Non-diseased Subjects Research Articles

Morphometric Assessment of the Ciliary Body in Patients With Marfan Syndrome and Ectopia Lentis: A Quantitative Study Using Ultrasound Biomicroscopy

To explore the biometric characteristics of the ciliary body in patients with Marfan syndrome (MFS) and ectopia lentis (EL). Cross-sectional study. Seventy-two consecutive patients with MFS and EL and 72 nondiseased control subjects were recruited. Ciliary body biometric parameters such as ciliary muscle cross-sectional area at 2000 µm from the scleral spur (CMA2000), ciliary muscle thickness at 1000 µm from the scleral spur (CMT1000), and maximum ciliary body thickness (CBTmax) were measured from multiple directions with ultrasound biomicroscopy (UBM). The relationship between ciliary body parameters and other ocular characteristics was also evaluated. Average CMA2000, CMT1000, and CBTmax were 0.692 ± 0.015 mm2, 0.405 ± 0.010 mm, and 0.855 ± 0.023 mm in eyes of patients with MFS, respectively, and were significantly smaller than these values in control subjects (all P < .001). The prevalence of ciliary body thinning was 22.2% in the MFS group vs 0 in the control group (P < .001); eyes with more severe EL had smaller CMA2000 (P=.050), thinner CMT1000 (P=.022), and shorter CBTmax (P=.015). Patients with microspherophakia (MSP) had even smaller CMA2000 (P=.033) and CMT1000 (P=.044) than those without MSP. The most common subluxation direction was in the superonasal quadrant (n=25; 39.7%), which probably correlates with the thinnest CMT1000 in the inferotemporal quadrant (P=.005). Patients with MFS and EL had thinner ciliary muscles, shorter ciliary processes, and a higher prevalence of ciliary body thinning, especially those with MSP. Both the extent and direction of subluxation were associated with ciliary body biometry.</ABSTRACT>.

Upregulation of endocytic protein expression in the Alzheimer’s disease male human brain

Amyloid-beta (Aβ) is produced from amyloid precursor protein (APP) primarily after APP is internalised by endocytosis and clathrin-mediated endocytic processes are altered in Alzheimer’s disease (AD). There is also evidence that cholesterol and flotillin affect APP endocytosis. We hypothesised that endocytic protein expression would be altered in the brains of people with AD compared to non-diseased subjects which could be linked to increased Aβ generation. We compared protein expression in frontal cortex samples from men with AD compared to age-matched, non-diseased controls. Soluble and insoluble Aβ40 and Aβ42, the soluble Aβ42/Aβ40 ratio, βCTF, BACE1, presenilin-1 and the ratio of phosphorylated:total GSK3β were significantly increased while the insoluble Aβ42:Aβ40 ratio was significantly decreased in AD brains. Total and phosphorylated tau were markedly increased in AD brains. Significant increases in clathrin, AP2, PICALM isoform 4, Rab-5 and caveolin-1 and 2 were seen in AD brains but BIN1 was decreased. However, using immunohistochemistry, caveolin-1 and 2 were decreased. The results obtained here suggest an overall increase in endocytosis in the AD brain, explaining, at least in part, the increased production of Aβ during AD.

The clinical meaning of the area under a receiver operating characteristic curve for the evaluation of the performance of disease markers.

The area under a receiver operating characteristic (ROC) curve (AUC) is a popular measure of pure diagnostic accuracy that is independent from the proportion of diseased subjects in the analysed sample. However, its actual usefulness in the clinical context has been questioned, because it does not seem to be directly related to the actual performance of a diagnostic marker in identifying diseased and non-diseased subjects in real clinical settings. This study evaluates the relationship between the AUC and the proportion of correct classifications (global diagnostic accuracy, GDA) in relation to the shape of the corresponding ROC curves. We demonstrate that AUC represents an upward-biased measure of GDA at an optimal accuracy cut-off for balanced groups. The magnitude of bias depends on the shape of the ROC plot and on the proportion of diseased and non-diseased subjects. In proper curves, the bias is independent from the diseased/non-diseased ratio and can be easily estimated and removed. Moreover, a comparison between 2 partial AUCs can be replaced by a more powerful test for the corresponding whole AUCs. Applications to 3 real datasets are provided: a marker for a hormone deficit in children, 2 tumour markers for malignant mesothelioma, and 2 gene expression profiles in ovarian cancer patients. The AUC is a measure of accuracy with potential clinical relevance for the evaluation of disease markers. The clinical meaning of ROC parameters should always be evaluated with an analysis of the shape of the corresponding ROC curve.

