Access to Prostate-Specific Antigen Testing and Mortality Among Men With Prostate Cancer.

Importance: Prostate-specific antigen (PSA) screening for prostate cancer is controversial but may be associated with benefit for certain high-risk groups. Objectives: To evaluate associations of county-level PSA screening prevalence with prostate cancer outcomes, as well as variation by sociodemographic and clinical factors. Design, Setting, and Participants: This cohort study used data from cancer registries based in 8 US states on Hispanic, non-Hispanic Black, and non-Hispanic White men aged 40 to 99 years who received a diagnosis of prostate cancer between January 1, 2000, and December 31, 2015. Participants were followed up until death or censored after 10 years or December 31, 2018, whichever end point came first. Data were analyzed between September 2023 and January 2024. Exposure: County-level PSA screening prevalence was estimated using the Behavior Risk Factor Surveillance System survey data from 2004, 2006, 2008, 2010, and 2012 and weighted by population characteristics. Main Outcomes and Measures: Multivariable logistic, Cox proportional hazards regression, and competing risks models were fit to estimate adjusted odds ratios (AOR) and adjusted hazard ratios (AHR) for associations of county-level PSA screening prevalence at diagnosis with advanced stage (regional or distant), as well as all-cause and prostate cancer-specific survival. Results: Of 814 987 men with prostate cancer, the mean (SD) age was 67.3 (9.8) years, 7.8% were Hispanic, 12.2% were non-Hispanic Black, and 80.0% were non-Hispanic White; 17.0% had advanced disease. There were 247 570 deaths over 5 716 703 person-years of follow-up. Men in the highest compared with lowest quintile of county-level PSA screening prevalence at diagnosis had lower odds of advanced vs localized stage (AOR, 0.86; 95% CI, 0.85-0.88), lower all-cause mortality (AHR, 0.86; 95% CI, 0.85-0.87), and lower prostate cancer-specific mortality (AHR, 0.83; 95% CI, 0.81-0.85). Inverse associations between PSA screening prevalence and advanced cancer were strongest among men of Hispanic ethnicity vs other ethnicities (AOR, 0.82; 95% CI, 0.78-0.87), older vs younger men (aged ≥70 years: AOR, 0.77; 95% CI, 0.75-0.79), and those in the Northeast vs other US Census regions (AOR, 0.81; 95% CI, 0.79-0.84). Inverse associations with all-cause mortality were strongest among men of Hispanic ethnicity vs other ethnicities (AHR, 0.82; 95% CI, 0.78-0.85), younger vs older men (AHR, 0.81; 95% CI, 0.77-0.85), those with advanced vs localized disease (AHR, 0.80; 95% CI, 0.78-0.82), and those in the West vs other US Census regions (AHR, 0.89; 95% CI, 0.87-0.90). Conclusions and Relevance: This population-based cohort study of men with prostate cancer suggests that higher county-level prevalence of PSA screening was associated with lower odds of advanced disease, all-cause mortality, and prostate cancer-specific mortality. Associations varied by age, race and ethnicity, and US Census region.

A qualitative approach to understanding the drivers of unequal receipt of definitive therapy for Black men with prostate cancer in Massachusetts.

