Christian Doppler Klinik

Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

This article describes a process theory based on active inference and belief propagation. Starting from the premise that all neuronal processing (and action selection) can be explained by maximizing Bayesian model evidence-or minimizing variational free energy-we ask whether neuronal responses can be described as a gradient descent on variational free energy. Using a standard (Markov decision process) generative model, we derive the neuronal dynamics implicit in this description and reproduce a remarkable range of well-characterized neuronal phenomena. These include repetition suppression, mismatch negativity, violation responses, place-cell activity, phase precession, theta sequences, theta-gamma coupling, evidence accumulation, race-to-bound dynamics, and transfer of dopamine responses. Furthermore, the (approximately Bayes' optimal) behavior prescribed by these dynamics has a degree of face validity, providing a formal explanation for reward seeking, context learning, and epistemic foraging. Technically, the fact that a gradient descent appears to be a valid description of neuronal activity means that variational free energy is a Lyapunov function for neuronal dynamics, which therefore conform to Hamilton's principle of least action.

INTRODUCTION In the early 2000s, a subcommittee of the American Clinical Neurophysiology Society (ACNS) set out to “standardize terminology of periodic and rhythmic EEG patterns in the critically ill to aid in future research involving such patterns.” The initial proposed terminology was published in 2005.1 This was presented at many meetings on several continents, subjected to multiple rounds of testing of interrater reliability, underwent many revisions, and was then published as an ACNS guideline in 2013.2 Interrater agreement of the 2012 version (published in early 2013) was very good, with almost perfect agreement for seizures, main terms 1 and 2, the +S modifier, sharpness, absolute amplitude, frequency, and number of phases.3 Agreement was substantial for the +F and +R modifiers (66% and 67%) but was only moderate for triphasic morphology (58%) and fair for evolution (21%, likely at least partly because of the short EEG samples provided).3 The authors concluded that interrater agreement for most terms in the ACNS critical care EEG terminology was high and that these terms were suitable for multicenter research on the clinical significance of these critical care EEG patterns. With the help of infrastructure funding from the American Epilepsy Society and administrative and website support from the ACNS, a database that incorporated the ACNS terminology was developed for clinical and research purposes, tested during routine clinical care in multiple centers,4 and made available at no cost on the ACNS website (https://www.acns.org/research/critical-care-eeg-monitoring-research-consortium-ccemrc/ccemrc-public-database). This greatly enhanced the ability to complete multicenter investigations. After the establishment of the standardized terminology and free access to a database incorporating these terms, there have been many investigations into the clinical significance of rhythmic and periodic patterns (RPPs) in critically ill patients. Patterns such as lateralized rhythmic delta activity (LRDA) were found to be highly associated with acute seizures,5,6 equivalent to the association found with lateralized periodic discharges (LPDs) in one study.5 The association of all the main patterns in the nomenclature with seizures was defined in a multicenter cohort of almost 5,000 patients, with seizure rates highest for LPDs, intermediate for LRDA and generalized periodic discharges (GPDs), and lowest for generalized rhythmic delta activity (GRDA).6 This and other studies have shown that several of the modifiers within the nomenclature do indeed have clinically relevant meaning. For example, studies have shown that higher frequency (especially >1.5 Hz), higher prevalence, longer duration, and having a “plus” modifier are all associated with a higher chance of acute seizures.6,7 On the other hand, whether a pattern was spontaneous or “stimulus-induced” did not seem to have a significant effect on its association with seizures.6 In other investigations, the “triphasic morphology” modifier was investigated blindly with multiple expert reviewers, calling into question its relationship with metabolic encephalopathy and its lack of a relationship with seizures.8,9 For patients with refractory status epilepticus treated with anesthetic-induced coma, the presence of “highly epileptiform” bursts suggested that an attempted wean off of anesthetics at that time was much more likely to lead to seizure recurrence than if the bursts were not highly epileptiform.10 Even long-term outcome seemed to be associated with some modifiers, with a higher risk of later epilepsy found if LPDs were more prevalent, had longer duration, or had a “plus” modifier.7 CHANGES IN THE 2021 VERSION OF THE TERMINOLOGY Although the previous version of the terminology was easy to use, reliable, and valuable for both research and clinical care, new terms and concepts have emerged. In this version, we incorporate recent research findings, add definitions of several new terms, and clarify a few definitions of old terms. Most of the old terms remain unchanged, but there have been some important clarifications and corrections (such as the calculation of the number of phases) and multiple additions. All changes have been summarized in Table 1. One new main term 1 was added (Unilateral Independent), and main term 2 “Lateralized” was updated to include “bilateral asynchronous” patterns. Electrographic seizures (ESz), electrographic status epilepticus (ESE), electroclinical seizures (ECSz), and electroclinical status epilepticus (ECSE) have now been defined, largely based on the “Salzburg criteria.”11,12 Brief potentially ictal rhythmic discharges (BIRDs) have been added based on recent publications13,14, and a consensus definition of the ictal-interictal continuum (IIC) has been proposed. We also added definitions of identical bursts,15 state changes, cyclic alternating pattern of encephalopathy (CAPE), and extreme delta brush (EDB).16 To facilitate daily use, we are also providing the “ACNS Standardized Critical Care EEG Terminology 2021: Condensed Version” (see Supplemental Digital Content, http://links.lww.com/JCNP/A149) and the “ACNS Standardized Critical Care EEG Terminology 2021: Reference Chart” (see Supplemental Digital Content, http://links.lww.com/JCNP/A150). Finally, for educational purposes and conceptual clarity, we provided extensive schematic diagrams (Figures 1–42) of most patterns to quickly demonstrate the core features and principles. Supplemental figures include EEG examples from 30 cases and are available as Supplemental Digital Content at http://links.lww.com/JCNP/A134. TABLE 1. - ACNS Standardized Critical Care EEG Terminology: Major and Minor Changes Between the 2012 and 2021 Versions Major changes EEG background • “Variability” and and now • of • bursts and Patterns and • 1 • • Patterns that in one and to the other now be as a lateralized • • For and only be to if or have a frequency and are these as electrographic seizures and be to as such than as or • in this terminology have a frequency of if a