Thyroid Stimulating Hormone, T3 and T4 Population-based Reference Range and Children Prevalence of Thyroid Dysfunction: First Report from South of Iran.

The TSH reference range's validity affects the thyroid dysfunction diagnosis. The primary objective of this study is to determine the reference range, which is established according to age and region. The data were collected retrospectively from people over the age of one who visited Motahari Clinic for routine health checkups between August 2017 and October 2019. TSH, T4, T3, personal drug usage, and thyroid history were collected. After excluding subjects with thyroid diseases and outliers, 1392 participants were analyzed. Hormone intervals of men and women ≥1 year old have been determined using the non-parametric method. The non-disease subjects' TSH, T3, and T4 reference ranges were 0.64 to 5.94 lU/mL, 0.91 to 2.47 ng/dL, and 5.53 to 12.48 g/dL, respectively. According to this range, total thyroid dysfunction prevalence in our study in children was 8.94%. There was no significant difference between TSH, T4 level, and gender in the non-disease population (P=0.46 and 0.13, respectively), but there was a statistical difference between sex and T3 (P =0.03). Our study also illustrates that for subjects under 18 years old and older, the hormones (TSH, T3, T4) concentration are statistically different (P≤0.001). We found a statistically difference between hormone values younger and older than age 18 (P=≤0.01); therefore, it is not appropriate to use the same reference range for children younger than age 18 and adults. There was male predominance in the population aged1-18 years old.

Refreg: An R Package for Estimating Conditional Reference Regions

Multivariate reference regions (MVR) represent the extension of the reference interval concept to the multivariate setting. A reference interval is defined by two threshold points between which a high percentage of healthy subjects' results, usually 95%, are contained. Analogously, an MVR characterizes the values of several diagnostic tests most frequently found among non-diseased subjects by defining a convex hull containing 95% of the results. MVRs have great applicability when working with diseases that are diagnosed via more than one continuous test, e.g., diabetes or hypothyroidism. The present work introduces refreg, an R package for estimating conditional MVRs. The reference region is non-parametrically estimated using a multivariate kernel density estimator, and its shape allowed to change under the influence of covariates. The effects of covariates on the multivariate variable means, and on their variance-covariance matrix, are estimated by flexible additive predictors. Continuous covariate non-linear effects can be estimated by penalized spline smoothers. The package allows the user to propose, for instance, an age-specific diagnostic rule based on the joint distribution of two non-Gaussian, continuous test results. The usefulness of the refreg package in clinical practice is illustrated with a real case in diabetes research, with an age-specific reference region proposed for the joint interpretation of two glycemia markers (fasting plasma glucose and glycated hemoglobin). To show that the refreg package can also be used in other, and indeed very different fields, an example is provided for the joint prediction of two atmospheric pollutants (SO$_2$, and NO$_x$). Additionally, the text discusses how, conceptually, this method could be extended to more than two dimensions.

Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis.

ObjectiveSporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses.MethodsIn this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non‐diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies.ResultsA total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses.InterpretationWe identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.

Characterization of Immunopathology and Small Airway Remodeling in Constrictive Bronchiolitis.

Rationale: Constrictive bronchiolitis (ConB) is a relatively rare and understudied form of lung disease whose underlying immunopathology remains incompletely defined. Objectives: Our objectives were to quantify specific pathological features that differentiate ConB from other diseases that affect the small airways and to investigate the underlying immune and inflammatory phenotype present in ConB. Methods: We performed a comparative histomorphometric analysis of small airways in lung biopsy samples collected from 50 soldiers with postdeployment ConB, 8 patients with sporadic ConB, 55 patients with chronic obstructive pulmonary disease, and 25 nondiseased control subjects. We measured immune and inflammatory gene expression in lung tissue using the NanoString nCounter Immunology Panel from six control subjects, six soldiers with ConB, and six patients with sporadic ConB. Measurements and Main Results: Compared with control subjects, we found shared pathological changes in small airways from soldiers with postdeployment ConB and patients with sporadic ConB, including increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and lymphocyte infiltration. Using principal-component analysis, we showed that ConB pathology was clearly separable both from control lungs and from small airway disease associated with chronic obstructive pulmonary disease. NanoString gene expression analysis from lung tissue revealed T-cell activation in both groups of patients with ConB with upregulation of proinflammatory pathways, including cytokine-cytokine receptor interactions, NF-κB (nuclear factor-κB) signaling, TLR (Toll-like receptor) signaling, T-cell receptor signaling, and antigen processing and presentation. Conclusions: These findings indicate shared immunopathology among different forms of ConB and suggest that an ongoing T-helper cell type 1-type adaptive immune response underlies airway wall remodeling in ConB.

