Enzymatic detection of α-hydroxybutyrate, an important marker of insulin resistance, and comparison with LC-MS/MS detection.

Aim: The metabolite α-hydroxybutyrate (α-HB) is an important marker of insulin resistance and impaired glucose tolerance allowing to identify patients at risk of developing diabetes and related metabolic disorders before any symptoms become apparent. At present, its exact quantification requires mass spectrometry (LC-MS), which is not compatible with routine laboratory use. Accordingly, a simple enzymatic-based method was assessed and its applicability and measuring accuracy compared with LC-MS was investigated. Methods: Standards, serum, and plasma samples containing α-HB were prepared with routine procedures and their α-HB contents measured with the XpressGT® enzymatic test kit photometrically or with LC-MS and multiple reaction monitoring. Results: α-HB detection with XpressGT® yielded highly linear calibration curves and 102 % recovery of stocks added to commercial samples. Stability of the analyte in serum and plasma samples prepared with various anti-coagulants was >90 % after 46 h for several widely used preparations and recovery after 3 freeze-thaw cycles was ≥95 % with these anti-coagulants. A direct comparison of 75 samples indicated very good agreement of α-HB levels determined by both methods, 86 % of XpressGT® samples being within ±20 % of LC-MS values and even 93 % within ±20 % considering only samples above 30 µM concentration. Conclusion: XpressGT®-based detection of α-HB is an easily applicable method which can be used for accurate and reliable quantification of the metabolite in clinical practice. Routine α-HB determination in patients at risk of developing diabetes would allow early establishment of preventive measures or pharmacological intervention reducing the risk for the onset of serious diabetes-related health problems.

Predicting Peak Productivity in Urologic Medicare Practice via Work-Relative Value Units.

OBJECTIVE: To explore factors associated with productivity in urologic practice. Work-relative value units (wRVUs), the basis for Center for Medicare & Medicaid Services (CMS) and private payer reimbursements, commonly serve to estimate physician productivity. Limited data describes which practice factors predict increased wRVU productivity. METHODS: The 2017 and 2018 CMS databases were retrospectively queried for urologic Medicare provider demographics and procedural/service details. Medical school graduation year was used to estimate years in practice and generation (Millennial, Gen X, Baby Boomer, or Post-War). Treated patients' demographics were obtained. Adjusted and unadjusted linear mixed models were performed to predict wRVU production. RESULTS: Included were 6773 Medicare-participating urologists across the United States. Millennials produced 1115 wRVUs per year, while Gen X and Baby Boomers produced significantly more (1997 and 2104, respectively, P <.01). Post-War urologists produced numerically more (1287, P = .88). In adjusted analyses, predictors of Medicare wRVU productivity included female and pelvic medicine and reconstructive surgery (exponentiated beta estimate (ß) 1.46, 95% CI 1.32-1.60), men's health (ß 1.22, 95% CI 1.13-1.32), and oncologic subspecialization (ß 1.08, 95% CI 1.02-1.14), female gender (ß 0.87, 95% CI 0.82-0.92), wRVUs generated from inpatient procedures (ß 1.08, 95% CI 1.06-1.09) and office visits (ß 0.88, 95% CI 0.87-0.89), and the level of education (ß 1.10, 95% CI 1.07-1.14) and percent impoverished patients (ß 0.85, 95% CI 0.83-0.88) in provider's practice zip code. CONCLUSION: Urologic experience, specialization, demographics, practice patterns, and patient demographics are significantly associated with wRVU productivity in Medicare settings. Further work should incorporate quality metrics into wRVUs and ensure patient demographics do not affect reimbursement.

Outcomes for Arthroplasties in Military Health: A Retrospective Analysis of Direct Versus Purchased Care.

