Semi-supervised mixture multi-source exchangeability model for leveraging real-world data in clinical trials.

The traditional trial paradigm is often criticized as being slow, inefficient, and costly. Statistical approaches that leverage external trial data have emerged to make trials more efficient by augmenting the sample size. However, these approaches assume that external data are from previously conducted trials, leaving a rich source of untapped real-world data (RWD) that cannot yet be effectively leveraged. We propose a semi-supervised mixture (SS-MIX) multisource exchangeability model (MEM); a flexible, two-step Bayesian approach for incorporating RWD into randomized controlled trial analyses. The first step is a SS-MIX model on a modified propensity score and the second step is a MEM. The first step targets a representative subgroup of individuals from the trial population and the second step avoids borrowing when there are substantial differences in outcomes among the trial sample and the representative observational sample. When comparing the proposed approach to competing borrowing approaches in a simulation study, we find that our approach borrows efficiently when the trial and RWD are consistent, while mitigating bias when the trial and external data differ on either measured or unmeasured covariates. We illustrate the proposed approach with an application to a randomized controlled trial investigating intravenous hyperimmune immunoglobulin in hospitalized patients with influenza, while leveraging data from an external observational study to supplement a subgroup analysis by influenza subtype.

Salmonella aortitis treated with endovascular aortic repair.

Salmonella aortitis is a known complication of Salmonella infection that usually requires surgical therapy. It is unknown whether endovascular aortic repair (EVAR) is an acceptable alternative to conventional aortic surgery for patients with Salmonella aortitis who are at high risk for perioperative complications. We therefore report 2 cases of Salmonella aortitis treated with EVAR and review the literature to further characterize previously published cases.

Impact of Povidone Application to Nares in Addition to Chlorhexidine Bath in Critically Ill Patients on Nosocomial Bacteremia and Central Line Blood Stream Infection.

Nosocomial Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in a significant increase in morbidity and mortality in hospitalized patients. We aimed to analyze the impact of applying 10% povidone iodine (PI) twice daily to both nares in addition to chlorhexidine (CHG) bathing on nosocomial (MRSA) bacteremia in critically ill patients. A quality improvement study was completed with pre and post-design. The study period was from January 2018 until February 2020 and February 2021 and June 2021. The control period (from January 2018 to May 2019) consisted of CHG bathing alone, and in the intervention period, we added 10% PI to the nares of critically ill patients. Our primary outcome is rates of nosocomial MRSA bacteremia, and our secondary outcome is central line associated blood stream infection (CLABSI) and potential cost savings. There were no significant differences in rates of MRSA bacteremia in critically ill patients. Nosocomial MRSA bacteremia was significantly lower during the intervention period on medical/surgical areas (MSA). CLABSIs were significantly lower during the intervention period in critically ill patients. There were no Staphylococcus aureus CLABSIs in critical care area (CCA)during the intervention period. The intervention showed potential significant cost savings. The application of 10% povidone iodine twice a day in addition to CHG bathing resulted in a significant decrease in CLABSIs in critically ill patients and a reduction in nosocomial MRSA in the non-intervention areas. Further trials are needed to tease out individual patients who will benefit from the intervention.

Encephalitis associated with a monoclonal protein band present in blood, urine and cerebrospinal fluid.

Introduction: Monoclonal protein bands are present mainly in blood and secondary in urine representing specific antibody produced in excess by abnormal lymphocytes or plasma cells.We describe a case of a patient with acute encephalitis associated with an unexpected finding of a monoclonal protein band present in blood, urine and in cerebrospinal fluid (CSF). Case presentation: This 50-year-old woman with no significant past medical history, with the exception of unintentional weight loss exceeding 5 kg over the last 3 months, presented to the emergency department with seizures and altered mental status, after 3 days of vomiting and headaches. Magnetic Resonance Imaging showed lesions suspicious for infectious encephalitis/meningitis and for ischemia possibly related to central nervous system (CNS) autoimmune vasculopathy/vasculitis. The patient died the following day after losing brainstem reflexes. Testing for the previously mentioned etiologies returned negative with the exception of high protein concentration and increased immunoglobulin gamma (IgG) concentration in the CSF. Protein electrophoresis, ordered in error, showed a well-defined IgG with lambda light chain monoclonal protein band running in similar positions in serum, urine and in CSF. Due to SARS-CoV-2 PCR positivity no autopsy was performed. Conclusion: The presence of this monoclonal protein band produced in the CNS suggests the diagnosis of CNS myeloma. The accelerated course in this case could be the result of the CNS myeloma or lymphoma responding to SARS-CoV-2 infection. Testing for monoclonal protein bands in CSF, in patients with pertinent clinical presentation would boost the awareness of this these diseases improving patient care.

Evaluating the Effectiveness of Hospital Antiseptics on Multidrug-Resistant Acinetobacter baumannii: Understanding the Relationship between Microbicide and Antibiotic Resistance.