BACKGROUND: Despite mandated insurance coverage since 2006 and robust health infrastructure in urban settings with high concentrations of minority patients, race-based disparities in prostate cancer (PCa) treatment persist in Massachusetts. In this qualitative study, the authors sought to identify factors driving inequities in PCa treatment in Massachusetts. METHODS: Four hospitals offering PCa treatment in Massachusetts were selected using a case-mix approach. Purposive sampling was used to conduct semistructured interviews with hospital stakeholders. Additional interviews were conducted with representatives from grassroots organizations providing PCa education. Two study staff coded the interviews to identify major themes and recurrent patterns. RESULTS: Of the 35 informants invited, 25 participated in the study. Although national disparities in PCa outcomes were readily discussed, one half of the informants were unaware that PCa disparities existed in Massachusetts. Informants and grassroots organization representatives acknowledged that patients with PCa are willing to face transportation barriers to receive treatment from trusted and accommodating institutions. Except for chief equity officers, most health care providers lacked knowledge on accessing or using metrics regarding racial disparities in cancer outcomes. Although community outreach was recognized as a potential strategy to reduce treatment disparities and engender trust, informants were often unable to provide a clear implementation plan. CONCLUSIONS: This statewide qualitative study builds on existing quantitative data on the nature and extent of disparities. It highlights knowledge gaps in recognizing and addressing racial disparities in PCa treatment in Massachusetts. Improved provider awareness, the use of disparity metrics, and strategic community engagement may ensure equitable access to PCa treatment. PLAIN LANGUAGE SUMMARY: Despite mandated insurance and urban health care access, racial disparities in prostate cancer treatment persist in Massachusetts. This qualitative study revealed that, although national disparities were acknowledged, awareness about local disparities are lacking. Stakeholders highlighted the importance of ancillary services, including translators, rideshares, and navigators, in the delivery of care. In addition, whereas hospital stakeholders were aware of collected equity outcomes, they were unsure whether and who is monitoring equity metrics. Furthermore, stakeholders agreed that community outreach showed promise in ensuring equitable access to prostate cancer treatment. Nevertheless, most interviewed stakeholders lacked clear implementation plans.

Smoking characteristics and years since quitting smoking of US adults diagnosed with lung and bladder cancer: A national health and nutrition examination survey analysis

ABSTRACT Purpose: Smoking is a recognized risk factor for bladder BC and lung cancer LC. We investigated the enduring risk of BC after smoking cessation using U.S. national survey data. Our analysis focused on comparing characteristics of LC and BC patients, emphasizing smoking status and the latency period from smoking cessation to cancer diagnosis in former smokers. Materials and Methods: We analyzed data from the National Health and Examination Survey (2003-2016), identifying adults with LC or BC history. Smoking status (never, active, former) and the interval between quitting smoking and cancer diagnosis for former smokers were assessed. We reported descriptive statistics using frequencies and percentages for categorical variables and median with interquartile ranges (IQR) for continuous variables. Results: Among LC patients, 8.9% never smoked, 18.9% active smokers, and 72.2% former smokers. Former smokers had a median interval of 8 years (IQR 2-12) between quitting and LC diagnosis, with 88.3% quitting within 0-19 years before diagnosis. For BC patients, 26.8% never smoked, 22.4% were active smokers, and 50.8% former smokers. Former smokers had a median interval of 21 years (IQR 14-33) between quitting and BC diagnosis, with 49.3% quitting within 0-19 years before diagnosis. Conclusions: BC patients exhibit a prolonged latency period between smoking cessation and cancer diagnosis compared to LC patients. Despite smoking status evaluation in microhematuria, current risk stratification models for urothelial cancer do not incorporate it. Our findings emphasize the significance of long-term post-smoking cessation surveillance and advocate for integrating smoking history into future risk stratification guidelines.

Silver carboxylate-TiO2/polydimethyl siloxane is a safe and effective antimicrobial with significant wound care potential.

Introduction: With the rise in antibiotic resistance, new methodologies are needed to combat musculoskeletal infections. Silver is an antimicrobial that can be synthesized in different forms, but its pharmacokinetics are difficult to control. This study details the antibacterial efficacy and cellular cytotoxicity of a formulation consisting of silver carboxylate (AgCar) released through a titanium dioxide/polydimethylsiloxane matrix with a predictable release profile on Pseudomonas aeruginosa, Acinetobacterium baumannii, and human-derived primary osteoblasts. Methods: Through an Institutional Animal Care and Use Committee and IRB-approved protocol, AgCar was applied to live Yucatan porcine skin and histologically analyzed for skin penetration. Graphite Furnace Atomic Absorption Spectroscopy (GFAAS) was used to measure elution of AgCar. Dose-response curves were generated through optical density to assess potency. Finally, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to quantify the cellular cytotoxicity of the novel formulation. The results were subject to statistical analysis using analysis of variance and post hoc Tukey tests. Results: The silver carboxylate coating demonstrated deep penetration into the epithelium at the level of the deep pilosebaceous glands in animal models. GFAAS testing demonstrated the extended elution profile of silver carboxylate over 96 hours, while 100% silver with no titanium dioxide-polydimethylsiloxane matrix fully eluted within 48 hours. 10x silver carboxylate demonstrated superior antimicrobial activity to antibiotics and other silver formulations and showed minimal cytotoxicity compared with other silver formulations. Discussion/Clinical Relevance: Current antimicrobial therapies in wound care and surgical antisepsis, such as chlorhexidine gluconate, have pitfalls including poor skin penetration and short duration of efficacy. The broad antimicrobial activity, extended elution, and deep skin penetration of this AgCar formulation show great promise for surgical site infection and wound care treatment. Novel technology to fight the growing threat of microbial resistance should be at the forefront of orthopaedic surgical site infection prevention and treatment.

