Laser Doppler Flare Imaging and Quantitative Thermal Thresholds Testing Performance in Small and Mixed Fiber Neuropathies

IntroductionSmall fiber neuropathy might be a part of typical mixed small and large fiber neuropathy, or a distinct entity, affecting exclusively small nerve fibers.ObjectivesExplore the utility of small nerve fiber testing in patients with clinical presentation suggesting small fiber neuropathy, with and without evidence for concomitant large fiber neuropathy.MethodsPatients attending the neuromuscular clinic from 2012 to 2015 with a clinical presentation suggesting small nerve fiber impairment, who had Laser Doppler flare imaging (LDI_Flare) and quantitative thermal testing (QTT) were evaluated for this study. Patients with clinical or electrophysiological evidence for concomitant large fiber neuropathy were not excluded.ResultsThe sensitivities of LDI_Flare, cooling and heat threshold testing were 64%, 36%, and 0% respectively for clinically highly suggestive small fiber neuropathy, 64%, 56%, and 19% respectively for mixed fiber neuropathy, and 86%, 79%, and 29% respectively for diabetic mixed fiber neuropathy.DiscussionLDI_Flare and cooling thresholds testing are non-invasive small nerve fiber testing modalities, with moderate performance in patients with small and mixed fiber neuropathy, and excellent performance in diabetic mixed fiber neuropathy.     

Small Sample Properties of Rank Tests for Incomplete Unbalanced Designs

A rank test is presented for analysis of incomplete unbalanced designs, i.e. for designs that may have been originally planned to be either balanced or unbalanced and where some observations may be missing at random. This test is a modification of the procedure of Benard and van El-teren (1953) based on a generalization of block weights proposed by Prentice (1979). It is compared with the tests of Haux, Schumacher, and Weckesser (1984) and Rai (1987). For incomplete or unbalanced designs with more than two treatments the quadratic forms proposed by these authors are proven to be invalid for small sample sizes, except for special cases. A necessary condition is given for test statistics to be valid also for small samples.     

No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function.     

Small Sample Comparison of Some Tests for Equality of Two Proportions

Powers of some tests of equality of two proportions are compared for small samples and approximate level .05. Numerical results indicate that the asymptotic results hold also for small and moderate sample sizes.     

Long-Term Survival of Individuals Born Small and Large for Gestational Age

Background

Little is known on long-term survival and causes of death among individuals born small or large for gestational age. This study investigates birth weight in relation to survival and causes of death over time.

Methods

A national cohort of 1.7 million live-born singletons in Denmark was followed during 1979–2011, using the Danish Civil Registration System, the Medical Birth Registry and the Cause of Death Registry. Cox proportional hazards were estimated for the impact of small (SGA) and large (LGA) gestation weight and mortality overall, by age group and birth cohort.

Results

Compared to normal weight children, SGA children were associated with increased risk of dying over time. Though most of the deaths occurred during the first year of life, the cumulative mortality risk was increased until 30 years of age. The hazard ratios [HR] for dying among SGA children ages <2 years were: 3.47 (95% CI, 3.30–3.64) and 1.06 (95% CI, 0.60–1.87) in 30 years and older. HR for dying among SGA adults (20–29 years) were: 1.20 (95% CI, 0.99–1.46) in years 1979–1982 and 1.61 (95% CI, 1.04–2.51) in years 1989–1994. The SGA born had increased risk of dying from infection, heart disease, respiratory disease, digestive disease, congenital malformation, perinatal conditions, and accidents, suicide, and homicide. Individuals born LGA were associated with decreased mortality risk, but with increased risk of dying from malignant neoplasm.

Conclusions

Survival has improved independently of birth weight the past 30 years. However, children born SGA remain at significantly increased risk of dying up till they turn 30 years of age. Individuals born LGA have lower mortality risk but only in the first two years of life.     

Locomotor Dysfunction and Pain: The Scylla and Charybdis of Fiber Sprouting After Spinal Cord Injury

Injury to the spinal cord (SCI) can produce a constellation of problems including chronic pain, autonomic dysreflexia, and motor dysfunction. Neuroplasticity in the form of fiber sprouting or the lack thereof is an important phenomenon that can contribute to the deleterious effects of SCI. Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia. At the same time, interruption of connections between supraspinal motor control centers and spinal cord output cells, due to lack of successful regenerative sprouting of injured descending fiber tracts, contributes to motor deficits. Similarities in the molecular control of axonal growth of motor and sensory fibers have made the development of cogent therapies difficult. In this study, we discuss recent findings related to the degradation of inhibitory barriers and promotion of sprouting of motor fibers as a strategy for the restoration of motor function and note that this may induce primary afferent fiber sprouting that can contribute to chronic pain. We highlight the importance of careful attentiveness to off-target molecular- and circuit-level modulation of nociceptive processing while moving forward with the development of therapies that will restore motor function after SCI.     

