Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.

BACKGROUND: Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis. OBJECTIVE: We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds. METHODS: We applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL. RESULTS: In the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs. CONCLUSIONS: While the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.

Antimicrobial Stewardship for a Geriatric Behavioral Health Population.

Antimicrobial resistance is a growing public health concern. Antimicrobial stewardship and multi-disciplinary intervention can prevent inappropriate antimicrobial use and improve patient care. Special populations, especially older adults and patients with mental health disorders, can be particularly in need of such intervention. The purpose of this project was to assess the impact of pharmacist intervention on appropriateness of antimicrobial prescribing on a geriatric psychiatric unit (GPU). Patients ≥18 years old prescribed oral antibiotics during GPU admission were included. Antimicrobial appropriateness was assessed pre- and post-pharmacist intervention. During the six-month pre- and post-intervention phase, 63 and 70 patients prescribed antibiotics were identified, respectively. Subjects in the post-intervention group had significantly less inappropriate doses for indication compared to the pre-intervention group (10.6% vs. 23.9%, p = 0.02), and significantly less antibiotics prescribed for an inappropriate duration (15.8% vs. 32.4%, p < 0.01). There were no significant differences for use of appropriate drug for indication or appropriate dose for renal function between groups. Significantly more patients in the post intervention group had medications prescribed with appropriate dose, duration, and indication (51% vs. 66%, p = 0.04). Pharmacist intervention was associated with decreased rates of inappropriate antimicrobial prescribing on a geriatric psychiatric unit.

Characterization of N'Durance: a nanohybrid composite based on new nano-dimer technology.

High molecular weight dimethacrylate systems within composite resins present a number of clinical deficiencies, including insufficient monomer conversion, polymerization shrinkage, and polymerization stresses. This study aimed to determine physical and chemical properties of a new high monomer conversion nanohybrid composite resin based on nano-dimer technology (N'Durance), compared to other principal products on the market. Specimens were polymerized using a visible light lamp following the manufacturers' instructions. Compressive and flexural strengths, flexural modulus, water sorption, and tensile strength were determined. Water absorption and solubility were measured. Monomer conversion, polymerization shrinkage, and polymerization stress were calculated. It was shown that products using conventional resin (Bis-GMA/TEGDMA) have an average conversion of 60% for the microhybrids and 50% for the nanofilled composites. The shrinkage stress and contraction with N'Durance are lower than most commercial products: shrinkage contraction was reduced from 2.3% (average of the regular composite) to 1.5%, and the shrinkage stress from 2.5% to 1.1%, with an increase of approximately 27% in the monomer conversion. For products that use conventional resin, volumetric shrinkage increases when the final double bond conversion is increased to reduce the unreacted monomers; however, N'Durance shows high conversion and low polymerization shrinkage.