Reimagining How We Synthesize Information to Impact Clinical Care, Policy, and Research Priorities in Real Time: Examples and Lessons Learned from COVID-19.

Real-time clinical care, policy, and research decisions need real-time evidence synthesis. However, as we found during the COVID-19 pandemic, it is challenging to rapidly address key clinical and policy questions through rigorous, relevant, and usable evidence. Our objective is to present three exemplar cases of rapid evidence synthesis products from the Veterans Healthcare Administration Evidence Synthesis Program (ESP) and, in the context of these examples, outline ESP products, challenges, and lessons learned. We faced challenges in (1) balancing scientific rigor with the speed in which evidence synthesis was needed, (2) sorting through rapidly evolving large bodies of evidence, and (3) assessing the impact of evidence synthesis products on clinical care, policy, and research. We found solutions in (1) engaging stakeholders early, (2) utilizing artificial intelligence capabilities, (3) building infrastructure to establish living reviews, and (4) planning for dissemination to maximize impact.

Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is approved for the treatment of adults hospitalized with COVID-19. PURPOSE: To update a living review of remdesivir for adults with COVID-19. DATA SOURCES: Several electronic U.S. Food and Drug Administration, company, and journal websites from 1 January 2020 through 19 October 2021. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. DATA EXTRACTION: One reviewer abstracted, and a second reviewer verified data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: Since the last update (search date 9 August 2021), 1 new RCT and 1 new subtrial comparing a 10-day course of remdesivir with control (placebo or standard care) were identified. This review summarizes and updates the evidence on the cumulative 5 RCTs and 2 subtrials for this comparison. Our updated results confirm a 10-day course of remdesivir, compared with control, probably results in little to no mortality reduction (5 RCTs). Updated results also confirm that remdesivir probably results in a moderate increase in the proportion of patients recovered by day 29 (4 RCTs) and may reduce time to clinical improvement (2 RCTs) and hospital length of stay (4 RCTs). New RCTs, by increasing the strength of evidence, lead to an updated conclusion that remdesivir probably results in a small reduction in the proportion of patients receiving ventilation or extracorporeal membrane oxygenation at specific follow-up times (4 RCTs). New RCTs also alter the conclusions for harms-remdesivir, compared with control, may lead to a small reduction in serious adverse events but may lead to a small increase in any adverse event. LIMITATION: The RCTs differed in definitions of COVID-19 severity and outcomes reported. CONCLUSION: In hospitalized adults with COVID-19, the findings confirm that remdesivir probably results in little to no difference in mortality and increases the proportion of patients recovered. Remdesivir may reduce time to clinical improvement and may lead to small reductions in serious adverse events but may result in a small increase in any adverse event. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19). PURPOSE: To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control. DATA SOURCES: Several sources from 1 January 2020 through 7 December 2020. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods. DATA EXTRACTION: 1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved. LIMITATION: Summarizing findings was challenging because of varying disease severity definitions and outcomes. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Remdesivir for Adults With COVID-19 : A Living Systematic Review for American College of Physicians Practice Points.

BACKGROUND: Few treatments exist for coronavirus disease 2019 (COVID-19). PURPOSE: To evaluate the effectiveness and harms of remdesivir for COVID-19. DATA SOURCES: Several databases, tables of contents of journals, and U.S. Food and Drug Administration and company websites were searched from 1 January through 31 August 2020. STUDY SELECTION: English-language, randomized trials of remdesivir treatments for adults with suspected or confirmed COVID-19. New evidence will be incorporated using living review methods. DATA EXTRACTION: Single-reviewer abstraction and risk-of-bias assessment verified by a second reviewer; GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods used for certainty-of-evidence assessments. DATA SYNTHESIS: Four randomized trials were included. In adults with severe COVID-19, remdesivir compared with placebo probably improves recovery by a large amount (absolute risk difference [ARD] range, 7% to 10%) and may result in a small reduction in mortality (ARD range, -4% to 1%) and a shorter time to recovery or clinical improvement. Remdesivir may have little to no effect on hospital length of stay. Remdesivir probably reduces serious adverse events by a moderate amount (ARD range, -6% to -8%). Compared with a 10-day remdesivir course, a 5-day course may reduce mortality, increase recovery or clinical improvement by small to moderate amounts, reduce time to recovery, and reduce serious adverse events among hospitalized patients not requiring mechanical ventilation. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity. LIMITATIONS: Low-certainty evidence with few published trials, including 1 preliminary report and 2 open-label trials. Trials excluded pregnant women and adults with severe kidney or liver disease. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement. For adults not receiving mechanical ventilation or extracorporeal membrane oxygenation, a 5-day course of remdesivir may provide similar benefits to and fewer harms than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development Service, and Evidence Synthesis Program.

Risk prediction models for diabetic foot ulcer development or amputation: a review of reviews.

BACKGROUND: In adults with diabetes, diabetic foot ulcer (DFU) and amputation are common and associated with significant morbidity and mortality. PURPOSE: Identify tools predicting risk of DFU or amputation that are prognostically accurate and clinically feasible. METHODS: We searched for systematic reviews (SRs) of tools predicting DFU or amputation published in multiple databases from initiation to January, 2023. We assessed risk of bias (ROB) and provided a narrative review of reviews describing performance characteristics (calibration and discrimination) of prognostically accurate tools. For such tools, we additionally reviewed original studies to ascertain clinical applicability and usability (variables included, score calculation, and risk categorization). RESULTS: We identified 3 eligible SRs predicting DFU or amputation risk. Two recent SRs (2020 and 2021) were rated as moderate and low ROB respectively. Four risk prediction models - Boyko, Martins-Mendes (simplified), Martins-Mendes (original), and PODUS 2020 had good prognostic accuracy for predicting DFU or amputation over time horizons ranging from 1- to 5-years. PODUS 2020 predicts absolute average risk (e.g., 6% risk of DFU at 2 years) and consists of 3-binary variables with a simple, summative scoring (0-4) making it feasible for clinic use. The other 3 models categorize risk subjectively (e.g., high-risk for DFU at 3 years), include 2-7 variables, and require a calculation device. No data exist to inform rescreening intervals. Furthermore, the effectiveness of targeted interventions in decreasing incidence of DFU or amputation in response to prediction scores is unknown. CONCLUSIONS: In this review of reviews, we identified 4 prognostically accurate models that predict DFU or amputation in persons with diabetes. The PODUS 2020 model, predicting absolute average DFU risk at 2 years, has the most favorable prognostic accuracy and is clinically feasible. Rescreening intervals and effectiveness of intervention based on prediction score are uncertain.

Pneumococcal pyomyositis: report of 2 cases and review of the literature.

Streptococcus pneumoniae is an uncommon cause of pyomyositis. It is unclear whether the clinical presentation and outcome of pneumococcal pyomyositis differ depending on the host's underlying immune status. We describe 2 patients with pneumococcal pyomyositis, review all published cases, and compare characteristics between apparently healthy hosts and at-risk hosts. A total of 35 cases of pneumococcal pyomyositis were identified, 11 in apparently healthy hosts and 24 in at-risk hosts. Two-thirds of the patients had an antecedent respiratory illness or meningitis. At-risk hosts tended to have a longer interval between the development of symptomatic muscle infection and the diagnosis of pyomyositis and a significantly higher risk of disseminated disease at presentation, as manifested by involvement of multiple noncontiguous muscles or presence of meningitis. Overall, other than 1 death, all patients recovered with antibiotics and surgical drainage, but as might be expected there was a significantly higher rate of complications among at-risk hosts.

Aspergillus Osteomyelitis Secondary to Chronic Necrotizing Pulmonary Aspergillosis in a Patient With Rheumatoid Arthritis.

Aspergillus spp. are ubiquitous molds that cause a wide range of clinical syndromes depending on the immune status of the host. Herein, we present a case of a patient with rheumatoid arthritis on long-term immunosuppressive medications, with a persistent dry cough and left-sided chest pain for over a year, who presented with acute sternal drainage. Computed tomography of the chest showed chronic pulmonary abnormalities, parasternal fluid, and bone destruction of the distal sternum and left sixth rib. The patient underwent debridement; sternal biopsy tissue showed septate hyphae with acute-angled branching, and Aspergillus fumigatus grew in culture. We suspected that the patient developed chronic necrotizing pulmonary aspergillosis (CNPA) that traversed tissue planes and caused chest wall osteomyelitis. The patient received voriconazole and surgical debridement, with clinical and radiological improvement. This case demonstrates the importance of considering CNPA as a diagnosis in patients with moderate degrees of immunosuppression and chronic respiratory symptoms, and Aspergillus spp. as an etiology of osteomyelitis in such patients.

Diagnosis and Management of Osteomyelitis Associated With Stage 4 Pressure Ulcers: Report of a Query to the Emerging Infections Network of the Infectious Diseases Society of America.

