Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

THE ROMANIAN VERSION OF THE THYROID-RELATED PATIENT-REPORTED OUTCOMES THYPRO AND THYPRO-39. TRANSLATION AND ASSESSMENT OF RELIABILITY AND CROSS-CULTURAL VALIDITY.

BACKGROUND: ThyPRO is a recently developed thyroid-specific quality of life (QoL) questionnaire applicable to patients with benign thyroid disorders(BTD). The aim of the present study was to translate ThyPRO and ThyPRO-39 into Romanian, and to evaluate reliability and cross-cultural validity. METHODS: Standard methodology for translation and linguistic validation of patient-reported outcomes (PRO) was applied. The questionnaire was completed by 130 patients with benign thyroid diseases seen at Department of Endocrinology in the Emergency County Hospital, Tîrgu Mures, Romania, between October 2015 and March 2016. Internal reliability of the Romanian version of the ThyPRO (ThyPROro) scales was assessed for multi-item scales using Cronbach's alpha coefficient. An efficient method for testing cross-cultural validity is analysis of differential item functioning (DIF). Uniform DIF between the Romanian and the original Danish sample was investigated using ordinal logistic regression. The translation process proceeded without difficulties, and any disagreements were revised by one of the developers and the language coordinator. RESULTS: Internal reliability for ThyPRO was satisfactory. Cronbach`s alpha coefficients for the 13 scales ranged from 0.78 to 0.93 for the ThyPROro and 0.78 to 0.87 for the ThyPROro-39. In the 85-item ThyPRO, nine instances of DIF were found. Most were minor, explaining <3% of the variation in scale score, but DIF in positively worded items were larger, with explained variance (R2's) around 10-15%. CONCLUSION: The ThyPROro questionnaire is ready for assessment of health-related quality of life in Romanian patients with benign thyroid diseases.

Mental health in early pregnancy is associated with pregnancy outcome in women with pregestational diabetes.

AIM: To explore the role of early pregnancy health-related quality of life, anxiety, depression and locus of control for pregnancy outcome in women with pregestational diabetes. METHODS: This was a cohort study of 148 pregnant women with pregestational diabetes (118 with Type 1 diabetes and 30 with Type 2 diabetes), who completed three internationally validated questionnaires: the 36-item Short-Form Health Survey, the Hospital Anxiety and Depression Scale and the Multidimensional Health Locus of Control survey at 8 weeks. Selected pregnancy outcomes were preterm delivery (< 37 weeks) and large for gestational age infants (birth weight > 90(th) percentile). Differences between groups in the questionnaires were analysed using an unpaired t-test. RESULTS: Women with preterm deliveries (n = 28) had lower (i.e. worse) mean (sd) quality-of-life scores for the two 36-item Short-Form Health Survey scales, Role-Emotional [58.3 (38.1) vs. 82.9 (31.3); P = 0.0005] and Mental Health [67.7 (20.4) vs. 75.2 (15.8), P = 0.04], and a lower score for the 36-item Short-Form Health Survey scale Mental Component Summary (42.8 (13.1) vs. 48.8 (9.7), P = 0.03) in early pregnancy, compared with women with term deliveries. Depression symptoms (Hospital Anxiety and Depression Scale depression score ≥ 8) were more frequent in women with preterm vs. term deliveries (seven (25%) vs. six women (5%); P = 0.003), while levels of anxiety and locus of control were similar in these two groups. No difference in early pregnancy scores for health-related quality of life, anxiety, depression and locus of control were seen in women delivering large or appropriate for gestational age infants. CONCLUSIONS: Poor mental quality of life and the presence of depressive symptoms in early pregnancy were associated with preterm delivery in women with pregestational diabetes.

Posttraumatic hypopituitarism is associated with an unfavorable body composition and lipid profile, and decreased quality of life 12 months after injury.

