Stress Modulation of Fracture Fixation Implants Beltran, Michael J; Collinge, Cory A; Gardner, Michael J
Journal of the American Academy of Orthopaedic Surgeons,
2016-October, Volume:
24, Issue:
10
Journal Article
Peer reviewed
Stress modulation is the concept of manipulating bridge plate variables to provide a flexible fixation construct that allows callus formation through uneventful secondary bone healing. Obtaining ...absolute stability through the anatomic reduction of all fracture fragments comes at the expense of fracture biology, whereas intramedullary nailing, which is more advantageous for diaphyseal fractures of the lower extremity, is technically demanding and often may not be possible when stabilizing many metaphyseal fractures. Overly stiff plating constructs are associated with asymmetric callus formation, early implant failure, and fracture nonunion. Numerous surgeon-controlled variables can be manipulated to increase flexibility without sacrificing strength, including using longer plates with well-spaced screws, choosing titanium or stainless steel implants, and using locking or nonlocking screws. Axially dynamic emerging concepts, such as far cortical locking and near cortical overdrilling, provide further treatment options when bridge plating techniques are used.
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a ...half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.
AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).
AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients.
AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic
. Although most global efforts have focused on severe illness in COVID-19, examining ...asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.
To better describe the pathoanatomy of young patients' femoral neck fractures with the goal of improving surgeons' decisions for treatment including reduction and fixation.
This is a retrospective ...study of patient records, plain radiographs, and the modern computed tomography scans to study the pathoanatomy of Pauwels II and III femoral neck fractures (coronal angle >30 degrees) in young adults.
One American College of Surgeons Level 1 trauma center.
All patients 18-49 years of age with a surgically repaired Pauwels' II and III (>30 degrees) femoral neck fracture between 2013 and 2017.
Fifty-six adult patients younger than 50 years were identified with a femoral neck fracture in the study period, of whom 30 met study criteria. We evaluated plain radiography and computed tomography data including fracture orientation, characteristics of fracture morphology including size, shape, and dimensions, comminution, displacement, and deformity.
Fracture morphology typically included a wide-based caudal head-neck segment (80%) that ends at a variable location along the medial calcar, sometimes as caudal as the lesser trochanter. Comminution was present in 90% of cases mostly located in the inferior quadrant, but anterior or posterior to the void left by the head-neck's caudal segment. The fractures orientations and deformities were reported by means and ranges.
We investigated and reported on the pathoanatomy of high-energy femoral neck fractures in young adults with the goal of increasing understanding of the injury and improving surgeons' ability to provide for improved treatment decisions and quality fracture repair.
Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Oryctes rhinoceros nudivirus (OrNV) is a double-stranded DNA (dsDNA) virus which has been used as a biocontrol agent to suppress the coconut rhinoceros beetle (
) in Southeast Asia and the Pacific ...Islands. A new wave of
incursions in Oceania is thought to be related to the presence of low-virulence isolates of OrNV or virus-tolerant haplotypes of beetles. In this study, chronically infected beetles were collected from Philippines, Fiji, Papua New Guinea (PNG), and the Solomon Islands (SI). RNA sequencing (RNA-seq) was performed to investigate the global viral gene expression profiles and for comparative genomic analysis of structural variations. Maximum likelihood phylogenic analysis indicated that OrNV strains from the SI and Philippines are closely related, while OrNV strains from PNG and Fiji formed a distinct adjacent clade. We detected several polymorphic sites with a frequency higher than 35% in 892 positions of the viral genome. Nonsynonymous mutations were detected in several hypothetical proteins and 15 nudivirus core genes, such as
,
,
, and
We found limited evidence of variation in viral gene expression among geographic populations. Only a few genes, such as
,
, and
, were differentially expressed among different strains. Additionally, small RNA sequencing from the SI population suggested that OrNV is targeted by the host RNA interference (RNAi) response with abundant 21-nucleotide small RNAs. Some of these genomic changes are specific to the geographic population and could be related to particular phenotypic characteristics of the strain, such as viral pathogenicity or transmissibility, and this requires further investigation.
Oryctes rhinoceros nudivirus has been an effective biocontrol agent against the coconut rhinoceros beetle in Southeast Asia and the Pacific Islands for decades. The recent outbreak of these beetles in many South Pacific islands has had a significant impact on livelihoods in the region. It has been suggested that the resurgence and spread of the pest are related to the presence of low-virulence isolates of OrNV or virus-tolerant haplotypes of beetles. We examined viral genomic and transcriptional variations in chronically infected beetles from different geographical populations. A high number of polymorphic sites among several geographical strains of OrNV were identified, but potentially only a few of these variations in the genome are involved in functional changes and can potentially alter the typical function. These findings provide valuable resources for future studies to improve our understanding of the OrNV genetic variations in different geographic regions and their potential link to virus pathogenicity.
