Human transcriptomic response to periprosthetic joint infection.

Periprosthetic joint infection (PJI), a devastating complication of total joint replacement, is of incompletely understood pathogenesis and may sometimes be challenging to clinically distinguish from other causes of arthroplasty failure. We characterized human gene expression in 93 specimens derived from surfaces of resected arthroplasties, comparing transcriptomes of subjects with infection- versus non-infection-associated arthroplasty failure. Differential gene expression analysis confirmed 28 previously reported potential biomarkers of PJI, including bactericidal/permeability increasing protein (BPI), cathelicidin antimicrobial peptide (CAMP), C-C-motif chemokine ligand 3 (CCL3), 4(CCL4) and C-X-C-motif chemokine ligand 2 (CXCL2), colony stimulating factor 2 receptor beta (CSF2RB), colony stimulating factor 3 (CSF3), alpha-defensin (DEFA4), Fc fragment of IgG receptor 1B (CD64B), intercellular adhesion molecule 1 (ICAM1), interferon gamma (IFNG), interleukin 13 receptor subunit alpha 2 (IL13RA2), interleukin 17D (IL17D), interleukin 1 (IL1A, IL1B, IL1RN), interleukin 2 receptors (IL2RA, IL2RG), interleukin 5 receptor (IL5RA), interleukin 6 (IL6), interleukin 8 (IL8), lipopolysaccharide binding protein (LBP), lipocalin (LCN2), lactate dehydrogenase C (LDHC), lactotransferrin (LTF), matrix metallopeptidase 3 (MMP3), peptidase inhibitor 3 (PI3), and vascular endothelial growth factor A (VEGFA), and identified three novel molecules of potential diagnostic use for detection of PJI, namely C-C-motif chemokine ligand CCL20, coagulation factor VII (F7), and B cell receptor FCRL4. Comparative analysis of infections caused by staphylococci versus bacteria other than staphylococci and Staphylococcus aureus versus Staphylococcus epidermidis showed elevated expression of interleukin 13 (IL13), IL17D, and MMP3 in staphylococcal infections, and of IL1B, IL8, and platelet factor PF4V1 in S. aureus compared to S. epidermidis infections. Pathway analysis of over-represented genes suggested activation of host immune response and cellular maintenance and repair functions in response to invasion of infectious agents. The data presented provides new potential targets for diagnosis of PJI and for differentiation of PJI caused by different infectious agents.

Botulinum Toxin A in Tissue Expander Breast Reconstruction: A Double-blinded Randomized Controlled Trial.

Subpectoral tissue expander breast reconstruction is often associated with muscle spasms, pain, and discomfort during tissue expansion. In this study, we hypothesized that an intraoperative injection of botulinum toxin A (BTX-A) in the pectoralis major muscle reduces the pain associated with tissue expansion and improves women's physical well-being. METHODS: Between May 2012 and May 2017, women undergoing immediate subpectoral tissue expander breast reconstruction were randomized to administer 100 units of BTX-A or a placebo injection. A numeric pain intensity scale and the physical well-being scale of the BREAST-Q: Reconstruction Module were used to test our hypothesis. Data on postoperative oral narcotic consumption were not collected. RESULTS: Of the 131 women included in the analysis, 48% were randomized to placebo and 52% to BTX-A. The preoperative median pain intensity score was 0 [interquartile range (IQR), 0-1], and the median preoperative BREAST-Q score was 91 (IQR, 81-100). The median slopes for the change in pain intensity scores from baseline throughout tissue expansion for those randomized to placebo and BTX-A were -0.01 (IQR, -0.02 to 0.00) and -0.01 (IQR, -0.02 to 0.00), respectively (P = 0.55). The median slopes for the change in BREAST-Q scores from baseline throughout tissue expansion for those randomized to placebo and BTX-A were 0.04 (IQR, -0.17 to 0.14) and 0.02 (IQR, -0.06 to 0.13), respectively (P = 0.89). CONCLUSION: In this study, we found that an intraoperative intramuscular injection of 100 units of BTX-A in the pectoralis major muscle did not reduce postoperative pain and patient-reported physical well-being when compared with placebo.

