Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination

Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers

The Eastern Origins of the Rise of the West and the “Return” of Asia

With the current interest in China (and India) proliferating within the Western Academy, this article claims that what we are witnessing today is not the rise but the “return” of China (and India). Many academics assume that the West has been the dominant civilization in the world economy in the last 500 years and that the current “rise” of China threatens to knock the West off its perch. However, this article provides an alternative take to this cherished axiom of Eurocentric world history by inverting the standard belief that the West pioneered modernity and then expanded outwards to remake the world. Thus, I argue not only that globalization preceded the rise of the West but that it was Eastern-led on the one hand and that it enabled the Western breakthrough into modernity on the other. This, in turn, rests on my claim that Chinese development stems back not to 1978 but to 960 ce as the Sung Dynasty emerged and subsequently undertook a quasi-industrial miracle. Moreover, between 1450/1492 and ca. 1830 China lay at the centre of the nascent global economy, fanning the integration process alongside other key non-Western regions such as India and West Asia/North Africa. And, while the West was the dominant player after ca. 1830 down to the turn of the third millennium, nevertheless, what we witness today is the return of China to the centre of the global economy whence it came

Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network.

OBJECTIVE: To gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middle-income country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR). DESIGN: A web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns. SETTING: 39 NNUs from 12 countries. PATIENTS: Any neonate admitted to one of the participating NNUs. INTERVENTIONS: This was an observational cohort study. RESULTS: The number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List 'Access' antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%. CONCLUSION: AMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally

Caracterización del delito de concierto para delinquir en instituciones del Estado

Artículo de investigaciónEste artículo de investigación se centra en el análisis del crimen organizado en el sector público en Colombia, esto a través de un estudio del tipo penal de concierto para delinquir tipificado en el artículo 340 del Código Penal colombiano. Se pretende a través de esta investigación documentar una realidad inminente que se presenta en la administración pública en el país, sobre los hechos de corrupción y grupos delictivos organizados dentro de las instituciones de gobierno. En este contexto, resulta relevante hacer un análisis sucinto de los comportamientos de los grupos de crimen organizado que han logrado permear la institucionalidad colombiana, y reflejan una carencia de valores en la función pública actualmente.INTRODUCCIÓN 1. CRIMEN ORGANIZADO Y ORGANIZACIÓN CRIMINAL. 2. LA LEY 1908 DE 2018 SOBRE CRIMEN ORGANIZADO EN COLOMBIA 3. CONDUCTA PUNIBLE DE CONCIERTO PARA DELINQUIR EN EL ORDENAMIENTO JURÍDICO COLOMBIANO. 4. LA SEGURIDAD PÚBLICA Y EL SERVICIO PÚBLICO. 5. EL CONCIERTO PARA COMETER DELITOS CONTRA INTERESES ESTATALES EN COLOMBIA. CONCLUSIONES. REFERENCIASPregradoAbogad