Interactions between the aging brain and motor task complexity across the lifespan: balancing brain activity resource demand and supply.

The Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) proposes a framework for understanding task-related brain activity changes as a function of healthy aging and task complexity. Specifically, it affords the following predictions: (i) all adult age groups display more brain activation with increases in task complexity, (ii) older adults show more brain activation compared with younger adults at low task complexity levels, and (iii) disproportionately increase brain activation with increased task complexity, but (iv) show smaller (or no) increases in brain activation at the highest complexity levels. To test these hypotheses, performance on a bimanual tracking task at 4 complexity levels and associated brain activation were assessed in 3 age groups (20-40, 40-60, and 60-80 years, n = 99). All age groups showed decreased tracking accuracy and increased brain activation with increased task complexity, with larger performance decrements and activation increases in the older age groups. Older adults exhibited increased brain activation at a lower complexity level, but not the predicted failure to further increase brain activity at the highest complexity level. We conclude that older adults show more brain activation than younger adults and preserve the capacity to deploy increased neural resources as a function of task demand.

Changes in quality of life after thyroidectomy in subjects with thyroid cancer in relation to the dose of levothyroxine.

PURPOSE: Previous studies demonstrated decreased quality of life (QoL) in differentiated thyroid cancer (DTC) survivors and suggested QoL variability related to time from thyroidectomy and levothyroxine dosage. The aims of this study were to evaluate QoL in thyroidectomized subjects in different levothyroxine states and to evaluate the association between TSH and thyroid hormones and QoL. METHODS: Prospective 5-year study enrolling 208 patients thyroidectomized for DTC, studied in one to four times according to levothyroxine dosage: withdrawal (WITHD), complete (C-SUPP) and mild TSH-suppression (M-SUPP), replacement (REPL). Each patient was allowed to participate into the study more than one time. A total of 300 evaluations were collected, consisting of detailed thyroid hormone profile and QoL assessment through the ThyPRO questionnaire. RESULTS: Comparing the four groups, significant differences were found for anxiety, impaired social and daily life and item 12 (overall impact of thyroid disease) domains (p < 0.05). Interestingly, C-SUPP subjects reported the best scores in almost all ThyPRO scales. Significant correlations were found between QoL and pituitary-thyroid axis function, as well as between QoL and gender, being females more affected. At multiple regression analyses fT3 demonstrated to be the best explanatory factor for overall impact of thyroid disease on the patient's life, followed by gender. CONCLUSIONS: TSH-suppressive doses of levothyroxine are more effective in improving QoL in DTC patients after thyroidectomy. These results confirm the urgent need of further studies aimed to define the best treatment of hypothyroidism, effective on well-being and harmless for patients.

Human chorionic gonadotropin and risk of pre-eclampsia: prospective population-based cohort study.

OBJECTIVES: Abnormal placentation in early pregnancy may play a role in the pathogenesis of pre-eclampsia. Human chorionic gonadotropin (hCG) regulates placental development and angiogenesis and may affect the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the serum. The aims of this study were to investigate the association of total hCG with the risk of pre-eclampsia and to examine the potential effect of pro- and anti-angiogenic factors on this association. METHODS: This was a population-based prospective cohort study of 7754 women with a singleton pregnancy. Total hCG was measured in the first available sample (median gestational age, 14.4 weeks; 95% range, 10.1-26.1 weeks) and sFlt-1 and PlGF concentrations in early (< 18 weeks; median, 13.2 weeks; 95% range, 9.6-17.6 weeks) and in mid- (18-25 weeks; median, 20.4 weeks; 95% range, 18.5-23.5 weeks) pregnancy. We tested the association of hCG concentration and risk of pre-eclampsia using regression analysis, adjusting for maternal age, ethnicity, body mass index, parity, education level, smoking status and fetal sex. Additionally, we assessed whether this association was affected by the sFlt-1/PlGF ratio. RESULTS: High hCG concentration was associated with a 1.5-2.7-fold increased risk of pre-eclampsia (P = 0.0001), depending on the cut-off used, and with increased sFlt-1/PlGF ratio during early pregnancy (P < 0.0001). The association between high hCG and pre-eclampsia attenuated by roughly 40% after adjustment for early-pregnancy sFlt-1/PlGF ratio (ß-estimate change from 0.19 ± 0.10 (P = 0.052) to 0.12 ± 0.10 (P = 0.22)). CONCLUSIONS: High total hCG concentration in early pregnancy is associated with an increased risk of pre-eclampsia. The effect of high hCG concentration on the balance between pro- and anti-angiogenic factors during pregnancy may have a role in the pathophysiology of pre-eclampsia. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss. METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

The nocebo effect challenges the non-medical infliximab switch in practice.