BACKGROUND: Few studies exist to guide the management of patients with stage 4 pressure ulcers with possible underlying osteomyelitis. We hypothesized that infectious disease (ID) physicians would vary widely in their approach to such patients. METHODS: The Emerging Infections Network distributed a 10-question electronic survey in 2018 to 1332 adult ID physicians in different practice settings to determine their approach to such patients. RESULTS: Of the 558 respondents (response rate: 42%), 17% had managed no such patient in the past year. Of the remaining 464 respondents, 60% usually felt confident in diagnosing osteomyelitis; the strongest clinical indicator of osteomyelitis reported was palpable or visible bone at the ulcer base. Approaches to diagnosing osteomyelitis in patients with visible and palpable bone varied: 41% of respondents would assume osteomyelitis, 27% would attempt pressure off-loading first, and 22% would perform diagnostic testing immediately. Preferred tests for osteomyelitis were bone biopsy (for culture and histopathology) and magnetic resonance imaging. Respondents differed widely on favored route(s) (intravenous, oral, or both) and duration of antimicrobial therapy but would treat longer in the absence, vs presence, of full surgical debridement (P < .001). Overall, 62% of respondents opined that osteomyelitis under stage 4 pressure ulcers is usually or almost always treated excessively, and most (59%) suggested multiple topics for future research. CONCLUSIONS: Regarding osteomyelitis underlying stage 4 pressure ulcers, ID physicians reported widely divergent diagnostic and treatment approaches. Most of the reported practice is not supported by the available evidence, which is quite limited and of low quality.

The association between pneumococcal pneumonia and acute cardiac events.

BACKGROUND: Increased cardiac stress, hypoxemia, and inflammation may contribute to acute cardiac events, such as myocardial infarction (MI), arrhythmia, and/or congestive heart failure (CHF). We sought to determine the incidence of such events in patients who were hospitalized for community-acquired pneumococcal pneumonia. METHODS: We studied the medical records of all patients who were admitted for pneumococcal pneumonia during a 5-year period (2001-2005) to identify those who had MI, atrial fibrillation or ventricular tachycardia, or new-onset or worsening CHF at the time of hospital admission. RESULTS: Of 170 patients, 33 (19.4%) had > or =1 of these major cardiac events. Twelve had MI, of whom 2 also had arrhythmia and 5 had new-onset or worsening CHF. Eight had new-onset atrial fibrillation or ventricular tachycardia; 6 of these also had new CHF. Thirteen had newly diagnosed or worsening CHF, without MI or new arrhythmias. Hypoxemia and anemia were prominent. Importantly, patients with concurrent pneumococcal pneumonia and cardiac events had a significantly higher mortality than those with pneumococcal pneumonia alone (P<.008). The coexistence of pulmonary and cardiac disease was often overlooked by admitting physicians who, seeking a unifying diagnosis, emphasized one diagnosis to the exclusion of the other. CONCLUSIONS: Patients with pneumococcal pneumonia are at substantial risk for a concurrent acute cardiac event, such as MI, serious arrhythmia, or new or worsening CHF. This concurrence significantly increases mortality due to pneumonia. Admitting physicians tend to seek a unifying diagnosis, but the frequent coexistence of pneumonia and cardiac events indicates the importance of considering multiple diagnoses.

Comparison of Side Effects of the 2015-2016 High-Dose, Inactivated, Trivalent Influenza Vaccine and Standard Dose, Inactivated, Trivalent Influenza Vaccine in Adults ≥65 Years.

BACKGROUND: High-dose, inactivated, trivalent influenza vaccine (HD) is associated with higher rates of side effects than standard dose (SD) vaccine, which may represent a barrier to use. METHODS: We surveyed subjects ≥65 years who received either HD or SD vaccine at the Minneapolis Veteran Affairs Health Care System clinics on October 27, 28, or 29, 2015. Research assistants conducted a 17-item telephone survey of influenza vaccine recipients to inquire about self-reported health and symptoms experienced the week after vaccination. RESULTS: A total of 547 HD recipients and 541 SD recipients responded to the survey. The 2 groups were similar at baseline with respect to age, gender, and presence of high-risk medical conditions. At least ≥95% of individuals in both HD and SD groups reported that their overall health was the same or better than usual during the week after vaccination. Thirty-seven percent of HD recipients and 22% of SD recipients reported a local or systemic side effect (P < .001), most of which were mild to moderate. Only 7 of 547 (1.3%) HD recipients and 3 of 541 (0.6%) SD recipients reported a severe side effect (P = .34). There was no significant difference in healthcare visits between the groups. CONCLUSIONS: Side effects were more common among subjects ≥65 years who received HD influenza vaccine compared with SD vaccine. These side effects were well tolerated and were not associated with impairment of general health status. These findings should reassure patients and their providers of the safety and tolerability of the HD influenza vaccine.

Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes.

An optimized antigen-presenting cell for tumor immunotherapy should produce a robust antigen specific cytotoxic T lymphocytes (CTL) response to tumor-associated antigens, which can persist in vivo and expand on antigen reencounter. Interleukin (IL)-21 synergizes with other gamma-chain cytokines to enhance the frequency and cytotoxicity of antigen-specific CTL. As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8(+) T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2(+) donors. We found that IL-21 modified TAPC enhanced both the proliferation and survival of MART-1 specific CD8(+) T cells, which were enriched by >8-fold over cultures with control nontransgenic TAPC. MART-1-specific CTL produced interferon-gamma in response to cognate peptide antigen and killed primary tumor cells expressing MART-1 in a major histocompatibility complex restricted manner. IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen. Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA(-), CD44(high), CD27(high), CD28(high), CD62L(high), and IL-7 receptor-alpha(high), contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21. Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.

Using dendritic cell maturation and IL-12 producing capacity as markers of function: a cautionary tale.

Effective dendritic cell (DC) function depends on sufficient expression of antigen and costimulatory molecules, and secretion of interleukin (IL)-12. We sought to augment DC stimulatory capacity by optimizing DC phenotype and IL-12 production. DCs, obtained by CD14-selection, were matured using 8 different cytokine cocktails, and expression of costimulatory/major histocompatibility complex molecules and IL-12 production at the end of maturation was assessed. DC stimulatory capacity was determined after pulsing with immunogenic adenoviral CD8 peptide epitopes or after transduction with an Ad5f35-null vector. Resultant T-cell cultures were analyzed using pentamer and interferon-gamma enzyme-linked immunosorbent spot assays. On the basis of DC expression of maturation markers and IL-12 production, we defined prototype "minimal" [tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2], "standard" (IL-1, IL-6, TNF-alpha, prostaglandin E2), and "optimal" (IL-1, IL-6, TNF-alpha, interferon-alpha, CD40 ligand) DC cocktails. Optimal DCs were functionally superior when pulsed with CD8 peptides, but when transduced with Ad5f35, functioned poorly as antigen-presenting cells. We investigated the mechanisms underlying this discrepancy and suggest that prolonged stimulation with potent cytokines (optimal cocktail) in combination with adenoviral transduction alters the kinetics of DC maturation such that the DCs are functionally exhausted by the traditional 48-hour maturation time point. Shortening the DC maturation period posttransduction restored optimal DC stimulatory capacity. Thus, maturation stimuli and viral transduction affects DC phenotype, IL-12 producing capacity, and kinetics of maturation, and all must be considered before designing protocols to generate the optimal DC for cytotoxic T lymphocyte generation.

Bactericidal activity of orally available agents against methicillin-resistant Staphylococcus aureus.

BACKGROUND: The recent proliferation of community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) has led to a marked increase in the need for outpatient treatment of MRSA infections. Many oral agents active against MRSA have been available for years, and a paucity of literature compares them, leaving physicians with little guidance for choosing among them. The purpose of the present study was to compare the bactericidal effects of orally available antibiotics against MRSA and to determine whether there were differences in antimicrobial killing activity against CA-MRSA and hospital-acquired (HA) MRSA isolates. METHODS: A total of 12 unique patient MRSA isolates were studied. Six strains were CA, carrying the staphylococcal chromosomal cassette (SCCmec) type IVa, while six were HA and carried SCCmec type II. Time-kill methods were used to study the bactericidal activity of the orally available antimicrobials linezolid, rifampicin, trimethoprim/sulfamethoxazole, clindamycin, minocycline, and moxifloxacin alone and in combination in vitro. RESULTS: Trimethoprim/sulfamethoxazole was rapidly bactericidal resulting in >2 log(10) cfu/mL decrease at 8 h and >3 log(10) cfu/mL decrease at 24 h in vitro. No antibiotic combination exhibited better killing than trimethoprim/sulfamethoxazole alone. Adding rifampicin to trimethoprim/sulfamethoxazole showed a trend towards antagonism in vitro. There were no differences in the bactericidal activity of any antimicrobial or antimicrobial combination against MRSA isolates carrying SCCmec type IVa versus those carrying SCCmec type II. CONCLUSION: Trimethoprim/sulfamethoxazole is rapidly bactericidal against MRSA in vitro when compared with most other orally available antimicrobials. No differences in bactericidal activity were detected when activities against CA-MRSA and HA-MRSA were compared.