Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity.

Background: Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae.

Methods: Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R.

Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia.

Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy.

The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors.

Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model.

Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time.

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of mutation status in a panel of wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs).

The SKMT Algorithm: A method for assessing and comparing underlying protein entanglement.

We present fast and simple-to-implement measures of the entanglement of protein tertiary structures which are appropriate for highly flexible structure comparison. These are performed using the SKMT algorithm, a novel method of smoothing the Cα backbone to achieve a minimal complexity curve representation of the manner in which the protein's secondary structure elements fold to form its tertiary structure. Its subsequent complexity is characterised using measures based on the writhe and crossing number quantities heavily utilised in DNA topology studies, and which have shown promising results when applied to proteins recently.

A De Novo Deleterious Variant Without Clinical Features of X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, is due to inactivation of resulting in increased circulating fibroblast growth factor 23. Consequent renal phosphate loss leads to hypophosphatemia, rickets, and progressive bow deformity. Inheritance is X-linked dominant, such that heterozygous females are affected, as well as hemizygous males.

Advancing diagnosis and management of liver disease in adults through exome sequencing.

Background: Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers.

kyphoscoliotic Ehlers-Danlos syndrome misdiagnosed as Larsen syndrome: a case report.

Hereditary connective tissue disorders have overlapping phenotypes, particularly in regard to musculoskeletal features. This contributes to the challenge of phenotype-based clinical diagnoses. However, some hereditary connective tissue disorders have distinct cardiovascular manifestations that require early intervention and specific management.

Combined charge and hydrophobicity-guided screening of antibacterial peptides: two-level approach to predict antibacterial activity and efficacy.

Antibacterial peptides can be a potential game changer in the fight against antibiotic resistance. In order for these peptides to become successful antibiotic alternatives, it is essential that they possess high efficacy in addition to just being antibacterial. In this study, we have developed a two-level SVM-based binary classification approach to predict the antibacterial activity of a given peptide (model 1) and thereafter classify its antibacterial efficacy as high/low (model 2) with respect to minimum inhibitory concentration (MIC) values against Staphylococcus aureus, one of the most common pathogens.

High-Frequency Linear Array (20 MHz) Based on Lead-Free BCTZ Crystal.

Centimeter-sized BaTiO3-based crystals grown by top-seeded solution growth from the BaTiO3-CaTiO3-BaZrO3 system were used to process a high-frequency (HF) lead-free linear array. Piezoelectric plates with (110)pc cut within 1° accuracy were used to manufacture two 1-3 piezo-composites with thicknesses of 270 and [Formula: see text] for resonant frequencies in air of 10 and 30 MHz, respectively. The electromechanical characterization of the BCTZ crystal plates and the 10-MHz piezocomposite yielded the thickness coupling factors of 40% and 50%, respectively.

Hepatology Genome Rounds: An interdisciplinary approach to integrate genomic data into clinical practice.

In the last decade, the utility of whole-exome sequencing in uncovering genetic aetiologies of a variety of liver diseases has been demonstrated. These new diagnoses have guided the management, treatment, and prognostication of previously undiagnosed patients, largely thanks to improved insight into the underlying pathogenesis of their conditions. Despite its clear benefits, the uptake of genetic testing by hepatologists has been limited, in part due to limited prior genetic training and/or opportunities for continuing education.

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%).

Rapid systematic review to identify key barriers to access, linkage, and use of local authority administrative data for population health research, practice, and policy in the United Kingdom.

Background: Improving data access, sharing, and linkage across local authorities and other agencies can contribute to improvements in population health. Whilst progress is being made to achieve linkage and integration of health and social care data, issues still exist in creating such a system. As part of wider work to create the Cambridge Child Health Informatics and Linked Data (Cam-CHILD) database, we wanted to examine barriers to the access, linkage, and use of local authority data.

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Chromosomal microarray analysis using single nucleotide polymorphism probes can detect regions of homozygosity (ROH). This confers a potential utility in revealing autosomal recessive (AR) diseases and uniparental disomy (UPD). Results of genetic testing among pediatric patients from 2015 to 2019 were evaluated.

D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia.

D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency.

Does Global Surgery Interest Influence the Choice of Surgical Residency Program?

Objective: Medical students actively seek global health opportunities. Surgical residents also show great enthusiasm for international missions, rotations and global surgery. Unfortunately, only 18% to 34% of all surgery residency programs offer such international opportunities.

Homogenization of periodic 1-3 piezocomposite using wave propagation: Toward an experimental method.

1-3 piezocomposites are first choice materials for integration in ultrasonic transducers due to their high electromechanical performance, particularly, in their thickness mode. The determination of a complete set of effective electroelastic parameters through a homogenization scheme is of primary importance for their consideration as homogeneous. This allows for the simplification of the transducer design using numerical methods.

Detection of cytogenomic abnormalities by OncoScan microarray assay for products of conception from formalin-fixed paraffin-embedded and fresh fetal tissues.

Background: The OncoScan microarray assay (OMA) using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP) loci enabled the detection of cytogenomic abnormalities of chromosomal imbalances and pathogenic copy number variants (pCNV). The small size of molecular inversion probes is optimal for SNP genotyping of fragmented DNA from fixed tissues. This retrospective study evaluated the clinical utility of OMA as a uniform platform to detect cytogenomic abnormalities for pregnancy loss from fresh and fixed tissues of products of conception (POC).

Novel homozygous variant in BMP1 associated with a rare osteogenesis imperfecta phenotype.

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1.

Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a podocytopathy leading to kidney failure, whose molecular cause frequently remains unresolved. Here, we describe a rare MYO9A loss of function nonsense heterozygous mutation (p.Arg701) as a possible contributor to disease in a sibling pair with familial FSGS/proteinuria.

Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss.

Purpose: Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss.

Methods: A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES.