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Assessing the persistence of chemicals in the environment is a key element in existing regulatory frameworks to protect human health and ecosystems. Persistence in the environment depends on many fate processes, including abiotic and biotic transformations and physical partitioning, which depend on substances' physicochemical properties and environmental conditions. A main challenge in persistence assessment is that existing frameworks rely on simplistic and reductionist evaluation schemes that may lead substances to be falsely assessed as persistent or the other way around-to be falsely assessed as nonpersistent. Those evaluation schemes typically assess persistence against degradation half-lives determined in single-compartment simulation tests or against degradation levels measured in stringent screening tests. Most of the available test methods, however, do not apply to all types of substances, especially substances that are poorly soluble, complex in composition, highly sorptive, or volatile. In addition, the currently applied half-life criteria are derived mainly from a few legacy persistent organic pollutants, which do not represent the large diversity of substances entering the environment. Persistence assessment would undoubtedly benefit from the development of more flexible and holistic evaluation schemes including new concepts and methods. A weight-of-evidence (WoE) approach incorporating multiple influencing factors is needed to account for chemical fate and transformation in the whole environment so as to assess overall persistence. The present paper's aim is to begin to develop an integrated assessment framework that combines multimedia approaches to organize and interpret data using a clear WoE approach to allow for a more consistent, transparent, and thorough assessment of persistence. Integr Environ Assess Manag 2022;18:868-887. © 2021 ExxonMobil Biomedical Sciences, Inc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental ToxicologyChemistry (SETAC).

PURPOSE: To report long term follow-up of the efficacy of subtotal prostate ablation using a “hockey-stick” template, including oncologic control and quality of life (QoL) impact. METHODS: We performed a prospective controlled trial to evaluate the efficacy of subtotal prostate ablation in selected men with baseline and confirmatory biopsy showing grade group (GG) 1–2 prostate cancer. “Hockey-stick” cryoablation that included the ipsilateral hemi-gland and contralateral anterior prostate was performed. Prostate biopsies and QOL queries were performed at 6, 18 and 36 months following regional ablation, and follow-up was updated to include subsequent clinic visits. RESULTS: Between August 2009 and January 2012, 72 men were screened for eligibility and 47 opted to undergo confirmatory biopsy. Of these, 23 were deemed eligible and treated with regional cryoablation. Median age was 64 years. Median follow-up was 74 months. A single patient had

Evidence suggests that visceral fat quantity may be associated with post-prostatectomy outcomes and risk of prostate cancer related death. We evaluated whether increased fat volume, normalized to prostate size, is associated with decreased risk of disease progression.Patients enrolled on a prospective active surveillance trial for at least 6 months who had magnetic resonance imaging within 2 years of enrollment were eligible. The surveillance protocol included a standardized followup regimen consisting of biennial prostate specific antigen and examination and yearly biopsy. Clinicopathological characteristics were collected at baseline. Three fat measurements were taken using prostate magnetic resonance imaging, including subcutaneous, linear periprostatic (pubic symphysis to prostate) and volumetrically defined periprostatic. Progression was defined as increase in Gleason grade group. Multivariable Cox proportional hazards models were used to evaluate fat volumes normalized by prostate size (stratified into tertiles).A total of 175 patients were included in the study. Average age was 62.5 years (SD 7.4) and average prostate specific antigen was 5.4 ng/dl (SD 3.9). Median followup was 42 months (IQR 18-60) and 50 patients (28.6%) had progression. Compared to the lowest tertile, the highest tertile of volumetric periprostatic fat measurement (HR 2.63, 95% CI 1.23-5.60, p=0.01) and linear periprostatic fat measurement (HR 2.30, 95% CI 1.01-5.22, p=0.05) were associated with worsened progression-free survival, while subcutaneous fat measurement (p=0.97) was not. Importantly, the model did not substantively change when accounting for patient body mass index and other factors.Increased periprostatic fat volume, normalized to prostate size, may be associated with shortened progression-free survival in men with prostate cancer on active surveillance.

Any new pulmonary edema warrants an urgent rule out of acute cardiac dysfunction. Because sepsis protocols emphasize rapid stabilization and treatment over etiologic evaluation, some cases of endocarditis may be missed as sepsis with acute respiratory distress syndrome.

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

PURPOSE Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature. PATIENTS AND METHODS A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269 ) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81). CONCLUSION The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.

BACKGROUND The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy. METHODS All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected. RESULTS A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P

Objective To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. Summary of background data The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. Methods The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. Results We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. Conclusions Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

ObjectiveSARS-CoV-2 has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming COVID-19 respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterise the likelihood of patients with COVID-19 to progress to severe hypoxemic respiratory failure are still needed.DesignWe conducted a retrospective cohort study to develop a model using demographic and clinical data collected in the first 12 hours of admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalised patients with COVID-19.SettingUniversity-based healthcare system including six hospitals located in the Galveston, Brazoria and Harris counties of Texas.ParticipantsAdult patients diagnosed with COVID-19 and admitted to one of six hospitals between 19 March and 30 June 2020.Primary outcomeThe primary outcome was defined as reaching a WHO ordinal scale between 6 and 9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation.ResultsWe included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), Quick Sequential Organ Failure Assessment score (OR 2.26) and neutrophil to lymphocyte ratio (OR 1.15) were significant predictors of severe disease. The final model showed an area under the curve of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies.ConclusionsOur study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.

BACKGROUND The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P

ObjectiveThe severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming Coronavirus-Disease-2019 (COVID-19) respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterize COVID-19 patients’ likely to progress to severe hypoxemic respiratory failure are still needed.DesignWe conducted a retrospective cohort study to develop a model utilizing demographic and clinical data collected in the first 12-hours admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalized COVID-19 patients.SettingUniversity based healthcare system including 6 hospitals located in the Galveston, Brazoria and Harris counties of Texas.ParticipantsAdult patients diagnosed with COVID-19 and admitted to one of six hospitals between March 19th and June 31st, 2020.Primary outcomeThe primary outcome was defined as reaching a WHO ordinal scale between 6-9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation.ResultsWe included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), qSOFA score (OR: 2.26), and neutrophil to lymphocyte ratio (OR:1.15) were significant predictors of severe disease. The final model showed an area under curve (AUC) of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies.ConclusionsOur study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.STRENGTHS AND LIMITATIONS OF THIS STUDY⍰Our study utilized objective and measurable demographic and clinical information regularly available in healthcare settings even among patients unable to communicate.⍰Our primary outcome corresponds to WHO ordinal score which would allow compare our results to other studies and in other settings.⍰Our model could serve as an effective point of service tool during early admission to assist in clinical management and allocation of resources to unvaccinated patients.⍰Our study is a retrospective study of unvaccinated COVID19 patients, and validation of our prediction model in the rest of our study population is still needed.⍰In addition, testing our model in a more recent cohort after emergence of new SARS-CoV-2 variants will be needed to assess its robustness.

INTRODUCTION AND OBJECTIVE:Robotic-assisted radical cystectomy with intracorporeal urinary diversion (RARC-ICUD) is now widely considered a standard of care treatment for muscle invasive bladder ca...

Gig economy compensation policy initiatives, such as California Prop 22, are increasing the number of US workers receiving piece rate pay (PRP) and other forms of insecure income. However, there is limited evidence about how this trend affects people's health. Using data from the 2008-19 IPUMS Medical Expenditure Panel Survey (MEPS), we examined associations between insecure compensation and US adults' self-reported overall health as well as psychological distress. We report significant associations with three types of insecure income - PRP, hourly, and daily pay - on overall health and psychological distress. These effects were robust to adjustment for suspected confounders, but point estimates suggested that the effect of each type of non-salary compensation differed by sex, level of education, income level, and health insurance coverage. These findings warrant policy makers' consideration as they balance the purported benefits of gig economy non-salary compensated work with implications for workers' health.

Objective This study aimed to identify factors associated with surgeon perception of robot‐assisted radical prostatectomy (RARP) difficulty. Patients and Methods This study surveyed surgeons performing RARP between 2017 and 2018 and asked them to rate operative conditions and difficulty as optimal, good, acceptable, or poor. These answers were stratified as optimal or suboptimal for this study. Associations between surgeon responses and variables hypothesized to affect surgical difficulty, including anatomic factors such as pelvic diameter and prostate volume:pelvic diameter ratio, were assessed. Results Between November 2017 and September 2018, a total of 100 patients were prospectively enrolled in the study of which 58 cases were rated as optimal and 42 were rated as suboptimal. Of the evaluated variables, only increasing clinical T stage (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.03–2.15, p = 0.03) and increasing body mass index (BMI) (OR 1.14, 95% CI 1.03–1.26, p = 0.01) were associated with increased difficulty; 90‐day complication rates were similar between the optimal and suboptimal cohorts (17.3% vs. 23.8%, respectively; p = 0.5). The number of patients with previous surgery, pelvic diameter, and prostate size:pelvic diameter ratio were not significantly different between cohorts (p > 0.05 for all). Operative time (ρ = 0.23, p = 0.02) and estimated blood loss (EBL) (ρ = 0.38, p = 0.0001) were correlated with suboptimal difficulty. Conclusion The factors associated with surgeon‐reported RARP difficulty were patient BMI and clinical T stage among surgeons with significant RARP experience. These data should be incorporated into surgical decision making and patient counseling prior to performing a RARP.

ObjectiveTo estimate the US incidence of thrombotic events and related rare diagnoses.DesignClaims-based retrospective cohort study of incidence.SettingUS commercial health insurance administrative claims database.ParticipantsAdults 25-65 years of age between 2015 and 2019 with a minimum of 12 consecutive thrombosis-free months of continuous enrollment beginning 2014 were selected.Main OutcomesAge (10-year intervals) and sex stratum specific incidence rates per 100,000 person-years were determined for: venous thromboembolism (VTE), cerebral venous thrombosis (CVT), and other major venous thrombotic events, and events of special interest, including immune thrombocytopenic purpura (ITP), hemolytic-uremic syndrome (HUS), and heparin-induced thrombocytopenia (HIT).ResultsOf 13,249,229 enrollees (half female/male), incidence of venous thromboembolic events (DVT, PE, CVT, or other major venous thrombotic conditions) was 247.89 per 100,000 person-years (95% CI: 245.96, 249.84). Incidence of VTE was 213.79 with ICD codes alone (95% CI: 211.99, 215.59) and 127.18 (95% CI: 125.80, 128.58) when also requiring a filled anticoagulation prescription. Incidence was 6.37 for CVT (95% CI: 6.07, 6.69), 26.06 for ITP (95% CI: 25.44, 26.78), 0.94 for HUS (95% CI: 0.82, 1.06), and 4.82 for HIT (95% CI: 4.56, 5.10). The co-occurrence of CVT with either ITP or HIT (diagnoses within 14 days of one another) was 0.090 (95% CI: 0.06, 0.13). Incidence tended to increase with age and was higher for women under 55. Incidence for CVT, HUS, and CVT with ITP or HIT was higher for women in all age groups. Incidence of PE and CVT increased significantly over the five-year period, while DVT rates decreased.ConclusionsThese results are the first US estimates for incidence of thrombotic and rare events of interest in a large, commercially-insured US population. Findings provide a critically important reference for determining excess morbidity associated with COVID-19 and more generally for vaccine pharmacovigilance.BOX POINTSWhat is already known on this topic?Incidence of venous thromboembolic diagnoses vary by country and date.There have been improvements in the past decade in thromboprophylaxis (e.g., for deep vein thrombosis) and detection (e.g., for cerebral venous thrombosis), but there are no recent comprehensive estimates for the United States.What this study addsOur results document the US incidence of thrombotic and related rare diagnoses for the most recent five-year pre-pandemic period (2015-2019) in an insured population.