Smoking characteristics and years since quitting smoking of US adults diagnosed with lung and bladder cancer: A national health and nutrition examination survey analysis.

PURPOSE: Smoking is a recognized risk factor for bladder BC and lung cancer LC. We investigated the enduring risk of BC after smoking cessation using U.S. national survey data. Our analysis focused on comparing characteristics of LC and BC patients, emphasizing smoking status and the latency period from smoking cessation to cancer diagnosis in former smokers. MATERIALS AND METHODS: We analyzed data from the National Health and Examination Survey (2003-2016), identifying adults with LC or BC history. Smoking status (never, active, former) and the interval between quitting smoking and cancer diagnosis for former smokers were assessed. We reported descriptive statistics using frequencies and percentages for categorical variables and median with interquartile ranges (IQR) for continuous variables. RESULTS: Among LC patients, 8.9% never smoked, 18.9% active smokers, and 72.2% former smokers. Former smokers had a median interval of 8 years (IQR 2-12) between quitting and LC diagnosis, with 88.3% quitting within 0-19 years before diagnosis. For BC patients, 26.8% never smoked, 22.4% were active smokers, and 50.8% former smokers. Former smokers had a median interval of 21 years (IQR 14-33) between quitting and BC diagnosis, with 49.3% quitting within 0-19 years before diagnosis. CONCLUSIONS: BC patients exhibit a prolonged latency period between smoking cessation and cancer diagnosis compared to LC patients. Despite smoking status evaluation in microhematuria, current risk stratification models for urothelial cancer do not incorporate it. Our findings emphasize the significance of long-term post-smoking cessation surveillance and advocate for integrating smoking history into future risk stratification guidelines.

Ecological Diversification in an Adaptive Radiation of Plants: The Role of De Novo Mutation and Introgression.

Adaptive radiations are characterized by rapid ecological diversification and speciation events, leading to fuzzy species boundaries between ecologically differentiated species. Adaptive radiations are therefore key systems for understanding how species are formed and maintained, including the role of de novo mutations versus preexisting variation in ecological adaptation and the genome-wide consequences of hybridization events. For example, adaptive introgression, where beneficial alleles are transferred between lineages through hybridization, may fuel diversification in adaptive radiations and facilitate adaptation to new environments. In this study, we employed whole-genome resequencing data to investigate the evolutionary origin of hummingbird-pollinated flowers and to characterize genome-wide patterns of phylogenetic discordance and introgression in Penstemon subgenus Dasanthera, a small and diverse adaptive radiation of plants. We found that magenta hummingbird-adapted flowers have apparently evolved twice from ancestral blue-violet bee-pollinated flowers within this radiation. These shifts in flower color are accompanied by a variety of inactivating mutations to a key anthocyanin pathway enzyme, suggesting that independent de novo loss-of-function mutations underlie the parallel evolution of this trait. Although patterns of introgression and phylogenetic discordance were heterogenous across the genome, a strong effect of gene density suggests that, in general, natural selection opposes introgression and maintains genetic differentiation in gene-rich genomic regions. Our results highlight the importance of both de novo mutation and introgression as sources of evolutionary change and indicate a role for de novo mutation in driving parallel evolution in adaptive radiations.

Exploring preventive care practices among unvaccinated individuals in the United States during the COVID-19 pandemic.

