Progressive decrease of heart period variability entropy-based complexity during graded head-up tilt.

Complexity (or its opposite, regularity) of heart period variability has been related to age and disease but never linked to a progressive shift of the sympathovagal balance. We compare several well established estimates of complexity of heart period variability based on entropy rates [i.e., approximate entropy (ApEn), sample entropy (SampEn), and correct conditional entropy (CCE)] during an experimental protocol known to produce a gradual shift of the sympathovagal balance toward sympathetic activation and vagal withdrawal (i.e., the graded head-up tilt test). Complexity analysis was carried out in 17 healthy subjects over short heart period variability series ( approximately 250 cardiac beats) derived from ECG recordings during head-up tilt with table inclination randomly chosen inside the set {0, 15, 30, 45, 60, 75, 90}. We found that 1) ApEn does not change significantly during the protocol; 2) all indices measuring complexity based on entropy rates, including ad hoc corrections of the bias arising from their evaluation over short data sequences (i.e., corrected ApEn, SampEn, CCE), evidence a progressive decrease of complexity as a function of the tilt table inclination, thus indicating that complexity is under control of the autonomic nervous system; 3) corrected ApEn, SampEn, and CCE provide global indices that can be helpful to monitor sympathovagal balance.     

Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome

Objective

To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS).

Methods

Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function.

Results

Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction.

Conclusions and Relevance

POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder.     

Usefulness of tilt testing in children with syncope: a survey of pediatric electrophysiologists

The role of tilt table testing as a diagnostic modality in children with unexplained syncope is unclear. We sent a questionnaire to members of the Pediatric and Congenital Electrophysiology Society to assess the current practice pattern. Of the 186 members, 97 (52%) replied. Twenty four percent of the pediatric electrophysiologists have completely stopped doing tilt table tests and of those performing the tests, a majority (76%) did < 10 tests/yr (median=3 tilts/yr, range 0-100/yr). Of those performing the test, 95% rarely or never accepted direct referrals from the general practioners and 62% felt that the frequency of tilt table tests being performed had decreased since they had started practicing. The median usefulness of the test was rated at 3 (range 1-9) on a scale of 1 to 10 with 10 being very useful. A majority (68%) felt they rarely or never altered treatment based on the results of the tilt test. Wide variability was noted in the test protocol including the tilt angle, tilt duration, use of pharmacologic agents and the duration of fasting prior to the test. We therefore conclude that there is significant lack of standardization in tilt table tests performed in children. Tilt table testing, as perceived by pediatric electrophysiologists, is of limited utility and progressively less used in children with syncope.     

Randomized Prospective Comparison of Two Protocols for Head-up Tilt Testing in Patients with Normal Heart and Recurrent Unexplained Syncope

BackgroundThis randomized study was aimed to compare the diagnostic value of two head-up tilt testing protocols using sublingual nitroglycerin for provocation in patients with recurrent unexplained syncope and normal heart.MethodsThe patients with normal findings in physical examination, electrocardiography and echocardiography were randomly submitted to one of upright tilt test protocols. The only difference between two protocols was that nitroglycerin was administered after a five minute resting phase in supine position during protocol B. We also considered eighty normal persons as the control group.ResultsOut of 290 patients that underwent tilt testing, 132 patients were in group A versus 158 patients in group B. Both groups had an identical distribution of clinical characteristics. Tilt test was positive in 79 patients in group A (25 in passive phase, 54 in active phase) versus 96 patients in group B (43 in passive phase, 53 in active phase). There was no significant difference between results in two groups (P value = 0.127). Forty cases were tested with protocol A and forty underwent tilt testing with protocol B. Tilt test was positive in 4 cases with protocol A versus 3 cases in protocol B. The positive rates of tilt testing with protocol A was 60% while it was 61% in protocol B. The specificity of testing with protocol A was 90% and it was 92.5% in protocol B.ConclusionsAccording to our data, adding a period of rest and returning to supine position before nitroglycerin administration had no additional diagnostic yield.     

