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Zi-Wei Yu,1,&ast; Sheng-Dan Pu,2,&ast; Xiao-Tong Sun,2 Xi-Chang Wang,1 Xin-Yuan Gao,2 Zhong-Yan Shan1 1Department of Endocrinology and Metabolism and the Institute of Endocrinology, The NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong-Yan Shan; Xin-Yuan Gao, Tel +8613804905018 ; +8613904517001, Email cmushanzhongyan@163.com; m15124768260@163.comPurpose: The prevalence of mild cognitive impairment (MCI) in patients with type 2 diabetes (T2D) is rapidly increasing. Thyroid hormones are key regulators of cognitive function in adults. The purpose of this study was to investigate the relationship between thyroid hormone sensitivity and MCI in euthyroid T2D patients.Patients and Methods: A total of 400 euthyroid T2D patients were enrolled in this cross-sectional study, including 218 patients with normal cognition and 182 MCI patients. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function. The free triiodothyronine to free thyroxine (FT3/FT4) ratio was calculated as a measure of peripheral sensitivity to thyroid hormones; the thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI) and thyroid feedback quantile-based index (TFQI) were calculated as measures of central sensitivity to thyroid hormones. Linear regression analysis and logistic regression analysis were performed to explore the relationships between these indices of thyroid hormone sensitivity and the MoCA score and MCI, respectively.Results: Compared with the normal cognitive function group, patients in the MCI group had higher TSHI, TT4RI and TFQI but a lower FT3/FT4 ratio (P< 0.05). The MoCA score was positively correlated with the FT3/FT4 ratio but negatively correlated with TSHI, TT4RI and TFQI (P< 0.05). Multivariate logistic regression analysis showed that a low FT3/FT4 ratio and high TSHI, TT4RI and TFQI were independently associated with MCI (P< 0.05). After adjustment for confounding factors, the odds ratio (OR) for the association between MCI and the highest tertile of the FT3/FT4 was 0.455 (95% CI: 0.264– 0.785), for the highest tertile of TSHI, the OR was 2.380 (95% CI: 1.376– 4.119), for the highest tertile of TT4RI, the OR was 2.342 (95% CI:1.353– 4.054), and for the highest tertile of TFQI, the OR was 2.536 (95% CI: 1.466– 4.387) (P< 0.05).Conclusion: Impaired sensitivity to thyroid hormones is associated with MCI in euthyroid T2D patients.Keywords: type 2 diabetes, mild cognitive impairment, thyroid hormones, sensitivity to thyroid hormones

Background: The Stroop task was used to investigate differences in cognitive function between Long COVID (LC), Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and healthy control subjects., Methods: Subjects viewed four color words or neutral (XXXX) stimuli with the same (congruent) or different color ink (incongruent). Cognitive conflict was inferred from response times for pairings of prestimuli and subsequent stimuli. Overall effects were assessed by univariate analysis with time courses determined for binned response times., Results: LC and ME/CFS had significantly longer response times than controls indicating cognitive dysfunction. Initial response times were ranked LC > ME > HC, and decreased according to power functions. At the end of the task (900s), times were ranked LC = ME > HC. Response times were significantly slower for stimuli following an incongruent prestimulus. Time series for Stroop effect, facilitation, interference, surprise index and practice power law parameters were generally similar in LC, ME/CFS and HC suggesting comparable patterns for recruitment of cognitive resources. The prestimulus data were analyzed and generated positive Stroop and interference effects that were distinct from stimulus effects., Conclusion: LC and ME/CFS have global slowing of response times that cannot be overcome by practice suggesting impaired communications between network nodes during problem solving. Analysis of matched prestimulus - stimulus effects adds a new dimension for understanding cognitive conflict., Brief Summary: Cognitive dysfunction in Long COVID and ME/CFS was demonstrated using the Stroop task which found global slowing of response times and limitations of practice effects., (© 2024. The Author(s).)

Background: The brainstem is a crucial component of the central autonomic nervous (CAN) system. Functional MRI (fMRI) of the brainstem remains challenging due to a range of factors, including diverse imaging protocols, analysis, and interpretation., Purpose: To develop an fMRI protocol for establishing a functional atlas in the brainstem., Study Type: Prospective cross-sectional study., Subjects: Ten healthy subjects (four males, six females)., Field Strength/sequence: Using a 3.0 Tesla MR scanner, we acquired T1-weighted images and three different fMRI scans using fMRI protocols of the optimized functional Imaging of Brainstem (FIBS), the Human Connectome Project (HCP), and the Adolescent Brain Cognitive Development (ABCD) project., Assessment: The temporal signal-to-noise-ratio (TSNR) of fMRI data was compared between the FIBS, HCP, and ABCD protocols. Additionally, the main normalization algorithms (i.e., FSL-FNIRT, SPM-DARTEL, and ANTS-SyN) were compared to identify the best approach to normalize brainstem data using root-mean-square (RMS) error computed based on manually defined reference points. Finally, a functional autonomic brainstem atlas that maps brainstem regions involved in the CAN system was defined using meta-analysis and data-driven approaches., Statistical Tests: ANOVA was used to compare the performance of different imaging and preprocessing pipelines with multiple comparison corrections (P ≤ 0.05). Dice coefficient estimated ROI overlap, with 50% overlap between ROIs identified in each approach considered significant., Results: The optimized FIBS protocol showed significantly higher brainstem TSNR than the HCP and ABCD protocols (P ≤ 0.05). Furthermore, FSL-FNIRT RMS error (2.1 ± 1.22 mm; P ≤ 0.001) exceeded SPM (1.5 ± 0.75 mm; P ≤ 0.01) and ANTs (1.1 ± 0.54 mm). Finally, a set of 12 final brainstem ROIs with dice coefficient ≥0.50, as a step toward the development of a functional brainstem atlas., Data Conclusion: The FIBS protocol yielded more robust brainstem CAN results and outperformed both the HCP and ABCD protocols., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach., Methods: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy., Results: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (β = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (β = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (β = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10 -5 ). These findings remained robust in the sensitivity analyses., Conclusions: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship., Limitations: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The underlying brain mechanisms of ketamine in treating chronic suicidality and the characteristics of patients who will benefit from ketamine treatment remain unclear. To address these gaps, we investigated temporal variations of brain functional synchronisation in patients with suicidality treated with ketamine in a 6-week open-label oral ketamine trial. The trial's primary endpoint was the Beck Scale for Suicide Ideation (BSS). Patients who experienced greater than 50% improvement in BSS scores or had a BSS score less than 6 at the post-treatment and follow-up (10 weeks) visits were considered responders and persistent responders, respectively. The reoccurring and transient connectivity pattern (termed brain state) from 29 patients (45.6 years ± 14.5, 15 females) were investigated by dynamic functional connectivity analysis of resting-state functional MRI at the baseline, post-treatment, and follow-up. Post-treatment patients showed significantly more (FDR-Q = 0.03) transitions among whole brain states than at baseline. We also observed increased dwelling time (FDR-Q = 0.04) and frequency (FDR-Q = 0.04) of highly synchronised brain state at follow-up, which were significantly correlated with BSS scores (both FDR-Q = 0.008). At baseline, persistent responders had higher fractions (FDR-Q = 0.03, Cohen's d = 1.39) of a cognitive control network state with high connectivities than non-responders. These findings suggested that ketamine enhanced brain changes among different synchronisation patterns and enabled high synchronisation patterns in the long term, providing a possible biological pathway for its suicide-prevention effects. Moreover, differences in cognitive control states at baseline may be used for precise ketamine treatment planning., (© 2024. The Author(s).)