Comparison of the binormal and Lehman receiver operating characteristic curves

In this article, we compared the binormal and the Lehmann receiver operating characteristic (ROC) curves using extensive simulation studies and real data sets related to HIV. We ran a large set of simulation studies with a wide range of distributions, varying sample sizes, and different degrees of overlap between the diseased and non-diseased population distributions. Simulation results suggest that the binormal ROC model performs better for normal data. However, for non-normal data, the Lehman model outperforms the binormal model. The discrepancies between the performances of the two models were more apparent for larger sample sizes or larger degree of separation between the distributions of the diseased and non-diseased subjects. Like the binormal model, the Lehman model provides smooth estimates of ROC curves and a closed-form expression for the area under the ROC curve. Moreover, the Lehmann model can also be used to obtain covariate-adjusted ROC curves and accommodates inference of correlated and longitudinal biomarkers. Thus, the Lehman model should be considered as an alternative when the restrictive distributional assumptions of the binormal model are not met.

Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson's Disease.

Parkinson’s disease is mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Together with the small number, the high vulnerability of the dopaminergic neurons is a major pathogenic culprit of Parkinson’s disease. Our previous findings of a higher survival of dopaminergic neurons in the substantia nigra co-expressing Nogo-A in an animal model of Parkinson’s disease suggested that Nogo-A may be associated with dopaminergic neurons resilience against Parkinson’s disease neurodegeneration. In the present study, we have addressed the expression of Nogo-A in the dopaminergic neurons in the substantia nigra in postmortem specimens of diseased and non-diseased subjects of different ages. For this purpose, in a collaborative effort we developed a tissue micro array (TMA) that allows for simultaneous staining of many samples in a single run. Interestingly, and in contrast to the observations gathered during normal aging and in the animal model of Parkinson’s disease, increasing age was significantly associated with a lower co-expression of Nogo-A in nigral dopaminergic neurons of patients with Parkinson’s disease. In sum, while Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in Parkinson’s disease. These observations suggest that Nogo-A might play a substantial role in the vulnerability of dopaminergic neurons in Parkinson’s disease.

Variable abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features.

Ascertain and quantify abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features based on a statistical predictive modeling strategy for PLR classification. Exploratory cohort analysis of pupillary kinetics in non-disease controls, PD subjects, and subjects with parkinsonism features using chromatic pupillometry. Receiver operating characteristic (ROC) curve interpretation of pupillary changes consistent with abnormality of intrinsically photosensitive retinal ganglion cells (ipRGCs) was employed using a thresholding algorithm to discriminate pupillary abnormality between study groups. Twenty-eight subjects were enrolled, including 17 PD subjects (age range 64-85, mean 70.65) and nine controls (age range 48-95, mean 63.89). Two subjects were described as demonstrating parkinsonism symptoms due to presumed Lewy body dementia and motor system atrophy (MSA) respectively. On aggregate analysis, PD subjects demonstrated abnormal but variable pupillary dynamics suggestive of ipRGC abnormality. Subjects with parkinsonism features did not demonstrate pupillary changes consistent with ipRGC abnormality. There was no relationship between levodopa equivalent dosage or PD severity and ipRGC abnormality. The pupillary test sensitivity in predicting PD was 0.75 and likelihood ratio was 1.2. ipRGC deficit is demonstrated in PD subjects; however, the degree and constancy of abnormality appear variable.

