Yet more evidence that non-aqueous myelin lipids can be directly imaged with ultrashort echo time (UTE) MRI on a clinical 3T scanner: a lyophilized red blood cell membrane lipid study.

Direct imaging of semi-solid lipids, such as myelin, is of great interest as a noninvasive biomarker of neurodegenerative diseases. Yet, the short T2 relaxation times of semi-solid lipid protons hamper direct detection through conventional magnetic resonance imaging (MRI) pulse sequences. In this study, we examined whether a three-dimensional ultrashort echo time (3D UTE) sequence can directly acquire signals from membrane lipids. Membrane lipids from red blood cells (RBC) were collected from commercially available blood as a general model of the myelin lipid bilayer and subjected to D2O exchange and freeze-drying for complete water removal. Sufficiently high MR signals were detected with the 3D UTE sequence, which showed an ultrashort T2* of ∼77-271 µs and a short T1 of ∼189 ms for semi-solid RBC membrane lipids. These measurements can guide designing UTE-based sequences for direct in vivo imaging of membrane lipids.

Anticipated imitation of multiple agents.

It is well-established that people tend to mimic one another's actions, a crucial aspect of social interactions. Anticipating imitation has been shown to boost motor activation and reaction times for congruent actions. However, prior research predominantly focused on dyads, leaving gaps in our knowledge regarding group dynamics. This study addresses this gap, conducting three experiments using extensive online data. Participants engaged in anticipated imitation tasks with one versus three virtual agents. The results across all three experiments (n = 77; n = 239; n = 457) consistently support the existence of an anticipated imitation effect, with faster reaction times for congruent actions. Furthermore, the research unveils a social facilitation effect, with participants reacting more swiftly when anticipating three agents compared to one. However, we did not find the expected increase of the congruency effect with multiple agents; rather, the data indicates that anticipating multiple agents instead decreases this effect. These findings are discussed within the framework of ideomotor theory, offering insights into how they relate to recent research on the automatic imitation of multiple agents.

Subnational inequalities in years of life lost and associations with socioeconomic factors in pre-pandemic Europe, 2009-19: an ecological study.

BACKGROUND: Health inequalities have been associated with shorter lifespans. We aimed to investigate subnational geographical inequalities in all-cause years of life lost (YLLs) and the association between YLLs and socioeconomic factors, such as household income, risk of poverty, and educational attainment, in countries within the European Economic Area (EEA) before the COVID-19 pandemic. METHODS: In this ecological study, we extracted demographic and socioeconomic data from Eurostat for 1390 small regions and 285 basic regions for 32 countries in the EEA, which was complemented by a time-trend analysis of subnational regions within the EEA. Age-standardised YLL rates per 100 000 population were estimated from 2009 to 2019 based on methods from the Global Burden of Disease study. Geographical inequalities were assessed using the Gini coefficient and slope index of inequality. Socioeconomic inequalities were assessed by investigating the association between socioeconomic factors (educational attainment, household income, and risk of poverty) and YLLs in 2019 using negative binomial mixed models. FINDINGS: Between Jan 1, 2009, and Dec 31, 2019, YLLs lowered in almost all subnational regions. The Gini coefficient of YLLs across all EEA regions was 14·2% (95% CI 13·6-14·8) for females and 17·0% (16·3 to 17·7) for males. Relative geographical inequalities in YLLs among women were highest in the UK (Gini coefficient 11·2% [95% CI 10·1-12·3]) and among men were highest in Belgium (10·8% [9·3-12·2]). The highest YLLs were observed in subnational regions with the lowest levels of educational attainment (incident rate ratio [IRR] 1·19 [1·13-1·26] for females; 1·22 [1·16-1·28] for males), household income (1·35 [95% CI 1·19-1·53]), and the highest poverty risk (1·25 [1·18-1·34]). INTERPRETATION: Differences in YLLs remain within, and between, EEA countries and are associated with socioeconomic factors. This evidence can assist stakeholders in addressing health inequities to improve overall disease burden within the EEA. FUNDING: Research Council of Norway; Development, and Innovation Fund of Hungary; Norwegian Institute of Public Medicine; and COST Action 18218 European Burden of Disease Network.

Bi-Exponential 3D UTE-T1ρ Relaxation Mapping of Ex Vivo Human Knee Patellar Tendon at 3T.

