Multiple sclerosis (MS) is characterized by focal inflammatory activity in the central nervous system and a diffuse, compartmentalized inflammation that is the primary driver of neuroaxonal damage and worsening disability. It is now recognized that higher-efficacy disease-modifying therapies (HE-DMT) are often required to treat the complex neuropathological changes that occur during the disease course and improve long-term outcomes. The optimal use of HE-DMTs in practice was addressed by a Canadian panel of 12 MS experts who used the Delphi method to develop 27 consensus recommendations. The HE-DMTs that were considered were the monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab) and the immune reconstitution agents (alemtuzumab, cladribine). The issues addressed included defining aggressive/severe disease, patient selection of the most appropriate candidates for HE-DMTs, baseline investigations and efficacy monitoring, defining suboptimal treatment response, use of serum neurofilament-light chain in evaluating treatment response, safety monitoring, aging and immunosenescence and when to consider de-escalating or discontinuing treatment. The goals of the consensus recommendations were to provide guidelines to clinicians on their use of HE-DMTs in practice and to improve long-term outcomes in persons with MS.

Premenstrual symptoms are a cyclic set of symptoms that affect women’s psychological and physical well-being. Growing evidence suggests that micronutrients may contribute to the risk and severity of premenstrual symptoms such as depression. Yet the relationship between folate and premenstrual symptoms remains inconclusive. The objective of this study was to determine the association between folate intake and MTHFR genotype with premenstrual symptoms. Females (n 678) aged 20–29 years from the Toronto Nutrigenomics and Health Study self-reported fifteen premenstrual symptoms. Dietary intake was measured using a validated 196-item Toronto-modified Harvard food frequency questionnaire. DNA was isolated from peripheral white blood cells and genotyped for the C677T MTHFR (rs1801133) polymorphism. Using logistic regression, the odds of experiencing premenstrual symptoms were compared between total folate intake below and above the median (647 mcg/d) and between MTHFR genotypes. We found associations between MTHFR genotype and some premenstrual symptoms. Among women with low folate intake, an additive association was observed between the Tallele of MTHFR and premenstrual depression. Compared with those with the CC genotype, the OR (95 % CI) for depression was 1·66 (0·98, 2·87) for those with the CT genotype and 2·41 (1·08, 5·38) for those with the TT genotype. No associations were observed between MTHFR genotype and premenstrual depression among those with higher habitual intakes of folate. Since the MTHFR genotype is involved in the folate metabolic pathway, these findings suggest that folate or its metabolites may be related to the risk of premenstrual depression.

Intelligence services have played pivotal and distinct roles in European political history since the Second World War, ranging from their position as a stronghold of authoritarian regimes to their role in protecting democracy from anti-democratic forces. Democratisation therefore requires the depoliticisation of intelligence services to prevent their reuse as tools of political oppression. Paradoxically, many examples show that the politicisation of intelligence often occurs in a context of democratisation. This article explains this paradox. It focuses on the persistent politicisation of the Greek intelligence service in the decades following the demise of the junta regime and its democratic consolidation (1974–2008). It shows that subsequent governments fought fire with fire in their efforts to democratise the service: they countered the junta heritage of the intelligence service by keeping it closely under their control and, consequently, aligning it with governing party interests. Moreover, a vibrant bottom-up, party-aligned labour union within the service became the main vehicle for the politicisation of the organisational culture. This research uses original oral history interviews with former service personnel, newspaper publications and parliamentary debates on the service between 1974 and 2008. This is the first research on the Greek intelligence service based on such large-scale, longitudinal and diverse empirical data collection. The results of this research are relevant beyond the specific case of Greece, as they point to the wider mechanisms of politicisation of intelligence services, especially in former authoritarian regimes in Southern and Eastern Europe.

