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Objective: To assess treatment-related spatio-temporal dynamics of active MRI lesions in relapsing-remitting multiple sclerosis (RRMS) patients.Methods: We performed a post-hoc analysis of MRI data acquired at weeks 4, 8, 12, and 16, in RRMS patients from the multicenter randomized IMPROVE study, which compares patients treated with 44 mcg subcutaneous interferon β-1a three times weekly (n = 120) versus placebo (n = 60). We created lesion probability maps (LPMs) of the cumulative combined unique active (CUA) lesions in each patient group at each time point. Group differences were tested in terms of lesion spatial distribution and frequency of occurrence.Results: Spatial distribution of CUA lesions throughout the study was less widespread in the treated than placebo group, with a 50% lower lesion accrual (24 vs. 48 cm3/month). Similar results were obtained with the WM tract analysis, with a reduction ranging from −47 to −66% in the treated group (p < 0.001). On voxel-wise analysis, CUA lesion frequency was lower in the treated group than the placebo group at week 4 (p = 0.07, corrected), becoming particularly pronounced (p ≤ 0.03, corrected) from week 8 onwards in large clusters of WM tracts, with peaks along fronto-parietal parts of the corticospinal tract, thalamic radiation, and superior longitudinal fascicle.Conclusion: LPM showed, in the short term, a treatment-related reduction of MRI lesion activity in RRMS patients in specific, clinically relevant brain locations. Such a quantitative approach might be a promising additional endpoint in future MS studies alongside the number and volume of WM lesions.Clinical Trial Registration:ClinicalTrials.gov identifier NCT00441103.

The Coronavirus Disease 2019 (COVID-19) pandemic has changed many social, economic, environmental and healthcare determinants of health. We applied an ensemble of 16 Bayesian models to vital statistics data to estimate the all-cause mortality effect of the pandemic for 21 industrialized countries. From mid-February through May 2020, 206,000 (95% credible interval, 178,100-231,000) more people died in these countries than would have had the pandemic not occurred. The number of excess deaths, excess deaths per 100,000 people and relative increase in deaths were similar between men and women in most countries. England and Wales and Spain experienced the largest effect: ~100 excess deaths per 100,000 people, equivalent to a 37% (30-44%) relative increase in England and Wales and 38% (31-45%) in Spain. Bulgaria, New Zealand, Slovakia, Australia, Czechia, Hungary, Poland, Norway, Denmark and Finland experienced mortality changes that ranged from possible small declines to increases of 5% or less in either sex. The heterogeneous mortality effects of the COVID-19 pandemic reflect differences in how well countries have managed the pandemic and the resilience and preparedness of the health and social care system.

We study the extent to which personal connections among legislators influence abstentions in the U.S. Congress. Our analysis is conducted by observing representatives' abstention for the universe of roll call votes held on bills in the 109th-113th Congresses. Our results show that a legislator's propensity to abstain increases when the majority of his or her alumni connections abstains, even after controlling for other well-known predictors of abstention choices and a vast set of fixed effects. We further reveal that a legislator is more prone to abstain than to take sides when the demands from personal connections conflict with those of the legislator's party. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