Introduction: The objective of this study was to assess the bi-exponential relaxation times and fractions of the short and long components of the human patellar tendon ex vivo using three-dimensional ultrashort echo time T1ρ (3D UTE-T1ρ) imaging. Materials and Methods: Five cadaveric human knee specimens were scanned using a 3D UTE-T1ρ imaging sequence on a 3T MR scanner. A series of 3D UTE-T1ρ images were acquired and fitted using single-component and bi-component models. Single-component exponential fitting was performed to measure the UTE-T1ρ value of the patellar tendon. Bi-component analysis was performed to measure the short and long UTE-T1ρ values and fractions. Results: The single-component analysis showed a mean single-component UTE-T1ρ value of 8.4 ± 1.7 ms for the five knee patellar tendon samples. Improved fitting was achieved with bi-component analysis, which showed a mean short UTE-T1ρ value of 5.5 ± 0.8 ms with a fraction of 77.6 ± 4.8%, and a mean long UTE-T1ρ value of 27.4 ± 3.8 ms with a fraction of 22.4 ± 4.8%. Conclusion: The 3D UTE-T1ρ sequence can detect the single- and bi-exponential decay in the patellar tendon. Bi-component fitting was superior to single-component fitting.

Whole knee joint mapping using a phase modulated UTE adiabatic T1ρ (PM-UTE-AdiabT1ρ ) sequence.

PURPOSE: To develop a 3D phase modulated UTE adiabatic T1ρ (PM-UTE-AdiabT1ρ ) sequence for whole knee joint mapping on a clinical 3 T scanner. METHODS: This new sequence includes six major features: (1) a magnetization reset module, (2) a train of adiabatic full passage pulses for spin locking, (3) a phase modulation scheme (i.e., RF cycling pair), (4) a fat saturation module, (5) a variable flip angle scheme, and (6) a 3D UTE Cones sequence for data acquisition. A simple exponential fitting was used for T1ρ quantification. Phantom studies were performed to investigate PM-UTE-AdiabT1ρ 's sensitivity to compositional changes and reproducibility as well as its correlation with continuous wave-T1ρ measurement. The PM-UTE-AdiabT1ρ technique was then applied to five ex vivo and five in vivo normal knees to measure T1ρ values of femoral cartilage, meniscus, posterior cruciate ligament, anterior cruciate ligament, patellar tendon, and muscle. RESULTS: The phantom study demonstrated PM-UTE-AdiabT1ρ 's high sensitivity to compositional changes, its high reproducibility, and its strong linear correlation with continuous wave-T1ρ measurement. The ex vivo and in vivo knee studies demonstrated average T1ρ values of 105.6 ± 8.4 and 77.9 ± 3.9 ms for the femoral cartilage, 39.2 ± 5.1 and 30.1 ± 2.2 ms for the meniscus, 51.6 ± 5.3 and 29.2 ± 2.4 ms for the posterior cruciate ligament, 79.0 ± 9.3 and 52.0 ± 3.1 ms for the anterior cruciate ligament, 19.8 ± 4.5 and 17.0 ± 1.8 ms for the patellar tendon, and 91.1 ± 8.8 and 57.6 ± 2.8 ms for the muscle, respectively. CONCLUSION: The 3D PM-UTE-AdiabT1ρ sequence allows volumetric T1ρ assessment for both short and long T2 tissues in the knee joint on a clinical 3 T scanner.

Inequalities in the burden of non-communicable diseases across European countries: a systematic analysis of the Global Burden of Disease 2019 study.

BACKGROUND: Although overall health status in the last decades improved, health inequalities due to non-communicable diseases (NCDs) persist between and within European countries. There is a lack of studies giving insights into health inequalities related to NCDs in the European Economic Area (EEA) countries. Therefore, the aim of the present study was to quantify health inequalities in age-standardized disability adjusted life years (DALY) rates for NCDs overall and 12 specific NCDs across 30 EEA countries between 1990 and 2019. Also, this study aimed to determine trends in health inequalities and to identify those NCDs where the inequalities were the highest. METHODS: DALY rate ratios were calculated to determine and compare inequalities between the 30 EEA countries, by sex, and across time. Annual rate of change was used to determine the differences in DALY rate between 1990 and 2019 for males and females. The Gini Coefficient (GC) was used to measure the DALY rate inequalities across countries, and the Slope Index of Inequality (SII) to estimate the average absolute difference in DALY rate across countries. RESULTS: Between 1990 and 2019, there was an overall declining trend in DALY rate, with larger declines among females compared to males. Among EEA countries, in 2019 the highest NCD DALY rate for both sexes were observed for Bulgaria. For the whole period, the highest DALY rate ratios were identified for digestive diseases, diabetes and kidney diseases, substance use disorders, cardiovascular diseases (CVD), and chronic respiratory diseases - representing the highest inequality between countries. In 2019, the highest DALY rate ratio was found between Bulgaria and Iceland for males. GC and SII indicated that the highest inequalities were due to CVD for most of the study period - however, overall levels of inequality were low. CONCLUSIONS: The inequality in level 1 NCDs DALYs rate is relatively low among all the countries. CVDs, digestive diseases, diabetes and kidney diseases, substance use disorders, and chronic respiratory diseases are the NCDs that exhibit higher levels of inequality across countries in the EEA. This might be mitigated by applying tailored preventive measures and enabling healthcare access.