Comparison of the Japan Society of Clinical Chemistry reference method and CDC method for HDL and LDL cholesterol measurements using fresh sera

ObjectivesIn 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method. Designand methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 ​mmol/L (1000 ​mg/dL). ResultsFor LDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.991x + 0.009 ​mmol/L; r ​= ​0.999; and Sy/x ​= ​0.025 ​mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.988x + 0.041 ​mmol/L, r ​= ​0.999, and Sy/x ​= ​0.019 ​mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method. ConclusionsThe JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.

High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer\u2019s Disease

We have previously shown that the expression of nicotinamide N-methyltransferase (NNMT) is significantly increased in the brains of patients who have died of Parkinson’s disease (PD). In this study, we have compared the expression of NNMT in post-mortem medial temporal lobe, hippocampus and cerebellum of 10 Alzheimer’s disease (AD) and 9 non-disease control subjects using a combination of quantitative Western blotting, immunohistochemistry and dual-label confocal microscopy coupled with quantitative analysis of colocalisation. NNMT was detected as a single protein of 29 kDa in both AD and non-disease control brains, which was significantly increased in AD medial temporal lobe compared to non-disease controls (7.5-fold, P < 0.026). There was no significant difference in expression in the cerebellum (P = 0.91). NNMT expression in AD medial temporal lobe and hippocampus was present in cholinergic neurones with no glial localisation. Cell-type expression was identical in both non-disease control and AD tissues. These results are the first to show, in a proof-of-concept study using a small patient cohort, that NNMT protein expression is increased in the AD brain and is present in neurones which degenerate in AD. These results suggest that the elevation of NNMT may be a common feature of many neurodegenerative diseases. Confirmation of this overexpression using a larger AD patient cohort will drive the future development of NNMT-targetting therapeutics which may slow or stop the disease pathogenesis, in contrast to current therapies which solely address AD symptoms.

Wild-type huntingtin regulates human macrophage function

The huntingtin (HTT) protein in its mutant form is the cause of the inherited neurodegenerative disorder, Huntington’s disease. Beyond its effects in the central nervous system, disease-associated mutant HTT causes aberrant phenotypes in myeloid-lineage innate immune system cells, namely monocytes and macrophages. Whether the wild-type form of the protein, however, has a role in normal human macrophage function has not been determined. Here, the effects of lowering the expression of wild-type (wt)HTT on the function of primary monocyte-derived macrophages from healthy, non-disease human subjects were examined. This demonstrated a previously undescribed role for wtHTT in maintaining normal macrophage health and function. Lowered wtHTT expression was associated, for instance, with a diminished release of induced cytokines, elevated phagocytosis and increased vulnerability to cellular stress. These may well occur by mechanisms different to that associated with the mutant form of the protein, given an absence of any effect on the intracellular signalling pathway predominantly associated with macrophage dysfunction in Huntington’s disease.

Nonparametric confidence regions for the symmetry point-based optimal cutpoint and associated sensitivity of a continuous-scale diagnostic test.

In medical research, diagnostic tests with continuous values are widely employed to attempt to distinguish between diseased and non-diseased subjects. The diagnostic accuracy of a test (or a biomarker) can be assessed by using the receiver operating characteristic (ROC) curve of the test. To summarize the ROC curve and primarily to determine an "optimal" threshold for test results to use in practice, several approaches may be considered, such as those based on the Youden index, on the so-called close-to-(0,1) point, on the concordance probability and on the symmetry point. In this paper, we focus on the symmetry point-based approach, that simultaneously controls the probabilities of the two types of correct classifications (healthy as healthy and diseased as diseased), and show how to get joint nonparametric confidence regions for the corresponding optimal cutpoint and the associated sensitivity (= specificity) value. Extensive simulation experiments are conducted to evaluate the finite sample performances of the proposed method. Real datasets are also used to illustrate itsapplication.

The Differential Expression of Long Noncoding RNAs in Type 2 Diabetes Mellitus and Latent Autoimmune Diabetes in Adults.