pattern and for or an electrographic seizure (see definitions this not as but as a • • of an now to patterns that are with evolution as a (see with evolution of an electrographic seizure and be as • • Electrographic and • Electrographic seizure • Electrographic status epilepticus • seizure • status epilepticus (ECSE) • electroclinical status epilepticus Brief (BIRDs) (IIC) Minor changes EEG background • background frequency • has now been added than only or • • from to • from to • from to of the • • now also be the of term 1 • • if multiple discharges are within the of bursts and at an of or if a potentially pattern at or within the of • if 2 or more discharges or are within the of bursts and at an of 1 or within a as the of the of discharges within a if a potentially pattern at or within the of • • or all activity has now been added as a and periodic patterns • • from to the definition of status epilepticus with the • from to • • from to • from to • from modifier to modifier All the definitions are based on extensive not only the authors of this but also many both and and was not complete consensus on some to the of for the was for most of these We changes from previous or from the such as the for electrographic seizures but because no consensus was was to a this was not 2021 ACNS EEG TERMINOLOGY EEG (RPPs) (BIRDs) (IIC) This terminology to be at all some terms not be for For the version of the This terminology for in the critically be in other as with the of terms most clinical Although on EEG be or such as an or and this a very important in some such as epilepsy all of these are within the terms or in this the pattern and are be provided and also be to several modifiers and This was into the available Critical Care EEG database that incorporated the previous version of this nomenclature new database with this 2021 nomenclature In this and the the term to to an EEG pattern during an whether clinical or as the term in EEG as an for for all of periodic or rhythmic to All in this are based on to to in a for an The term or to of of discharges in a periodic of of a rhythmic or of the for a background EEG 1. in on an of or in frequency of to 1 or frequency in in in and of the features are be for Most or After or frequency are be to with to frequency to frequency to the but with of the of or of of are but of the higher of are for to the of the that or this in are this to as or This as with other from the ACNS pattern of alternating with higher with to of the of or pattern of alternating with higher with to of the of (see EEG Supplemental Digital Content or (see EEG 2, Supplemental Digital Content The term with and have at least at least for definition of number of if or be defined main term 2, within or to 30 an the on one of the (see and and or the of the that or This from to or but not or For example, a with 2 bursts alternating with of be with a of or the of the that or This from to or but not For example, a with 2 bursts alternating with of as shown be with a of patterns also the of be the terms in 1 that to rhythmic and periodic generalized with or of bursts and of a the defined The presence or of if or more discharges or are within most bursts and at an of 1 or within a as the of the of discharges within a (see EEG Supplemental Digital Content frequency and or as defined in if a potentially pattern within most frequency and if this The presence or of if the or longer of or of of 2 or more bursts in all in most bursts (see EEG Supplemental Digital Content or of the of as defined or activity but not as whether or of based on at on the and on the but the This be an of generalized with based on than be of on the and other the bursts on the with a on the This an of are not bursts because there a relationship the activity the patterns are not longer of longer of The or longer of are in all only 1 in most in a The or longer of of 2 or more bursts in a are in all only 1 in most in EEG activity to This include in or frequency, of of be and a of testing with multiple of activity or not as as the suggested that if an EEG one of a of standardized be to the and be with the in and the on or we this important in the the only or discharges This or (see multiple testing have not been there was much to the or there was a of a in activity but not was not tested or was the EEG Changes if there are at least 2 of background EEG to the of or at least to as a be to the from the to more changes also The more pattern the EEG pattern for the state changes as the with and but with • both and as the and but frequency, but least 2 of background 1. The background activity to of or to as a be to the from the to more The more state the changes also The presence of state changes the presence of the presence of not the presence of state changes because the of to changes in background patterns include at least and alternating the 2 patterns in a for at least to to the of time the both whether in the more state or state if pattern and of if this pattern with of other such as and of Changes in EEG background pattern 1 and pattern 2, 1. pattern at least the patterns in a For at least pattern of this as the presence of state be with and at least one of the for a to have and no state most or all activity in with from to most or all activity in with from to but not as all activity the background or EEG background to the higher at in the there a and least 1 to of and such that are in and higher are in defined but with a to of and but effect to EEG activity or a and of activity of higher and sharpness, of with the of the with the on the of the This to and and as defined in the of terms most clinical defined as from background with at a time and from to with at the EEG defined but with a of to or or with a than but be the and a or associated with some other of the to 2 or more in a with no and as if alternating with or a highly within The of discharges and be as but not be to the and number of discharges are but than 1 but than (RPPs) All terms of main terms, with modifiers added as term 1 to the of the pattern and main term 2 the of 1. or and pattern (see and Supplemental Digital Content if has a and periodic In this the pattern pattern that with based on amplitude, higher on and based on on the and but not of the lateralized to one be With one the time suggested that a more term be “bilateral but this was for several 1. many lateralized patterns are also (see definition of this more to and the has been to to seizures, and that are not in this has also been in many studies in the to critical care EEG and in the previous 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The prevalence of obesity and related disorders such as metabolic syndrome has vastly increased throughout the world. Recent insights have generated an entirely new perspective suggesting that our microbiota might be involved in the development of these disorders. Studies have demonstrated that obesity and metabolic syndrome may be associated with profound microbiotal changes, and the induction of a metabolic syndrome phenotype through fecal transplants corroborates the important role of the microbiota in this disease. Dietary composition and caloric intake appear to swiftly regulate intestinal microbial composition and function. As most findings in this field of research are based on mouse studies, the relevance to human biology requires further investigation.

Many studies, reviews, and meta-analyses have reported elevated mental health problems for sexual minority (SM) individuals. This systematic review provides an update by including numerous recent studies, and explores whether SM individuals are at increased risk across selected mental health problems as per dimensions of sexual orientation (SO), genders, life-stages, geographic regions, and in higher quality studies. A systematic search in PubMed produced 199 studies appropriate for review. A clear majority of studies reported elevated risks for depression, anxiety, suicide attempts or suicides, and substance-related problems for SM men and women, as adolescents or adults from many geographic regions, and with varied SO dimensions (behaviour, attraction, identity), especially in more recent and higher quality studies. One notable exception is alcohol-related problems, where many studies reported zero or reversed effects, especially for SM men. All SM subgroups were at increased risk, but bisexual individuals were at highest risk in the majority of studies. Other subgroup and gender differences are more complex and are discussed. The review supports the long-standing mental health risk proposition for SM individuals, overall and as subgroups.

Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-beta (IKKbeta), a kinase located proximal of nuclear factor-kappaB (NF-kappaB), participate in this process. Hepatocyte-specific overexpression of NF-kappaB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.

This paper offers an active inference account of choice behaviour and learning. It focuses on the distinction between goal-directed and habitual behaviour and how they contextualise each other. We show that habits emerge naturally (and autodidactically) from sequential policy optimisation when agents are equipped with state-action policies. In active inference, behaviour has explorative (epistemic) and exploitative (pragmatic) aspects that are sensitive to ambiguity and risk respectively, where epistemic (ambiguity-resolving) behaviour enables pragmatic (reward-seeking) behaviour and the subsequent emergence of habits. Although goal-directed and habitual policies are usually associated with model-based and model-free schemes, we find the more important distinction is between belief-free and belief-based schemes. The underlying (variational) belief updating provides a comprehensive (if metaphorical) process theory for several phenomena, including the transfer of dopamine responses, reversal learning, habit formation and devaluation. Finally, we show that active inference reduces to a classical (Bellman) scheme, in the absence of ambiguity.

Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes ("essential comorbidities"), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly "more aggressive" treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.

We convened an international group of experts to standardize definitions of New-Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in-person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion-Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super-refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.

This study used foci from 17 original studies on functional abnormalities in the dyslexic brain to identify brain regions with consistent under- or overactivation. Studies were included when reading or reading-related tasks were performed on visually presented stimuli and when results reported coordinates for group differences. Activation likelihood estimation (ALE) was used for quantification. Maxima of underactivation were found in inferior parietal, superior temporal, middle and inferior temporal, and fusiform regions of the left hemisphere. With respect to left frontal abnormalities, we found underactivation in the inferior frontal gyrus to be accompanied by overactivation in the primary motor cortex and the anterior insula. Tentative functional interpretations of the activation abnormalities are provided.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. FUNDING: Gates Foundation.