Earlier age of onset in multiple system atrophy with smoking and heavy alcohol use.

OBJECTIVE: To determine whether smoking or alcohol use impacts the age of onset and disease duration in multiple system atrophy (MSA). METHODS: All patients diagnosed with MSA at Mayo Clinic, Rochester between 1998 and 2012 completed standardized questionnaires surveying smoking and alcohol use at the time of presentation. RESULTS: Of 551 patients with smoking and alcohol use data, 281 were past or present smokers with age of onset of 60.76 years compared to 62.97 years in controls (p = 0.0144). Age of onset in the 87 heavy alcohol users was 56.87 years compared to 62.97 years in controls (p = 0.0133). There was no difference in disease duration for smokers (p = 0.2758) or heavy alcohol users (p = 0.4820) compared to controls. CONCLUSION: Our findings show that smoking history and/or heavy alcohol use is associated with younger age of onset in MSA but do not influence survival.

Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.

OBJECTIVE: This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). METHODS: Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS). RESULTS: Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect. CONCLUSIONS: Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.

Extremely Elevated Erythrocyte Sedimentation Rates: Associations With Patients' Diagnoses, Demographic Characteristics, and Comorbidities.

OBJECTIVE: To study associations between extreme erythrocyte sedimentation rate (ESR) elevations (≥100 mm/h) and diseases, age, sex, race, Charlson Comorbidity Index (CCI), and C-reactive protein (CRP) level. PATIENTS AND METHODS: This was a retrospective cohort study of 4807 patients with extreme ESR values examined at Mayo Clinic, Rochester, Minnesota, from January 1, 2002, through December 31, 2011. Independent variables included diseases (infection, autoimmune, malignancy, renal disease, or miscellaneous), subcategories of diseases, patient demographic characteristics (age, sex, and race), CRP level, and CCI. The Wilcoxon rank sum test was used to assess comparisons of ESR between patients with and without disease as well as relationships between extreme ESR values and demographic characteristics of patients within disease categories. Associations between ESR and CRP level were determined using the Pearson correlation coefficient. RESULTS: The leading diagnosis associated with extreme ESR elevations (n [%]) was infection (1932 [40]), followed by autoimmune (1839 [38]) and malignancy (1736 [36]) (P<.01). Extreme elevations in ESR varied by sex, with higher ESRs in men (mean, 117±13.3 mm/h) than in women (mean, 115.9±12.5 mm/h) (P=.008). Extreme ESR elevations correlated inversely with the CCI (P=.008) and did not correlate with the CRP level. There were no correlations between extreme elevations in ESR and age or race. CONCLUSION: We found that almost all patients have an identifiable etiology for extreme ESR elevations and that infection is the most common disease association. Unlike previous research, we identified higher ESRs in men than in women and no associations with age, race, and comorbid illness. These findings may enhance the diagnostic evaluation of patients with extreme ESR elevations.

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults.

