Clinical Effectiveness of Transversus Abdominis Plane (TAP) Block versus Local Anesthesia Wound Infiltration for Postoperative Pain Relief After Laparoscopic Appendicectomy in Children: A Study Protocol for a Multicenter Double-Blind Randomized Controlled Phase III Trial

Geoffrey Bloy,1 Amelie Jurine,1 Yann Chaussy,2 Frederic Auber,2 Pierre-Gregoire Guinot,3 Belaid Bouhemad,3 Michel Francois,4 Lucie Vettoretti,1 Sebastien Pili-Floury,5 Maxime Nguyen,3 Guillaume Besch5 1CHU Besançon, Département d’Anesthésie Réanimation Chirurgicale, Besançon, F-25000, France; 2Université de Franche-Comté, CHU Besançon, SINERGIES, Service de Chirurgie Pédiatrique, Besançon, F-25000, France; 3University of Burgundy and Franche-Comté, Dijon University Hospital, INSERM LNC UMR1231, FCS Bourgogne Franche-Comté LipSTIC LabEx, Dijon, F-21000, France; 4Université de Bourgogne, CHU Dijon, Service de Chirurgie Pédiatrique, Dijon, F-21000, France; 5Université de Franche-Comté, CHU Besançon, SINERGIES, Département d’Anesthésie Réanimation Chirurgicale, Besançon, F-25000, FranceCorrespondence: Guillaume Besch, Département d’Anesthésie Réanimation Chirurgicale, CHU Besançon, 3 bvd Alexandre Fleming, Besançon, 25030, France, Tel +3381218958, Fax +3381669331, Email [email protected]: Postoperative pain relief after laparoscopic appendicectomy is a key determinant of early rehabilitation in children. Recent guidelines recommend performing either a transversus abdominis plane (TAP) block or local anesthesia (LA) wound infiltration as part of multimodal postoperative analgesia after appendectomy. To date, the clinical effectiveness of TAP block versus LA wound infiltration has never been compared. The hypothesis of this study is that the TAP block may provide a greater opioid-sparing effect after laparoscopic appendicectomy in children than LA wound infiltration.Study Design and Methods: We designed a multicenter double-blind randomized controlled phase III trial and aim to include 110 children who undergo laparoscopic appendicectomy. Children are randomized to receive either TAP block (TAP group) or LA wound infiltration (infiltration group). Multimodal analgesia is standardized in the two groups using the same protocol, which includes the stepwise prescription of paracetamol, phloroglucinol, ketoprofene, and nalbuphine according to the hetero-evaluation of pain performed by the nurses who were blinded to the treatment allocated using the validated FLACC scale. The primary outcome is the total dose of nalbuphine administered within 24 hours after surgery.Discussion: No study has specifically compared the clinical effectiveness of TAP block versus LA wound infiltration for postoperative pain relief after laparoscopic appendectomy in children. This paper describes the protocol for a randomized trial that addresses this issue. The results of this trial will be useful for editing guidelines with a higher level of evidence on this topic.Keywords: laparoscopic appendectomy, TAP block, wound infiltration, analgesia, childre

Predicting River Macroinvertebrate Communities Distributional Shifts under Future Global Change Scenarios in the Spanish Mediterranean Area

Several studies on global change over the next century predict increases in mean air temperatures of between 1°C to 5°C that would affect not only water temperature but also river flow. Climate is the predominant environmental driver of thermal and flow regimes of freshwater ecosystems, determining survival, growth, metabolism, phenology and behaviour as well as biotic interactions of aquatic fauna. Thus, these changes would also have consequences for species phenology, their distribution range, and the composition and dynamics of communities. These effects are expected to be especially severe in the Mediterranean basin due its particular climate conditions, seriously threatening Southern European ecosystems. In addition, species with restricted distributions and narrow ecological requirements, such as those living in the headwaters of rivers, will be severely affected. The study area corresponds to the Spanish Mediterranean and Balearic Islands, delimited by the Köppen climate boundary. With the application of the MEDPACS (MEDiterranean Prediction And Classification System) predictive approach, the macroinvertebrate community was predicted for current conditions and compared with three posible scenarios of watertemperature increase and its associated water flow reductions. The results indicate that the aquatic macroinvertebrate communities will undergo a drastic impact, with reductions in taxa richness for each scenario in relation to simulated current conditions, accompanied by changes in the taxa distribution pattern. Accordingly, the distribution area of most of the taxa (65.96%) inhabiting the mid-high elevations would contract and rise in altitude. Thus, families containing a great number of generalist species will move upstream to colonize new zones with lower water temperatures. By contrast, more vulnerable taxa will undergo reductions in their distribution area.This work was funded by GUADALMED-II (REN2001-3438-C07-06/HID), a project of excellence from “Junta de Andalucía” (RNM-02654/FEDER), the Spanish “Ministerio de Ciencia e Innovación” (CGL2007-61856/BOS), projects and a collaboration agreement between the “Spanish Ministerio de Medio Ambiente, Medio Rural y Marino” and the University of Granada (21.812-0062/8511)

