Statins and thyroid eye disease (TED): a systematic review.

PURPOSE: Thyroid eye disease (TED) is the foremost extrathyroidal manifestation of Graves' disease (GD). Currently, available treatments do not entirely prevent the long-term consequences of TED and have distinct disadvantages. Therefore, this systematic review explored available evidence regarding the efficacy of statins in preventing and treating TED. METHODS: Relevant studies investigating statin usage in patients with GD or TED were identified by searching Medline (Pubmed and Ovid), Scopus, Web of Science, ProQuest, and Cochrane Library databases (from the database inception to September 2023). The review was done according to the PRISMA statement. Web searching was done independently by two investigators. Two researchers independently extracted the data, and any disagreement was adjudicated by consensus. Based on the study design, the studies' quality appraisal was done using the Newcastle-Ottawa Scale (NOS) and Version 2 of the Cochrane risk-of-bias tool (RoB2). RESULTS: The literature search identified 145 publications, of which four met the inclusion criteria (Three retrospective cohort studies and one randomized clinical trial) and were reviewed in full text. The two retrospective cohort studies demonstrated the beneficial effects of statins on TED in newly diagnosed GD Stein et al. showed that statins, regardless of the type, prevent or delay TED (HR: 0.74 (0.65-0.84)), especially in men or treatment duration of more than one year. Nilsson et al. fascinatingly revealed that at least 60 days of statin usage in the preceding year could decrease the risk of TED development by around 40%. One RCT showed a higher treatment response for active moderate-to-severe TED in patients with hypercholesterolemia who took atorvastatin 20 mg in addition to ivGC for 24 weeks without any increase in serious side effects. The retrospective study revealed that the need for reconstructive surgery was reduced in patients with severe TED who received statin therapy. CONCLUSION: Statin therapy could be a potential adjunctive modality for preventing and treating TED. TRIAL REGISTRATION: PROSPERO registration number: CRD42022315522.

Glucagon-Like Peptide 1 (GLP-1) Receptor Variants and Glycemic Response to Liraglutide: A Pharmacogenetics Study in Iranian People with Type 2 Diabetes Mellitus.

INTRODUCTION: Pharmacogenetics studies suggest that genetic variants have a possible influence on the inter-individual differences in therapeutic response to glucagon-like peptide 1 receptor agonists (GLP-1 RAs). We aimed to examine the potential role of genetic variability of glucagon-like peptide 1 receptor (GLP-1R) on glycemic response to GLP-1 RAs in a population of Iranian people with type 2 diabetes mellitus (T2DM). METHODS: In this study, we analyzed the data from participants in a non-inferiority randomized clinical trial between 2019 and 2020. Patients received liraglutide 1.8 mg/day subcutaneously for 24 weeks. They were stratified by the baseline hemoglobin A1c (HbA1c) into four categories: 7-7.99, 8-8.99, 9-9.99, and ≥ 10%. In each category, subjects with HbA1c reduction greater than the median ΔHbA1c value for that group were defined as optimal responders. The pooled number of optimal/suboptimal responders in the four groups was used for the comparison. We evaluated two genetic variants of GLP-1R, rs6923761 and rs10305420, using Sanger sequencing. Logistic regression analyses were performed to examine the associations of the GLP-1R variants with the glycemic response in different genetic models. RESULTS: Out of 233 participants, 120 individuals were optimal responders. Median HbA1c reduction was - 2.5% in the optimal responder group compared with - 1.0% in the suboptimal responder group (P < 0.001). In genetic models, rs10305420 T allele homozygosity was associated with optimal glycemic response to liraglutide compared with heterozygous and wild-type homozygous states (recessive model: OR 3.28, 95% CI 1.41-7.65, P = 0.006; codominant model: OR 2.52, 95% CI 1.03-6.13, P = 0.04). No significant association was found between rs6923761 variant and HbA1c reduction. CONCLUSION: GLP-1R rs10305420 polymorphism can explain some of the inter-individual differences in glycemic response to liraglutide in a population of Iranian people with T2DM.