INTRODUCTION: Building on a Canadian study associating unvaccinated individuals to increased car accidents, we examined the relationship between COVID-19 vaccination status and US preventive care practices. METHODS: We queried the 2021 National Health Interview Survey. First, we fitted a model to identify respondent-level factors associated with receipt of at least one COVID-19 vaccination. Second, we fitted a survey-weighted logistic regression model adjusted for respondent-level characteristics to examine whether the receipt of at least one COVID-19 vaccination predicted the receipt of preventive care services. Preventive care services assessed included serum cholesterol, glucose, and blood pressure measurements, as well as guideline-concordant cancer screening including breast, cervical, colorectal, and prostate cancer screening. RESULTS: Factors predicting receipt of COVID-19 vaccination were age (adjusted Odds Ratio (aOR) 1.03; 95 % confidence interval (CI) [1.03-1.03]), Hispanic (aOR 1.25; 95 % CI [1.08-1.44]), and non-Hispanic Asian (aOR 3.52; 95 % CI [2.74-4.52]) ethnicity/race, and history of cancer (aOR 1.61; 95 % CI [1.13-2.30]). Unvaccinated respondents were less likely to have received serum cholesterol (aOR 0.69; 95 % CI [0.50-0.70), serum glucose (aOR 0.65; 95 % CI [0.56-0.75]), or blood pressure measurements (aOR 0.47; 95 % CI [0.33-0.66]); and were less likely to have received breast cancer (aOR 0.35; 95 % CI [0.25-0.48]), colorectal cancer (aOR 0.52; 95 % CI [0.46-0.60]) and prostate cancer screening (aOR 0.61; 95 % CI [0.48-0.76]). There was no significant association between unvaccinated respondents receiving cervical cancer screening (aOR 0.96; 95 % CI [0.81-1.13]; p = 0.616). CONCLUSION: Non-receipt of COVID-19 vaccination was associated with non-receipt of preventive care services including cancer screening. Further studies are needed to assess if this association is due to system-level factors or reflects a general distrust of medical preventive care amongst this population.

The effect of limited english proficiency on prostate-specific antigen screening in American men.

PURPOSE: To evaluate how limited English proficiency (LEP) impacts the prevalence of prostate-specific antigen (PSA) screening in a contemporary, nationally representative cohort of men in the USA. METHODS: The Medical Expenditure Panel Survey was utilized to identify the prevalence of PSA screening between 2013 and 2016 among men ≥ 55. Men who speak a language other than English at home were stratified by self-reported levels of English proficiency (men who speak English very well, well, not well, or not at all). Survey weights were applied, and groups were compared using the adjusted Wald test. A multivariable logistic regression model was used to identify predictors of PSA screening adjusting for patient-level covariates. RESULTS: The cohort included 2,889 men, corresponding to a weighted estimate of 4,765,682 men. 79.6% of men who speak English very well reported receiving at least one lifetime PSA test versus 58.4% of men who do not speak English at all (p < 0.001). Men who reported not speaking English at all had significantly lower prevalence of PSA screening (aOR 0.56; 95% CI 0.35-0.91; p = 0.019). Other significant predictors of PSA screening included older age, income > 400% of the federal poverty level, insurance coverage, and healthcare utilization. CONCLUSIONS: Limited English proficiency is associated with significantly lower prevalence of PSA screening among men in the USA. Interventions to mitigate disparities in prostate cancer outcomes should account for limited English proficiency among the barriers to guideline-concordant care.

Racial Disparities in Prostate Cancer Screening: The Role of Shared Decision Making.

INTRODUCTION: The 2018 U.S. Preventive Services Task Force recommendations endorsed shared decision making for men aged 55-69 years, encouraging consideration of patient race/ethnicity for prostate-specific antigen screening. This study aimed to assess whether a proxy shared decision-making variable modified the impact of race/ethnicity on the likelihood of prostate-specific antigen screening. METHODS: A cross-sectional analysis of men aged between 55 and 69 years, who responded to the prostate-specific antigen screening portions of the 2020 U.S.-based Behavioral Risk Factor Surveillance System survey, was performed between September and December 2022. Complex sample multivariable logistic regression models with an interaction term combining race and estimated shared decision making were used to test whether shared decision making modified the impact of race/ethnicity on screening. RESULTS: Of a weighted sample of 26.8 million men eligible for prostate-specific antigen screening, 25.7% (6.9 million) reported for prostate-specific antigen screening. In adjusted analysis, estimated shared decision making was a significant predictor of prostate-specific antigen screening (AOR=2.65, 95% CI=2.36, 2.98, p<0.001). The interaction between race/ethnicity and estimated shared decision making on the receipt of prostate-specific antigen screening was significant (pint=0.001). Among those who did not report estimated shared decision making, both non-Hispanic Black (OR=0.77, 95% CI=0.61, 0.97, p=0.026) and Hispanic (OR=0.51, 95% CI=0.39, 0.68, p<0.001) men were significantly less likely to undergo prostate-specific antigen screening than non-Hispanic White men. On the contrary, among respondents who reported estimated shared decision making, no race-based differences in prostate-specific antigen screening were found. CONCLUSIONS: Although much disparities research focuses on race-based differences in prostate-specific antigen screening, research on strategies to mitigate these disparities is needed. Shared decision making might attenuate the impact of race/ethnic disparities on the likelihood of prostate-specific antigen screening.