The Covid-19 pandemic affects mortality directly through infection as well as through changes in the social, environmental and healthcare determinants of health1. The impacts on mortality are likely to vary across countries in magnitude, timing, and age and sex composition. Here, we applied an ensemble of 16 Bayesian probabilistic models to vital statistics data, by age group and sex, to consistently and comparably estimate the impacts of the first phase of the pandemic on all-cause mortality for 17 industrialised countries. The models accounted for factors that affect death rates including seasonality, temperature, and public holidays, as well as for medium-long-term secular trends and the dependency of death rates in each week on those in preceding week(s). From mid-February through the end of May 2020, an estimated 202,900 (95% credible interval 179,400-224,900) more people died in these 17 countries than would have had the pandemic not taken place. Nearly three quarters of these excess deaths occurred in England and Wales, Italy and Spain, where less than half of the total population of these countries live. When all-cause mortality is considered, the total number of deaths, deaths per 100,000 people, and relative increase in deaths were similar between men and women in most countries. Further, in many countries, the balance of excess deaths changed from male-dominated early in the pandemic to being equal or female-dominated later on.Taken over the entire first phase of the pandemic, there was no detectable rise in all-cause mortality in New Zealand, Bulgaria, Hungary, Norway, Denmark and Finland and for women in Austria and Switzerland (posterior probability of an increase in deaths 99%. After accounting for population size, England and Wales and Spain experienced the highest death toll, nearly 100 deaths per 100,000 people; they also had the largest relative (percent) increase in deaths (37% (95% credible interval 30-44) in England and Wales; 38% (31-44) in Spain). New Zealand, Bulgaria, Hungary, Norway, Denmark and Finland experienced changes in deaths that ranged from possible slight declines to increases of no more than 5%. The large impact in England and Wales stems partly from having experienced (together with Spain) the highest weekly increases in deaths, more than doubling in some weeks, and having had (together with Sweden) the longest duration when deaths exceeded levels that would be expected in the absence of the pandemic.The heterogeneous magnitude and character of the excess deaths due to the Covid-19 pandemic reflect differences in how well countries have managed the pandemic (e.g., timing, extent and adherence to lockdowns and other social distancing measures; effectiveness of test, trace and isolate mechanisms), and the resilience and preparedness of the health and social care system (e.g., effective facility and community care pathways; minimising spread of infection within hospitals and care homes, and between them and the community).

Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions — the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research., In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group reviews the application of brain and spinal cord atrophy in clinical practice in the management of MS and makes consensus statements and recommendations for future research.

We present an informational theory of public protests, according to which public protests allow citizens to aggregate privately dispersed information and signal it to the policy maker. The model predicts that information sharing of signals within social groups can facilitate information aggregation when the social groups are sufficiently large even when it is not predicted with individual signals. We use experiments in the laboratory and on Amazon Mechanical Turk to test these predictions. We find that information sharing in social groups significantly affects citizens' protest decisions and as a consequence mitigates the effects of high conflict, leading to greater efficiency in policy makers' choices. Our experiments highlight that social media can play an important role in protests beyond simply a way in which citizens can coordinate their actions; and indeed that the information aggregation and the coordination motives behind public protests are intimately connected and cannot be conceptually separated. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

Our objective was to develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using (18)F-DPA-714 translocator protein PET and to explore the relationship between these maps and individual trajectories of worsening disability in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of worsening disability over the 2 y preceding study entry were calculated, and healthy controls (n = 19) underwent MRI and (18)F-DPA-714 PET. A threshold for significant activation of (18)F-DPA-714 binding was calculated with a voxelwise randomized permutation-based comparison between patients and controls and used to classify each WM voxel in all subjects as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were used to calculate the extent of activation in WM regions of interests and to classify each WM lesion as DPA-active, DPA-inactive, or unclassified. Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM (NAWM) (NAWM in patients, 24.6% ± 1.4%; WM in controls, 14.6% ± 2.0%; P < 0.001). In patients with MS, the percentage of DPA+ voxels increased significantly from the NAWM to the perilesional areas, T2 hyperintense lesions, and T1 hypointense lesions (38.1% ± 2.6%, 45.0% ± 2.6%, 51.8% ± 2.6%, respectively; P < 0.001). Among the 1,379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (odds ratio, 1.13; P = 0.009), a higher percentage of DPA+ voxels in the NAWM (odds ratio, 1.16; P = 0.009), and a higher percentage of DPA+ voxels in T1 spin-echo lesions (odds ratio, 1.06; P = 0.036) were significantly associated with a retrospectively more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with innate immune cell activation inside and around WM lesions. (18)F-DPA-714 PET may provide a promising biomarker to identify patients at risk of a severe clinical trajectory.

