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.

Imipenem-Relebactam Susceptibility Testing of Gram-Negative Bacilli by Agar Dilution, Disk Diffusion, and Gradient Strip Methods Compared with Broth Microdilution.

This study aimed to determine whether agar dilution, research-use-only disk diffusion (Mast Group Ltd., Bootle Merseyside, UK), Etest (bioMérieux, Inc., Durham, NC), and MIC test strip (MTS) (Liofilchem, Inc., Waltham, MA) methods yield equivalent results to those of broth microdilution (BMD) for imipenem-relebactam susceptibility testing using a collection of 297 Gram-negative bacilli, including members of the order Enterobacterales and Pseudomonas aeruginosa, enriched for drug resistance. MIC and disk diameter results were interpreted using United States Food and Drug Administration breakpoints. Overall, 76.8% of the isolates tested were susceptible to imipenem-relebactam by BMD. MIC values for agar dilution, Etest, and MTS were not significantly different from that for BMD, although they tended to be 1 to 2 dilutions higher. Essential agreement was 95.6% for agar dilution, 90.6% for Etest, and 85.2% for MTS. Categorical agreement was 98.0% for agar dilution, 73.1% for disk diffusion, 96.3% for Etest, and 96.6% for MTS. In conclusion, agar dilution and Etest yielded comparable results to BMD for imipenem-relebactam.

Predicting phenoconversion in pure autonomic failure.

OBJECTIVE: To determine predicting factors and frequency of phenoconversion from pure autonomic failure (PAF) into a synucleinopathy with motor or cognitive involvement of multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB). METHODS: We performed a retrospective review of all patients with PAF from 2001 to 2011 evaluated at Mayo Clinic, Rochester. Clinical follow-up and patient telephone calls were used to assess for development of symptoms and diagnosis of MSA, PD, or DLB. Clinical and laboratory variables were extracted with factors predictive of evolution assessed using group comparison, odds ratio, and logistical regression. RESULTS: Among 275 patients with PAF at presentation, 67 (24%) phenoconverted to a synucleinopathy with motor or cognitive involvement; 34 met criteria for MSA, while 33 met criteria for PD or DLB. Age at onset was younger in MSA phenoconverters. Clinical features at presentation influenced phenoconversion: severe bladder symptoms were more common in MSA phenoconverters; subtle motor signs were more frequent in MSA and PD/DLB phenoconverters. MSA phenoconverters were more likely to have higher supine norepinephrine levels and preganglionic pattern of anhidrosis. Presentation variables predicting MSA phenoconversion included subtle motor signs, supine norepinephrine levels, severe bladder symptoms, and dream enactment behavior. Presentation variables predictive of PD/DLB phenoconversion included subtle motor signs, dream enactment behavior, and constipation. CONCLUSIONS: Our findings suggest that at least a quarter of patients with PAF phenoconvert to MSA, PD, or DLB. Presentation features determine patients at risk for evolution with specific patterns indicative of phenoconversion to MSA vs PD/DLB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that several presentation variables including subtle motor signs, severe bladder symptoms, and dream enactment behavior are associated with an increased risk of developing a synucleinopathy with motor or cognitive involvement.

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.

Causes of Death in Status Epilepticus.

OBJECTIVES: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. DESIGN: Retrospective cohort. SETTING: Single-center neuroscience ICU. PARTICIPANTS: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. INTERVENTIONS: Review of electronic medical records. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42-76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2-4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications (p = 0.0091), refractory seizures (p = 0.0077), and in those who required anesthetic drugs for seizure control (p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143-0.608; p = 0.0009). CONCLUSIONS: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality.

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.

Sex and gender influence symptom manifestation and survival in multiple system atrophy.

To evaluate the influence of sex and gender on clinical characteristics and survival in multiple system atrophy (MSA), we reviewed MSA patients with autonomic testing 1998-2012. Of 685 patients, 52% were male. Median survival overall was 7.3 years for males, 7.6 years for females. Survival from diagnosis was 2.9 years in males, 3.8 years in females. Females were more likely to initially manifest motor symptoms. Males were more likely to have orthostatic intolerance and early catheterization. In conclusion, our data show longer survival from diagnosis in females and slight overall survival benefit which may be related to initial motor manifestations.

Refined Quantitation of Sweat Gland Innervation.

