Reference Subjects Research Articles

POS0835 DECLINE IN FORCED VITAL CAPACITY (FVC) IN SUBJECTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) IN THE SENSCIS TRIAL VERSUS HYPOTHETICAL REFERENCE SUBJECTS WITHOUT LUNG DISEASE

Background:In the randomized SENSCIS trial in subjects with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks (mL/year) by 44% compared to placebo. Healthy individuals have varied FVC depending on age, sex, ethnicity and height; expected values can be determined using internationally recognised reference equations.Objectives:To provide further context to the FVC declines observed in the SENSCIS trial, we compared the decline in FVC observed in subjects with SSc-ILD in the SENSCIS trial with the decline in FVC that would be expected in hypothetical subjects without ILD matched for age, sex, ethnicity and height.Methods:The SENSCIS trial enrolled subjects with SSc-ILD aged ≥18 years with first non-Raynaud symptom ≤7 years before screening, extent of fibrotic ILD ≥10% on HRCT, FVC ≥40% predicted and DLco 30–89% predicted. Baseline FVC (mL) and changes in FVC (mL) at week 52 were assessed in the nintedanib and placebo groups, with missing values at week 52 imputed using predictions from the primary analysis model (random slope and intercept model). Changes in FVC in the SENSCIS trial were compared to values in hypothetical healthy reference subjects matched to the SENSCIS subjects for age, sex, ethnicity and height. FVC values in these healthy reference subjects were derived from the equations published by the European Respiratory Society Global Lung Function Initiative in 2012, which were derived from data from over 70,000 subjects.1Results:In the nintedanib and placebo groups of the SENSCIS trial, respectively, mean (SD) time since onset of first non-Raynaud symptom was 3.5 (1.6) and 3.5 (1.8) years. In the nintedanib group, mean (SD) FVC at baseline was 2460 (737) mL, compared with 3403 (787) mL in the healthy reference subjects. In the placebo group, mean (SD) FVC at baseline was 2544 (817) mL compared with 3516 (887) mL in the healthy reference subjects. The difference in the change from baseline in FVC at week 52 between the nintedanib-treated subjects in the SENSCIS trial (n=287) and the healthy reference subjects was 26.6 mL ([95% CI: 1.2, 52.0]; p=0.04). The difference in the change from baseline in FVC at week 52 between the placebo-treated subjects in the SENSCIS trial (n=286) and the reference subjects was 77.5 mL ([95% CI: 51.4, 103.7]; p<0.001) (Figure 1).Conclusion:Subjects with SSc-ILD who participated in the SENSCIS trial had marked lung function impairment at baseline compared with healthy matched reference subjects, despite a mean duration of SSc of 3.5 years. Over 52 weeks, the decline in FVC in subjects with SSc-ILD who received placebo was 4-fold greater than in healthy reference subjects. Subjects with SSc-ILD who were treated with nintedanib had a decline in FVC that was only slightly greater than the decline observed in the matched healthy subjects. These data support the clinical relevance of the reduction in the rate of FVC decline provided by nintedanib in patients with SSc-ILD.

Depressive hypertension: A proposed human endotype of brain/gut microbiome dysbiosis

Hypertension (HTN) is frequently linked with depression (DEP) in adults with cardiovascular disease (CVD), yet the underlying mechanism and successful management remain elusive. We approached this knowledge gap through the lens that humans are eukaryote-prokaryote "meta-organisms," such that cardiovascular disease dysregulation is a mosaic disorder involving dysbiosis of the gut. We hypothesized that patients diagnosed with hypertension plus depression harbor a unique gut microbial ecology with attending functional genomics engaged with their hosts' gut/brain axis physiology. Stool microbiome DNA was analyzed by whole metagenome shotgun sequencing in 54 subjects parsed into cohorts diagnosed with HTN only (N = 18), DEP only (N = 7), DEP plus HTN (DEP-HTN) (N = 8), or reference subjects with neither HTN nor DEP (N = 21). A novel battery of machine-learning multivariate analyses of de-noised data yielded effect sizes and permutational covariance-based dissimilarities that significantly differentiated the cohorts (false discovery rate (FDR)-adjusted P ≤ .05); data clustering within 95% confidence interval). Metagenomic significant differences extricated the four cohorts. Data of the cohort exhibiting DEP-HTN were germane to the interplay of central control of blood pressure concomitant with the neuropathology of depressive disorders. DEP-HTN gut bacterial community ecology was defined by co-occurrence of Eubacterium siraeum, Alistipes obesi, Holdemania filiformis, and Lachnospiraceae bacterium 1.1.57FAA with Streptococcus salivariu. The corresponding microbial functional genomics of DEP-HTN engaged pathways degrading GABA and beneficial short chain fatty acids (SCFA), and are associated with enhanced sodium absorption and inflammasome induction. These data suggest a new putative endotype of hypertension, which we denote "depressive-hypertension" (DEP-HTN), for which we posit a model that is distinctive from either HTN alone or DEP alone. An "endotype" is a subtype of a heterogeneous pathophysiological mechanism. The DEP-HTN model incorporates a unique signature of microbial taxa and functional genomics with crosstalk that putatively intertwines host pathophysiology involving the gastrointestinal tract with disruptions in central control of blood pressure and mood. The DEP-HTN endotype model engages cardiology with gastroenterology and psychiatry, providing a proof-of-concept foundation to explore future treatments, diagnosis, and prevention of HTN-coupled mood disorders.