INTRODUCTION: The Department of Defense is reforming the military health system where surgeries are increasingly referred from military treatment facilities (MTFs) with direct care to higher-volume civilian hospitals under purchased care. This shift may have implications on the quality and cost of care for TRICARE beneficiaries. This study examined the impact of care source and surgical volume on perioperative outcomes and cost of total hip arthroplasties (THAs) and total knee arthroplasties (TKAs). MATERIALS AND METHODS: We examined TRICARE claims for patients who underwent THA or TKA between 2006 and 2019. The 30-day readmissions, complications, and costs between direct and purchased care were evaluated using the logistic regression model for surgical outcomes and generalized linear models for cost. RESULTS: We included 71,785 TKA and THA procedures. 11,013 (15.3%) were performed in direct care. They had higher odds of readmissions (odds ratio, OR 1.29 [95% CI, 1.12-1.50]; P < 0.001) but fewer complications (OR 0.83 [95% CI, 0.75-0.93]; P = 0.002). Within direct care, lower-volume facilities had more complications (OR 1.27 [95% CI, 1.01-1.61]; P = 0.05). Costs for index surgeries were significantly higher at MTFs $26,022 (95% CI, $23,393-$28,948) vs. $20,207 ($19,339-$21,113). Simulating transfer of care to very high-volume MTFs, estimated cost savings were $4,370/patient and $20,229,819 (95% CI, $17,406,971-$25,713,571) in total. CONCLUSIONS: This study found that MTFs are associated with lower odds of complications, higher odds of readmission, and higher costs for THA and TKA compared to purchased care facilities. These findings mean that care in the direct setting is adequate and consolidating care at higher-volume MTFs may reduce health care costs.

Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes.

Microneedle lactate sensors may be used to continuously measure lactate concentration in the interstitial fluid in a minimally invasive and pain-free manner. First- and second-generation enzymatic sensors produce a redox-active product that is electrochemically sensed at the electrode surface. Direct electron transfer enzymes produce electrons directly as the product of enzymatic action; in this study, a direct electron transfer enzyme specific to lactate has been immobilized onto a microneedle surface to create lactate-sensing devices that function at low applied voltages (0.2 V). These devices have been validated in a small study of human volunteers; lactate concentrations were raised and lowered through physical exercise and subsequent rest. Lactazyme microneedle devices show good agreement with concurrently obtained and analyzed serum lactate levels.

Neurocognitive impairment associated with traditional and novel androgen receptor signaling inhibitors ± androgen deprivation therapy: a pharmacovigilance study.

BACKGROUND: Conflicting evidence exists regarding whether hormone therapy for prostate cancer is associated with neurotoxicity. Thus, we aim to characterize the association between different types of hormone therapy and neurocognitive impairment in a real-world pharmacovigilance database. METHODS: We queried VigiBase, the World Health Organization's international pharmacovigilance database, for reports of neurocognitive impairment among men who took hormone therapy from 1968 to 2021. We performed disproportionality analysis comparing rates of neurocognitive impairment with different types of hormone therapy versus other VigiBase drugs. Traditional hormonal therapy was defined as androgen deprivation therapy (ADT: gonadotropin-releasing-hormone agonists or antagonists) or first-generation androgen receptor (AR) antagonists. Novel AR signaling inhibitors (ARSIs) were defined as ARSIs with or without ADT. Differences were assessed using reporting odds ratio (ROR) with 95% confidence intervals (CI) and Empirical Bayes Estimator (EBE) values ≥1.0 signifying statistical significance. RESULTS: Odds of neurocognitive impairment were significantly elevated with traditional hormone therapy (ROR 1.47, 95% CI 1.34-1.62, EBE = 1.35) and novel ARSIs (ROR 2.40, 95% CI 2.28-2.54, EBE = 2.26). Odds of neurocognitive impairment were significantly elevated with enzalutamide (ROR 2.89, 95% CI 2.73-3.05, EBE = 2.70) and numerically increased with apalutamide (ROR 3.31, 95% CI 1.57-7.00, EBE = 0.98), but were decreased with abiraterone (ROR 0.68, 95% CI 0.55-0.84, EBE = 0.57). CONCLUSIONS: This study demonstrates elevated odds of neurocognitive impairment with hormone therapy in a real-world data set. Neurotoxicity risk was higher with novel ARSIs than traditional agents, and higher with enzalutamide than abiraterone. Due to limitations inherent to disproportionality analysis (measuring associations, not risk) and incomplete data prohibiting the ability to control for factors such as age or use of secondary drugs (e.g., concurrent use of novel ARSIs with ADT), results are exploratory in nature. The amalgamation of these and other conflicting data may contribute to clinical decision-making for men with prostate cancer eligible for treatment with these therapies, especially those with significant neurologic comorbidities.