Modified calibration protocol evaluated in a model-based testing of SBR flexibility

The purpose of this paper is to refine the BIOMATH calibration protocol for SBR systems, in particular to develop a pragmatic calibration protocol that takes advantage of SBR information-rich data, defines a simulation strategy to obtain proper initial conditions for model calibration and provides statistical evaluation of the calibration outcome. The updated calibration protocol is then evaluated on a case study to obtain a thoroughly validated model for testing the flexibility of an N-removing SBR to adapt the operating conditions to the changing influent wastewater load. The performance of reference operation using fixed phase length and dissolved oxygen set points and two real-time control strategies is compared to find optimal operation under dynamic conditions. The results show that a validated model of high quality is obtained using the updated protocol and that the optimization of the system’s performance can be achieved in different manners by implementing the proposed control strategies.     

Validation testing to determine the sensitivity of lateral flow testing for asymptomatic SARS-CoV-2 detection in low prevalence settings: Testing frequency and public health messaging is key

Lateral flow devices (LFDs) are quickly being implemented for use in large-scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city-wide screening in the city of Liverpool and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Here, we present data on the performance of LFDs to test almost 8,000 students at the University of Birmingham between December 2 and December 9, 2020. The performance is validated against almost 800 samples using PCR performed in the University Pillar 2 testing lab and theoretically validated on thousands of Pillar 2 PCR testing results performed on low-prevalence care home testing samples. Our data show that LFDs do not detect infections presenting with PCR Ct values over 29 to 30 as determined using the Thermo Fisher TaqPath asssay. This may be of particular importance in detecting individuals that are either at the early, or late stages of infection, and reinforces the need for frequent, recurrent testing.

Antigen-detecting lateral flow tests are faster than PCR tests in detecting SARS-CoV-2 infection and are being implemented for use in large-scale population surveillance in the UK. An evaluation of the performance of the lateral flow devices, validated using PCR, concludes that lateral flow devices do not detect infections presenting with higher PCR Ct values, reinforcing the need for frequent, recurrent testing.     

Cardiovascular Autonomic Regulation,ETCO2 and the Heart Rate Response to the Tilt Table Test in Patients with Orthostatic Intolerance

Chronic orthostatic intolerance (COI) is defined by changes in heart rate (HR), blood pressure (BP), respiration, symptoms of cerebral hypoperfusion and sympathetic overactivation. Postural tachycardia syndrome (POTS) is the most common form of COI in young adults and is defined by an orthostatic increase in heart rate (HR) of?≥?30 bpm in the absence of orthostatic hypotension. However, some patients referred for evaluation of COI symptoms do not meet the orthostatic HR response criterion of POTS despite debilitating symptoms. Such patients are ill defined, posing diagnostic and therapeutic challenges. This study explored the relationship among cardiovascular autonomic control, the orthostatic HR response, EtCO₂ and the severity of orthostatic symptoms and fatigue in patients referred for evaluation of COI. Patients (N?=?108) performed standardized testing protocol of the Autonomic Reflex Screen and completed the Composite Autonomic Symptom Score (COMPASS-31) and the Fatigue Severity Scale (FSS). Greater severity of COI was associated with younger age, larger phase IV amplitude in the Valsalva maneuver and lower adrenal baroreflex sensitivity. Greater fatigue severity was associated with a larger reduction in ETCO₂ during 10 min of head-up tilt (HUT) and reduced low-frequency (LF) power of heart rate variability. This study suggests that hemodynamic changes associated with the baroreflex response and changes in EtCO₂ show a stronger association with the severity of orthostatic symptoms and fatigue than the overall orthostatic HR response in patients with COI.

     

Reproducibility analysis of upper limbs reachable workspace,and effects of acquisition protocol,sex and hand dominancy

None of the physical testing, nor the goniometers currently used to assess upper limb function have a high validity, sensitivity or reliability. The reachable workspace, i.e. the area covered by the farthest points a subject can reach by hand without moving his/her body, shows promise but has yet to be validated, particularly in terms of reproducibility. Therefore, this study aims to evaluate the reproducibility of the reachable workspace over a period of several weeks, and to assess the effects of two proposed acquisition protocols, as well as those of gender, and hand dominancy. Shoulder movements were recorded using a motion capture system on 10 female and 10 male healthy subjects during a random protocol, i.e. simply asking them to achieve the farthest points they could reach with their hands, and during a standardized protocol, i.e. asking them to perform predefined shoulder elevations while keeping their trunk and elbow straight. The standardized protocol was repeated 7 weeks later. Repeated measures showed no significant difference, good to excellent intraclass correlation coefficients (0.46–0.81) and small bias (0.0–1.2%). The random protocol provided significantly lower and more scattered values for the reachable workspace (80.0 ± 22.6% vs. 91.0 ± 8.1%, p = .004), whereas gender and hand-dominancy had no effect. This study showed that the reachable workspace was highly reliable over a period of 7 weeks and that both upper limbs provided similar results. It could be used to monitor various pathologies of the upper limbs and to assess treatment efficiency, using a subject’s healthy limb as reference.     

Noninvasive approach for study of human reaction and transferring velocity of nervous system by using a new instrumentation devised for concurrent microscopic observation and analysis of sweat secretion on human body under 1G and microgravity

Human sweating is generally caused by thermal and mental stimuli. The former role is well known as a response for thermo regulation. The insensible perspiration may be generally controlled by the autonomic nervous system, and the responses due to mental and/or emotional stress by the sympathetic nervous system. As human sweating is directly concerned with some nervous systems, sweating may be a good indicator for the body reactions of feeling, surprise, emotional stress and etc. The measuring of sweat secretion and microscopic observation of active sweat glands can be presented the direct information of working of sympathetic nervous system and sudomotor. In the present report, we devised an instrumentation for the estimation of time lag of sweating [correction of seating] after physical stimuli. Variation of gravity during parabolic flights is a kind of physical stimulus. Iwase et al reported the changes of sympathetic outflow to muscle in humans during short periods of microgravity. We studied also the variation of number of active sweat glands under this condition for the evaluation of human sympathetic nervous system.     

Considerations in the U.S. Environmental Protection Agency's testing approach for mutagenicity.

OPP: This paper provides the rationale and support for the decisions the OPP will make in requiring and reviewing mutagenicity information. The regulatory requirement for mutagenicity testing to support a pesticide registration is found in the 40 CFR Part 158. The guidance as to the specific mutagenicity testing to be performed is found in the OPP's Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals (referred to as the Subdivision F guideline). A revised Subdivision F guideline has been presented that becomes the current guidance for submitters of mutagenicity data to the OPP. The decision to revise the guideline was the result of close examination of the version published in 1982 and the desire to update the guidance based on developments since then and current state-of-the-science. After undergoing Agency and public scrutiny, the revised guideline is to be published in 1991. The revised guideline consists of an initial battery of tests (the Salmonella assay, an in vitro mammalian gene mutation assay and an in vivo cytogenetics assay which may be either a bone marrow assay for chromosomal aberrations or for micronuclei formation) that should provide an adequate initial assessment of the potential mutagenicity of a chemical. Follow-up testing to clarify results from the initial testing may be necessary. After this information as well as all other relevant information is obtained, a weight-of-evidence decision will be made about the possible mutagenicity concern a chemical may present. Testing to pursue qualitative and/or quantitative evidence for assessing heritable risk in relation to human beings will then be considered if a mutagenicity concern exists. This testing may range from tests for evidence of gonadal exposure to dominant lethal testing to quantitative tests such as the specific locus and heritable translocation assays. The mutagenicity assessment will be performed in accordance with the Agency's Mutagenicity Risk Assessment Guidelines. The mutagenicity data would also be used in the weight-of-evidence consideration for the potential carcinogenicity of a chemical in accordance with the Agency's Carcinogen Risk Assessment Guidelines. In instances where there are triggers for carcinogenicity testing, mutagenicity data may be used as one of the triggers after a consideration of available information. It is felt that the revised Subdivision F guideline will provide appropriate, and more specific, guidance concerning the OPP approach to mutagenicity testing for the registration of a pesticide. It also provides a clearer understanding of how the OPP will proceed with its evaluation and decision making concerning the potential heritable effects of a test chemical.(ABSTRACT TRUNCATED AT 400 WORDS)     

Some simple tests for spatial effects around putative sources of health risk

The need for tests dealing with different features of small area health data is less important with the increase in computation speed of computers and the access to MCMC methods. However there are many situations where exploratory testing could be useful and where MCMC methods are not readily usable or available. In this paper, a number of simple tests are derived for the logistic model for case events. This model assumes that a control disease is available and that the events have a binary label relating to case or control state. The tests are derived from likelihood considerations and Monte Carlo critical regions are examined. A simulated evaluation of the tests is presented in terms of Monte Carlo power. A data example is considered.     

Tilt determination in MEMS inertial vestibular prosthesis

BACKGROUND: There is a clear need for a prosthesis that improves postural stability in the balance impaired. Such a device would be used as a temporary aid during recovery from ablative inner-ear surgery, a postural monitor during rehabilitation (for example, hip surgery), and as a permanent prosthesis for those elderly prone to falls. METHOD OF APPROACH: Recently developed, small instruments have enabled wearable prostheses to augment or replace vestibular functions. The current prosthesis communicates by vibrators mounted on the subject's trunk. In this paper we emphasize the unique algorithms that enable tilt indication with modestly performing micromachined gyroscopes and accelerometers. RESULTS: For large angles and multiple axes, gyro drift and unwanted lateral accelerations are successfully rejected. In single-axis tests, the most dramatic results were obtained in standard operating tests where balance-impaired subjects were deprived of vision and proprioceptive inputs. Balance-impaired subjects who fell (into safety restraints) when not aided were able to stand with the prosthesis. Initial multiaxis tests with healthy subjects have shown that sway is reduced in both forward-back and sideward directions. CONCLUSIONS: Positive results in initial testing and a sound theoretical basis for the hardware warrant continued development and testing, which is being conducted at three sites.     

A Bond Graph Model of the Cardiovascular System

The study of the autonomic nervous system (ANS) function has shown to provide useful indicators for risk stratification and early detection on a variety of cardiovascular pathologies. However, data gathered during different tests of the ANS are difficult to analyse, mainly due to the complex mechanisms involved in the autonomic regulation of the cardiovascular system (CVS). Although model-based analysis of ANS data has been already proposed as a way to cope with this complexity, only a few models coupling the main elements involved have been presented in the literature. In this paper, a new model of the CVS, representing the ventricles, the circulatory system and the regulation of the CVS activity by the ANS, is presented. The models of the vascular system and the ventricular activity have been developed using the Bond Graph formalism, as it proposes a unified representation for all energetic domains, facilitating the integration of mechanic and hydraulic phenomena. In order to take into account the electro-mechanical behaviour of both ventricles, an electrophysiologic model of the cardiac action potential, represented by a set of ordinary differential equations, has been integrated. The short-term ANS regulation of heart rate, cardiac contractility and peripheral vasoconstriction is represented by means of continuous transfer functions. These models, represented in different continuous formalisms, are coupled by using a multi-formalism simulation library. Results are presented for two different autonomic tests, namely the Tilt Test and the Valsalva Manoeuvre, by comparing real and simulated signals.     

A protocol for conducting 7-day daily renewal tests with Lemna gibba

Lemna gibba (a duckweed) is a freshwater macrophyte commonly used in toxicity testing, and Lemna spp are currently the only aquatic higher plants required for evaluation of pesticides under the pesticide registration guidelines of the EPA. The methods currently available for toxicity testing by various organizations and agencies, including ASTM, OECD, EPA and Environment Canada, are largely static or semistatic tests with unspecified renewal intervals (OECD) and may not provide a consistent means of exposure owing to short toxicant half-life in aquatic media, uptake of chemical by plants and evaporation of nutrient media. The procedure outlined here details a simple and efficient 7-day daily static renewal procedure for conducting toxicity tests with L. gibba, the appropriate end points to assess, the statistical criteria necessary for analyzing the toxicity data, as well as the steps required to culture and maintain L. gibba. This protocol is based on a modified version of a widely accepted static method.     

Application of dynamic point process models to cardiovascular control

The development of statistical models that accurately describe the stochastic structure of biological signals is a fast growing area in quantitative research. In developing a novel statistical paradigm based on Bayes' theorem applied to point processes, we are focusing our recent research on characterizing the physiological mechanisms involved in cardiovascular control. Results from a tilt table study point at our statistical framework as a valid model for the heart beat, as generated from complex mechanisms underlying cardiovascular control. The point process analysis provides new quantitative indices that could have important implications for research studies of cardiovascular and autonomic regulation and for monitoring of heart rate and heart rate variability measures in clinical settings.     

A simplified model to predict stress fracture in young elite combat recruits

The purpose of the study was to develop a simple prediction model for stress fractures (SFs) in young male recruits to identify risk factors for SF. Data were collected from 57 young (18.5 ± 0.5 years) male athletes before elite combat basic training (BT). Measurements included anthropometric variables, blood samples, fitness tests, bone quality (peripheral quantitative computed tomography [pQCT]), psychological assessment, nutritional habits, and history of physical activity. A medical evaluation was done periodically. The SFs were clinically diagnosed during the 1-year training and thereafter confirmed by bone scintigraphy. Three "simple to monitor" variables were found to be significantly (p < 0.05) related to SF occurrence during basic and advanced training: aerobic training frequency, aerobic training duration, and waist circumference. From these 3 variables, a new model was constructed that successfully predicted 85% of the soldiers with (n = 23) and without (n = 34) SF as follows:(Equation is included in full-text article.)where PSF is the stress fracture prediction according to the Log Odds (SF), Odds(SF) is the ratio between the probability of SF existence and nonexistence, ATn is the aerobic training (times per week), ATt is the aerobic training duration (minutes per week), and waist is the circumference (centimeters). This model was validated on a different database taken from another 59 elite combat recruits before BT and successfully predicted 76.5% of the soldiers with SF (n = 22) and without SF (n = 37). A young male recruit for elite combat unit is at a greater risk of developing SF if, before entering BT, he trained aerobically <2 times per week with each training >40 minutes and has a waist circumference of <75 cm. However, further evaluation is required for different combat recruits, ages, and training programs to validate these results.     

Increased power of microarray analysis by use of an algorithm based on a multivariate procedure

MOTIVATION: The power of microarray analyses to detect differential gene expression strongly depends on the statistical and bioinformatical approaches used for data analysis. Moreover, the simultaneous testing of tens of thousands of genes for differential expression raises the 'multiple testing problem', increasing the probability of obtaining false positive test results. To achieve more reliable results, it is, therefore, necessary to apply adjustment procedures to restrict the family-wise type I error rate (FWE) or the false discovery rate. However, for the biologist the statistical power of such procedures often remains abstract, unless validated by an alternative experimental approach. RESULTS: In the present study, we discuss a multiplicity adjustment procedure applied to classical univariate as well as to recently proposed multivariate gene-expression scores. All procedures strictly control the FWE. We demonstrate that the use of multivariate scores leads to a more efficient identification of differentially expressed genes than the widely used MAS5 approach provided by the Affymetrix software tools (Affymetrix Microarray Suite 5 or GeneChip Operating Software). The practical importance of this finding is successfully validated using real time quantitative PCR and data from spike-in experiments. AVAILABILITY: The R-code of the statistical routines can be obtained from the corresponding author. CONTACT: Schuster@imise.uni-leipzig.de     

Process validation and clinical evaluation of a protocol to generate gene-modified T lymphocytes for imunogene therapy for metastatic renal cell carcinoma: GMP-controlled transduction and expansion of patient's T lymphocytes using a carboxy anhydrase IX-specific scFv transgene

BACKGROUND: Adoptive transfer of autologous T cells that are gene-transduced to express Ag-specific receptors represents an experimental strategy to provide tumor-specific immunity to cancer patients. We studied this concept in patients with metastatic renal cell cancer (RCC) using retroviral transduction of T cells with a single-chain Ab-G250 chimeric receptor [scFv(G250)]. We describe the validation of our clinical protocol for gene transduction and expansion of human T lymphocytes. METHODS: A batch of scFv(G250) transgene-containing retrovirus was produced under conditions of good manufacturing practice (GMP). In addition to quality control and safety testing of the virus batch, extensive potency testing was performed, i.e. assessment of its functional transduction efficiency in primary human T cells. Subsequently, the clinical gene transduction and cell-expansion protocol was subjected to a series of process validations and a clinical evaluation using T cells obtained from healthy donors and three RCC patients. RESULTS: The clinical batch of scFv(G250) transgene-containing retrovirus met the quality and safety control criteria. Small-scale transductions yielded 62-92% scFv(G250)+ T cells and, at a clinical scale, 50-84% transduction efficiencies were obtained. Patient and healthy donor T cells showed similar expansion potencies, and also yielded similar levels of scFv(G250)-mediated immune functions, i.e. specific cytolysis of G250-ligand expressing RCC cells and production of IFN-gamma upon stimulation with such cells. All T cell cultures were free of replication competent retroviruses. DISCUSSION: We have shown that the validated batch of scFv(G250) transgene-containing retrovirus in combination with our GMP T-cell transduction and expansion protocol successfully generates clinically relevant numbers of functional scFv(G250) gene-modified T cells for patient treatment.