Impaired Muscle Strength and Performance in Patients With Mild Autonomous Cortisol Secretion

Background: Glucocorticoid-induced myopathy is well-recognized in overt Cushing syndrome (CS), but the impact of mild cortisol secretion on muscle is unclear. Recent data suggest that patients with mild autonomous cortisol secretion (MACS) are frailer and report more weakness than patients with non-functioning adrenal adenomas. We hypothesized that MACS is associated with 1) objective measures of impaired muscle strength and performance and 2) increased tissue accumulation of advanced glycation end products (AGEs), a measure of accelerated aging. Aim: To determine the effect of MACS on muscle mass, strength, performance, and tissue accumulation of AGEs. Methods: We conducted a cross-sectional analysis as part of an ongoing cohort study in patients with MACS compared to age and sex-matched referent subjects without cortisol excess. MACS was defined as serum cortisol >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST), in the absence of overt signs and symptoms of CS. We measured hand grip strength with hand grip dynamometer and evaluated functional performance on the timed up and go test, 6 minute walk test, and gait speed assessment. Tissue accumulation of AGEs was measured with point-of-care AGE reader. Appendicular lean mass was calculated and adjusted for height in participants who underwent body composition scan. Results: A total of 23 patients with MACS and 23 age and sex-matched referent subjects without cortisol excess were enrolled. The median age of diagnosis was 63 years (range, 51–81), and 26 (56%) were women. In the MACS cohort, median cortisol following 1 mg DST was 2.6 µg/dL (range, 1.9–13.0), median DHEA-S 37 µg/dL (range, 5.0- 141.0), and median ACTH 8.5 pg/mL (range, 5.0–38.0). Patients with MACS had lower hand grip strength (median 29.3 vs. 32.5 kg, p=0.052), slower gait speed (median 1.1 vs. 1.4 m/s, p=0.001), covered less distance during the 6 minute walk test (median 453 vs. 510 m, p=0.001), and took longer to complete the timed up and go test (median 10.1 vs. 8.6 s, p=0.04) than referent subjects without cortisol excess. Accumulation of AGEs was higher in patients with MACS (median 2.9 vs. 2.4, p=0.01). No significant difference was observed in appendicular lean mass (n=19 pairs, 7.8 vs. 7.5 kg/m2, p=0.57). Conclusions: MACS is associated with decreased muscle strength and performance without a significant change in muscle mass, suggesting poor muscle quality. We also observed increased tissue accumulation of AGEs in MACS patients, consistent with our hypothesis of MACS-induced accelerated aging. These findings may help explain the increased frailty observed in MACS, and suggest muscle assessment be considered in all patients with autonomous cortisol secretion. Further studies should examine the impact of muscle and functional impairments on morbidity in MACS, and its possible reversal with either a structured exercise intervention or adrenalectomy.