Flavin Mononucleotide-Dependent l-Lactate Dehydrogenases: Expanding the Toolbox of Enzymes for l-Lactate Biosensors.

The development of L-lactate biosensors has been hampered in recent years by the lack of availability and knowledge about a wider range and diversity of L-lactate-oxidizing enzymes that can be used as bioelements in these sensors. For decades, L-lactate oxidase of Aerococcus viridans (AvLOx) has been used almost exclusively in the field of L-lactate biosensor development and has achieved somewhat like a monopoly status as a biocatalyst for these applications. Studies on other L-lactate-oxidizing enzymes are sparse and are often missing biochemical data. In this work, we made use of the vast amount of sequence information that is currently available on protein databases to investigate the naturally occurring diversity of L-lactate-utilizing enzymes of the flavin mononucleotide (FMN)-dependent α-hydroxy acid oxidoreductase (HAOx) family. We identified the HAOx sequence space specific for L-lactate oxidation and additionally discovered a not-yet described class of soluble and FMN-dependent L-lactate dehydrogenases, which are promising for the construction of second-generation biosensors or other biotechnological applications. Our work paves the way for new studies on α-hydroxy acid biosensors and proves that there is more to the HAOx family than AvLOx.

Does Veteran Status Mitigate Racial Disparities in Prostate Cancer Screening? Analysis of Prostate Specific Antigen Screening Patterns in the 2018 Behavioral Risk Factor Surveillance System Data.

PURPOSE: We examined the effect of veteran status on prostate specific antigen (PSA) screening and whether health coverage available to veterans mitigates racial disparities in PSA screening. MATERIALS AND METHODS: We conducted a cross-sectional analysis of non-Hispanic White (NHW) and non-Hispanic Black (NHB) men aged between 55 and 69 years who responded to the PSA screening survey in the 2018 Behavioral Risk Factor Surveillance System data. Complex weighted logistic regression models were used to evaluate predictors of PSA screening. RESULTS: Screening prevalence was 43% in veterans (95% CI 42%-45%) versus 40% in nonveterans (95% CI 39%-40%, p <0.001). Among nonveterans, the prevalence of PSA screening was significantly lower in NHB (34%, 95% CI 31%-37%) versus NHW men (40%, 95% CI 39%-41%, p <0.001). Among veterans, NHB men had a significantly higher screening prevalence (48%, 95% CI 43%-54%) versus NHW men (42%, 95% CI 41%-44%, p=0.04). In adjusted analysis, veteran status (OR 1.11, 95% CI 1.01-1.21, p=0.02) and NHB race (OR 1.29, 95% CI 1.12-1.48, p <0.001) were significantly associated with receipt of PSA screening. Given that we found an interaction between veteran status and race (pint=0.03), a marginal analysis was performed. Compared to NHB nonveterans, NHB veterans had higher odds of undergoing PSA screening (OR 1.46, 95% CI 1.11-1.91, p=0.01). However, this association was not demonstrated when comparing NHW veterans versus nonveterans (OR 1.06, CI 0.97-1.16, p=0.22). CONCLUSIONS: Veteran status and NHB race were found to be independent predictors of PSA screening. The interaction between veteran status and race suggests that access to health coverage available to veterans may mitigate racial differences in prostate cancer screening behaviors. Further studies are needed to translate such findings into the civilian health care system.

Engineering the Turnover Stability of Cellobiose Dehydrogenase toward Long-Term Bioelectronic Applications.

Cellobiose dehydrogenase (CDH) is an attractive oxidoreductase for bioelectrochemical applications. Its two-domain structure allows the flavoheme enzyme to establish direct electron transfer to biosensor and biofuel cell electrodes. Yet, the application of CDH in these devices is impeded by its limited stability under turnover conditions. In this work, we aimed to improve the turnover stability of CDH by semirational, high-throughput enzyme engineering. We screened 13 736 colonies in a 96-well plate setup for improved turnover stability and selected 11 improved variants. Measures were taken to increase the reproducibility and robustness of the screening setup, and the statistical evaluation demonstrates the validity of the procedure. The selected CDH variants were expressed in shaking flasks and characterized in detail by biochemical and electrochemical methods. Two mechanisms contributing to turnover stability were found: (i) replacement of methionine side chains prone to oxidative damage and (ii) the reduction of oxygen reactivity achieved by an improved balance of the individual reaction rates in the two CDH domains. The engineered CDH variants hold promise for the application in continuous biosensors or biofuel cells, while the deduced mechanistic insights serve as a basis for future enzyme engineering approaches addressing the turnover stability of oxidoreductases in general.