Skin biopsies have gained increasing popularity as a tool to evaluate disorders affecting small nerve fibers. While reports on sweat gland nerve fiber density (SGNFD) to quantitate sudomotor innervation have been promising, methodologies vary significantly. Although conventional stereology is commonly used, no standard technique has been established. We sought to develop an accurate and reproducible technique to quantify SGNFD. Skin punch biopsies from healthy individuals were cut and stained. Images of sweat glands (SGs) were acquired using confocal and widefield microscopes, and optimized using deconvolution. Nerve fibers were reconstructed and nerve fiber length (NFL) was quantified using three-dimensional (3D) automated software. SGNFD was obtained by dividing NFL by SG volume. SGNFD was also assessed using stereology for comparison. Ninety-two SGs from 10 healthy subjects were analyzed by independent observers. Using confocal microscopy, the software reliably traced nerve fibers. In contrast, rendering of nerve fibers was inferior using widefield microscopy. Interobserver reliability was suboptimal using widefield images compared to confocal (ICC = 0.82 vs ICC = 0.98). Correlation between 3D-reconstruction and stereology was poor (ICC = 0.38). The newly developed technique of SGNFD quantitation using 3D reconstruction of SG innervation with confocal microscopy reliably traces nerve fibers, shows outstanding reproducibility, is almost completely unbiased, and superior to conventional stereology methods.

Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy?

INTRODUCTION: Loss of brainstem serotonergic neurons in MSA patients is implicated in respiratory dysfunction including stridor and may increase the risk of sudden death. Augmenting serotonergic transmission through selective serotonergic reuptake inhibitors (SSRIs) has been proposed to improve stridor and prolong survival in multiple system atrophy (MSA). We sought to determine whether MSA patients on an SSRI during their disease course have improved survival compared to those not on an SSRI. METHODS: Review of all MSA patients from 1998 to 2012 at Mayo Clinic, Rochester who completed autonomic function testing. Use of SSRI medications was obtained from patient-provided medication lists in the electronic medical record. Clinical symptoms were collected from patient histories; the presence of stridor was obtained from clinical histories and polysomnogram. Surviving patients were called to assess for stridor and SSRI use. RESULTS: Of 685 MSA patients, 132 (19%) were on an SSRI. Median time from symptom onset to death was 7.5 years with no difference based on SSRI use (p = .957). Rates of stridor were similar in SSRI users and non-users based on patient report and polysomnography (p = .494 and p = .181, respectively). SSRI use was associated with parkinsonism (p = .027) and falls (p = .002). Stridor was similar in SSRI users and those not on an SSRI. CONCLUSIONS: There was no difference in survival in MSA patients on an SSRI. However, SSRI use was associated with higher rates of parkinsonism and falls.

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.

Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction.

BACKGROUND: The objective of this study was to characterize the degree, pattern, lesion site, and temporal evolution of sudomotor dysfunction in multiple system atrophy (MSA) and to evaluate differences by parkinsonian (MSA-parkinsonism) and cerebellar (MSA-cerebellar) subtypes. METHODS: All cases of MSA evaluated at Mayo Clinic Rochester between 2005 and 2010 with postganglionic sudomotor testing and thermoregulatory sweat test were reviewed. Pattern and lesion site (preganglionic, postganglionic, or mixed) were determined based on thermoregulatory sweat test and postganglionic sudomotor testing. RESULTS: The majority of the 232 patients were MSA-parkinsonism (145, 63%). Initial postganglionic sudomotor testing was abnormal in 59%, whereas thermoregulatory sweat test was abnormal in 95% of all patients. MSA-parkinsonism patients were more likely to have an abnormal thermoregulatory sweat test compared with MSA-cerebellar (98% versus 90%, P = 0.006) and had a higher mean percentage of anhidrosis (57%) compared with MSA-cerebellar (48%; P = 0.033). Common anhidrosis patterns were regional (38%) and global (35%). The site of the lesion was preganglionic in 47% and mixed (preganglionic and postganglionic) in 41%. The increase in anhidrosis per year was 6.2% based on 70 repeat thermoregulatory sweat tests performed on 29 patients. The frequency of postganglionic sudomotor abnormalities increased over time. CONCLUSIONS: Our findings suggest: (1) sudomotor dysfunction is almost invariably present in MSA and even more common and severe in MSA-parkinsonism than MSA-cerebellar; (2) a preganglionic pattern of sweat loss is common in MSA; however, pre- and postganglionic abnormalities may coexist; and (3) the increasing frequency of postganglionic sudomotor dysfunction over time suggests involvement of postganglionic fibers or sweat glands later in the disease course. © 2016 International Parkinson and Movement Disorder Society.

Rating the Quality of Entrustable Professional Activities: Content Validation and Associations with the Clinical Context.