Risk of Mental and Sleep Disorders After the Diagnosis of Adrenal Adenomas: A Population-Based Cohort Study

Background: Adrenal adenomas are incidentally diagnosed in 7% of adults undergoing abdominal imaging. Mild autonomous cortisol secretion is present in 50% of adrenal adenomas, and even “nonfunctioning” adrenal adenomas demonstrate abnormal steroid profile. We aimed to 1) investigate the prevalence of mental and sleep disorders in patients with adrenal adenomas and to 2) determine the risk of mental and sleep disorders after the diagnosis of adrenal adenoma in patients compared to the referent subjects from the same population Methods: Using a medical records linkage system, we identified adult patients living in the Olmsted County, MN diagnosed with an adrenal adenoma during 1995–2017. Patients with overt hormone excess were excluded. Every patient with adenoma was matched by sex and age to a referent subject from the same population. Subjects were followed until death or end of the study. Mental health related comorbidities and sleep disorders were assessed at baseline and during follow up. Results: Our cohort included 1004 patients with adrenal adenomas and 1004 referent subjects (58% women, median age of 63 years). Patients were more likely to smoke (70% vs 54%, p <0.001) and had a higher BMI (30 kg/m2 vs 28 kg/m2, p < 0.001). Within 5 years prior to the index date (diagnosis of adenoma), and after adjusting for BMI and smoking, patients demonstrated a higher prevalence of depression (Odds ratio, OR of 1.3 (CI95% 1.1–1.6), p=0.02), anxiety (OR of 1.4 (CI95% 1.1–1.8, p=0.003), substance abuse disorders (OR of 2.4 (CI 95% 1.7–3.4), p<0.001), but not insomnia (OR of 1.2 (CI95% 0.9–1.7) and sleep related breathing disorders (OR of 1.3 (CI 95% 0.9–1.7). During follow-up, starting 1 year after the diagnosis, patients demonstrated a higher risk of new onset depression (HR of 1.9, CI95%1.5–2.4), anxiety (HR of 1.5,CI95% 1.2–1.9), schizophrenia (HR of 1.7, CI95% 1.2–2.4), and substance abuse disorders (HR of 1.6, CI95% 1.2–2.0). Risk of sleep disorders 1 year after diagnosis was also high for insomnia (HR of 1.4, CI95% 1.1–1.9), sleep-related breathing disorders (HR of 1.8, CI95% 1.4–2.3), hypersomnias of central origin (HR of 2.0, CI95%1.04–3.96), parasomnias (HR of 2.4, CI95%1.2–4.7), and sleep-related movement disorders(HR of 1.9, CI95%1.3–2.6). Conclusion: Patients with adenomas are at increased risk for mental and sleep disorders, possibly explained by the underlying subtle cortisol secretion. Further prospective studies with an in-depth characterization of both hormonal secretion and mental/sleep disorders are needed. Reversibility or improvement of mental health and sleep disorders with adrenalectomy should be investigated.

Incident Cardiometabolic Outcomes in Adrenal Adenomas: A Population-Based Cohort Study of 1,004 Patients

Abstract Background: Adrenal adenomas have been linked with cardiovascular morbidity in selected patient populations from specialized referral centers. Population-based data examining the association of adrenal adenomas with cardiometabolic outcomes are lacking. Aim: To determine the incidence of cardiometabolic outcomes in a population-based cohort of patients with adrenal adenomas. Methods: We conducted a population-based cohort study of patients diagnosed with adrenal adenomas while living in a defined community from 1995–2017. Eligible patients were retrospectively identified by a medical records linkage system and confirmed on chart review. Adenomas were classified as mild autonomous cortisol secretion (MACS) if the serum cortisol concentration was &amp;gt;1.8 mcg/dL after 1 mg overnight dexamethasone suppression test (DST), nonfunctioning adrenal tumor (NFAT) if serum cortisol after DST was ≤1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if DST was not performed. Patients with overt hormone excess were excluded. Cardiometabolic outcomes were assessed at the time of adrenal adenoma diagnosis. Patients were then followed until death, migration out of the community, or through December 31, 2017. Incident outcomes were assessed starting at 1 year following the diagnosis and excluded those with the outcome of interest at baseline, except for myocardial infarction (MI) and coronary intervention, which were adjusted for in the analysis. Results: were compared to 1:1 age and sex-matched referent subjects without adrenal adenomas from the same community. Results: Adrenal adenomas were diagnosed in 1004 patients with 141 (14%) NFAT, 81 (8%) MACS, and 782 (78%) AUCS. The median age of diagnosis was 63 years (range, 20–96), and 582 (58%) were women. The baseline data was previously presented and showed higher prevalence of hypertension, diabetes, peripheral vascular disease (PVD), and heart failure (HF) in the adenoma group, after adjusting for BMI and tobacco use. During a median follow-up of 6.8 years (range, 0–22), patients with adrenal adenomas were more likely than referent subjects to develop new-onset dyslipidemia (HR 1.31, 95% CI 1.03–1.67), diabetes (HR 1.68, 95% CI 1.28–2.22), chronic kidney disease (HR 1.77, 95% CI 1.39–2.25), atrial fibrillation (HR 1.32 (1.03–1.70), PVD (HR 1.61, 95% CI 1.24–2.09), and HF (HR 1.46, 95% CI 1.15–1.85). In addition, the adenoma group had higher risk for incident MI (HR 1.62, 95% CI 1.16–2.25) and coronary intervention (HR 1.70, 95% CI 1.25–2.31). Conclusions: Adrenal adenomas are associated with increased incidence of adverse cardiometabolic outcomes in this population-based cohort study. While these results are potentially explained by different degrees of cortisol excess, the majority of patients received suboptimal hormone evaluation, suggesting a knowledge gap in the workup of adrenal adenomas in the broader medical community.

