Reprogramming of the circadian clock by nutritional challenge.

Circadian rhythms and cellular metabolism are intimately linked. Here, we reveal that a high-fat diet (HFD) generates a profound reorganization of specific metabolic pathways, leading to widespread remodeling of the liver clock. Strikingly, in addition to disrupting the normal circadian cycle, HFD causes an unexpectedly large-scale genesis of de novo oscillating transcripts, resulting in reorganization of the coordinated oscillations between coherent transcripts and metabolites. The mechanisms underlying this reprogramming involve both the impairment of CLOCK:BMAL1 chromatin recruitment and a pronounced cyclic activation of surrogate pathways through the transcriptional regulator PPARγ. Finally, we demonstrate that it is specifically the nutritional challenge, and not the development of obesity, that causes the reprogramming of the clock and that the effects of the diet on the clock are reversible.

Trajectory of Healthcare Contact Days for Veterans With Advanced Gastrointestinal Malignancy.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021. Among 468 decedents, the median overall survival was 4 months. Patients spent 1 in 3 days with healthcare contact. Over the course of illness, the percentage of contact days followed a "U-shaped" pattern, with an initial post-diagnosis peak, a lower middle trough, and an eventual rise as patients neared the end-of-life. Contact days varied by clinical factors and by sociodemographics. These data have important implications for improving care delivery, such as through care coordination and communicating expected burdens to and supporting patients and care partners.

Oncologist Participation and Performance in the Merit-Based Incentive Payment System.

The merit-based incentive payment system (MIPS) is a value-based payment model created by the Centers for Medicare & Medicaid Services (CMS) to promote high-value care through performance-based adjustments of Medicare reimbursements. In this cross-sectional study, we examined the participation and performance of oncologists in the 2019 MIPS. Oncologist participation was low (86%) compared to all-specialty participation (97%). After adjusting for practice characteristics, higher MIPS scores were observed among oncologists with alternative payment models (APMs) as their filing source (mean score, 91 for APMs vs. 77.6 for individuals; difference, 13.41 [95% CI, 12.21, 14.6]), indicating the importance of greater organizational resources for participants. Lower scores were associated with greater patient complexity (mean score, 83.4 for highest quintile vs. 84.9 for lowest quintile, difference, -1.43 [95% CI, -2.48, -0.37]), suggesting the need for better risk-adjustment by CMS. Our findings may guide future efforts to improve oncologist engagement in MIPS.

Examining Public Communication About Surgical Cancer Care on Twitter.

INTRODUCTION: Social media platforms like Twitter are highly utilized for communicating about cancer care. Although surgery is the primary curative treatment for solid malignancies, little is known about online communication behaviors regarding this treatment modality. This study tracked online discussions and characterized participants to better characterize the content of public communication about surgical cancer care. METHODS: Tweets referencing cancer surgery were collected from 2018 to 2021 using Twitter's Application Programming Interface. Metadata (e.g., profile biography, follower count) was used to predict user demographic information. Natural language processing was performed using Latent Dirichlet Allocation to identify common themes of conversation and mentioned cancer sites. RESULTS: There were 442,840 tweets about cancer surgery by 262,168 users, including individuals (65%), influencers (1.5%), surgeons (1%), and oncologists (0.5%). Following the onset of the COVID-19 pandemic, tweets mentioning delays in care increased by 21.7% (1971-57,846 tweets). Individuals commonly mentioned surgical costs (20.3%) and postoperative recovery (21.6%). Surgeons and oncologists frequently mentioned research (52.7%), but infrequently mentioned community support (7.8%) or survivorship (9.3%). Relative to their prevalence, neurologic cancers were most discussed (231 tweets per 1000 operations) while thoracic (29 tweets per 1000 operations) and urologic cancers were least discussed (12 tweets per 1000 operations). CONCLUSIONS: Twitter was utilized by patients to discuss real-time issues such as COVID-19-related surgical delays and the financial burden of cancer surgery. Further efforts to improve community outreach may be optimized by targeting greater discussion of undermentioned cancer types and encouraging clinicians to participate in discussions about community-centered themes.

What Factors Are Associated With Early Career Attrition Among Orthopaedic Surgeons in the United States?