BACKGROUND: Entrustable professional activities (EPAs) have been developed to assess resident physicians with respect to Accreditation Council for Graduate Medical Education (ACGME) competencies and milestones. Although the feasibility of using EPAs has been reported, we are unaware of previous validation studies on EPAs and potential associations between EPA quality scores and characteristics of educational programs. OBJECTIVES: Our aim was to validate an instrument for assessing the quality of EPAs for assessment of internal medicine residents, and to examine associations between EPA quality scores and features of rotations. DESIGN: This was a prospective content validation study to design an instrument to measure the quality of EPAs that were written for assessing internal medicine residents. PARTICIPANTS: Residency leadership at Mayo Clinic, Rochester participated in this study. This included the Program Director, Associate program directors and individual rotation directors. INTERVENTIONS: The authors reviewed salient literature. Items were developed to reflect domains of EPAs useful for assessment. The instrument underwent further testing and refinement. Each participating rotation director created EPAs that they felt would be meaningful to assess learner performance in their area. These 229 EPAs were then assessed with the QUEPA instrument to rate the quality of each EPA. MAIN MEASURES: Performance characteristics of the QUEPA are reported. Quality ratings of EPAs were compared to the primary ACGME competency, inpatient versus outpatient setting and specialty type. KEY RESULTS: QUEPA tool scores demonstrated excellent reliability (ICC range 0.72 to 0.94). Higher ratings were given to inpatient versus outpatient (3.88, 3.66; p = 0.03) focused EPAs. Medical knowledge EPAs scored significantly lower than EPAs assessing other competencies (3.34, 4.00; p < 0.0001). CONCLUSIONS: The QUEPA tool is supported by good validity evidence and may help in rating the quality of EPAs developed by individual programs. Programs should take care when writing EPAs for the outpatient setting or to assess medical knowledge, as these tended to be rated lower.

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.

Clinical features and autonomic testing predict survival in multiple system atrophy.

Multiple system atrophy is characterized by autonomic failure along with motor symptoms of parkinsonism and/or cerebellar ataxia. There are differing reports on the influence of certain clinical features, including motor subtype (multiple system atrophy-parkinsonism versus multiple system atrophy-cerebellar ataxia), age of onset, gender, and early autonomic symptoms, on the survival in patients with multiple system atrophy. We sought to evaluate overall survival and predictors of survival in a large cohort of patients with multiple system atrophy seen at a single referral centre where objective autonomic testing is routinely performed for this indication. All cases of multiple system atrophy evaluated at Mayo Clinic, Rochester and assessed with an autonomic reflex screen between January 1998 and December 2012 were retrospectively reviewed. A total of 685 patients were identified; 594 met criteria for probable multiple system atrophy, and 91 for possible multiple system atrophy. Multiple system atrophy-parkinsonism was the predominant subtype in 430 patients (63%). Average age of onset was earlier in multiple system atrophy-cerebellar ataxia (58.4 years) compared to multiple system atrophy-parkinsonism (62.3 years; P < 0.001). Median disease duration from symptom onset to death was 7.51 years (95% confidence interval 7.18-7.78) while time from diagnosis to death was 3.33 years (95% confidence interval 2.92-3.59). There was no difference in survival between motor subtypes of multiple system atrophy (P = 0.232). An initial motor symptom was most common (61%) followed by autonomic onset (28%) and combined motor and autonomic symptoms (11%). The initial onset of either motor or autonomic symptoms did not influence length of survival. However, a number of clinical and autonomic laboratory features predicted unfavourable survival in a univariate analysis. A multivariate model retained the following unfavourable predictors of survival: (i) falls within 3 years of onset (hazard ratio 2.31, P < 0.0001); (ii) bladder symptoms (hazard ratio 1.96, P < 0.0001); (iii) urinary catheterization within 3 years of symptom onset (hazard ratio 1.67, P < 0.003); (iv) orthostatic intolerance within 1 year of symptom onset (hazard ratio 1.28, P < 0.014); (v) older age of onset (hazard ratio 1.02, P = 0.001); and (vi) degree of autonomic failure as measured by a validated composite autonomic severity score (hazard ratio 1.07, P < 0.0023). We conclude that carefully selected clinical features can be used to predict survival in patients with multiple system atrophy. Autonomic testing adds an additional, independent predictor of survival, demonstrating its value not only in the diagnosis of multiple system atrophy but also as prognostic marker.

Positive Fluid Balance Is Associated With Poor Outcomes in Subarachnoid Hemorrhage.

BACKGROUND: Strict maintenance of normovolemia is standard of care in the treatment of aneurysmal subarachnoid hemorrhage (aSAH), and induced hypervolemia is often used to treat delayed cerebral ischemia from vasospasm. We tested the hypothesis that positive fluid balance could adversely affect clinical outcomes in aSAH. METHODS: We reviewed 288 patients with aSAH admitted to the Neuroscience Intensive Care Unit (NICU) from October 2001 to June 2011. We collected data on fluid balance during NICU stay, clinical and radiographic evidence of vasospasm, cardiopulmonary complications, and functional outcomes by modified Rankin Scale (mRS) on follow-up (mean 8 ± 8 months). Poor functional outcome was defined as an mRS score 3-6. Associations of variables of interest with outcome were assessed using univariable and multivariable logistic regression. Propensity scores were estimated to account for imbalances between patients with positive versus negative fluid balance and were included in multivariable models. RESULTS: Average net fluid balance during the NICU stay was greater in patients with poor functional outcome (3.52 ± 5.51 L versus -.02 ± 5.30 L in patients with good outcome; P < .001). On multivariate analysis, positive fluid balance (P = .002) was independently associated with poor functional outcome along with World Federation of Neurosurgical Societies grade (P < .001), transfusion (P = .003), maximum glucose (P = .005), and radiological evidence of cerebral infarction (P = .008). After regression adjustment with propensity scores, the association of positive fluid balance with poor functional outcome remained significant (odds ratio, 1.18; 95% confidence interval, 1.08-1.29; P < .001). CONCLUSIONS: Greater positive net fluid balance is independently associated with poorer functional outcome in patients with aSAH.

Genitourinary Procedures as Risk Factors for Prosthetic Hip or Knee Infection: A Hospital-Based Prospective Case-Control Study.

Background. The purpose of this study was to determine the risk of prosthetic joint infection (PJI) as a complication of routine genitourinary (GU) procedures in patients with total hip arthroplasty (THA) or total knee arthroplasty (TKA) and to study the impact of antibiotic prophylaxis administered prior to these procedures. Methods. We conducted a prospective, single-center, case-control study between December 1, 2001 and May 31, 2006. Case patients were hospitalized with total hip or knee PJI. Control subjects underwent a THA or TKA and were hospitalized during the same period on the same orthopedic floor without a PJI. Data regarding demographic features and potential risk factors were collected. The outcome measure was the odds ratio (OR) of PJI after GU procedures performed within 2 years of admission. Results. A total of 339 case patients and 339 control subjects were enrolled in the study. Of these, 52 cases (15%) and 55 controls (16%) had undergone a GU procedure in the preceding 2 years. There was no increased risk of PJI for patients undergoing a GU procedure with or without antibiotic prophylaxis (adjusted OR [aOR] = 1.0, 95% confidence interval [CI] = 0.2-4.5, P = .95 and aOR = 1.0, 95% CI = 0.6-1.7, P = .99, respectively). Results were similar in a subset of patients with a joint age less than 6 months, less than 1 year, or greater than 1 year. Conclusions. Genitourinary procedures were not risk factors for subsequent PJI. The use of antibiotic prophylaxis before GU procedures did not decrease the risk of subsequent PJI in our study.

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.

Post-cardiac arrest mortality is declining: a study of the US National Inpatient Sample 2001 to 2009.

BACKGROUND: Despite several advances in postresuscitation care over the past decade, population-based mortality rates for patients hospitalized with cardiac arrest in the United States have not been studied over this time period. The aim of this study was to determine the annual in-hospital mortality rates of patients with cardiac arrest from 2001 to 2009. METHODS AND RESULTS: The US mortality rates for hospitalized patients with cardiac arrest were determined using the 2001 to 2009 US National Inpatient Sample, a national hospital discharge database. Using the International Classification of Diseases, 9(th) Edition, code 427.5, we identified patients hospitalized in the United States with cardiac arrest from 2001 to 2009. The main outcome measure was in-hospital mortality. A total of 1 190 860 patients were hospitalized with a diagnosis of cardiac arrest in the United States from 2001 to 2009. The in-hospital mortality rate decreased each year from 69.6% in 2001 to 57.8% in 2009. In multivariable analysis, when controlling for age, sex, race, and comorbidities, earlier year was a strong independent predictor of in-hospital death. The mortality rate declined across all analyzed subgroups, including sex, age, race, and stratification by comorbidity. CONCLUSIONS: The in-hospital mortality rate of patients hospitalized with cardiac arrest in the United States decreased by 11.8% from 2001 to 2009.