Thermal energy storage using phase change materials (PCMs) has great potential to reduce the weather dependency of sustainable energy sources. However, the low thermal conductivity of most PCMs is a long-standing bottleneck for large-scale practical applications. In modifications to increase the thermal conductivity of PCMs, the interfacial thermal resistance (ITR) between PCMs and discrete additives or porous networks reduces the effective thermal energy transport. In this work, we investigated the ITR between a metal (gold) and a polyol solid-liquid PCM (erythritol) at various temperatures including temperatures below the melting point (300 and 350 K), near the melting point (390, 400, 410 K, etc) and above the melting point (450 and 500 K) adopting non-equilibrium molecular dynamics. Since the gold-erythritol interfacial thermal conductance (ITC) is low regardless of whether erythritol is melted or not (<40 MW m -2 K -1 ), self-assembled monolayers (SAMs) were used to boost the interfacial thermal energy transport. The SAM with carboxyl groups was found to increase the ITC most (by a factor of 7-9). As the temperature increases, the ITC significantly increases (by ∼50 MW m -2 K -1 ) below the melting point but decreases little above the melting point. Further analysis revealed that the most obvious influencing factor is the interfacial binding energy. This work could build on existing composite PCM solutions to further improve heat transfer efficiency of energy storage applications in both liquid and solid states., (© 2024 IOP Publishing Ltd.)

Ongoing stress results in hippocampal neuro-structural alterations which produce pathological consequences, including depression and suicidality. Ketamine may ameliorate stress related illnesses, including suicidality, via neuroplasticity processes. This novel study sought to determine whether oral ketamine treatment specifically affects hippocampal (whole and subfield) volumes in patients with chronic suicidality and MDD. It was hypothesised that oral ketamine treatment would differentially alter hippocampal volumes in trial participants categorised as ketamine responders, versus those who were non-responders. Twenty-eight participants received 6 single, weekly doses of oral ketamine (0.5-3 mg/kg) and underwent MRI scans at pre-ketamine (week 0), post-ketamine (week 6), and follow up (week 10). Hippocampal subfield volumes were extracted using the longitudinal pipeline in FreeSurfer. Participants were grouped according to ketamine response status and then compared in terms of grey matter volume (GMV) changes, among 10 hippocampal regions, over 6 and 10 weeks. Mixed ANOVAs were used to analyse interactions between time and group. Post treatment analysis revealed a significant main effect of group for three left hippocampal GMVs as well in the left and right whole hippocampus. Ketamine acute responders (Week 6) showed increased GMVs in both left and right whole hippocampus and in three subfields compared to acute non-responders, across all three timepoints, suggesting that pre-treatment increased hippocampal GMVs (particularly left hemisphere) may be predictive biomarkers of acute treatment response. Future studies should further investigate the potential of hippocampal volumes as a biomarker of ketamine treatment response., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Ketamine has recently been proposed as a treatment option for suicidality. Whilst its mechanism of action has been explored at molecular levels, the effect on the brain at the organ level remains unclear. Here we investigate immediate post-treatment and prolonged large-scale resting-state neural network changes to elucidate the neuronal underpinnings associated with ketamine's therapeutic effects., Methods: Twenty-eight adults (aged 22-72 years) participated in the Oral Ketamine Trial On Suicidality, which is an open-label trial of weekly sub-anaesthetic doses of oral ketamine over 6 weeks. MRI was acquired at baseline, post-treatment, and follow-up. Functional connectivity changes at post-treatment and follow-up were examined using seed based and independent component analysis., Results: The seed-based connectivity analysis revealed significantly reduced connectivity at post-treatment from the right hippocampus to both right and left superior frontal gyrus, from the left anterior parahippocampus to right superior frontal gyrus, left superior frontal gyrus, right middle frontal gyrus, and left frontal operculum cortex. Compared with baseline, the ICA showed reduced anterior default mode network connectivities to bilateral posterior cingulate cortex, middle and anterior cingulate cortex, lingual gyrus, and cuneus and increased connectivity of the frontoparietal network to the right superior parietal lobule at post-treatment., Limitations: Open label pilot study., Conclusions: We have shown sub-anaesthetic doses of ketamine alters connectivity in networks which have been shown to be aberrantly hyper-connected in numerous psychiatric conditions. These neurocircuitry changes are supported by significant reductions in suicide ideation. Our results provide support for the use of ketamine as a treatment for suicidality., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Iodine is an essential trace element for human and an antioxidant. It not only participates in the synthesis of thyroid hormone, but also plays a role in metabolic diseases. Previous studies mainly focused on the effect of iodine on thyroid diseases, but ignored the effect on metabolism. After the implementation of the universal salt iodization (USI) of China, the possible consequences of excessive iodine were emphasized while the harm of iodine deficiency was forgetten. The paper re-examines the effects of iodine nutrition on thyroid diseases and metabolism. Iodine deficiency can lead to an increased risk of iodine deficiency disorders and thyroid diseases, and increase prevalence of metabolic syndrome and its components. Moderate iodine excess is beneficial to metabolism, but it can increase the risk of hyperthyroidism and subclinical hypothyroidism. The average urinary iodine concentration in 100-299 μg/L is the appropriate iodine nutrition state. According to the present iodized content of salt in China, iodized salt is an economical and effective way to ensure adequate iodine nutrition.

Objective: To observe the prevalence and related factors of thyroid diseases in different iodine intake areas from 2015 to 2017 after the implementation of national salt iodization policy in China for 20 years. Methods: A cross-sectional survey. Multi-stage stratified cluster random sampling was used to randomly select subjects meeting the inclusion criteria from 31 provinces, municipalities and autonomous regions in China from January 2015 to December 2017, and stratified by age and sex. The survey included questionnaire, physical examination and thyroid ultrasonography. At the same time, the concentrations of serum thyrotropin, thyroxine, thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb) and urinary iodine were measured.To determine whether the patient has a certain thyroid disease according to the above results. Different iodine nutrition areas were defined according to urinary iodine concentration, and the influence of iodine nutrition status in different iodine intake areas on thyroid diseases was analyzed. Results: A total of 78 470 adults were included, including 39 893 in the area of moderate iodine, 28 779 in the area of adequate iodine, and 9 798 in the area of excessive iodine.In the above three regions, the prevalence of subclinical hyperthyroidism (hyperthyroidism) was 0.45% (95% CI : 0.39%-0.52%), 0.50%(95% CI : 0.35%-0.70%)and 0.27%(95% CI : 0.20%-0.35%), respectively, with statistical significance( χ ²=6.92, P =0.003). The prevalence of subclinical hypothyroidism (hypothyroidism) was 11.36% (95% CI : 10.73%-12.02%), 13.57%(95% CI : 11.70%-15.69%) and 16.18%(95% CI : 12.41%-20.82%), respectively, with statistical significance( χ ²=5.08, P =0.009). The prevalence rates of Graves' disease, TPOAb, goiter and thyroid nodule among the three regions were statistically significant (all P <0.05). There were no significant differences in the prevalence of clinical hyperthyroidism and clinical hypothyroidism and the positive rate of TgAb among the three regions (all P >0.05). Multivariate logistic regression model analysis showed that excess iodine was a risk factor for subclinical hypothyroidism ( OR =1.24, 95% CI : 1.06-1.44), and a protective factor for thyroid nodules ( OR =0.73, 95% CI : 0.57-0.94). Iodine overdose was a risk factor for subclinical hypothyroidism ( OR =1.47, 95% CI : 1.08-2.01), while it was a protective factor for subclinical hyperthyroidism ( OR =0.56, 95% CI : 0.41-0.77), and TPOAb positive ( OR =0.93, 95% CI : 0.87-0.99), goiter ( OR =0.33, 95% CI : 0.17-0.66) and thyroid nodule ( OR =0.77, 95% CI : 0.61-0.97). Conclusions: There are significant differences in the prevalence of subclinical hyperthyroidism, subclinical hypothyroidism, positive TPOAb, thyroid nodule and goiter in different iodine intake regions. Different iodine intake levels have an effect on the incidence of thyroid diseases.

Background: Prediabetes risk assessment models derived from large sample sizes are scarce., Aim: To establish a robust assessment model for prediabetes and to validate the model in different populations., Methods: The China National Diabetes and Metabolic Disorders Study (CNDMDS) collected information from 47325 participants aged at least 20 years across China from 2007 to 2008. The Thyroid Disorders, Iodine Status and Diabetes Epidemiological Survey (TIDE) study collected data from 66108 participants aged at least 18 years across China from 2015 to 2017. A logistic model with stepwise selection was performed to identify significant risk factors for prediabetes and was internally validated by bootstrapping in the CNDMDS. External validations were performed in diverse populations, including populations of Hispanic (Mexican American, other Hispanic) and non-Hispanic (White, Black and Asian) participants in the National Health and Nutrition Examination Survey (NHANES) in the United States and 66108 participants in the TIDE study in China. C statistics and calibration plots were adopted to evaluate the model's discrimination and calibration performance., Results: A set of easily measured indicators (age, education, family history of diabetes, waist circumference, body mass index, and systolic blood pressure) were selected as significant risk factors. A risk assessment model was established for prediabetes with a C statistic of 0.6998 (95%CI: 0.6933 to 0.7063) and a calibration slope of 1.0002. When externally validated in the NHANES and TIDE studies, the model showed increased C statistics in Mexican American, other Hispanic, Non-Hispanic Black, Asian and Chinese populations but a slightly decreased C statistic in non-Hispanic White individuals. Applying the risk assessment model to the TIDE population, we obtained a C statistic of 0.7308 (95%CI: 0.7260 to 0.7357) and a calibration slope of 1.1137. A risk score was derived to assess prediabetes. Individuals with scores ≥ 7 points were at high risk of prediabetes, with a sensitivity of 60.19% and specificity of 67.59%., Conclusion: An easy-to-use assessment model for prediabetes was established and was internally and externally validated in different populations. The model had a satisfactory performance and could screen individuals with a high risk of prediabetes., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis. A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca 2+ influx in adjacent neurons and astrocytes. In turn, increased Ca 2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.This study investigates NVC using multimodal MRIs: (1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modeled from a cognitive task fMRI; (2) respiration response function (RRF) represents autoregulation of regional blood flow due to carbon dioxide and will be modeled from breath-holding fMRI; (3) neural activity associated glutamate changes will be modeled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework., Methods and Analysis: This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by consensus diagnosis made by two clinicians using the Canadian Consensus Criteria 2003. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, sex, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.The data will be randomly divided into a training ( N = 188) and a validation ( N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator-regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group., Ethics and Study Registry: This study was reviewed and approved by University of the Sunshine Coast University Ethics committee (A191288) and has been registered with The Australian New Zealand Clinical Trials Registry (ACTRN12622001095752)., Dissemination of Results: The results will be disseminated through peer reviewed scientific manuscripts and conferences and to patients through social media and active engagement with ME/CFS associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shan, Mohamed, Andersen, Rendall, Kwiatek, Fante, Calhoun, Bhuta and Lagopoulos.)

Each human brain has a unique functional synchronisation pattern (functional connectome) analogous to a fingerprint that underpins brain functions and related behaviours. Here we examine functional connectome (whole-brain and 13 networks) maturation by measuring its uniqueness in adolescents who underwent brain scans longitudinally from 12 years of age every four months. The uniqueness of a functional connectome is defined as its ratio of self-similarity (from the same subject at a different time point) to the maximal similarity-to-others (from a given subject and any others at a different time point). We found that the unique whole brain connectome exists in 12 years old adolescents, with 92% individuals having a whole brain uniqueness value greater than one. The cingulo-opercular network (CON; a long-acting 'brain control network' configuring information processing) demonstrated marginal uniqueness in early adolescence with 56% of individuals showing uniqueness greater than one (i.e., more similar to her/his own CON four months later than those from any other subjects) and this increased longitudinally. Notably, the low uniqueness of the CON correlates (β = -18.6, FDR-Q < < 0.001) with K10 levels at the subsequent time point. This association suggests that the individualisation of CON network is related to psychological distress levels. Our findings highlight the potential of longitudinal neuroimaging to capture mental health problems in young people who are undergoing profound neuroplasticity and environment sensitivity period., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We provided the dataset of brain connectome matrices, their similarities measures to self and others longitudinally, and Kessler's psychological distress scales (K10) including the response to each question. The dataset can be used to replicate the results of the manuscript titled "A longitudinal study of functional connectome uniqueness and its association with psychological distress in adolescence". The functional connectome (whole-brain and 13 networks) matrices were calculated from the resting-state functional MRIs (rs-fMRIs). We collected rs-fMRI and Kessler's psychological distress scale (K10) in 77 adolescents longitudinally up to 9 times from 12 years of age every four months. After removal of data with excessive motion, 262 functional connectome matrices were provided with this paper. The 300 regions of interest (ROIs) were defined using the Greene lab brain atlas. The functional connectome matrices were calculated as correlations between time series from any pair of ROIs extracted from pre-processed fMRIs. This dataset could be potentially used to1.Understand developmental changes in the functional brain connectivity,2.As a normal control database of functional connectome matrices,3.Develop and validate connectome and network-related analysing methods., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Developmental stuttering is thought to be underpinned by structural impairments in the brain. The only way to support the claim that these are causal is to determine if they are present before onset., Materials and Methods: Magnetic resonance imaging (MRI) was conducted on 18 neonates, aged 8-18 weeks, 6 of whom were determined to be genetically at risk of stuttering., Results: With tract-based spatial statistics (TBSS) analysis, no statistically significant differences were found between the at-risk group and the control group. However, fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) in the corpus callosum of the at-risk group were lower (uncorrected) than in the control group. Automated Fiber Quantification (AFQ) yielded lower FA in the at-risk group than in the control group in the medial section of the callosum forceps minor., Discussion: The findings, albeit with a small number of participants, support the proposition that reduced integrity of white matter in the corpus callosum has a causal role in developmental stuttering. Longitudinal research to determine if children with this impairment at birth later start to stutter is needed to confirm this. The left arcuate fasciculus is thought to develop as speech develops, which likely explains why there were no abnormal findings in this area in our at-risk neonates so soon after birth. This is the first study to investigate the brains of children before the onset of stuttering, and the findings warrant further research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To compare the efficacy and safety of Changsulin ® with Lantus ® in treating patients with type 2 diabetes mellitus (T2DM). Methods: This was a phase Ⅲ, multicenter, randomized, open-label, parallel-group, active-controlled clinical trial. A total of 578 participants with T2DM inadequately controlled on oral hypoglycemic agents were randomized 3∶1 to Changsulin ® or Lantus ® treatment for 24 weeks. The efficacy measures included changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2h postprandial plasma glucose (2hPG), 8-point self-monitoring of blood glucose (SMBG) profiles from baseline, and proportions of subjects achieving targets of HbA1c and FPG. The safety outcomes included rates of hypoglycemia, adverse events (AEs) and anti-insulin glargine antibody. Results: After 24 weeks of treatment, mean HbAlc decreased 1.16% and 1.25%, FPG decreased 3.05 mmol/L and 2.90 mmol/L, 2hPG decreased 2.49 mmol/L and 2.38 mmol/L in Changsulin ® and in Lantus ® , respectively. No significant differences could be viewed in above parameters between the two groups (all P> 0.05). There were also no significant differences between Changsulin ® and Lantus ® in 8-point SMBG profiles from baseline and proportions of subjects achieving the targets of HbA1c and FPG (all P> 0.05). The rates of total hypoglycemia (38.00% and 39.01% for Changsulin ® and Lantus ® , respectively) and nocturnal hypoglycemia (17.25% and 16.31% for Changsulin ® and Lantus ® , respectively) were similar between the two groups (all P> 0.05). Most of the hypoglycemia events were asymptomatic, and no severe hypoglycemia were found in both groups. No differences were observed in rates of AEs (61.77% vs.52.48%) and anti-insulin glargine antibody (after 24 weeks of treatment, 6.91% vs.3.65%) between the two groups (all P> 0.05). Conclusions: Changsulin ® shows similar efficacy and safety profiles compared with Lantus ® and Changsulin ® treatment was well tolerated in patients with T2DM.