Racial differences in the treatment and outcomes for prostate cancer in Massachusetts.

BACKGROUND: Massachusetts is a northeastern state with universally mandated health insurance since 2006. Although Black men have generally worse prostate cancer outcomes, emerging data suggest that they may experience equivalent outcomes within a fully insured system. In this setting, the authors analyzed treatments and outcomes of non-Hispanic White and Black men in Massachusetts. METHODS: White and Black men who were 20 years old or older and had been diagnosed with localized intermediate- or high-risk nonmetastatic prostate cancer in 2004-2015 were identified in the Massachusetts Cancer Registry. Adjusted logistic regression models were used to assess predictors of definitive therapy. Adjusted and unadjusted survival models compared cancer-specific mortality. Interaction terms were then used to assess whether the effect of race varied between counties. RESULTS: A total of 20,856 men were identified. Of these, 19,287 (92.5%) were White. There were significant county-level differences in the odds of receiving definitive therapy and survival. Survival was worse for those with high-risk cancer (adjusted hazard ratio [HR], 1.50; 95% CI, 1.4-1.60) and those with public insurance (adjusted HR for Medicaid, 1.69; 95% CI, 1.38-2.07; adjusted HR for Medicare, 1.2; 95% CI, 1.14-1.35). Black men were less likely to receive definitive therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.83) but had a 17% lower cancer-specific mortality (adjusted HR, 0.83; 95% CI, 0.7-0.99). CONCLUSIONS: Despite lower odds of definitive treatment, Black men experience decreased cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population. LAY SUMMARY: There is a growing body of evidence showing that the excess risk of death among Black men with prostate cancer may be caused by disparities in access to care, with few or no disparities seen in universally insured health systems such as the Veterans Affairs and US Military Health System. Therefore, the authors sought to assess racial disparities in prostate cancer in Massachusetts, which was the earliest US state to mandate universal insurance coverage (in 2006). Despite lower odds of definitive treatment, Black men with prostate cancer experience reduced cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.

Comparison of comorbidity indices for prediction of morbidity and mortality after major surgical procedures.

BACKGROUND: Assessing perioperative risk is essential for surgical decision-making. Our study compares the accuracy of comorbidity indices to predict morbidity and mortality. METHODS: Analyzing the National Surgical Quality Improvement Program, 16 major procedures were identified and American Society of Anesthesiologists (ASA), Charlson Comorbidity Index and modified Frailty Index were calculated. We fit models with each comorbidity index for prediction of morbidity, mortality, and prolonged length of stay (pLOS). Decision Curve Analysis determined the effectiveness of each model. RESULTS: Of 650,437 patients, 11.7%, 6.0%, 17.0% and 0.75% experienced any, major complication, pLOS, and mortality, respectively. Each index was an independent predictor of morbidity, mortality, and pLOS (p < 0.05). While the indices performed similarly for morbidity and pLOS, ASA demonstrated greater net benefit for threshold probabilities of 1-5% for mortality. CONCLUSIONS: Models including readily available factors (age, sex) already provide a robust estimation of perioperative morbidity and mortality, even without considering comorbidity indices. All comorbidity indices show similar accuracy for prediction of morbidity and pLOS, while ASA, the score easiest to calculate, performs best in prediction of mortality.

Is the current referral trend a threat to the Military Health System? Perioperative outcomes and costs after colorectal surgery in the Military Health System versus civilian facilities.