Performance of Encounternet Tags: Field Tests of Miniaturized Proximity Loggers for Use on Small Birds

Proximity logging is a new tool for understanding social behavior as it allows for accurate quantification of social networks. We report results from field calibration and deployment tests of miniaturized proximity tags (Encounternet), digital transceivers that log encounters between tagged individuals. We examined radio signal behavior in relation to tag attachment (tag, tag on bird, tag on saline-filled balloon) to understand how radio signal strength is affected by the tag mounting technique used for calibration tests. We investigated inter-tag and inter-receiver station variability, and in each calibration test we accounted for the effects of antennae orientation. Additionally, we used data from a live deployment on breeding barn swallows (Hirundo rustica erythrogaster) to analyze the quality of the logs, including reciprocal agreement in dyadic logs. We evaluated the impact (in terms of mass changes) of tag attachment on the birds. We were able to statistically distinguish between RSSI values associated with different close-proximity (<5m) tag-tag distances regardless of antennae orientation. Inter-tag variability was low, but we did find significant inter-receiver station variability. Reciprocal agreement of dyadic logs was high and social networks were constructed from proximity tag logs based on two different RSSI thresholds. There was no evidence of significant mass loss in the time birds were wearing tags. We conclude that proximity loggers are accurate and effective for quantifying social behavior. However, because RSSI and distance cannot be perfectly resolved, data from proximity loggers are most appropriate for comparing networks based on specific RSSI thresholds. The Encounternet system is flexible and customizable, and tags are now light enough for use on small animals (<50g).     

Evidence for Complementation of Plant Potyvirus Pathogenic Strains in Mixed Infection

Several strains of soybean mosaic virus (SMV) can be differentiated on the basis of the phenotypic response of various soybean cultivars (e.g., the soybean line Williams ‘82 is susceptible to all SMV strains, whereas the lines P. I. 96983, L78-379, and Davis are functionally immune to SMV strain G2 but susceptible to strains G7 and G7a). Inoculation of the immune lines with G2, followed 2 days later by inoculation with G7 or G7a, resulted in systemic spread of the avirulent SMV G2. Further evidence, suggests that complementation groups of SMV strains may exist.     

Evidence for the Uptake of Large Anions through Stomatal Pores

Experiments were conducted with leek (Allium porrum L.) leaves to investigate whether aqueous solutions are able to penetrate stomata. Epidermal strips were used for the determination of transport rates. Stomata were opened by fusicoccin or closed by darkness or abscisic acid. A droplet containing the anionic fluorescent dye, uranine, was placed on the physiologically outer side of the epidermis and allowed to dry. With open stomata 30 times more uranine penetrated through the epidermal strips than with closed stomata (comparison of medians). In another experiment droplets of uranine solution were placed on leaf segments and epidermal strips were removed after drying of the droplets. Penetration of uranine through stomata was detectable under the microscope both with epidermal strips from the transport experiments and with strips obtained after application on leaf segments. As maximum uptake rates occurred during the drying process, it is concluded that penetration took place via water films. These results show that the physical restrictions preventing stomatal penetration of static droplets are not decisive for drying droplets and that stomatal uptake of dissolved ionic substances occurs under natural conditions, i.e. without surfactants or applied pressure.     

Evaluation of SLS: APG Mixed Surfactant Systems as Carrier for Solid Dispersion

The present investigation aims at studying the effect of mixed surfactant system of sodium lauryl sulphate (SLS) and alkyl polyglucosides (C₁₀APG, C₁₂APG and C_12/14APG) on dissolution rate enhancement of poorly water soluble drug. Aceclofenac—a non-steroidal anti-inflammatory agent was used as a model drug as it has limited water solubility. The influence of the surfactant concentration in various blends on dissolution rate of Solid Dispersion (SD), prepared using solution method with ethanol as the solvent was studied and the advantage of mixed surfactant systems over the individual surfactants was illustrated by differences in the in-vitro dissolution profiles of SD. Physico chemical evaluation (critical micellar concentration, zeta potential and β-parameter calculations) was carried out to study the mixed surfactant systems. Solid mixtures were characterized by Infrared spectroscopy (FT-IR); X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). It was seen that the dissolution rate of aceclofenac from SD increased with the increase in the APG proportion relative to SLS with the optimum ratio of 0.2 SLS:0.8 APG showing the best effect in all cases. Results obtained from physico-chemical evaluation (the decrease in the value of critical micelle concentration and higher negative value of β-parameters) suggested the existence of synergism between surfactants blends. The observed results in the dissolution rate enhancement could be attributed to the drug—surfactant interactions as evident from FT-IR, SEM and XRD results.     

Line Transect Sampling in Small and Large Regions

Melville and Welsh (2001, Biometrics 57, 1130-1137) consider an approach to line transect sampling using a separate calibration study to estimate the detection function g. They present a simulation study contrasting their results with poor results from a traditional estimator, labeled the "Buckland" estimator and referenced to Buckland et al. (1993, Distance Sampling: Estimating Abundance of Biological populations). The poor results from the "Buckland" estimator can be explained by the following observations: (i) the estimator is designated for untruncated distance data, but was applied by Melville and Welsh to truncated distance data; (ii) distance data were not pooled across transects, contrary to standard practice; and (iii) bias of the estimator was evaluated with respect to a fixed rather than a randomized grid of transect lines. We elaborate on the points above and show that the traditional methods perform to expectation when applied correctly. We also emphasize that the estimator labeled the "Buckland" estimator by Melville and Welsh is not an estimator recommended by Buckland et al. for practical survey applications.     