Impaired Cognitive Performance in Patients With Mild Autonomous Cortisol Secretion

Abstract Background: Cognitive deficits in memory, language, and executive function have been described in Cushing’s syndrome, but the impact of mild cortisol secretion on cognition is unclear. Rather than overt hypercortisolism, mild autonomous cortisol secretion (MACS) is typically associated with abnormal circadian cortisol production. Aim: To characterize the effect of MACS on cognitive performance. Methods: We conducted a cross-sectional analysis as part of an ongoing cohort study in patients with MACS compared to age and sex-matched referent subjects without cortisol excess. MACS was defined as serum cortisol concentration &amp;gt;1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST), in the absence of signs and symptoms of overt Cushing syndrome. We used the National Institute of Health Toolbox Cognition Battery to assess cognitive performance. A series of seven IPad-based tests were administered to evaluate five key domains: 1) executive function, 2) episodic memory, 3) working memory, 4) language, and 5) processing speed. Performance was reported using fully corrected T-scores for age, sex, education, and race with a normative mean of 50 and a standard deviation of 10. T-scores were generated for the individual components as well as three summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), 2) crystallized cognition (includes language), and 3) total cognition (composite of fluid and crystalized cognition). Results: A total of 23 patients with MACS and 23 age and sex-matched referent subjects without cortisol excess were enrolled. The median age of diagnosis was 63 years (range, 51–81), and 26 (56%) were women. In the MACS cohort, median cortisol following 1 mg DST was 2.6 ug/dL (range, 1.9–13.0) with median ACTH of 8.5 pg/mL (range, 5.0–38.0) and median DHEA-S of 37 mcg/dL (range, 5.0- 141.0). On cognitive assessment, patients with MACS had lower total cognition (T-scores 50 vs. 54, p=0.05) and fluid cognition (T-scores 48 vs. 53, p=0.01) composite scores compared to referent subjects without cortisol excess. In particular, patients with MACS performed worse on tests of executive function (Dimensional Change Card Sort: T-scores 55 vs. 63, p= 0.02 and Flanker Inhibitory Control and Attention: T-scores 45 vs. 52, p=0.01). There were no significant differences observed in the remaining individual domains of language, processing speed, working memory, and episodic memory, or crystallized cognition. Conclusions: MACS is associated with impaired total cognition, and in particular, executive function and fluid cognition. These findings suggest that patients with MACS are susceptible to cortisol-mediated changes in the brain. Additional studies should examine the contribution of neuropsychiatric symptoms on cognition in MACS, and possible improvement following treatment for cortisol excess.

Altered regional cerebral blood flow in obstructive sleep apnea is associated with sleep fragmentation and oxygen desaturation

Altered cerebral perfusion has been reported in obstructive sleep apnea (OSA). Using dynamic susceptibility contrast MRI, we compared cerebral perfusion between male OSA patients and male healthy reference subjects and assessed correlations of perfusion abnormalities of OSA patients with sleep parameters and neuropsychological deficits at 3 T MRI, polysomnography and neuropsychological tests in 68 patients with OSA and 21 reference subjects. We found lower global and regional cerebral blood flow and cerebral blood volume, localized mainly in bilateral parietal and prefrontal cortices, as well as multiple focal cortical and deep structures related to the default mode network and attention network. In the correlation analysis between regional hypoperfusion and parameters of polysomnography, different patterns of regional hypoperfusion were distinctively associated with parameters of intermittent hypoxia and sleep fragmentation, which involved mainly parietal and orbitofrontal cortices, respectively. There was no association between brain perfusion and cognition in OSA patients in areas where significant association was observed in reference subjects, largely overlapping with nodes of the default mode network and attention network. Our results suggest that impaired cerebral perfusion in important areas of functional networks could be an important pathomechanism of neurocognitive deficits in OSA.