ObjectivesTo provide a sub-national analysis of excess mortality during the COVID-19 pandemic in Italy.DesignPopulation-based on all-cause mortality official data, available as counts by age and sex.SettingThe 7,904 municipalities in Italy.ParticipantsAll residents in Italy in the years 2016 to 2020.Main outcome measuresAll-cause mortality weekly rates for each municipality, based on the first four months of 2016 – 2019. Predicted all-cause weekly deaths and mortality rates at municipality level for 2020, based on the modelled spatio-temporal trends.ResultsThere was strong evidence of excess mortality for Northern Italy; Lombardia showed higher mortality rates than expected from the end of February, with 23,946 (23,013 to 24,786) total excess deaths. North-West and North-East regions showed higher mortality from the beginning of March, with 6,942 (6,142 to 7,667) and 8,033 (7,061 to 9,044) total excess deaths respectively. After discounting for the number of COVID-19-confirmed deaths, Lombardia still registered 10,197 (9,264 to 11,037) excess deaths, while regions in the North-West and North-East had 2,572 (1,772 to 3,297) and 2,047 (1,075 to 3,058) extra deaths, respectively. We observed marked geographical differences at municipality level. The city of Bergamo (Lombardia) showed the largest percent excess 88.9% (81.9% to 95.2%) at the peak of the pandemic. An excess of 84.2% (73.8% to 93.4%) was also estimated at the same time for the city of Pesaro (Central Italy), in stark contrast with the rest of the region, which does not show evidence of excess deaths.ConclusionsOur study gives a comprehensive picture of the evolution of all-cause mortality in Italy from 2016 to 2020 and describes the spatio-temporal differences in excess mortality during the COVID-19 pandemic. Our model shows heterogeneous impact of COVID-19, and it can be used to help policy- makers target measures to limit the burden on the health-care system as well as reducing social and economic consequences. Our probabilistic methodology is useful for real-time mortality surveillance, continuously monitoring local temporal trends and flagging where and when mortality rates deviate from the expected range, which might suggest a second wave of the pandemic.

We examine the effect of hearing cases alongside female judicial colleagues on the probability that a federal judge hires a female law clerk. Federal judges are assigned to cases and to judicial panels at random and have few limitations on their choices of law clerks: these two features make the federal court system a unique environment in which to study the effect of professional interactions and beliefs in organizations. We constructed a unique dataset by aggregating federal case records from 2007-2017 to collect information on federal judicial panels, and by merging this data with judicial hiring information from the Judicial Yellow Book, a directory of federal judges and clerks. We find that a one standard deviation increase in the fraction of co-panelists who are female increases a judge’s likelihood of hiring a female clerk by 4 percentage points. This finding suggests that increases in the diversity of the upper rungs of a profession can shift attitudes in a way that creates opportunities at the entry level of a profession. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

In this article, SIENA-XL, a new segmentation-based longitudinal pipeline is introduced, for: (i) increasing the precision of longitudinal volume change estimation for white (WM) and gray (GM) matter separately, compared with cross-sectional segmentation methods such as SIENAX; and (ii) avoiding potential biases in registration-based methods when Jacobians are used, with a smoothing extent larger than spatial scale between tissue-interfaces, which is where atrophy usually occurs. SIENA-XL implements a new brain extraction procedure and a multi-time-point intensity equalization step before performing the final segmentation that also includes separate segmentation of deep GM structures by using FMRIB's Integrated Registration and Segmentation Tool. The detection of GM and WM volume changes with SIENA-XL was evaluated using different healthy control (HC) and multiple sclerosis (MS) MRI datasets and compared with the traditional SIENAX and two Jacobian-based approaches, SPM12 and SIENAX-JI (a version of SIENAX including Jacobian integration - JI). In scan-rescan data from HCs, SIENA-XL showed: (i) a significant decrease in error, of 50-70% when compared with SIENAX; (ii) no significant differences in error when compared with SIENAX-JI and SPM12 in a scan-rescan HC dataset that included repositioning. When tested in a HC dataset with scan-rescan both at baseline and after 1 year of follow-up, SIENA-XL showed: (i) significantly higher precision (P < 0.01) than SIENAX; (ii) no significant differences to SIENAX-JI and SPM12. Finally, in a dataset of 79 MS patients with a 2 years follow-up, SIENA-XL showed a substantial reduction of sample size, by comparison with SIENAX, SIENAX-JI, and SPM12, for detecting treatment effects of 25, 30, and 50%. Hum Brain Mapp 39:1063-1077, 2018. © 2017 Wiley Periodicals, Inc.