OBJECTIVE: Our objective was to describe body composition, lipid profile, and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) in relation to the development of posttraumatic hypopituitarism. DESIGN: This is a cross-sectional evaluation with a nested prospective substudy. PATIENTS: The cross-sectional cohort included 104 hospitalized patients with TBI [26 females/78 males; median age 41 yr (range 18-64); body mass index (BMI) 25 kg/m(2) (range 17-39); and severity, mild (Glasgow Coma Scale score (GCS) 13-15) n = 44, moderate (GCS 9-12) n = 20, and severe (GCS <9) n = 40)]. A nested cohort of 46 patients was followed prospectively. MEASUREMENTS: BMI, waist circumference, lipid profile, total- and regional-fat mass were assessed 3 and 12 months (prospective) or only 12 months (cross-sectional) posttraumatically. HRQL questionnaires (Nottingham Health Profile, EuroQoL-5D, and the GH deficiency (GHD) specific instrument, Quality of Life Assessment of GHD in Adults) were completed "pre-traumatically," 3 and 12 months (prospective), or only 12 months (cross-sectional) posttraumatically. RESULTS: Patients with posttraumatic hypopituitarism had higher age-, gender-, and BMI-adjusted 12-month low-density lipoprotein-cholesterol, waist circumference, and total fat mass (P < 0.05 in all cases), and a higher increase in total cholesterol (P = 0.01) during follow-up compared with sufficient patients. These findings were unrelated to 12-month IGF-I and IGF-I sd scores. Hypopituitary patients also had worse age, BMI, and TBI severity adjusted overall EuroQoL-5D visual analog scale (P = 0.03) and Quality of Life Assessment of GHD in Adults (P = 0.01) scores, and worse Nottingham Health Profile dimension scores of sleep (P = 0.03), energy (P = 0.02), and social isolation (P = 0.04), compared with patients with an intact pituitary function. CONCLUSION: Posttraumatic hypopituitarism was an independent predictor of the classical phenotypical features of hypopituitarism, including an unfavorable lipid and body composition profile, as well as worsened HRQL.

A consolidated analysis of the physiologic and molecular responses induced under acid stress in the legume-symbiont model-soil bacterium Sinorhizobium meliloti.

Abiotic stresses in general and extracellular acidity in particular disturb and limit nitrogen-fixing symbioses between rhizobia and their host legumes. Except for valuable molecular-biological studies on different rhizobia, no consolidated models have been formulated to describe the central physiologic changes that occur in acid-stressed bacteria. We present here an integrated analysis entailing the main cultural, metabolic, and molecular responses of the model bacterium Sinorhizobium meliloti growing under controlled acid stress in a chemostat. A stepwise extracellular acidification of the culture medium had indicated that S. meliloti stopped growing at ca. pH 6.0-6.1. Under such stress the rhizobia increased the O2 consumption per cell by more than 5-fold. This phenotype, together with an increase in the transcripts for several membrane cytochromes, entails a higher aerobic-respiration rate in the acid-stressed rhizobia. Multivariate analysis of global metabolome data served to unequivocally correlate specific-metabolite profiles with the extracellular pH, showing that at low pH the pentose-phosphate pathway exhibited increases in several transcripts, enzymes, and metabolites. Further analyses should be focused on the time course of the observed changes, its associated intracellular signaling, and on the comparison with the changes that operate during the sub lethal acid-adaptive response (ATR) in rhizobia.

A case-control study of diet in newly diagnosed NIDDM in the Wanigela people of Papua New Guinea.

OBJECTIVE--To study the association between diet and newly diagnosed NIDDM in the Wanigela people of Papua New Guinea, a population with an extraordinary susceptibility for NIDDM. RESEARCH DESIGN AND METHODS--We performed a case-control study of Wanigela people from an urban settlement (Koki). Case patients (n = 145) were asymptomatic subjects in whom NIDDM was newly diagnosed using a 2-h 75-g oral glucose tolerance test. Control subjects with glucose tolerance (n = 140) were group-matched on the basis of age and sex. A detailed food frequency questionnaire was used to determine energy and nutrient intakes. Nutrient intakes were compared directly and after calculation of residuals to correct for energy intake. Odds ratios for NIDDM were computed in relation to total energy and specific nutrient intakes, adjusting for age, sex, BMI, waist-to-hip ratio, and physical activity. RESULTS--There were no differences between case patients and control subjects in mean values of total energy-adjusted nutrient intakes. In logistic regression models, neither total energy nor any specific nutrients were associated with increased risk of NIDDM. When models were repeated with nutrients categorized by textiles, there were marginally significant associations with intakes of fiber (positive) and cholesterol, protein, and sugar (negative). CONCLUSIONS--This study does not support the hypothesis that saturated fat is an independent risk factor for NIDDM. The weak associations of intakes of fiber and cholesterol with newly diagnosed NIDDM were in the opposite directions to those expected and are probably due to chance. Relative homogeneity of diet within a community, such as that found in Koki, makes it difficult to demonstrate risk factor-disease associations. However, changes in diet and reduced levels of physical activity accompanying urbanization undoubtedly contribute to the high prevalence of obesity observed in this community, and hence diet is likely to contribute to NIDDM risk at least by indirect means.