Background: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible., Method: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported., Results: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies., Conclusion: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

Purpose: The aim of the present prospective follow-up study was to explore the early indicators of hypothyroidism and the final changes in thyroid volume in subacute thyroiditis (SAT) patients. Methods: We enrolled 61 SAT patients and followed them up for 2 years to assess the incidence of hypothyroidism and changes in thyroid volume. Binary logistic regression and receiver operating characteristic (ROC) curves were used for data analysis. Results: During the 2 years follow-up period, we found that the volumes of the thyroid gland in SAT patients at 1 and 2 years were significantly smaller than those in the healthy control group, which were significantly smaller compared to the initial thyroid volumes after SAT onset ( p < 0.001). Also, the thyroid volumes of SAT patients with hypothyroidism were significantly smaller than those of SAT patients without hypothyroidism. The early maximum thyroid-stimulating hormone (TSH) values (within 3 months after SAT onset) were closely related to the incidence of hypothyroidism at 2 years. The OR value was 1.18 (95% CI = 1.01-1.38, p = 0.032). The early maximum TSH value had a maximum area under the ROC curve (AUC) of 0.866 for the development of hypothyroidism 2 years after SAT onset vs . euthyroidism ( p < 0.001). Conclusions: The thyroid volumes of patients increased significantly after the onset of SAT, while during the follow-up these volumes decreased; the thyroid volumes at 1 and 2 years were significantly smaller than those of normal healthy subjects, especially in SAT patients with hypothyroidism. Furthermore, the early maximum TSH value could be used as an effective indicator of the development of hypothyroidism 2 years after the onset of SAT., (Copyright © 2020 Zhao, Wang, Cui, Huang, Wang, Li, Zhao, Wan, Li, Shan and Teng.)

Background: Thyroxine-binding globulin (TBG; the gene product of SERPINA7 ) is the main transporter of thyroid hormones in humans. Mutations in the TBG gene may lead to inherited TBG deficiency. There have been 28 reported mutations that associate with complete TBG deficiency (TBG-CD). Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family., Case Summary: A 46-year-old Chinese man was referred to our hospital with normal free thyroxine, free triiodothyronine, thyrotropin, but lower total thyroxine and total triiodothyronine, and undetectable serum TBG, indicative of TBG-CD. Blood samples were obtained from the patient's family members and thyroid function and serum TBG were evaluated. Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s). Quantitative PCR high-resolution melting curve analysis was used to screen TBG -Poly (L283F) among 117 Chinese men. A novel mutation of TBG (p.Phe135Alafs*21), a 19-nucleotide insertion in exon 1, was identified, which resulted in a truncated TBG protein product and caused TBG-CD. The other mutation, identified in the proband's father, is a known polymorphism, TBG -Poly (L283F). The frequency of the TBG -Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%., Conclusion: A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family. Additionally, it was found that 21.37% of Chinese males had TBG -Poly (L283F)., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age., Methods: Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 μg/L and iron overload (IO) was defined as ferritin >150 μg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders., Results: The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ = 10.264, P = 0.002; 6.25% vs. 3.70%, χ = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241-3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011-3.282, P = 0.046, respectively)., Conclusion: ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive., Clinical Trial Registration: ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.

Purpose: Running gait retraining via peak tibial shock biofeedback has been previously shown to reduce impact loading and mitigate running-related symptoms. In previous research, peak tibial shock is typically measured and trained for one limb at a single constant training speed during all training sessions. The goal of this study was to determine how runners transfer learning in the trained limb to the untrained limb at different unconstrained speeds., Methods: Thirteen runners (3 females, age = 41.1 ± 6.9 yr, running experience = 6.8 ± 4.4 yr, weekly running distance = 30.7 ± 22.2 km) underwent running gait biofeedback retraining via continuous tibial acceleration measured at the right distal tibia. Before and after the training, participants were asked to run at their self-selected constrained training speeds (2.8 ± 0.2 m·s) and at 110% and 90% of the training speed. Pretraining and posttraining peak tibial shock values for each limb were compared., Results: Participants reduced peak tibial shock in the trained limb by 35% to 37% (P < 0.05, Cohen's d = 0.78-0.85), and in the untrained limb by 20% to 23% (P < 0.05, Cohen's d = 0.51-0.71) across the three testing speeds. The reduction was not significantly different between the trained and untrained limbs (P = 0.31-0.79, Cohen's d = 0.18-0.45). Similarly, there was no difference in peak tibial shock reduction among the three running speeds (P = 0.48-0.61, Cohen's d = 0.06-0.45)., Conclusion: Participants demonstrated transfer learning effects evidenced by concomitant reduced peak tibial shock in the untrained limb, and the learning effects were retrained when running at a 10% variance of the training speed.

Purpose: Kinesio tape (KT) is claimed to be able to facilitate muscle activation and promote muscle strength. Previous studies have proposed that placebo effect could be a major attributing factor. This study sought to compare the effects of facilitatory KT on muscle activity and performance between regular KT-users and non-users., Methods: Sixty participants, including 27 regular KT-users and 33 non-users, performed maximal grip assessment with and without facilitatory KT, which was applied to their wrist extensor muscles of the dominant forearm from the direction of origin to insertion at 75% of its maximal tension. Within-subject comparisons of normalized root mean square of the wrist extensors electromyographic activity, maximal grip strength, and perceived performance were conducted., Results: KT-users showed an increase in grip strength with application of facilitatory KT, when compared to tapeless condition (p = 0.030, Cohen's d = 0.16). Non-users demonstrated similar grip strength with and with KT application (p = 0.232). No significant differences were found in the muscle activity (p > 0.198) and perceived performance (p > 0.400) in both groups., Conclusions: Facilitatory KT promotes maximal grip strength only among regular KT users, but its effect is trivial. Interestingly, such effect is not related to any electrophysiological change in the KT applying muscle, which may indicate an indirect working mechanism leading to the increased grip strength.