Acinetobacter baumannii hospital infections are difficult to treat due to the rapid emergence of multidrug-resistant (MDR) strains. In addition, A. baumannii can survive in numerous adverse environments, including in the presence of common hospital antiseptics. We hypothesized that in addition to accumulating drug resistance determinants, MDR A. baumannii strains also accumulate mutations that allow for greater microbicide tolerance when compared to pan-susceptible (PS) strains. To test this hypothesis, we compared the survival of five MDR and five PS patient isolates when exposed to bleach, ethanol, quaternary ammonium compounds, chlorhexidine gluconate, and povidone. We evaluated bacteria in a free-living planktonic state and under biofilm conditions. Each disinfectant eliminated 99.9% of planktonic bacteria, but this was not the case for bacterial biofilms. Next, we characterized strains for the presence of the known microbicide-resistance genes cepA, qacEΔ1, qacE, and qacA. MDR strains did not survive more than PS strains in the presence of microbicides, but microbicide-resistant strains had higher survival rates under some conditions. Interestingly, the PS strains were more likely to possess microbicide-resistance genes. Microbicide resistance remains an important topic in healthcare and may be independent of antimicrobial resistance. Hospitals should consider stricter isolation precautions that take pan-susceptible strains into account.

Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study.

BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) mediated tryptophan (TRP) depletion has antimicrobial and immuno-regulatory effects. Increased kynurenine (KYN)-to-TRP (KT) ratios, reflecting increased IDO activity, have been associated with poorer outcomes from several infections. METHODS: We performed a case-control (1:2; age and sex matched) analysis of adults hospitalized with influenza A(H1N1)pdm09 with protocol-defined disease progression (died/transferred to ICU/mechanical ventilation) after enrollment (cases) or survived without progression (controls) over 60 days of follow-up. Conditional logistic regression was used to analyze the relationship between baseline KT ratio and other metabolites and disease progression. RESULTS: We included 32 cases and 64 controls with a median age of 52 years; 41% were female, and the median durations of influenza symptoms prior to hospitalization were 8 and 6 days for cases and controls, respectively (P = .04). Median baseline KT ratios were 2-fold higher in cases (0.24 mM/M; IQR, 0.13-0.40) than controls (0.12; IQR, 0.09-0.17; P ≤ .001). When divided into tertiles, 59% of cases vs 20% of controls had KT ratios in the highest tertile (0.21-0.84 mM/M). When adjusted for symptom duration, the odds ratio for disease progression for those in the highest vs lowest tertiles of KT ratio was 9.94 (95% CI, 2.25-43.90). CONCLUSIONS: High KT ratio was associated with poor outcome in adults hospitalized with influenza A(H1N1)pdm09. The clinical utility of this biomarker in this setting merits further exploration. CLINICALTRIALSGOV IDENTIFIER: NCT01056185.

Candida albicans Sacral Osteomyelitis Causing Necrosis of a Sacral Nerve Root: A Case Report.

CASE: A 31-year-old immunocompetent woman presented with a large sacral mass on the left side, concerning for a neoplastic process. A biopsy specimen demonstrated fungal osteomyelitis. Intraoperatively, the left S1 sacral nerve root was found to be necrotic, consistent with the symptoms of numbness and weakness. The infection was resolved with aggressive surgical debridement and long-term therapy with antifungal medication. CONCLUSION: Fungal osteomyelitis of the sacrum is rare, especially in an immunocompetent patient, and untreated infections can cause nerve root necrosis. We recommend aggressive surgical and antifungal management to avoid neurologic compromise.

Resistant gram-negative infections.

This article reviews the global crisis of resistant gram-negative bacilli in the intensive care unit. The authors discuss drugs used for treating these infections and the different strategies used to maximize the effect of antimicrobials.

Targeting the lipopolysaccharides: still a matter of debate?

PURPOSE OF REVIEW: The intention of this article is to review endotoxin, host response to endotoxin, clinical significance of endotoxemia, past failed therapies targeting endotoxin, current therapeutic efforts in this area and the authors' opinion on the future of such therapy. RECENT FINDINGS: Endotoxin or lipopolysaccharide is implicated in the activation of cytokine release with the potential to lead to severe sepsis. Therapies targeting endotoxin are very appealing and remain a matter of study and debate. Antiendotoxin antibody studies did not show consistent benefit to warrant its approval for use. Lipid A analog, phospholipid emulsion, and ethyl pyruvate are currently being evaluated for potential clinical use. Polymyxin B as an antiendotoxin strategy has an unacceptable toxicity profile for routine use as an intravenous agent and its use in plasmapheris is too cumbersome. Curcumin and lipopolysaccharide binding peptides, although having a potentially desirable effect on ameliorating endotoxin toxicity, remain to be shown effective in clinical trials. The development of a vaccine against endotoxin carries promise. SUMMARY: The benefits of therapies targeting endotoxin remain to be elucidated. Clinical trials targeting populations with documented endotoxemia are more likely to provide an adequate test of this therapeutic approach. Prophylaxis of high-risk populations should also be considered.