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As a step towards the realization of cryogenic-detector experiments to search for neutrinoless double-beta decay (such as CROSS, BINGO, and CUPID), we investigated a batch of 10 Ge light detectors (LDs) assisted by Neganov-Trofimov-Luke (NTL) signal amplification. Each LD was assembled with a large cubic light-emitting crystal (45 mm side) using the recently developed CROSS mechanical structure. The detector array was operated at milli-Kelvin temperatures in a pulse-tube cryostat at the Canfranc underground laboratory in Spain. We achieved good performance with scintillating bolometers from CROSS, made of Li $_{2}$ $^{100}\\(MoO\\)_4\\( crystals and used as reference detectors of the setup, and with all LDs tested (except for a single device that encountered an electronics issue). No leakage current was observed for 8 LDs with an electrode bias up to 100 V. Operating the LDs at an 80 V electrode bias applied in parallel, we obtained a gain of around 9 in the signal-to-noise ratio of these devices, allowing us to achieve a baseline noise RMS of \\)O$ (10 eV). Thanks to the strong current polarization of the temperature sensors, the time response of the devices was reduced to around half a millisecond in rise time. The achieved performance of the LDs was extrapolated via simulations of pile-up rejection capability for several configurations of the CUPID detector structure. Despite the sub-optimal noise conditions of the LDs (particularly at high frequencies), we demonstrated that the NTL technology provides a viable solution for background reduction in CUPID.

CUPID is a next-generation bolometric experiment to search for neutrinoless double-beta decay (\\(0\\nu\\beta\\beta\\)) of \\(^{100}\\)Mo using Li\\(_2\\)MoO\\(_4\\) scintillating crystals. It will operate 1596 crystals at \\(\\sim\\)10 mK in the CUORE cryostat at the Laboratori Nazionali del Gran Sasso in Italy. Each crystal will be facing two Ge-based bolometric light detectors for \\(\\alpha\\) rejection. We compute the discovery and the exclusion sensitivity of CUPID to \\(0\\nu\\beta\\beta\\) in a Frequentist and a Bayesian framework. This computation is done numerically based on pseudo-experiments. For the CUPID baseline scenario, with a background and an energy resolution of \\(1.0 \\times 10^{-4}\\) counts/keV/kg/yr and 5 keV FWHM at the Q-value, respectively, this results in a Bayesian exclusion sensitivity (90% c.i.) of \\(\\hat{T}_{1/2} > 1.6 \\times 10^{27} \\ \\mathrm{yr}\\), corresponding to the effective Majorana neutrino mass of \\(\\hat{m}_{\\beta\\beta} < \\ 9.6\\) -- \\(28 \\ \\mathrm{meV}\\). The Frequentist discovery sensitivity (3\\(\\sigma\\)) is \\(\\hat{T}_{1/2}= 1.0 \\times 10^{27} \\ \\mathrm{yr}\\), corresponding to \\(\\hat{m}_{\\beta\\beta}= \\ 12\\) -- \\(36 \\ \\mathrm{meV}\\).

Introduction The consequences of the withdrawal of marketing authorisation of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs. The potential concomitant changes in the reporting of adverse reactions concerning these alternatives have been studied less often. Objective The objective of this study was to analyse the changes in the reporting of adverse events (AEs) for therapeutic alternatives after the withdrawal of three medicines (dextropropoxyphene, pioglitazone and tetrazepam) from the market for safety reasons. Methods This study was performed using both the French pharmacovigilance database and the Echantillon Généraliste des Bénéficiaires (a random sample of French health insurance affiliates). For dextropropoxyphene, pioglitazone and tetrazepam alternatives, the number and types of case reports were studied for both the year preceding the first official safety warning and the year following the withdrawal. Reporting rates expressed per 10,000 reimbursements (RR Reimb ) and per 10,000 treated patients (RR Pat ) were also compared for the two periods. Results After dextropropoxyphene withdrawal, case reports and reimbursements increased for tramadol (case reports: +23%, reimbursements: +13%) and codeine (case reports: +74%, reimbursements: +47%), RR Pat being significantly increased for tramadol (0.92 vs. 1.06, p  = 0.02). After pioglitazone withdrawal, case reports increased for dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides, and glucagon-like peptide 1 (GLP-1) analogues (+84%, +22% and +5%, respectively) and reimbursements (+55, +11 and +50%, respectively); both decreased for sulfonylureas (case reports: −6%, reimbursements: −2%). RR Pat increased for DPP-4 inhibitors (1.63 vs. 2.26, p  = 0.008). After tetrazepam withdrawal, case reports increased for diazepam, methocarbamol and thiocolchicoside (+110, +86 and +157%, respectively), as lesser did reimbursements. RR Pat increased for diazepam (1.78 vs. 2.41, p  = 0.054) and thiocolchicoside (0.14 vs. 0.24, p  = 0.013). Conclusion For the three drug withdrawals investigated, the number of case reports involving alternatives increased to a larger extent than the numbers of prescriptions. This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs.

Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS. In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18–76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12–18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete. From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0·81 [95% CI 0·54–1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0·32 [0·14–0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001–1·0005], p=0·001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0·52 [0·30–0·89], p=0·016) in the 70% of the population with low (750–3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68–2·75], p=0·38). With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS. European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.