Non-alcoholic fatty liver disease and compromised endothelial function in people with type 2 diabetes.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM) and synergistically contributes to the development of atherosclerosis. Flow-mediated dilation (FMD) is a commonly used noninvasive test for assessing endothelial function. The main objective of this study was to explore FMD in patients with T2DM with and without NAFLD. METHODS: In this cross-sectional study, conducted on people with T2DM, NAFLD was defined as controlled attenuation parameter (CAP) score > 302 dB/m. Endothelial dysfunction was detected when arterial FMD of brachial artery was equal or less than 0.7%. Regression analyses were applied to assess factors associated with impaired FMD. RESULT: A total of 147 patients (72 with NAFLD and 75 without NAFLD) were included in the final analysis. Patients with NAFLD were more likely to develop FMD ≤ 7% (77.8% vs. 58.7%, P = 0.01). In multivariate analysis, NAFLD (OR = 2.581, 95% CI (1.18-5.62), P = 0.017) and hypertension (HTN) (OR = 3.114, 95% CI (1.31-7.35), P = 0.010) were associated with an increased risk of impaired FMD. However, female sex was associated with a decreased risk of impaired FMD (OR = 0.371, 95% CI (0.15-0.87), P = 0.024). CONCLUSION: NAFLD is associated with endothelial dysfunction in people with T2DM. This risk is comparable with the risk imposed by HTN, highlighting the importance of screening and management of NAFLD in these patients.

Children with autism spectrum disorder who demonstrate normal language scores use a bottom-up semantic processing strategy: Evidence from N400 recordings.

INTRODUCTION: The N400 is an electrophysiological component that reflects lexical access and integration of words with mental representations. METHODS: Thirty-five young children with a range of language capabilities (n = 21 neurotypical controls, 10 males, mean age = 6.3 ± 0.9 years; n = 14 children with autism, 12 males, mean age = 6.4 ± 1.1 years) completed an auditory semantic categorization paradigm to evoke the N400. Electroencephalograph (EEG) data were acquired with a 64-channel electrode cap as children listened via ear inserts to binaurally presented single syllable words and decided whether the words were congruent (in) or incongruent (out) with a pre-specified category. EEG data were filtered, epoched, and averaged referenced, and global field power (GFP) was computed. The amplitude of the N400 peak in the GFP was submitted to a multiple linear regression analysis. RESULTS: N400 amplitude was found to predict language scores only for the children with ASD who have language scores in the normal range (r2  = 0.72). CONCLUSIONS: This finding that N400 amplitude only predicted language scores in children with ASD and normal language scores suggests that these children may rely more on basic semantic processing (as reflected by the N400) and less on anticipating and predicting upcoming words. This suggests preferential utilization of a bottom-up strategy to access higher order language.

Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis.

BACKGROUND: Aberrant brain insulin signaling has been posited to lie at the crossroads of several metabolic and cognitive disorders. Intranasal insulin (INI) is a non-invasive approach that allows investigation and modulation of insulin signaling in the brain while limiting peripheral side effects. OBJECTIVES: The objective of this systematic review and meta-analysis is to evaluate the effects of INI on cognition in diverse patient populations and healthy individuals. METHODS: MEDLINE, EMBASE, PsycINFO, and Cochrane CENTRAL were systematically searched from 2000 to July 2021. Eligible studies were randomized controlled trials that studied the effects of INI on cognition. Two independent reviewers determined study eligibility and extracted relevant descriptive and outcome data. RESULTS: Twenty-nine studies (pooled N = 1,726) in healthy individuals as well as those with Alzheimer's disease (AD)/mild cognitive impairment (MCI), mental health disorders, metabolic disorders, among others, were included in the quantitative meta-analysis. Patients with AD/MCI treated with INI were more likely to show an improvement in global cognition (SMD = 0.22, 95% CI: 0.05-0.38 p = <0.00001, N = 12 studies). Among studies with healthy individuals and other patient populations, no significant effects of INI were found for global cognition. CONCLUSIONS: This review demonstrates that INI may be associated with pro-cognitive benefits for global cognition, specifically for individuals with AD/MCI. Further studies are required to better understand the neurobiological mechanisms and differences in etiology to dissect the intrinsic and extrinsic factors contributing to the treatment response of INI.

Gut Microbiota and Their Associated Metabolites in Diabetes: A Cross Talk Between Host and Microbes-A Review.

Dysbiosis of the gut microbiota's composition and function is important in developing insulin resistance and diabetes. Diabetes has also been linked to changes in the circulating and fecal metabolites. Evidence suggests the associations between the gut microbiota and the aberrant diabetes-related metabolome. Metabolites play a crucial role in the host-microbiota interactions. Researchers have used a combination of metagenomic and metabolomic approaches to investigate the relationships between gut microbial dysbiosis and metabolic abnormalities in diabetes. We summarized current discoveries on the associations between the gut microbiota and metabolites in type 1 diabetes, type 2 diabetes, and gestational diabetes mellitus in the scoping review. According to research, the gut microbiota changes might involve in the development of diabetes through modulating the host's metabolic pathways such as immunity, energy metabolism, lipid metabolism, and amino acid metabolism. These results add to our understanding of the interplay between the host and gut microbiota metabolism.

Prevalence and Antibiotic Resistance of Clostridioides (Clostridium difficile) In Meat and Meat Products: A Systematic Review and Meta-Analysis.

Background: Meat and meat products are introduced as one of the frequent sources of Clostridioides difficile. We aimed to determine the prevalence and antibiotic resistance of C. difficile isolates in meat and meat products using a systematic review and meta-analysis. Methods: A literature search was performed in the primary international and bibliographic databases such as MEDLINE (PubMed), Cochrane Library, Embase, Scopus, and Web of Science to achieve all articles related to the prevalence and antibiotic resistance rates from 2007 to 2022. Results: The 278 retrieved articles were reduced to 54 worldwide eligible studies after screening and matching inclusion/exclusion criteria. C. difficile was examined in different types of samples and its resistance to 10 antibiotics. The pooled prevalence of C. difficile was 3.4% in all samples. C. difficile pooled prevalence was detected in fish, poultry, and red meat groups with 6.9%, 5.2%, and 3.2%, respectively. Regarding antibiotic resistance, the highest pooled prevalence was for ciprofloxacin (86.6%), followed by clindamycin (42.6%) and erythromycin (34%). The lowest pooled prevalence was observed in metronidazole (7.6%), vancomycin (6.6%), and chloramphenicol (6%). Conclusion: Low resistance was found to commonly used drugs for C. difficile infection (CDI) treatment. Since each antibiotic can be predisposing cause for CDI development, this finding possibly will be warning from a One Health viewpoint about the misuse of antibiotics in the chain of farm to fork including agriculture, animal husbandry and the food industry and also their injudicious use in medicine.

Attitude and Belief of Healthcare Professionals Towards Effective Obesity Care and Perception of Barriers; An Updated Systematic Review and Meta-analysis.

BACKGROUND: Obesity is a serious chronic disease that adversely affects health and quality of life. However, a significant percentage of people do not participate in or adhere to weight loss programs. Therefore, a multidisciplinary approach is needed to identify critical barriers to effective obesity management and to examine health practitioners' attitudes and behaviors towards effective obesity treatment. METHODS: This systematic review was conducted in accordance with PRISMA 2020. Eligible studies were identified through a systematic review of the literature using Medline, Scopus, Cochrane, Google Scholar, Web of Science, and Embase databases from January 1, 2011 to March 2, 2021. RESULTS: A total of 57 articles were included. Data on 12663 physicians were extracted from a total of 35 quantitative articles. Some of the most commonly perceived attitude issues included "obesity has a huge impact on overall health", "obesity is a disease" and "HCPs are to blame". Health professionals were more inclined to believe in "using BMI to assess obesity," "advice to increase physical activity," and "diet/calorie reduction advice." The major obstacles to optimal treatment of obesity were "lack of motivation", "lack of time" and "lack of success". CONCLUSION: Although the majority of health care professionals consider obesity as a serious disease which has a large impact on overall health, counseling for lifestyle modification, pharmacologic or surgical intervention occur in almost half of the visits. Increasing the length of physician visits as well as tailoring appropriate training programs could improve health care for obesity.

