Modeling financial outcomes and quantifying risk in episode-based payment models.

OBJECTIVES: Health systems and provider groups currently lack a systematic mechanism to evaluate the financial implications of value-based alternative payments. We sought to develop a method to prospectively quantify the financial implications, including risk and uncertainty of (1) transitioning from a fee-for-service to an episode-based payment model and (2) modifying episode-specific clinical cost drivers. Finally, we highlight practical applications for the model to help facilitate stakeholder engagement in the transition to value-based payment models. STUDY DESIGN: We created a financial simulation from empirical data to demonstrate the feasibility and potential use cases within the context of a hypothetical episode-based payment model for prostate cancer surgery (prostatectomy). METHODS: We used Monte Carlo simulation methods to predict financial outcomes under various clinical and payment model scenarios for our pilot prostatectomy episode use case. We input patient-level empirical cost, reimbursement, and clinical data for a cohort of 157 patients at our institution into our model to quantify expected financial outcomes (payments, financial margins) and financial risk for stakeholders (payer, hospital, providers) under an episode-based payment model. RESULTS: Compared with the status quo, there is a range of expected financial outcomes for various stakeholders depending on the financial parameters (episode price, shared savings, downside risk, stop-loss) in an episode-based payment model. Modifying clinical cost drivers has a profound impact on these outcomes. Uncertainty is high due to the small number of episodes. CONCLUSIONS: The simulation demonstrates that both financial parameters and clinical cost drivers significantly affect the expected financial outcomes for stakeholders in value-based payment models.

Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.

Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a/p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes (Arhgap35, Atp8b4, Brca1, Ift172, Kif21b, Nckap5, Pcdha2, and Zfp869). RNA-seq analysis of transcriptomes from HP and HPN primary melanomas identified a 32-gene signature (HPN lung metastasis signature) for which decreased expression is strongly associated with lung metastatic potential. Analysis of transcriptome data from The Cancer Genome Atlas revealed expression profiles of these genes that predict improved survival of patients with cutaneous or uveal melanoma. Silencing of three representative HPN lung metastasis signature genes (ARRDC3, NYNRIN, RND3) in human melanoma cells resulted in increased invasive activity, consistent with roles for these genes as mediators of the metastasis suppressor function of NME1 and NME2. In conclusion, our studies have identified a family of genes that mediate suppression of melanoma lung metastasis, and which may serve as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma.

What Genes Can Tell: A Closer Look at Vestibular Schwannoma.

OBJECTIVE: Comprehensive molecular profiling of radioresistant and cystic vestibular schwannoma (VS) subtypes. STUDY DESIGN: Our study utilized whole-exome sequencing (WES), RNA-sequencing (RNAseq), and correlated clinical data from 12 samples (2 samples of solid sporadic subtype, 8 with cystic changes, and 2 previously irradiated). SETTING: Academic medical center. PATIENTS: Patients diagnosed with VS who required surgical treatment. Inclusion: Cystic and radioresistant tumors matched to age and tumor volume, with solid sporadic VS samples as control; Exclusion: NF-2 patients. INTERVENTION(S): WES using custom probes for copy number analysis. A modified version of the Agilent Human Whole Exome sequencing hybrid capture system was used to process samples. Recurrent variants were identified and compared between groups. Leukocyte-derived DNA was utilized as internal control to reduce false-positives. MAIN OUTCOME MEASURE(S): Analysis of genetic landscape of VS subtypes (naive solid VS, cystic VS, and previously irradiated VS) by performing deep next-generation sequencing. RESULTS: WES data achieved a mean coverage of 202X and RNAseq generated an average of 74 million total reads. As a group, 25% of samples had 22q loss. Somatic analysis identified previously reported genes and multiple novel mutations across samples. Differential expression analysis of RNAseq data found significantly mutated genes such as COL6A3, CLMP, ART4, Lumican that were shared by both cystic VS and irradiated VS, but not seen in sporadic VS. CONCLUSIONS: Using WES we were able to demonstrate that cystic and irradiated samples are subtypes of VS with an increased mutation burden and a unique genetic fingerprint. We identified differences between the genomic and molecular profile of cystic VS and radioresistant VS. Our results help advance the understanding of the pathophysiology of these tumor subtypes and suggest possible molecular targets for novel treatment strategies.

Cancer transcriptomic profiling from rapidly enriched circulating tumor cells.