The [11C]PIB PET tracer, originally developed for amyloid imaging, has been recently repurposed to quantify demyelination and remyelination in multiple sclerosis (MS). Myelin PET imaging, however, is limited by its low resolution that deteriorates the quantification accuracy of white matter (WM) lesions. Here, we introduce a novel partial volume correction (PVC) method called Multiresolution–Multimodal Resolution-Recovery (MM-RR), which uses the wavelet transform and a synergistic statistical model to exploit MRI structural images to improve the resolution of [11C]PIB PET myelin imaging. MM-RR performance was tested on a phantom acquisition and in a dataset comprising [11C]PIB PET and MR T1- and T2-weighted images of 8 healthy controls and 20 MS patients. For the control group, the MM-RR PET images showed an average increase of 5.7% in WM uptake while the grey-matter (GM) uptake remained constant, resulting in +31% WM/GM contrast. Furthermore, MM-RR PET binding maps correlated significantly with the mRNA expressions of the most represented proteins in the myelin sheath (R2 = 0.57 ± 0.09). In the patient group, MM-RR PET images showed sharper lesion contours and significant improvement in normal-appearing tissue/WM-lesion contrast compared to standard PET (contrast improvement > +40%). These results were consistent with MM-RR performances in phantom experiments.

Key points A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. Abstract It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

We exploit the exogenous variation in peer groups generated by high school to college transitions to study the theoretical predictions of Battaglini et al.’s (2005) model of self-control in peer groups. We find evidence consistent with the two key predictions of this theory regarding the relationship between an agent's expected level of self-control and the size and composition of his or her social circles: (i) students embedded in social circles have more self-control than those who are alone and their self-control is increasing in the size of their social group; (ii) students’ self-control is, however, a non-monotonic hump-shaped function of the average self-control of their friends.

Background: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. Methods: In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years’ treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Results: Compared with placebo (–0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (–0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (–0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p Conclusions: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

Definition of benign multiple sclerosis (BMS) remains controversial. Moreover, a sizeable proportion of classically defined BMS patients may be no longer benign (NLB) when re-assessed in the long-term. In a previous work, we found that after a five-year follow-up, a clinical score was able to identify patients at risk of losing their benign status.In this 12-year reappraisal of the same cohort, we aimed at assessing the predictive value of the same score in the long-term.After a mean follow-up of 12.6 + 0.4 years, patients still having an EDSS score 3.0 were classified as "still benign" (SB), whereas patients having an EDSS score ≥3.5 were defined as NLB. The predictive value of the mentioned score was re-assessed using survival analysis.By the end of the follow-up, 20 (32.8%) were classified as NLB. Patients were grouped on the basis of the above mentioned score. Patients with score 2-3 were at higher risk of NLB status at the follow-up (HR = 3.5; 95%CI 1.5-8.6; p = 0.005, accuracy = 70.5%).In patients with established BMS, prognostic prediction of longer-term disease course remains of critical value. In this study, a clinical score was able to predict disease evolution in the long term.