Background Interdisciplinary research teams can increase productivity among academic researchers, yet many junior investigators do not have the training or financial resources to build productive teams. We developed and tested the acceptability and feasibility of three low-cost services to help junior faculty build and maintain their own research teams. Methods At an urban academic medical centre, we implemented three types of consultation services: 1) giving talks on evidence-based best practices for building teams; 2) providing easy-to-use team building resources via email; and 3) offering a year-long consultation service—co-led by students—that taught faculty to build and maintain research teams. Our primary outcome was the number of faculty who used each service. For the yearlong consultation service, we asked faculty participants to complete three online self-assessments to rate their leadership confidence, the team’s performance, and which of the consultation components were most helpful. We used descriptive statistics to evaluate faculty assessment scores at three timepoints by comparing median scores and interquartile ranges. Results We gave 31 talks on team building to 328 faculty and postdoctoral fellows from 2014 to 2020. Separately, 26 faculty heard about our research team building expertise and requested materials via email. For the consultation service, we helped build or enhance 45 research teams from 2014 to 2020. By the end of the consultation, 100% of the faculty reported they were still maintaining their team. In the initial survey, the majority of participants (95.7%, n  = 22) reported having no or few experiences in building teams. Further, when asked to rate their team’s performance at 12-months, faculty highly rated many elements of both teamwork and taskwork, specifically their team’s productivity (6/7 points), morale (6/7 points), and motivation (6/7 points). By the end of the program, faculty participants also highly rated two components of the consultation program: recruitment assistance (7/10 points) and provision of team management tools (7/10 points). Conclusions For participating faculty, our program provided valued guidance on recruitment assistance and team management tools. The high demand for team-building resources suggests that junior faculty urgently need better training on how to develop and manage their own team.

While evolutionary biology traditionally focuses on the spread of mutations within populations, the dynamics of mutational spread within individuals, particularly in long-lived clonally, spreading organisms remain poorly understood. Here we examine the genetic structure of 'Pando', Earth's largest known quaking aspen ( ) clone. We sequenced over 500 samples across Pando and neighboring clones, including multiple tissue types. At fine spatial scales, we detected significant genetic structure, particularly in leaf tissue, but this signal weakened across larger distances, suggesting either rapid root growth homogenizes the system over time or mechanisms exist that prevent widespread mutation transmission. Phylogenetic analyses date Pando between ~12,000 and 37,000 years old, supported by continuous aspen pollen presence in nearby lake sediments. Tissues accumulated mutations at different rates, with leaves showing significantly higher mutation loads than roots or branches. This work provides the first quantitative age estimate for this remarkable organism and reveals how massive clonal plants maintain genetic integrity while accumulating potentially adaptive variation over millennia. Our findings illuminate evolutionary processes in long-lived modular organisms and demonstrate how within-organism selection might operate in species lacking regular unicellular bottlenecks.

Understanding how mutations arise and spread through individuals and populations is fundamental to evolutionary biology. Most organisms have a life cycle with unicellular bottlenecks during reproduction. However, some organisms like plants, fungi, or colonial animals can grow indefinitely, changing the manner in which mutations spread throughout both the individual and the population. Furthermore, clonally reproducing organisms may also achieve exceedingly long lifespans, making somatic mutation an important mechanism of creating heritable variation for Darwinian evolution by natural selection. Yet, little is known about intra-organism mutation rates and evolutionary trajectories in long-lived species. Here, we study the Pando aspen clone, the largest known quaking aspen (Populus tremuloides) clone founded by a single seedling and thought to be one of the oldest studied organisms. Aspen reproduce vegetatively via new root-borne stems forming clonal patches, sometimes spanning several hectares. To study the evolutionary history of the Pando clone, we collected and sequenced over 500 samples from Pando and neighboring clones, as well as from various tissue types within Pando, including leaves, roots, and bark. We applied a series of filters to distinguish somatic mutations from the pool of both somatic and germline mutations, incorporating a technical replicate sequencing approach to account for uncertainty in somatic mutation detection. Despite root spreading being spatially constrained, we observed only a modest positive correlation between genetic and spatial distance, suggesting the presence of a mechanism preventing the accumulation and spread of mutations across units. Phylogenetic models estimate the age of the clone to between ~16,000-80,000 years. This age is generally corroborated by the near-continuous presence of aspen pollen in a lake sediment record collected from Fish Lake near Pando. Overall, this work enhances understanding of mutation accumulation and dispersal within and between ramets of long-lived, clonally-reproducing organisms.Understanding how mutations arise and spread through individuals and populations is fundamental to evolutionary biology. Most organisms have a life cycle with unicellular bottlenecks during reproduction. However, some organisms like plants, fungi, or colonial animals can grow indefinitely, changing the manner in which mutations spread throughout both the individual and the population. Furthermore, clonally reproducing organisms may also achieve exceedingly long lifespans, making somatic mutation an important mechanism of creating heritable variation for Darwinian evolution by natural selection. Yet, little is known about intra-organism mutation rates and evolutionary trajectories in long-lived species. Here, we study the Pando aspen clone, the largest known quaking aspen (Populus tremuloides) clone founded by a single seedling and thought to be one of the oldest studied organisms. Aspen reproduce vegetatively via new root-borne stems forming clonal patches, sometimes spanning several hectares. To study the evolutionary history of the Pando clone, we collected and sequenced over 500 samples from Pando and neighboring clones, as well as from various tissue types within Pando, including leaves, roots, and bark. We applied a series of filters to distinguish somatic mutations from the pool of both somatic and germline mutations, incorporating a technical replicate sequencing approach to account for uncertainty in somatic mutation detection. Despite root spreading being spatially constrained, we observed only a modest positive correlation between genetic and spatial distance, suggesting the presence of a mechanism preventing the accumulation and spread of mutations across units. Phylogenetic models estimate the age of the clone to between ~16,000-80,000 years. This age is generally corroborated by the near-continuous presence of aspen pollen in a lake sediment record collected from Fish Lake near Pando. Overall, this work enhances understanding of mutation accumulation and dispersal within and between ramets of long-lived, clonally-reproducing organisms.