Technical Factors Contributing to Nonunion in Supracondylar Distal Femur Fractures Treated With Lateral Locked Plating: A Risk-Stratified Analysis.

OBJECTIVE: To identify technical factors associated with nonunion after operative treatment with lateral locked plating. DESIGN: Retrospective cohort study. SETTING: Ten Level I trauma centers. PATIENT SELECTION CRITERIA: Adult patients with supracondylar distal femur fractures (OTA/AO type 33A or C) treated with lateral locked plating from 2010 through 2019. OUTCOME MEASURES AND COMPARISONS: Surgery for nonunion stratified by risk for nonunion. RESULTS: The cohort included 615 patients with supracondylar distal femur fractures. The median patient age was 61 years old (interquartile range: 46 -72years) and 375 (61%) were female. Observed were nonunion rates of 2% in a low risk of nonunion group (n = 129), 4% in a medium-risk group (n = 333), and 14% in a high-risk group (n = 153). Varus malreduction with an anatomic lateral distal femoral angle greater than 84 degrees, was associated with double the odds of nonunion compared to those without such varus [odds ratio, 2.1; 95% confidence interval (CI), 1.1-4.2; P = 0.03]. Malreduction by medial translation of the articular block increased the odds of nonunion, with 30% increased odds per 4 mm of medial translation (95% CI, 1.0-1.6; P = 0.03). Working length increased the odds of nonunion in the medium risk group, with an 18% increase in nonunion per 10-mm increase in working length (95% CI, 1.0-1.4; P = 0.01). Increased proximal screw density was protective against nonunion (odds ratio, 0.71; 95% CI, 0.53-0.92; P = 0.02) but yielded lower mRUST scores with each 0.1 increase in screw density associated with a 0.4-point lower mRUST (95% CI, -0.55 to -0.15; P < 0.001). Lateral plate length and type of plate material were not associated with nonunion. ( P > 0.05). CONCLUSIONS: Malreduction is a surgeon-controlled variable associated with nonunion after lateral locked plating of supracondylar distal femur fractures. Longer working lengths were associated with nonunion, suggesting that bridge plating may be less likely to succeed for longer fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Pediatric Hand and Wrist Fractures in Osteogenesis Imperfecta: An Analysis of Incidence, Patient-specific Risk Factors, and Fracture-specific Characteristics.

BACKGROUND: Children with osteogenesis imperfecta (OI) frequently present with fractures; however, hand and wrist fractures (HWFs), those distal to the radial and ulnar diaphysis, are seldom observed. Yet, HWFs remain among the most common fractures in children with non-OI. The objective of this study was to identify the incidence of OI HWFs. Secondary objectives aimed at identifying patient-specific risk factors for HWFs in OI and comparing clinical courses to non-OI HWFs. METHODS: A retrospective cohort study was conducted. Database query by ICD-10 codes identified 18 patients with OI HWF, 451 patients with OI without HWFs, and 26,183 patients with non-OI HWF. Power analysis estimated appropriate sample sizes and random sampling was utilized to collect patients. Patient demographics, OI-specific variables, fracture morphology, and fracture clinical courses were recorded. Data were analyzed for patient-specific and fracture-specific factors affecting OI HWF incidence. RESULTS: Of patients with OI, 3.8% (18/469) sustained HWFs. Patients with OI HWF were significantly older than patients with OI without HWFs ( P = 0.002) with no differences in height, weight, ethnicity, sex, or ambulatory status. Compared with non-OI HWFs, patients with OI HWF were significantly shorter ( P < 0.001), weighed less ( P = 0.002), and were less likely to be ambulatory ( P < 0.001). OI HWFs were more commonly on the side of hand dominance ( P < 0.001) with transverse patterns ( P = 0.001). OI HWFs were less frequent in the thumb ( P = 0.048) and trended towards significance in the metacarpals ( P = 0.054). All OI HWFs were treated nonoperatively with similar union rates and refracture rates to non-OI HWFs. Multivariate regression showed that older patient age (odds ratio: 1.079, 95% CI: 1.005,1.159, P = 0.037) and OI type I (odds ratio: 5.535, 95% CI: 1.069, 26.795, P = 0.041) were significant prognosticators for HWFs in patients with OI. CONCLUSION: OI HWFs are uncommon (3.8%, 18/469) but specific HWF morphologies and locations are more common in patients with OI; however, these are not pathognomonic. Older patients with mild penetrance of type I OI are at the highest risk for HWFs. OI HWFs do well when managed nonoperatively with noninferior clinical courses compared with non-OI HWFs. LEVEL OF EVIDENCE: Level III.

