Defining the Expression, Production, and Signaling Roles of Specialized Metabolites during Bacillus subtilis Differentiation.

Bacterial specialized (or secondary) metabolites are structurally diverse molecules that mediate intra- and interspecies interactions by altering growth and cellular physiology and differentiation. Bacillus subtilis, a Gram-positive model bacterium commonly used to study biofilm formation and sporulation, has the capacity to produce more than 10 specialized metabolites. Some of these B. subtilis specialized metabolites have been investigated for their role in facilitating cellular differentiation, but only rarely has the behavior of multiple metabolites been simultaneously investigated. In this study, we explored the interconnectivity of differentiation (biofilm and sporulation) and specialized metabolites in B. subtilis. Specifically, we interrogated how development influences specialized metabolites and vice versa. Using the sporulation-inducing medium DSM, we found that the majority of the specialized metabolites examined are expressed and produced during biofilm formation and sporulation. Additionally, we found that six of these metabolites (surfactin, ComX, bacillibactin, bacilysin, subtilosin A, and plipastatin) are necessary signaling molecules for proper progression of B. subtilis differentiation. This study further supports the growing body of work demonstrating that specialized metabolites have essential physiological functions as cell-cell communication signals in bacteria. IMPORTANCE Bacterially produced specialized metabolites are frequently studied for their potential use as antibiotics and antifungals. However, a growing body of work has suggested that the antagonistic potential of specialized metabolites is not their only function. Here, using Bacillus subtilis as our model bacterium, we demonstrated that developmental processes such as biofilm formation and sporulation are tightly linked to specialized metabolite gene expression and production. Additionally, under our differentiation-inducing conditions, six out of the nine specialized metabolites investigated behave as intraspecific signals that impact B. subtilis physiology and influence biofilm formation and sporulation. Our work supports the viewpoint that specialized metabolites have a clear role as cell-cell signaling molecules within differentiated populations of bacteria.

Insurer coverage of prostate cancer biomarkers.

INTRODUCTION: Several recently-developed prostate cancer (CaP) biomarkers are recommended per national guidelines, yet feasibility of obtaining these tests is unknown. We used a national database to assess insurance coverage of CaP biomarkers. MATERIALS AND METHODS: Insurance policies regarding 4K Score, ExoDx, My Prostate Score, Prostate Cancer Antigen 3, Prostate Health Index, and SelectMDx as of January 1, 2022 were extracted from the policy reporter database. Coverage was defined as a biomarker being deemed medically necessary, conditionally covered, or covered with prior authorization. Overall rates of biomarker coverage were compared by insurance type and region using Chi-squared test. SelectMDx was not covered by any queried policies and was omitted from analysis. RESULTS: A total of 186 insurance plans were identified among 131 payers. Of the 186 plans, 109 (59%) covered at least one biomarker, with prior authorization required for 38 (35%) of these plans. Prostate Cancer Antigen 3 and 4K Score had higher rates of coverage compared to ExoDx, Prostate Health Index, and My Prostate Score (52% and 43% vs. 26%, 26%, and 5%, respectively, P < 0.01). Medicare plans had higher rates of coverage compared to non-Medicare plans (80% Medicare vs. 17% commercial, 15% federal employer, and 13% Medicaid, P < 0.01), and nationwide plans had higher coverage rates compared to regional plans (43% nationwide vs. 32% midwest, 27% northeast, 25% south, 24% west, P < 0.01). Covered biomarkers under Medicare plans were less likely to require prior authorization compared to those covered by non-Medicare plans (12% Medicare vs. 63% commercial, 100% federal employer, 70% Medicaid, P < 0.01). CONCLUSIONS: Coverage of novel CaP biomarkers are relatively robust for Medicare plans but sparse for non-Medicare plans, with the majority of non-Medicare plans requiring prior authorization. Non-Medicare eligible men may face significant barriers to obtaining these tests.

Adoption and Outcomes of Holmium Laser Enucleation of the Prostate in the United States.

OBJECTIVE: To investigate the utilization of holmium laser enucleation of the prostate (HoLEP) using a large real-world cohort. We compare the safety, readmission, and retreatment rates of HoLEP to other widely used endoscopic surgical interventions for benign prostatic hyperplasia (BPH) including transurethral resection of the prostate (TURP), photoselective vaporization of the prostate, and prostatic urethral lift. METHODS: Men who underwent endoscopic treatments for BPH from 2000 to 2019 were identified in the Premier Healthcare Database (n = 218,793). We compared the relative proportion of each procedure performed and annual physician volume data to identify trends in adoption and utilization. Readmission and retreatment rates were determined at both 30- and 90-days postoperation. Multivariable logistic regression was used to assess the association between procedure type and outcomes. RESULTS: HoLEP accounted for 3.2% (n = 6967) of all the BPH procedures performed between 2000 and 2019 and increased from 1.1% of the procedures in 2008 to 4% in 2019. Patients undergoing HoLEP had lower odds of 90-days readmission compared to TURP (Odds ratio (OR) 0.87, p = 0.025). HoLEP had similar odds of retreatment compared to TURP at both 1-year (OR 0.96, p = 0.7) and 2-years (OR 0.98, p = 0.9), while patients undergoing photoselective vaporization of the prostate and prostatic urethral lift were more likely to retreat within 2-years (OR 1.20, P < 0.001; OR 1.87, P < 0.001). CONCLUSION: HoLEP is a safe therapy for BPH with lower readmission and comparable retreatment rates to the gold standard TURP. Despite this, the utilization of HoLEP has lagged behind other endoscopic procedures and remains low.