Background Long noncoding RNAs (lncRNAs) were previously found to be closely related to the pathogenesis of diabetes. Objectives To reveal the differentially expressed lncRNAs and messenger RNAs (mRNAs) involved in type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA) and predict the lncRNA target genes to derive their expression profiles for the diagnosis of T2DM and LADA and their differential diagnosis. Methods Twelve venous blood samples were collected from T2DM patients, LADA patients, and nondiseased subjects to obtain total RNAs. After removing rRNA from total RNAs to establish the desired library for sequencing, quality control and quantification analyses were carried out. The fragments per kilobase of exon model per million reads mapped (FPKM) of lncRNAs were calculated to construct the gene expression profiles of lncRNAs and mRNAs. Fold changes (fold change: 2.0) and p values (p values (Results Compared to nondiseased controls, 68,763 versus 28,523 lncRNAs and 133 versus 1035 mRNAs were significantly upregulated and significantly downregulated, respectively, in T2DM patients. For LADA patients, 68,748 versus 28,538 lncRNAs and 219 versus 805 mRNAs were significantly upregulated and significantly downregulated, respectively, relative to nondiseased controls. Compared to T2DM patients, 74,207 versus 23,079 lncRNAs and 349 versus 137 mRNAs were significantly upregulated and significantly downregulated, respectively, in LADA patients. Based on the correlation analysis, seven lncRNA-mRNA pairs (BTG2, A2M, HECTD4, MBTPS1, DBH, FLVCR1, and NCBP2) were significantly coexpressed, and two lncRNAs (ENST00000608916 and ENST00000436373) were newly discovered. Conclusion Significant differences in lncRNA expression were discovered among the three groups. Furthermore, after predicting lncRNA expression profiles, GO/KEGG pathway analysis could deduce the target gene function.

A Permutation Test for Comparing Two Correlated Receiver Operating Characteristic Curves

The area under the Receiver Operating Characteristic (ROC) curve (AUC) is a summary measure when comparing two ROC curves. However, this summary measure is less informative when two ROC curves cross and have the same AUCs. In order to detect differences between ROC curves and to be able to tackle the problem of exchangeability of the labels between two diagnostic tests within subject, an alternative permutation test based on between-subject permutations of the labels of the subjects within each diagnostic test is proposed for assessing a change in the AUCs in a continuous matched pair of data from two diagnostic test procedures having both non-diseased and diseased subject in each of the test. The Wilcoxon signed rank test statistic was modified as a permutation test under the null hypothesis of equality of AUCs. An algorithm for carrying out complete enumeration of all the distinct permutations of the paired test results was developed which provides exact p-values. Using simulated data, the proposed test compares in statistical power to the modified sign test proposed by Braun and Alonzo but the proposed test has better operating characteristics, that is greater statistical power to detect a crossing alternative and is less conservative in test size and in the range of parameters of at least 0.8 of AUCs on the average with a correlation of at least 0.4 and small to moderately large sample sizes. Similarly in applying real life data, the proposed test has the more likelihood of rejecting null hypothesis of equality of AUC1 and AUC2 at nominal level of 0.05 with the proposed test having a p-value of 0.0312 against the Braun and Alonzo’s test with a p-value of 0.0387. This is because the proposed test is modified to adjust for the presence of zero differences in values and considers the signs of values as well as the absolute ranks of values. Also the estimates of AUC1 and AUC2 for the two diagnostic tests are 0.668 and 0.887 respectively showing that AUC2, that is 2hour 100g Oral Glucose Tolerance Test (OGTT) is superior to AUC1 (2hour 70g OGTT) at a time that the specificity is greater than 0.7.

Variability of Paranasal Sinus Pneumatization in the Absence of Sinus Disease.

Background: Paranasal sinus pneumatization is a complex process, and numerous computed tomography (CT) studies document developmental variations in the setting of underlying sinus disease. The purpose of this study was to investigate variation in paranasal sinus pneumatization in a population of nondiseased subjects using a metric validated for tracking individual anatomic variants as well as total sinus volume.Methods: A total of 591 consecutive sinus and maxillofacial CT scans were considered for study inclusion. After patients with inflammatory sinus or respiratory disease were excluded, 323 CT scans were scored using the Assessment of Pneumatization of the Paranasal Sinuses (APPS) instrument, and relevant demographic data were recorded for each scan. APPS findings were compared according to demographic characteristics and laterality.Results: Laterality and sex were associated with differences in paranasal sinus pneumatization in a nondiseased population. Based on APPS score, the left side (4.95) was more pneumatized than the right (4.74, P=0.006), and males (10.16) were more extensively pneumatized than females (9.18, P=0.005). We found no correlation of age with sinus pneumatization (ρ=0.025). The probability of perceptible asymmetry in any given individual's paranasal sinus pneumatization was 69%, and the probability of left-sided dominance was 53%.Conclusion: Substantial anatomic variation exists in paranasal sinus anatomy, even among patients without sinus disease. Significant differences are found between males and females and between the left and right sides. Continued systematic research of paranasal sinus anatomy may facilitate a standard for CT sinus assessment that will aid clinician evaluation of anatomic variation and surgical decision making.