Complication Rates in Patients With Classic and Radiographic Variants of Seymour Fractures.

BACKGROUND: At a tertiary-care, level 1 pediatric trauma center, we have observed fractures of the distal phalanx involving the physis, with associated nail bed injuries, that are distinct from the classic description of the Seymour fracture. We investigated the time to definitive management and the associated morbidity of these Seymour fracture variants compared with classically described Seymour fractures. We hypothesize that these Seymour variants are similarly problematic in terms of complications and delays to the definitive treatment and thus warrant increased awareness. METHODS: A retrospective chart review was performed of all patients with distal phalanx fractures involving the physis and associated nail bed injuries that were treated with operative intervention at a single pediatric specialty institution over a 9-year period. Radiographs and clinical photographs were reviewed to determine if the patient presented with a classic Seymour fracture or variant. Primary outcomes included time from injury to definitive treatment and complication rate. RESULTS: Of the 66 Seymour fractures identified in the chart review, 36 (55%) were identified as classic Seymour fractures and 30 (45%) were identified as variants. The mean time to operative intervention in the classic and variant groups was 7.3 versus 12.7 days (P=0.216). The complication rates in the classic and variant groups were 11.1% versus 23.3% (P=0.185), with infections accounting for nearly all complications identified. Overall infection rates for the classic and variant cohorts were 8.3% and 20.0% (P=0.169), respectively, with the majority presenting preoperatively (5.6% vs. 13.3%, P=0.274). CONCLUSIONS: We found that patients with classic Seymour fractures or radiographic variants had statistically similar incidence rates, complication rates, and delays in treatment, with a trend towards higher complication rates and delayed time to treatment in patients with variant-type injuries. We propose a minor expansion of the definition of Seymour fractures to include common variants to increase awareness of these problematic injuries, minimize delays in treatment, and decrease complications. LEVEL OF EVIDENCE: Level III; Retrospective Comparative Study.

Accuracy and Safety of Non-Image Guided Trigger Finger Injections: A Cadaveric Study.

BACKGROUND: Stenosing flexor tenosynovitis is commonly treated by injection of corticosteroids into the flexor tendon sheath. However, there is no consensus in the literature regarding the optimal technique, specifically when not utilizing ultrasound guidance. Here, we present a cadaver study in which 3 common techniques of flexor sheath injection were compared with regard to their accuracy and safety profiles. METHODS: Fifteen fresh-frozen cadaver hands (60 digits) were evenly divided into 3 groups (20 digits per group). Digits in each group were injected with methylene blue dye using 1 of the 3 techniques (palmar-to-bone, palmar supra-tendinous, and mid-axial). The fingers were then dissected and were inspected for location of dye, as well as injury to tendon or digital nerves. RESULTS: The mid-axial technique demonstrated the greatest accuracy with the highest rate of all intra-sheath injection, 15 of 20 digits (75%), while the palmar-to-bone technique produced the most combined intra- and extra-sheath injections, 13 of 20 digits, (65%) and the palmar supra-tendinous technique resulted in the most all extra-sheath injections, 9 of 20 digits (45%). The difference in rates of all intra-sheath injection was significant (P = .01). The mid-axial technique also produced the fewest intra-tendinous injections 0 of 20, although this result did not reach statistical significance (P = .15). CONCLUSIONS: Compared to other common non-image guided flexor tendon sheath injection techniques, the mid-axial injection technique was found to be the most accurate in producing all intra-sheath injection and least likely to result in intra-tendinous injection.

Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases.

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.

Radial Collateral Ligament Injuries of the Thumb Metacarpophalangeal Joint.

