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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.

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 Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practice. The Medical Genome Initiative consortium was formed to provide practical guidance and support the development of standards for the use of clinical WGS.

Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice.

Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.

Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS.

Urethral diverticulum with distal stricture is a common entity. We are presenting a rare case of urethral diverticulum with proximal stricture. This is an uncommon case of a 55- year-old male paraplegic patient, who had urethrocutaneous fistula with distal urethral diverticulum and proximal urethral stricture. The patient was successfully managed by single-stage diverticulectomy and urethroplasty.

The objective of this paper is to find a sequence of jobs for the permutation flow shop to minimise the makespan. The shop consists of 10 machines. A feed-forward back-propagation artificial neural network (ANN) is used to solve the problem. The network is trained with the optimal sequences for five-, six- and seven-job problems. This trained network is then used to solve a problem with a greater number of jobs. The sequence obtained using the neural network is used to generate the initial population for the genetic algorithm (GA) using the random insertion perturbation scheme (RIPS). The makespan of the sequence obtained by this approach (ANN-GA-RIPS) is compared with that obtained using GA starting with a random population (ANN-GA). It was found that the ANN-GA-RIPS approach performs better than ANN-GA starting with a random population. The results obtained are compared with those obtained using the Nawaz, Enscore and Ham (NEH) heuristic and upper bounds of Taillard's benchmark problems. ANN-GA-RIPS performs better than the NEH heuristic and the results are found to be within 5% of the upper bounds. [ABSTRACT FROM AUTHOR]

The performance of majority engineering systems made of composite laminates can be improved by increasing strength to weight ratio. Variable thickness approach (VTA), in discrete form, used in this study is capable of finding minimum laminate thickness in one stage only, instead of two stage methodology defined by other researchers, with substantial accuracy for the given load conditions. This minimum required laminate thickness can be used by designers in multiple ways. Current study reveals that effectiveness of VTA in this regard depends on ply thickness increment value and number of plies. Maximum Stress theory, Tsai Wu theory and Tsai Hill theory are used as constraints, while ply angles, ply thicknesses and number of plies in discrete form are used as design variables in current simulation studies. Optimization is carried out using direct value coded genetic algorithm. The effect of design variables such as ply angles, ply thicknesses and number of plies in discrete form on optimum solution is investigated considering Uniform Thickness Approach (UTA) and Variable Thickness Approach (VTA) for various load cases.

Organ shortage is the greatest challenge facing the field of organ transplantation today. We aimed to study the attitude and knowledge toward organ donation among health-care professionals (HCPs) in rural India. The study was conducted in a rural town in Konkan region of Maharashtra in India. A questionnaire testing knowledge and attitude about various aspects of organ donation was distributed to HCPs. One hundred percent of the respondents were aware about organ donation. Nearly 40.6% and 21.9% believed that a healthy person and a cardiac dead person can be donors, respectively. Fifty percent believed that a brain dead person can be a donor and 3.1% clearly stated as to be having no idea regarding the health status of a donor. Almost 37.5% were ready to believe a heart beating person declared as “brain dead” as dead. Nearly 15.6% were ready to accept a brain dead person as “legally” dead. Highest awareness was observed regarding eye donation, i.e., 87.5%. High awareness was also observed regarding liver, kidney, heart, skin, and body donations, i.e., 78.1%, 65.6%, 37.5%, 31.3%, and 25.0%, respectively. Awareness regarding organ donation of other tissues and organs was poor. Nearly 46.9% HCPs stated that they felt need for an educational session on organ donation. Awareness regarding concept of organ donation among HCPs in rural India is high. Awareness regarding details of organ donation needs further awareness drives. There is a lack of understanding regarding various aspects of brain death and its importance in organ donation.