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-) β , arginase 1 (Arg1), and mannose receptor C-type 1 (Mrc1) were decreased by rapamycin in peritoneal macrophages. LC3-II was also obviously enhanced, though polarization markers were unchanged in rapamycin-treated foam cells. Moreover, lipid accumulation was inhibited in rapamycin-treated macrophage cells but was unchanged in rapamycin-treated foam cells. For FTY720, LC3-II did not change, whereas TGF- β , Arg1 and Mrc1 were augmented, and IL-6 was suppressed in macrophages. However, LC3-II was increased, and TGF- β , ARG1 and MRC1 were strikingly augmented, whereas IL-6, COX2 and iNOS could be suppressed in foam cells. Furthermore, lipid accumulation was alleviated in FTY720-treated foam cells. Additionally, S1pr1 was markedly decreased in foam cells ( P < .05); S1pr2, S1pr3, S1pr4 and S1pr5 were unchanged in rapamycin-treated foam cells. In FTY720-treated foam cells, S1pr3 and S1pr4 were decreased, and S1pr1, S1pr2 and S1pr5 were unchanged. Therefore, we deduced that rapamycin stimulated classically activated macrophages and supressed early atherosclerosis. Rapamycin may also stabilize artery plaques by preventing apoptosis and S1PR1 in advanced atherosclerosis. FTY720 allowed transformation of foam cells into alternatively activated macrophages through the autophagy pathway to alleviate advanced atherosclerosis.

A stable gaze is necessary to optimize visual conditions during running. Head accelerations generally remain stable when looking in front; however, it is unclear if this response is similar when the head is turned sideways, and whether other adaptive strategies are present to maintain this stability. The purpose of this study, therefore, was to examine whether runners maintained stable head accelerations while gazing at fixed targets in front and to their sides. The authors collected biomechanical data from 13 runners as they directed their gaze to visual targets located in front, 45°, and 90° to the sides at a random sequence. Vertical head and tibial accelerations were the primary outcome measures, while vertical loading rate, footstrike angle, contact time, stride length, and stride rate were the secondary measures. A reduction in vertical head accelerations was found in the rightmost direction (P = .04), while an increase in vertical tibial accelerations was found on the same direction (P = .02). No other significant differences were observed for the other variables. The results of this study suggest that the tibia accommodated the increased shock to maintain head stability.

Pretibial myxedema (PTM), an uncommon manifestation of Graves' disease (GD), is a local autoimmune reaction in the cutaneous tissue. The treatment of PTM is a clinical challenge. We herein report on a patient with PTM who achieved complete remission by multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application for a self-controlled study. A 53-year-old male presented with a history of GD for 3.5 years and a history of PTM for 1.5 years. Physical examination revealed slight exophthalmos, a diffusely enlarged thyroid gland, and PTM of both lower extremities. One milliliter of triamcinolone acetonide (40 mg) was mixed well with 9 mL of 2% lidocaine in a 10 mL syringe. Multipoint intralesional injections into the skin lesions of the right lower extremity were conducted with 0.5 mL of the premixed solution. A halometasone ointment was used once daily for PTM of the left lower extremity until the PTM had remitted completely. The patient's PTM achieved complete remission in both legs after an approximately 5-mo period of therpy that included triamcinolone injections once a week for 8 wk and then once a month for 2 mo for the right lower extremity and halometasone ointment application once daily for 8 wk and then once 3-5 d for 2 mo for the left lower extremity. The total dosage of triamcinolone acetonide for the right leg was 200 mg. Our experience with this patient suggests that multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application are safe, effective, and convenient treatments. However, the topical application of a glucocorticoid ointment is a more convenient treatment for patients with PTM., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interests.

Background: To assess whether elevated thyroid-stimulating hormone (TSH) levels before conception can predict poor outcomes of assisted reproductive technology (ART)., Methods: Prior to July 2018, we searched the PubMed, EMBASE, COCHRANE, Google Scholar, and CNKI databases for studies. Retrospective or prospective reports that compared ART results in patients with subclinical hypothyroidism (SCH) with normal thyroid function were selected. Two reviewers separately reviewed each potential article for qualification, analyzed the quality of the studies according to the Newcastle-Ottawa scale, and extracted the data. The PRISMA guidelines were adopted., Results: We selected a total of 18 publications that included 14,846 participants for this meta-analysis. When the TSH cut-off value for SCH was set at 2.5 mIU/L, no significant differences were observed in ART-related outcomes between SCH patients and normal women. The evaluated outcomes included the live birth rate (LBR) (OR: 0.93; 95% CI (0.77,1.12), P = 0.43), clinical pregnancy rate (CPR) (OR:1.02; 95% CI (0.90,1.17); P = 0.74), pregnancy rate (PR) (OR: 1.00; 95% CI (0.89,1.12); P = 0.99), and miscarriage rate (MR) (OR:1.24; 95% CI (0.85, 1.80); P = 0.26). Furthermore, when a higher TSH level was used as the cut-off value to diagnose SCH (i.e., 3.5-5 mIU/L), a significant difference was found in the MR (OR: 1.91; 95% CI (1.09, 3.35); P = 0.02) between the two groups of ART-treated women. However, when a broader cut-off value was used to define SCH, no significant differences were observed in the LBR (OR: 0.72; 95% CI (0.47,1.11); P = 0.14), CPR (OR: 0.82; 95% CI (0.66,1.00); P = 0.052), or PR (OR: 1.07; 95% CI (0.72,1.60); P = 0.74) between the two groups of ART-treated women., Conclusion: No difference was observed in ART outcomes when a TSH cut-off value of 2.5 mIU/L was used. However, when a broader TSH cut-off value was used, preconception SCH resulted in a higher miscarriage rate than in normal women.

The objective of this study was to evaluate the relationship between subclinical hypothyroidism (SCH) and depression. We also analysed the effect of levothyroxine (L-T4) on depression in SCH patients. We found an insignificant difference for the composite endpoint: standard mean difference (SMD) of 0.23 (95% confidence interval (CI) -0.03, 0.48, P = 0.08, I 2  = 73.6%). The odds ratio (OR) for depressive patients was 1.75 (95% CI 0.97, 3.17 P = 0.064, I 2  = 64.6%). Furthermore, sub-group analysis according to age found that SCH was related to depression in younger patients (<60 years old), as defined by the diagnosis of depression: OR of 3.8 (95% CI 1.02, 14.18, P = 0.047, I 2  = 0.0%) or an increase on the depressive scale: SMD of 0.42 (95% CI 0.03, 0.82, P = 0.036, I 2  = 66.6%). Meanwhile, SCH did not associate with depression in older patients (≥60 years old), as defined by the diagnosis of depression: OR of 1.53 (95% CI 0.81, 2.90, P = 0.193, I 2  = 71.3%) or an increase on the depressive scale: SMD of 0.03 (95%CI -0.31, 0.37, P = 0.857, I 2  = 79.8%). We also found an insignificant difference in the composite endpoint between the L-T4 supplementation group and placebo group in SCH patients. The estimated SMD was 0.26 (95% CI -0.09, 0.62, P = 0.143, I 2  = 52.9%). This meta-analysis demonstrates that SCH is not connected to depression. However, sub-group analysis according to age found that SCH is related to depression in younger patients, but not in older patients. Furthermore, we failed to find an effect of L-T4 supplementation treatment for SCH on depression.