Ecological diversification in an adaptive radiation of plants: the role of de novo mutation and introgression.

Adaptive radiations are characterized by rapid ecological diversification and speciation events, leading to fuzzy species boundaries between ecologically differentiated species. Adaptive radiations are therefore key systems for understanding how species are formed and maintained, including the role of de novo mutations vs. pre-existing variation in ecological adaptation and the genome-wide consequences of hybridization events. For example, adaptive introgression, where beneficial alleles are transferred between lineages through hybridization, may fuel diversification in adaptive radiations and facilitate adaptation to new environments. In this study, we employed whole-genome resequencing data to investigate the evolutionary origin of hummingbird-pollinated flowers and to characterize genome-wide patterns of phylogenetic discordance and introgression in Penstemon subgenus Dasanthera, a small and diverse adaptive radiation of plants. We found that magenta hummingbird-adapted flowers have apparently evolved twice from ancestral blue-violet bee-pollinated flowers within this radiation. These shifts in flower color are accompanied by a variety of inactivating mutations to a key anthocyanin pathway enzyme, suggesting that independent de novo loss-of-function mutations underlie parallel evolution of this trait. Although patterns of introgression and phylogenetic discordance were heterogenous across the genome, a strong effect of gene density suggests that, in general, natural selection opposes introgression and maintains genetic differentiation in gene-rich genomic regions. Our results highlight the importance of both de novo mutation and introgression as sources of evolutionary change and indicate a role for de novo mutation in driving parallel evolution in adaptive radiations.

High HIV prevalence in gestational trophoblastic neoplasia patients.

OBJECTIVE: To assess the HIV prevalence in patients diagnosed with gestational trophoblastic neoplasia (GTN). DESIGN: A retrospective single centre cohort study. METHODS: A database from the Sheffield Trophoblastic Disease Centre (STDC), Sheffield, UK was searched between 1st January 2015 and 31st December 2021. A total of 3,591 patients were referred to STDC with a diagnosis of gestational trophoblastic disease (GTD), of which 221 (6.2%) were treated for GTN. The prevalence of HIV-positive tests in GTN patients was assessed. RESULTS: HIV testing was performed in 93% GTN patients ( n  = 205/221). Overall, 1.3% of GTN patients ( n  = 3/221) were HIV-positive, involving two known HIV-positive patients and one new diagnosis. This equates to a HIV prevalence of 14 : 1000, which is ∼7 to 9× higher than the HIV prevalence in Sheffield (1.9 per 1000) and Yorkshire and Humber (1.5 per 1000). CONCLUSION: Given the extremely high HIV prevalence in our population, 'opt out' HIV testing is recommended within our specialist trophoblastic centre for all referred GTD and GTN patients. There is little reason to suspect that the prevalence of HIV-positive patients is any lower in the cohort of GTD patients referred to specialist trophoblastic centres for hCG screening alone, without requiring chemotherapy, particularly considering that most GTN arises from GTD.

The Association of County-level Prostate-specific Antigen Screening with Metastatic Prostate Cancer and Prostate Cancer Mortality.

BACKGROUND AND OBJECTIVE: There exists ongoing debate about the benefits and harms of prostate-specific antigen (PSA) screening for prostate cancer. This study sought to evaluate the association of county-level PSA screening rates with county-level incidence of metastatic prostate cancer and prostate cancer mortality in the USA. METHODS: This ecological study used data from the 2004-2012 Behavioral Risk Factor Surveillance System (BRFSS) to build a multilevel mixed-effect model with poststratification using US Census data to estimate county-level PSA screening rates for all 3143 US counties adjusted for age, race, ethnicity, and county-level poverty rates. The exposure of interest was average county-level PSA screening rate from 2004 to 2012, defined as the proportion of men aged 40-79 yr who underwent PSA screening within the prior 2 yr. The primary outcomes were county-level age-adjusted incidence of regional/distant prostate cancer during 2015-2019 and age-adjusted prostate cancer mortality during 2016-2020. KEY FINDINGS AND LIMITATIONS: A total of 416 221 male BRFSS respondents aged 40-79 yr met the inclusion criteria and were used in the multilevel mixed-effect model. The model was poststratified using 63.4 million men aged 40-79 yr from all 3143 counties in the 2010 Decennial Census. County-level estimated PSA screening rates exhibited geographic variability and were pooled at the state level for internal validation with direct BRFSS state-level estimates, showing a strong correlation with Pearson correlation coefficients 0.77-0.90. A 10% higher county-level probability of PSA screening in 2004-2012 was associated with a 14% lower county-level incidence of regional/distant prostate cancer in 2015-2019 (rate ratio 0.86, 95% confidence interval [CI] 0.85-0.87, p < 0.001) and 10% lower county-level prostate cancer mortality in 2016-2020 (rate ratio 0.90, 95% CI 0.89-0.91, p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: In this population-based ecological study of all US counties, higher PSA screening rates were associated with a lower incidence of regional/distant prostate cancer and lower prostate cancer mortality at extended follow-up. PATIENT SUMMARY: US counties with higher rates of prostate-specific antigen (PSA) screening had significantly lower rates of metastatic prostate cancer and prostate cancer mortality in subsequent years. These data may inform shared decision-making regarding PSA screening for prostate cancer.

A genome-wide overexpression screen reveals Mycobacterium smegmatis growth inhibitors encoded by mycobacteriophage Hammy.

During infection, bacteriophages produce diverse gene products to overcome bacterial antiphage defenses, to outcompete other phages, and to take over cellular processes. Even in the best-studied model phages, the roles of most phage-encoded gene products are unknown, and the phage population represents a largely untapped reservoir of novel gene functions. Considering the sheer size of this population, experimental screening methods are needed to sort through the enormous collection of available sequences and identify gene products that can modulate bacterial behavior for downstream functional characterization. Here, we describe the construction of a plasmid-based overexpression library of 94 genes encoded by Hammy, a Cluster K mycobacteriophage closely related to those infecting clinically important mycobacteria. The arrayed library was systematically screened in a plate-based cytotoxicity assay, identifying a diverse set of 24 gene products (representing ∼25% of the Hammy genome) capable of inhibiting growth of the host bacterium Mycobacterium smegmatis. Half of these are related to growth inhibitors previously identified in related phage Waterfoul, supporting their functional conservation; the other genes represent novel additions to the list of known antimycobacterial growth inhibitors. This work, conducted as part of the HHMI-supported Science Education Alliance Gene-function Exploration by a Network of Emerging Scientists (SEA-GENES) project, highlights the value of parallel, comprehensive overexpression screens in exploring genome-wide patterns of phage gene function and novel interactions between phages and their hosts.

Pathway2Targets: an open-source pathway-based approach to repurpose therapeutic drugs and prioritize human targets.

Background: Recent efforts to repurpose existing drugs to different indications have been accompanied by a number of computational methods, which incorporate protein-protein interaction networks and signaling pathways, to aid with prioritizing existing targets and/or drugs. However, many of these existing methods are focused on integrating additional data that are only available for a small subset of diseases or conditions. Methods: We have designed and implemented a new R-based open-source target prioritization and repurposing method that integrates both canonical intracellular signaling information from five public pathway databases and target information from public sources including OpenTargets.org. The Pathway2Targets algorithm takes a list of significant pathways as input, then retrieves and integrates public data for all targets within those pathways for a given condition. It also incorporates a weighting scheme that is customizable by the user to support a variety of use cases including target prioritization, drug repurposing, and identifying novel targets that are biologically relevant for a different indication. Results: As a proof of concept, we applied this algorithm to a public colorectal cancer RNA-sequencing dataset with 144 case and control samples. Our analysis identified 430 targets and ~700 unique drugs based on differential gene expression and signaling pathway enrichment. We found that our highest-ranked predicted targets were significantly enriched in targets with FDA-approved therapeutics for colorectal cancer (p-value < 0.025) that included EGFR, VEGFA, and PTGS2. Interestingly, there was no statistically significant enrichment of targets for other cancers in this same list suggesting high specificity of the results. We also adjusted the weighting scheme to prioritize more novel targets for CRC. This second analysis revealed epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and two mitogen-activated protein kinases (MAPK14 and MAPK3). These observations suggest that our open-source method with a customizable weighting scheme can accurately prioritize targets that are specific and relevant to the disease or condition of interest, as well as targets that are at earlier stages of development. We anticipate that this method will complement other approaches to repurpose drugs for a variety of indications, which can contribute to the improvement of the quality of life and overall health of such patients.

