Automated detection of auditory response: applying sequential detection strategies with constant significance level to magnitude-squared coherence

Objective: The detection of the auditory steady-state responses is usually performed by an appropriate objective response detector applied to stimulus-related epochs of the raw electroencephalogram (EEG). In order to improve the detection time, sequential detection strategies are usually used. These multiple tests strategies increase the probability of mistakenly detecting a response. The aim of this study was to develop strategies to determine the critical values for the sequential detection strategies based on constant significance level tests.

Design: Extensive Monte Carlo simulations were used to test these strategies for the magnitude-squared coherence (MSC) detector. The performances of these strategies were compared with previous works found in the literature.

Study sample: All strategies were applied to synthetic and real EEG datasets.

Results: The strategies ensure the desired significance level at the end of the sequential detection strategy. The simulated results are in accordance with the real data results.

Conclusions: For the MSC detector, where the critical value depends on the number of epochs, the proposed sequential detection strategies obtain better performance regarding test time and detection rate, but worse overall detection rate compared to applying a test only once.     

Identification and Characterization of Protective T Cells in hsp65 DNA-Vaccinated and Mycobacterium tuberculosis-Infected Mice

Immunization by intramuscular injection of plasmid DNA expressing mycobacterial 65-kDa heat shock protein (hsp65) protects mice against challenge with virulent Mycobacterium tuberculosis H37Rv. During infection or after immunization, CD4⁺/CD8⁻ and CD8⁺/CD4⁻ hsp65-reactive T cells increased equally in spleens. During infection, the majority of these cells were weakly CD44 positive (CD44^lo) and produced interleukin 4 (IL-4) whereas after immunization the majority were highly CD44 positive (CD44^hi) and produced gamma interferon (IFN-γ). In adoptive transfer of protection to naive mice, the total CD8⁺/CD4⁻ cell population purified from spleens of immunized mice was more protective than that from infected mice. When the cells were separated into CD4⁺/CD8⁻ and CD8⁺/CD4⁻ types and then into CD44^hi and CD44^lo types, CD44^lo cells were essentially unable to transfer protection, the most protective CD44^hi cells were CD8⁺/CD4⁻, and those from immunized mice were much more protective than those from infected mice. Thus, whereas the CD44^lo IL-4-producing phenotype prevailed during infection, protection was associated with the CD8⁺/CD44^hi IFN-γ-producing phenotype that predominated after immunization. This conclusion was confirmed and extended by analysis of 16 hsp65-reactive T-cell clones from infected mice and 16 from immunized mice; the most protective clones, in addition, displayed antigen-specific cytotoxicity.

Tuberculosis is a classic example of an infectious disease in which the disease process is caused by the immune response directed at the infectious agent. The bacteria and their products are, in themselves, not very toxic, and the extensive tissue damage, wasting, and death of the diseased individual largely constitute the immunopathology of the cell-mediated immune response. Nevertheless, it is also the cell-mediated response that protects against the disease by arresting, killing, and removing the multiplying bacteria. Whether this protective effect occurs early or late, and temporarily or permanently, determines disease progression by regulating the supply of antigen that drives the immunopathology. An important question that arises from this balance between the protective and harmful effects of the immune response is whether the antigens and immune responses that protect can be distinguished from those that harm. If so, they might be separately manipulated in new vaccines or in immunotherapy of the disease.The T lymphocytes that regulate cellular immunity can be divided not only into the CD4⁺/CD8⁻ and CD8⁺/CD4⁻ phenotypes that primarily recognize exogenous and endogenous antigens, respectively (8), or into activated (memory) and nonactivated cells according to highly CD44-positive (CD44^hi) and weakly CD44-positive (CD44^lo) expression (5) but also into two major functionally distinct types on the basis of the profiles of cytokines that they produce. Type 1 cells (Th1 or TC1) favor development of cellular immunity (typified by gamma interferon [IFN-γ], interleukin 2 [IL-2], and IL-12 production). Type 2 cells (Th2 or TC2) favor development of antibody response (typified by IL-4, IL-6, and IL-10 production). Each type promotes differentiation of precursors into the same phenotype and inhibits development of the other phenotype (2, 27), and in consequence the type of response initiated in a microenvironment tends to be self-sustaining. IFN-γ is essential for the development of protective immunity (38) and is probably the most important factor that activates macrophages for antimycobacterial action, at least in mice (13, 34, 35). Therefore protection would be expected to be associated with an immune response in which the type 1 cytokine profile predominated. We have found that immunization procedures that present mycobacterial hsp65 to the immune system as an endogenous antigen generate strong protection against tuberculosis challenge and that this is associated with the presence of a splenic T-cell population in which CD8⁺/CD44^hi IFN-γ-producing cytotoxic cells are prominent (28a). However, cells with a type 2 profile are also present in substantial numbers following infection (22, 39) or Mycobacterium bovis BCG vaccination (24), and the question of what contribution the other phenotypes make to protection arises. To help to answer this question we have used here the combined approaches of comparing the frequency of the different phenotypes in spleens of hsp65 DNA-vaccinated and Mycobacterium tuberculosis-infected mice and testing the different phenotypes, either as purified subpopulations or as T-cell clones, in adoptive transfer of protection.     

