Efficacy of liposomal bupivacaine and bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a periarticular anesthetic for patients undergoing knee replacement : a randomized clinical trial

Importance: Over half of patients report significant acute post-operative pain following knee replacement. Objective: To evaluate the clinical and cost effectiveness of peri-articular liposomal bupivacaine (LB) for recovery and pain following knee replacement. Design, Setting and Participants: This multi-centre, patient-blinded, pragmatic, randomized controlled superiority trial (RCT) involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29th, 2018 and February 29th, 2020 and followed up for one year after surgery. Interventions: LB (266mg) admixed with bupivacaine hydrochloride (100mg) compared to bupivacaine hydrochloride (100mg) alone (control) administered by peri-articular injection at the time of surgery. Main Outcome and Measures: The co-primary outcomes were Quality of Recovery 40 (QoR-40) score at 72hours and pain visual analogue score (VAS) area under the curve (AUC) 6 to 72hours. Secondary outcomes included: QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2 and 3, cumulative opioid consumption over 72hours, functional outcomes and quality of life at 6weeks, 6months and 1year, and cost-effectiveness over 1year. Adverse Events and Serious Adverse Events up to 12months post-randomization were also assessed. Results: 533 participants, mean age 69years were randomized with baseline characteristics balanced between arms. There was no difference in QoR-40 at 72hours nor pain VAS AUC 6 to 72hours between LB and control arm (adjusted mean difference for QoR-40: 0.54 (97.5% CI -2.05 to 3.13, p=0.643); pain VAS AUC -21.5 (97.5% CI -46.8 to 3.8; p=0.057)). Analyses of pain VAS and QoR-40 scores demonstrated only one statistically significant difference, with the LB arm having lower pain scores the evening of surgery (day 0; adjusted difference -0.54, 97.5% CI - 1.07 to -0.02; p=0.021). No difference in cumulative opioid consumption and functional outcomes was detected. LB was not cost-effective compared to control. No difference in adverse or serious adverse events was found between LB and control arms. Conclusion and Relevance: This study found no difference in post-operative recovery associated with the use of peri-articular LB compared to bupivacaine hydrochloride alone. This study does not support the use of peri-articular LB for knee replacement. Trial Registration: ISRCTN 54191675, registered on 14 November 2017. http://www.isrctn.com/ISRCTN5419167

Tracking down carbon inputs underground from an arid zone Australian calcrete.

Freshwater ecosystems play a key role in shaping the global carbon cycle and maintaining the ecological balance that sustains biodiversity worldwide. Surficial water bodies are often interconnected with groundwater, forming a physical continuum, and their interaction has been reported as a crucial driver for organic matter (OM) inputs in groundwater systems. However, despite the growing concerns related to increasing anthropogenic pressure and effects of global change to groundwater environments, our understanding of the dynamics regulating subterranean carbon flows is still sparse. We traced carbon composition and transformations in an arid zone calcrete aquifer using a novel multidisciplinary approach that combined isotopic analyses of dissolved organic carbon (DOC) and inorganic carbon (DIC) (δ13CDOC, δ13CDIC, 14CDOC and 14CDIC) with fluorescence spectroscopy (Chromophoric Dissolved OM (CDOM) characterisation) and metabarcoding analyses (taxonomic and functional genomics on bacterial 16S rRNA). To compare dynamics linked to potential aquifer recharge processes, water samples were collected from two boreholes under contrasting rainfall: low rainfall ((LR), dry season) and high rainfall ((HR), wet season). Our isotopic results indicate limited changes and dominance of modern terrestrial carbon in the upper part (northeast) of the bore field, but correlation between HR and increased old and 13C-enriched DOC in the lower area (southwest). CDOM results show a shift from terrestrially to microbially derived compounds after rainfall in the same lower field bore, which was also sampled for microbial genetics. Functional genomic results showed increased genes coding for degradative pathways-dominated by those related to aromatic compound metabolisms-during HR. Our results indicate that rainfall leads to different responses in different parts of the bore field, with an increase in old carbon sources and microbial processing in the lower part of the field. We hypothesise that this may be due to increasing salinity, either due to mobilisation of Cl- from the soil, or infiltration from the downstream salt lake during HR. This study is the first to use a multi-technique assessment using stable and radioactive isotopes together with functional genomics to probe the principal organic biogeochemical pathways regulating an arid zone calcrete system. Further investigations involving extensive sampling from diverse groundwater ecosystems will allow better understanding of the microbiological pathways sustaining the ecological functioning of subterranean biota

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions