Local administration of vancomycin powder in orthopaedic fracture surgery: current practice and trends

Abstract. Objectives:. Surgical site infections in orthopaedic trauma are a significant problem with meaningful patient and health care system–level consequences. Direct application of antibiotics to the surgical field has many potential benefits in reducing surgical site infections. However, to date, the data regarding the local administration of antibiotics have been mixed. This study reports on the variability of prophylactic vancomycin powder use in orthopaedic trauma cases across 28 centers. Methods:. Intrawound topical antibiotic powder use was prospectively collected within three multicenter fracture fixation trials. Fracture location, Gustilo classification, recruiting center, and surgeon information were collected. Differences in practice patterns across recruiting center and injury characteristics were tested using chi-square statistic and logistic regression. Additional stratified analyses by recruiting center and individual surgeon were performed. Results:. A total of 4941 fractures were treated, and vancomycin powder was used in 1547 patients (31%) overall. Local administration of vancomycin powder was more frequent in open fractures 38.8% (738/1901) compared with closed fractures 26.6% (809/3040) (P < 0.001). However, the severity of the open fracture type did not affect the rate at which vancomycin powder was used (P = 0.11). Vancomycin powder use varied substantially across the clinical sites (P < 0.001). At the surgeon level, 75.0% used vancomycin powder in less than one-quarter of their cases. Conclusions:. Prophylactic intrawound vancomycin powder remains controversial with varied support throughout the literature. This study demonstrates wide variability in its use across institutions, fracture types, and surgeons. This study highlights the opportunity for increased practice standardization for infection prophylaxis interventions. Level of Evidence:. Prognostic—III

CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies

Association between Tunneled Pleural Catheter Use and Infection in Patients Immunosuppressed from Antineoplastic Therapy: A Multicenter Study.

RATIONALE: Patients with malignant/paramalignant pleural effusions (MPE/PMPEs) may have tunneled pleural catheter (TPC) management withheld due to infection concerns from immunosuppression associated with antineoplastic therapy. OBJECTIVE: To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency and overall survival (OS)? METHODS: We performed an international, multi-institutional study of MPE/PMPE patients undergoing TPC management from 2008-2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or were immunocompromised or not. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional-hazards modeling were performed to examine for independent effects on OS. RESULTS: A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%) or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range: 19-87) days following TPC insertion. Multivariable competing risk analyses demonstrated longer TPC duration was associated with a higher risk of TPC-related infection [subdistribution hazard ratio (95% CI): 1.03 (1.00-1.06), p=0.028]. Cox proportional-hazards analysis showed antineoplastic therapy was associated with better OS [hazard ratio (95% CI): 0.84 (0.73-0.97), p=0.015]. CONCLUSION: The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable to immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE/PMPE regardless of plans for antineoplastic therapy

OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin.

Item does not contain fulltextWe ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.

Contains fulltext : 53630.pdf (publisher's version ) (Closed access)Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Loken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, termed collectively as ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifying alleles to clinically distinct disorders. Here we show that mutations in TTC21B/IFT139, encoding a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP) and syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD). Moreover, although systematic medical resequencing of a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations unmasked a significant enrichment of pathogenic alleles in cases, suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy patients. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies, as well as interact in trans with other disease-causing genes, and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of disorders