Enantioselective analysis of the metabolites of hydroxychloroquine and application to an in vitro metabolic study

A one-step chiral method for the quantification of the enantiomers of two hydroxychloroquine (HCQ) metabolites, desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) by HPLC is described, in addition to its application to the in vitro study of HCQ metabolism in rat liver microsomes. Liquid-liquid extraction was used to extract the enantiomers from microsome samples and the separation was performed on a Chiralpak AD-RH column protected with an RP-8 guard column using hexane:isopropanol (92:8, v/v) plus 0.1% diethylamine as the mobile phase, at a flow rate of 1.0 mL min(-1). The detection was carried out at 343 nm. The method proved to be linear in the range of 50-5000 ng mL(-1) for DCQ enantiomers and 125-2500ngmL(-1) for DHCQ enantiomers, with a quantification limit of 50 and 125 ng mL(-1), respectively. Precision and accuracy, demonstrated by within-day and between-day assays, were lower than 15%. The metabolic study demonstrated that metabolism is stereoselective for HCQ. The major metabolites formed in the incubation of racemic HCQ were (-)-(R)-DCQ and (-)-(R)-DHCQ with R/S ratios of 2.2 and 3.3, respectively.     

The Heartsink Patient: A Preliminary Study

Eight GPs identified 78 heartsink patients; in an open-endedinterview they were asked to explain why they regarded themin this way. A GP's definition of a heartsink patient was influencedby GP sex, practice location, and time of surgery, althoughthe number of participating GPs was too low to make any definiteassertions. Practitioners' anticipations of heartsink consultationswere generally over-exaggerated, with most of the encountersgoing better than expected. GPs expressed the view that thesepatients raised serious professional issues for them, whilstthere was also a dislike for these patients' personalities andbehaviour. Two levels of the heartsink state are hypothesized:one, a state of inertia, is when the heartsink patient has beena chronic high user of the primary health care system, and aGP has exhausted all avenues. The other is an acute situationwith those heartsink patients who have been low users of thesystem in the past. Recent, new events in these patients' liveshave raised an issue that is just as much to do with patientand doctor reaction to these events, as it is about findinga diagnosis or solution to the problem. We present the results and hypotheses to provoke further discussionand research.     

The Contingency of Contingent Valuation How Much Are People Willing to Pay against Alzheimer's Disease?

The present work focuses on the choice of the elicitation technique within a contingent valuation (CV) framework. We simultaneously apply three different elicitation techniques to elicit willingness-to-pay (WTP) values for three programs against Alzheimer's disease. First, the dichotomous choice approach is used, which is the standard procedure. However, giving respondents only a yes/no response alternative seems to result in overestimated WTP values. Therefore, we secondly apply the dissonance-minimizing format which screens respondents for their preferences and thus avoids possible yea-saying and protest answers against the payment vehicle. The third format, a modified version of the payment card, allows respondents to express a level of voting certainty and to make less of a commitment. With our findings we show that a well-designed CV method is a suitable instrument for helping decision makers in the health care sector and that the Swiss population favors highly a program which improves the situation of informal caregivers.     

Serum CA 19-9 in the postsurgical follow-up of patients with pancreatic cancer

In the last few years serum CA 19-9 has been shown to be a highly sensitive marker of pancreatic adenocarcinoma. This study assesses the value of serum CA 19-9 assay in the postsurgical follow-up of patients undergoing pancreatic cancer resection. In 14 patients with cancer in the head of the pancreas and abnormal preoperative serum CA 19-9 values (greater than 40 U/ml), a pancreatoduodenectomy was performed. In all patients the CA 19-9 antigen was immunohistochemically demonstrated on the removed tumoral tissue. Postoperative serum CA 19-9 concentrations were serially measured 15 days after surgery and then every other month. Serum CA 19-9 scores returned to the normal range only in 7 (50%) of the resected patients. All patients with a normal postoperative value and none of those with a persistently elevated one survived longer than 7 months. Early postoperative serum CA 19-9 assay was superior to perioperative staging of the tumor as a prognostic index. All of the seven patients with postoperative normal values exhibited a subsequent increase within 16 months. In all cases the elevation of CA 19-9 occurred at least 2 months before ultrasound (US) could detect local recurrences of hepatic metastasis. Our data indicate that a normal early postoperative CA 19-9 score is a relatively favourable prognostic index in patients who undergo radical surgery for pancreatic cancer and that the CA 19-9 test can be used, as an early marker of recurrence, in monitoring these patients.     

Using hierarchical clustering methods to classify motor activities of COPD patients from wearable sensor data

Background

Advances in miniature sensor technology have led to the development of wearable systems that allow one to monitor motor activities in the field. A variety of classifiers have been proposed in the past, but little has been done toward developing systematic approaches to assess the feasibility of discriminating the motor tasks of interest and to guide the choice of the classifier architecture.

Methods

A technique is introduced to address this problem according to a hierarchical framework and its use is demonstrated for the application of detecting motor activities in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation. Accelerometers were used to collect data for 10 different classes of activity. Features were extracted to capture essential properties of the data set and reduce the dimensionality of the problem at hand. Cluster measures were utilized to find natural groupings in the data set and then construct a hierarchy of the relationships between clusters to guide the process of merging clusters that are too similar to distinguish reliably. It provides a means to assess whether the benefits of merging for performance of a classifier outweigh the loss of resolution incurred through merging.

Results

Analysis of the COPD data set demonstrated that motor tasks related to ambulation can be reliably discriminated from tasks performed in a seated position with the legs in motion or stationary using two features derived from one accelerometer. Classifying motor tasks within the category of activities related to ambulation requires more advanced techniques. While in certain cases all the tasks could be accurately classified, in others merging clusters associated with different motor tasks was necessary. When merging clusters, it was found that the proposed method could lead to more than 12% improvement in classifier accuracy while retaining resolution of 4 tasks.

Conclusion

Hierarchical clustering methods are relevant to developing classifiers of motor activities from data recorded using wearable systems. They allow users to assess feasibility of a classification problem and choose architectures that maximize accuracy. By relying on this approach, the clinical importance of discriminating motor tasks can be easily taken into consideration while designing the classifier.