A global study of the association of cesarean rate and the role of socioeconomic status in neonatal mortality rate in the current century.

INTRODUCTION: Caesarean section (C/S) rates have significantly increased across the world over the past decades. In the present population-based study, we sought to evaluate the association between C/S and neonatal mortality rates. MATERIAL AND METHODS: This retrospective ecological study included longitudinal data of 166 countries from 2000 to 2015. We evaluated the association between C/S rates and neonatal mortality rate (NMR), adjusting for total fertility rate, human development index (HDI), gross domestic product (GDP) percentage, and maternal age at first childbearing. The examinations were also performed considering different geographical regions as well as regions with different income levels. RESULTS: The C/S rate and NMR in the 166 included countries were 19.97% ± 10.56% and 10 ± 10.27 per 1000 live birth, respectively. After adjustment for confounding variables, C/S rate and NMR were found correlated (r = -1.1, p < 0.001). Examination of the relationship between C/S rate and NMR in each WHO region resulted in an inverse correlation in Africa (r = -0.75, p = 0.005), Europe (r = -0.12, p < 0.001), South-East Asia (r = -0.41, p = 0.01), and Western Pacific (r = -0.13, p = 0.02), a direct correlation in America (r = 0.06, p = 0.04), and no correlation in Eastern Mediterranean (r = 0.01, p = 0.88). Meanwhile, C/S rate and NMR were inversely associated in regions with upper-middle (r = -0.15, p < 0.001) and lower-middle (r = -0.24, p < 0.001) income levels, directly associated in high-income regions (r = 0.02, p = 0.001), and not associated in low-income regions (p = 0.13). In countries with HDI below the centralized value of 1 (the real value of 0.9), the correlation between C/S rate and NMR was negative while it was found positive in countries with HDI higher than the mentioned cut-off. CONCLUSIONS: This study indicated that NMR associated with C/S is dependent on various socioeconomic factors such as total fertility rate, HDI, GDP percentage, and maternal age at first childbearing. Further attentions to the socioeconomic status are warranted to minimize the NMR by modifying the C/S rate to the optimum cut-off.

Evaluation of the association between osteoporosis and periodontitis in postmenopausal women: A clinical and radiographic study.

Background: This study aimed to assess the relationship between the osteoporotic condition and periodontitis in postmenopausal women. Materials and Methods: Ninety-four women aged 50-80 years were studied in this cross-sectional study. Bone mineral density (BMD) of lumbar vertebra BMD (LBMD), total hip BMD (HBMD), and neck of femur BMD (NBMD) was assessed using standardized dual-energy X-ray absorptiometry (DXA) (normal: T-score ≥-1, osteopenic: -2.5 ≤ t-score <-1, osteoporotic: T-score <-2.5). Bleeding point index (BI), O'Leary plaque index (PI), and clinical attachment loss (CAL) were recorded. Cementoenamel junction, alveolar-crest distance (CEJ-AC) was measured from cone-beam computed tomography images. Periodontitis severity was represented by CAL and CEJ-AC distance. One-way analysis of variance followed by Post hoc Tukey was performed for examining differences among the groups for different variables. Pearson correlation coefficient® and backward regression analysis were used to investigate the effect of confounding variables on CEJ-AC as the dependent variable. Significance was considered at P < 0.05. Results: Mean CEJ-AC was significantly higher in the osteoporotic and osteopenic groups compared to the normal group (P = 0.001). There was a significant positive correlation between CEJ-AC and NBMD and LBMD (P < 0.001). The associations between LBMD and CEJ-AC existed even after adjusting for confounding factors (P = 0.002). The differences in BI, PI, and CAL were not statistically different between the groups (P > 0.05). Conclusion: Although osteoporosis is not the main cause of periodontitis, it can indirectly affect periodontal status by increasing CEJ-AC. Early diagnosis of osteoporosis followed by early referral to a dentist for the treatment of potential existing periodontal diseases is important to avoid complications among postmenopausal women.

An Electroconductive, Thermosensitive, and Injectable Chitosan/Pluronic/Gold-Decorated Cellulose Nanofiber Hydrogel as an Efficient Carrier for Regeneration of Cardiac Tissue.

Myocardial infarction is a major cause of death worldwide and remains a social and healthcare burden. Injectable hydrogels with the ability to locally deliver drugs or cells to the damaged area can revolutionize the treatment of heart diseases. Herein, we formulate a thermo-responsive and injectable hydrogel based on conjugated chitosan/poloxamers for cardiac repair. To tailor the mechanical properties and electrical signal transmission, gold nanoparticles (AuNPs) with an average diameter of 50 nm were physically bonded to oxidized bacterial nanocellulose fibers (OBC) and added to the thermosensitive hydrogel at the ratio of 1% w/v. The prepared hydrogels have a porous structure with open pore channels in the range of 50−200 µm. Shear rate sweep measurements demonstrate a reversible phase transition from sol to gel with increasing temperature and a gelation time of 5 min. The hydrogels show a shear-thinning behavior with a shear modulus ranging from 1 to 12 kPa dependent on gold concentration. Electrical conductivity studies reveal that the conductance of the polymer matrix is 6 × 10−2 S/m at 75 mM Au. In vitro cytocompatibility assays by H9C2 cells show high biocompatibility (cell viability of >90% after 72 h incubation) with good cell adhesion. In conclusion, the developed nanocomposite hydrogel has great potential for use as an injectable biomaterial for cardiac tissue regeneration.

Memory retrieval brain-behavior disconnection in mild traumatic brain injury: A magnetoencephalography and diffusion tensor imaging study.

Mild traumatic brain (mTBI) injury is often associated with long-term cognitive and behavioral complications, including an increased risk of memory impairment. Current research challenges include a lack of cross-modal convergence regarding the underlying neural-behavioral mechanisms of mTBI, which hinders therapeutics and outcome management for this frequently under-treated and vulnerable population. We used multi-modality imaging methods including magnetoencephalography (MEG) and diffusion tensor imaging (DTI) to investigate brain-behavior impairment in mTBI related to working memory. A total of 41 participants were recruited, including 23 patients with a first-time mTBI imaged within 3 months of injury (all male, age = 29.9, SD = 6.9), and 18 control participants (all male, age = 27.3, SD = 5.3). Whole-brain statistics revealed spatially concomitant functional-structural disruptions in brain-behavior interactions in working memory in the mTBI group compared with the control group. These disruptions are located in the hippocampal-prefrontal region and, additionally, in the amygdala (measured by MEG neural activation and DTI measures of fractional anisotropy in relation to working memory performance; p < .05, two-way ANCOVA, nonparametric permutations, corrected). Impaired brain-behavior connections found in the hippocampal-prefrontal and amygdala circuits indicate brain dysregulation of memory, which may leave mTBI patients vulnerable to increased environmental demands exerting memory resources, leading to related cognitive and emotional psychopathologies. The findings yield clinical implications and highlight a need for early rehabilitation after mTBI, including attention- and sensory-based behavioral exercises.

A systematic review of molecular alterations in invasive non-functioning pituitary adenoma.

PURPOSE: Invasive non-functional pituitary adenomas (NFPAs) constitute 35% of NFPAs. Despite a relatively large body of molecular investigations on the invasiveness of NFPA, the underlying molecular mechanisms of invasiveness are yet to be determined. Herein, we aimed to provide an overview of gene/microRNA(miRNAs) expression alterations in invasive NFPA. METHODS: This article describes a systematic literature review of articles published up to March 23, 2021, on the transcriptional alterations of invasive NFPA. Five digital libraries were searched, and 42 articles in total fulfilled the eligibility criteria. Pathway enrichment was conducted, and protein interactions among the identified deregulated genes were inferred. RESULTS: In total 133 gene/protein transcriptional alterations, comprising 87 increased and 46 decreased expressions, were detected in a collective number of 1001 invasive compared with 1007 non-invasive patients with NFPA. Deregulation of CDH1, PTTG1, CCNB1, SNAI1, SLUG, EZR, and PRKACB, which are associated with epidermal-mesenchymal transition (EMT), was identified. Moreover, six members of the angiogenesis pathway, i.e., VEGFA, FLT1, CCND1, CTNNB1, MYC(c-MYC), and PTTG1, were detected. SLC2A1, FLT1, and VEGFA were also recognized in the hypoxia pathway. Physical interactions of CTNNB1 with FLT1, CCND1, and EZR as well as its indirect interactions with VEGFA, MYC, CCNB1, and PCNA indicate the tight interplay between EMT, angiogenesis, and hypoxia pathways in invasive NFPAs. In addition, Hippo, JAK-STAT, MAPK, Wnt, PI3K-Akt, Ras, TGF-b, VEGF, and ErbB were identified as interwoven signaling pathways. CONCLUSION: In conclusion, invasive NFPA shares very common deregulated signaling pathways with invasive cancers. A large amount of heterogeneity in the reported deregulations in different studies necessitates the validation of the expressional changes of the suggested biomarkers in a large number of patients with invasive NFPA.