Clinical stage and grade migration of localized prostate cancer at diagnosis during the past decade.

OBJECTIVES: Early 2010s data suggest a reverse stage and grade migration towards more aggressive prostate cancer (PCa) at diagnosis, accelerated by the 2012 US Preventive Services Task Force recommendation against PSA screening. Using the National Cancer Database, we investigated the impact of the 2018 USPSTF recommendation and the COVID-19 outbreak on this shift. We hypothesized that the COVID-19 outbreak would further contribute to a stage and grade migration towards more aggressive disease. MATERIAL AND METHODS: We identified men with localized PCa diagnosed between 2010 and 2020. We analyzed the shift in the proportion of PCa stratified according to D'Amico risk classification. We used multivariable logistic regression models to assess the association between year of diagnosis and dichotomous variables related to clinical stage and grade of PCa. Predicted probabilities with 95% CI were computed through marginal effect analyses. RESULTS: We identified 910,898 men with localized PCa. The proportion of low-risk PCa almost halved from 34.9% in 2010 to 17.7% in 2020 (P < 0.001). Compared to 2010, we found in each year increased odds of: PSA≥10 ng/dL starting from 2012 (aOR2012 1.05; 95% CI, 1.02-1.08); cT3-T4 starting from 2015 (aOR2015 1.10; 95% CI, 1.03-1.17); ISUP GG 3-5 starting from 2011 (aOR2011 1.06; 95% CI, 1.03-1.08); and consequently, D'Amico intermediate/high-risk class starting from 2011 (aOR2011 1.03; 95% CI, 1.01-1.05). Fluctuations in the probabilities of PSA≥10 ng/dL and cT3-T4 at diagnosis were observed over time (all P < 0.001). The probability of PSA≥10 ng/dL peaked at 29.0% (95% CI, 28.0%-29.0%) in 2018, while the probability of cT3-T4 peaked at 3.7% (95% CI, 3.6%-3.8%) in 2020. All other outcome variables demonstrated a consistent upward shift (all P < 0.001), with the highest probabilities in 2020 for ISUP GG 3-5 (42.3%, 95% CI, 41.9%-42.6%) and D'Amico intermediate/high-risk (81.3%, 95% CI, 81.0%-81.6%). CONCLUSIONS: Our study confirms an enduring shift towards a higher proportion of aggressive PCa at diagnosis, likely influenced by the COVID-19 pandemic. The impact of the 2018 USPSTF PCa screening recommendation on the proportion of aggressive PCa seems restricted and likely affected by the pandemic outbreak. Future investigations should evaluate the long-term effects of the 2018 USPSTF recommendations in the postpandemic setting.

Validating a forced-choice method for eliciting quality-of-reasoning judgments.

In this paper we investigate the criterion validity of forced-choice comparisons of the quality of written arguments with normative solutions. Across two studies, novices and experts assessing quality of reasoning through a forced-choice design were both able to choose arguments supporting more accurate solutions-62.2% (SE = 1%) of the time for novices and 74.4% (SE = 1%) for experts-and arguments produced by larger teams-up to 82% of the time for novices and 85% for experts-with high inter-rater reliability, namely 70.58% (95% CI = 1.18) agreement for novices and 80.98% (95% CI = 2.26) for experts. We also explored two methods for increasing efficiency. We found that the number of comparative judgments needed could be substantially reduced with little accuracy loss by leveraging transitivity and producing quality-of-reasoning assessments using an AVL tree method. Moreover, a regression model trained to predict scores based on automatically derived linguistic features of participants' judgments achieved a high correlation with the objective accuracy scores of the arguments in our dataset. Despite the inherent subjectivity involved in evaluating differing quality of reasoning, the forced-choice paradigm allows even novice raters to perform beyond chance and can provide a valid, reliable, and efficient method for producing quality-of-reasoning assessments at scale.