IMPORTANCE: Classic Purkinje cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia. OBJECTIVES: To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study conducted at Mayo Clinic, Rochester, Minnesota, included 118 patients who had ataxia, were 18 years or older, were seropositive for at least 1 neural autoantibody, had received at least 1 immunotherapy or cancer therapy, and had neurologist-reported outcomes documented from January 1, 1989, through December 31, 2013. Data were collected from May 14, 2013, through August 9, 2014, and analyzed from August 9, 2014, through April 27, 2015. Responses to immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressants) and ambulatory outcomes were compared between different subgroups. Subgroups were classified as paraneoplastic vs nonparaneoplastic disorders; neuronal nuclear and/or cytoplasmic (NNC) antibody positivity vs plasma membrane protein (PMP) antibody positivity; and glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody positivity vs PMP antibody positivity. MAIN OUTCOMES AND MEASURES: Response to therapy and ambulatory ability, with univariate logistic regression and Kaplan-Meier analyses. RESULTS: Inclusion criteria were met by 118 patients. Median age at onset of neurologic symptoms was 58 (range, 27-83) years, and 87 patients (73.7%) were women. Median duration from symptom onset to last follow-up was 25 (range, 2-223) months. Sixty-three patients had paraneoplastic and 55 patients had nonparaneoplastic ataxic disorders. Eighty-one patients were seropositive for NNC antibodies (most commonly PCA-1 [anti-Yo], antineuronal nuclear antibody type 1 [anti-Hu], and GAD65 antibody); 22 patients, for neural PMP receptor or ion channel antibodies (most commonly targeting P/Q- or N-type voltage-gated calcium channels); and 15 patients, for antibodies from both categories. Neurologic improvements occurred in 54 patients (with a robust change in ambulatory ability in 22) attributable to immunotherapy; univariate regression analysis revealed that improvements were significantly more common among patients with nonparaneoplastic disorders (P = .03) and those with exclusively PMP antibodies (P = .02). Kaplan-Meier analyses revealed that progression to wheelchair dependence occurred significantly faster among patients with NNC antibody positivity only (P = .02), although those with GAD65 autoimmunity progressed to wheelchair dependence at a rate similar to those with PMP autoimmunity (P = .92). CONCLUSIONS AND RELEVANCE: Although autoimmune ataxia is usually severe, treatment responses can be gratifying, particularly in patients with nonparaneoplastic disorders and in those harboring autoantibodies directed against GAD65 or neural PMPs.

Indicators of central fever in the neurologic intensive care unit.

IMPORTANCE: Fever is common in critically ill neurologic patients. Knowledge of the indicators of central fever may allow greater antibiotic stewardship in this era of rapidly developing super-resistant microorganisms. OBJECTIVE: To develop a model to differentiate central from infectious fever in critically ill neurologic patients with fever of an undetermined cause. DESIGN, SETTING, AND PARTICIPANTS: Retrospective data collection from January 1, 2006, through December 31, 2010, at a 20-bed neurologic intensive care unit of a large teaching hospital. Consecutive patients 18 years and older admitted for 48 hours or longer with a core body temperature higher than 38.3 °C on at least 1 measurement for 2 consecutive days. Patients with alternative identified causes of noninfectious fever were excluded. In total, 526 patients were included in the final analysis. MAIN OUTCOMES AND MEASURES: Percentage incidence and odds ratios of variables associated with central fever. Fever was classified as infectious if there was culture growth of a pathogenic species or documented clinical diagnosis of infection treated with antibiotics. Remaining patients were considered to have central fever. Continuous fever lasting longer than 6 hours for 2 or more consecutive days was considered persistent. RESULTS Fever was central in 246 patients (46.8%). Patients with infectious fever were older (mean, 57.4 vs 53.5 years; P = .01) and had a longer length of stay in the neurologic intensive care unit (mean, 12.1 vs 8.8 days; P < .001). Central fever was more likely to occur within 72 hours of admission to the neurologic intensive care unit (76.4% vs 60.7%; P < .001) and tended to be persistent (26.4% vs 18.6%; P = .04). Blood transfusion (odds ratio [OR], 3.06; 95% CI, 1.63-5.76); absence of infiltrate on chest x-ray (3.02; 1.81-5.05); diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor (6.33; 3.72-10.77); and onset of fever within 72 hours of hospital admission (2.20; 1.23-3.94) were independent predictors of central fever on multivariable analysis. The combination of negative cultures; absence of infiltrate on chest radiographs; diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor; and onset of fever within 72 hours of admission predicted central fever with a probability of .90. CONCLUSIONS AND RELEVANCE: We provide a reliable model to differentiate central fever from infectious fever in critically ill neurologic patients, allowing clinicians to select patients in whom antibiotics may be safely discontinued despite ongoing fever.