Dynamic functional brain network connectivity during pseudoword processing relates to children's reading skill.

Learning to read requires children to link print (orthography) with its corresponding speech sounds (phonology). Yet, most EEG studies of reading development focus on emerging functional specialization (e.g., developing increasingly refined orthographic representations), rather than directly measuring the functional connectivity that links orthography and phonology in real time. In this proof-of-concept study we relate children's reading skill to both orthographic specialization for print (via the N170, also called the N1, event related potential, ERP) and orthographic-phonological integration (via dynamic/event-related EEG phase synchronization - an index of functional brain network connectivity). Typically developing English speaking children (n = 24; 4-14 years) and control adults (n = 20; 18-35 years) viewed pseudowords, consonants and unfamiliar false fonts during a 1-back memory task while 64-channel EEG was recorded. Orthographic specialization (larger N170 for pseudowords vs. false fonts) became more left-lateralized with age, but not with reading skill. Conversely, children's reading skill correlated with functional brain network connectivity during pseudoword processing that requires orthography-phonology linking. This was seen during two periods of simultaneous low frequency synchronization/high frequency desynchronization of posterior-occipital brain network activity. Specifically, in stronger readers, left posterior-occipital activity showed more delta (1-3Hz) synchronization around 300-500 ms (simultaneous with gamma 30-80 Hz desynchronization) and more gamma desynchronization around 600-1000 ms (simultaneous with theta 3-7Hz synchronization) during pseudoword vs. false font processing. These effects were significant even when controlling for age (moderate - large effect sizes). Dynamic functional brain network connectivity measures the brain's real-time sound-print linking. It may offer an under-explored, yet sensitive, index of the neural plasticity associated with reading development.

Post-treatment heterogeneity of cardiometabolic risk in patients with acromegaly: The impact of GH and IGF-1.

BACKGROUND: Metabolic abnormalities are frequently seen in patients with acromegaly. However, it is not clear to what extent growth hormone/insulin-like growth factor-1 (GH/IGF-1) contributes to the development of these abnormalities. OBJECTIVE: This study aimed to explore the impact of postoperative GH/IGF-1 on different aspects of metabolic abnormalities in patients with acromegaly. METHODS: This retrospective, registry-based study conducted on 102 patients with acromegaly. The impact of GH/IGF-1 on the cardiometabolic risk factors at 3-12 months after surgery has been investigated using linear and logistic regression models. RESULTS: In this study, each 1 ng/ml increase in the level of GH was significantly associated with a 2 mg/dl increase in the level of fasting blood glucose (FBG), a 0.5 mmHg increase in the level of systolic blood pressure (SBP), and a 0.9 mmHg increase in the level of diastolic blood pressure (DBP). Upon multivariate analysis, GH, but not IGF-1, significantly increased the odds of diabetes mellitus (DM) (OR; 1.2, 95% CI; 1.0-1.4, p = .025). CONCLUSIONS: Our findings indicated at early postoperative stage, GH is significantly associated with the levels of FBG, SBP, and DBP. Moreover, GH, but not IGF-1, appears as a predictive factor for the presence of DM. However, neither GH nor IGF-1 could predict the presence of hypertension HTN, or dyslipidemia in this study. ABBREVIATIONS: CVD: Cardiovascular disease; GH: Growth hormone; IGF-1: Insulin-like growth factor 1; BMI: Body mass index; HTN: hypertension; IPTR: Iran Pituitary Tumor Registry; WC: Waist circumference; MRI: Magnetic resonance imaging; FBG: Fasting blood glucose; HbA1C: Glycated hemoglobin; TG: Triglyceride; LDL: Low density lipoprotein; HDL: High density lipoprotein; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

