Citations

We compared the diagnosis of malaria in 297 patients from Thailand by a real-time polymerase chain reaction (PCR) assay using the LightCycler with conventional microscopy using Giemsa-stained thick and thin blood films. The PCR assay can be completed in one hour and has the potential to detect and identify four species of Plasmodium in a single reaction by use of melting temperature curve analysis (however, we did not detect Plasmodium ovale in this study). Blood was collected, stored, and transported on IsoCode STIX, which provide a stable matrix for the archiving and rapid simple extraction of DNA. A genus-specific primer set corresponding to the 18S ribosomal RNA was used to amplify the target sequence. Fluorescence resonance energy technology hybridization probes were designed for P. falciparum over a region containing basepair mismatches, which allowed differentiation of the other Plasmodium species. The PCR results correlated with the microscopic results in 282 (95%) of 297 patient specimens. Most of these were single-species infections caused by P. vivax (150) and P. falciparum (120), along with 5 P. malariae, 2 mixed infections (P. falciparum and P. vivax), and 5 negative specimens. No negative microscopy specimens were positive by PCR (100% specificity for detection of any Plasmodium). The 15 discrepant results could not be resolved, but given the subjective nature of microscopy and the analytical objectivity of the PCR, the PCR results may be correct. The ability of the PCR method to detect mixed infections or to detect P. ovale could not be determined in this study. Within the limitations of initial equipment costs, this real-time PCR assay is a rapid, accurate, and efficient method for the specific diagnosis of malaria. It may have application in clinical laboratories, as well as in epidemiologic studies and antimalarial efficacy trials.

AbstractBackgroundRenal dysfunction occurs commonly after heart transplantation (HTx) with wide inter‐individual variability but whether a genetic predisposition exists in these patients is unknown. Genomewide association studies (GWAS) have not been performed to assess the association of genetic variation with change in renal function after HTx.MethodsClinical and demographic data of patients who underwent HTx and provided blood samples and consent for genetic analysis were included. Genotyping was performed using Illumina Infinium Human CoreExome v1.0 analysis kit. A GWAS utilizing linear regression models was performed with estimated glomerular filtration rate (eGFR) at 1 year as the phenotype after adjusting for baseline eGFR prior to HTx and conversion from calcineurin inhibitor to sirolimus as primary immunosuppression therapy.ResultsA total of 251 HTx recipients were genotyped for 314,903 single nucleotide polymorphisms (SNPs). The mean (SD) age was 50 (12.5) years; most patients were of European origin (n = 243, 96.8%) and males (n = 179, 71.3%). After adjustment for potential confounders, two variants, rs17033285 (P = 4.3 × 10−7) and rs4917601 (P = 6.46 × 10−7), in a long non‐coding RNA (lncRNA) gene LINC01121 and a pseudogene BTBD7P2, were identified to have a significant association with change in GFR at 1 year after HTx.ConclusionsOur first of its kind GWAS demonstrates that genetic variation affects renal function after HTx independent of other risk factors. Agnostic genetic approaches such as these may lead to identification of novel biological pathways such as the role of lncRNAs in the development of renal dysfunction post‐HTx.

ABSTRACTBackground: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD.Objectives: The objective of this study was to generate and test a PD diagnostic criteria termed “clinically established early PD.”Methods: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626‐patient validation study.Results: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of “clinically established early PD.” Among 212 PD and 152 non‐PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity.Conclusions: We describe high‐specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society

