Planck-scale dual-curvature lensing and spacetime noncommutativity

It was recently realized that Planck-scale momentum-space curvature, which is expected in some approaches to the quantum-gravity problem, can produce dual-curvature lensing, a feature which mainly affects the direction of observation of particles emitted by very distant sources. Several gray areas remain in our understanding of dual-curvature lensing, including the possibility that it might be just a coordinate artifact and the possibility that it might be in some sense a by product of the better studied dual-curvature redshift. We stress that data reported by the IceCube neutrino telescope should motivate a more vigorous effort of investigation of dual-curvature lensing, and we observe that studies of the recently proposed "$\rho$-Minkowski noncommutative spacetime" could be valuable from this perspective. Through a dedicated $\rho$-Minkowski analysis, we show that dual-curvature lensing is not merely a coordinate artifact and that it can be present even in theories without dual-curvature redshift

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Burden of non-communicable diseases among adolescents aged 10–24 years in the EU, 1990–2019: a systematic analysis of the Global Burden of Diseases Study 2019

Background Disability and mortality burden of non-communicable diseases (NCDs) have risen worldwide; however, the NCD burden among adolescents remains poorly described in the EU. Methods Estimates were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Causes of NCDs were analysed at three different levels of the GBD 2019 hierarchy, for which mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were extracted. Estimates, with the 95% uncertainty intervals (UI), were retrieved for EU Member States from 1990 to 2019, three age subgroups (10–14 years, 15–19 years, and 20–24 years), and by sex. Spearman's correlation was conducted between DALY rates for NCDs and the Socio-demographic Index (SDI) of each EU Member State. Findings In 2019, NCDs accounted for 86·4% (95% uncertainty interval 83·5–88·8) of all YLDs and 38·8% (37·4–39·8) of total deaths in adolescents aged 10–24 years. For NCDs in this age group, neoplasms were the leading causes of both mortality (4·01 [95% uncertainty interval 3·62–4·25] per 100 000 population) and YLLs (281·78 [254·25–298·92] per 100 000 population), whereas mental disorders were the leading cause for YLDs (2039·36 [1432·56–2773·47] per 100 000 population) and DALYs (2040·59 [1433·96–2774·62] per 100 000 population) in all EU Member States, and in all studied age groups. In 2019, among adolescents aged 10–24 years, males had a higher mortality rate per 100 000 population due to NCDs than females (11·66 [11·04–12·28] vs 7·89 [7·53–8·23]), whereas females presented a higher DALY rate per 100 000 population due to NCDs (8003·25 [5812·78–10 701·59] vs 6083·91 [4576·63–7857·92]). From 1990 to 2019, mortality rate due to NCDs in adolescents aged 10–24 years substantially decreased (–40·41% [–43·00 to –37·61), and also the YLL rate considerably decreased (–40·56% [–43·16 to –37·74]), except for mental disorders (which increased by 32·18% [1·67 to 66·49]), whereas the YLD rate increased slightly (1·44% [0·09 to 2·79]). Positive correlations were observed between DALY rates and SDIs for substance use disorders (rs=0·58, p=0·0012) and skin and subcutaneous diseases (rs=0·45, p=0·017), whereas negative correlations were found between DALY rates and SDIs for cardiovascular diseases (rs=–0·46, p=0·015), neoplasms (rs=–0·57, p=0·0015), and sense organ diseases (rs=–0·61, p=0·0005)

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy

IntroductionSeizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated.MethodsConsecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development.ResultsOne hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs.ConclusionOur data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Indicatori ambientali nello studio EpiAir2: I dati di qualit\ue0 dell'aria per la sorveglianza epidemiologica