Models of the Translation Process and the Free Energy Principle.

Translation process research (TPR) has generated a large number of models that aim at explaining human translation processes. In this paper, I suggest an extension of the monitor model to incorporate aspects of relevance theory (RT) and to adopt the free energy principle (FEP) as a generative model to elucidate translational behaviour. The FEP-and its corollary, active inference-provide a general, mathematical framework to explain how organisms resist entropic erosion so as to remain within their phenotypic bounds. It posits that organisms reduce the gap between their expectations and observations by minimising a quantity called free energy. I map these concepts on the translation process and exemplify them with behavioural data. The analysis is based on the notion of translation units (TUs) which exhibit observable traces of the translator's epistemic and pragmatic engagement with their translation environment, (i.e., the text) that can be measured in terms of translation effort and effects. Sequences of TUs cluster into translation states (steady state, orientation, and hesitation). Drawing on active inference, sequences of translation states combine into translation policies that reduce expected free energy. I show how the notion of free energy is compatible with the concept of relevance, as developed in RT, and how essential concepts of the monitor model and RT can be formalised as deep temporal generative models that can be interpreted under a representationalist view, but also support a non-representationalist account.

Anatomical and functional outcomes after bilateral sacrospinous colposuspension (BSC) for the treatment of female genital prolapse.

BACKGROUND: Pelvic organ prolapse is a bothersome condition affecting many women at advanced age, but also frequently observed in young women with certain risk factors. Various surgical techniques have been developed with the aim of providing effective surgical treatment for apical prolapse. The vaginal bilateral sacrospinous colposuspension surgery (BSC) with ultralight mesh and utilization of the i- stich is a relatively new minimal invasive technique with very promising outcomes. The technique offers apical suspension, in the presence or absence of the uterus. The objective of this study is to evaluate the anatomical and functional outcomes of bilateral sacrospinous colposuspension with ultralight mesh in 30 Patients treated with the vaginal single incision standardized technique. METHODS: In this retrospective study, 30 patients were treated by BSC for significant vaginal, uterovaginal or cervical prolapse. A simultaneous anterior colporrhaphy, posterior colporrhaphy or both were performed when indicated. Anatomical and functional outcomes were assessed 1 year postoperatively using the Pelvic Organ Prolapse Quantification system (POP-Q) and the standardised Prolapse Quality of Life (P-QOL) questionnair. RESULTS: The POP-Q parameters were significantly improved at twelve months after surgery compared to baseline. The total score and all four subdomains of the P-QOL-questionnaire showed positive trends and improvement at twelve months after surgery when compared to preoperative values. All patients were asymptomatic and expressed high satisfaction one year after surgery. No intraoperative adverse events were recorded for all patients. Only minimal postoperative complications were recorded and they all resolved completely with conservative management. CONCLUSION: This study highlights the functional and anatomical outcomes of the minimally invasive vaginal bilateral sacrospinal colposuspension with ultralight mesh for the management of apical prolapse. The one year postoperative results of the proposed procedure reflect excellent outcomes with minimal complications. The data published here are very promising and warrant further investigations and more studies to evaluate the long-term outcomes of BSC in the surgical management of apical defects. TRIAL REGISTRATION: The study protocol was approved by the Ethics Committee at the University Hospital of Cologne, Germany (Date of registration: 08.02.2022) (Registration number: 21-1494-retro) (retrospectively registered).

Genome-wide association studies reveal novel loci for resistance to groundnut rosette disease in the African core groundnut collection.

