Documented Penicillin Allergies Should Not Preclude Use of Preoperative Cefazolin in Hip and Knee Arthroplasty.

INTRODUCTION: Perioperative cefazolin administration for total joint arthroplasty is a first-line antibiotic recommended by the American Academy of Orthopaedic Surgeons (AAOS) guidelines for the prevention of periprosthetic joint infections (PJIs). We aim to analyze the clinical viability of giving patients with a documented penicillin allergy (PA) a perioperative full-strength cefazolin "test dose" under anesthesia. METHODS: This is a retrospective chart review of 2,451 total joint arthroplasties from a high-volume arthroplasty orthopaedic surgeon over a 5-year period from January 2013 through December 2017. This surgeon routinely gave patients with a documented PA a full-strength cefazolin test dose while under anesthesia instead of administrating a second-line antibiotic. The primary outcomes examined were allergic reaction and postoperative infection. RESULTS: Cefazolin was given to 87.1% of all patients (1,990) and 46.0% of patients with a PA (143). The total rate of allergic reactions among all patients was 0.5% (11). Only one patient with a documented PA who received cefazolin had an allergic reaction. The reaction was not severe and did not require any additional treatment. In patients who had no reported allergies and received cefazolin, 0.3% (6) had an allergic reaction. There was no statistically significant difference in the rate of allergic reaction when comparing patients with and without a PA (P = 0.95). Patients receiving cefazolin had an overall PJI rate of 2.9% (57) versus those patients receiving antibiotics other than cefazolin who sustained a 5.5% PJI rate (16), which was statistically significant (P = 0.02). CONCLUSION: This study found that utilization of a full-strength test dose of cefazolin in patients with a documented PA is a feasible, safe, and effective way of increasing the rate of cefazolin administration and thus mitigating the risk of PJIs.

The Student You Know: Orthopedic Surgery Home Program Match Rates and Geographic Relationships Before and After COVID-19.

OBJECTIVE: In March 2020, COVID-19 was declared a pandemic by the World Health Organization. This led to the outright cancellation of away rotations and in person residency interviews for the class of 2021. This study aims to identify the geographic relationships in the orthopedic match and further explore COVID-19's effect on these geographic relationships. Furthermore, we aim to compare the home program match rates before and after COVID-19. SETTING: Southern Illinois University School of Medicine, Department of Orthopedic Surgery (tertiary, university-based). DESIGN AND PARTICIPANTS: Residency websites and social media sites were used to record basic residency information as well as each resident's year, matriculated medical school, and matriculated medical school geographic data. This information was used to evaluate the proportion of orthopedic residents from "home program" medical schools and evaluate the geographic relationship of matched orthopedic residents. 202 Orthopedic residencies were initially identified and 134 allopathic and nonmilitary residency programs met the inclusion criteria. In all, 3253 of the 3931 (82.7%) current U.S orthopedic residents were included in the analysis. RESULTS: In the 4 orthopedic surgery residency classes before the pandemic (2017-2020), 21.8% of residency slots were filled by home program students. During the pandemic match cycle (2021), this number jumped to 28.2% (p < 0.0006). The increase was observed consistently across residency subgroup analysis: class size, doximity rank, and doximity research rank. Correspondingly, there was a statistically significant increase from 34.7% (2017-2020) to 39.3% (2021) (p = 0.0318) in residencies matching with same state medical students. Regional trends stayed consistent. Our study showed that residency programs matched applicants who went to same region medical schools during the 2020 to 2021 cycle at nearly the exact same rate as they did pre-pandemic (63.6%, up from 63.3%). CONCLUSIONS: Our study demonstrates that despite widespread virtual away rotations and virtual open houses, residency programs showed an increased preference for their home program students. This trend was significant and widespread, highlighting the generalized nationwide hesitation of both residency programs and students on the virtual interview process.

Utility of Head Computed Tomography Scans Before Outpatient Follow-up for Low-Risk Mild Traumatic Brain Injury.

