Evaluation of an Opt-Out Protocol for Antibiotic De-Escalation in Patients With Suspected Sepsis: A Multicenter, Randomized, Controlled Trial.

BACKGROUND: Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. METHODS: We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. RESULTS: Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. CONCLUSIONS: An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. CLINICAL TRIALS REGISTRATION: NCT03517007.

Parallel publication of articles and congress presentations for industry-sponsored research: strategies for success.

Recent increases in the practice of parallel publication, during which a peer-reviewed manuscript is published concurrently with the first dissemination of the same key data at a medical congress as a late-breaking abstract, have highlighted substantial value for this method of publication. Parallel publication can increase access to new clinical information for healthcare providers and patients, as well as promote engagement and reach of the publication and presentation. As the practice becomes more common, there is a need for strategies to address the multiple challenges involved in the development process, such as shortened timelines, journal and congress policies, and stakeholder alignment. We surveyed journals, congresses, and publication professionals on the challenges of parallel publication and recommendations for success. Recommendations from journal editors and congress officials included the importance of adhering to timelines and early communication. Insights from a community of publication professionals showed that timelines and the author review process were among the key challenges of parallel publication development and stressed the importance of clear roles and expectations for authors. To provide real-world insights, we present 3 case studies of successful parallel publication development, highlighting the crucial role of journal selection, planning around data availability, and adapting to unpredictable circumstances. The recommendations described here may provide publication professionals with strategies to successfully plan, execute, and carry out parallel publication.

Assessment of hepatitis C risk factors and infection prevalence in a jail population.

OBJECTIVES: We sought to validate previous reports of HCV prevalence in jails, identify HCV risk factors prevalence, and identify risk factors associated with HCV infection in this population. METHODS: Inmates at the Buzz Westfall Justice Center (BWJC) in St. Louis, Missouri, were offered risk factor screening for HCV and anti-HCV antibody testing from December 2012 through May 2013. Demographic and risk factor information were assessed for significant associations with positive HCV antibody results. Risk factors that were significantly associated in univariate analysis were assessed using binary logistic regression to model the relationship between positive HCV results and the risk factors and demographics. RESULTS: Fifty of 304 inmates were positive for HCV, with a prevalence of 16.4%. The risk factors significantly associated with increased risk for positive HCV antibody were age (odds ratio [OR] = 1.09; 95% confidence interval [CI] = 1.04, 1.15 for each year), injection drug use (OR = 53.87; 95% CI = 17.78, 163.21), sex with HCV-positive partner (OR = 7.35; 95% CI = 1.41, 38.20), and tattoos by a nonlicensed provider (OR = 2.62; 95% CI = 1.09, 6.33). Prevalence for women was 3 times that of men (38% vs 12%). CONCLUSIONS: Prevalence of HCV at BWJC was similar to previous jail studies, which is lower than reported prison rates and higher than the general population.

Anti-DFS70/LEDGF antibodies are more prevalent in healthy individuals compared to patients with systemic autoimmune rheumatic diseases.

OBJECTIVE: Antinuclear antibodies (ANA) are a serological hallmark of systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE). While a number of ANA patterns detected by indirect immunofluorescence (IIF) have diagnostic significance, autoantibodies producing the dense fine speckled (DFS) pattern have been reported to be more prevalent in healthy individuals than in SARD. METHODS: Sequential samples submitted for ANA testing were screened for anti-DFS antibodies by IIF (n = 3263). Samples with the DFS pattern were tested for anti-DFS70/lens epithelium-derived growth factor (LEDGF) antibodies by ELISA and by a novel chemiluminescence assay (CIA, Quanta Flash DFS70). Sera from patients with various diseases and healthy individuals were tested for anti-DFS70/LEDGF antibodies by CIA. A cohort of 251 patients with SLE was used to analyze serological and clinical associations of anti-DFS70 antibodies. RESULTS: The frequency of anti-DFS antibodies by IIF was 1.62%. The prevalence of anti-DFS70/LEDGF antibodies as detected by CIA in the different cohorts was 8.9% in healthy individuals, 2.8% in SLE, 2.6% in rheumatoid arthritis, 4.0% in asthma, 5.0% in interstitial cystitis, 1.7% in Graves' disease, and 6.0% in Hashimoto's thyroiditis. Of note, the prevalence of anti-DFS70/LEDGF antibodies was significantly higher in healthy individuals compared to patients with SARD (p = 0.00085). In SLE results, anti-DFS70/LEDGF antibodies were not significantly associated with clinical features or other autoantibodies typically found in SLE. Only 1/7 SLE sera showed anti-DFS70/LEDGF, but no other autoantibody reactivity. CONCLUSION: "Monospecific" anti-DFS70/LEDGF antibodies may represent a biomarker for differentiating SARD from non-SARD individuals, but there is a need for a reliable assay to ensure reactivity to DFS70.