PURPOSE OF REVIEW: Injuries to the radial collateral ligament (RCL) of the thumb are thought to be relatively uncommon, especially when compared to the ulnar collateral ligament. However, the radial collateral ligament is increasingly recognized as critical for the overall stability of the thumb metacarpophalangeal joint. This article sets out to provide a comprehensive review of RCL injuries of the thumb MCP joint, including epidemiology, biomechanics, diagnosis, and treatment. RECENT FINDINGS: Although traditionally thought to respond well to conservative management, especially when compared to injuries to the ulnar collateral ligament, there is mounting evidence that chronic RCL injury leads to thumb metacarpophalangeal joint instability and can accelerate post-traumatic joint degeneration. Thus, much of the recent literature details surgical treatment options for radial collateral ligament injury, including repair and reconstruction. While incomplete tears of the thumb RCL respond well to immobilization, complete tears should generally be treated with operative management, either direct repair or anatomic reconstruction, depending on tissue quality. Even subacute and chronic injuries may be amenable to direct repair, with good to excellent outcomes, including in high-demand patient populations, such as professional athletes.

Efficacy and Safety of a Krabbe Disease Gene Therapy.

Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9. Building on our experience developing CSF-delivered, AAV-based drug products for a variety of neurodegenerative disorders, we conducted efficacy, pharmacology, and safety studies of AAVhu68 delivered to the CSF in two relevant natural Krabbe animal models, and in nonhuman primates. In newborn Twitcher mice, the highest dose (1 × 1011 genome copies [GC]) of AAVhu68.hGALC injected into the lateral ventricle led to a median survival of 130 days compared to 40.5 days in vehicle-treated mice. When this dose was administered intravenously, the median survival was 49 days. A single intracisterna magna injection of AAVhu68.cGALC at 3 × 1013 GC into presymptomatic Krabbe dogs increased survival for up to 85 weeks compared to 12 weeks in controls. It prevented psychosine accumulation in the CSF, preserved peripheral nerve myelination, ambulation, and decreased brain neuroinflammation and demyelination, although some regions remained abnormal. In a Good Laboratory Practice-compliant toxicology study, we administered the clinical candidate into the cisterna magna of 18 juvenile rhesus macaques at 3 doses that displayed efficacy in mice. We observed no dose-limiting toxicity and sporadic minimal degeneration of dorsal root ganglia (DRG) neurons. Our studies demonstrate the efficacy, scalability, and safety of a single cisterna magna AAVhu68 administration to treat Krabbe disease. ClinicalTrials.Gov ID: NCT04771416.

Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology.

The administration of adeno-associated virus (AAV) vectors to nonhuman primates (NHP) via the blood or cerebrospinal fluid (CSF) can lead to dorsal root ganglion (DRG) pathology. The pathology is minimal to moderate in most cases; clinically silent in affected animals; and characterized by mononuclear cell infiltrates, neuronal degeneration, and secondary axonopathy of central and peripheral axons on histopathological analysis. We aggregated data from 33 nonclinical studies in 256 NHP and performed a meta-analysis of the severity of DRG pathology to compare different routes of administration, dose, time course, study conduct, age of the animals, sex, capsid, promoter, capsid purification method, and transgene. DRG pathology was observed in 83% of NHP that were administered AAV through the CSF, and 32% of NHP that received an intravenous (IV) injection. We show that dose and age at injection significantly affected the severity whereas sex had no impact. DRG pathology was minimal at acute time points (i.e., <14 days), similar from one to 5 months post-injection, and was less severe after 6 months. Vector purification method had no impact, and all capsids and promoters that we tested resulted in some DRG pathology. The data presented here from five different capsids, five different promoters, and 20 different transgenes suggest that DRG pathology is almost universal after AAV gene therapy in nonclinical studies using NHP. None of the animals receiving a therapeutic transgene displayed any clinical signs. Incorporation of sensitive techniques such as nerve-conduction velocity testing can show alterations in a minority of animals that correlate with the severity of peripheral nerve axonopathy. Monitoring sensory neuropathies in human central nervous system and high-dose IV clinical studies seems prudent to determine the functional consequences of DRG pathology.