BACKGROUND: Neurosurgeons are frequently consulted for traumatic brain injuries (TBIs) resulting in intracranial hemorrhage (ICH). After inpatient confirmation of hemorrhage stability, outpatient head computed tomography (CT) is often performed to assess for hemorrhage resolution. Our objective was to assess the practice patterns and clinical utility of routine outpatient head CT scans for patients with mild TBI (mTBI). MATERIALS AND METHODS: A retrospective review was performed on all adult mTBI patients with ICH who presented to a level I trauma center over a 4-year period. A combination of the patient's initial clinical evaluation and CT findings was used to identify mTBI patients at low risk for neurologic deterioration and neurosurgical intervention. Findings from the outpatient follow-up clinical evaluation and head CT were assessed. Patients without outpatient follow-up within 3 months were excluded. RESULTS: Forty-nine patients met inclusion criteria for the study. Thirty-two had an outpatient head CT before their follow-up appointment. Twenty-one patients had at least 1 neurologic finding at the earliest follow-up appointment. All patients except those with a subdural hematoma (SDH) had smaller or resolving ICH on outpatient CT scans. Seven patients with an SDH had unchanged or expanded hemorrhage on outpatient imaging, 2 of whom had traumatic brain injury-related hospitalizations and 1 of whom underwent neurosurgical intervention due to an enlarging SDH. CONCLUSIONS: Routine outpatient head CT scans before follow-up for low-risk mTBI patients without an SDH appears to have limited clinical utility. In low-risk mTBI patients with an SDH, obtaining an outpatient head CT is reasonable to monitor for resolution.

Assessing the efficacy of mild traumatic brain injury management.

OBJECTIVE: Intracranial hemorrhage (ICH) is frequently found on computed tomography (CT) after mild traumatic brain injury (mTBI) prompting transfer to centers with neurosurgical coverage and repeat imaging to confirm hemorrhage stability. Studies suggest routine repeat imaging has little utility in patients with minimal ICH, no anticoagulant/antiplatelet use, and no neurological decline. Additionally, it is unclear which mTBI patients benefit from transfer for neurosurgery consultation. The authors sought to assess the clinical utility and cost effectiveness of routine repeat head CTs and transfer to tertiary centers in patients with low-risk, mTBI. METHODS: Retrospective evaluation of patients receiving a neurosurgical consultation for TBI during a 4-year period was performed at a level 1 trauma center. Patients were stratified according to risk for neurosurgical intervention based on their initial clinical evaluation and head CT. Only patients with low-risk, mTBI were included. RESULTS: Of 531 patients, 119 met inclusion criteria. Eighty-eight (74.0 %) received two or more CTs. Direct cost of repeat imaging was $273,374. Thirty-seven (31.1 %) were transferred to our facility from hospitals without neurosurgical coverage, costing $61,384. No patient had neurosurgical intervention or mTBI-related in-hospital mortality despite enlarging ICH on repeat CT in three patients. Two patients had mTBI related 30-day readmission for seizure without ICH expansion. CONCLUSION: Routine repeat head CT or transfer of low-risk, mTBI patients to a tertiary center did not result in neurosurgical intervention. Serial neurological examinations may be a safe, cost-effective alternative to repeat imaging for select mTBI patients. A large prospective analysis is warranted for further evaluation.

Renal cell tumors convert natural killer cells to a proangiogenic phenotype.

Natural killer (NK) cells are classically associated with immune surveillance and destruction of tumor cells. Inconsistent with this function, NK cells are found in advanced human tumors including renal cell carcinoma (RCC). NK cells with non-classical phenotypes (CD56+CD16dim/neg; termed decidua NK (dNK) cells) accumulate at the maternal-fetal interface during embryo implantation. These dNK cells are poorly cytotoxic, proangiogenic, and facilitate placenta development. As similarities between embryo implantation and tumor growth exist, we tested the hypothesis that an analogous shift in NK cell phenotype and function occurs in RCC tumors. Our results show that peripheral NK (pNK) cells of RCC patients were uniformly CD56+CD16bright, but lacked full cytotoxic ability. By comparison, RCC tumor-infiltrated NK (TiNK) cells were significantly enriched for CD56+CD16dim-neg cells, a phenotype of dNK cells. Gene expression analysis revealed that angiogenic and inflammatory genes were significantly increased for RCC TiNK versus RCC pNK populations, with enrichment of genes in the hypoxia inducible factor (HIF) 1α pathway. Consistent with this finding, NK cells cultured under hypoxia demonstrated limited cytotoxicity capacity, but augmented production of vascular endothelial growth factor (VEGF). Finally, comparison of gene expression data for RCC TiNK and dNK cells revealed a shared transcriptional signature of genes with known roles in angiogenesis and immunosuppression. These studies confirm conversion of pNK cells to a dNK-like phenotype in RCC tumors. These characteristics are conceivably beneficial for placentation, but likely exploited to support early tumor growth and promote metastasis.

Complete primary repair of bladder exstrophy: a systematic review.

