a Médecins Sans Frontières (MSF) clinic in Irbid, Jordan, in the context of social suffering. Methods This qualitative study involved sixteen semi-structured interviews with Syrian refugee and Jordanian patients and two focus groups with Syrian refugees attending MSF’s NCD services in Irbid, and eighteen semi-structured interviews with MSF clinical, managerial and administrative staff. These were conducted by research staff in August 2017 in Irbid, Amman and via Skype. Thematic analysis was used. Results Respondents describe immense suffering and clearly perceived the interconnectedness of their physical wellbeing, mental health and social circumstances, in keeping with Kleinman’s theory of social suffering. There was a ‘disconnect’ between staff and patients’ perceptions of the potential role of the NCD and mental health service in alleviating this suffering. Possible explanations identified included respondent’s low expectations of the ability of the service to impact on the root causes of their suffering, normalisation of distress, the prevailing biomedical view of mental ill-health among national clinicians and patients, and humanitarian actors’ own cultural standpoints. Conclusion Syrian and Jordanian NCD patients recognise the psychological dimensions of their illness but may not utilize clinic-based humanitarian mental health and psychosocial support services. Humanitarian agencies must engage with NCD patients to elicit their needs and design culturally relevant services.