BACKGROUND: TRICARE military beneficiaries are increasingly referred for major surgeries to civilian hospitals under "purchased care." This loss of volume may have a negative impact on the readiness of surgeons working in the "direct-care" setting at military treatment facilities and has important implications under the volume-quality paradigm. The objective of this study is to assess the impact of care source (direct versus purchased) and surgical volume on perioperative outcomes and costs of colorectal surgeries. METHODS: We examined TRICARE claims and medical records for 18- to 64-year-old patients undergoing major colorectal surgery from 2006 to 2015. We used a retrospective, weighted estimating equations analysis to assess differences in 30-day outcomes (mortality, readmissions, and major or minor complications) and costs (index and total including 30-day postsurgery) for colorectal surgery patients between purchased and direct care. RESULTS: We included 20,317 patients, with 24.8% undergoing direct-care surgery. Mean length of stay was 7.6 vs 7.7 days for direct and purchased care, respectively (P = .24). Adjusted 30-day odds between care settings revealed that although hospital readmissions (odds ratio 1.40) were significantly higher in direct care, overall complications (odds ratio 1.05) were similar between the 2 settings. However, mean total costs between direct and purchased care differed ($55,833 vs $30,513, respectively). Within direct care, mean total costs ($50,341; 95% confidence interval $41,509-$59,173) were lower at very high-volume facilities compared to other facilities ($54,869; 95% confidence interval $47,822-$61,916). CONCLUSION: Direct care was associated with higher odds of readmissions, similar overall complications, and higher costs. Contrary to common assumptions regarding volume and quality, higher volume in the direct-care setting was not associated with fewer complications.

Risk of Dementia and Depression in Young and Middle-aged Men Presenting with Nonmetastatic Prostate Cancer Treated with Androgen Deprivation Therapy.

BACKGROUND: Previous studies have found an association between androgen deprivation therapy (ADT) and an increased risk of dementia and depression in elderly men. This association remains controversial, and little is known about the effects of ADT in younger men. OBJECTIVE: To examine the association between the receipt of ADT and these outcomes in young men aged 40-64 yr presenting with nonmetastatic prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: For this observational study, we identified 9117 men aged 40-64 yr diagnosed with localized PCa between 2007 and 2014, without a pre-existing neurocognitive diagnosis, using the TRICARE military database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves were fitted to compare ADT versus no ADT. We also performed a subgroup analysis in patients undergoing ADT for ≥12 mo. The association between ADT and new-onset dementia or depression was evaluated using inverse-probability-of treatment-weight-adjusted Cox proportional hazards regression analysis. RESULTS AND LIMITATIONS: Patients receiving ADT had a significantly higher incidence of depression (30.2 vs 15.8 per 1000 person years) and dementia (17.9 vs 7.5 per 1000 person years). The risk of developing either outcome was higher in the ADT cohort (depression: hazard ratio [HR] 2.07, p < 0.001; dementia: HR 1.70, p = 0.052). Additionally, there was a dose-response relationship between the duration of ADT and either outcome. CONCLUSIONS: In our cohort of young men with PCa, the receipt of ADT was associated with an increased risk of developing dementia and depression. Long-term use of ADT was associated with the highest risk of neurocognitive outcomes. PATIENT SUMMARY: In this study, we looked at the risk of dementia and depression in patients <65 yr of age undergoing androgen deprivation therapy (ADT) for prostate cancer. We found that these patients had a higher risk of dementia and depression than those who did not undergo ADT.

Contemporary Treatment Patterns for Non-muscle-invasive Bladder Cancer: Has the Use of Radical Cystectomy Changed in the BCG Shortage Era?

OBJECTIVE: To examine recent treatment trends for non-muscle-invasive bladder cancer (NMIBC), and specifically, to assess whether there was a change in use radical cystectomy (RC) between 2008 and 2015 using data from the Surveillance, Epidemiology, and End Results database. METHODS: We identified patients presenting with high-grade T1 (T1HG) NMIBC at diagnosis during the study period. Treatment was dichotomized into "RC" and "local treatment" (which included transurethral resection and intravesical therapies). We then employed multivariable logistic regression models to assess the odds of undergoing RC across the study period. Additionally we examined the rates of RC for T1HG NMIBC during the period of BCG-shortage, defined as 2012-2015. RESULTS: We identified 21,817 individuals diagnosed with T1HG bladder cancer during the study period. The majority of patients underwent local treatment (94.5%). During the shortage period, the rate of RC for T1HG NMIBC was significantly lower compared to the preshortage era (5.1% vs 5.9%, P = .007). Across the study period, the utilization of RC for T1HG NMIBC decreased significantly (odds ratio 0.99 per quarter, 95% confidence interval 0.98-0.99, P = .017). CONCLUSION: In our cohort of patients diagnosed with T1HG bladder cancer, we found a significant decrease in the use of radical cystectomy across the study period. Contrary to the hypothesis of increasing rates of RC in the face of BCG shortage, the rate of RC was significantly higher in the pre-shortage era. Further examination of NMIBC treatment patterns will be necessary to assess the impact of BCG availability on therapeutic pathways and oncologic outcomes in patients with high-grade NMIBC.

