Demographic and disease-related factors impact on cerebrospinal fluid neurofilament light chain levels in multiple sclerosis.

BACKGROUND: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. METHODS: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41). RESULTS: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. CONCLUSIONS: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.

Trauma Mechanisms and Surgical Outcomes in the Elderly Patient with Chronic Subdural Hematoma.

Background: Chronic subdural hematoma is the preeminent neurosurgical condition in the older population. This retrospective single-centre study focuses on outcome after surgery of chronic subdural hematoma in patients over 70 years. Methods: Patients treated at a single neurosurgical referral centre between 2010 and 2014 were screened. Included patients were assessed for comorbid conditions, lifestyle factors, and outcomes including recurrence, mortality, and postoperative complications. Results: A total of 511 patients (70-97 yrs) were identified. 50.7% of patients were treated with anticoagulants and/or antiplatelet therapy. A known probable cause for the hematoma was found in 68.1% of patient's histories. Mortality rate was 3.1% and recurrence was seen in 49 patients (9.6%). Postoperative complications were more common in patients with excessive use of alcohol (p value = .02). Neurological function was improved in 78.1% of patients after the initial surgery. A strategy of delayed contralateral surgery in bilateral hematomas showed low rates of recurrence. Conclusion: Fall injuries are the most common underlying trauma mechanism in the elderly with chronic subdural hematoma. Recurrence is not more common in the elderly patient group compared to the general population. Excessive alcohol use is a risk factor for post-operative complications.

Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients.

BACKGROUND: Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY). METHODS: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination. RESULTS: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression. CONCLUSION: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.

Mesothelin-specific Immune Responses Predict Survival of Patients With Brain Metastasis.

BACKGROUND: Patients with advanced malignancies, e.g. lung cancer, ovarian cancer or melanoma, frequently present with brain metastases. Clinical presentation and disease progression of cancer is in part shaped by the interaction of the immune system with malignant cells. Antigen-targeted immune responses have been implicated in the prolonged survival of patients with cancer. This includes the tumor-associated antigen (TAA) mature mesothelin, a 40kDa cell surface-bound antigen that is overexpressed in several malignancies including lung ovarian and pancreatic cancer. We examined in an observational, prospective study the survival of patients with brain metastases in association with clinical parameters and cellular immune responses to molecularly defined TAAs or viral (control) target antigens. METHODS: Immune cells in peripheral blood obtained from thirty-six patients with brain metastases were tested for cytokine production in response to a broad panel of defined viral and TAA target antigens, including full-length mesothelin. Incubation of immune cells with antigenic targets was carried out in i) medium alone, (ii) in a cytokine cocktail of interleukin (IL)-2/IL-15/IL-21, or (iii) IL-2/IL-7. Supernatants were tested for interferon gamma (IFN-γ) production, after which univariate and multivariate analyses (Cox stepwise regression model) were performed to identify independent clinical and immunological factors associated with patient survival. Patients were followed-up for at least 500days after surgery or until death. FINDINGS: Univariate analysis identified age, gender, radiotherapy and mutational load as clinical parameters affecting survival of patients with brain metastases. Cox multivariate analysis showed that radiotherapy (P=0·004), age (P=0·029) and IFN-γ responses to mature mesothelin, conditioned by IL-2/IL-7 (P=0·045) were independent predictors of the survival of patients from surgery up to follow-up or death. INTERPRETATION: This is the first evidence that immune responses to mesothelin serve as a marker of increased overall survival in patients with brain metastases, regardless of the primary tumor origin. Analyses of immunological markers could potentially serve as prognostic markers in patients with brain metastases and help to select patients in need for adjunct, immunological, treatment strategies.

Diagnostic Performance of Five Assays for Anti-Hepatitis E Virus IgG and IgM in a Large Cohort Study.

Determination of anti-hepatitis E virus (anti-HEV) antibodies is still enigmatic. There is no gold standard, and results obtained with different assays often diverge. Herein, five assays were compared for detection of anti-HEV IgM and IgG. Serum samples from 500 Swedish blood donors and 316 patients, of whom 136 had suspected HEV infection, were analyzed. Concordant results for IgM and IgG with all assays were obtained only for 71% and 70% of patients with suspected hepatitis E, respectively. The range of sensitivity for anti-HEV detection was broad (42% to 96%); this was reflected in the detection limit, which varied up to 19-fold for IgM and 17-fold for IgG between assays. HEV RNA was analyzed in all patients and in those blood donors reactive for anti-HEV in any assay, and it was found in 26 individuals. Among all of the assays, both anti-HEV IgG and IgM were detected in 10 of those individuals. Twelve had only IgG and, in 7 of those 12, IgG was only detected with the two most sensitive assays. Three of the HEV-RNA-positive samples were negative for anti-HEV IgM and IgG in all assays. With the two most sensitive assays, anti-HEV IgG was identified in 16% of the blood donor samples and in 66% of patients with suspected HEV infection. Because several HEV-RNA-positive samples had only anti-HEV IgG without anti-HEV IgM or lacked anti-HEV antibodies, analysis for HEV RNA may be warranted as a complement in the laboratory diagnosis of ongoing HEV infection.

Functional anatomic dissociation of description and picture naming in the left temporal lobe.

Functional magnetic resonance imaging (fMRI) was used in a non-patient experimental sample to assess the neuroanatomical dissociation of picture and description naming (PN and DN) in temporal lobe (TL). The purpose was to determine the generalizability of findings in semantic organization in the epilepsy patient population to the broader population. It was hypothesized that, akin to patient derived findings, DN would uniquely activate left TL regions anterior to those associated with PN, while overlapping in middle and posterior left TL. Participants (n = 16) underwent fMRI while silently naming target words during a picture naming task (PNT; line drawings) and description naming task (DNT; orthographic phrases). Analysis was a priori restricted to the left TL. Group results of direct contrasts (DNT > PNT and PNT > DNT) confirmed the hypothesized dissociation with DNT > PNT activating anterior left TL. Within-condition contrasts (DNT and PNT alone) yielded additional support, revealing areas of shared and unique activation in each condition. This is the first imaging study to contrast DN and PN in the same sample. The results suggest DN and PN are meaningfully different constructs subserved by converging and diverging TL neuroanatomy and may be differentially affected by disease.

A model for the electronic support of practice-based research networks.

PURPOSE: The principal goal of the electronic Primary Care Research Network (ePCRN) is to enable the development of an electronic infrastructure to support clinical research activities in primary care practice-based research networks (PBRNs). We describe the model that the ePCRN developed to enhance the growth and to expand the reach of PBRN research. METHODS: Use cases and activity diagrams were developed from interviews with key informants from 11 PBRNs from the United States and United Kingdom. Discrete functions were identified and aggregated into logical components. Interaction diagrams were created, and an overall composite diagram was constructed describing the proposed software behavior. Software for each component was written and aggregated, and the resulting prototype application was pilot tested for feasibility. A practical model was then created by separating application activities into distinct software packages based on existing PBRN business rules, hardware requirements, network requirements, and security concerns. RESULTS: We present an information architecture that provides for essential interactions, activities, data flows, and structural elements necessary for providing support for PBRN translational research activities. The model describes research information exchange between investigators and clusters of independent data sites supported by a contracted research director. The model was designed to support recruitment for clinical trials, collection of aggregated anonymous data, and retrieval of identifiable data from previously consented patients across hundreds of practices. CONCLUSIONS: The proposed model advances our understanding of the fundamental roles and activities of PBRNs and defines the information exchange commonly used by PBRNs to successfully engage community health care clinicians in translational research activities. By describing the network architecture in a language familiar to that used by software developers, the model provides an important foundation for the development of electronic support for essential PBRN research activities.

Deficits in retention for verbally presented medical information.

BACKGROUND: Anesthesiologists deliver large quantities of verbal information to patients during preoperative teaching. Basic principles of cognitive psychology dictate that much of this information is likely to be forgotten. Exactly how much and what type of information can be retained and recalled remains an open question. METHODS: With Institutional Review Board approval, 98 healthy, educated volunteers viewed a brief video containing a preoperative explanation of anesthetic options and instructions. Subjects were then asked to engage in free and cued recall of information from the video, and to complete a recognition task. We developed a coding scheme to objectively score the free and cued recall tasks for the quantity of information recalled relative to the quantity presented in the video. Data are presented as descriptive statistics. RESULTS: Subjects spontaneously recalled less than 25% of the information presented. Providing retrieval cues greatly enhanced recall: Subjects recalled 67%, on average, of the material queried in the cued recall task. Performance was even stronger on the multiple-choice test (83% of items correctly answered), indicating that the information was initially encoded. The category of information that was consistently least-remembered was presurgical medication instructions. CONCLUSIONS: Under realistic conditions for recall, most medical instruction given to patients will not be recalled, even if it is initially encoded. Given the limits of short-term memory, clinicians should carefully consider their patterns of information giving. Improvement of memory performance with cues for retrieval indicates that providing printed instructions for later review may be beneficial.

Psychometric properties of the Rosenberg Self-Esteem Scale: overall and across demographic groups living within the United States.

The purpose of this study was twofold: (a) to evaluate the scaling assumptions and component structure of and present normative data for the Rosenberg Self-Esteem Scale (RSES) using a sample of US adults (N = 503), both overall and across demographic subgroups and (b) to provide new data regarding the relationship between the two RSES subcomponents of self-competence (SC) and self-liking (SL), and other demographic and clinical variables. As hypothesized, all psychometric tests supported the underlying structure of the RSES. Overall RSES scores varied significantly across age, racial and ethnic, education, employment status, income, and marital status groups. Furthermore, differences between SC and SL were also found across groups differing in gender, age, employment status, and marital status groups. The implications and limitations of this study are discussed, with an emphasis on clinical relevance.

A controlled study of the effects of patient information-elicitation style on clinician information-giving.

Although effective communication improves the quality of the relationships between patients and medical clinicians, resulting in better outcomes for patients, little is known about how patients influence that communication. Using a controlled, repeated measures design we investigated the role that patient question-asking plays in shaping the communication behaviors of health care providers. Medical students participated in simulated medical consultations with confederate patients adopting different information-elicitation styles. We examined the effects of passive, neutral, and highly-assertive questioning on the quantity of information delivered. Passive patients, who asked no questions and avoided eye contact, received less information (95.4 +/- 27.4 discrete items) than neutral patients (122.6 +/- 33.0 items). Highly-assertive patients, who engaged in active question-asking, sustained eye contact and used positive body language received the most information (135.6 +/- 46.9 items). The greater quantity of information given to highly-assertive patients was not accounted for solely by answers to questions. The increased information delivery elicited by highly-assertive patients is especially important when considered in light of memory limitations.

Clinicians consistently exceed a typical person's short-term memory during preoperative teaching.

INTRODUCTION: Patient education is a critical part of preparation for surgery. Little research on provider-to-patient teaching has been conducted with systematic focus on the quantity of information provided to patients. This is important to assess because short-term memory capacity for information such as preoperative instruction is limited to roughly seven units of content. METHODS: We studied the information-giving practices of anesthesiologists and nurse practitioners during preoperative teaching by examining transcripts from 26 tape recorded preoperative evaluation appointments. We developed a novel coding system to measure: 1) quantity of information, 2) frequency of medical terminology, 3) number of patient questions, and 4) number of memory reinforcements used during the consultation. Results are reported as mean +/- sd. RESULTS: Anesthesiologists and nurse practitioners vastly exceeded patients' short-term memory capacity. Nurse practitioners gave significantly more information to patients than did physicians (112 +/- 37 vs 49 +/- 25 items per interview, P < 0.01). This higher level of information-giving was not influenced by the question-asking behaviors of the patients. Nurse practitioners and physicians used similar numbers of medical terms (4.0 +/- 2.4 vs 3.7 +/- 2.8 explained terms per interview), and memory-supporting reinforcements (2.3 +/- 3.0 vs 1.4 +/- 2.0 reinforcements per interview). DISCUSSION: Given the known limits of short-term memory, clinicians would be well advised to carefully consider their patterns of information-giving and their use of memory-reinforcing strategies for critical information.

Real-time checking of electronic anesthesia records for documentation errors and automatically text messaging clinicians improves quality of documentation.

INTRODUCTION: The quality of electronic anesthesia documentation is important for downstream communication and to demonstrate appropriate diligence to care. Documentation quality will also impact the success of reimbursement contracts that require timely and complete documentation of specific interventions. We implemented a system to improve completeness of clinical documentation and evaluated the results over time. METHODS: We used custom software to continuously scan for missing clinical documentation during anesthesia. We used patient allergies as a test case, taking advantage of a unique requirement in our system that allergies be manually entered into the electronic record. If no allergy information was entered within 15 min of the "start of anesthesia care" event, a one-time prompt was sent via pager to the person performing the anesthetic. We tabulated the daily fraction of cases missing allergy data for the 6 mo before activating the alert system. We then obtained the same data for the subsequent 9 mo. We tested for systematic performance changes using statistical process control methodologies. RESULTS: Before initiating the alert system, the fraction of charts without an allergy comment was slightly more than 30%. This decreased to about 8% after initiating the alerts, and was significantly different from baseline within 5 days. Improvement lasted for the duration of the trial. Paging was suspended on nights, weekends, and holidays, yet weekend documentation performance also improved, indicating that weekday reminders had far-reaching effects. DISCUSSION: Electronic anesthesia documentation performance can be rapidly managed and improved by using an automatic process monitoring and alerting system.

Inflammatogenic and adjuvant properties of HEMA in mice.

2-Hydroxyethylmethacrylate (HEMA), a common constituent in dental materials, is known to cause hypersensitivity reactions. While the means by which this small molecule causes adverse responses has not been ascertained, we have previously demonstrated that it binds to protein and in mice induces the production of autoantibodies to HEMA-conjugated self-protein. The present study explores the inflammatory and adjuvant properties of HEMA in response to the subcutaneous injection of HEMA and a protein. Ovalbumin (OVA) was used as a 'reporter antigen', and mouse serum albumin (MSA), conjugated in vitro with HEMA (MSA(H)) to a low degree (0.5 molecules of HEMA per molecule of MSA on average), was used to mimic a possible in vivo situation. Inflammatory responses at injection sites were scored by using an ordinal scale, and immunoglobulin (Ig)G1, IgG2a, and IgE activities to OVA or MSA were assessed by enzyme-linked immunosorbent assay (ELISA). Injections of 20 micromol HEMA induced overt inflammatory skin responses, the severity of which was influenced by the co-administered substances. A significantly higher IgG1 and IgE response to OVA was induced by the presence of HEMA. Interestingly, injections with low conjugated MSA(H) only induced the production of autoantibodies if free HEMA was included at the time of immunization. These findings suggest that HEMA is an inflammatogenic substance with adjuvant properties.