Propensity Score-Weighted Analysis of Postoperative Infection in Patients With and Without Preoperative Urine Culture.

Importance: Although recent guidelines recommend against performance of preoperative urine culture before nongenitourinary surgery, many clinicians still order preoperative urine cultures and prescribe antibiotics for treatment of asymptomatic bacteriuria in an effort to reduce infection risk. Objective: To assess the association between preoperative urine culture testing and postoperative urinary tract infection (UTI) or surgical site infection (SSI), independent of baseline patient characteristics or type of surgery. Design, Setting, and Participants: This cohort study analyzed surgical procedures performed from January 1, 2017, to December 31, 2019, at any of 112 US Department of Veterans Affairs (VA) medical centers. The cohort comprised VA enrollees who underwent major elective noncardiac, nonurological operations. Machine learning and inverse probability of treatment weighting (IPTW) were used to balance the characteristics between those who did and did not undergo a urine culture. Data analyses were performed between January 2023 and January 2024. Exposures: Performance of urine culture within 30 days prior to surgery. Main Outcomes and Measures: The 2 main outcomes were UTI and SSI occurring within 30 days after surgery. Weighted logistic regression was used to estimate odds ratios (ORs) for postoperative infection based on treatment status. Results: A total of 250 389 VA enrollees who underwent 288 858 surgical procedures were included, with 88.9% (256 753) of surgical procedures received by males and 48.9% (141 340) received by patients 65 years or older. Baseline characteristics were well balanced among treatment groups after applying IPTW weights. Preoperative urine culture was performed for 10.5% of surgical procedures (30 384 of 288 858). The IPTW analysis found that preoperative urine culture was not associated with SSI (adjusted OR [AOR], 0.99; 95% CI, 0.90-1.10) or postoperative UTI (AOR, 1.18; 95% CI, 0.98-1.40). In analyses limited to orthopedic surgery and neurosurgery as a proxy for prosthetic implants, the adjusted risks for UTI and SSI were also not associated with preoperative urine culture performance. Conclusions and Relevance: This cohort study found no association between performance of a preoperative urine culture and lower risk of postoperative UTI or SSI. The results support the deimplementation of urine cultures and associated antibiotic treatment prior to surgery, even when using prosthetic implants.

Predicting Antibiotic Susceptibility Among Patients With Recurrent Urinary Tract Infection Using a Prior Culture.

PURPOSE: Recurrent cystitis guidelines recommend relying on a local antibiogram or prior urine culture to guide empirical prescribing, yet little data exist to quantify the predictive value of a prior culture. We constructed a urinary antibiogram and evaluated test metrics (sensitivity, specificity, and Bayes' positive and negative predictive values) of a prior gram-negative organism on predicting subsequent resistance or susceptibility among patients with uncomplicated, recurrent cystitis. MATERIALS AND METHODS: We performed a retrospective database study of adults with recurrent, uncomplicated cystitis (cystitis occurring 2 times in 6 months or 3 times in 12 months) from urology or primary care clinics between November 1, 2016, and December 31, 2018. We excluded pregnant females, patients with complicated cystitis, or pyelonephritis. Test metrics were calculated between sequential, paired cultures using standard formulas. RESULTS: We included 597 visits from 232 unique patients wherein 310 (51.2%) visits had a urine culture and 165 had gram-negative uropathogens isolated. Patients with gram-negative uropathogens were mostly females (97%), with a median age of 58.5 years. Our antibiogram found 38.0%, 27.9%, and 5.5% of Escherichia coli isolates had resistance to trimethoprim-sulfamethoxazole, ciprofloxacin, and nitrofurantoin, respectively. Prior cultures (within 2 years) had good predictive value for detecting future susceptibility to first-line agents nitrofurantoin (0.85) and trimethoprim-sulfamethoxazole (0.78) and excellent predictive values (≥0.90) for cefepime, ceftriaxone, cefuroxime, ciprofloxacin, levofloxacin, gentamicin, tobramycin, piperacillin-tazobactam, and imipenem. CONCLUSIONS: Considerable antibiotic resistance was detected among E coli isolates in patients with recurrent, uncomplicated cystitis. Using a prior culture as a guide can enhance the probability of selecting an effective empirical agent.

Analysis of recurrent urinary tract infection management in women seen in outpatient settings reveals opportunities for antibiotic stewardship interventions.

Objectives: We characterized antibiotic prescribing patterns and management practices among recurrent urinary tract infection (rUTI) patients, and we identified factors associated with lack of guideline adherence to antibiotic choice, duration of treatment, and urine cultures obtained. We hypothesized that prior resistance to nitrofurantoin or trimethoprim-sulfamethoxazole (TMP-SMX), shorter intervals between rUTIs, and more frequent rUTIs would be associated with fluoroquinolone or ß-lactam prescribing, or longer duration of therapy. Methods: This study was a retrospective database study of adult women with International Classification of Diseases, Tenth Revision (ICD-10) cystitis codes meeting American Urological Association rUTI criteria at outpatient clinics within our academic medical center between 2016 and 2018. We excluded patients with ICD-10 codes indicative of complicated UTI or pyelonephritis. Generalized estimating equations were used for risk-factor analysis. Results: Among 214 patients with 566 visits, 61.5% of prescriptions comprised first-line agents of nitrofurantoin (39.7%) and TMP-SMX (21.5%), followed by second-line choices of fluoroquinolones (27.2%) and ß-lactams (11%). Most fluoroquinolone prescriptions (86.7%), TMP-SMX prescriptions (72.2%), and nitrofurantoin prescriptions (60.2%) exceeded the guideline-recommended duration. Approximately half of visits lacked a urine culture. Receiving care through urology via telephone was associated with receiving a ß-lactam (adjusted odds ratio [aOR], 6.34; 95% confidence interval [CI], 2.58-15.56) or fluoroquinolone (OR, 2.28; 95% CI, 1.07-4.86). Having >2 rUTIs during the study period and seeking care from a urology practice (RR, 1.28, 95% CI, 1.15-1.44) were associated with longer antibiotic duration. Conclusions: We found low guideline concordance for antibiotic choice, duration of therapy and cultures obtained among rUTI patients. These factors represent new targets for outpatient antibiotic stewardship interventions.

Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma.

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. SIGNIFICANCE: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825.

Events, care, and outcomes after hernia mesh explantation for infection.

BACKGROUND: Mesh explantation for infection after hernia surgery sets a cascade of events that has not been previously described. The purpose of this study is to review the care of these patients and outcomes. METHODS: We obtained data on all Veterans Health Administration enrollees undergoing hernia repair during 2008-2015. All mesh explantation cases were identified and manually reviewed through December 2020 to identify surgical site occurrences, re-repairs, and subsequent explantations. RESULTS: We identified 332 index explantations due to infection. A first subsequent repair was performed in 82.5% (274/332); a second repair in 18.2% (50/274); a third repair in 16.0% (8/50); and a fourth repair in 25% (2/8). Overall recurrence rate over a 12 year-period was 160/332 (48.1%). CONCLUSIONS: Mesh explantation due to infection sets a cascade of complications and hernia recurrences necessitating re-operation. Complications resulting from mesh explantation suggest that resolution of the initial abdominal wall infection is crucial to prevent future mesh infections.

Risk of Hernia Mesh Explantation following Early Versus Late Onset Skin and Soft Tissue Infection.