The Relationship Between Health Literacy and Nonrecommended Cancer Screening.

INTRODUCTION: Health literacy affects how patients behave within the healthcare system. Overutilization of screening procedures inconsistent with the U.S. Preventive Services Task Force guidelines contributes to the high cost of health care. The authors hypothesize that higher health literacy supports guideline-concordant screening. This study assesses the effect of health literacy on nonrecommended prostate, breast, and cervical cancer screening in patients older than the recommended screening age limit. METHODS: The 2016 Behavioral Risk Factor Surveillance System included health literacy modules. Respondents self-reported their ability to obtain and understand health information, resulting in 4 health literacy rankings. The authors calculated the population-weighted proportion of respondents in each health literacy category who underwent screening past the Task Force‒recommended age limit. The ORs of nonrecommended screening for each malignancy were calculated, with low health literacy as the ref category. RESULTS: Individuals with higher health literacy underwent more nonrecommended screening. Nonrecommended prostate cancer screening was performed in 27.4% (95% CI=23.7%, 31.4%) and 47.7% (95% CI=44.1%, 51.3%) of respondents with low and high health literacy, respectively (p<0.001). Nonrecommended breast cancer screening was performed in 46.8% (95% CI=42.6%, 51.1%) and 67.7% (95% CI=64.2%, 71.1%) of respondents with low and high health literacy, respectively (p=0.002). Nonrecommended cervical cancer screening was performed in 33.8% (95% CI=31.1%, 36.5%) and 48.4% (95% CI=46.3%, 50.5%) of respondents with low and high health literacy, respectively (p<0.001). Individuals with high health literacy were significantly more likely than those with low health literacy to screen against the recommendations for prostate (OR=1.73, 95% CI=1.34, 2.23, p<0.001), cervical (OR=1.533, 95% CI=1.31, 1.80, p<0.001), and breast (OR=8.213, 95% CI=4.90, 13.76, p<0.001) cancer. CONCLUSIONS: Higher health literacy correlates with increased rates of screening beyond the recommended age, contrary to the study hypothesis. Breast cancer demonstrated the highest rates of nonrecommended screening.

Trends in Surgical Volume in the Military Health System-A Potential Threat to Mission Readiness.

INTRODUCTION: The Military Health System (MHS) is tasked with a dual mission both to provide medical services for covered patients and to ensure that its active duty medical personnel maintain readiness for deployment. Knowledge, skills, and attitudes (KSA) is a metric evaluating the transferrable skills incorporated into a given surgery or medical procedure that are most relevant for surgeons deployed to a theatre of war. Procedures carrying a high KSA value are those utilizing skills with high relevance for maintaining deployment readiness. Given ongoing concerns regarding surgical volumes at MTFs and the potential adverse impact on military surgeon mission readiness were high-value surgeries to be lost to the civilian sector, we evaluated trends in the setting of high-value surgeries for beneficiaries within the MHS. METHODS: We retrospectively analyzed inpatient admissions data from MTFs and TRICARE claims data from civilian hospitals, 2005-2019, to identify TRICARE-covered patients covered under "purchased care" (referred to civilian facilities) or receiving "direct care" (undergoing treatment at MTFs) and undergoing seven high-value/high-KSA surgeries: colectomy, pancreatectomy, hepatectomy, open carotid endarterectomy, abdominal aortic aneurysm (AAA) repair, esophagectomy, and coronary artery bypass grafting (CABG). Overall and procedure-specific counts were captured, MTFs were categorized into quartiles by volume, and independence between trends was tested with a Cochran-Armitage test, hypothesizing that the proportion of cases referred for purchased care was increasing. RESULTS: We captured 292,411 cases, including 7,653 pancreatectomies, 4,177 hepatectomies, 3,815 esophagectomies, 112,684 colectomies, 92,161 CABGs, 26,893 AAA repairs, and 45,028 carotid endarterectomies. The majority of cases included were referred for purchased care (90.3%), with the proportion of cases referred increasing over the study period (P < .01). By procedure, all cases except AAA repairs were increasingly referred for treatment over the study period (all P < .01, except esophagectomy P = .04). On examining volume, we found that even the highest-volume-quartile MTFs performed a median of less than one esophagectomy, hepatectomy, or pancreatectomy per month. The only included procedure performed once a month or more at the majority of MTFs was CABG. CONCLUSION: On examining volume and referral trends for high-value surgeries within the MHS, we found low surgical volumes at the vast majority of included MTFs and an increasing proportion of cases referred to civilian hospitals over the last 15 years. Our findings illustrate missed opportunities for maintaining the mission readiness of military surgical personnel. Prioritizing the recapture of lost surgical volume may improve the surgical teams' mission readiness.