Down-Regulation of NF-κB Target Genes by the AP-1 and STAT Complex during the Innate Immune Response in Drosophila

The activation of several transcription factors is required for the elimination of infectious pathogens via the innate immune response. The transcription factors NF-κB, AP-1, and STAT play major roles in the synthesis of immune effector molecules during innate immune responses. However, the fact that these immune responses can have cytotoxic effects requires their tight regulation to achieve restricted and transient activation, and mis-regulation of the damping process has pathological consequences. Here we show that AP-1 and STAT are themselves the major inhibitors responsible for damping NF-κB–mediated transcriptional activation during the innate immune response in Drosophila. As the levels of dAP-1 and Stat92E increase due to continuous immune signaling, they play a repressive role by forming a repressosome complex with the Drosophila HMG protein, Dsp1. The dAP-1–, Stat92E-, and Dsp1-containing complexes replace Relish at the promoters of diverse immune effector genes by binding to evolutionarily conserved cis-elements, and they recruit histone deacetylase to inhibit transcription. Reduction by mutation of dAP-1, Stat92E, or Dsp1 results in hyperactivation of Relish target genes and reduces the viability of bacterially infected flies despite more efficient pathogen clearance. These defects are rescued by reducing the Relish copy number, thus confirming that mis-regulation of Relish, not inadequate activation of dAP-1, Stat92E, or Dsp1 target genes, is responsible for the reduced survival of the mutants. We conclude that an inhibitory effect of AP-1 and STAT on NF-κB is required for properly balanced immune responses and appears to be evolutionarily conserved

Effective but Costly, Evolved Mechanisms of Defense against a Virulent Opportunistic Pathogen in Drosophila melanogaster

Drosophila harbor substantial genetic variation for antibacterial defense, and investment in immunity is thought to involve a costly trade-off with life history traits, including development, life span, and reproduction. To understand the way in which insects invest in fighting bacterial infection, we selected for survival following systemic infection with the opportunistic pathogen Pseudomonas aeruginosa in wild-caught Drosophila melanogaster over 10 generations. We then examined genome-wide changes in expression in the selected flies relative to unselected controls, both of which had been infected with the pathogen. This powerful combination of techniques allowed us to specifically identify the genetic basis of the evolved immune response. In response to selection, population-level survivorship to infection increased from 15% to 70%. The evolved capacity for defense was costly, however, as evidenced by reduced longevity and larval viability and a rapid loss of the trait once selection pressure was removed. Counter to expectation, we observed more rapid developmental rates in the selected flies. Selection-associated changes in expression of genes with dual involvement in developmental and immune pathways suggest pleiotropy as a possible mechanism for the positive correlation. We also found that both the Toll and the Imd pathways work synergistically to limit infectivity and that cellular immunity plays a more critical role in overcoming P. aeruginosa infection than previously reported. This work reveals novel pathways by which Drosophila can survive infection with a virulent pathogen that may be rare in wild populations, however, due to their cost

The relationships between biotic uniqueness and abiotic uniqueness are context dependent across drainage basins worldwide