To estimate the relative risk of explantation in patients with skin and soft tissue infection onset within 90 days of hernia surgery, compared with days 91-365 and after 1 year. BACKGROUND: Infectious complications occurring after hernia repair with synthetic mesh require prolonged treatment, and eventual mesh explantation. Little is known whether early versus late onset infection is associated with differential risk of mesh removal, and whether treatment with long-term antibiotics or debridement are associated with mesh salvage. METHODS: This was a retrospective observational cohort study. We obtained data on all inguinal, umbilical, and ventral hernia repairs with implanted synthetic mesh performed in Veterans Affairs hospitals during 2008-2015. Participants without a 5-year infection after hernia surgery were excluded. Logistic regression estimated the association of mesh explantation with exposure to mesh-related infection during postoperative days 0-90, versus days 91-365 versus after 1 year. Additional covariates included any subsequent abdominal operation, antibiotic administration, and incision and drainage (I&D) or debridement procedures. RESULTS: One thousand eight hundred eighty-five patients underwent index hernia repair and developed a skin and soft tissue infection within 5 years. Infection onset during days 91-365 was associated with increased explantation risk (OR, 1.62; 95% CI, 1.04-2.48), as was increased antibiotic use (OR, 1.04; 95% CI, 1.03-1.05) and surgical treatments (OR, 3.74; 95% CI, 3.02-4.67). Subsequent abdominal operation was associated with lower explantation risk (OR, 0.46; 95% CI, 0.33-0.61). CONCLUSIONS: Early infections may be more suitable for conservative management. Later-onset infections have lower probability of mesh salvage and should be considered for earlier explantation to save the patients prolonged courses of antibiotics and surgical interventions.

Diosmetin Induces Modulation of Igf-1 and Il-6 Levels to Alter Rictor-Akt-PKCα Cascade in Inhibition of Prostate Cancer.

Growth signals, which typically originate from the surrounding microenvironment, are important for cells. However, when stimulation by growth factors becomes excessive and exceeds their threshold limit, deleterious effects may ensue. In patients with cancer, maintenance of tumors depends, at least in part, on growth factor stimulation, which can also facilitate cancer progression into advanced stages. This is particularly important when the tumor grows beyond its tissue boundaries or when it invades and colonizes other tissues. These aforementioned malignant events are known to be partly supported by elevated cytokine levels. Among the currently known growth signals, insulin-like growth factor (IGF)-1 and IL-6 have been previously studied for their roles in prostate cancer. Both IGF-1 and IL-6 have been reported to activate the RAPTOR independent companion of MTOR complex 2 (Rictor)/AKT/protein kinase C α (PKCα) signaling pathway as one of their downstream mechanisms. At present, research efforts are mainly focused on the exploration of agents that alter growth factor (such as IGF-1) and cytokine (such as IL-6) signaling for their potential application as therapeutic agents, as both of these have been reported to modulate disease outcome. In the present study, IGF-1 and IL-6 served distinct roles in the androgen responsive LNCaP cell line and in the androgen refractory PC-3 cell line in a dose- and time-dependent manner. Increased phosphorylation of Rictor at the Thr-1135 residue, AKT at the Ser-473 residue and PKCα at the Ser-657 residue were observed after treatment with IGF-1 and IL-6. Subsequently, it was found that diosmetin, a natural plant aglycone, had the potential to modulate the downstream signaling cascade of Rictor/AKT/PKCα to inhibit the progression of prostate cancer. Treatment of LNCaP and PC-3 cells with diosmetin inhibited the phosphorylation of Rictor (Thr-1135), AKT (Ser-473) and PKCα (Ser-657) in a dose-dependent manner. Furthermore, the Bax/Bcl-2 expression ratio was increased in response to diosmetin treatment, which would result in increased apoptosis. Based on these observations, diosmetin may represent a novel therapeutic target for prostate cancer.

Thioredoxin reductase is a major regulator of metabolism in leukemia cells.

Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.

Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.

Development of a fully automated surgical site infection detection algorithm for use in cardiac and orthopedic surgery research.