OBIETTIVO: costruzione di indicatori ambientali di inquinamento aerodiffuso per finalit\ue0 di sorveglianza epidemiologica in 25 citt\ue0 italiane per il progetto EpiAir2 (2006-2010) e presentazione dei dati di dieci anni di sorveglianza in 10 citt\ue0 italiane (2001-2010). DISEGNO: sono stati raccolti dati di particolato (nelle frazioni PM10 e PM2.5 ), biossido di azoto (NO2 ) e ozono (O3 ), considerati fattori di rischio per la salute. I datimeteorologici considerati come confondenti nell\u2019analisi dell\u2019effetto degli inquinanti sono stati: temperatura, umidit\ue0 relativa (e la variabile derivata \u201ctemperatura apparente\u201d) e pressione barometrica. I criteri per la selezione delle stazioni dimonitoraggio e imetodi di calcolo per la costruzione di indicatori ambientali a partire dalle serie giornaliere disponibili sono stati scelti in continuit\ue0 con la precedente edizione di EpiAir. Per tutte le citt\ue0, \ue8 stata verificata l\u2019omogeneit\ue0 dei dati selezionati nel rappresentare l\u2019esposizione delle popolazioni. SETTING E PARTECIPANTI: il progetto EpiAir2 coinvolge per gli anni 2006-2010 le citt\ue0 diMilano,Mestre-Venezia,Torino, Bologna, Firenze, Pisa, Roma,Taranto,Cagliari e Palermo, gi\ue0 presenti nello studio EpiAir. A questo elenco vanno aggiunte le citt\ue0 di Treviso, Trieste, Padova, Rovigo, Piacenza, Parma, Ferrara, Reggio Emilia, Modena, Genova, Rimini, Ancona, Bari, Napoli e Brindisi. RISULTATI: nel periodo considerato \ue8 stato osservato un decremento delle concentrazioni di particolato nella maggior parte delle citt\ue0 in analisi, mentre non si pu\uf2 giungere a conclusioni cos\uec nette per NO2 e ozono. L\u2019analisi dell\u2019andamento temporale degli indicatori ha evidenziato valori medi annuali di PM10 superiori ai 40 \u3bcg/m3 in alcune citt\ue0 della Pianura Padana, e valori medi annuali di NO2 costantemente superiori ai 40 \u3bcg/m3 nelle citt\ue0 di Trieste, Milano, Padova, Torino, Modena, Bologna, Roma e Napoli. CONCLUSIONE: l\u2019ampliamento del progetto EpiAir, con l\u2019inclusione di ulteriori 13 citt\ue0, ha permesso di evidenziare peculiarit\ue0 legate alle differenti aree geografiche in studio e numerose situazioni di criticit\ue0 con superamenti dei valori di concentrazione limite fissati dalla legislazione corrente. I risultati dello studio EpiAir2 confermano la necessit\ue0 di un sistema di sorveglianza dell\u2019inquinamento aerodiffuso nei centri urbani e industriali al fine di ottenere stime affidabili dell\u2019esposizione della popolazione residente e di monitorarne l\u2019andamento nel tempo

Le politiche per la promozione della mobilit\ue0 sostenibile e la riduzione dell'inquinamento atmosferico causato dal traffico veicolare nelle citt\ue0 partecipanti allo studio EpiAir2

OBIETTIVO: fornire un quadro sintetico delle politiche di mobilit\ue0 adottate negli ultimi anni (2006-2010) dalle amministrazioni di alcuni Comuni italiani attraverso la rilevazione degli interventi sulla mobilit\ue0 urbana e relativa efficacia. DISEGNO E SETTING: i dati presentati si riferiscono alle quindici citt\ue0 inizialmente partecipanti al progetto EpiAir2: Torino, Milano, Venezia, Bologna, Firenze, Pisa, Roma, Taranto, Palermo, Cagliari, Trieste, Genova, Ancona, Napoli, Bari. RISULTATI: da questa indagine emergono debolezze e punti di forza delle citt\ue0 italiane nell\u2019affrontare il tema della mobilit\ue0 sostenibile. Le modifiche della consistenza del parco circolante sono state accompagnate da un suo rinnovamento con conseguente riduzione dei veicoli rispondenti agli standard emissivi pi\uf9 vecchi, seppur con differenze marcate tra le varie citt\ue0. Tra le debolezze pi\uf9 rilevanti nella gestione locale della mobilit\ue0 urbana \ue8 da segnalare in primo luogo lo sviluppo ridotto di metropolitane e di sistemi tranviari e il ritardo nell\u2019ammodernamento delle reti ferroviarie suburbane, che pongono le citt\ue0 italiane in una posizione evidentemente svantaggiata rispetto ad altre realt\ue0 urbane europee analoghe. Per quanto riguarda gli altri aspetti della mobilit\ue0 urbana (offerta/domanda di trasporto pubblico, ZTL, zone pedonali, km di piste ciclabili, servizi di car sharing e bike sharing), si segnala una situazione estremamente disomogenea tra le varie citt\ue0 italiane. CONCLUSIONI: le disomogeneit\ue0 tra le diverse realt\ue0 sono in parte spiegabili con le peculiarit\ue0 strutturali e culturali locali, oltre che da una diversa attenzione \u201cstorica\u201d alle problematiche ambientali e a un\u2019estemporaneit\ue0 delle scelte effettuate dalle rispettive amministrazioni. Pur in presenza di molte iniziative settoriali, pare sia mancata una strategia nazionale che, pur rispettosa del livello di autonomia locale, abbia fornito linee di indirizzo per affrontare in maniera adeguata e coordinata il tema della mobilit\ue0 sostenibile e dell\u2019inquinamento atmosferico da traffico veicolare