To evaluate mechanical treatment failure in a large patient cohort sustaining a distal femur fracture treated with a distal femoral locking plate (DFLP).
This retrospective case-control series ...evaluated mechanical treatment failures of DFLPs.
The study was conducted at 8 Level I trauma centers from 2010 to 2017.
One hundred one patients sustaining OTA/AO 33-A and C distal femur fractures were treated with DFLPs that experienced mechanical failure.
The intervention included the treatment of a distal femur fracture with a DFLP, affected by mechanical failure (implant failure by loosening or breakage).
The main outcome measures included injury and DFLP details; modes and timing of failure were studied.
One hundred forty-six nonunions were found overall (13.4%) including 101 mechanical failures (9.3%). Failures occurred in different manners, locations, and times depending on the DFLPs. For example, 33 of 101 stainless steel (SS) plates (33%) failed by bending or breaking in the working length, whereas no Ti plates failed here ( P < 0.05). Eleven of 12 failures with titanium-Less Invasive Stabilization System (92%) occurred by lost shaft fixation, mostly by the loosening of unicortical screws (91%). Sixteen of 44 variable -angled-LCP failures (36%) occurred at the distal plate-screw junction, whereas only 5 of 61 other DFLPs (8%) failed this way ( P < 0.05). Distal failures occurred on average at 23.7 weeks compared with others that occurred at 38.4 weeks ( P < 0.05). Variable -angled-LCP distal screw-plate junction failures occurred earlier (mean 21.4 weeks).
Nonunion and mechanical failure occurred in 14% and 9% of patients, respectively, in this large series of distal femur fracture treated with a DFLP. The mode, location, presence of a prosthesis, and timing of failure varied depending on the characteristics of DFLP. This information should be used to optimize implant usage and design to prolong the period of stable fixation before potential implant failures occur in patients with a prolonged time to union.
Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.
We present Interactome INSIDER, a tool to link genomic variant information with structural protein-protein interactomes. Underlying this tool is the application of machine learning to predict protein ...interaction interfaces for 185,957 protein interactions with previously unresolved interfaces in human and seven model organisms, including the entire experimentally determined human binary interactome. Predicted interfaces exhibit functional properties similar to those of known interfaces, including enrichment for disease mutations and recurrent cancer mutations. Through 2,164 de novo mutagenesis experiments, we show that mutations of predicted and known interface residues disrupt interactions at a similar rate and much more frequently than mutations outside of predicted interfaces. To spur functional genomic studies, Interactome INSIDER (http://interactomeinsider.yulab.org) enables users to identify whether variants or disease mutations are enriched in known and predicted interaction interfaces at various resolutions. Users may explore known population variants, disease mutations, and somatic cancer mutations, or they may upload their own set of mutations for this purpose.
To compare implant positioning in the distal femur between 2 cohorts of elderly patients treated for a hip fracture with a long 200- or 150-cm radius of curvature (ROC) cephalomedullary nail. We ...theorized that the 150-cm ROC nails would more closely approximate the femoral bow and result in fewer implant-related complications.
Retrospective Comparative Study.
Single Level II Trauma Center.
Fifty-eight geriatric patients with a hip fracture (26 in 200-cm nail cohort and 32 in 150-cm nail cohort).
Long cephalomedullary nailing using single hip fracture nail and instrumentation system (InterTAN) before and after transition from a 200- to 150-cm ROC long hip nail.
Anteroposterior position of distal nail tip on intraoperative lateral radiograph (where 0.50 indicates midaxial, perfectly central placement) and implant-related complications (anterior cortical abutment, perforation, or fracture).
The average position of nails with a 150-cm ROC was closer to the midaxial line of the distal femur compared with 200-cm nails (0.63 vs. 0.55, P = 0.02). Only 1 of 26 (3.8%) 200-cm ROC nails was placed at the midaxial line and none were posterior, whereas 9 of 32 (28%) 150-cm ROC nails were positioned at or posterior to this line (P = 0.006). Only 1 nail with a 150-cm ROC abutted the distal femur's anterior cortex compared with 3 in the 200-cm cohort-including one that caused a fracture.
Femoral nails with a 150-cm ROC more closely approximate the femoral bow of geriatric hip fracture patients than 200-cm ROC nails, appearing less likely to cause complications such as anterior cortical abutment, perforation, or fracture.
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Periarticular fractures of the lower extremity can be difficult injuries to stabilize effectively. Modern advances in technique and implant design now allow many of these fractures to be fixed with ...an extreme intramedullary nail. When nailing is not possible, less invasive plating through percutaneous incisions is a reliable option. The decision to perform extreme nailing is multifactorial and is based on the fracture pattern, the condition of the soft tissues, the medical condition of the patient, and the importance of earlier or immediate weightbearing.
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