OBJECTIVE: To develop a fully automated algorithm using data from the Veterans' Affairs (VA) electrical medical record (EMR) to identify deep-incisional surgical site infections (SSIs) after cardiac surgeries and total joint arthroplasties (TJAs) to be used for research studies. DESIGN: Retrospective cohort study. SETTING: This study was conducted in 11 VA hospitals. PARTICIPANTS: Patients who underwent coronary artery bypass grafting or valve replacement between January 1, 2010, and March 31, 2018 (cardiac cohort) and patients who underwent total hip arthroplasty or total knee arthroplasty between January 1, 2007, and March 31, 2018 (TJA cohort). METHODS: Relevant clinical information and administrative code data were extracted from the EMR. The outcomes of interest were mediastinitis, endocarditis, or deep-incisional or organ-space SSI within 30 days after surgery. Multiple logistic regression analysis with a repeated regular bootstrap procedure was used to select variables and to assign points in the models. Sensitivities, specificities, positive predictive values (PPVs) and negative predictive values were calculated with comparison to outcomes collected by the Veterans' Affairs Surgical Quality Improvement Program (VASQIP). RESULTS: Overall, 49 (0.5%) of the 13,341 cardiac surgeries were classified as mediastinitis or endocarditis, and 83 (0.6%) of the 12,992 TJAs were classified as deep-incisional or organ-space SSIs. With at least 60% sensitivity, the PPVs of the SSI detection algorithms after cardiac surgeries and TJAs were 52.5% and 62.0%, respectively. CONCLUSIONS: Considering the low prevalence rate of SSIs, our algorithms were successful in identifying a majority of patients with a true SSI while simultaneously reducing false-positive cases. As a next step, validation of these algorithms in different hospital systems with EMR will be needed.

Neural Network Model to Detect Long-Term Skin and Soft Tissue Infection after Hernia Repair.

Background: Skin and soft tissue infection (SSTI) after hernia surgery is infrequent yet catastrophic and is associated with mesh infection, interventions, and hernia recurrence. Although hernia repair is one of the most common general surgery procedures, uncertainty persists regarding incidence of long-term infections. Our goal is to develop a machine learning regression model that detects the occurrence of long-term hernia-associated SSTI. Patients and Methods: The data set consisted of veterans receiving hernia repair with implanted synthetic mesh during 2008-2015. The outcome of interest was occurrence of SSTI related to the index hernia surgery over a five-year follow-up. A neural network regression was fit on a medical record reviewed sample, then applied to the study population. Results: The study population was 96,435 surgeries, of which 76,886 (79.7%) were inguinal, 11,177 (11.6%) were umbilical, and 8,372 (8.7%) were ventral. In the training set, 40 patients had SSTI probability ≥90%, of whom 38 (95%) had a true SSTI. In 249 patients with SSTI probability <10%, only five (2%) patients had a true SSTI. In the testing set, nine patients were assigned a probability >90% and all were true-positives. In 100 patients with probability <10%, only two (2%) patients had a true infection. C-statistics were 0.929 in the training set and 0.901 in the testing set. Conclusions: The model showed excellent discrimination between those with and without infection and had good calibration. The model could be used to reduce the cost of detecting long-term infections.

Validating Use of Electronic Health Data to Identify Patients with Urinary Tract Infections in Outpatient Settings.

OBJECTIVE: To validate the use of electronic algorithms based on International Classification of Diseases (ICD)-10 codes to identify outpatient visits for urinary tract infections (UTI), one of the most common reasons for antibiotic prescriptions. METHODS: ICD-10 symptom codes (e.g., dysuria) alone or in addition to UTI diagnosis codes plus prescription of a UTI-relevant antibiotic were used to identify outpatient UTI visits. Chart review (gold standard) was performed by two reviewers to confirm diagnosis of UTI. The positive predictive value (PPV) that the visit was for UTI (based on chart review) was calculated for three different ICD-10 code algorithms using (1) symptoms only, (2) diagnosis only, or (3) both. RESULTS: Of the 1087 visits analyzed, symptom codes only had the lowest PPV for UTI (PPV = 55.4%; 95%CI: 49.3-61.5%). Diagnosis codes alone resulted in a PPV of 85% (PPV = 84.9%; 95%CI: 81.1-88.2%). The highest PPV was obtained by using both symptom and diagnosis codes together to identify visits with UTI (PPV = 96.3%; 95%CI: 94.5-97.9%). CONCLUSIONS: ICD-10 diagnosis codes with or without symptom codes reliably identify UTI visits; symptom codes alone are not reliable. ICD-10 based algorithms are a valid method to study UTIs in primary care settings.