KEY MESSAGE: We identified markers associated with GRD resistance after screening an Africa-wide core collection across three seasons in Uganda Groundnut is cultivated in several African countries where it is a major source of food, feed and income. One of the major constraints to groundnut production in Africa is groundnut rosette disease (GRD), which is caused by a complex of three agents: groundnut rosette assistor luteovirus, groundnut rosette umbravirus and its satellite RNA. Despite several years of breeding for GRD resistance, the genetics of the disease is not fully understood. The objective of the current study was to use the African core collection to establish the level of genetic variation in their response to GRD, and to map genomic regions responsible for the observed resistance. The African groundnut core genotypes were screened across two GRD hotspot locations in Uganda (Nakabango and Serere) for 3 seasons. The Area Under Disease Progress Curve combined with 7523 high quality SNPs were analyzed to establish marker-trait associations (MTAs). Genome-Wide Association Studies based on Enriched Compressed Mixed Linear Model detected 32 MTAs at Nakabango: 21 on chromosome A04, 10 on B04 and 1 on B08. Two of the significant markers were localised on the exons of a putative TIR-NBS-LRR disease resistance gene on chromosome A04. Our results suggest the likely involvement of major genes in the resistance to GRD but will need to be further validated with more comprehensive phenotypic and genotypic datasets. The markers identified in the current study will be developed into routine assays and validated for future genomics-assisted selection for GRD resistance in groundnut.

Apparent Diffusion Coefficient Reproducibility Across 3 T Scanners in a Breast Diffusion Phantom.

BACKGROUND: To date, the accuracy and variability of diffusion-weighted MRI (DW-MRI) metrics have been reported in a limited number of scanner/protocol/coil combinations. PURPOSE: To evaluate the reproducibility of DW-MRI estimates across multiple scanners and DW-MRI protocols and to assess the effects of using an 8-channel vs. 16-channel breast coil in a breast phantom. STUDY TYPE: Prospective. PHANTOM: Breast phantom containing tubes of water and differing polyvinylpyrrolidone (PVP) concentrations with apparent diffusion coefficients (ADCs) matching breast tissue. FIELD STRENGTH/SEQUENCE: 3 T (three standard and one wide bore), three DW-MRI single-shot echo planar imaging protocols of varying acquired spatial resolution. ASSESSMENT: Accuracy of estimated ADCs was assessed using percent differences (PD) relative to nuclear magnetic resonance spectroscopy-derived reference values. Coefficients of variation (CV) were calculated to determine variation across scanners. CVs based on the median standard deviation (CVM ) were used to evaluate tube-specific dispersion using 8- or 16-channel coils at a single scanner. ADCs of PVP-containing tubes were additionally normalized by the median water tube ADC to account for temperature effects. STATISTICAL TESTS: Two-way repeated measures analysis of variance and post hoc tests were used to evaluate differences in ADC, CV, and CVM across scanners and protocols (α = 0.05). RESULTS: ADCs were within 11% (interquartile range [IQR] 7%) of reference values and significantly improved to 2% (IQR 7%) after normalization to an internal water reference. Normalization significantly reduced interscanner variability of ADC estimates from 7% to 4%. DW-MRI protocol did not affect ADC accuracy; however, the clinical and higher-resolution clinical protocols resulted in the greatest (9%) and least (6%) interscanner variability, respectively. The 8- and 16-channel receive coils yielded similar accuracy (PD: 12% vs. 16%) and precision (CVM : 2.7% vs. 2.9%). DATA CONCLUSION: Normalization by an internal reference improved interscanner ADC reproducibility. High-resolution protocols yielded comparably accurate and significantly less variable ADCs compared to a clinical standard protocol. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Empathic pain observation does not influence automatic imitation in an online setting.

Previous research has shown that empathic pain observation can lead to motor facilitation in the form of faster reaction times. However, it is unclear whether participants are focusing on the others' pain or simply focusing on their own discomfort/distress (from watching the videos) during the task. This is an important issue as self- vs other-oriented focusing plays a key role in empathic processing. To address this issue, we combined empathic pain observation with the automatic imitation task (AIT). Previous work has shown that AIT effects are smaller after experiencing pain, which has been interpreted as the result of the experience of pain leading to a self-oriented focus. If empathic pain observation similarly leads to a self-oriented focus, then we should expect similar AIT results after pain observation (smaller AIT effects); however, if it instead leads to an other-oriented focus, then we should see the opposite (larger AIT effects). Although we found initial evidence for the latter hypothesis (Experiment 1), subsequent failed replications suggests that we do not have sufficient evidence to claim that pain observation influences automatic imitation one way or the other (Experiment 2 and 3). We discuss some possible reasons for finding null results in these experiments and suggest future avenues of research to better elucidate this topic.