We present a model of the U.S. Congress in which social connections among Congress members are endogenous and matter for their legislative activity. We propose a novel equilibrium concept for the network formation game that allows for a sharp characterization of equilibrium behavior and that yields a unique prediction under testable conditions. While the equilibrium is characterized by a large number of nonlinear equations, we show that the model can be structurally estimated by an appropriately designed Approximate Bayesian Computation method. Estimating the model using data from the 109th to 113th U.S. Congresses, we show that social connections are important for legislators' productivities and we identify some of the key determinants of social centralities in Congress.

To study the role of tax professionals, we merge tax records of 2.5 million taxpayers in Italy with the respective audit files from the tax revenue agency. Our data covers the entire population of sole proprietorship taxpayers in seven regions, followed over seven fiscal years. We first document that tax evasion is systematically correlated with the average evasion of other customers of the same tax professional. We then exploit the unique structure of our dataset to study the channels through which these social spillover effects are generated. Guided by an equilibrium model of tax compliance with tax professionals and auditing, we highlight two mechanisms that may be behind this phenomenon: self-selection of taxpayers who sort themselves into professionals of heterogeneous tolerance for tax evasion; and informational externalities generated by the tax professional activities. We provide evidence supporting the simultaneous presence of both mechanisms.

In recent decades, democratic countries have negotiated hundreds of international treaties and agreements. This paper analyzes the equilibrium design of treaties negotiated by political incumbents seeking reelections. We show that incumbents are prone to negotiate treaties that are "weak" in that they may or may not be complied with: this makes it possible to differentiate the alternative candidates in a way that favors the incumbent. We also show that political economy considerations lead to overambitious treaties that rely too much on technology instead of sanctions to motivate compliance. Our theory can rationalize several puzzles associated with treaties.

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions. In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature with respect to K-nearest neighbour algorithm (currently used for lesion probability map estimation in BIANCA). Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort, a vascular cohort and the cohorts available publicly as a part of a segmentation challenge. We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance, when compared to the global thresholding. It allowed to detect more deep lesions and provided better segmentation of periventricular lesion boundaries, despite the differences in the lesion spatial distribution and load across datasets. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease, and healthy controls, showing that LOCATE adapts well to wide variations in lesion load and spatial distribution., Highlights • We aim to improve BIANCA to handle population- and subject-wise lesion variability. • Age-based population lesion probability maps did not improve BIANCA performance. • Among 5 classifiers tested, K-Nearest Neighbour still gives the best performance. • LOCally Adaptive Threshold Estimation (LOCATE) proposed for lesion probability maps. • LOCATE improves lesion segmentation and adapts well to lesion load and distribution.

The persistence of mortality decline at all ages, and particularly at older ages, means that an increasing number of individuals are becoming centenarians and semi-super centenarians. Our hypothesis is that the gender differences in mortality level in old ages had an impact on the number of men and women reaching 100 years and so on the gender gap. Work-related international migration was also an important characteristic of Italian cohorts born in the last decades of the Nineteenth century, and in the first decades of the Twentieth, as these migrations affected more men than women. Referring to the Istat (Italian National Institute of Statistics) mortality data (Cause of Death Survey and Deaths of Resident Population survey) and the Semi super and Super centenarians Surve -SSC, that has been realized by Istat since 2009, the aim of this paper is to present the development of the gender gap for the cohorts born between 1870 and 1912 beyond 100 and 105 years old. We have confirmed our hypothesis, explaining the characteristics of this development on the basis of estimates of the role played by the different migratory histories of the two genders and, above all, by the differences in the male and female survival trajectories of the cohorts in the study.

We provide here normative values of yearly percentage brain volume change (PBVC/y) as obtained with Structural Imaging Evaluation, using Normalization, of Atrophy, a widely used open-source software, developing a PBVC/y calculator for assessing the deviation from the expected PBVC/y in patients with neurological disorders. We assessed multicenter (34 centers, 11 acquisition protocols) magnetic resonance imaging data of 720 healthy participants covering the whole adult lifespan (16–90 years). Data of 421 participants with a follow-up > 6 months were used to obtain the normative values for PBVC/y and data of 392 participants with a follow-up

The Coronavirus Disease 2019 (COVID-19) pandemic has changed many social, economic, environmental and healthcare determinants of health. We applied an ensemble of 16 Bayesian models to vital statistics data to estimate the all-cause mortality effect of the pandemic for 21 industrialized countries. From mid-February through May 2020, 206,000 (95% credible interval, 178,100-231,000) more people died in these countries than would have had the pandemic not occurred. The number of excess deaths, excess deaths per 100,000 people and relative increase in deaths were similar between men and women in most countries. England and Wales and Spain experienced the largest effect: ~100 excess deaths per 100,000 people, equivalent to a 37% (30-44%) relative increase in England and Wales and 38% (31-45%) in Spain. Bulgaria, New Zealand, Slovakia, Australia, Czechia, Hungary, Poland, Norway, Denmark and Finland experienced mortality changes that ranged from possible small declines to increases of 5% or less in either sex. The heterogeneous mortality effects of the COVID-19 pandemic reflect differences in how well countries have managed the pandemic and the resilience and preparedness of the health and social care system.

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years.

A theory of endogenous fiscal policy and growth is developed. Fiscal policy–debt, income tax, spending on local public goods, and public investment–is determined through legislative bargaining. Economic growth depends directly on public investment, private investment in human capital, and, via learning-by-doing, labor supply. The model economy converges to a balanced growth path. During the transition to the balanced growth path, public debt grows faster than GDP, provisions of public goods and infrastructure grow slower than GDP, and the tax rate declines. The model is used to assess welfare implications of austerity programs.

BACKGROUND AND PURPOSE: The automatic segmentation of MS lesions could reduce time required for image processing together with inter- and intraoperator variability for research and clinical trials. A multicenter validation of a proposed semiautomatic method for hyperintense MS lesion segmentation on dual-echo MR imaging is presented. MATERIALS AND METHODS: The classification technique used is based on a region-growing approach starting from manual lesion identification by an expert observer with a final segmentation-refinement step. The method was validated in a cohort of 52 patients with relapsing-remitting MS, with dual-echo images acquired in 6 different European centers. RESULTS: We found a mathematic expression that made the optimization of the method independent of the need for a training dataset. The automatic segmentation was in good agreement with the manual segmentation (dice similarity coefficient = 0.62 and root mean square error = 2 mL). Assessment of the segmentation errors showed no significant differences in algorithm performance between the different MR scanner manufacturers (P > .05). CONCLUSIONS: The method proved to be robust, and no center-specific training of the algorithm was required, offering the possibility for application in a clinical setting. Adoption of the method should lead to improved reliability and less operator time required for image analysis in research and clinical trials in MS.

Background Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS. Methods Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel-wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination. Results At baseline, there was a progressive reduction in [11C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index. Interpretation [11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738

This paper analyzes the impact of a balanced budget rule that requires that legislators do not run deficits in the political economy model of Battaglini and Coate (2008). The main finding is that the rule leads to a gradual reduction in the level of public debt. Legislators reduce debt in periods when the demand for public goods is relatively low. They do so because the rule, by restricting future fiscal policies, raises the expected costs of carrying debt. Whether the rule increases citizen welfare depends on a comparison of the benefits of a lower debt burden with the costs of greater volatility in taxes and less responsive public good provision. A quantitative version of the model is developed in which costs and benefits can be evaluated. A welfare loss results if the debt level when the rule is imposed lies in the support of the long-run distribution associated with the unconstrained equilibrium.