Pathogenic properties of enterohepatic Helicobacter spp. isolated from rhesus macaques with intestinal adenocarcinoma.

Considerable progress has been made in understanding the roles of Helicobacter pylori in inflammation and gastric cancer; however, far less is known about the roles of enterohepatic Helicobacter species (EHS) in carcinogenesis and their zoonotic or pathogenic potential. We determined the prevalence of EHS infection in a cohort of geriatric rhesus monkeys in which intestinal adenocarcinoma (IAC) is common and investigated the association between EHS infection and IAC. The cohort consisted of 36 animals, 14 of which (age 26-35 years) had IAC. Of the 36 rhesus, 35 (97%) were positive for EHS using PCR or bacterial isolation from faeces, colonic or tumour tissues. Only a single rhesus, which had IAC, was negative for EHS by all detection methods. The EHS identified by 16S rRNA sequencing in this study were from three Helicobacter taxa: Helicobacter macacae (previously rhesus monkey taxon 1), Helicobacter sp. rhesus monkey taxon 2, previously described from strain MIT 99-5507, and Helicobacter sp. rhesus monkey taxon 4, related to Helicobacter fennelliae. Thirteen of 14 monkeys with IAC were positive for either H. macacae (7/13, 54%), EHS rhesus monkey taxon 4 (4/13, 31%) or a mixture of the two EHS (2/13, 15%). These results indicate that EHS are prevalent among aged rhesus macaques with IAC. Using Helicobacter genus-specific florescent in situ hybridization, EHS were detected on the surface of colonic epithelia of infected monkeys. All Helicobacter isolates, including H. macacae, effectively adhered to, invaded, and significantly induced proinflammatory genes, including IL-8, IL-6, TNF-α and iNOS, while downregulating genes involved in the function of inflammasomes, particularly IL-1ß, CASPASE-1, NRLP3, NLRP6 and NLRC4 in the human colonic T84 cell line (P<0.0001). These results suggest that EHS may represent an aetiological agent mediating diarrhoea, chronic inflammation, and possibly intestinal cancer in non-human primates, and may play a role in similar disease syndromes in humans. Downregulation of inflammasome function may represent an EHS strategy for long-term persistence in the host and play a role in inducing pathological changes in the host's lower bowel.

A jugular bleeding technique in rabbits.

When studying pharmacokinetics in rabbits, researchers must often take multiple blood samples from conscious rabbits. Researchers usually collect these samples via the auricular vein, typically through a port or an indwelling catheter. The authors have developed an easy and efficient alternative method for obtaining multiple blood samples from conscious rabbits via the external jugular vein. This jugular bleeding technique serves as a refinement to blood sampling methods that require rabbits to undergo surgery (e.g., to insert a port) because it requires no alleviation of pain. During a 2-year period, the authors have taken multiple blood samples from more than 400 rabbits and have seen no adverse events attributed to this procedure.

Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density.

Intracellular accumulation of PHFtau in Alzheimer's disease (AD) disrupts the neuronal cytoskeleton and other neuronal machinery and contributes to axonal and dendritic degeneration, and neuronal death. Furthermore, amyloid-beta (Abeta) has been reported to be toxic to neurons and neurites. While loss of presynaptic elements is an established feature of AD, the nature and extent of dendritic degeneration has been infrequently studied. We investigated MAP2-immunoreactive dendrites using a novel method of high-throughput quantification and also measured cortical thickness and the densities of NeuN-immunoreactive neurons, PHFtau neurofibrillary tangles (NFTs), and Abeta plaque burden in the subiculum in AD and elderly controls. Corrected for atrophy, the "dendritic arborization index" was significantly reduced by up to 66% in all three layers of the subiculum. Laminar thickness was reduced by an average 33% and there was a marked reduction in neuron density of approximately 50%. As expected, NFTs and Abeta plaques were significantly increased in AD. Dendritic arborization indices negatively correlated with NFT densities while no significant correlations were found with Abeta plaque densities. The pattern of dendritic loss in the subiculum and the correlations with NFT densities respectively suggest that deafferentation and intrinsic neurofibrillary degeneration both may contribute to dendritic loss in AD.

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease.

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.