Interleukin-6 expression in response to innate immune regulatory factor stimulation.

Innate immune regulatory factor (IIRF) is a serum-derived biological response modifier, or agent that modifies/bolsters the pathogenic immune response. IIRF has been shown to provide protection (e.g., increase host survival) against a variety of pathogenic challenges including Salmonella typhimurium and Pasteurella multocida. In this report, we analyzed cytokine production in mice, whole blood and cultured cells in response to IIRF challenge. When IIRF was administered to mice, it stimulated the release of pro-inflammatory cytokines. Both IL-6 and IL-10 were temporally stimulated when IIRF was introduced. Serum IL-6 peaked at 3h (3957pg/ml) before returning to baseline by 8h, while IL-10 began to appear at 3h, peaked at 8h (734.5pg/ml), and returned to baseline by 36h. IIRF challenge also increased the expression of two positive acute phase proteins: haptoglobin increased 61-fold, while serum amyloid A levels increased ∼3500-fold in mice. A whole blood immunoassay indicated the effect of IIRF on production of IL-6 was dose- and time-dependent. Anti-asialo GM 1.1 provided to partially (>95%) eliminate functional natural killer cells elevated IL-6 in whole blood. IIRF was also able to induce the production of IL-6 in cultured human monocytic THP-1 cells. Based upon this study and previously reported data, we propose that IIRF activates the innate immune response via induction of IL-6 production.

The roles of translation initiation regulation in ultraviolet light-induced apoptosis.

Ultraviolet light (UV) inhibits translation initiation through activation of kinases that phosphorylate the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha). Two eIF2alpha kinases, PERK and GCN2, are known to phosphorylate the Serine-51 of eIF2alpha in response to UV-irradiation. In this report, we present evidence that phosphorylation of eIF2alpha plays a role in UV-induced apoptosis. Our data show that wild-type mouse embryo fibroblasts (MEF(s/s)) are less sensitive to UV-induced apoptosis than MEF(A/A) cells in which the phosphorylation site, Ser51, of eIF2alpha is replaced with a non-phosphorylatable Ala (Ser51Ala). PARP expression in MEF(A/A) cells is reduced without being cleaved after UV-irradiation. In contrast, PARP is cleaved without a significant decrease in parental PARP in MEF(S/S) cells after UV-irradiation. Our data also show that MEF(GCN2-/-) cells, in which GCN2 is knocked out, are more sensitive to UV-irradiation, agreeing with the observation from MEF(A/A) cells. However, MEF(PERK-/-) cells, in which PERK is knocked out, are less sensitive to UV-irradiation. In addition, MCF-7-PERKDeltaC cells, which are stably transfected with a kinase domain deleted mutant of PERK (PERKDeltaC), are more resistant to UV-induced apoptosis than parental MCF-7 cells. Overexpression of wild-type PERK sensitizes MCF-7 cells to UV-induced apoptosis without directly inducing cell death. These results suggest that the level of eIF2alpha phosphorylation impacts PARP expression upon UV-irradiation. The eIF2alpha kinases may mediate UV-induced apoptosis via an eIF2alpha dependent or independent signaling pathway.

Reducing mortality in Salmonella enterica serovar Typhimurium-infected mice with a tripeptidic serum fraction.

Salmonellosis-induced mortality in female Swiss Webster mice decreased significantly when tripeptidic immunostimulant (TPI) was administered prophylactically. Prophylactic benefits developed in a dose-dependent manner wherein 15 mg of TPI given 1 day before challenge reduced mortality by 70%.