Muscle thickness, measured with ultrasound, may be an indicator of lean tissue wasting in multiple organ failure in the presence of edema.

Multiple organ failure (MOF) is accompanied by muscle wasting, but changes in body composition are frequently obscured by fluid retention (edema), mainly in superficial and visceral tissue. There is a need to assess body composition and changes in body composition in these circumstances independently of edema. A relation was sought between fat-free (lean tissue) mass [calculated from body weight and skinfold thicknesses and measured by using dual-energy X-ray absorptiometry (DXA)] and muscle thickness (measured using ultrasound at a variety of sites accessible in an unconscious supine subject) to determine which sites correlated best with lean body mass. The three best sites were midbiceps, midforearm anteriorly, and midthigh anteriorly: R2 for the simple sum of the three sites correlated with fat-free mass from skinfold thicknesses was 71.1%, and with lean tissue mass from DXA was 76.1%. Serial measurements of both muscle thickness and midupper-arm circumference in nine patients with MOF showed a complete dissociation; in all nine there was a significant negative correlation of muscle thickness with time (P < 0.05) but changes in arm circumference were random. Only one patient showed a significant negative correlation with time, seven showed no change, and one other showed a significant increase. The muscle thicknesses that correlate best with lean body mass are measured over the biceps, anterior forearm, and anterior thigh. Monitoring muscle thicknesses at these three sites identifies wasting in edematous patients as it is happening.

Posterior fascicular block versus posteroinferior myocardial infarction in left posterior excitation disturbances.

To delineate electrocardiographic similarities and differences in ventricular depolarization between left posterior fascicular block and posteroinferior myocardial infarction, these lesions were produced in two and three stage experiments in dogs and baboons. The observed QRS changes of left posterior fascicular block were found to be immediate, little influenced by healing of the acute lesion, and partially correctable by pacing viable myocardium distal to the block. In contrast, the QRS changes of posteroinferior myocardial infarction occurred later with cicatrization and were essentially unaffected by pacing. The intrinsic deflection in direct posterior epicardial leads was more delayed by left posterior fascicular block than by posteroinferior myocardial infarction. Both lesions accounted for Q waves in leads II, III and aVF. However, R amplitude in these same leads was increased after left posterior fascicular block but decreased after posteroinferior myocardial infarction. The mean QRS axis in the frontal plane was shifted toward the vertical in left posterior fascicular block but little changed or shifted slightly away from the vertical in posteroinferior myocardial infarction. When left posterior fascicular block and posteroinferior myocardial infarction coexist, there may be masking, imitation or enhancement of the effects of one lesion by the presence of the other. To assist in recognition, distinguishing features are described.

Tests of data quality, scaling assumptions, and reliability of the Danish SF-36.

We used general population data (n = 4084) to examine data completeness, response consistency, tests of scaling assumptions, and reliability of the Danish SF-36 Health Survey. We compared traditional multitrait scaling analyses to analyses using polychoric correlations and Spearman correlations. The frequency of missing values was low, except for elderly people and people with lower levels of education. Response consistency was high and compared well with results for the U.S. SF-36. For respondents with computable scales in all eight domains, scaling assumptions (item internal consistency, item discriminant validity, equal item-own scale correlations, and equal variances) were satisfactory in the total sample and in all subgroups. The SF-36 could discriminate between levels of health in all subgroups, but there were skewness, kurtosis, and ceiling effects in many subgroups (elderly people and people with chronic diseases excepted). Concerning correlation methods, we found interesting differences indicating advantages of using methods that do not assume a normal distribution of answers as an addition to traditional methods.