Impact of Index Surgical Care Setting on Perioperative Outcomes and Cost Following Penile Prosthesis Surgery.

BACKGROUND: Penile prosthesis surgery has witnessed a migration from the inpatient to ambulatory surgical care setting. However, little is known about the cost savings afforded by this change in care setting and whether or not these savings come at the expense of worse perioperative outcomes. AIM: The aim of this study was to identify predictors of index penile prosthesis (PP) surgery care setting, and whether ambulatory vs inpatient surgery is associated with comparable perioperative outcomes and costs. METHODS: This was a retrospective cohort study using all-payer claims data from the 2014 Healthcare Cost and Utilization Project State Databases from Florida and New York. Patient demographics, regional data, total charges (converted to costs), and 30-day revisit rates were abstracted for all patients undergoing index placement of an inflatable or malleable PP. Multivariable logistic and linear regression adjusted for facility clustering was utilized. OUTCOMES: The outcomes were index surgical and 30-day postoperative costs, as well as 30-day revisit rates. RESULTS: Of the 1,790 patients undergoing an index surgery, 394 (22.0%) received care in the inpatient setting compared to 1,396 (78.0%) in the ambulatory setting. Adjusted index procedural ($9,319.66 vs $ 10,191.35; P < .001) and 30-day acute care costs ($9,461.74 vs $10,159.42; P < .001) were lower in the ambulatory setting. The underinsured experienced lower odds of receiving surgery in the ambulatory setting (Medicaid vs private: odds ratio [OR] 0.19; 95% CI 0.06-0.55; P < .001). There was no difference in risk-adjusted odds of experiencing a 30-day revisit between patients undergoing surgery in the ambulatory vs inpatient settings (OR 1.31; 95% CI 0.78-2.21; P = .3). CLINICAL TRANSLATION: Ambulatory PP surgery confers significant cost savings and is associated with comparable perioperative outcomes relative to inpatient-based surgery. CONCLUSIONS: Both clinical and nonclinical factors predict the care setting of index PP surgery. Notably, underinsured patients experienced lower odds of undergoing ambulatory surgery. Ambulatory surgery was less costly with similar 30-day revisit rates relative to inpatient-based care. Berger A, Friedlander DF, Herzog P, et al. Impact of Index Surgical Care Setting on Perioperative Outcomes and Cost Following Penile Prosthesis Surgery. J Sex Med 2019;16:1451-1458.

Versatile Oxidase and Dehydrogenase Activities of Bacterial Pyranose 2-Oxidase Facilitate Redox Cycling with Manganese Peroxidase In Vitro.