Noncathartic CT colonography with stool tagging: performance with and without electronic stool subtraction.

OBJECTIVE: The purpose of our study was to evaluate the performance of noncathartic, dietary unrestricted CT colonography, without and with the aid of electronic stool subtraction, for detecting colorectal neoplasia in a high-prevalence referral population. MATERIALS AND METHODS: Patients with known or suspected colorectal neoplasms were potentially eligible for participation, regardless of the presence or absence of gastrointestinal symptoms. Subjects ingested 21.6 g of barium in nine divided doses. CT colonography was performed in the standard fashion. Data sets were randomly evaluated by two of three experienced radiologists, with subsequent reanalysis of each data set after electronic stool subtraction at least 6 weeks later. Optical colonoscopy was performed after purgation and served as the reference standard. RESULTS: One hundred thirty-one adenomatous neoplasms were identified among 114 subjects. On a per subject basis, the sensitivity for detecting adenomas 6-9 or > or = 10 mm in diameter ranged from 53% to 88% and 84% to 93% without stool subtraction, respectively. By including stool subtraction, these sensitivity estimates improved to 68% to 92% and 93% to 94%, respectively. Specificity ranged from 71% to 91% and 88% to 100% for lesions 6-9 and > or = 10 mm in size, respectively. Double reading resulted in detection of 27 (87%) of 31 and 65 (96%) of 68 patients with 6-9 and > or = 10 mm adenomas, respectively. With double reading, the area under the receiver operating characteristic curve for large adenomas was 0.97. CONCLUSION: In this increased-risk referral population, CT colonography in the non-cathartic-tagged colon without dietary restrictions compared favorably with optical colonoscopy.

Effect of slice thickness and primary 2D versus 3D virtual dissection on colorectal lesion detection at CT colonography in 452 asymptomatic adults.

OBJECTIVE: The objective of our study was to compare the performance of primary 3D search using 360 degree virtual dissection with primary 2D search using a 2.5- versus a 1.25-mm slice thickness. SUBJECTS AND METHODS: Four hundred fifty-two asymptomatic patients underwent CT colonography (CTC) and colonoscopy. Examinations were reconstructed to 1.25- and 2.5-mm slice thicknesses and interpreted using primary 3D search (360 degree virtual dissection) and primary 2D search. Two of three experienced reviewers were randomly assigned to each case; 1,808 interpretations were performed. RESULTS: There were 64 adenomas > or = 6 mm, 26 of which were large adenomas > or = 1 cm. For adenomas 6-9 mm in diameter, the area under the receiver operating characteristic curve (AUC) using 2.5-mm data sets was 0.66, 0.62, 0.90 and 0.78, 0.69, 0.67 for reviewers 1, 2, and 3, respectively, using primary 3D versus 2D search (p = not significant [NS]). For neoplasms > or = 10 mm, the AUC using 2.5-mm data sets was 0.74, 0.85, 0.89 and 0.66, 0.86, 0.92 for reviewers 1, 2, and 3 using primary 3D versus 2D search (p = NS). There was no significant difference using 1.25-mm collimation. Double review using both primary 3D and 2D search yielded sensitivities of 84% (16/19) and 95% (18/19) for large neoplasms (> or = 1 cm) using 2.5- and 1.25-mm data sets, respectively. Five of five (100%) adenocarcinomas were identified. The sensitivity of colonoscopy for large neoplasms was 77% (20/26) (20% [1/5] for adenocarcinoma). CONCLUSION: No advantage exists for 1.25- or 2.5-mm slice thickness or for primary 3D versus 2D search at CTC. Double review using primary 3D (virtual dissection) and 2D search reduces interobserver variability and competes with colonoscopy for the detection of large lesions.