Background: Obesity is a known risk factor for wound complications; however, unlike elective upper extremity procedures, where obesity can be modified preoperatively, excision of soft tissue sarcomas (STSs) is not elective, and as such, obesity cannot be modified. There is a paucity of data concerning the impact of obesity on wound healing in upper extremity sarcoma surgery. Methods: A total of 261 (159 males and 102 females) patients with a STS of the upper extremity from 2006-2014 were reviewed. The mean age and body mass index (BMI) were 56 (18-97) years and 26.6 (15.4-40.8) kg/m 2 , respectively. Sixty-nine patients (26%) were classified as obese (BMI ⩾30 kg/m 2 ): class I (obese, BMI = 30-34.9 kg/m 2 ; n = 48, 18%), class II (severely obese, BMI = 35.0-39.9 kg/m 2 ; n = 16, 6%), and class III (morbidly obese, BMI ≥ 40 kg/m 2 ; n = 5, 2%). Functional outcomes were also compared between obese and nonobese patients using the Musculoskeletal Tumor Society (MSTS) 1993 rating system and Toronto Extremity Salvage Scores (TESS). Results: Forty-nine patients (19%) sustained a wound dehiscence, delayed healing, or infection. Class III obesity increased the risk of wound complications (hazard ratio [HR] = 8.19, 95% confidence interval [CI] = 1.96-22.96, P < .001) and infection (HR = 10.09, 95% CI = 1.60-34.83, P = .01). There was no difference in the mean TESS (93 vs 90, P = .13) or MSTS93 (95 vs 93, P = .39) between obese and nonobese patients. Conclusions: The results of this study indicate morbid obesity significantly increased the risk of a postoperative wound complication and infection. However, following upper extremity limb salvage surgery, obese patients should expect to have excellent functional outcome.

Abstract BACKGROUND Emergency department (ED) overuse is a costly and often neglected source of postdischarge resource utilization after spine surgery. Failing to investigate drivers of ED visits represents a missed opportunity to improve the value of care in spine patients. OBJECTIVE To identify the prevalence, drivers, and timing of ED visits following elective spine surgery. METHODS Patients undergoing elective spine surgery for degenerative disease at a major medical center were enrolled in a prospective longitudinal registry. Patient and surgery characteristics, and patient-reported outcomes were recorded at baseline and 3 mo after surgery, along with self-reported 90-d ED visits. A multivariable regression model was used to identify independent factors associated with 90-d ED visits. For a sample of patients presenting to our institution's ED, charts were reviewed to identify the reason and time to ED postdischarge. RESULTS Of 2762 patients, we found a 90-d ED visit rate of 9.4%. One-third of patients presented to our institution's ED and of these, 70% presented due to pain or medical concerns at 9 and 7 d postdischarge, respectively, with 60% presenting outside normal clinic hours. Independent risk factors for 90-d ED visits included younger age, preoperative opioid use, chronic obstructive pulmonary disorder, and more vertebral levels involved. CONCLUSION Nearly 10% of elective spine patients had 90-d ED visits not requiring readmission. Pain and medical concerns accounted for 70% of visits at our center, occurring within 10 d of discharge. This study provides the clinical details and a timeline necessary to guide individualized interventions to prevent unnecessary, costly ED visits after spine surgery.

Abstract Glioblastoma multiforme (GBM) remains the most common and deadly primary brain tumor with minimal advances in therapeutic development for pharmacological treatment. Tumor resection followed by temozolomide (TMZ) and radiotherapy adds months to survival; however, tumor recurrence usually occurs. The fibroblast growth factor-inducible 14 (Fn14) receptor has been shown to be up-regulated in the GBM cells left behind after surgery and contributes to an invasive and pro-survival phenotype, providing a desirable molecule to target after removal of the primary tumor. Previously, L524-0366 was reported by our lab to be the first antagonist of Fn14 signaling; however, minimal efficacy/potency has limited this drug from progressing from a useful research tool to preclinical studies. Structure activity relationship (SAR) studies using the parent L524-0366 compound gave rise to K78, which was found to bind to Fn14 with enhanced affinity, while showing no binding to the structurally-related TNFα receptor. Furthermore, K78 was able to abate the downstream signaling effects initiated by the Fn14 ligand, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), as well as sensitize GBM cells to the cytotoxic effects of TMZ. TWEAK-induced cellular migration was also mitigated with co-treatment of K78 in GBM cells, compared to a vehicle control. It is anticipated that further development of Fn14 antagonists will be of great importance for the advancement of GBM patient treatment and warrant further investigation as primary and combination therapy, especially for the prevention of recurrent disease. Citation Format: Bryan Harder, Chris Sereduk, Harshil Dhruv, Nghia Millard, Anthony Kim, Jeffrey Winkles, Graeme Woodworth, Holly Yin, Nhan L. Tran. Development of an antagonist to the TWEAK-Fn14 ligand-receptor interaction with enhanced efficacy/potency in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4910.