Are extra locking bolts or fibular plating more important in extreme nailing of distal tibia fractures? A cadaveric biomechanical analysis.

OBJECTIVES: In far-distal extra-articular tibia fracture "extreme" nailing, debate surrounds the relative biomechanical performance of plating the fibula compared with extra distal interlocks. This study aimed to evaluate several constructs for extreme nailing including one interlock (one medial-lateral interlock), one interlock + plate (one medial-lateral interlock with lateral fibula compression plating), and two interlocks (one medial-lateral interlock and one anterior-posterior interlock). METHODS: Fifteen pairs of fresh cadaver legs were instrumented with a tibial nail to the physeal scar. A 1 cm segment of bone was resected from the distal tibia 3.5 cm from the joint and an oblique osteotomy was made in the distal fibula. We loaded specimens with three different distal fixation constructs (one interlock, one interlock + plate, and two interlocks) through 10,000 cycles form 100N-700 N of axial loading. Load to failure (Newtons), angulation and displacement were also measured. RESULTS: Mean load to failure was 2092 N (one interlock), 1917 N (one interlock + plate), and 2545 N (two interlocks). Linear mixed effects modeling demonstrated that two interlocks had a load to failure 578 N higher than one interlock alone (95 % CI, 74N-1082 N; P = 0.02), but demonstrated no significant difference between one interlock and one interlock + plate. No statistically significant difference in rates or timing of displacement >2 mm or angulation >10° were demonstrated. CONCLUSIONS: When nailing far-distal extra-articular tibia and fibula fractures, adding a second interlock provides more stability than adding a fibular plate. Distal fibula plating may have minimal biomechanical effect in extreme nailing.

Does the OTA Open Fracture Classification Align With the Gustilo-Anderson Classification? A Study of 2215 Open Fractures.

OBJECTIVES: To characterize the Orthopaedic Trauma Association Open Fracture Classification (OTA-OFC) and Gustilo-Anderson classification of open extremity fractures and determine if there is meaningful alignment between these grading systems. DESIGN: Retrospective case series. SETTING: Level I academic trauma center. PATIENT SELECTION CRITERIA: Adult patients with at least 1 operatively treated open extremity fracture and surgeon-assigned OTA-OFC and Gustilo-Anderson classification. OUTCOME MEASURES AND COMPARISONS: Frequency, distribution, and association measures of OTA-OFC category scores and Gustilo-Anderson classification types. RESULTS: Two thousand twenty-seven patients (mean age, 43.1 ± 17.5 years) with 2215 fractures were included. Gustilo-Anderson type I or II fractures (n = 961; 43%) most frequently had the least severe scores for all OTA-OFC categories. Type IIIA fractures (n = 978; 44%) were most often assigned intermediate scores for OTA-OFC Bone Loss (n = 564; 58%). Type IIIB fractures (n = 204, 9%) were most often assigned intermediate OTA-OFC Skin scores (n = 120; 59%). Type IIIC fractures (n = 72; 3%) were most often assigned the most severe OTA-OFC Arterial score (n = 60; 83%). In the multivariable model, OTA-OFC Contamination scores showed little association (ß = 0.05; 95% confidence interval [CI], 0.01-0.09) with Gustilo-Anderson classification severity. Conversely, higher OTA-OFC Arterial (ß = 0.50; 95% CI 0.44-0.56) and Skin (ß = 0.46; 95% CI, 0.40-0.51) scores were strongly associated with more severe Gustilo-Anderson classifications. CONCLUSIONS: OTA-OFC Contamination scores were weakly associated with Gustilo-Anderson classification severity for open fractures. The study findings suggest that the current Gustilo-Anderson classification does not adequately account for injury contamination, a known predictor of infection. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease.

RATIONALE: An increased tricuspid regurgitation jet velocity (TRV > 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). OBJECTIVES: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. METHODS: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n = 10) and with pulmonary hypertension (n = 10, 90% accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n = 49) versus normal (n = 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P < 0.005), four trans-acting (P < 2.1 × 10(-7)) and one cis-acting (P = 0.6 × 10(-4)) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). CONCLUSIONS: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.