After 30 years of relative neglect, Canada’s notwithstanding clause has been invoked in six different provincial laws since 2018. We argue that this resurgence can be explained by the growing judicial invalidation of provincial statutes and federal-provincial partisan conflicts. Drawing from an original dataset of Charter cases decided by the Supreme Court of Canada (1982–2020), we show that provincial statutes have been invalidated at much higher rates since 2010. We also show how increasing partisan conflicts between conservative provincial governments and the Liberal federal government have helped frame the notwithstanding clause as a partisan tool for resisting centralizing rights decisions. The strategic environment facing provinces has shifted as partisan federalism conflicts lower the political costs of using the clause, while rising invalidation rates incentivize provinces to use it to protect their jurisdiction. This supports the “regime politics” understanding of judicial power as partly a function of federal (central) regime power.

Double aortic arch is an exceedingly rare congenital vascular anomaly, and its association with anomalous origins of the vertebral arteries is even more uncommon. Enhanced computed tomography revealed a double aortic arch with the left common carotid artery, left vertebral artery, and left subclavian artery originating from the left arch, and the right common carotid artery, right vertebral artery, and right subclavian artery arising from the right arch. To our knowledge, this is the first report of a double aortic arch with six distinct vessels originating from both arches. Enhanced CT should be considered in double aortic arch patients to identify such anomalous origins of branch arteries.

This research note introduces the Canadian Vote Intention Dataset, a new, integrated, publicly available database of nearly eight decades of public opinion surveys from Gallup, Environics, Pollara, the Canadian Election Study and the Consortium on Electoral Democracy. The dataset contains 1,019,639 responses on Canadians’ federal vote intention as well as a suite of demographic and geographic variables, including age, gender, religion, language, education, union membership, occupation, community size, province and region. We describe the dataset and custom survey weights, as well as the R package and interactive online application we developed to accompany the dataset. We then demonstrate the dataset’s utility through new analyses of the long-term evolution of gender, education and community size gaps in Canadian party support from 1945 to 2022.

Two-way fixed effects (TWFE) models are widely used in political science to establish causality, but recent methodological discussions highlight their limitations under heterogeneous treatment effects (HTE) and violations of the parallel trends (PT) assumption. This growing literature has introduced numerous new estimators and procedures, causing confusion among researchers about the reliability of existing results and best practices. To address these concerns, we replicated and reanalyzed 49 studies from leading journals that employ TWFE models for causal inference using observational panel data with binary treatments. Using six HTE-robust estimators, diagnostic tests, and sensitivity analyses, we find: (i) HTE-robust estimators yield qualitatively similar but highly variable results; (ii) while a few studies show clear signs of PT violations, many lack evidence to support this assumption; and (iii) many studies are underpowered when accounting for HTE and potential PT violations. We emphasize the importance of strong research designs and rigorous validation of key identifying assumptions.

The field of Quaternary entomology has focused primarily on the study of beetles (Coleoptera) and, to a lesser degree, nonbiting midges (Diptera: Chironomidae). Beetles typically predominate because they have heavily sclerotised exoskeletons, and they are abundant in a great variety of habitats. Because of taphonomy and scarcity, other Quaternary invertebrates have been less studied. Only a few records of fleas (Siphonaptera) and mites (Acari) are reported from Pleistocene deposits that span the Seward Peninsula in Alaska, United States of America, to the Klondike goldfields in central Yukon Territory, Canada. Grasshoppers (Orthoptera) and thrips (Thysanoptera) have not been reported previously from Quaternary deposits across the Arctic’s Beringia region. However, recent extensive sampling of Arctic ground squirrel, Urocitellus parryii Richardson (Rodentia: Sciuridae), middens from permafrost deposits of the Klondike goldfields has yielded specimens from each of these underrepresented invertebrate groups. Here, we present records of fleas (Oropsylla alaskensis Baker (Ceratophyllidae)), mites (including Fusacarus Michael (Astigmata: Glycyphagidae) and cf. Haemogamasus Berlese (Mesostigmata: Laelapidae)), and the first records of grasshoppers (Acrididae: Gomphocerinae) and thrips (Thysanoptera: Thripidae) from Beringia from six middens spanning approximately 80 000–13 500 years BP. We also provide brief reviews of the fossil history of each major taxon.