[EN] Context: Global change, including land-use change and habitat degradation, has led to a decline in biodiversity, more so in freshwater than in terrestrial ecosystems. However, the research on freshwaters lags behind terrestrial and marine studies, highlighting the need for innovative approaches to comprehend freshwater biodiversity. Objectives: We investigated patterns in the relationships between biotic uniqueness and abiotic environmental uniqueness in drainage basins worldwide. Methods: We compiled high-quality data on aquatic insects (mayflies, stoneflies, and caddisflies at genus-level) from 42 drainage basins spanning four continents. Within each basin we calculated biotic uniqueness (local contribution to beta diversity, LCBD) of aquatic insect assemblages, and four types of abiotic uniqueness (local contribution to environmental heterogeneity, LCEH), categorized into upstream land cover, chemical soil properties, stream site landscape position, and climate. A mixed-effects meta-regression was performed across basins to examine variations in the strength of the LCBD-LCEH relationship in terms of latitude, human footprint, and major continental regions (the Americas versus Eurasia). Results: On average, relationships between LCBD and LCEH were weak. However, the strength and direction of the relationship varied among the drainage basins. Latitude, human footprint index, or continental location did not explain significant variation in the strength of the LCBD-LCEH relationship. Conclusions: We detected strong context dependence in the LCBD-LCEH relationship across the drainage basins. Varying environmental conditions and gradient lengths across drainage basins, land-use change, historical contingencies, and stochastic factors may explain these findings. This context dependence underscores the need for basin-specific management practices to protect the biodiversity of riverine systemsSIOpen Access funding provided by University of Oulu (including Oulu University Hospital). The work for this article was supported by the Academy of Finland’s grant to JHeino for the project GloBioTrends (Grant No. 331957). JGG was funded by the European Union Next Generation EU/PRTR (Grant No. AG325). Work by LMB has been continuously supported by the National Council for Scientifc & Technological Development (CNPq) and Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) (grants 308974/2020–4 and 465610/2014–5). PB and ZC were fnancially supported by the National Research Development and Innovation Ofce (NKFIH FK 135 136), and PB was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences BO-00106–21. LB thanks the National Council for Scientifc and Technological Development (CNPq) for the Scientifc Initiation Fellowship for JVASS and the productivity fellowship in research to LSB (process nº. 305929/2022–4). MC was awarded National Council for Scientifc & Technological Development (CNPq) research productivity grant 304060/2020–8 and received grants (PPM 00104–18, APQ-00261–22) from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais. SD and JRGM acknowledge funding by the Leibniz Competition (Grant No. J45/2018) and the German Federal Ministry of Education and Research (BMBF grant agreement number no. 033W034A). DRM was supported by National Council for Scientifc & Technological Development (CNPq) (Grant No. PQ-309763–2020-7). DMPC received a postdoctoral scholarship from P&D Aneel- Cemig GT-611. PH was partially funded by the eLTER PLUS project (Grant Agreement No. 871128). LJ is grateful to 33 Forest, CIKEL Ltd. and Instituto de Floresta Tropical (IFT), Biodiversity Research Consortium Brazil-Norway (BRC), and Norsk Hydro for the fnancial and logistical support for sampling. Brazilian National Council for Scientifc and Technological Development (CNPq) is acknowledged for fnancing the projects and for granting a research productivity fellowship to LJ (304710/2019–9). APJF was supported by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq, Brazil, process no. 449315/2014–2 and 481015/2011–6). RL also received a research productivity fellowship from CNPq (grant # 312531/2021–4). MSL received a postdoctoral scholarship from ANEEL/CEMIG (Project GT-599). Part of feld sampling and aquatic insects processing were funded by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq; 403758/2021–1); Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM; Programa Biodiversa) and INCT ADAPTA II – (CNPq: 465540/2014–7; FAPEAM: 062.1187/2017). NH (308970/2019–5) received productivity fellowships from CNPq. RTM received a fellowship from Biodiversa/FAPEAM (01.02.016301.03271/2021–93). KLM acknowledges fnancial support from the Swiss Federal Ofce for the Environment to undertake data collection. Funding for the Segura River basin project was provided by the Seneca Foundation and the European Fund of Regional Development (PLP10/FS/97). FOR was supported by CNPq research grant. TS was partially funded by grant 13/50424–1 and 21/00619–7 from the São Paulo Research Foundation (FAPESP), and by grant 309496/2021–7 from the Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq). FVN was supported by grant #2021/13299–0, São Paulo Research Foundation (FAPESP). ALA acknowledges Brazilian National Council for Scientifc and Technological Development (CNPq, Brazil) for granting a postdoctoral scholarship to her (process number: 167873/2022–9

A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity

Previously, we discovered a conserved interaction between RB proteins and the Condensin II protein CAP-D3 that is important for ensuring uniform chromatin condensation during mitotic prophase. The Drosophila melanogaster homologs RBF1 and dCAP-D3 co-localize on non-dividing polytene chromatin, suggesting the existence of a shared, non-mitotic role for these two proteins. Here, we show that the absence of RBF1 and dCAP-D3 alters the expression of many of the same genes in larvae and adult flies. Strikingly, most of the genes affected by the loss of RBF1 and dCAP-D3 are not classic cell cycle genes but are developmentally regulated genes with tissue-specific functions and these genes tend to be located in gene clusters. Our data reveal that RBF1 and dCAP-D3 are needed in fat body cells to activate transcription of clusters of antimicrobial peptide (AMP) genes. AMPs are important for innate immunity, and loss of either dCAP-D3 or RBF1 regulation results in a decrease in the ability to clear bacteria. Interestingly, in the adult fat body, RBF1 and dCAP-D3 bind to regions flanking an AMP gene cluster both prior to and following bacterial infection. These results describe a novel, non-mitotic role for the RBF1 and dCAP-D3 proteins in activation of the Drosophila immune system and suggest dCAP-D3 has an important role at specific subsets of RBF1-dependent genes

Characterisation and Skin Distribution of Lecithin-Based Coenzyme Q10-Loaded Lipid Nanocapsules

The purpose of this study was to investigate the influence of the inner lipid ratio on the physicochemical properties and skin targeting of surfactant-free lecithin-based coenzyme Q10-loaded lipid nanocapsules (CoQ10-LNCs). The smaller particle size of CoQ10-LNCs was achieved by high pressure and a lower ratio of CoQ10/GTCC (Caprylic/capric triglyceride); however, the zeta potential of CoQ10-LNCs was above /− 60 mV/ with no distinct difference among them at different ratios of CoQ10/GTCC. Both the crystallisation point and the index decreased with the decreasing ratio of CoQ10/GTCC and smaller particle size; interestingly, the supercooled state of CoQ10-LNCs was observed at particle size below about 200 nm, as verified by differential scanning calorimetry (DSC) in one heating–cooling cycle. The lecithin monolayer sphere structure of CoQ10-LNCs was investigated by cryogenic transmission electron microscopy (Cryo-TEM). The skin penetration results revealed that the distribution of Nile red-loaded CoQ10-LNCs depended on the ratio of inner CoQ10/GTCC; moreover, epidermal targeting and superficial dermal targeting were achieved by the CoQ10-LNCs application. The highest fluorescence response was observed at a ratio of inner CoQ10/GTCC of 1:1. These observations suggest that lecithin-based LNCs could be used as a promising topical delivery vehicle for lipophilic compounds

Regulation of Hemocytes in Drosophila Requires dappled Cytochrome b5

A major category of mutant hematopoietic phenotypes in Drosophila is melanotic tumors or nodules, which consist of abnormal and overproliferated blood cells, similar to granulomas. Our analyses of the melanotic mutant dappled have revealed a novel type of gene involved in blood cell regulation. The dappled gene is an essential gene that encodes cytochrome b5, a conserved hemoprotein that participates in electron transfer in multiple biochemical reactions and pathways. Viable mutations of dappled cause melanotic nodules and hemocyte misregulation during both hematopoietic waves of development. The sexes are similarly affected, but hemocyte number is different in females and males of both mutants and wild type. Additionally, initial tests show that curcumin enhances the dappled melanotic phenotype and establish screening of endogenous and xenobiotic compounds as a route for analysis of cytochrome b5 function. Overall, dappled provides a tractable genetic model for cytochrome b5, which has been difficult to study in higher organisms

Time series of freshwater macroinvertebrate abundances and site characteristics of European streams and rivers

Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, fltering water, controlling primary producers, and providing food for predators. Their diferences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, eforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specifc taxa to assessing the success of legislative and management restoration eforts.publishedVersio