Pyranose 2-oxidase (POx) has long been accredited a physiological role in lignin degradation, but evidence to provide insights into the biochemical mechanisms and interactions is insufficient. There are ample data in the literature on the oxidase and dehydrogenase activities of POx, yet the biological relevance of this duality could not be established conclusively. Here we present a comprehensive biochemical and phylogenetic characterization of a novel pyranose 2-oxidase from the actinomycetous bacterium Kitasatospora aureofaciens (KaPOx) as well as a possible biomolecular synergism of this enzyme with peroxidases using phenolic model substrates in vitro A phylogenetic analysis of both fungal and bacterial putative POx-encoding sequences revealed their close evolutionary relationship and supports a late horizontal gene transfer of ancestral POx sequences. We successfully expressed and characterized a novel bacterial POx gene from K. aureofaciens, one of the putative POx genes closely related to well-known fungal POx genes. Its biochemical characteristics comply with most of the classical hallmarks of known fungal pyranose 2-oxidases, i.e., reactivity with a range of different monosaccharides as electron donors as well as activity with oxygen, various quinones, and complexed metal ions as electron acceptors. Thus, KaPOx shows the pronounced duality of oxidase and dehydrogenase similar to that of fungal POx. We further performed efficient redox cycling of aromatic lignin model compounds between KaPOx and manganese peroxidase (MnP). In addition, we found a Mn(III) reduction activity in KaPOx, which, in combination with its ability to provide H2O2, implies this and potentially other POx as complementary enzymatic tools for oxidative lignin degradation by specialized peroxidases.IMPORTANCE Establishment of a mechanistic synergism between pyranose oxidase and (manganese) peroxidases represents a vital step in the course of elucidating microbial lignin degradation. Here, the comprehensive characterization of a bacterial pyranose 2-oxidase from Kitasatospora aureofaciens is of particular interest for several reasons. First, the phylogenetic analysis of putative pyranose oxidase genes reveals a widespread occurrence of highly similar enzymes in bacteria. Still, there is only a single report on a bacterial pyranose oxidase, stressing the need of closing this gap in the scientific literature. In addition, the relatively small K. aureofaciens proteome supposedly supplies a limited set of enzymatic functions to realize lignocellulosic biomass degradation. Both enzyme and organism therefore present a viable model to study the mechanisms of bacterial lignin decomposition, elucidate physiologically relevant interactions with specialized peroxidases, and potentially realize biotechnological applications.

Evolving stability and pH-dependent activity of the high redox potential Botrytis aclada laccase for enzymatic fuel cells.

Fungal high redox potential laccases are proposed as cathodic biocatalysts in implantable enzymatic fuel cells to generate high cell voltages. Their application is limited mainly through their acidic pH optimum and chloride inhibition. This work investigates evolutionary and engineering strategies to increase the pH optimum of a chloride-tolerant, high redox potential laccase from the ascomycete Botrytis aclada. The laccase was subjected to two rounds of directed evolution and the clones screened for increased stability and activity at pH 6.5. Beneficial mutation sites were investigated by semi-rational and combinatorial mutagenesis. Fourteen variants were characterised in detail to evaluate changes of the kinetic constants. Mutations increasing thermostability were distributed over the entire structure. Among them, T383I showed a 2.6-fold increased half-life by preventing the loss of the T2 copper through unfolding of a loop. Mutations affecting the pH-dependence cluster around the T1 copper and categorise in three types of altered pH profiles: pH-type I changes the monotonic decreasing pH profile into a bell-shaped profile, pH-type II describes increased specific activity below pH 6.5, and pH-type III increased specific activity above pH 6.5. Specific activities of the best variants were up to 5-fold higher (13 U mg-1) than BaL WT at pH 7.5.

MRI predictors of clinical success in MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids: results from a single centre.

OBJECTIVES: To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. MATERIALS AND METHODS: A total of 252 women (mean age, 42.1 ± 6.9 years) with uterine fibroids underwent MRgFUS. All patients underwent MRI before treatment. Results were evaluated with respect to post-treatment nonperfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. RESULTS: NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MR images and in fibroids distant from the spine (>3 cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p < 0.001). NPV ratio was highly correlated with clinical success: NPV of more than 80 % resulted in clinical success in more than 80 % of patients. Reintervention rate was 12.7 % (mean follow-up time, 19.4 ± 8 months; range, 3-38). Expulsion of fibroids (21 %) was significantly correlated with a high clinical success rate. No severe adverse events were reported. CONCLUSIONS: Adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine-sparing treatment options. KEY POINTS: • MRgFUS appears to be a valid alternative to other uterus-preserving therapies • Patient selection is a significant factor in achieving high NPV ratios • MRI screening parameters correlate with the amount of fibroid ablation in MRgFUS • NPV results of more than 80 % correlate with higher clinical success rates.