Major depressive disorder (MDD) is characterized by altered intrinsic functional connectivity within (intra-iFC) intrinsic connectivity networks (ICNs), such as the Default Mode- (DMN), Salience- (SN) and Central Executive Network (CEN). It has been proposed that aberrant switching between DMN-mediated self-referential and CEN-mediated goal-directed cognitive processes might contribute to MDD, possibly explaining patients' difficulties to disengage the processing of self-focused, often negatively biased thoughts. Recently, it has been shown that the right anterior insula (rAI) within the SN is modulating DMN/CEN interactions. Since structural and functional alterations within the AI have been frequently reported in MDD, we hypothesized that aberrant intra-iFC in the SN's rAI is associated with both aberrant iFC between DMN and CEN (inter-iFC) and severity of symptoms in MDD. Twenty-five patients with MDD and 25 healthy controls were assessed using resting-state fMRI (rs-fMRI) and psychometric examination. High-model-order independent component analysis (ICA) of rs-fMRI data was performed to identify ICNs including DMN, SN, and CEN. Intra-iFC within and inter-iFC between distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Patients with MDD showed (1) decreased intra-iFC within the SN's rAI, (2) decreased inter-iFC between the DMN and CEN, and (3) increased inter-iFC between the SN and DMN. Moreover, decreased intra-iFC in the SN's rAI was associated with severity of symptoms and aberrant DMN/CEN interactions, with the latter losing significance after correction for multiple comparisons. Our results provide evidence for a relationship between aberrant intra-iFC in the salience network's rAI, aberrant DMN/CEN interactions and severity of symptoms, suggesting a link between aberrant salience mapping, abnormal coordination of DMN/CEN based cognitive processes and psychopathology in MDD.

Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liège) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 ± 18 years, range 11-87; 16 traumatic, 32 non-traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post-insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each network's capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale-Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics.

BACKGROUND: Spinal cord injury (SCI) is a major cause of health loss due to premature mortality and long-term disability. We aimed to report on the global, regional, and national incidence, prevalence, and years of life lived with disability (YLDs) for SCI from 1990 to 2019, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: Using GBD 2019 data pooled in DisMod-MR 2.1, a Bayesian meta-regression tool, we systematically derived numbers and age-standardised rate changes with 95% uncertainty intervals (95% UIs) for the incidence, prevalence, and YLDs for SCI from 1990 to 2019 for the whole world, 21 GBD regions, and 204 countries and territories. We report trends based on age, sex, year, cause of injury, and level of injury. FINDINGS: Globally, 20·6 million (95% UI 18·9 to 23·6) individuals were living with SCI in 2019. The incidence of SCI was 0·9 million (0·7 to 1·2) cases with an estimated 6·2 million (4·5 to 8·2) YLDs. SCI rates increased substantially from 1990 to 2019 for global prevalence (81·5%, 74·2 to 87·1), incidence (52·7%, 30·3 to 69·8), and YLDs (65·4%, 56·3 to 76·0). However, global age-standardised rates per 100 000 population showed small changes in prevalence (5·8%, 2·6 to 9·5), incidence (-6·1%, -17·2 to 1·5), and YLDs (-1·5%, -5·5 to 3·2). Data for 2019 shows that the incidence of SCI increases sharply until age 15-19 years, where it remains reasonably constant until 85 years of age and older. By contrast, prevalence and YLDs showed similar patterns to each other, with one peak at around age 45-54 years. The incidence, prevalence, and YLDs of SCI have consistently been higher in men than in women globally, with a slight and steady increase for both men and women from 1990 to 2019. Between 1990 and 2019, SCI at neck level was more common than SCI below neck level in terms of incidence (492 thousand [354 to 675] vs 417 thousand [290 to 585]), prevalence (10·8 million [9·5 to 13·9] vs 9·7 million [9·2 to 10·4]), and YLDs (4·2 million [3·0 to 5·8] vs 1·9 million [1·3 to 2·5]). Falls (477 thousand [327 to 683] cases) and road injuries (230 thousand [122 to 389] cases) were the two leading causes of SCI globally in 2019. INTERPRETATION: Although age-standardised rates of incidence, prevalence, and YLDs for SCI changed only slightly, absolute counts increased substantially from 1990 to 2019. Geographical heterogeneity in demographic, spatial, and temporal patterns of SCI, at both the national and regional levels, should be considered by policy makers aiming to reduce the burden of SCI. FUNDING: Bill & Melinda Gates Foundation.

Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.