BACKGROUND: The attrition of medical personnel in the United States healthcare system has been an ongoing concern among physicians and policymakers alike. Prior studies have shown that reasons for leaving clinical practice vary widely and may range from professional dissatisfaction or disability to the pursuit of alternative career opportunities. Whereas attrition among older personnel has often been understood as a natural phenomenon, attrition among early-career surgeons may pose a host of additional challenges from an individual and societal perspective. QUESTIONS/PURPOSES: (1) What percentage of orthopaedic surgeons experience early-career attrition, defined as leaving active clinical practice within the first 10 years after completion of training? (2) What are the surgeon and practice characteristics associated with early-career attrition? METHODS: In this retrospective analysis drawn from a large database, we used the 2014 Physician Compare National Downloadable File (PC-NDF), a registry of all healthcare professionals in the United States participating in Medicare. A total of 18,107 orthopaedic surgeons were identified, 4853 of whom were within the first 10 years of training completion. The PC-NDF registry was chosen because it has a high degree of granularity, national representativeness, independent validation through the Medicare claims adjudication and enrollment process, and the ability to longitudinally monitor the entry and exit of surgeons from active clinical practice. The primary outcome of early-career attrition was defined by three conditions, all of which had to be simultaneously satisfied ("condition one" AND "condition two" AND "condition three"). The first condition was presence in the Q1 2014 PC-NDF dataset and absence from the same dataset the following year (Q1 2015 PC-NDF). The second condition was consistent absence from the PC-NDF dataset for the following 6 years (Q1 2016, Q1 2017, Q1 2018, Q1 2019, Q1 2020, and Q1 2021), and the third condition was absence from the Centers for Medicare and Medicaid Services Opt-Out registry, which tracks clinicians who have formally discontinued enrollment in the Medicare program. Of the 18,107 orthopaedic surgeons identified in the dataset, 5% (938) were women, 33% (6045) were subspecialty-trained, 77% (13,949) practiced in groups of 10 or more, 24% (4405) practiced in the Midwest, 87% (15,816) practiced in urban areas, and 22% (3887) practiced at academic centers. Surgeons not enrolled in the Medicare program are not represented in this study cohort. A multivariable logistic regression model with adjusted odds ratios and 95% confidence intervals was constructed to investigate characteristics associated with early-career attrition. RESULTS: Among the 4853 early-career orthopaedic surgeons identified in the dataset, 2% (78) were determined to experience attrition between the first quarter 2014 and the same point in 2015. After controlling for potential confounding variables such as years since training completion, practice size, and geographic region, we found that women were more likely than men to experience early-career attrition (adjusted OR 2.8 [95% CI 1.5 to 5.0]; p = 0.006]), as were academic orthopaedic surgeons compared with private practitioners (adjusted OR 1.7 [95% CI 1.02 to 3.0]; p = 0.04), while general orthopaedic surgeons were less likely to experience attrition than subspecialists (adjusted OR 0.5 [95% CI 0.3 to 0.8]; p = 0.01). CONCLUSION: A small but important proportion of orthopaedic surgeons leave the specialty during the first 10 years of practice. Factors most-strongly associated with this attrition were academic affiliation, being a woman, and clinical subspecialization. CLINICAL RELEVANCE: Based on these findings, academic orthopaedic practices might consider expanding the role of routine exit interviews to identify instances in which early-career surgeons face illness, disability, burnout, or any other forms of severe personal hardships. If attrition occurs because of such factors, these individuals could benefit from connection to well-vetted coaching or counseling services. Professional societies might be well positioned to conduct detailed surveys to assess the precise reasons for early attrition and characterize any inequities in workforce retention across a diverse range of demographic subgroups. Future studies should also determine whether orthopaedics is an outlier, or whether 2% attrition is similar to the proportion in the overall medical profession.

The pervasiveness and plasticity of circadian oscillations: the coupled circadian-oscillators framework.