Fatigue in the Danish general population. Influence of sociodemographic factors and disease.

OBJECTIVE: To measure the levels of fatigue in the general population, and to examine how disease and sociodemographic factors influence fatigue. DESIGN: Cross sectional questionnaire study in the Danish general population. SUBJECTS: A random, age stratified sample of 1608 people aged 20-77 with an equal gender distribution (response rate 67%). MAIN OUTCOME MEASURES: Five fatigue scales from the questionnaire Multidimensional Fatigue Inventory: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation and Mental Fatigue. RESULTS: Fatigue scores were skewed towards absence of fatigue. The General Fatigue and Physical Fatigue scales showed the highest fatigue levels while the Reduced Motivation scale showed lowest levels. Gender differences in fatigue scores were small, but the variability among women was higher-that is, more women had high scores. A multiple linear regression analysis showed that respondents of low social status and respondents with a depression had high fatigue scores on all scales, independent of other factors. Chronic somatic disease had an independent direct effect on Mental Fatigue, but for the rest of the scales, the effect of somatic disease depended on age, gender and/or whether the person was living alone. For example, General and Physical Fatigue decreased with age among healthy people, whereas scores on these scales increased with age among those with a somatic disease. CONCLUSIONS: Physical and mental diseases play essential parts for the level of fatigue and as modulators of the associations between sociodemographic factors and fatigue. These interactions should be taken into account in future research on fatigue and sociodemographic factors and when data from clinical studies are compared with normative data from the general population.

Dilantin toxicity presenting as mutism following severe head injury: case report.

A case is presented in which a patient was placed on phenytoin following open depressed skull fracture. He subsequently was lost to follow-up, and then presented with several complaints, among them mutism, found to be related to phenytoin toxicity. There are no reports to date of this condition being caused by phenytoin. The issue is again raised of the risk versus benefits of long-term anticonvulsant prophylaxis following severe head injury.

Increased risk of long-term sickness absence, lower rate of return to work, and higher risk of unemployment and disability pensioning for thyroid patients: a Danish register-based cohort study.

CONTEXT: Little is known about how thyroid diseases affect work ability. OBJECTIVE: The objective of this study was to evaluate the risk of work disability for patients with thyroid disease compared with the general population. DESIGN, SETTING, AND PARTICIPANTS: In a longitudinal register study, outpatients (n = 862) with nontoxic goiter, hyperthyroidism, Graves' orbitopathy (GO), autoimmune hypothyroidism, or other thyroid diseases and their matched controls (n = 7043) were observed in the years 1994-2011 in Danish national registers of social benefits, health, and work characteristics. Cox regression analyses estimated adjusted hazard ratios (HRs) for the first year after diagnosis and subsequent years. MAIN OUTCOME MEASURES: Transitions between work, long-term sickness absence, unemployment, and disability pension were measured. RESULTS: Patients differed significantly from the general population with regard to sickness absence, disability pension, return from sickness absence, and unemployment. In the first year after diagnosis, higher risks of sickness absence was seen for GO (HR 6.94) and other hyperthyroid patients (HR 2.08), who also had lower probability of returning from sickness absence (HR 0.62) and higher risk of disability pension (HR 4.15). Patients with autoimmune hypothyroidism showed a lower probability of returning from sickness absence (HR 0.62). In subsequent years, GO patients had significantly higher risk of sickness absence (HR 2.08), lower probability of return from sickness absence (HR 0.51), and unemployment (HR 0.52) and a higher risk of disability pension (HR 4.40). Hyperthyroid patients also had difficulties returning from sickness absence (HR 0.71). CONCLUSIONS: Thyroid patients' risk of work disability is most pronounced in the first year after diagnosis and attenuates in subsequent years. GO patients have the highest risk of work disability.

Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131)I therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study.

BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.