OBJECTIVES: Complete primary repair of exstrophy (CPRE) was established as a method to reduce numbers of procedures for the reconstruction of bladder exstrophy (BE). Performed since 1989, some suggest it as a replacement for the staged reconstructive procedure, the gold standard. Does CPRE reduce the numbers of procedures for reconstruction of BE? METHODS: Literature was reviewed from 1989 to 2016, and articles evaluating outcomes of patients undergoing CPRE, extracted. Effort was made to obtain final data from each reporting institution/group. Eleven articles meeting criteria were evaluated for qualitative systematic review. Age at initial closure, complications, additional procedures, and outcomes were evaluated to provide an overview of CPRE. RESULTS: Ten groups reported BE management using the CPRE technique. 236 patients (153 boys; 72 girls; 11 unknown sex) had primary closure ranging from birth to 5.6 years. Osteotomy was favored by most in infants closed beyond the first 72 h of life along with spica cast immobilization. Three groups recommended concomitant augmentation for infants with small bladder capacities. Ureteral reimplantation was required in 58 patients with recurrent urinary tract infections resistant to prophylaxis. Hypospadias repair was required for most boys having complete penile disassembly, and most children eventually required bladder neck reconstruction (BNR) for continence. Overall, voiding without BNR was noted in 16-37% of children in the reported series. CONCLUSIONS: Complete primary repair of exstrophy has been suggested as a single procedure for the management of BE. Literature review suggests most patients require multiple procedures to complete reconstruction and attain continence.

Adjacent-segment disease following two-level axial lumbar interbody fusion.

OBJECTIVEWhile long-term studies have evaluated adjacent-segment disease (ASD) following posterior lumbar spine arthrodesis, no such studies have assessed the incidence and prevalence of ASD following axial lumbar interbody fusion (AxiaLIF). The aim of this study was to estimate the incidence of ASD following AxiaLIF.METHODSThe authors retrospectively reviewed the medical records of 149 patients who underwent two-level index AxiaLIF and had at least 2 years of radiographic and clinical follow-up. ASD and pre- and postoperative lumbar lordosis were evaluated in each patient. ASD was defined as both radiographic and clinically significant disease at a level adjacent to a previous fusion requiring surgical intervention. The mean duration of follow-up was 6.01 years.RESULTSTwenty (13.4%) of the 149 patients developed ASD during the data collection period. Kaplan-Meier analysis predicted a disease-free ASD survival rate of 95.3% (95% CI 90.4%-97.7%) at 2 years and 89.1% (95% CI 82.8%-93.2%) at 5 years for two-level fusion. A laminectomy adjacent to a fusion site was associated with 5.1 times the relative risk of developing ASD. Furthermore, the ASD group had significantly greater loss of lordosis than the no-ASD group (p = 0.033).CONCLUSIONSFollowing two-level AxiaLIF, the rate of symptomatic ASD warranting either decompression or arthrodesis was found to be 4.7% at 2 years and 10.9% at 5 years. Adjacent-segment decompression and postoperative loss of lumbar lordosis predicted future development of ASD. To the authors' knowledge, this is the largest reported cohort of patients to undergo two-level AxiaLIF in the United States.

Effects of 5-ALA dose on resection of glioblastoma.

PURPOSE: Fluorescence-guided surgery (FGS) with the use of 5-aminolevulinic acid (5-ALA) leads to more extensive resection of high-grade glioma (HGG) and longer overall survival (OS) of patients compared to conventional resection. The purpose of this study is to investigate the effect of 5-ALA dosages on residual tumor volume (RTV) and OS in patients with glioblastoma. METHODS: A retrospective cohort study for patients who participated in a phase I and II dose-escalation clinical trial on 5-ALA for resection of HGG. A total of 25 patients were found to have newly diagnosed glioblastoma on histology and enrolled in our study. Patients receiving low doses of 5-ALA (10-30 mg/kg) (n = 6) were compared to those receiving high doses (40-50 mg/kg) (n = 19). Pre- and post-operative contrast enhanced T1W MRI were evaluated with volumetric analysis. RESULTS: Median RTV was 0.69 cm3 and 0.00 cm3 in the low and high dose groups respectively (p = 0.975). A gross total resection (GTR) was more likely in the high dose group, though this was not statistically significant. No significant difference was found in median OS between the high and low dose groups (p = 0.6787). CONCLUSIONS: High doses of 5-ALA FGS are associated with less RTV and greater probability of GTR. 5-ALA dose was not associated with OS. Further studies with a larger patient cohort are warranted.

Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae.

Heterochromatin contains a significant part of nuclear DNA. Little is known about the mechanisms that govern heterochromatic DNA stability. We show here that in the yeast Saccharomyces cerevisiae (i) DNA mismatch repair (MMR) is required for the maintenance of heterochromatic DNA stability, (ii) MutLα (Mlh1-Pms1 heterodimer), MutSα (Msh2-Msh6 heterodimer), MutSß (Msh2-Msh3 heterodimer), and Exo1 are involved in MMR at heterochromatin, (iii) Exo1-independent MMR at heterochromatin frequently leads to the formation of Pol ζ-dependent mutations, (iv) MMR cooperates with the proofreading activity of Pol ε and the histone acetyltransferase Rtt109 in the maintenance of heterochromatic DNA stability, (v) repair of base-base mismatches at heterochromatin is less efficient than repair of base-base mismatches at euchromatin, and (vi) the efficiency of repair of 1-nt insertion/deletion loops at heterochromatin is similar to the efficiency of repair of 1-nt insertion/deletion loops at euchromatin.

Engaging rural communities in genetic research: challenges and opportunities.

Statistical analyses of health and disease in rural communities is frequently limited by low sample counts. Still, some studies indicate increased risk for some diseases even after adjustment for known risk factors. It has been hypothesized that the context of community formation in rural areas facilitates the propagation of genetic founder effects-potentially impacting disease susceptibility. However, outright examination of genetic diversity in such communities has not been performed. Our objective was to engage otherwise research-inexperienced rural communities of largely European descent in genomic research in the context of cancer susceptibility. From September 2015 to February 2016, we implemented a systematic process of progressive community engagement. This iterative method sought project buy-in from first the town mayor, then village council. If approved by both, a focus group of community members examined how residents might view the research, informed consent and specimen collection, and issues of privacy. We were successful in engaging three of the four communities approached for the research project. There was universal enthusiasm for the project by all mayors and village councils. The focus groups' main point of discussion involved wording in the informed consent, with little concern regarding the research question or privacy. Perhaps contrary to popular thought, we found each community we approached to be both welcoming and enthusiastic about collaborating in research on genomic diversity. The systematic method of engagement did much to preserve community respect and autonomy and facilitated buy-in.

Transcription factor-microRNA-target gene networks associated with ovarian cancer survival and recurrence.

The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2*) were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497) were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05) with ovarian cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival.

BACKGROUND: Alternative exon usage (AEU) is an important component of gene regulation. Exon expression platforms allow the detection of associations between AEU and phenotypes such as cancer. Numerous studies have identified associations between gene expression and the brain cancer glioblastoma multiforme (GBM). The few consistent gene expression biomarkers of GBM that have been reported may be due to the limited consideration of AEU and the analytical approaches used. The objectives of this study were to develop a model that accounts for the variations in expression present between the exons within a gene and to identify AEU biomarkers of GBM survival. METHODS: The expression of exons corresponding to 25,403 genes was related to the survival of 250 individuals diagnosed with GBM in a training data set. Genes exhibiting AEU in the training data set were confirmed in an independent validation data set of 78 patients. A hierarchical mixed model that allows the consideration of covariation between exons within a gene and of the effect of the epidemiological characteristics of the patients was developed to identify associations between exon expression and patient survival. This general model describes all three possible scenarios: multi-exon genes with and without AEU, and single-exon genes. RESULTS: AEU associated with GBM survival was identified on 2477 genes (P-value < 5.0E-04 or FDR-adjusted P-value < 0.05). G-protein coupled receptor 98 (Gpr98) and epidermal growth factor (Egf) were among the genes exhibiting AEU with 30 and 9 exons associated with GBM survival, respectively. Pathways enriched among the AEU genes included focal adhesion, ECM-receptor interaction, ABC transporters and pathways in cancer. In addition, 24 multi-exon genes without AEU and 8 single-exon genes were associated with GBM survival (FDR-adjusted P-value < 0.05). CONCLUSIONS: The inferred patterns of AEU were consistent with in silico AS models. The hierarchical model used offered a flexible and simple way to interpret and identify associations between survival that accommodates multi-exon genes with or without AEU and single exon genes. Our results indicate that differential expression of AEU could be used as biomarker for GBM and potentially other cancers.

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival.

BACKGROUND: Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival. METHODS: A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers. RESULTS: A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events.Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. CONCLUSIONS: Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.