MOTIVATION: Circadian oscillations have been observed in animals, plants, fungi and cyanobacteria and play a fundamental role in coordinating the homeostasis and behavior of biological systems. Genetically encoded molecular clocks found in nearly every cell, based on negative transcription/translation feedback loops and involving only a dozen genes, play a central role in maintaining these oscillations. However, high-throughput gene expression experiments reveal that in a typical tissue, a much larger fraction ([Formula: see text]) of all transcripts oscillate with the day-night cycle and the oscillating species vary with tissue type suggesting that perhaps a much larger fraction of all transcripts, and perhaps also other molecular species, may bear the potential for circadian oscillations. RESULTS: To better quantify the pervasiveness and plasticity of circadian oscillations, we conduct the first large-scale analysis aggregating the results of 18 circadian transcriptomic studies and 10 circadian metabolomic studies conducted in mice using different tissues and under different conditions. We find that over half of protein coding genes in the cell can produce transcripts that are circadian in at least one set of conditions and similarly for measured metabolites. Genetic or environmental perturbations can disrupt existing oscillations by changing their amplitudes and phases, suppressing them or giving rise to novel circadian oscillations. The oscillating species and their oscillations provide a characteristic signature of the physiological state of the corresponding cell/tissue. Molecular networks comprise many oscillator loops that have been sculpted by evolution over two trillion day-night cycles to have intrinsic circadian frequency. These oscillating loops are coupled by shared nodes in a large network of coupled circadian oscillators where the clock genes form a major hub. Cells can program and re-program their circadian repertoire through epigenetic and other mechanisms. AVAILABILITY AND IMPLEMENTATION: High-resolution and tissue/condition specific circadian data and networks available at http://circadiomics.igb.uci.edu. CONTACT: pfbaldi@ics.uci.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Circadian acetylome reveals regulation of mitochondrial metabolic pathways.

The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock(-/-)) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock(-/-) mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.

Coordination of the transcriptome and metabolome by the circadian clock.

The circadian clock governs a large array of physiological functions through the transcriptional control of a significant fraction of the genome. Disruption of the clock leads to metabolic disorders, including obesity and diabetes. As food is a potent zeitgeber (ZT) for peripheral clocks, metabolites are implicated as cellular transducers of circadian time for tissues such as the liver. From a comprehensive dataset of over 500 metabolites identified by mass spectrometry, we reveal the coordinate clock-controlled oscillation of many metabolites, including those within the amino acid and carbohydrate metabolic pathways as well as the lipid, nucleotide, and xenobiotic metabolic pathways. Using computational modeling, we present evidence of synergistic nodes between the circadian transcriptome and specific metabolic pathways. Validation of these nodes reveals that diverse metabolic pathways, including the uracil salvage pathway, oscillate in a circadian fashion and in a CLOCK-dependent manner. This integrated map illustrates the coherence within the circadian metabolome, transcriptome, and proteome and how these are connected through specific nodes that operate in concert to achieve metabolic homeostasis.

Mapping the protein interaction network of the human COP9 signalosome complex using a label-free QTAX strategy.

The COP9 signalosome (CSN) is a multi-subunit protein complex that performs critical roles in controlling diverse cellular and developmental processes. Aberrant regulation of the CSN complex has been shown to lead to tumorigenesis. Despite its biological significance, our current knowledge of the function and regulation of the CSN complex is very limited. To explore CSN biology, we have developed and employed a new version of the tag team-based QTAX strategy (quantitative analysis of tandem affinity purified in vivo cross-linked (X) protein complexes) by incorporating a label-free MS method for quantitation. Coupled with protein interaction network analysis, this strategy produced a comprehensive and detailed assessment of the protein interaction network of the human CSN complex. In total, we quantitatively characterized 825 putative CSN-interacting proteins, with 270 classified as core interactors (captured by all three bait purifications). Biochemical validation further confirms the validity of selected identified interactors. This work presents the most complete analysis of the CSN interaction network to date, providing an inclusive set of physical interaction data consistent with physiological roles for the CSN. Moreover, the methodology described here is a general proteomic tool for the comprehensive study of protein interaction networks.

Mapping the structural topology of the yeast 19S proteasomal regulatory particle using chemical cross-linking and probabilistic modeling.