Transcriptomic profiling of metastatic cancer can illuminate mechanisms of progression and lead to new therapies, but standard biopsy is invasive and reflects only a single metastatic site. In contrast, circulating tumor cell (CTC) profiling is noninvasive and repeatable, reflecting the dynamic and systemic nature of advanced disease. To date, transcriptomic profiling of CTCs has not delivered on its full potential, because white blood cells (WBCs) vastly outnumber CTCs. Current profiling strategies either lack cancer sensitivity and specificity or require specialized CTC capture protocols that are not readily scalable to large patient cohorts. Here, we describe a new strategy for rapid CTC enrichment and transcriptomic profiling using commercially available WBC depletion, microfluidic enrichment and RNA sequencing. When applied to blood samples from patients with advanced prostate cancer (PC), transcriptomes from enriched samples cluster with cancer positive controls and previously undetectable prostate-specific transcripts become readily measurable. Gene set enrichment analysis reveals multiple significantly enriched signaling pathways associated with PC, as well as novel pathways that merit further study. This accessible and scalable approach yields cancer-specific transcriptomic data and can be applied repeatedly and noninvasively in large cancer patient cohorts to discover new therapeutic targets in advanced disease.

Financial Margins for Prostate Cancer Surgery: Quantifying the Impact of Modifiable Cost Inputs in an Episode Based Reimbursement Model.

PURPOSE: The United States health care system is rapidly moving away from fee for service reimbursement in an effort to improve quality and contain costs. Episode based reimbursement is an increasingly relevant value based payment model of surgical care. We sought to quantify the impact of modifiable cost inputs on institutional financial margins in an episode based payment model for prostate cancer surgery. MATERIALS AND METHODS: A total of 157 consecutive patients underwent robotic radical prostatectomy in 2016 at a tertiary academic medical center. We compiled comprehensive episode costs and reimbursements from the most recent urology consultation for prostate cancer through 90 days postoperatively and benchmarked the episode price as a fixed reimbursement to the median reimbursement of the cohort. We identified 2 sources of modifiable costs with undefined empirical value, including preoperative prostate magnetic resonance imaging and perioperative functional recovery counseling visits, and then calculated the impact on financial margins (reimbursement minus cost) under an episode based payment. RESULTS: Although they comprised a small proportion of the total episode costs, varying the use of preoperative magnetic resonance imaging (33% vs 100% of cases) and functional recovery counseling visits (1 visit in 66% and 2 in 100%) reduced average expected episode financial margins up to 22.6% relative to the margin maximizing scenario in which no patient received these services. CONCLUSIONS: Modifiable cost inputs have a substantial impact on potential operating margins for prostate cancer surgery under an episode based payment model. High cost health systems must develop the capability to analyze individual cost inputs and quantify the contribution to quality to inform value improvement efforts for multiple service lines.

The collaborative effect of scientific meetings: A study of the International Milk Genomics Consortium.

Collaboration among scientists has a major influence on scientific progress. Such collaboration often results from scientific meetings, where scientists gather to present and discuss their research and to meet potential collaborators. However, most scientific meetings have inherent biases, such as the availability of research funding or the selection bias of professional societies that make it difficult to study the effect of the meeting per se on scientific productivity. To evaluate the effects of scientific meetings on collaboration and progress independent of these biases, we conducted a study of the annual symposia held by the International Milk Genomics Consortium (IMGC) over a 12-year period. In our study, we conducted permutation testing to analyze the effectiveness of the IMGC in facilitating collaboration and productivity in a community of milk scientists who were meeting attendees relative to non-attendees. Using the number of co-authorships on published papers as a measure of collaboration, our analysis revealed that scientists who attended the symposium were associated with more collaboration than were scientists who did not attend. Furthermore, we evaluated the scientific progress of consortium attendees by analyzing publication rate and article impact. We found that IMGC attendees, in addition to being more collaborative, were also more productive and influential than were non-attendees who published in the same field. The results of our study suggest that the annual symposium encouraged interactions among disparate scientists and increased research productivity, exemplifying the positive effect of scientific meetings on both collaboration and progress.

Sustained Growth of a University-Based Endocrine Surgery Program Over 10 Years.

BACKGROUND: Endocrine surgery continues to mature as a subspecialty field. We describe the clinical performance of an academic endocrine surgery program (ESP) over its first 10 years. METHODS: We examined all endocrine procedures performed during the 10-year period (2006-2015) following the inception of the ESP. Institutional and state-level data on case volume, patient geographic origin, and hospital-side costs were obtained. RESULTS: Endocrine case volume increased by approximately ninefold over the study period (from 102 cases in 2006 to 919 cases in 2015). The rate of growth remained approximately linear, and was driven by geographic expansion of referral regions coupled with transitioning low- to moderate-acuity operations to venues outside of the main tertiary care hospital. Market share across the eight-county Southern California region grew by more than twofold over the study period. Increased utilization of outpatient surgery led to cost reductions, averaging 11.1% per case by 2015. CONCLUSIONS: Establishment of an academic ESP can lead to sustained clinical growth and a fundamental shift in regional referral patterns. The nation's continued need for skilled high-volume endocrine surgeons represents opportunities for medical centers to institute their own dedicated endocrine surgery programs.

Molecular dyads comprising metalloporphyrin and alkynylplatinum(II) polypyridine terminal groups for use as a sensitizer in dye-sensitized solar cells.

A new class of molecular dyads comprising metalloporphyrin-linked alkynylplatinum(II) polypyridine complexes with carboxylic acids as anchoring groups has been designed and synthesized. These complexes can sensitize nanocrystalline TiO2 in dye-sensitized solar cell (DSSC) studies. The photophysical, electrochemical, and luminescence properties of the complexes were studied and their excited-state properties were investigated by nanosecond transient absorption spectroscopy, with the charge-separated [Por(.-)-{(C≡C)Pt(tBu3 tpy)}(.+)] state observed upon excitation. Excited-state redox potentials were determined; the electrochemical data supports the capability of the complexes to inject an electron into the conduction band of TiO2 . The complexes sensitize nanocrystalline TiO2 and exhibited photovoltaic properties, as characterized by current-voltage measurements under illumination of air mass 1.5 G sunlight (100 mWcm(-2)). A DSSC based on one of the complexes showed a short-circuit photocurrent of 10.1 mAcm(-2), an open-circuit voltage of 0.64 V, and a fill factor of 0.52, giving an overall power conversion efficiency of 3.4 %.

Organic photovoltaic devices based on a new class of oligothienylenevinylene derivatives as donor materials.

A new class of donor-acceptor-containing oligothienylenevinylenes with a triphenylamine donor and a dicyanovinyl group as acceptor has been synthesized and characterized. By extending the oligothiophene backbone, both the optical bandgaps and the charge-transport properties can be tuned. These oligothienylenevinylene derivatives show intense charge-transfer absorption bands that cover the entire visible spectrum, with low optical bandgaps of approximately 1.64 eV. In addition, electrochemical studies reveal that these compounds possess relatively large ionization potentials of approximately 5.5 eV. On the basis of these newly developed dicyanovinyl-substituted chromophores as donor materials and C(60) as acceptor material, bilayer organic photovoltaic devices have been fabricated, with the best device showing a high power conversion efficiency (PCE) of 2.0%, with an open-circuit voltage of 0.68 V and a fill factor of 0.60 after thermal annealing. The obvious morphology change with the formation of small domains in thin films and the reduction of series resistance are believed to be responsible for the dramatic performance improvement upon thermal annealing.

Electrogenerated chemiluminescence of platinum(II) alkynyl terpyridine complex with peroxydisulfate as coreactant.

A Pt(II) alkynyl terpyridine complex containing a carbazole moiety, [Pt((t)Bu(3)tpy)(C≡C-C(6)H(4)-4-carbazole-9)](+) ((t)Bu(3)tpy = 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine) 1, has been synthesized and characterized. The photophysical behavior has been studied, and the molecular structure has been determined by X-ray crystallography. The complex was found to exhibit intense electrogenerated chemiluminescence (ECL) using peroxydisulfate (S(2)O(8)(2-)) as coreactant in acetonitrile/water (1-25%, v/v) mixture at both glassy carbon and gold electrodes, representing the first ECL example of the Pt(II) alkynyl family. The ECL was produced at potential corresponding to the first reduction wave (-0.90 V vs SCE), significantly shifted by ∼0.65 V toward more positive potential compared with that of [Ru(bpy)(3)](2+) (bpy = 2,2'-bipyridine). The ECL spectrum was found to be identical to the photoluminescence spectrum recorded in the same medium, indicating the formation of the same excited state of dπ(Pt) → π*((t)Bu(3)tpy) (3)MLCT mixed with π(C≡CR) → π*((t)Bu(3)tpy) (3)LLCT in both cases. The ECL mechanism was proposed involving the formation of the strongly oxidizing intermediate, SO(4)(•-), mainly generated during the catalytic reduction of S(2)O(8)(2-) by the electrogenerated 1(-). Chemiluminescence of 1/S(2)O(8)(2-) based on reduction with Al metal is also described.