Triple blockade of Ido-1, PD-L1 and MEK as a potential therapeutic strategy in NSCLC.

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination. METHODS: We analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor. RESULTS: In NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment. CONCLUSIONS: We show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients' derived three dimensional cultures.

Feasibility of ultrashort echo time quantitative susceptibility mapping with a 3D cones trajectory in the human brain.

Purpose: Quantitative susceptibility mapping (QSM) has surfaced as a promising non-invasive quantitative biomarker that provides information about tissue composition and microenvironment. Recently, ultrashort echo time quantitative susceptibility mapping (UTE-QSM) has been investigated to achieve QSM of short T2 tissues. As the feasibility of UTE-QSM has not been demonstrated in the brain, the goal of this study was to develop a UTE-QSM with an efficient 3D cones trajectory and validate it in the human brain. Materials and methods: An ultrashort echo time (UTE) cones sequence was implemented in a 3T clinical MRI scanner. Six images were acquired within a single acquisition, including UTE and gradient recalled echo (GRE) images. To achieve QSM, a morphology-enabled dipole inversion (MEDI) algorithm was incorporated, which utilizes both magnitude and phase images. Three fresh cadaveric human brains were scanned using the 3D cones trajectory with eight stretching factors (SFs) ranging from 1.0 to 1.7. In addition, five healthy volunteers were recruited and underwent UTE-QSM to demonstrate the feasibility in vivo. The acquired data were processed with the MEDI-QSM pipeline. Results: The susceptibility maps estimated by UTE-QSM showed reliable tissue contrast. In the ex vivo experiment, high correlations were found between the baseline (SF of 1.0) and SFs from 1.1 to 1.7 with Pearson's correlations of 0.9983, 0.9968, 0.9959, 0.9960, 0.9954, 0.9943, and 0.9879, respectively (all p-values < 0.05). In the in vivo experiment, the measured QSM values in cortical gray matter, juxtacortical white matter, corpus callosum, caudate, and putamen were 25.4 ± 4.0, -21.8 ± 3.2, -22.6 ± 10.0, 77.5 ± 18.8, and 53.8 ± 7.1 ppb, consistent with the values reported in the literature. Conclusion: Ultrashort echo time quantitative susceptibility mapping enables direct estimation of the magnetic susceptibility in the brain with a dramatically reduced total scan time by use of a stretched 3D cones trajectory. This technique provides a new biomarker for susceptibility mapping in the in vivo brain.

Impact of COVID-19 on pregnancy-related healthcare utilisation: a prospective nationwide registry study.

OBJECTIVE: To assess the impact of COVID-19 on pregnancy-related healthcare utilisation and differences across social groups. DESIGN: Nationwide longitudinal prospective registry-based study. SETTING: Norway. PARTICIPANTS: Female residents aged 15-50 years (n=1 244 560). MAIN OUTCOME MEASURES: Pregnancy-related inpatient, outpatient and primary care healthcare utilisation before the COVID-19 pandemic (prepandemic: 1 January to 11 March 2020), during the initial lockdown (first wave: 12 March to 3 April 2020), during the summer months of low restrictions (summer period: 4 April to 31 August 2020) and during the second wave to the end of the year (second wave: 1 September to 31 December 2020). Rates were compared with the same time periods in 2019. RESULTS: There were 130 924 inpatient specialist care admissions, 266 015 outpatient specialist care consultations and 2 309 047 primary care consultations with pregnancy-related diagnostic codes during 2019 and 2020. After adjusting for time trends and cofactors, inpatient admissions were reduced by 9% (adjusted incidence rate ratio (aIRR)=0.91, 95% CI 0.87 to 0.95), outpatient consultations by 17% (aIRR=0.83, 95% CI 0.71 to 0.86) and primary care consultations by 10% (aIRR=0.90, 95% CI 0.89 to 0.91) during the first wave. Inpatient care remained 3%-4% below prepandemic levels throughout 2020. Reductions according to education, income and immigrant background were also observed. Notably, women born in Asia, Africa or Latin America had a greater reduction in inpatient (aIRR=0.87, 95% CI 0.77 to 0.97) and outpatient (aIRR 0.90, 95% CI 0.86 to 0.95) care during the first wave, compared with Norwegian-born women. We also observed that women with low education had a greater reduction in inpatient care during summer period (aIRR=0.88, 95% CI 0.83 to 0.92), compared with women with high educational attainment. CONCLUSION: Following the introduction of COVID-19 mitigation measures in Norway in March 2020, there were substantial reductions in pregnancy-related healthcare utilisation, especially during the initial lockdown and among women with an immigrant background.