This study examined the effects of KT tape (KT) applied in an inhibitory manner on muscle activity, measured maximal grip strength, and perceived maximal grip strength in regular KT-users and non-users. This study was a single-blinded crossover study with sixty participants including 27 kT-users and 33 non-users. Participants underwent maximal grip strength tests with and without inhibitory KT applied across the wrist extensors. Muscle activity and maximal grip strength were measured, while perceived maximal grip strength was rated using a visual analogue scale. No significant interaction effect was found between taping conditions and participant KT-experience for muscle activity (F = 0.825, p = 0.367), measured grip strength (F = 1.018, p = 0.317) or perceived grip strength (F = 0.122, p = 0.728). No significant differences were observed in the EMG activity between taping conditions for either KT-users (p = 0.367) or non-users (p = 0.215). A similar trend was found in the measured grip strength (KT-users: p = 0.317; non-users: p = 0.294) and perceived grip strength (KT-users: p = 0.728; non-users: p = 0.063). KT applied in an inhibitory manner does not impede EMG activity, measured maximal grip strength, or perceived maximal grip strength in adults, regardless of their preconceived notions of KT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The mechanism underlying neurological dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is yet to be established. This study investigated the temporal complexity of blood oxygenation level dependent (BOLD) changes in response to the Stroop task in CFS patients. 43 CFS patients (47.4 ± 11.8 yrs) and 26 normal controls (NCs, 43.4 ± 13.9 yrs) were included in this study. Their mental component summary (MCS) and physical component summary (PCS) from the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Their Stroop colour-word task performance was measured by accuracy and response time (RT). The BOLD changes associated with the Stroop task were evaluated using a 2-level general linear model approach. The temporal complexity of the BOLD responses, a measure of information capacity and thus adaptability to a challenging environment, in each activated region was measured by sample entropy (SampEn). The CFS patients showed significantly longer RTs than the NCs ( P  < 0.05) but no significant difference in accuracy. One sample t -tests for the two groups (Family wise error adjusted P FWE  < 0.05) showed more BOLD activation regions in the CFS, although a two sample group comparison did not show significant difference. BOLD SampEns in ten regions were significantly lower (FDR-q < 0.05) in CFS patients. BOLD SampEns in 15 regions were significantly associated with PCS (FDR-q < 0.05) and in 9 regions were associated with MCS (FDR-q < 0.05) across all subjects. SampEn of the BOLD signal in the medioventral occipital cortex could explain 40% and 31% of the variance in the SF-36 PCS and MCS scores, and those in the precentral gyrus could explain an additional 16% and 7% across all subjects. This is the first study to investigate BOLD signal SampEn in response to tasks in CFS. The results suggest the brain responds differently to a cognitive challenge in patients with CFS, with recruitment of wider regions to compensate for lower information capacity.

The chronic fatigue syndrome (CFS)/myalgic encephalomyelitis is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) to understand the pathophysiology of CFS and to identify potential biomarkers. Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798 sec, we evaluated the DMN using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps, and complexity of activity. General linear model univariate analysis was used for intergroup comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores. BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (p < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (p < 0.05) during resting state, whereas during task mPFC-left IPL and mPFC-PCC were weaker (p < 0.05). The DFCs between the DMN hubs were more complex in CFS (p < 0.05) during task. Each of these differences accounted for 7-11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potentially used as a diagnostic biomarker for CFS.

We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans. After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, P FWE = 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster P FWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R 2 = 0.31, P = 0.00007) and healthy controls (R 2 = 0.34, P = 0.0009), and the regressions were co-linear. This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem - sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Iodine deficiency (ID) during early pregnancy has an adverse effect on children's psychomotor and motor function but the mechanism has not been clarified. Therefore, our aim was to study the effect of maternal marginal ID on cerebellar neurodevelopment and the underlying mechanism. After obtaining marginal ID rats, we examined interactions between Bergmann glia cells (BGs) and Purkinje cells (PCs) using immunofluorescence and expression of the glutamate transporter and receptor by western blot. Our results showed that marginal ID reduced the number of contacted points between BGs and PCs, and disturbed expression of the glutamate transporter and receptor. Our results support the hypothesis that marginal ID inhibits interactions of BGs-PCs, which may be involved in abnormal regulation of the glutamate transporter and receptor., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T 1 weighted (MT-T1w) intensities, and T 1 weighted (T1w) and T 2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, P FWE  < 0.05) and between PSQI and T1w intensities (P FWE  < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: To examine progressive brain changes associated with chronic fatigue syndrome (CFS)., Materials and Methods: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy., Results: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, P FWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (P FWE < 0.05) and decreased GM and blood volumes in contralateral regions (P FWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (P FWE < 0.05)., Conclusion: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311., (© 2016 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Multiple endocrine neoplasia 2A (MEN2A) is characterized by the coexistence of tumors that involve two or more endocrine glands within the same patient, and is defined as the occurrence of medullary thyroid carcinoma in association with pheochromocytoma (PHEO) and parathyroid tumors or hyperparathyroidism. The pathogenesis of MEN2A is due to the mutation of a tyrosine kinase receptor that is encoded by the rearrangement during transfection (RET) proto-oncogene. The mutation often occurs in exon 10q11.2. The present study reports the case of a 73-year-old man with severe hypercalcemia, bilateral adrenal PHEO and a thyroid nodule. A genetic panel was obtained, and the RET mutation was indicated. The pedigree of the patient was also studied. Genetic testing of the patient's son indicated heterozygosity for the same mutation at codon 634. The first symptom of the two patients was PHEO, which is uncommon. In addition, varied phenotypes were identified in the two patients. In the present study, the association between the phenotypic variation of the RET gene and the occurrence of MEN2A is discussed.