ObjectiveTo estimate relative risk (RR) of statin-associated musculoskeletal symptoms by statin therapy intensity.SettingNetwork meta-analysis assessing multicentre randomised controlled trials (RCTs) across several countries.ParticipantsPubMed, Web of Science, Cochrane database and ClinicalTrials.gov were searched through January 2021 for doubled-blinded RCTs testing the effect of statin therapy on lipids with at least 1000 participants and 2 years of intended treatment. Two coders assessed articles for final inclusion, quality and outcomes. Treatment intensity was categorised according to American Heart Association definitions.OutcomesPairwise and network meta-analysis (NMA) estimated RR and risk difference with random effects modelling. Heterogeneity was evaluated with the I2 statistic. Outcomes included muscle symptoms (any, myalgia and attrition due to muscle symptoms), rhabdomyolysis and elevated creatine kinase (CK) (>10 × upper limit of normal).ResultsOf 2919 RCTs, 24 (n=152 461) met inclusion criteria. NMA results indicated risk was significantly greater for high compared with moderate intensity statin therapy for any muscle problem (RR=1.04, 95% CI 1.00 to 1.07; I2=0%), myalgia (RR=1.04, 95% CI 1.00 to 1.08; I2=0%, number needed to harm (NNH)=173), attrition due to muscle problems (RR=1.37, 95% CI 1.09 to 1.73, I2=0%, NNH=218) and elevated CK (RR=4.69, 95% CI 2.50 to 8.80; I2=7%, NNH=527). Risk also was significantly higher for high intensity compared with placebo for any muscle problem (RR=1.05, 95% CI 1.01 to 1.09, I2=0%), myalgia (RR=1.13, 95% CI 1.05 to 1.23; I2=0%, NNH=182), attrition due to muscle problems (RR=1.55, 95% CI 1.15 to 2.08, I2=0%, NNH=187) and elevated CK (RR=5.37, 95% CI 2.48 to 11.61; I2=7%, NNH=589). Due to inconsistency of results across sensitivity analyses, estimates were inconclusive for rhabdomyolysis and CK. There were no significant differences in risk between moderate intensity therapy and placebo for all outcomes.ConclusionsFor approximately each 200 patients on high intensity statins, one additional patient may experience myalgia or discontinue therapy due to muscle problems compared with moderate intensity therapy.Trial registration numberCRD42019112758.

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.

Background We aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in men with National Comprehensive Cancer Network (NCCN) favorable-intermediate risk (F-IR) prostate cancer (PCa), and to better select F-IR candidates for active surveillance (AS). Methods In all, 647 patients diagnosed with NCCN very low/low risk (VL/LR) or F-IR prostate cancer were identified from a multi-institutional PCa biopsy database; all underwent RP with complete postoperative clinicopathological information and Decipher genomic risk scores. The performance of all risk assessment tools was evaluated using logistic regression model for the endpoint of AP, defined as grade group 3−5, pT3b or higher, or lymph node invasion. Results The median age was 61 years (interquartile range 56–66) for 220 patients with NCCN F-IR disease, 53% classified as low-risk by Cancer of the Prostate Risk Assessment (CAPRA 0−2) and 47% as intermediate-risk (CAPRA 3−5). Decipher classified 79%, 13% and 8% of men as low-, intermediate- and high-risk with 13%, 10%, and 41% rate of AP, respectively. Decipher was an independent predictor of AP with an odds ratio of 1.34 per 0.1 unit increased (p value = 0.002) and remained significant when adjusting by CAPRA. Notably, F-IR with Decipher low or intermediate score did not associate with significantly higher odds of AP compared to VL/LR. Conclusions NCCN risk groups, including F-IR, are highly heterogeneous and should be replaced with multivariable risk-stratification. In particular, incorporating Decipher may be useful for safely expanding the use of AS in this patient population.