The national utilization of nonoperative management for small renal masses over 10 years.

BACKGROUND: Management of small renal masses often involves a nonoperative approach, but there is a paucity of information about the use and associated predictors of such approaches. This study aimed to determine the trends in and predictors of use of nonoperative management of small renal masses. METHODS: Using data from the National Cancer Database for localized small renal masses (N0/M0, cT1a) diagnosed between 2010 and 2020, we conducted a cross-sectional study. Nonoperative management was defined as expectant management (active surveillance or watchful waiting) or focal ablation. Adjusted odds ratios (AORs) were calculated using multivariable logistic regression models. RESULTS: Of the 156 734 patients included, 10.5% underwent expectant management, and 13.9% underwent focal ablation. Later year of diagnosis was associated with a higher likelihood of nonoperative management. In 2020, the odds of receiving expectant management and focal ablation were 90% (AOR = 1.90, 95% confidence interval [CI] = 1.71 to 2.11) and 44% (AOR = 1.44, 95% CI = 1.31 to 1.57) higher, respectively, than in 2010. Black patients had increased odds of expectant management (AOR = 1.47, 95% CI = 1.39 to 1.55) but decreased odds of focal ablation (AOR = 0.93, 95% CI = 0.88 to 0.99). CONCLUSION: Over the decade, the use nonoperative management of small renal masses increased, with expectant management more frequently used than focal ablation among Black patients. Possible explanations include race-based differences in physicians' risk assessments and resource allocation. Adjusting for Black race in calculations for glomerular filtration rate could influence the differential uptake of these techniques through deflated glomerular filtration rate calculations. These findings highlight the need for research and policies to ensure equitable use of less invasive treatments in small renal masses.

Uncovering the Changing Treatment Landscape for Low-risk Prostate Cancer in the USA from 2010 to 2020: Insights from the National Cancer Data Base.

The management of prostate cancer (PCa) has evolved from a paradigm of "treat when caught early" to "treat only when necessary". Despite inconsistency in its use, active surveillance has evolved over the past two decades into the gold standard for management of low-risk PCa. Our objective was to investigate whether the use of expectant management (active surveillance, watchful waiting, no treatment) as a first-line approach for low-risk PCa has increased over the past decade. We queried the US National Cancer Data Base for men diagnosed with localized PCa between 2010 and 2020. Two multivariable logistic regression models with different two-way interaction terms (year of diagnosis × D'Amico risk classification, and year of diagnosis × International Society of Urological Pathology [ISUP] grade group) were fitted to predict the probability of undergoing expectant management versus active treatment. The predicted probability of expectant management increased from 13.7% in 2010 to 64.4% in 2020 for men with low-risk PCa, and from 12.9% in 2010 to 61.6% in 2020 for ISUP grade group 1 PCa (both pinteraction < 0.001). The frequency of expectant management for low-risk PCa has increased dramatically during the past decade. We expect this trend to further increase owing to the growing awareness of the harms of overtreatment of indolent disease. PATIENT SUMMARY: We examined the use of expectant management for prostate cancer between 2010 and 2020 in a large hospital-based registry from the USA. We found that the proportion of men receiving expectant management for low-risk prostate cancer is increasing. We conclude that growing awareness of the harms of overtreatment has profoundly affected trends for prostate cancer treatment in the USA.

Development of an Endoscopic Spine Surgery Program: Overview and Basic Considerations for Implementation.

Endoscopic spine surgery (ESS) is an innovative technique allowing for minimally invasive, direct visualization of spinal abnormalities. The growth of ESS in the United States has been stunted by high start-up costs, low reimbursement rates, and the steep learning curve associated with mastering endoscopic techniques. Hergrae, we describe the current state and future direction of ESS and provide key action items for ESS program implementation.