Decision-Making about Healthcare Related Tests and Diagnostic Strategies: User Testing of GRADE Evidence Tables

Objective

To develop guidance on what information to include and how to present it in tables summarizing the evidence from systematic reviews of test accuracy following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Methods

To design and refine the evidence tables, we used an iterative process based on the analysis of data from four rounds of discussions, feedback and user testing. During the final round, we conducted one-on-one user testing with target end users. We presented a number of alternative formats of evidence tables to participants and obtained information about users’ understanding and preferences.

Results

More than 150 users participated in initial discussions and provided their formal and informal feedback. 20 users completed one-on-one user testing interviews. Almost all participants preferred summarizing the results of systematic reviews of test accuracy in tabular format rather than plain text. Users generally preferred less complex tables but found presenting sensitivity and specificity estimates only as too simplistic. Users found the presentation of test accuracy for several values of prevalence initially confusing but modifying table layout and adding sample clinical scenarios for each prevalence reduced this confusion. Providing information about clinical consequences of testing result was viewed as not feasible for authors of systematic reviews.

Conclusion

We present the current formats for tables presenting test accuracy following the GRADE approach. These tables can be developed using GRADEpro guidelines development tool (www.guidelinedevelopment.org or www.gradepro.org) and are being further developed into electronic interactive tables that will suit the needs of different end users. The formatting of these tables, and how they influence result interpretation and decision-making will be further evaluated in a randomized trial.     

Estimation and Tests of Mendelian Inheritance in Small Samples of Human Families

Estimation of parameters in human genetics is usually performed by Maximum Likelihood methods for large samples relying on asymptotic results. With the aim of evaluating the importance of the bias resulting from sample size, two sets of human family data have been analysed. The bias is not very important, but programs have been elaborated, giving better estimations. The tests of hypotheses from these estimations have also been considered.     

Pituitary Stalk Thickening in a Large Cohort: Toward More Accurate Predictors of Pituitary Dysfunction and Etiology

Objective: To summarize the characteristics of patients with pituitary stalk thickening, analyze the association between pituitary stalk width and hypopituitarism, and develop a diagnostic model to differentiate neoplastic and inflammatory origins.Methods: A total of 325 patients with pituitary stalk thickening in a tertiary teaching hospital between January 2012 and February 2018 were enrolled. Basic characteristics and hormonal status were evaluated. Indicators to predict etiology in patients with histologic diagnoses were analyzed.Results: Of the 325 patients, 62.5% were female. Deficiency in gonadotropin was most common, followed by corticotropin, growth hormone, and thyrotropin. The increase in pituitary stalk width was associated with a risk of central diabetes insipidus (odds ratio &lsqb;OR], 3.57; P<.001) and with a combination of central diabetes insipidus and anterior pituitary deficiency (OR, 2.28; P = .029). The cut-off pituitary stalk width of 4.75 mm had a sensitivity of 69.2% and a specificity of 71.4% for the presence of central diabetes insipidus together with anterior pituitary deficiency. Six indicators (central diabetes insipidus, pattern of pituitary stalk thickening, pituitary stalk width, neutrophilic granulocyte percentage, serum sodium level, and gender) were used to develop a model having an accuracy of 95.7% to differentiate neoplastic from inflammatory causes.Conclusion: Pituitary stalk width could indicate the presence of anterior pituitary dysfunction, especially in central diabetes insipidus patients. With the use of a diagnostic model, the neoplastic and inflammatory causes of pituitary stalk thickening could be preliminarily differentiated.Abbreviations: APD = anterior pituitary dysfunction; AUC = area under the curve; CDI = central diabetes insipidus; GH = growth hormone; MRI = magnetic resonance imaging; OR = odd ratio; PHBS = posterior hypophyseal bright spots; PST = pituitary stalk thickening; PSW = pituitary stalk width     

Sample Size Requirements for Evaluation of Bridging Evidence

This paper addresses issues concerning methodologies on the sample size required for statistical evaluation of bridging evidence for a registration of pharmaceutical products in a new region. The bridging data can be either in the Complete Clinical Data Package (CCDP) generated during clinical drug development for submission to the original region or from a bridging study conducted in the new region after the pharmaceutical product was approved in the original region. When the data are in the CCDP, the randomized parallel dose‐response design stratified to the ethnic factors and region will generate internally valid data for evaluating similarity concurrently between the regions for assessment of the ability of extrapolation to the new region. Formula for sample size under this design is derived. The required sample size for evaluation of similarity between the regions can be at least four times as large as that needed for evaluation of treatment effects only. For a bridging study conducted in the new region in which the data of the foreign and new regions are not generated concurrently, a hierarchical model approach to incorporating the foreign bridging information into the data generated by the bridging study is suggested. The sample size required is evaluated. In general, the required sample size for the bridging trials in the new region is inversely proportional to equivalence limits, variability of primary endpoints, and the number of patients of the trials conducted in the original region.