Structural characterization of proteasome complexes is an essential step toward understanding the ubiquitin-proteasome system. Currently, high resolution structures are not available for the 26S proteasome holocomplex as well as its subcomplex, the 19S regulatory particle (RP). Here we have employed a novel integrated strategy combining chemical cross-linking with multistage tandem mass spectrometry to define the proximity of subunits within the yeast 19S RP to elucidate its topology. This has resulted in the identification of 174 cross-linked peptides of the yeast 19S RP, representing 43 unique lysine-lysine linkages within 24 nonredundant pair-wise subunit interactions. To map the spatial organization of the 19S RP, we have developed and utilized a rigorous probabilistic framework to derive maximum likelihood (ML) topologies based on cross-linked peptides determined from our analysis. Probabilistic modeling of the yeast 19S AAA-ATPase ring (i.e., Rpt1-6) has produced an ML topology that is in excellent agreement with known topologies of its orthologs. In addition, similar analysis was carried out on the 19S lid subcomplex, whose predicted ML topology corroborates recently reported electron microscopy studies. Together, we have demonstrated the effectiveness and potential of probabilistic modeling for unraveling topologies of protein complexes using cross-linking data. This report describes the first study of the 19S RP topology using a new integrated strategy combining chemical cross-linking, mass spectrometry, and probabilistic modeling. Our results have provided a solid foundation to advance our understanding of the 19S RP architecture at peptide level resolution. Furthermore, our methodology developed here is a valuable proteomic tool that can be generalized for elucidating the structures of protein complexes.

Neighborhood Environmental Burden and Cardiovascular Health in the US.

Importance: Cardiovascular disease is the leading cause of death in the US. However, little is known about the association between cumulative environmental burden and cardiovascular health across US neighborhoods. Objective: To evaluate the association of neighborhood-level environmental burden with prevalence of cardiovascular risk factors and diseases, overall and by levels of social vulnerability. Design, Settings, and Participants: This was a national cross-sectional study of 71 659 US Census tracts. Environmental burden (EBI) and social vulnerability indices from the US Centers for Disease Control and Prevention (CDC) and Agency for Toxic Substances and Disease Registry were linked to the 2020 CDC PLACES data set. Data were analyzed from March to October 2023. Exposures: The EBI, a measure of cumulative environmental burden encompassing 5 domains (air pollution, hazardous or toxic sites, built environment, transportation infrastructure, and water pollution). Main Outcomes and Measures: Neighborhood-level prevalence of cardiovascular risk factors (hypertension, diabetes, and obesity) and cardiovascular diseases (coronary heart disease and stroke). Results: Across the US, neighborhoods with the highest environmental burden (top EBI quartile) were more likely than those with the lowest environmental burden (bottom EBI quartile) to be urban (16 626 [92.7%] vs 13 414 [75.4%]), in the Midwest (5191 [28.9%] vs 2782 [15.6%]), have greater median (IQR) social vulnerability scores (0.64 [0.36-0.85] vs 0.42 [0.20-0.65]), and have higher proportions of adults in racial or ethnic minority groups (median [IQR], 34% [12-73] vs 12% [5-30]). After adjustment, neighborhoods with the highest environmental burden had significantly higher rates of cardiovascular risk factors than those with the lowest burden, including hypertension (mean [SD], 32.83% [7.99] vs 32.14% [6.99]; adjusted difference, 0.84%; 95% CI, 0.71-0.98), diabetes (mean [SD], 12.19% [4.33] vs 10.68% [3.27]; adjusted difference, 0.62%; 95% CI, 0.53-0.70), and obesity (mean [SD], 33.57% [7.62] vs 30.86% [6.15]; adjusted difference, 0.77%; 95% CI, 0.60-0.94). Similarly, neighborhoods with the highest environmental burden had significantly higher rates of coronary heart disease (mean [SD], 6.66% [2.15] vs 6.82% [2.41]; adjusted difference, 0.28%; 95% CI, 0.22-0.33) and stroke (mean [SD], 3.65% [1.47] vs 3.31% [1.12]; adjusted difference, 0.19%; 95% CI, 0.15-0.22). Results were consistent after matching highest and lowest environmentally burdened neighborhoods geospatially and based on other covariates. The associations between environmental burden quartiles and cardiovascular risk factors and diseases were most pronounced among socially vulnerable neighborhoods. Conclusions and Relevance: In this cross-sectional study of US neighborhoods, cumulative environmental burden was associated with higher rates of cardiovascular risk factors and diseases, although absolute differences were small. The strongest associations were observed in socially vulnerable neighborhoods. Whether initiatives that address poor environmental conditions will improve cardiovascular health requires additional prospective investigations.

Development of a novel cross-linking strategy for fast and accurate identification of cross-linked peptides of protein complexes.