Reference ranges for clinical electrophysiology of vision

IntroductionEstablishing robust reference intervals for clinical procedures has received much attention from international clinical laboratories, with approved guidelines. Physiological measurement laboratories have given this topic less attention; however, most of the principles are transferable.MethodsHerein, we summarise those principles and expand them to cover bilateral measurements and one-tailed reference intervals, which are common issues for those interpreting clinical visual electrophysiology tests such as electroretinograms (ERGs), visual evoked potentials (VEPs) and electrooculograms (EOGs).ResultsThe gold standard process of establishing and defining reference intervals, which are adequately reliable, entails collecting data from a minimum of 120 suitable reference individuals for each partition (e.g. sex, age) and defining limits with nonparametric methods. Parametric techniques may be used under some conditions. A brief outline of methods for defining reference limits from patient data (indirect sampling) is given. Reference intervals established elsewhere, or with older protocols, can be transferred or verified with as few as 40 and 20 suitable reference individuals, respectively. Consideration is given to small numbers of reference subjects, interpretation of serial measurements using subject-based reference values, multidimensional reference regions and age-dependent reference values. Bilateral measurements, despite their correlation, can be used to improve reference intervals although additional care is required in computing the confidence in the reference interval or the reference interval itself when bilateral measurements are only available from some of subjects.DiscussionGood quality reference limits minimise false-positive and false-negative results, thereby maximising the clinical utility and patient benefit. Quality indicators include using appropriately sized reference datasets with appropriate numerical handling for reporting; using subject-based reference limits where appropriate; and limiting tests for each patient to only those which are clinically indicated, independent and highly discriminating.

Impaired glymphatic function in idiopathic intracranial hypertension.

Idiopathic intracranial hypertension is a brain disease incorporating cerebrospinal fluid disturbance, increased intracranial pressure and visual failure, but with unknown cause. This study examined a hypothesis that glymphatic function is impaired in idiopathic intracranial hypertension patients. The MRI contrast agent gadobutrol was utilized as a cerebrospinal fluid tracer following intrathecal administration. Consecutive standardized T1 MRI acquisitions over 48 h were done to assess tracer distribution within brain of 15 idiopathic intracranial hypertension patients and 15 reference individuals who were comparable in age and gender distribution. Using FreeSurfer software, we semi-quantified tracer level in multiple brain regions as T1 MRI signal change. The tracer enriched the entire brain of idiopathic intracranial hypertension and reference subjects. In idiopathic intracranial hypertension, tracer enrichment was increased and clearance of tracer delayed from a wide range of brain regions, including both grey and white matter. Differences were most evident in frontal and temporal regions. The pulsatile intracranial pressure was measured overnight and tracer propagation in brain compared between individuals with pathological and normal pulsatile intracranial pressure. In individuals with pathological pulsatile intracranial pressure, tracer enrichment was stronger and clearance from brain delayed, particularly in regions nearby large artery trunks at the brain surface. The present in vivo observations provide evidence for impaired glymphatic function in several brain regions of idiopathic intracranial hypertension patients. Glymphatic failure may imply altered clearance of metabolic byproducts, which may precede neurodegeneration. Further studies are needed to characterize glymphatic failure in idiopathic intracranial hypertension.

Theoretical aspects of modern security threats. Definitions, typologies, evolution

In the literature on the subject, the term “security” is accompanied by the terms “non-threatening state”, “non-threatening state of peace”, “state of peace”, “state of certainty”. The lexical meaning of the term (Latin sine cura – no worries) should be understood as a situation in which there are no threats. In the context of lexical meaning, the term security means a risk-free situation. Contemporary understanding of the term focuses its attention on learning security understood as the resultant of the theory and practice of providing a reference subject with the possibility of survival (existence) and the pursuit of own interests, particularly using opportunities, taking challenges, minimizing risk and counteracting all types of threats. Definitive approaches to the term security indicate that it should be understood as a state and process. The state of security should be understood as a sense of confidence of the subject and guarantee of its survival, while the process – as chance for improvement and development of state’s means to protect and defend it. The current catalog of security threats proposed by Barry Buzan was extended in the second half of the 20th century from military nature threats to threats of a political, economic, social, and environmental nature. These changes have redefined the modern understanding of security. The main research problem was formulated as the question: what are the theoretical aspects of contemporary security threats? The article aims to analyze and diagnose contemporary definitions of security and its threats. The research process uses methodological methods of scientific cognition, mainly analysis and criticism of literature.

