Modernizing Medical Research to Benefit People and Animals

In the context of widespread public and political concern around the use of animals in research, we sought to examine the scientific, ethical, and economic arguments around the replacement of animals with New Approach Methodologies (NAMs) and to situate this within a regulatory context. We also analyzed the extent to which animal replacement aligns with British public and policymakers’ priorities and explored global progress towards this outcome. The global context is especially relevant given the international nature of regulatory guidance on the safety testing of new medicines. We used a range of evidence to analyze this area, including scientific papers; expert economic analysis; public opinion polls and the Hansard of the UK Parliament. We found evidence indicating that replacing animals with NAMs would benefit animal welfare, public health and the economy. The majority of the British public is in favor of efforts to replace animals and focusing on this area would help to support the British Government’s current policy priorities. We believe that this evidence underlines the need for strong action from policymakers to accelerate the transition from animal experiments to NAMs. The specific measure we suggest is to introduce a new ministerial to coordinate and accelerate the replacement of animals with NAMs

Fair Domestic Allocation of Monkeypox Virus Countermeasures

Countermeasures for mpox (formerly known as monkeypox), primarily vaccines, have been in limited supply in many countries during outbreaks. Equitable allocation of scarce resources during public health emergencies is a complex challenge. Identifying the objectives and core values for the allocation of mpox countermeasures, using those values to provide guidance for priority groups and prioritisation tiers, and optimising allocation implementation are important. The fundamental values for the allocation of mpox countermeasures are: preventing death and illness; reducing the association between death or illness and unjust disparities; prioritising those who prevent harm or mitigate disparities; recognising contributions to combating an outbreak; and treating similar individuals similarly. Ethically and equitably marshalling available countermeasures requires articulating these fundamental objectives, identifying priority tiers, and recognising trade-offs between prioritising the people at the highest risk of infection and the people at the highest risk of harm if infected. These five values can provide guidance on preferable priority categories for a more ethically sound response and suggest methods for optimising allocation of countermeasures for mpox and other diseases for which countermeasures are in short supply. Properly marshalling available countermeasures will be crucial for future effective and equitable national responses to outbreaks

Reading the crisis: legal, philosophical and literary perspectives

Almost a decade has passed since the outbreak of the economic crisis; from its original nucleus, its effects have quickly affected the social and geopolitical fields. Such wide impact and its complex implications make the crisis an object susceptible of multiple readings. The particular aim of the studies collected in this volume is to explore the impact of the crisis on law, culture and society, in order to test the depth of the problem, by comparing the analytical perspectives obtainable from legal and human sciences. The book focuses on three main issues: the crisis as a social object, in order to consider the crisis in terms of its attributing force; the problem of democracy, which is becoming an increasingly central question now, as the changes imposed by the crisis have begun to settle down; the interdisciplinary challenge that, in time of crisis, questions paradigms of knowledge, competences and methods, in order to enable an heuristic dialogue between human, social and legal sciences.Introduction / Massimo Meccarelli (pp. 9-12). -- The Crisis as a Social Object : -- Narrating the Crisis: Fictions of Finance in Contemporary British Novels / Silvana Colella (pp. 15-37). -- Social Rights in Crisis: Any Role for the Court of Justice of the EU? / Francesco Costamagna (pp. 39-64). -- Ripensare la nazione ottocentesca. Vecchi e nuovi paradigmi tra storia, diritto e globalità / Eliana Augusti (pp. 65-97). -- Ma cos'è questa crisi? / Carla Canullo (pp. 99-113). -- The Problem of Democracy : -- Defending Collective Sociality: The Oresteia at Shakespeare's Globe / Louise Owen (pp. 117-131). -- Representation of the Crisis vs Representative Democracy in Italy / Roberta Calvano (pp. 133-148). -- The Unbearable Lightness of the Freedom of Movement: An Analysis of the Relationship Between Brexit and Inmigration / Lucia Barbone, Erik Longo (pp.149-174). -- Représentation, perception de la crise et modification de la «sécurité sociale». Entre prédiction et anticipation, que signifie agir das un monde incertain? / Jean-Philipe Pierron (pp. 175-188). -- The Interdisciplinary Challenge : -- Intercultural Categories of Thought in Times of Crisis: The Challenge of Inter/Multi-discipinary Research / Flavia Stara (pp. 191-198). -- An Interdisciplinary Approach to International Law? Some Cursory Remarks / Paolo Palchetti (pp. 199-208). -- Rights in Times of Crisis: An Interdisciplinary Issue for Legal Studies / Massimo Meccarelli (pp. 209-219). -- Contributors (pp. 221-224)

Fair domestic allocation of monkeypox virus countermeasures

Countermeasures for mpox (formerly known as monkeypox), primarily vaccines, have been in limited supply in many countries during outbreaks. Equitable allocation of scarce resources during public health emergencies is a complex challenge. Identifying the objectives and core values for the allocation of mpox countermeasures, using those values to provide guidance for priority groups and prioritisation tiers, and optimising allocation implementation are important. The fundamental values for the allocation of mpox countermeasures are: preventing death and illness; reducing the association between death or illness and unjust disparities; prioritising those who prevent harm or mitigate disparities; recognising contributions to combating an outbreak; and treating similar individuals similarly. Ethically and equitably marshalling available countermeasures requires articulating these fundamental objectives, identifying priority tiers, and recognising trade-offs between prioritising the people at the highest risk of infection and the people at the highest risk of harm if infected. These five values can provide guidance on preferable priority categories for a more ethically sound response and suggest methods for optimising allocation of countermeasures for mpox and other diseases for which countermeasures are in short supply. Properly marshalling available countermeasures will be crucial for future effective and equitable national responses to outbreaks