Knowledge of elaborate structures of protein complexes is fundamental for understanding their functions and regulations. Although cross-linking coupled with mass spectrometry (MS) has been presented as a feasible strategy for structural elucidation of large multisubunit protein complexes, this method has proven challenging because of technical difficulties in unambiguous identification of cross-linked peptides and determination of cross-linked sites by MS analysis. In this work, we developed a novel cross-linking strategy using a newly designed MS-cleavable cross-linker, disuccinimidyl sulfoxide (DSSO). DSSO contains two symmetric collision-induced dissociation (CID)-cleavable sites that allow effective identification of DSSO-cross-linked peptides based on their distinct fragmentation patterns unique to cross-linking types (i.e. interlink, intralink, and dead end). The CID-induced separation of interlinked peptides in MS/MS permits MS(3) analysis of single peptide chain fragment ions with defined modifications (due to DSSO remnants) for easy interpretation and unambiguous identification using existing database searching tools. Integration of data analyses from three generated data sets (MS, MS/MS, and MS(3)) allows high confidence identification of DSSO cross-linked peptides. The efficacy of the newly developed DSSO-based cross-linking strategy was demonstrated using model peptides and proteins. In addition, this method was successfully used for structural characterization of the yeast 20 S proteasome complex. In total, 13 non-redundant interlinked peptides of the 20 S proteasome were identified, representing the first application of an MS-cleavable cross-linker for the characterization of a multisubunit protein complex. Given its effectiveness and simplicity, this cross-linking strategy can find a broad range of applications in elucidating the structural topology of proteins and protein complexes.

Risk of Mortality After a Diagnosis of Melanoma In Situ.

Importance: The incidence of melanoma in situ (MIS) is increasing more rapidly than any invasive or in situ cancer in the US. Although more than half of melanomas diagnosed are MIS, information about long-term prognosis following a diagnosis of MIS remains unknown. Objective: To evaluate mortality and factors associated with mortality after a diagnosis of MIS. Design, Setting, and Participants: This population-based cohort study of adults with a diagnosis of first primary MIS from 2000 to 2018 included data from the US Surveillance, Epidemiology, and End Results Program, which were analyzed from July to September 2022. Main Outcomes and Measures: Mortality after a diagnosis of MIS was evaluated using 15-year melanoma-specific survival, 15-year relative survival (ie, compared with similar individuals without MIS), and standardized mortality ratios (SMRs). Cox regression was used to estimate hazard ratios (HRs) for death by demographic and clinical characteristics. Results: Among 137 872 patients with a first-and-only MIS, the mean (SD) age at diagnosis was 61.9 (16.5) years (64 027 women [46.4%]; 239 [0.2%] American Indian or Alaska Native, 606 [0.4%] Asian, 344 [0.2%] Black, 3348 [2.4%] Hispanic, and 133 335 [96.7%] White individuals). Mean (range) follow-up was 6.6 (0-18.9) years. The 15-year melanoma-specific survival was 98.4% (95% CI, 98.3%-98.5%), whereas the 15-year relative survival was 112.4% (95% CI, 112.0%-112.8%). The melanoma-specific SMR was 1.89 (95% CI, 1.77-2.02); however, the all-cause SMR was 0.68 (95% CI, 0.67-0.7). Risk of melanoma-specific mortality was higher for older patients (7.4% for those 80 years or older vs 1.4% for those aged 60-69 years; adjusted HR, 8.2; 95% CI, 6.7-10.0) and patients with acral lentiginous histology results (3.3% for acral lentiginous vs 0.9% for superficial spreading; HR, 5.3; 95% CI, 2.3-12.3). Of patients with primary MIS, 6751 (4.3%) experienced a second primary invasive melanoma and 11 628 (7.4%) experienced a second primary MIS. Compared with patients without a subsequent melanoma, the risk of melanoma-specific mortality was increased for those with a second primary invasive melanoma (adjusted HR, 4.1; 95% CI, 3.6-4.6) and was decreased for those with a second primary MIS (adjusted HR, 0.7; 95% CI, 0.6-0.9). Conclusions and relevance: The results of this cohort study suggest that patients with a diagnosis of MIS have an increased but low risk of melanoma-specific mortality and live longer than people in the general population, suggesting that there is significant detection of low-risk disease among health-seeking individuals. Factors associated with death following MIS include older age (≥80 years) and subsequent primary invasive melanoma.

Association of Medicare Program Type with Health Care Access, Utilization, and Affordability among Cancer Survivors.

BACKGROUND: The Medicare Advantage program provides care to nearly half of Medicare beneficiaries, including a rapidly growing population of cancer survivors. Despite its increased adoption, it is still unknown whether or not the program improves healthcare access, outcomes, and affordability for cancer survivors. METHODS: We performed a cross-sectional study of Medicare beneficiaries aged ≥ 65 years with a self-reported history of cancer from the 2019 National Health Interview Survey. We used multivariable logistic regression to evaluate the association between Medicare program type (Medicare Advantage vs. traditional Medicare) and measures of healthcare access, acute care utilization, and affordability. RESULTS: We identified 4451 beneficiaries with a history of cancer, corresponding to 26.6 million weighted cancer survivors in 2019. Of the beneficiaries, 35.8% were enrolled in Medicare Advantage, whereas 64.2% were enrolled in traditional Medicare. The age, sex, racial and ethnic composition, household income, primary site of cancer, and comorbidity burden of Medicare Advantage and traditional Medicare beneficiaries were similar. In the adjusted analysis, there were no differences in healthcare access or acute care utilization between traditional Medicare and Medicare Advantage beneficiaries. However, cancer survivors enrolled in Medicare Advantage were more likely to worry about (34.3% vs. 29.4%; aOR, 1.3 (95% CI, 1.1-1.5)) or have problems paying (13.6% vs. 11.1%; aOR, 1.4 (95% CI, 1.1-1.8)) medical bills. CONCLUSIONS: We found no evidence that Medicare Advantage beneficiaries with cancer had better healthcare access, affordability, or acute care utilization than traditional Medicare beneficiaries did. Furthermore, Medicare Advantage beneficiaries were more likely to report financial strain and have difficulty paying for their medical bills than were those with traditional Medicare. Despite the generous benefits and attractive incentives, Medicare Advantage plans may not be more cost-effective than traditional Medicare is for cancer survivors. Our study informs ongoing congressional deliberations to re-evaluate the role of Medicare Advantage in promoting equity among beneficiaries with cancer.

Incorporating Cost Measures Into the Merit-Based Incentive Payment System: Implications for Oncologists.

PURPOSE: The Merit-Based Incentive Payment System (MIPS) is currently the only federally mandated value-based payment model for oncologists. The weight of cost measures in MIPS has increased from 0% in 2017 to 30% in 2022. Given that cost measures are specialty-agnostic, specialties with greater costs of care such as oncology may be unfairly affected. We investigated the implications of incorporating cost measures into MIPS on physician reimbursements for oncologists and other physicians. METHODS: We evaluated physicians scored on cost and quality in the 2018 MIPS using the Doctors and Clinicians database. We used multivariable Tobit regression to identify physician-level factors associated with cost and quality scores. We simulated composite MIPS scores and payment adjustments by applying the 2022 cost-quality weights to the 2018 category scores and compared changes across specialties. RESULTS: Of 168,098 identified MIPS-participating physicians, 5,942 (3.5%) were oncologists. Oncologists had the lowest cost scores compared with other specialties (adjusted mean score, 58.4 for oncologists v 71.0 for nononcologists; difference, -12.66 [95% CI, -13.34 to -11.99]), while quality scores were similar (82.9 v 84.2; difference, -1.31 [95% CI, -2.65 to 0.03]). After the 2022 cost-quality reweighting, oncologists would receive a 4.3-point (95% CI, 4.58 to 4.04) reduction in composite MIPS scores, corresponding to a four-fold increase in magnitude of physician penalties ($4,233.41 US dollars [USD] in 2018 v $18,531.06 USD in 2022) and greater reduction in exceptional payment bonuses compared with physicians in other specialties (-42.8% [95% CI, -44.1 to -41.5] for oncologists v -23.6% [95% CI, -23.8 to -23.4] for others). CONCLUSION: Oncologists will likely be disproportionally penalized after the incorporation of cost measures into MIPS. Specialty-specific recalibration of cost measures is needed to ensure that policy efforts to promote value-based care do not compromise health care quality and outcomes.