The optimisation of inter-island transportation systems constitutes a critical determinant of regional economic development and the efficacy of mobility infrastructure. This study presents a comparative analysis of passenger mode selection between short-sea shipping (SSS) and road transport alternatives through stated preference surveys conducted via anonymised questionnaires. Employing advanced discrete choice modelling techniques – specifically the multinomial logit (MNL), random parameter logit (RPL) and latent class (LC) frameworks – we quantitatively disentangle the complex determinants influencing modal preferences. Our systematic sensitivity analysis reveals distinct behavioural patterns: passengers opting for SSS prioritise journey convenience, whereas road transport users exhibit stronger cost sensitivity. These findings provide actionable insights for formulating evidence-based policies to enhance intermodal transportation networks in the Zhoushan Archipelago of China. Beyond its immediate geographical focus, this research contributes methodological innovations by applying finite mixture models to capture unobserved heterogeneity in maritime transport decisions. The framework demonstrates significant transferability potential for island territories globally and urban freight corridor optimisation challenges, particularly in contexts requiring trade-off analyses between maritime efficiency and terrestrial logistics constraints.

How did one become an astronomer in imperial China? Where did one start? What texts did would-be astronomers study, and what criteria did they have to meet? Combining the regulation of the Yuan (1271–1368) Bureau of Astronomy with biographies of astronomers who worked in different sections of the Bureau, this paper explores the physical, technical, and literary skills required for this profession in late medieval China. It underscores the pivotal role of family in training astronomers and offers fresh insights into the relationship between bureaucracy and science in imperial China.

Several studies have indicated a potential inverse association between caffeine intake from dietary sources – assessed through dietary questionnaires – and uric acid (UA) levels. However, to date, no study has examined the relationship between urinary caffeine metabolites, which serve as a reliable biomarker of caffeine intake and UA levels. Our aim was to evaluate the association between caffeine metabolites in urine and serum UA levels. A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2011–2012, involving 1252 individuals aged 20–80 years. The study assessed caffeine and fourteen metabolites in spot urine samples, as well as serum UA levels. Hyperuricaemia was defined as UA levels exceeding 7·0 mg/dl for men and 6·0 mg/dl for women. In logistic regression analyses, theobromine (OR: 0·99, 95 % CI: 0·980, 0·999), 3-methyluric acid (OR: 0·91, 95 % CI: 0·837, 0·996), 7-methyluric acid (OR: 0·99, 95 % CI: 0·989, 0·998) and 3-methylxanthine (OR: 0·99, 95 % CI: 0·992, 0·999) were associated with decreased odds of hyperuricaemia. In linear regression analyses, paraxanthine (β = −0·004, P = 0·006), theobromine (β = −0·004, P =< 0·001), 7-methyluric acid (β = −0·003, P = 0·003), 3,7-dimethyluric acid (β = −0·029, P = 0·024), 3-methylxanthine (β = −0·001, P = 0·038) and 7-methylxanthine (β = −0·001, P = 0·001) were inversely associated with serum UA levels. In conclusion, our results indicate that several urinary caffeine metabolites are inversely associated with UA levels. These findings should be interpreted with caution due to the small magnitude of the observed associations.

When kidney transplantation evolved from an experimental into a clinical treatment of end-stage renal disease (ESRD) in the 1960s, it was conceptualised as a collaborative therapy. Before specific immunosuppressants were introduced in the 1980s, the best chances for patient and graft survival were expected from finding ‘good’ matches between donor and recipient tissues. Therefore, the pioneers of clinical transplantation in Europe started to recombine their growing patient pools. They created trans-border organ exchange organisations such as Eurotransplant and Intertransplant, based on shared patient databases.

The article traces international and transnational co-operation in kidney exchange using the example of state-socialist Germany. How did the German Democratic Republic (GDR) get involved with the interconnected networks of knowledge, data, and organ exchange in ESRD treatment? In what ways did the domestic system of kidney transplantation depend on intra- and trans-bloc exchange? How did the GDR profit, and what did it have to offer on an international scale, both in the First and the Second World? The article sheds light on the under-explored transplantation history of the socialist East and thereby investigates the possibilities and limits of trans-bloc collaboration in Cold War Europe.