IMPORTANCEIn the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs. OBJECTIVE To assess the use and safety of outpatient management of acute appendicitis. DESIGN, SETTING, AND PARTICIPANTS This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25

ImportanceA patient’s belief in the likely success of a treatment may influence outcomes, but this has been understudied in surgical trials.ObjectiveTo examine the association between patients’ baseline beliefs about the likelihood of treatment success with outcomes of antibiotics for appendicitis in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial.Design, Setting, and ParticipantsThis was a secondary analysis of the CODA randomized clinical trial. Participants from 25 US medical centers were enrolled between May 3, 2016, and February 5, 2020. Included in the analysis were participants with appendicitis who were randomly assigned to receive antibiotics in the CODA trial. After informed consent but before randomization, participants who were assigned to receive antibiotics responded to a baseline survey including a question about how successful they believed antibiotics could be in treating their appendicitis.InterventionsParticipants were categorized based on baseline survey responses into 1 of 3 belief groups: unsuccessful/unsure, intermediate, and completely successful.Main Outcomes and MeasuresThree outcomes were assigned at 30 days: (1) appendectomy, (2) high decisional regret or dissatisfaction with treatment, and (3) persistent signs and symptoms (abdominal pain, tenderness, fever, or chills). Outcomes were compared across groups using adjusted risk differences (aRDs), with propensity score adjustment for sociodemographic and clinical factors.ResultsOf the 776 study participants who were assigned antibiotic treatment in CODA, a total of 425 (mean [SD] age, 38.5 [13.6] years; 277 male [65%]) completed the baseline belief survey before knowing their treatment assignment. Baseline beliefs were as follows: 22% of participants (92 of 415) had an unsuccessful/unsure response, 51% (212 of 415) had an intermediate response, and 27% (111 of 415) had a completely successful response. Compared with the unsuccessful/unsure group, those who believed antibiotics could be completely successful had a 13–percentage point lower risk of appendectomy (aRD, −13.49; 95% CI, −24.57 to −2.40). The aRD between those with intermediate vs unsuccessful/unsure beliefs was −5.68 (95% CI, −16.57 to 5.20). Compared with the unsuccessful/unsure group, those with intermediate beliefs had a lower risk of persistent signs and symptoms (aRD, −15.72; 95% CI, −29.71 to −1.72), with directionally similar results for the completely successful group (aRD, −15.14; 95% CI, −30.56 to 0.28).Conclusions and RelevancePositive patient beliefs about the likely success of antibiotics for appendicitis were associated with a lower risk of appendectomy and with resolution of signs and symptoms by 30 days. Pathways relating beliefs to outcomes and the potential modifiability of beliefs to improve outcomes merit further investigation.Trial RegistrationClinicalTrials.gov Identifier: NCT02800785

Survivors of sepsis exhibit persistent immunosuppression. Epigenetic events may be responsible for some of these immunosuppressive changes. During sepsis circulating exosomes contain large quantities of DNA methyltransferase (DNMT) mRNAs. We hypothesized that exosomes directly transfer DNMTmRNAs to recipient monocytes with resultant methylation events and immunosuppression. Methods: Exosomes containing DNMT mRNA were generated by stimulating monocytes with LPS. Confocal microscopy was used to determine uptake kinetics in the presence of pharmacologic inhibition. Expression and packaging of specific DNMT mRNA was controlled using DNMT siRNAs. Whole genome and gene specific methylation was assessed using bisulfite sequencing. Ingenuity pathway analysis was performed to determine the biological function of significance of differentially methylated regions. Results: Exosomes effectively transferred DNMT mRNA to recipient monocytes. Pharmacologic inhibition of exosome uptake prevented this increase in DNMT mRNA expression. Recipient monocytes exhibited hypermethylation changes and gene suppression. siRNAs decreased the packaging of DNMT mRNAs and prevented TNFa gene suppression, restoring immunocompetence. Conclusion: These data support a role for exosome-mediated transfer of DNMT mRNA with resultant methylation and gene silencing. Pharmacologic uptake inhibition or targeted siRNA mediated DNMT gene silencing prevented DNMT mRNA transfer and maintained the cell's ability to express TNFa in response to LPS. This highlights the potential therapeutic value of targeting these exosome-mediated epigenetic events to maintain the host immune response during sepsis.

The field of pharmacogenomics aims to incorporate individual patient genomic information into treatment selection. This is a rapidly evolving field with significant clinical promise. Implementation into clinical practice has several challenges that must be overcome. Genomics-based information encompasses large databases and requires expert knowledge for interpretation. Existing research suggests there are already several areas where pharmacogenomics-based decision-making is ripe for adoption into clinical practice. Impediments exist that must be overcome prior to large-scale implementation of existing pharmacogenomics-based therapies. There are several institutions and corporations at the forefront of implementation that are leading the development; however, larger systems-based approaches will be necessary. This article will discuss some of the present successes and future challenges that are necessary to overcome in order to implement a more patient-centered healthcare system.

Background As more patients with appendicitis are treated with antibiotics, factors associated with recurrence may help inform individualized prognostication and decision-making. Methods This cohort study, using data from the Comparison of Outcomes of Antibiotic Drugs and Appendectomy trial, examined patients treated with antibiotics who did not undergo appendicectomy in the first 30 days. Patients who had appendicectomy between 30 days and 1 year were compared with those who did not. Marginalized logistic regression models were used to calculate adjusted risk differences (RDs) to estimate the association between baseline patient factors and the risk of undergoing an appendicectomy between 30 days and 1 year. Results Of 601 patients treated with antibiotics who did not undergo appendicectomy within 30 days (mean age 38.0 years; 217 women (36.1 per cent)), 144 had an appendicectomy and 56 were lost to follow-up between 30 days and 1 year. The estimated rate of appendicectomy between 30 days and 1 year was 28.6 (95 per cent c.i. 25.0 to 32.8) per cent. After adjustment for other factors, nausea, vomiting, or anorexia at baseline presentation was associated with an increased rate of appendicectomy between 30 days and 1 year (adjusted RD 17.52, 95 per cent c.i. 8.64 to 26.40). The presence of an appendicolith (adjusted RD 3.64, −6.08 to 13.36), or an abscess, perforation, or fat stranding on initial imaging (adjusted RD −7.23, −17.41 to 2.95) was not strongly associated with appendicectomy between 30 days and 1 year. Conclusion Most factors commonly associated with appendicitis severity were not strongly associated with an increased risk of undergoing appendicectomy in the longer term after treatment with antibiotics.