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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Intestinal calcium and bile salts facilitate germination of <i>Clostridium difficile</i> spores

<div><p><i>Clostridium difficile</i> (<i>C</i>. <i>difficile</i>) is an anaerobic gram-positive pathogen that is the leading cause of nosocomial bacterial infection globally. <i>C</i>. <i>difficile</i> infection (CDI) typically occurs after ingestion of infectious spores by a patient that has been treated with broad-spectrum antibiotics. While CDI is a toxin-mediated disease, transmission and pathogenesis are dependent on the ability to produce viable spores. These spores must become metabolically active (germinate) in order to cause disease. <i>C</i>. <i>difficile</i> spore germination occurs when spores encounter bile salts and other co-germinants within the small intestine, however, the germination signaling cascade is unclear. Here we describe a signaling role for Ca²⁺ during <i>C</i>. <i>difficile</i> spore germination and provide direct evidence that intestinal Ca²⁺ coordinates with bile salts to stimulate germination. Endogenous Ca²⁺ (released from within the spore) and a putative AAA+ ATPase, encoded by <i>Cd630_32980</i>, are both essential for taurocholate-glycine induced germination in the absence of exogenous Ca²⁺. However, environmental Ca²⁺ replaces glycine as a co-germinant and circumvents the need for endogenous Ca²⁺ fluxes. <i>Cd630_32980</i> is dispensable for colonization in a murine model of <i>C</i>. <i>difficile</i> infection and <i>ex vivo</i> germination in mouse ileal contents. Calcium-depletion of the ileal contents prevented mutant spore germination and reduced WT spore germination by 90%, indicating that Ca²⁺ present within the gastrointestinal tract plays a critical role in <i>C</i>. <i>difficile</i> germination, colonization, and pathogenesis. These data provide a biological mechanism that may explain why individuals with inefficient intestinal calcium absorption (<i>e</i>.<i>g</i>., vitamin D deficiency, proton pump inhibitor use) are more prone to CDI and suggest that modulating free intestinal calcium is a potential strategy to curb the incidence of CDI.</p></div

Proposed model for the role of calcium in <i>C</i>. <i>difficile</i> germination.

<p>Tc binds to CspC (A) facilitating movement of glycine or calcium through the spore coat and outer membrane (B). Glycine then interacts with an unknown receptor (C) inducing the release of Ca²⁺ from the spore core (D). Ca²⁺ from the environment or the spore core activates CspB (E), which processes pro-SleC (F) subsequently initiating cortex hydrolysis (G). This leads to full core rehydration (H), complete release of DPA (I) and spore outgrowth.</p

Exogenous calcium induces <i>C</i>. <i>difficile</i> germination in concert with taurocholate.

<p>Cd630, VPI 10463, or R20291 spores were incubated with the indicated combinations of 0.2% Tc, 60 mM Ca-DPA, 50 mM glycine, 60 mM CaCl₂, or 60 mM DPA (A-G, I, J). Activation of SleC was assessed by western blot analyses. Cd630 spores were incubated for 15 minutes at 37°C with the indicated combinations of 1% Tc, 50 mM glycine, 60 mM CaCl₂, 60 mM DPA, or 60 mM Ca-DPA. Spores were subsequently lysed and assayed for levels of pro-SleC and SleC (K). <i>Bacillus anthracis</i> strain Sterne 34F₂ spores were incubated with the indicated combinations of either 60 mM CaCl₂, 60 mM DPA, or 60 mM CaDPA (H). Germination was measured either by tracking the loss of OD₆₀₀ over time (A-H), measuring loss of heat resistance at 37°C after 1 hour (I), or measuring release of DPA at 37°C after 1 hour (J). Germination assays were performed in triplicate. Germination assays and western blots are representative of three independent spore preps. Error bars are mean plus or minus SD. Statistical analysis was performed using one-way ANOVA. (****) p<0.0001.</p