Sequestosome-1 (p62) expression reveals chaperone-assisted selective autophagy in immune-mediated necrotizing myopathies.

Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune‐mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone‐assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB‐crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2‐associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM‐specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.

Association of Obesity with Quantitative Chest CT Measured Airway Wall Thickness in WTC Workers with Lower Airway Disease.

We previously reported that wall area percent (WAP), a quantitative CT (QCT) indicator of airway wall thickness and, presumably, inflammation, is associated with adverse longitudinal expiratory flow trajectories in WTC workers, but that obesity and weight gain also seemed to be independently predictive of the latter. Previous studies have reported no association between WAP and obesity, so we investigated that association in nonsmoking WTC-exposed individuals and healthy unexposed controls. We assessed WAP using the Chest Imaging Platform QCT system in a segmental bronchus in 118 former WTC workers, and 89 COPDGene® WTC-unexposed and asymptomatic subjects. We used multiple regression to model WAP vs. body mass index (BMI) in the two groups, adjusting for important subject and CT image characteristics. Unadjusted analyses revealed significant differences between the two groups with regards to WAP, age, gender, scan pixel spacing and slice interval, but not BMI or total lung capacity. In adjusted analysis, there was a significant interaction between BMI and WTC exposure on WAP. BMI was significantly and positively associated with WAP in the WTC group, but not in the COPDGene® group, but stratified analyses revealed that the effect was significant in WTC subjects with clinical evidence of lower airway disease (LAD). Unlike non-diseased subjects, BMI was significantly associated with WAP in WTC workers and, in stratified analyses, the association was significant only among those with LAD. Our findings suggest that this adverse effect of obesity on airway structure and inflammation may be confined to already diseased individuals.

Comparison of Two or More Correlated AUCs in Paired Sample Design

Purpose of study Methods of comparing the accuracy of diagnostic tests are of increasing necessity in biomedical science. When a test result is measured on a continuous scale, an assessment of the performance of the overall value of the test can be made using the Receiver Operating Characteristic (ROC) curve. This curve describes the discrimination ability of a diagnosis test in terms of diseased subjects from non-diseased subjects. The area under the ROC curve (AUC) describes the probability that a randomly chosen diseased subject will have higher probability of having disease than a randomly chosen non-diseased subject. For comparing two or more diagnostic test results, the difference between AUCs is often used. This paper proposes a non-parametric alternative method of comparing two or more correlated area under the curve (AUCs) of diagnostic tests for paired sample data. This method is based on Chi-square test statistic. Methods This paper investigated both parametric and non-parametric methods of comparing the equality of two AUCs and proposed a Chi-square test for the comparison of two or more diagnostic test processes. The proposed method does not require the knowledge of true status of subjects or gold standard in evaluating the accuracy of tests unlike other existing methods. The proposed method is most suitable for paired sample design. It also offers reliable statistical inferences even in small sample problems and circumvent the difficulties of deriving the statistical moments of complex summary statistics as seen in the Delong method. The proposed method provides for further analysis to determine the possible reason for rejecting the null hypothesis of equality of AUCs. Results The proposed method when applied on real data, avoids the lengthy and more difficult procedures of estimating the variances of two AUCs as a way of determining if two AUCs differ significantly. The method is validated using the Cochran Q test and was shown to compare favourably. The proposed method recommended for comparing two or more correlated AUCs when the data is paired. It is simple and does not require prior knowledge of true status of subjects unlike other existing methods. Keywords: Chi-square test, Cochran Q test, cut-off value, area under the curve, receiver operating characteristic, Dichotomous data DOI : 10.7176/JNSR/9-9-06 Publication date :May 31 st 2019