•MDD can be clinically divided into subtypes, such as atypical and melancholic MDD.•Inflammation seems not to have the same impact on every MDD subtype.•Neuroinflammation shows a regional specificity ...in ACC.•This specificity overlaps with neuronal patterns potentially distinguishing subtypes.•Subtype-specific clinical features coincide with functional associations of ACC.
Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points toward an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset. Next, we examine the regional specificity of neuroinflammation, which shows striking overlaps with neural patterns activated in atypical MDD. Furthermore, we outline how inflammation may translate to subtype-specific clinical features and we suggest how this could be used for diagnostic and treatment purposes. By providing a link back to a dysregulated immune system as a contributing factor to MDD subtypes, we explain how brain regions particularly affected by certain subtypes may regulate the cortisol circuitry.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient ...preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition.
The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group.
Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded.
One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
Major depression is a prevalent disorder that imposes a significant burden on society, yet objective laboratory-style tests to assist in diagnosis are lacking. We employed network-based analyses of ..."resting state" functional neuroimaging data to ascertain group differences in the endogenous cortical activity between healthy and depressed subjects.We additionally sought to use machine learning techniques to explore the ability of these network-based measures of resting state activity to provide diagnostic information for depression. Resting state fMRI data were acquired from twenty two depressed outpatients and twenty two healthy subjects matched for age and gender. These data were anatomically parcellated and functional connectivity matrices were then derived using the linear correlations between the BOLD signal fluctuations of all pairs of cortical and subcortical regions.We characterised the hierarchical organization of these matrices using network-based matrics, with an emphasis on their mid-scale "modularity" arrangement. Whilst whole brain measures of organization did not differ between groups, a significant rearrangement of their community structure was observed. Furthermore we were able to classify individuals with a high level of accuracy using a support vector machine, primarily through the use of a modularity-based metric known as the participation index.In conclusion, the application of machine learning techniques to features of resting state fMRI network activity shows promising potential to assist in the diagnosis of major depression, now suggesting the need for validation in independent data sets.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An unrecognised copy (1665) in Kant’s private library of Michael Piccart’s Isagoge (1605), an introduction to the system of Aristotelian philosophy together with Kant’s own remarks on this author ...(Refl 4160, AA 17, p. 439) can be established as an original source for the Kantian ‘ideosphere’. First, I point out contexts and consequences of Piccart’s Altdorfian Aristotelianism, in contrast to the Königsbergian Aristotelianism (emphasised by Tonelli’s research). To further check the quality of Piccart as a source of Kant’s, a conceptual case-study is elaborated with Kant’s critical distinction between analytics as a “logic of truth” (KrV, B 85) and dialectics as a “logic of illusion” (KrV, B 86). Hereby, dialectics is understood as part of an Aristotelian division of logic in analytics, dialectics and sophistics (Königsberg/Rabe versus Altdorf/Piccart). As will be shown by the paradigmatic case of the famous Königsbergian proponent of Aristotelianism, Paul Rabe, Kant cannot have received the suggestion for his own critical distinction from Rabe’s Cursus Philosophicus. Instead, Piccart refers to a passage of Aristotle’s Metaphysics, which suggests the very distinction between an analytic philosopher who searches for scientific truth and dialecticians and sophists. For different reasons, they do not claim any scientific seriousness.
Postpartum depression (PPD) is a detrimental health condition that affects 12% of new mothers. Despite negative effects on mothers' and children's health, many women do not receive adequate care. ...Preventive interventions are cost-efficient among high-risk women, but our ability to identify these is poor. We leveraged the power of clinical, demographic, and psychometric data to assess if machine learning methods can make accurate predictions of postpartum depression. Data were obtained from a population-based prospective cohort study in Uppsala, Sweden, collected between 2009 and 2018 (BASIC study, n = 4313). Sub-analyses among women without previous depression were performed. The extremely randomized trees method provided robust performance with highest accuracy and well-balanced sensitivity and specificity (accuracy 73%, sensitivity 72%, specificity 75%, positive predictive value 33%, negative predictive value 94%, area under the curve 81%). Among women without earlier mental health issues, the accuracy was 64%. The variables setting women at most risk for PPD were depression and anxiety during pregnancy, as well as variables related to resilience and personality. Future clinical models that could be implemented directly after delivery might consider including these variables in order to identify women at high risk for postpartum depression to facilitate individualized follow-up and cost-effectiveness.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic ...system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Major depressive disorder (MDD) is a leading cause of disability worldwide. After the first episode, patients with remitted MDD have a 60% chance of experiencing a second episode. Consideration of ...therapy continuation should be viewed in terms of the balance between the adverse effects of medication and the need to prevent a possible relapse. Relapse during the early stages of MDD could be prevented more efficiently by conducting individual risk assessments and providing justification for continuing therapy. Our previous work established the neuroimaging markers of relapse by comparing patients with recurrent major depressive disorder (rMDD) in depressive and remitted states. However, it is not known which of these markers are trait markers that present before initial relapse and, consequently, predict disease course. Here, we first describe how inflammation can be translated to subtype-specific clinical features and suggest how this could be used to facilitate clinical diagnosis and treatment. Next, we address the central and peripheral functional state of the immune system in patients with MDD. In addition, we emphasize the important link between the number of depressive episodes and rMDD and use neuroimaging to propose a model for the latter. Last, we address how inflammation can affect brain circuits, providing a possible mechanism for rMDD. Our review suggests a link between inflammatory processes and brain region/circuits in rMDD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Long‐term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)‐based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen ...elastography to assess potential regression of cirrhosis and portal hypertension 3 years post‐treatment. Fifty‐four patients with HCV‐associated cirrhosis and DAA‐induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post‐treatment by transient liver elastography (L‐TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L‐ARFI) and spleen (S‐ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L‐TE decreased between BL median (range), 32.5(9.1–75) kPa and EOT 21.3(6.7–73.5) kPa; p < .0001 and EOT and FU144 16(4.1–75) kPa; p = .006. L‐ARFI values improved between EOT 2.5(1.2–4.1) m/s and FU144 1.7(0.9–4.1) m/s; p = .001, while spleen stiffness remained unchanged. Overall, L‐TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L‐ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L‐ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L‐TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The locus coeruleus (LC) is involved in numerous crucial brain functions and several disorders like depression and Alzheimer's disease. Recently, the LC resting‐state functional connectivity (rs‐fc) ...has been investigated in functional MRI by calculating the blood oxygen level–dependent (BOLD) response extracted using Montreal Neurological Institute (MNI) space masks. To corroborate these results, we aimed to investigate the LC rs‐fc at native space by improving the identification of the LC location using a neuromelanin sensitive sequence. Twenty‐five healthy male participants (mean age 24.8 ± 4.2) were examined in a Siemens MAGNETOM Prisma 3 T MRT applying a neuromelanin sensitive T1TSE sequence and functional MRI. We compared the rs‐fc of LC calculated by a MNI‐based approach with extraction of the BOLD signal at the exact individual location of the LC after applying CompCor and field map correction. As a measure of advance, a marked increase of regional homogeneity (ReHo) of time series within LC could be achieved with the subject‐specific approach. Furthermore, the methods differed in the rs‐fc to the right temporoparietal junction, which showed stronger connectivity to the LC in the MNI‐based method. Nevertheless, both methods comparably revealed LC rs‐fc to multiple brain regions including ACC, bilateral thalamus, and cerebellum. Our results are relevant for further research assessing and interpreting LC function, especially in patient populations examined at 3 T MRI.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ((90)Y-DOTA-TOC) in ...neuroendocrine cancers.
In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of (90)Y-DOTA-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface (90)Y-DOTA-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity.
Overall, 1,109 patients received 2,472 cycles of (90)Y-DOTA-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio HR, 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003).
This study documents the long-term outcome of (90)Y-DOTA-TOC treatment in a large cohort. Response to (90)Y-DOTA-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after (90)Y-DOTA-TOC treatment and occurrence of renal toxicity.
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