Association Between Geospatial Access to Trauma Center Care and Motor Vehicle Crash Mortality in the United States.

BACKGROUND: Motor vehicle crashes (MVCs) are a leading cause of preventable trauma death in the United States (US). Access to trauma center care is highly variable nationwide. The objective of this study was to measure the association between geospatial access to trauma center care and MVC mortality. METHODS: This was a population-based study of MVC-related deaths that occurred in 3,141 US counties (2017-2020). ACS and state-verified level I-III trauma centers were mapped. Geospatial network analysis estimated the ground transport time to the nearest trauma center from the population-weighted centroid for each county. In this way, the exposure was the predicted access time to trauma center care for each county population. Hierarchical negative binomial regression measured the risk-adjusted association between predicted access time and MVC mortality, adjusting for population demographics, rurality, access to trauma resources, and state traffic safety laws. RESULTS: We identified 92,398 crash fatalities over the four-year study period. Trauma centers mapped included 217 level I, 343 level II, and 495 level III trauma centers. The median county predicted access time was 47 min (IQR 26-71 min). Median county MVC mortality was 12.5 deaths/100,000 person-years (IQR 7.4-20.3 deaths/100,000 person-years). After risk-adjustment, longer predicted access times were significantly associated with higher rates of MVC mortality (>60 min vs. <15 min; MRR 1.36; 95%CI 1.31-1.40). This relationship was significantly more pronounced in urban/suburban vs. rural/wilderness counties (p for interaction, <0.001). County access to trauma center care explained 16% of observed state-level variation in MVC mortality. CONCLUSIONS: Geospatial access to trauma center care is significantly associated with MVC mortality and contributes meaningfully to between-state differences in road traffic deaths. Efforts to improve trauma system organization should prioritize access to trauma center care to minimize crash fatalities. LEVEL OF EVIDENCE: Level III, Epidemiological.

Health Care Contact Days Experienced by Decedents With Advanced GI Cancer.

PURPOSE: Frequent visits to health care facilities can be time intensive and all-consuming for people with cancer. We measured health care contact days (days with healthcare contact outside the home) among decedents with advanced GI cancer and examined sources of contact days, their associations with demographic and clinical factors, and their temporal patterns over the course of illness. METHODS: We conducted a retrospective cohort study using a tumor registry and electronic medical record data for decedents with stage IV GI cancer between 2011 and 2019 in a large health care network in MN. We determined contact days from diagnosis to death using chart review. Using multivariable beta regression adjusted for sociodemographic and clinical characteristics offset by survival, we calculated adjusted estimates of contact days and determined patient-level factors associated with percentage of contact days. RESULTS: We identified 809 patients eligible for analysis (median [IQR] age at diagnosis, 65 [56-73] years). The median (IQR) overall survival was 175 (56-459) days. Patients spent a median (IQR) of 25.8% (17.4%-39.1%) of these as contact days. Of these days, 83.6% were spent on outpatient visits. In the multivariable analysis, older age, Black race, and never receiving systemic cancer-directed treatment were associated with a higher percentage of contact days. The percentage of contact days was highest in the first month after diagnosis (39.6%) and before death (32.2%), with a more moderate middle phase (U-shaped curve). CONCLUSION: Decedents with advanced GI cancer spend 1 in 4 days alive with health care contact, despite a median survival of under 6 months. This is even higher immediately postdiagnosis and near death. These findings highlight the need to understand sources of variation, benchmark appropriate care, and deliver more efficient care for this vulnerable population with limited time.

#ColonCancer: Social Media Discussions About Colorectal Cancer During the COVID-19 Pandemic.