Trajectory of Healthcare Resource Utilization in Giant Cell Arteritis: A Population-based Study.

To estimate the healthcare resource utilization (HRU) in patients with giant cell arteritis (GCA) compared with the general population in southern Sweden. The study sample comprised 653 patients with GCA along with 10 age-, sex-, and residency area-matched reference subjects per patient. Data on public and private healthcare consultations and hospitalizations were extracted from the Skåne Healthcare Register. We assessed trajectories of primary and specialist healthcare visits, as well as hospital admissions and inpatient days from 3 years before through 5 years after the date of GCA diagnosis for patients and matched references. HRU was analyzed using generalized estimating equations adjusted for sex, age at the index year, calendar year of diagnosis, education, income, marital status, place of birth, and Charlson Comorbidity Index. Inverse probability weighting was used to account for dropout during study. Patients with GCA had higher rates of healthcare visits than the references from the year before GCA diagnosis and up to 4 years after diagnosis, with the largest relative (rate ratio 1.85, 95% CI 1.68-2.05) and absolute (mean difference 10.2, 95% CI 8.1-12.3 visits per person) differences in the year of diagnosis. Similar trajectories were observed for primary and specialist healthcare visits. For hospital admissions and inpatient days, the differences disappeared 1 year after diagnosis date. Patients with GCA utilized healthcare services at a significantly higher rate than the reference population. The increased utilization among Swedish patients with GCA was evident 1 year before and prolonged up to 4 years after diagnosis date.

Negatively valenced questions with the Korean subject particle ka: Interactional practices for managing discrepancies in knowledge, understanding, or expectations

This study illustrates Korean speakers' routine practice of deploying the so-called subject particle ka in negatively valenced questions that display incipient disagreement, express disbelief, or make a challenge or complaint. An examination of 18 naturally occurring face-to-face conversations shows that a speaker's selection of the particle in such questions is contingent on neither the grammatical role of the referent (subject) nor the referent's information state (new vs. old). It is instead consistently contingent on the interactional job being done by the question (action formation) and the question's position in the sequential and interactional environment: the speaker questions how a referent is represented or understood in a prior turn, or notes a problem with the current state of the referent, as departing from the speaker's knowledge, understanding, or expectations. The particle serves to bring the target referent to the fore as the object of trouble at that moment of the interaction while leaving other possible candidates behind. This study illuminates the interactional import of the particle ka by demonstrating how it contributes to speakers' practices for managing discrepancies in their knowledge, understanding, or expectations regarding objects or matters in the material and social world with other participants of the talk-in-interaction.

Irritable Bowel Syndrome and Risk of Parkinson's Disease in Finland: A Nationwide Registry-Based Cohort Study.

Background:The gastrointestinal tract is considered as a potential origin of Parkinson’s disease (PD) pathology. Besides constipation, appendectomy and inflammatory bowel disease have also been associated with a higher PD-risk, but findings have been inconsistent. To date, there is only one previous study suggesting that irritable bowel syndrome (IBS) is associated with an increased risk of PD.Objective:To evaluate whether IBS is associated with a higher risk of PD.Methods:In this retrospective registry-based cohort study, we identified 28,150 patients that were diagnosed with IBS (IBS+) during the years 1998–2014, using data from the Finnish Care Register for Health Care. In addition, 98,789 IBS-free reference subjects (IBS-) of same age and gender and living in the same municipality were included. The study subjects were followed until the end of the year 2014 to analyze the incidence of PD. The association between IBS and PD was assessed by a Cox proportional hazards model.Results:Diagnosis of IBS was associated with a higher hazard of PD with an adjusted hazard ratio (aHR) of 1.70 (95% CI 1.27–2.26). However, the ratio of hazard rates for PD between IBS+ and IBS- subjects was not constant over time. The Cox model with time-varying coefficient for IBS status showed that the hazard of PD was significantly higher in IBS patients only during the first two years of follow-up (aHR 2.96, 95% CI 1.78–4.92).Conclusion:Our findings indicate that the association between IBS and PD is likely explained by reverse causation and detection bias. It remains open whether IBS is an actual risk factor or a prodromal symptom of PD.

Risk of bone fractures after the diagnosis of adrenal adenomas: a population-based cohort study.

Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. Population-based cohort study, Olmsted County, Minnesota, USA, 1995-2017. Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20-96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0-21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07-1.52) for developing a new fracture during follow up when compared to referent subjects. Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Interaction between Cadmium and Zinc Levels in the Biological Samples of Type 1 Diabetic Mellitus Children, Reside in Different Areas of Sindh, Pakistan

Type 1 Diabetes mellitus (T1DM) is one of the familiar childhood immune-mediated onsets and can lead to early mortalities and morbidities. It can arise at any stage, but the peak of occurrence is reported less than 18 years of age. T1DM cases in Pakistan were less than 2% of the total diabetic population. The current work designed to assess the concentration of cadmium (Cd) and zinc (Zn) in blood, scalp hair and serum samples of T1DM children, age ranged 1 - 14 years of both genders. For comparison purpose, the age-matched referent subjects of both genders were tested. The microwave-assisted acid digestion procedure was used to determine the elemental analysis in the biological samples of T1DM children and referent subjects. The resulted data of certified reference material of blood, scalp hair, and serum validated the certainty of the designed method. The analysis of Zn was performed by flame atomic absorption spectrometry, while the Cd contents were determined by electrothermal atomic absorption spectrometry. T1DM affected children of both genders have lower Zn level in the blood, scalp hair, and serum samples. Whereas, the levels of Cd were found to be higher in the biological samples of T1DM affected children as compared to referent subjects. The finding of the current study is a significant hypothesis for medical experts, to diagnose the deficiency of essential (Zn) and toxicity of heavy/toxic element (Cd) in the biological specimen of T1DM affected children.

Chromium Manganese and Zinc Levels in the Biological Samples of Type 1 Diabetic Mellitus Children Reside in Different Areas of Sindh Pakistan

T1DM is the most acquainted childhood immune-caused onset and may lead to early mortalities and morbidities. It can emanate in any age group but is highest reported in lesser than 18 years of age. In Pakistan only, T1DM institutes ~ 2% of the all diabetic population. This work was formulated to assess the concentration of manganese (Mn), zinc (Zn) and chromium (Cr) in blood, scalp hair and serum samples of diabetic mellitus type 1 children age ranged (1–5), (6-10) and (11-14) years of both genders (male and female), compared with similar sex and age referent subjects. For sample pretreatment, microwave-aided acid digestion procedure (MAD) was employed for elemental analysis in the biological samples of T1DM children. The employed method was validated by using certified reference samples of blood, scalp hair, and serum. Digests biological specimen were analyzed by AAS. The Zn was analyzed by FAAS, while the assessment of Mn and Cr were measured by ETAAS. The Mn, Zn and Cr, presents significantly low levels in the samples of scalp hair, blood and serum of female and male of age group of (1-5) (6-10) and (11-14) of diabetic mellitus type 1 children, compared with referent subjects. These data present an important hypothesis to doctors and other clinical experts to investigate insufficiency of these essential micronutrients (Cr, Mn, andamp; Zn) in biological specimen of blood, scalp hairs and serum of T1DM children.

Chromium Manganese and Zinc Levels in the Biological Samples of Type 1 Diabetic Mellitus Children Reside in Different Areas of Sindh Pakistan

T1DM is the most acquainted childhood immune-caused onset and may lead to early mortalities and morbidities. It can emanate in any age group but is highest reported in lesser than 18 years of age. In Pakistan only, T1DM institutes ~ 2% of the all diabetic population. This work was formulated to assess the concentration of manganese (Mn), zinc (Zn) and chromium (Cr) in blood, scalp hair and serum samples of diabetic mellitus type 1 children age ranged (1–5), (6-10) and (11-14) years of both genders (male and female), compared with similar sex and age referent subjects. For sample pretreatment, microwave-aided acid digestion procedure (MAD) was employed for elemental analysis in the biological samples of T1DM children. The employed method was validated by using certified reference samples of blood, scalp hair, and serum. Digests biological specimen were analyzed by AAS. The Zn was analyzed by FAAS, while the assessment of Mn and Cr were measured by ETAAS. The Mn, Zn and Cr, presents significantly low levels in the samples of scalp hair, blood and serum of female and male of age group of (1-5) (6-10) and (11-14) of diabetic mellitus type 1 children, compared with referent subjects. These data present an important hypothesis to doctors and other clinical experts to investigate insufficiency of these essential micronutrients (Cr, Mn, andamp; Zn) in biological specimen of blood, scalp hairs and serum of T1DM children.