Association of Postoperative Infection With Risk of Long-term Infection and Mortality.

Importance: Surgical site infection has been shown to decrease survival in veterans by up to 42%. The association of 30-day postoperative infections with long-term infections in the overall surgical population remains unknown. Objective: To determine whether exposure to 30-day postoperative infection is associated with increased incidence of infection and mortality during postoperative days 31 to 365. Design, Setting, and Participants: In this retrospective observational cohort study, veterans undergoing major surgery through the Veterans Health Administration from January 2008 to December 2015 were included. Stabilized inverse probability of treatment weighting was used to balance baseline characteristics of the control and exposure groups. Cox proportional hazards regression was used to estimate hazard ratios of long-term infection and mortality. Data were analyzed from September 2018 to May 2019. Exposures: Any 30-day postoperative infection (exposure group) vs no 30-day infection (control group). Main Outcomes and Measures: Number of days between index surgery and the occurrence of death or the patient's first infection during postoperative days 31 to 365. Patients who died before having a long-term infection were censored for the infection outcome. Results: Of the 659 486 included patients, 604 534 (91.7%) were male, and the mean (SD) age was 59.7 (13.6) years. Among these patients, 23 815 (3.6%) had a 30-day infection, 43 796 (6.6%) had a long-term infection, and 24 810 (3.8%) died during follow-up. The most frequent 30-day infections were surgical site infection (9574 [40.2%]), urinary tract infection (6545 [27.5%]), pneumonia (3515 [14.8%]), and bloodstream infection (1906 [8.0%]). Long-term infection types included urinary tract infection (21 420 [48.7%]), skin and soft tissue infection (14 348 [32.6%]), bloodstream infection (3862 [8.8%]), and pneumonia (2543 [5.8%]). Patients in the exposure group had a higher observed incidence of long-term infection (5187 of 23 815 [21.8%]) and mortality (3067 of 23 815 [12.9%]) compared with those without 30-day infection (38 789 of 635 671 [6.1%] and 21 743 of 635 671 [3.4%], respectively). The estimated hazard ratio for long-term infection was 3.17 (95% CI, 3.05-3.28) and for mortality was 1.89 (95% CI, 1.79-1.99). Conclusions and Relevance: At any given point during the follow-up period, patients with 30-day postoperative infection had a 3.2-fold higher risk of 1-year infection and a 1.9-fold higher risk of mortality compared with those who had no 30-day infection. Cost-benefit calculations for surgical infection prevention programs should include the increased risk and costs of long-term infection and death. Preventive efforts in the first 30 days postoperatively may improve long-term patient outcomes.

Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells.

NK cell adoptive therapy is a promising cancer therapeutic approach, but there are significant challenges that limiting its feasibility and clinical efficacy. One difficulty is the paucity of clinical grade manufacturing platforms to support the large scale expansion of highly active NK cells. We created an NK cell feeder cell line termed 'NKF' through overexpressing membrane bound IL-21 that is capable of inducing robust and sustained proliferation (>10,000-fold expansion at 5 weeks) of highly cytotoxic NK cells. The expanded NK cells exhibit increased cytotoxic function against a panel of blood cancer and solid tumor cells as compared to IL-2-activated non-expanded NK cells. The NKF-expanded NK cells also demonstrate efficacy in mouse models of human sarcoma and T cell leukemia. Mechanistic studies revealed that membrane-bound IL-21 leads to an activation of a STAT3/c-Myc pathway and increased NK cell metabolism with a shift towards aerobic glycolysis. The NKF feeder cell line is a promising new platform that enables the large scale proliferation of highly active NK cells in support of large scale third party NK cell clinical studies that have been recently intiatied. These results also provide mechanistic insights into how membrane-bound IL-21 regulates NK cell expansion.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.