PURPOSE: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Social media platforms such as Twitter are extensively used to communicate about cancer care, yet little is known about the role of these online platforms in promoting early detection or sharing the lived experiences of patients with CRC. This study tracked Twitter discussions about CRC and characterized participating users to better understand public communication and perceptions of CRC during the COVID-19 pandemic. METHODS: Tweets containing references to CRC were collected from January 2020 to April 2021 using Twitter's Application Programming Interface. Account metadata was used to predict user demographic information and classify users as either organizations, individuals, clinicians, or influencers. We compared the number of impressions across users and analyzed the content of tweets using natural language processing models to identify prominent topics of discussion. RESULTS: There were 72,229 unique CRC-related tweets by 31,170 users. Most users were male (66%) and older than 40 years (57%). Individuals accounted for most users (44%); organizations (35%); clinicians (19%); and influencers (2%). Influencers made the most median impressions (35,853). Organizations made the most overall impressions (1,067,189,613). Tweets contained the following topics: bereavement (20%), appeals for early detection (20%), research (17%), National Colorectal Cancer Awareness Month (15%), screening access (14%), and risk factors (14%). CONCLUSION: Discussions about CRC largely focused on bereavement and early detection. Online coverage of National Colorectal Cancer Awareness Month and personal experiences with CRC effectively stimulated goal-oriented tweets about early detection. Our findings suggest that although Twitter is commonly used for communicating about CRC, partnering with influencers may be an effective strategy for improving communication of future public health recommendations related to CRC.

Perceptions of Life Support and Advance Care Planning During the COVID-19 Pandemic: A Global Study of Twitter Users.

BACKGROUND: The COVID-19 pandemic has presented new challenges surrounding end-of-life planning and has been associated with increased online discussion about life support. RESEARCH QUESTION: How has online communication about advance care planning (ACP) and specific life-sustaining interventions (LSIs) changed during the pandemic? STUDY DESIGN AND METHODS: Conversations on Twitter containing references to LSIs (eg, "ECMO") or ACP (eg, "DNR/DNI") were collected between January 2019 and May 2021. User account metadata were used to predict user demographic information and to classify users as organizations, individuals, clinicians, or influencers. The number of impressions was compared across these user categories and the content of tweets analyzed by using natural language processing models to identify topics of discussion and associated emotional sentiment. RESULTS: There were 202,585 unique tweets about LSIs and 67,162 unique tweets about ACP. Users who were younger, male, or influencers were more likely to discuss LSIs online. Tweets about LSIs were associated with more positive emotional sentiment scores than tweets about ACP (LSIs, 0.3; ACP, -0.2; P < .001). Among tweets about ACP, most contained personal experiences related to the death of loved ones (27%) or discussed discrimination through do-not-resuscitate orders directed at the elderly and disabled (19%). Personal experiences had the greatest retweet-to-tweet-ratio (4.7), indicating high levels of user engagement. Tweets about discrimination contained the most negative net sentiment score (-0.5). INTERPRETATION: The observed increase in tweets regarding LSIs and ACP suggests that Twitter was consistently used to discuss treatment modalities and preferences related to intensive care during the pandemic. Future interventions to increase online engagement with ACP may consider leveraging influencers and personal stories. Finally, we identified do-not-resuscitate-related discrimination as a commonly held public fear, which should be further explored as a barrier to ACP completion and can be proactively addressed by clinicians during bedside goals-of-care discussions.

MotifMap: integrative genome-wide maps of regulatory motif sites for model species.

BACKGROUND: A central challenge of biology is to map and understand gene regulation on a genome-wide scale. For any given genome, only a small fraction of the regulatory elements embedded in the DNA sequence have been characterized, and there is great interest in developing computational methods to systematically map all these elements and understand their relationships. Such computational efforts, however, are significantly hindered by the overwhelming size of non-coding regions and the statistical variability and complex spatial organizations of regulatory elements and interactions. Genome-wide catalogs of regulatory elements for all model species simply do not yet exist. RESULTS: The MotifMap system uses databases of transcription factor binding motifs, refined genome alignments, and a comparative genomic statistical approach to provide comprehensive maps of candidate regulatory elements encoded in the genomes of model species. The system is used to derive new genome-wide maps for yeast, fly, worm, mouse, and human. The human map contains 519,108 sites for 570 matrices with a False Discovery Rate of 0.1 or less. The new maps are assessed in several ways, for instance using high-throughput experimental ChIP-seq data and AUC statistics, providing strong evidence for their accuracy and coverage. The maps can be usefully integrated with many other kinds of omic data and are available at http://motifmap.igb.uci.edu/. CONCLUSIONS: MotifMap and its integration with other data provide a foundation for analyzing gene regulation on a genome-wide scale, and for automatically generating regulatory pathways and hypotheses. The power of this approach is demonstrated and discussed using the P53 apoptotic pathway and the Gli hedgehog pathways as examples.