Calcium and Lead Levels in the Biological Samples and Their Effect on the Biochemical Parameters of Indoor and Outdoor Workers of Five Zonal Areas of Coal Mining Field

Workers of the Lakhra coal mining Sindh Pakistan were affected by a multi-factorial exposure of heavy metals. The prevalence of lead (Pb) exposures in work-related symptoms among workers of indoor and outdoor mining of Lakhra coal mining was evaluated in detail. The biological samples (scalp hair and blood) of 270 workers of Lakhra coal mining {official and control subjects} (indoor and outdoor) 18 to 55 years age group and 70 referent subjects of same age-groups were examined. The biological samples (blood and scalp hair) of workers of Lakhra coal mining and referent subjects were analyzed for calcium (Ca) and lead (Pb). Flame atomic absorption spectrometry was applied for the determination of the Ca in digested samples of studied subjects by the microwave oven whereas, the Pb contents were measured by electrothermal atomic absorption spectrometry. The validity of the methodology was checked by using the certified human hair material (BCR 397) and lyophilized human blood (Clincheck). The results indicated the higher contents of Pb in biological samples of indoor and outdoor mining workers than referents. However, the levels of Ca were found to be lower in indoor and outdoor mining workers than those of referents. It can be concluded that immediate action should be taken by recommended authorities to improve the ventilation and hygiene practices inside the industries, mines, and other workplaces.

A multiplexed ion-exchange membrane-based miRNA (MIX·miR) detection platform for rapid diagnosis of myocardial infarction.

Micro RNAs (miRNAs) have shown great potential as rapid and discriminating biomarkers for acute myocardial infarction (AMI) diagnosis. We have developed a multiplexed ion-exchange membrane-based miRNA (MIX·miR) preconcentration/sensing amplification-free platform for quantifying in parallel a panel of miRNAs, including miR-1, miR-208b, and miR-499, from the same plasma samples from: 1) reference subjects with no evident coronary artery disease (NCAD); 2) subjects with stable coronary artery disease (CAD); and 3) subjects experiencing ST-elevation myocardial infarction (STEMI) prior to (STEMI-pre) and following (STEMI-PCI) percutaneous coronary intervention. The picomolar limit of detection from raw plasma and 3-decade dynamic range of MIX·miR permits detection of the miRNA panel in untreated samples from disease patients and its precise standard curve, provided by large 0.1 to 1 V signals and eliminates individual sensor calibration. The use of molecular concentration feature reduces the assay time to less than 30 minutes and increases the detection sensitivity by bringing all targets close to the sensors. miR-1 was low for NCAD patients but more than one order of magnitude above the normal value for all samples from three categories (CAD, STEMI-pre, and STEMI-PCI) of patients with CAD. In fact, miR-1 expression levels of stable CAD, STEMI-pre and STEMI-PCI are each more than 10-fold higher than the previous class, in that order, well above the 95% confidence level of MIX·miR. Its overexpression estimate is significantly higher than the PCR benchmark. This suggests that, in contrast to protein biomarkers of myocardial injury, miR-1 appears to differentiate ischemia from both reperfusion injury and non-AMI CAD patients. The battery-operated MIX·miR can be a portable and low-cost AMI diagnostic device, particularly useful in settings where cardiac catheterization is not readily available to determine the status of coronary reperfusion.

SOME REMARKS CONCERNING THE REFERENCE OF MENTAL AND LANGUAGE REPRESENTATIONS

This paper is an attempt to answer the question, what is exactly represented by our thoughts or language expressions. At the beginning, the article presents the main philosophical problems regarding the understanding of the nature of the subject of reference of such representations as names or descriptions. Is the name directly referred to the real object or rather to the content of thought? What about cases when the name cannot be referred to the real object? What is the relation between the intentional subject connected with every name (or description) and the external object to which only some names can be referred to, and which one is prior to the constitution of representation? The idea to understand the subject of mental or language representations as a complex structure which has a relational nature is the solution proposed in this paper. This structure is constituted by cognition and ties internal elements of a given representation such as the content with the elements which are external with regard to this given representation. This structure reflects such elements as the content of representation, the way in which this content is given, the correlate of the content and its mode of existence as well as additional systemic information coordinated with given representation. Some consequences of this proposal are discussed at the end of the article. It is explained how the differentiation of the elements of this structure can lead to different types of reference. The basis to understand the issue in question is the relation between internal and external object of reference. It can be interpreted (as is suggested in the paper) as a connection between internal elements of the described structure.