Although the increase in the number of centenarians is well documented today in countries with advanced demographic data, the same is not true for those aged 105 years and over. The first aim of this paper was to analyze the demographic characteristics of the 4,626 validated semisuper and 102 supercentenarians for the cohorts born between 1896 and 1910, referring to Italian Semi-Supercentenarians Survey. Then, starting from this data and from the survival histories in old ages-reconstructed by Vincent's Extinct - Cohort Method-for the cohorts born between 1870 and 1904, the most important aim was to analyze longevity history and the trend of gender gap of the Italian oldest cohorts beyond 100 years old. The Italian centenarians and semisupercentenarians increase from the first to the last cohort is due to the survival rise in old ages and the increase in the gender gap at extreme ages depends on the higher survival of women than men after 60 years old. Around 110-112 for both genders (for women in particular) a kind of resistance to further progress seems to appear in our analysis as in more recent studies on supercentenarians.

We experimentally investigate the informational theory of legislative committees (Gilligan and Krehbiel 1989). Two committee members provide policy-relevant information to a legislature under alternative legislative rules. Under the open rule, the legislature is free to make any decision; under the closed rule, the legislature chooses between a member’s proposal and a status quo. We find that even in the presence of biases, the committee members improve the legislature’s decision by providing useful information. We obtain evidence for two additional predictions: the outlier principle, according to which more extreme biases reduce the extent of information transmission; and the distributional principle, according to which the open rule is more distributionally efficient than the closed rule. When biases are less extreme, we find that the distributional principle dominates the restrictive-rule principle, according to which the closed rule is more informationally efficient. Overall, our findings provide experimental support for Gilligan and Krehbiel’s informational theory.

This paper studies how interest groups allocate campaign contributions when congressmen are connected by social ties. We establish conditions for the existence of a unique Nash equilibrium in pure ...

This paper presents a political economy theory of fiscal policy and unemployment. The underlying economic model is one in which unemployment can arise but can be mitigated by tax cuts and public spending increases. Such policies are fiscally costly, but can be financed by issuing government debt. Policy decisions are made by a legislature consisting of representatives from different political districts. The theory provides a positive account of the simultaneous determination of fiscal policy and unemployment. The most important implication of the theory is that debt and unemployment levels should be positively correlated. Some evidence in support of this prediction is provided using data from a panel of developed countries.

We conduct a laboratory experiment to study the incentives of a privileged group (the “yellows”) to share political power with another group (the “blues”). The yellows collectively choose the voting rule for a general election: a simple-majority rule that favors them, or a proportional rule. In two treatments, the blues can use a costly punishment option. We find that the yellows share power voluntarily only to a small extent, but they are more inclined to do so under the threat of punishment, despite the fact that punishments are not sub-game perfect. The blue group conditions punishments both on the voting rule and the electoral outcome.

ObjectiveGrey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.MethodsWe analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.ResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; pppInterpretationThis large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.

Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.

Besides its well known function on bone metabolism, vitamin D role in cerebrovascular pathologies including cerebral small vessel disease has been confirmed by recent meta-analysis. In this study, we measured vitamin D levels in 56 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients (mean age 49.9) with no or minimal disability (modified Ranking Score, mRS ≤2) and in 56 age, sex and seasonality matched healthy controls. History of ischemic events was recorded and cognitive functions were assessed using the Mini-Mental State Examination. White matter hyperintensities on brain T2-weighted magnetic resonance images were classified according to a modified Fazekas scale. Comparison of vitamin D levels between patients and controls showed significant lower values (p

Technological advances and the development of social media have made petitions, public protests, and other form of spontaneous activism increasingly common tools for individuals to influence decision makers. To study these phenomena, in this article I present a theory of petitions and public protests that explores their limits as mechanisms to aggregate information. The key assumption is that valuable information is dispersed among citizens. Through petitions and protests, citizens can signal their private information to the policy maker, who can then choose to use it or not. I first show that if citizens’ individual signals are not sufficiently precise, information aggregation is impossible, no matter how large is the population of informed citizens, even if the conflict with the policy maker is small. I then characterize the conditions on conflict and the signal structure that guarantee information aggregation. When these conditions are satisfied, I show that full information aggregation is possible as the population grows to infinity. When they are not satisfied, I show that information aggregation may still be possible if social media are available.

A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders.It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.