Impact of Magnetic Resonance Imaging Targeting on Pathologic Upgrading and Downgrading at Prostatectomy: A Systematic Review and Meta-analysis.

CONTEXT: The evidence supporting multiparametric magnetic resonance imaging (MRI) targeting for biopsy is nearly exclusively based on biopsy pathologic outcomes. This is problematic, as targeting likely allows preferential identification of small high-grade areas of questionable oncologic significance, raising the likelihood of overdiagnosis and overtreatment. OBJECTIVE: To estimate the impact of MRI-targeted, systematic, and combined biopsies on radical prostatectomy (RP) grade group concordance. EVIDENCE ACQUISITION: PubMed MEDLINE and Cochrane Library were searched from July 2018 to January 2022. Studies that conducted systematic and MRI-targeted prostate biopsies and compared biopsy results with pathology after RP were included. We performed a meta-analysis to assess whether pathologic upgrading and downgrading were influenced by biopsy type and a net-benefit analysis using pooled risk difference estimates. EVIDENCE SYNTHESIS: Both targeted only and combined biopsies were less likely to result in upgrading (odds ratio [OR] vs systematic of 0.70, 95% confidence interval [CI] 0.63-0.77, p < 0.001, and 0.50, 95% CI 0.45-0.55, p < 0.001), respectively). Targeted only and combined biopsies increased the odds of downgrading (1.24 (95% CI 1.05-1.46), p = 0.012, and 1.96 (95% CI 1.68-2.27, p < 0.001) compared with systematic biopsies, respectively. The net benefit of targeted and combined biopsies is 8 and 7 per 100 if harms of up- and downgrading are considered equal, but 7 and -1 per 100 if the harm of downgrading is considered twice that of upgrading. CONCLUSIONS: The addition of MRI-targeting results in lower rates of upgrading as compared to systematic biopsy at RP (27% vs 42%). However, combined MRI-targeted and systematic biopsies are associated with more downgrading at RP (19% v 11% for combined vs systematic). Strong heterogeneity suggests further research into factors that influence the rates of up- and downgrading and that distinguishes clinically relevant from irrelevant grade changes is needed. Until then, the benefits and harms of combined MRI-targeted and systematic biopsies cannot be fully assessed. PATIENT SUMMARY: We reviewed the ability of magnetic resonance imaging (MRI)-targeted biopsies to predict cancer grade at prostatectomy. We found that combined MRI-targeted and systematic biopsies result in more cancers being downgraded than systematic biopsies.

Predictors and Trends of Opioid-Sparing Radical Prostatectomy From a Large National Cohort.

OBJECTIVE: To examine the use of pain medications after radical prostatectomy using a large national database. METHODS: The Premier Hospital Database was queried to identify all robotic and laparoscopic radical prostatectomies from January 2015 to March 2020 with length of stay more than or equal to 1 day. "Opioid-sparing" was defined as absence of intravenous opioid use after post-operative day 0 and absence of oral opioid use throughout admission. Comparisons were made between opioid-sparing and non-opioid-sparing prostatectomy. Logistic multivariable regression was used to identify predictors of opioid-sparing prostatectomy. RESULTS: A total of 62,660 patients were included, of whom 14,806 (23.6%) underwent opioid-sparing prostatectomy. Opioid-sparing prostatectomy was associated with older age (65 vs 63 years, P <.01), white versus black race (76.3% vs 73.4%, P <.01), high-volume surgeons (75.2% vs 70.0%, P <.01), and use of intravenous ketorolac (62.2% vs 48.0%, P <.01), intravenous acetaminophen (32.5% vs 30.1%, P <.01), and liposomal bupivacaine (5.4% vs 4.9%, P <.01). On multivariable regression, ketorolac was the strongest predictor of opioid-sparing prostatectomy (odds ratio: 1.86, 95% confidence interval: 1.79-1.93, P <.01), and black race was predictive of non-opioid sparing prostatectomy (odds ratio: 0.75, 95% confidence interval: 0.71-0.80, P <.01). Ketorolac was not associated with increased risk of postoperative bleeding (0.3% vs 0.3%, P =1.0) or dialysis requirement (<0.1% vs <0.1%, P =.91). CONCLUSION: Opioid-sparing radical prostatectomy was feasible and associated with administration of each of the non-opioid pain medications assessed. Ketorolac was the strongest predictor of opioid-sparing prostatectomy and was not associated with increased risk of bleeding or dialysis.