Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Transcriptomic changes in coral holobionts provide insights into physiological challenges of future climate and ocean change

Tropical reef-building coral stress levels will intensify with the predicted rising atmospheric CO2 resulting in ocean temperature and acidification increase. Most studies to date have focused on the destabilization of coral-dinoflagellate symbioses due to warming oceans, or declining calcification due to ocean acidification. In our study, pH and temperature conditions consistent with the end-of-century scenarios of the Intergovernmental Panel on Climate Change (IPCC) caused major changes in photosynthesis and respiration, in addition to decreased calcification rates in the coral Acropora millepora. Population density of symbiotic dinoflagellates (Symbiodinium) under high levels of ocean acidification and temperature (Representative Concentration Pathway, RCP8.5) decreased to half of that found under present day conditions, with photosynthetic and respiratory rates also being reduced by 40%. These physiological changes were accompanied by evidence for gene regulation of calcium and bicarbonate transporters along with components of the organic matrix. Metatranscriptomic RNA-Seq data analyses showed an overall down regulation of metabolic transcripts, and an increased abundance of transcripts involved in circadian clock control, controlling the damage of oxidative stress, calcium signaling/homeostasis, cytoskeletal interactions, transcription regulation, DNA repair, Wnt signaling and apoptosis/immunity/ toxins. We suggest that increased maintenance costs under ocean acidification and warming, and diversion of cellular ATP to pH homeostasis, oxidative stress response, UPR and DNA repair, along with metabolic suppression, may underpin why Acroporid species tend not to thrive under future environmental stress. Our study highlights the potential increased energy demand when the coral holobiont is exposed to high levels of ocean warming and acidification

Unfolding the secrets of coral - algal symbosis

Dinoflagellates from the genus Symbiodinium form a mutualistic symbiotic relationship with reef-building corals. Here we applied massively parallel Illumina sequencing to assess genetic similarity and diversity among four phylogenetically diverse dinoflagellate clades (A, B, C and D) that are commonly associated with corals. We obtained more than 30 000 predicted genes for each Symbiodinium clade, with a majority of the aligned transcripts corresponding to sequence data sets of symbiotic dinoflagellates and \u3c2% of sequences having bacterial or other foreign origin. We report 1053 genes, orthologous among four Symbiodiniumclades, that share a high level of sequence identity to known proteins from the SwissProt (SP) database. Approximately 80% of the transcripts aligning to the 1053 SP genes were unique to Symbiodinium species and did not align to other dinoflagellates and unrelated eukaryotic transcriptomes/genomes. Six pathways were common to all four Symbiodinium clades including the phosphatidylinositol signaling system and inositol phosphate metabolism pathways. The list of Symbiodiniumtranscripts common to all four clades included conserved genes such as heat shock proteins (Hsp70 and Hsp90), calmodulin, actin and tubulin, several ribosomal, photosynthetic and cytochrome genes and chloroplast-based heme-containing cytochrome P450, involved in the biosynthesis of xanthophylls. Antioxidant genes, which are important in stress responses, were also preserved, as were a number of calcium-dependent and calcium/calmodulin-dependent protein kinases that may play a role in the establishment of symbiosis. Our findings disclose new knowledge about the genetic uniqueness of symbiotic dinoflagellates and provide a list of homologous genes important for the foundation of coral–algal symbiosis

A proposed model of cellular events occurring in response to future Representative Concentration Pathway RCP8.5 scenario with increased temperature and high CO₂ conditions (for gene list see S3 Table).

<p>These changes lead to compromised health in <i>Acropora millepora</i> (reduction in symbiont cells, decreased photosynthesis and respiration and reduced calcification). The schematic depicts an endodermal cell which contains the <i>Symbiodinium</i> cell. Cellular events depicted here, especially acid base regulation at the cell membrane are also likely to occur in other cell types which do not contain symbiont cells. Exposure to increased temperature and seawater carbonate chemistry leads to changes in acid base regulation and ion transport at the cell membrane both in coral host and in the symbiont cell. Despite regulatory changes at the cell membrane cellular homeostasis may not be reached and acidosis may occur. The result may be an increase in reactive oxygen species due to a disruption (*) in the symbiont cell (S) and /or in the coral host mitochondrion (M), which may also produce reactive nitrogen species. In addition DNA damage may increase and not equal repair mechanisms in the cell nucleus (N) and / or M and S, which can lead to cell cycle arrest and /or cell death. Oxidative stress and endoplasmic reticulum (ER) stress, due to mis-folded protein accumulation and increased ubiquitin mediated proteolysis, may also lead to cell cycle arrest and eventually cell death, in addition to affecting cell calcium homeostasis/signaling, which in turn may lead to modifications in the extracellular matrix, cytoskeletal interactions and cell signaling. Oxidative stress can also affect immunity and /or cell death through the NF-κB pathway. In addition to the disruption in both S and M leading to suppression of metabolism, the coral circadian clock can also be influenced by oxidative stress and/or change in cell metabolism and in turn affect coral host metabolic pathways, which in this case is metabolic depression. Black arrows indicate up regulation and white arrows indicate down regulation.</p

KEGG pathway analysis.

<p>Gene enrichment analysis showing KEGG pathways involved in thermal and ocean acidification stress for <i>Acropora millepora</i> exposed to reduced emissions Representative Concentration Pathway (RCP4.5) and business as usual (RCP8.5) scenarios.</p

The effect of past and future changes in seawater temperature and pCO₂ (Pre Industrial, PI, Present Day, PD, Representative Concentration Pathway RCP4.5 and RCP8.5) conditions on coral-algal physiology.

<p>(A) <i>Symbiodinium</i> cell number (B) chlorophyll <i>a</i> levels per surface area (C) photosynthetic capacity per surface area measured as P_net max, light enhanced dark respiration(LEDR) and P_gross max (P_net max—LEDR) (D) photosynthetic capacity per symbiont cell measured as P_net max, light enhanced dark respiration(LEDR) and P_gross max (P_net max—LEDR) (E) dark respiration (R_dark) (F) relative calcification/growth as % change in weight (G) total lipid content and (H) total water soluble protein content. Error bars represent the standard error of the mean (n = 16). <i>Post hoc</i> differences are provided above the relevant data in letter symbols.</p

Gene enrichment analysis.

<p>Gene enrichment analysis (P<0.05) of biological processes for differentially expressed genes in <i>Acropora millepora</i> holobiont exposed to Pre Industrial (PI) vs Present Day (PD) conditions (A) Representative Concentration Pathway RCP4.5 vs PD conditions (B) and RCP8.5 vs PD conditions (C). The program DAVID was used to test for enriched GO categories among differentially expressed genes. Each pie segment is annotated for specific GO category and the sizes of the pie segments are proportional to the total number of genes enriched.</p

Summary of mean seawater temperature and pCO₂ concentration.

<p>Seawater parameters were determined for the 5 week experimental period along with carbonate parameters estimated for experimental treatments, where RCP stands for Representative Concentration Pathway. The five week mean represents the mean of all the parameters over the course of the experiment. Total alkalinity (AT) is a mean of 8 seawater replicate samples per treatment (n = 8) collected weekly both at noon and midnight. Measured parameters are presented with ± standard error of the mean. Output parameters were estimated using the program CO2SYS.</p