BACKGROUND: In clinical practice, non-medical switching of biological medication may provoke nocebo effects due to unexplained deterioration of therapeutic benefits. Indication extrapolation, idiosyncratic reactions, and interchangeability remain challenged in clinical practice after biosimilar approval by the European Medicines Agency. The principle of "first do no harm" may be challenged in a patient when switching from originator to biosimilar biological. AIM: To describe the 1-year results of a pragmatic study on infliximab biosimilar implementation in immune-mediated inflammatory disease patients on the basis of shared decision-making under effectiveness and safety monitoring. METHODS: Inflammatory bowel disease and rheumatology patients on infliximab originator were converted to infliximab biosimilar after providing informed consent. Nocebo response patients were monitored after switch back to originator. Linear mixed models were used to analyze continuous endpoints on effectiveness and laboratory outcomes to determine significance (P ≤ 0.05) of change over time after switching. RESULTS: After inviting 146 patients, a group of 125 patients enrolled in the project over time, respectively, 73 Crohn's disease, 28 ulcerative colitis, nine rheumatoid arthritis, ten psoriatic arthritis, and five ankylosing spondylitis patients. No statistically significant changes in effectiveness and safety were observed in any of the indications after a median of 4 infusions in 9 months of study. An overall nocebo response of 12.8% was found among the patients during a minimal observation period of 6 months after the transition to biosimilar infliximab. The overall nocebo response rate did not differ between the studied indications. CONCLUSIONS: In inflammatory bowel disease and rheumatological patients, similar effectiveness and safety were demonstrated on the transition into infliximab biosimilar. In our series, patient empowerment and registration of treatment outcomes delineated biosimilar transition, an approach that hypothetically could reduce nocebo response rates which are relevant to account for regarding biosimilar implementation.

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).

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

The association of maternal thyroid function with placental hemodynamics.

STUDY QUESTION: What is the clinical association of maternal thyroid function with placental hemodynamic function? SUMMARY ANSWER: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance. WHAT IS KNOWN ALREADY: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion. STUDY DESIGN, SIZE, DURATION: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHOD: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women. MAIN RESULTS AND THE ROLE OF CHANCE: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively. LIMITATIONS, REASONS FOR CAUTION: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes. WIDER IMPLICATIONS OF THE FINDINGS: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Method selection for sustainability assessments: The case of recovery of resources from waste water.

Sustainability assessments provide scientific support in decision procedures towards sustainable solutions. However, in order to contribute in identifying and choosing sustainable solutions, the sustainability assessment has to fit the decision context. Two complicating factors exist. First, different stakeholders tend to have different views on what a sustainability assessment should encompass. Second, a plethora of sustainability assessment methods exist, due to the multi-dimensional characteristic of the concept. Different methods provide other representations of sustainability. Based on a literature review, we present a protocol to facilitate method selection together with stakeholders. The protocol guides the exploration of i) the decision context, ii) the different views of stakeholders and iii) the selection of pertinent assessment methods. In addition, we present an online tool for method selection. This tool identifies assessment methods that meet the specifications obtained with the protocol, and currently contains characteristics of 30 sustainability assessment methods. The utility of the protocol and the tool are tested in a case study on the recovery of resources from domestic waste water. In several iterations, a combination of methods was selected, followed by execution of the selected sustainability assessment methods. The assessment results can be used in the first phase of the decision procedure that leads to a strategic choice for sustainable resource recovery from waste water in the Netherlands.

Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer.