Cognitive Science in a Nutshell.

We propose a novel characterization of the core of cognitive science as the study of how agents perform tasks, where agents and tasks are both broadly construed. We motivate the focus on agents and tasks through a discussion of their prevalence in cognitive science, their utility in identifying topics close to and distant from cognitive science, and their applicability to prominent issues in the field. We argue that our proposal clearly and succinctly highlights the distinctive characteristics of cognitive science and simultaneously motivates its interdisciplinary approach without losing sight of its roots in the study of information processing and cognitive representations.

The sense of agency for brain disorders: A comprehensive review and proposed framework.

Sense of Agency (SoA) refers to the feeling of control over voluntary actions and the outcomes of those actions. Several brain disorders are characterized by an abnormal SoA. To date, there is no robust treatment for aberrant agency across disorders; this is, in large part, due to gaps in our understanding of the cognitive mechanisms and neural correlates of the SoA. This apparent gap stems from a lack of synthesis in established findings. As such, the current review reconciles previously established findings into a novel neurocognitive framework for future investigations of the SoA in brain disorders, which we term the Agency in Brain Disorders Framework (ABDF). In doing so, we highlight key top-down and bottom-up cues that contribute to agency prospectively (i.e., prior to action execution) and retrospectively (i.e., after action execution). We then examine brain disorders, including schizophrenia, autism spectrum disorders (ASD), obsessive-compulsive disorders (OCD), and cortico-basal syndrome (CBS), within the ABDF, to demonstrate its potential utility in investigating neurocognitive mechanisms underlying phenotypically variable presentations of the SoA in brain disorders.

Changes in life expectancy and disease burden in Norway, 1990-2019: an analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Geographical differences in health outcomes are reported in many countries. Norway has led an active policy aiming for regional balance since the 1970s. Using data from the Global Burden of Disease Study (GBD) 2019, we examined regional differences in development and current state of health across Norwegian counties. METHODS: Data for life expectancy, healthy life expectancy (HALE), years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) in Norway and its 11 counties from 1990 to 2019 were extracted from GBD 2019. County-specific contributors to changes in life expectancy were compared. Inequality in disease burden was examined by use of the Gini coefficient. FINDINGS: Life expectancy and HALE improved in all Norwegian counties from 1990 to 2019. Improvements in life expectancy and HALE were greatest in the two counties with the lowest values in 1990: Oslo, in which life expectancy and HALE increased from 71·9 years (95% uncertainty interval 71·4-72·4) and 63·0 years (60·5-65·4) in 1990 to 81·3 years (80·0-82·7) and 70·6 years (67·4-73·6) in 2019, respectively; and Troms og Finnmark, in which life expectancy and HALE increased from 71·9 years (71·5-72·4) and 63·5 years (60·9-65·6) in 1990 to 80·3 years (79·4-81·2) and 70·0 years (66·8-72·2) in 2019, respectively. Increased life expectancy was mainly due to reductions in cardiovascular disease, neoplasms, and respiratory infections. No significant differences between the national YLD or DALY rates and the corresponding age-standardised rates were reported in any of the counties in 2019; however, Troms og Finnmark had a higher age-standardised YLL rate than the national rate (8394 per 100 000 [95% UI 7801-8944] vs 7536 per 100 000 [7391-7691]). Low inequality between counties was shown for life expectancy, HALE, all level-1 causes of DALYs, and exposure to level-1 risk factors. INTERPRETATION: Over the past 30 years, Norway has reduced inequality in disease burden between counties. However, inequalities still exist at a within-county level and along other sociodemographic gradients. Because of insufficient Norwegian primary data, there remains substantial uncertainty associated with regional estimates for non-fatal disease burden and exposure to risk factors. FUNDING: Bill & Melinda Gates Foundation, Research Council of Norway, and Norwegian Institute of Public Health.

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes. Funding: UNITAID, Wellcome, MRC, BMGF.