Mild traumatic brain injury impairs the coordination of intrinsic and motor-related neural dynamics.

Mild traumatic brain injury (mTBI) poses a considerable burden on healthcare systems. Whilst most patients recover quickly, a significant number suffer from sequelae that are not accompanied by measurable structural damage. Understanding the neural underpinnings of these debilitating effects and developing a means to detect injury, would address an important unmet clinical need. It could inform interventions and help predict prognosis. Magnetoencephalography (MEG) affords excellent sensitivity in probing neural function and presents significant promise for assessing mTBI, with abnormal neural oscillations being a potential specific biomarker. However, growing evidence suggests that neural dynamics are (at least in part) driven by transient, pan-spectral bursting and in this paper, we employ this model to investigate mTBI. We applied a Hidden Markov Model to MEG data recorded during resting state and a motor task and show that previous findings of diminished intrinsic beta amplitude in individuals with mTBI are largely due to the reduced beta band spectral content of bursts, and that diminished beta connectivity results from a loss in the temporal coincidence of burst states. In a motor task, mTBI results in diminished burst amplitude, altered modulation of burst probability during movement, and a loss in connectivity in motor networks. These results suggest that, mechanistically, mTBI disrupts the structural framework underlying neural synchrony, which impairs network function. Whilst the damage may be too subtle for structural imaging to see, the functional consequences are detectable and persist after injury. Our work shows that mTBI impairs the dynamic coordination of neural network activity and proposes a potent new method for understanding mTBI.

Mild traumatic brain injury is associated with dysregulated neural network functioning in children and adolescents.

Mild traumatic brain injury is highly prevalent in paediatric populations, and can result in chronic physical, cognitive and emotional impairment, known as persistent post-concussive symptoms. Magnetoencephalography has been used to investigate neurophysiological dysregulation in mild traumatic brain injury in adults; however, whether neural dysrhythmia persists in chronic mild traumatic brain injury in children and adolescents is largely unknown. We predicted that children and adolescents would show similar dysfunction as adults, including pathological slow-wave oscillations and maladaptive, frequency-specific, alterations to neural connectivity. Using magnetoencephalography, we investigated regional oscillatory power and distributed brain-wide networks in a cross-sectional sample of children and adolescents in the chronic stages of mild traumatic brain injury. Additionally, we used a machine learning pipeline to identify the most relevant magnetoencephalography features for classifying mild traumatic brain injury and to test the relative classification performance of regional power versus functional coupling. Results revealed that the majority of participants with chronic mild traumatic brain injury reported persistent post-concussive symptoms. For neurophysiological imaging, we found increased regional power in the delta band in chronic mild traumatic brain injury, predominantly in bilateral occipital cortices and in the right inferior temporal gyrus. Those with chronic mild traumatic brain injury also showed dysregulated neuronal coupling, including decreased connectivity in the delta range, as well as hyper-connectivity in the theta, low gamma and high gamma bands, primarily involving frontal, temporal and occipital brain areas. Furthermore, our multivariate classification approach combined with functional connectivity data outperformed regional power in terms of between-group classification accuracy. For the first time, we establish that local and large-scale neural activity are altered in youth in the chronic phase of mild traumatic brain injury, with the majority presenting persistent post-concussive symptoms, and that dysregulated interregional neural communication is a reliable marker of lingering paediatric 'mild' traumatic brain injury.

Teasing apart trauma: neural oscillations differentiate individual cases of mild traumatic brain injury from post-traumatic stress disorder even when symptoms overlap.

Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are highly prevalent and closely related disorders. Affected individuals often exhibit substantially overlapping symptomatology - a major challenge for differential diagnosis in both military and civilian contexts. According to our symptom assessment, the PTSD group exhibited comparable levels of concussion symptoms and severity to the mTBI group. An objective and reliable system to uncover the key neural signatures differentiating these disorders would be an important step towards translational and applied clinical use. Here we explore use of MEG (magnetoencephalography)-multivariate statistical learning analysis in identifying the neural features for differential PTSD/mTBI characterisation. Resting state MEG-derived regional neural activity and coherence (or functional connectivity) across seven canonical neural oscillation frequencies (delta to high gamma) were used. The selected features were consistent and largely confirmatory with previously established neurophysiological markers for the two disorders. For regional power from theta, alpha and high gamma bands, the amygdala, hippocampus and temporal areas were identified. In line with regional activity, additional connections within the occipital, parietal and temporal regions were selected across a number of frequency bands. This study is the first to employ MEG-derived neural features to reliably and differentially stratify the two disorders in a multi-group context. The features from alpha and beta bands exhibited the best classification performance, even in cases where distinction by concussion symptom profiles alone were extremely difficult. We demonstrate the potential of using 'invisible' neural indices of brain functioning to understand and differentiate these debilitating conditions.

Efficacy and safety of peptide receptor radionuclide therapy in advanced radioiodine-refractory differentiated thyroid cancer and metastatic medullary thyroid cancer: a systematic review.

BACKGROUND: It has been shown that a subgroup of patients with differentiated thyroid cancer (DTC) and medullary thyroid carcinoma (MTC) would progress to advanced stages of thyroid cancer. Therefore, the present study was done to systematically review available evidence in order to investigate efficacy and safety of peptide receptor radionuclide therapy (PRRT) in the patients with advanced radioiodine refractory differentiated thyroid cancer (RR-DTC) and metastatic MTC. METHODS: For this purpose, relevant studies investigated safety and efficacy of PRRT in the patients with advanced RR-DTC and metastatic MTC were identified by searching Medline (Pubmed, Ovid, and Ebsco), Scopus, Embase, Web of Science, and Cochrane Library databases (from database inception to March 24, 2021). The review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Searching was done independently by two investigators. Two researchers independently extracted the data and any disagreement was adjudicated by consensus. Quality of the studies was assessed using the tool of case reports/series in systematic reviews. RESULTS: Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with 177Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported. CONCLUSION: Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events. TRIAL REGISTRATION: PROSPERO registration number: CRD42019125245 .

The Association between Presence of Comorbidities and COVID-19 Severity: A Systematic Review and Meta-Analysis.

AIM: Several studies reported the accompaniment of severe COVID-19 with comorbidities. However, there is not a systematic evaluation of all aspects of this association. Therefore, this meta-analysis aimed to assess the association between all underlying comorbidities in COVID-19 infection severity. METHODS: Electronic literature search was performed via scientific search engines. After the removal of duplicates and selection of articles of interest, 28 studies were included. A fixed-effects model was used; however, if heterogeneity was high (I2 > 50%) a random-effects model was applied to combine the data. RESULTS: A total of 6,270 individuals were assessed (1,615 severe and 4,655 non-severe patients). The median age was 63 (95% confidence interval [CI]: 49-74) and 47 (95% CI: 19-63) years in the severe and non-severe groups, respectively. Moreover, about 41% of patients had comorbidities. Severity was higher in patients with a history of cerebrovascular disease: OR 4.85 (95% CI: 3.11-7.57). The odds of being in a severe group increase by 4.81 (95% CI: 3.43-6.74) for a history of cardiovascular disease (CVD). This was 4.19 (95% CI: 2.84-6.19) for chronic lung disease and 3.18, 95% CI: 2.09-4.82 for cancer. The odds ratios of diabetes and hypertension were 2.61 (95% CI: 2.02-3.3) and 2.37 (95% CI: 1.80-3.13), respectively. CONCLUSIONS: The presence of comorbidities is associated with severity of COVID-19 infection. The strongest association was observed for cerebrovascular disease, followed by CVD, chronic lung disease, cancer, diabetes, and hypertension.