BACKGROUND: Levothyroxine (LT4) is the standard of care in patients with hypothyroidism. Despite this replacement therapy, quality of life (QoL) remains impaired in a substantial amount of patients. The reasons for this are still a matter of debate. Suggested causes include lack of endogenous T3 secretion by the thyroid, changes in other thyroid hormone metabolites and interference by autoimmune processes. OBJECTIVE: To investigate the association between thyroid function tests (TFTs) and QoL in patients with a history of differentiated thyroid cancer on LT4 monotherapy. These patients lack endogenous thyroidal T3 secretion in the absence of autoimmune disease. MATERIALS AND METHODS: This is a cross-sectional study in 143 patients (69·2% female). Initial therapy consisted of total thyroidectomy followed by radioiodine ablation minimally one year before inclusion. We assessed health-related QoL (RAND-36), thyroid-specific QoL (ThyPRO) and fatigue with the Multidimensional Fatigue Inventory. Extensive TFTs were assessed, including 3,5-diiodo-L-thyronine (3,5-T2). RESULTS: Mean age was 50·2 years and mean time since diagnosis was 8·4 years. Median TSH was 0·042 mU/l, total T4 145·0 nmol/l, free T4 25·6 pmol/l, total T3 1·93 nmol/l, reverse T3 0·53 nmol/l and 3,5-T2 0·86 nmol/l. Multiple linear regression analyses did not show any association between QoL and the different TFTs, including T4/T3 and 3,5-T2/T3 ratios reflecting peripheral metabolism. CONCLUSION: We did not find any association between TFTs and QoL in athyreotic patients on LT4 monotherapy. Our data do not provide evidence that a slight increase in dose improves fatigue or well-being in hypothyroid patients on LT4 therapy.

A human homologue of monkey F5c.

Area F5c is a monkey premotor area housing mirror neurons which responds more strongly to grasping observation when the actor is visible than when only the actor's hand is visible. Here we used this characteristic fMRI signature of F5c in seven imaging experiments - one in macaque monkeys and six in humans - to identify the human homologue of monkey F5c. By presenting the two grasping actions (actor, hand) and varying the low level visual characteristics, we localized a putative human homologue of area F5c (phF5c) in the inferior part of precentral sulcus, bilaterally. In contrast to monkey F5c, phF5c is asymmetric, with a right-sided bias, and is activated more strongly during the observation of the later stages of grasping when the hand is close to the object. The latter characteristic might be related to the emergence, in humans, of the capacity to precisely copy motor acts performed by others, and thus imitation.

Reliability of Repeated Measurements on Post-Burn Scars with Corneometer CM 825(®).

BACKGROUND/PURPOSE: The water content in burn scars, the parameter of stratum corneum water holding capacity, is an important feature in evaluation of biophysical properties of scars. Nevertheless, quantifiying this parameter is a challenge. In this study, the reliability of repeated water content measurements with Corneometer CM825(®) on (burn) scars was investigated. METHODS: Intra-observer reliability, inter-observer reliability and day-by-day variability were examined on 30 scars by means of intra-class correlation coefficient (ICC) and within-subject coefficient of variation (WSCV). Bland-Altman plots with '95% limits of agreement' were constructed. RESULTS: Results revealed excellent ICC values (ICCintra  = 0.985; ICCinter  = 0.984) with relatively low WSCV (WSCVintra  = 6.3%; WSCVinter  = 10.6%) for respectively intra- and inter-observer reliability. However, the Bland-Altman plot showed that more than 5% of differences were expected to exceed 4 a.u., the limit of what has been defined as a clinically acceptable difference. Results for day-by-day variability showed good ICC value (ICCday-by-day  = 0.849) and higher WSCV (WSCVday-by-day  = 20.5%). CONCLUSION: The Corneometer CM825(®) is an objective and sensitive instrument for water content measurements. On the basis of our results, we concluded that the instrument can be used in clinical trials, but only under very strict conditions with standardized test protocol, preferably in combination with the evaluation of other physiological parameters.

Noninvasive reconstruction of cardiac electrical activity: update on current methods, applications and challenges.

Electrical activity at the level of the heart muscle can be noninvasively reconstructed from body-surface electrocardiograms (ECGs) and patient-specific torso-heart geometry. This modality, coined electrocardiographic imaging, could fill the gap between the noninvasive (low-resolution) 12-lead ECG and invasive (high-resolution) electrophysiology studies. Much progress has been made to establish electrocardiographic imaging, and clinical studies appear with increasing frequency. However, many assumptions and model choices are involved in its execution, and only limited validation has been performed. In this article, we will discuss the technical details, clinical applications and current limitations of commonly used methods in electrocardiographic imaging. It is important for clinicians to realise the influence of certain assumptions and model choices for correct and careful interpretation of the results. This, in combination with more extensive validation, will allow for exploitation of the full potential of noninvasive electrocardiographic imaging as a powerful clinical tool to expedite diagnosis, guide therapy and improve risk stratification.

The thyroid axis 'setpoints' are significantly altered after long-term suppressive LT4 therapy.

The aim of the study was to investigate the changes in the thyroid axis setpoint after long-term suppressive levothyroxine therapy for differentiated thyroid carcinoma and the resulting changes in levothyroxine requirement. Ninety-nine differentiated thyroid cancer patients were reviewed. All patients had at least one known TSH-level≥0.01 mU/l (lower detection limit) and <1.0 mU/l within 2 years of initial treatment (time 1) and had at least one TSH-value≥0.01 mU/l and <1.0 mU/l after continuous LT4 therapy for a minimum of 5 years (time 2).At time 2 the mean LT4 dosage/kg body weight, TSH, FT3, and FT4 levels were significantly lower than at time 1, while body weight was higher. At time 2, the FT3/FT4 ratio rate had dropped significantly (p<0.001). At time 1, patients would require 2.96 µg/kg body weight to reach total TSH suppression. The dose of levothyroxine/kg required for suppression can be lowered by about 0.05 µg/kg body weight for each year of suppressive therapy. After a median of 12.7 years of continuous suppressive levothyroxine therapy, patients would require 2.25 µg/kg body weight (-23.5%) to reach total TSH-suppression. At least part of this reduction was independent of aging. As a result of changes in thyroid hormone metabolism and thyroid axis setpoint, long-term TSH-suppressive therapy contributes to a reduction in the dosage of levothyroxine per kilogram body weight required for full TSH suppression over time.

Identifying barriers to vaccination intention at walk-in vaccination facilities in deprived neighbourhoods: A cross-sectional survey.

OBJECTIVES: Low COVID-19 vaccination adherence in deprived neighbourhoods is problematic since the prevalence of chronic diseases associated with mortality rates due to COVID-19 is higher in these populations. The aim of this study is to provide an insight about beliefs and considerations relating to vaccination intention among inhabitants of deprived neighbourhoods in the Netherlands. DESIGN: Cross-sectional survey. SETTING: Easily accessible vaccination facilities at markets in deprived neighbourhoods in the Netherlands. PARTICIPANTS: Participants were recruited at three vaccination facilities that were set up at markets in deprived neighbourhoods in Rotterdam. A total of 124 surveys were retained for analysis. MAIN OUTCOME MEASURE: Intention to get vaccinated against COVID-19. RESULTS: The survey was filled out by 124 respondents; 62 % had - prior to visiting the easily accessible locations - intended to get a COVID-19 vaccine and 38 % were hesitant (22.3 % had doubts and 15.7 % did not plan to get vaccinated). Many people mentioned the convenience of an easily accessible location nearby. At the bivariate level, the influence of information from the family was associated with vaccination intention (p < 0.01). In a logistic regression model, both fear of vaccination and fear of side-effects were significantly associated with vaccination intention (ORs 0.56 (CI 0.35-0.89) and 0.47 (CI 0.30-0.73)). CONCLUSION: The accessibility of a vaccination facility, family influence and fear are relevant factors for the intention to get vaccinated against COVID-19 in people living in deprived neighbourhoods. Interventions should address these factors in order to increase vaccination uptake.

Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol.

Background: Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis: The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination: Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

Spinal cord stimulation modulates cerebral function: an fMRI study.

INTRODUCTION: Although spinal cord stimulation (SCS) is widely used for chronic neuropathic pain after failed spinal surgery, little is known about the underlying physiological mechanisms. This study aims to investigate the neural substrate underlying short-term (30 s) SCS by means of functional magnetic resonance imaging in 20 patients with failed back surgery syndrome (FBSS). METHODS: Twenty patients with FBSS, treated with externalized SCS, participated in a blocked functional magnetic resonance imaging design with stimulation and rest phases of 30 s each, repeated eight times in a row. During scanning, patients rated pain intensity over time using an 11-point numerical rating scale with verbal anchors (0 = no pain at all to 10 = worst pain imaginable) by pushing buttons (left hand, lesser pain; right hand, more pain). This scale was back projected to the patients on a flat screen allowing them to manually direct the pain indicator. To increase the signal-to-noise ratio, the 8-min block measurements were repeated three times. RESULTS: Marked deactivation of the bilateral medial thalamus and its connections to the rostral and caudal cingulate cortex and the insula was found; the study also showed immediate pain relief obtained by short-term SCS correlated negatively with activity in the inferior olivary nucleus, the cerebellum, and the rostral anterior cingulate cortex. CONCLUSIONS: Results indicate the key role of the medial thalamus as a mediator and the involvement of a corticocerebellar network implicating the modulation and regulation of averse and negative affect related to pain. The observation of a deactivation of the ipsilateral antero-medial thalamus might be used as a region of interest for further response SCS studies.