Functionalized alkynylplatinum(II) polypyridyl complexes for use as sensitizers in dye-sensitized solar cells.

A series of platinum(II) alkynyl-based sensitizers has been synthesized and found to show light-to-electricity conversion properties. These dyes were developed as sensitizers for the application in nanocrystalline TiO(2) dye-sensitized solar cells (DSSCs). Their photophysical and electrochemical properties were studied. The excited-state property was probed using nanosecond transient absorption spectroscopy, which showed the formation of a charge-separated state that arises from the intramolecular photoinduced charge transfer from the platinum(II) alkynylbithienylbenzothiadiazole moiety (donor) to the polypyridyl ligand (acceptor). A lifetime of 3.4 µs was observed for the charge-separated state. A dye-sensitized solar cell based on one of the complexes showed a short-circuit photocurrent of 7.12 mA cm(-2), an open circuit voltage of 780 mV, and a fill factor of 0.65, thus giving an overall power conversion efficiency of 3.6%.

Validation and evaluation of biomarkers in workers exposed to benzene in China.

This study was conducted to validate biomarkers for early detection of benzene exposure and effect in 2 phases. The main purpose of phase 1 was to determine whether these biomarkers could reliably detect differences between workers with high exposure levels and unexposed subjects, which is the minimal screening criterion for a biomarker assay. Phase 2 of the study mainly focused on evaluating the exposure-response relation, confounding factors, and sensitivities of biomarkers for low benzene exposures. The Chinese occupational population studied had a broad range of benzene exposures. On the day of biological sample collection, exposures ranged from 0.06 to 122 ppm with a median exposure of 3.2 ppm. The median of the 4-week mean benzene exposures was 3.8 ppm, and the median lifetime cumulative exposure was 51.1 ppm-years. Compared with benzene levels in collected samples, toluene levels were relatively high, with a median of 12.6 ppm (mean, 26.3 ppm), but xylene levels were low, with a median of 0.30 ppm (mean, 0.40 ppm). The biomarkers evaluated were urinary metabolites S-phenylmercapturic acid (S-PMA*), trans,trans-muconic acid (t,t-MA), hydroquinone (HQ), catechol (CAT), and phenol; albumin adducts of benzene oxide and 1,4-benzoquinone (BO-Alb and 1,4-BQ-Alb, respectively) in blood; blood cell counts; and chromosomal aberrations. Blood cell counts in this population, including red blood cells (RBCs), white blood cells (WBCs), and neutrophils, decreased significantly with increased exposures but remained in normal ranges. Chromosomal aberration data showed significant increases of chromatid breaks and total chromosomal aberrations in exposed subjects compared with unexposed subjects. Among the urinary metabolites, the levels of S-PMA and t,t-MA were significantly elevated after benzene exposures. Both markers showed significant exposure-response trends even over the exposure range from 0 to 1 ppm. However, HQ, CAT, and phenol showed significant increases only for benzene exposure levels above 5 ppm. Multiple regression analyses of these urinary metabolites on benzene exposure indicated that toluene exposure, smoking status, and cotinine levels had no significant effects on urinary metabolite levels. A time-course study estimated the half-lives of S-PMA, t,t-MA, HQ, CAT, and phenol to be 12.8, 13.7, 12.7, 15.0, and 16.3 hours, respectively. Both BO-Alb and 1,4-BQ-Alb showed strong exposure-response associations with benzene. Regression analyses showed that after adjustment for potential confounding by smoking, there was still a strong association between benzene exposure and these markers. Furthermore, the analyses for correlations among biomarkers revealed that the urinary metabolites correlated substantially with each other. The albumin adducts also correlated well with the urinary biomarkers, especially with S-PMA. BO-Alb and 1,4-BQ adducts also correlated well with each other (r = 0.74). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposures at around 0.1 ppm and 1 ppm, respectively. But S-PMA was clearly superior to t,t-MA as a biomarker for low levels of benzene exposure.