To evaluate the genotype-phenotype relationship of Gitelman syndrome in Chinese patients. We selected patients with Gitelman syndrome presenting hypokalemia. Medical history, clinical manifestations, laboratory test results, and imaging data of these patients were collected for analysis. Target gene sequencing was performed to evaluate the genotype-phenotype relationship. Gitelman syndrome was diagnosed based on medical history, clinical manifestations, laboratory test results, and imaging data. The causative gene for Gitelman syndrome, SLC12A3, and the causative gene for the classic Bartter syndrome, CLCNKB, were screened for disease-causing mutations by direct sequencing. Clinical diagnoses of ten patients were consistent with Gitelman syndrome. Disease-causing mutations in the SLC12A3 gene were found in six patients. Among the variants, T60M in exon 1 was the hot spot in Chinese patients. Additionally, we found a small deletion of ACGG in exon 3 and L671P in exon 16; these have not been reported in previous studies. No disease-causing mutations were observed in the other four patients. Since mutations in the SLC12A3 and CLCNKB genes are not present in all patients with clinical manifestations of Gitelman syndrome, genetic screening after clinical diagnosis is essential.

Background: Type 2 diabetes mellitus (T2DM) has traditionally been considered to affect mainly the elderly; however, the age at diagnosis has gradually reduced in recent years. Although the incidence of young-onset T2DM is increasing, it is still not fully clear the onset characteristics and risk factors of early-onset T2DM. The aim of this study was to describe the initiating characteristics of early-onset T2DM in Chinese patients and evaluate the risk factors for diabetes mellitus., Methods: This cross-sectional controlled study was performed using a questionnaire survey method in outpatients of multiple centers in China. A total of 1545 patients with T2DM with an age at onset of <40 years were included, and the control group consisted of subjects aged <40 years with normal blood glucose level., Results: In patients with young-onset T2DM, the mean age and initial hemoglobin 1Ac at diagnosis were 32.96 ± 5.40 years and 9.59 ± 2.71%, respectively. Most of the patients were obese, followed irregular diet pattern and sedentary lifestyle, had life or work pressure, and had a family history of diabetes mellitus. Compared with subjects with normal blood glucose level, logistic regression analysis showed that waist-to-hip ratio (odds ratio [OR] 446.99, 95% confidence interval [CI] 42.37-4714.87), family history of diabetes mellitus (OR 23.46, CI 14.47-38.03), dyslipidemia (OR 2.65, CI 1.54-4.56), diastolic blood pressure (OR 1.02, CI 1.00-1.04), and body mass index (OR 0.95, CI 0.92-0.99) are independent factors for early-onset T2DM., Conclusions: We observed that abdominal obesity, family history of diabetes mellitus, and medical history of hypertension and dyslipidemia are independent risk factors for early-onset T2DM. It is, therefore, necessary to apply early lifestyle intervention in young people with risk of diabetes mellitus.

Carotid atherosclerosis is associated with many serious cardiovascular diseases; hence, it is necessary to identify factors related to its occurrence in order to develop preventive and therapeutic strategies. This study was conducted to identify risk factors associated with carotid atherosclerosis among the population residing in Northeast China.This epidemiological survey was conducted in a representative group of relatively healthy community residents. All participants answered questions about their medical histories and underwent physical examination, blood biochemical analysis, and ultrasonography examinations of their necks and abdomens. The prevalence rates of carotid atherosclerosis under different factors and conditions were then analyzed.The results of this study showed that age, gender, and diabetes significantly affected the prevalence of carotid atherosclerosis in this Northeast Chinese population. In addition, gender-based subgroup analysis revealed additional factors correlated with the prevalence of carotid atherosclerosis in men or women, although their correlations were not significant in the overall population. While high serum TC and LDL-C levels were risk factors for carotid atherosclerosis in men, it showed no clear correlation with the prevalence of carotid atherosclerosis in women. In contrast, the prevalence of carotid atherosclerosis in female participants with high serum TG level, hypertension, obesity and nonalcoholic fatty liver disease were higher than that of the control population, a trend not observed in male participants.Older age, male sex, and diabetes were independently associated with increased risk of carotid atherosclerosis in Northeast China. These findings could lead to improved screening for carotid atherosclerosis for better disease management., Competing Interests: The authors have no conflict of interest to disclose.

Mouse parthenogenetic embryonic stem cells (PgESCs) could be applied to study imprinting genes and are used in cell therapy. Our previous study found that stem cells established by aggregation of two parthenogenetic embryos at 8-cell stage (named as a2 PgESCs) had a higher efficiency than that of PgESCs, and the paternal expressed imprinting genes were observably upregulated. Therefore, we propose that increasing the number of parthenogenetic embryos in aggregation may improve the development of parthenogenetic mouse and imprinting gene expression of PgESCs. To verify this hypothesis, we aggregated four embryos together at the 4-cell stage and cultured to the blastocyst stage (named as 4aPgB). qPCR detection showed that the expression of imprinting genes Igf2, Mest, Snrpn, Igf2r, H19, Gtl2 in 4aPgB were more similar to that of fertilized blastocyst (named as fB) compared to 2aPgB (derived from two 4-cell stage parthenogenetic embryos aggregation) or PgB (single parthenogenetic blastocyst). Post-implantation development of 4aPgB extended to 11 days of gestation. The establishment efficiency of GFP-a4 PgESCs which derived from GFP-4aPgB is 62.5%. Moreover, expression of imprinting genes Igf2, Mest, Snrpn, notably downregulated and approached the level of that in fertilized embryonic stem cells (fESCs). In addition, we acquired a 13.5-day fetus totally derived from GFP-a4 PgESCs with germline contribution by 8-cell under zona pellucida (ZP) injection. In conclusion, four embryos aggregation improves parthenogenetic development, and compensates imprinting genes expression in PgESCs. It implied that a4 PgESCs could serve as a better scientific model applied in translational medicine and imprinting gene study., (© 2016 Japanese Society of Developmental Biologists.)