A molecular approach to drought-induced reduction in leaf CO2 exchange in drought-resistant Quercus ilex

Drought-induced reduction of leaf gas exchange entails a complex regulation of the plant leaf metabolism. We used a combined molecular and physiological approach to understand leaf photosynthetic and respiratory responses of 2-year-old Quercus ilex seedlings to drought. Mild drought stress resulted in glucose accumulation while net photosynthetic CO2 uptake (Pn) remained unchanged, suggesting a role of glucose in stress signaling and/or osmoregulation. Simple sugars and sugar alcohols increased throughout moderate-to-very severe drought stress conditions, in parallel to a progressive decline in Pn and the quantum efficiency of photosystem II; by contrast, minor changes occurred in respiration rates until drought stress was very severe. At very severe drought stress, 2-oxoglutarate dehydrogenase complex gene expression significantly decreased, and the abundance of most amino acids dramatically increased, especially that of proline and γ-aminobutyric acid (GABA) suggesting enhanced protection against oxidative damage and a reorganization of the tricarboxylic cycle acid cycle via the GABA shunt. Altogether, our results point to Q. ilex drought tolerance being linked to signaling and osmoregulation by hexoses during early stages of drought stress, and enhanced protection against oxidative damage by polyols and amino acids under severe drought stress.Funding was provided by the Spanish Ministry of Economy and Competitiveness (AGL2012-35580 and AGL2015-66925-R MINECO/FEDER, UE). C. A. gratefully acknowledges support from FCT Investigator Programme (IF/00376/2012/CP0165/CT0003) by Fundação para a Ciência e a Tecnologia (FCT), Portugal, ITQB NOVA R&D GREEN-it ‘Bioresources for sustainability’ (UID/Multi/04551/2013), and LabMet Metabolomics Facility at CTBE (Campinas, Brazil) for GC-TOF-MS metabolite profiling services. A. M. R. acknowledges FCT for the PhD fellowship (PD/BD/114417/2016) and the ITQB NOVA International PhD Programme ‘Plants for Life’ (PD/00035/2013). O. K. A. acknowledges the support of the Australian Research Council (CE140100008). P. P. acknowledges funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n∘ PIEF-GA-2013-627761

Effect of losartan on performance and physiological responses to exercise at high altitude (5035 m)

Objective: Altitude-related and exercise-related elevations in blood pressure (BP) increase the likelihood of developing pulmonary hypertension and high-altitude illness during high-altitude sojourn. This study examined the antihypertensive effect and potential exercise benefit of the angiotensin II receptor antagonist losartan when taken at altitude. Methods: Twenty participants, paired for age and ACE genotype status, completed a double-blinded, randomised study, where participants took either losartan (100 mg/day) or placebo for 21 days prior to arrival at 5035 m (Whymper Hut, Mt Chimborazo, Ecuador). Participants completed a maximal exercise test on a supine cycle ergometer at sea level (4 weeks prior) and within 48 hours of arrival to 5035 m (10-day ascent). Power output, beat-to-beat BP, oxygen saturation (SpO2) and heart rate (HR) were recorded during exercise, with resting BP collected from daily medicals during ascent. Before and immediately following exercise at 5035 m, extravascular lung water prevalence was assessed with ultrasound (quantified via B-line count). Results: At altitude, peak power was reduced relative to sea level (p<0.01) in both groups (losartan vs placebo: down 100±29 vs 91±28 W, p=0.55), while SpO2 (70±6 vs 70±5%, p=0.96) and HR (146±21 vs 149±24 bpm, p=0.78) were similar between groups at peak power, as was the increase in systolic BP from rest to peak power (up 80±37 vs 69±33 mm Hg, p=0.56). Exercise increased B-line count (p<0.05), but not differently between groups (up 5±5 vs 8±10, p=0.44). Conclusion: Losartan had no observable effect on resting or exercising BP, exercise-induced symptomology of pulmonary hypertension or performance at 5035 m

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

© 2023 The Author(s). ALTEX. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four “maps” of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.Peer reviewe

Unlocking the bottleneck in forward genetics using whole-genome sequencing and identity by descent to isolate causative mutations

Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis.The High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics is funded by Wellcome Trust grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070. This study was supported by Wellcome Trust Strategic Award 082030 (CCG), Wellcome Trust Studentship 094446/Z/10/Z (KRB), the Oxford NIHR Biomedical Research Centre, and the MRC Human Immunology Unit (RJC). AJR and GL were supported by Wellcome Trust grant 090532/Z/ 09/Z, CCG and AE by a Major initiative Award from the Clive and Vera Ramaciotti Foundation, and AE by an NHMRC Career Development Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript