Prospective validation of a hospital triage predictive model to decrease undertriage: an EAST multicenter study.

Background: Tiered trauma team activation (TTA) allows systems to optimally allocate resources to an injured patient. Target undertriage and overtriage rates of <5% and <35% are difficult for centers to achieve, and performance variability exists. The objective of this study was to optimize and externally validate a previously developed hospital trauma triage prediction model to predict the need for emergent intervention in 6 hours (NEI-6), an indicator of need for a full TTA. Methods: The model was previously developed and internally validated using data from 31 US trauma centers. Data were collected prospectively at five sites using a mobile application which hosted the NEI-6 model. A weighted multiple logistic regression model was used to retrain and optimize the model using the original data set and a portion of data from one of the prospective sites. The remaining data from the five sites were designated for external validation. The area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC) were used to assess the validation cohort. Subanalyses were performed for age, race, and mechanism of injury. Results: 14 421 patients were included in the training data set and 2476 patients in the external validation data set across five sites. On validation, the model had an overall undertriage rate of 9.1% and overtriage rate of 53.7%, with an AUROC of 0.80 and an AUPRC of 0.63. Blunt injury had an undertriage rate of 8.8%, whereas penetrating injury had 31.2%. For those aged ≥65, the undertriage rate was 8.4%, and for Black or African American patients the undertriage rate was 7.7%. Conclusion: The optimized and externally validated NEI-6 model approaches the recommended undertriage and overtriage rates while significantly reducing variability of TTA across centers for blunt trauma patients. The model performs well for populations that traditionally have high rates of undertriage. Level of evidence: 2.

Arsenic Exposure in Well Water From the Perspective of Patients and Providers.

BACKGROUND: Arsenic is a well-known toxin which may contaminate household water. It is harmful when ingested over prolonged periods of time. As a result, public health experts recommend that water should be screened and treated to prevent arsenic ingestion. In the United States, the responsibility of testing and treatment of private wells falls on homeowners. Despite recommendations for routine screening, this is rarely done. OBJECTIVES: To assess the prevalence of well water use in a Midwestern patient population, how patients and clinicians perceive the risks of arsenic in well water, and whether additional resources on well water testing are desired. These findings will be used to influence tools for clinicians regarding symptom and examination findings of chronic arsenic exposure and potentiate the distribution of informational resources on well water testing. METHODS: Surveys were sent via email to all actively practicing primary care clinicians at the Mayo Clinic in the United States Midwest, and all active adult patients at the Mayo Clinic in the same region. Our team analyzed survey data to determine whether both patients and clinicians are aware of the health effects of chronic arsenic toxicity from well water, the need for routine well water testing and whether each group wants more information on the associated risks. RESULTS: Both patients and primary care clinicians worry about arsenic exposure. Patients with well water are concerned about their water safety yet feel uninformed about testing options. Clinicians do not know how prevalent well water use is among their patients, feel uninformed about the chronic risks of arsenic exposure and the physical examination associated with it. Both groups unanimously want more information on testing options. CONCLUSIONS: Our findings show a significant reliance on well water use in the American Midwest, and unanimous support for the need for further well water testing information and resources for patients and their clinicians.

A Metabolic-Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer.

Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple-negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and toward fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic-epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.

Fragmenting projectiles: a case report and literature review of the G2 Radically Invasive Projectile.

Innovations in projectile design present unique challenges for trauma surgeons when treating gunshot victims. The G2 Radically Invasive Projectile (G2 Research, Winder, Georgia, USA) (G2RIP) is a frangible, rapidly expanding bullet resulting in a distinct pattern of injury consisting of diffuse hemorrhage with multicavity trauma as well as unique radiographic features of the projectile. To efficiently manage patients injured by the G2RIP, trauma surgeons must be aware of these distinct characteristics, and of previous patterns in effective management such as liberal damage control and extensive use of CT. Understanding previous presentation and management of patients injured by the G2RIP can aid in improving patient care in the trauma center.

Neutrophil-dependent hepatic platelet accumulation and liver injury revealed by acetaminophen dose-response studies.

Background: Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure (ALF). Neutrophil activation has been associated with poor outcomes in patients with ALF and is proposed to amplify coagulation in this context. However, the precise role of neutrophils in APAP-induced liver injury is not known. Methods: We used a dual antibody-mediated neutrophil depletion strategy to determine the role of neutrophils in mice challenged with different doses of APAP (300 or 600 mg/kg) that produce hepatotoxicity and ALF-like pathology. Results: Flow cytometry confirmed depletion of neutrophils in whole blood prior to APAP challenge. Mice given isotype control and challenged with 300 mg/kg APAP developed marked hepatocellular necrosis and showed an increase in biomarkers of coagulation cascade activation. Neutrophil depletion (anti-Ly6G) did not affect either liver injury or coagulation activation in mice challenged with 300 mg/kg APAP. Mice given isotype control and challenged with 600 mg/kg APAP developed hepatic necrosis alongside marked hemorrhage and congestion indicative of vascular injury. Interestingly, hepatic neutrophil and platelet accumulation were increased in mice given 600 mg/kg APAP compared with those given the lower APAP dose. Neutrophil depletion significantly reduced the severity of liver necrosis in mice challenged with 600 mg/kg APAP, without significantly impacting biomarkers of coagulation activity. Notably, neutrophil depletion significantly reduced hepatic platelet accumulation in mice challenged with 600 mg/kg APAP. Conclusion: The results indicate a role of neutrophils in APAP-induced liver injury that is dependent on the APAP dose and suggest involvement of neutrophil-platelet interactions in promoting hepatic injury in experimental APAP-induced ALF.

Interleukin-10-producing monocytes contribute to sex differences in pain resolution in mice and humans.

Pain is closely associated with the immune system, which exhibits sexual dimorphism. For these reasons, neuro-immune interactions are suggested to drive sex differences in pain pathophysiology. However, our understanding of peripheral neuro-immune interactions on sex differences in pain resolution remains limited. Here, we have shown, in both a mouse model of inflammatory pain and in humans following traumatic pain, that males had higher levels of interleukin (IL)-10 than females, which were correlated with faster pain resolution. Following injury, we identified monocytes (CD11b+ Ly6C+ Ly6G-F4/80 mid ) as the primary source of IL-10, with IL-10-producing monocytes being more abundant in males than females. In a mouse model, neutralizing IL-10 signaling through antibodies, genetically ablating IL-10R1 in sensory neurons, or depleting monocytes with clodronate all impaired the resolution of pain hypersensitivity in both sexes. Furthermore, manipulating androgen levels in mice reversed the sexual dimorphism of pain resolution and the levels of IL-10-producing monocytes. These results highlight a novel role for androgen-driven peripheral IL-10-producing monocytes in the sexual dimorphism of pain resolution. These findings add to the growing concept that immune cells play a critical role in resolving pain and preventing the transition into chronic pain.

Respiration is essential for aerobic growth of Zymomonas mobilis ZM4.

Zymomonas mobilis is an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels due to its efficient ethanol fermentation and low biomass generation. Z. mobilis is aerotolerant and encodes a complete respiratory electron transport chain, but the benefit of respiration for growth in oxic conditions has never been confirmed, despite decades of research. Growth and ethanol production of wild-type Z. mobilis is poor in oxic conditions indicating that it does not benefit from oxidative phosphorylation. Additionally, in previous studies, aerobic growth improved significantly when respiratory genes were disrupted (ndh) or acquired point mutations (cydA and cydB), even if respiration was significantly reduced by these changes. Here, we obtained clean deletions of respiratory genes ndh and cydAB, individually and in combination, and showed, for the first time, that deletion of cydAB completely inhibited O2 respiration and dramatically reduced growth in oxic conditions. Both respiration and aerobic growth were restored by expressing a heterologous, water-forming NADH oxidase, noxE. Oxygen can have many negative effects, including formation of reactive oxygen species (ROS) or directly inactivating oxygen sensitive enzymes. Our results suggest that the effect of molecular oxygen on enzymes had a greater negative impact on Z. mobilis than formation of ROS. This result shows that the main role of the electron transport chain in Z. mobilis is reducing the intracellular concentration of molecular oxygen, helping to explain why it is beneficial for Z. mobilis to use electron transport chain complexes that have little capacity to contribute to oxidative phosphorylation. IMPORTANCE A key to producing next-generation biofuels is to engineer microbes that efficiently convert non-food materials into drop-in fuels, and to engineer microbes effectively, we must understand their metabolism thoroughly. Zymomonas mobilis is a bacterium that is a promising candidate biofuel producer, but its metabolism remains poorly understood, especially its metabolism when exposed to oxygen. Although Z. mobilis respires with oxygen, its aerobic growth is poor, and disruption of genes related to respiration counterintuitively improves aerobic growth. This unusual result has sparked decades of research and debate regarding the function of respiration in Z. mobilis. Here, we used a new set of mutants to determine that respiration is essential for aerobic growth and likely protects the cells from damage caused by oxygen. We conclude that the respiratory pathway of Z. mobilis should not be deleted from chassis strains for industrial production because this would yield a strain that is intolerant of oxygen, which is more difficult to manage in industrial settings.

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Prostatic proliferative inflammatory atrophy: welcome to the club†.

Single-cell RNA sequencing studies in the human prostate have defined a population of epithelial cells with transcriptional similarities to club cells in the lung. However, the localization of club-like cells in the human prostate, and their relationship to prostate cancer, is poorly understood. In a new article in The Journal of Pathology, RNA in situ hybridization was used to demonstrate that club cell markers are expressed in luminal cells adjacent to inflammation in the peripheral zone of the human prostate, where prostate cancer tends to arise. These club-like cells are commonly found in proliferative inflammatory atrophy (PIA) lesions and express markers consistent with an intermediate epithelial cell-type. Future studies will be needed to understand the functional role of club-like cells in human prostate inflammation, regeneration, and disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain.

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or δOR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naïve state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.

Disparities in Diabetes Care: Differences Between Rural and Urban Patients Within a Large Health System.

PURPOSE: We sought to ascertain factors associated with the quality of diabetes care, comparing rural vs urban diabetic patients in a large health care system. METHODS: We conducted a retrospective cohort study assessing patients' attainment of the D5 metric, a diabetes care metric having 5 components (no tobacco use, glycated hemoglobin [A1c] level less than 8%, blood pressure less than 140/90 mm Hg, low-density lipoprotein cholesterol level at goal or statin prescribed, and aspirin use consistent with clinical recommendations). Covariates included age, sex, race, adjusted clinical group (ACG) score as a marker of complexity, insurance type, primary care clinician type, and health care use data. RESULTS: The study cohort consisted of 45,279 patients with diabetes, 54.4% of whom resided in rural locations. The D5 composite metric was met in 39.9% of rural patients and 43.2% of urban patients (P <.001). Rural patients were significantly less likely to have attained all metric goals than urban counterparts (adjusted odds ratio [AOR] = 0.93; 95% CI, 0.88-0.97). The rural group had fewer outpatient visits (mean number of visits = 3.2 vs 3.9, P <.001) and less often had an endocrinology visit (5.5% vs 9.3%, P <.001) during the 1-year study period. Patients with an endocrinology visit were less likely to have met the D5 metric (AOR = 0.80; 95% CI, 0.73-0.86), whereas the more outpatient visits patients had, the greater their likelihood of attainment (AOR per visit = 1.03; 95% CI, 1.03-1.04). CONCLUSIONS: Rural patients had worse diabetes quality outcomes than their urban counterparts, even after adjustment for other contributing factors and despite being part of the same integrated health system. Lower visit frequency and less specialty involvement in the rural setting are possible contributing factors.

Recent Advances in Responsive Membrane Functionalization Approaches and Applications.

In recent years, significant advances have been made in the field of functionalized membranes. With the functionalization using various materials, such as polymers and enzymes, membranes can exhibit property changes in response to an environmental stimulation, such as heat, light, ionic strength, or pH. The resulting responsive nature allows for an increased breadth of membrane uses, due to the developed functionalization properties, such as smart-gating filtration for size-selective water contaminant removal, self-cleaning antifouling surfaces, increased scalability options, and highly sensitive molecular detection. In this review, new advances in both fabrication and applications of functionalized membranes are reported and summarized, including temperature-responsive, pH-responsive, light-responsive, enzyme-functionalized, and two-dimensional material-functionalized membranes. Specific emphasis was given to the most recent technological improvements, current limitations, advances in characterization techniques, and future directions for the field of functionalized membranes.

Phosphatidylserine-Exposing Annexin A1-Positive Extracellular Vesicles: Potential Cancer Biomarkers.

Under physiological conditions, phosphatidylserine (PS) predominantly localizes to the cytosolic leaflet of the plasma membrane of cells. During apoptosis, PS is exposed on the cell surface and serves as an "eat-me" signal for macrophages to prevent releasing self-immunogenic cellular components from dying cells which could potentially lead to autoimmunity. However, increasing evidence indicates that viable cells can also expose PS on their surface. Interestingly, tumor cell-derived extracellular vesicles (EVs) externalize PS. Recent studies have proposed PS-exposing EVs as a potential biomarker for the early detection of cancer and other diseases. However, there are confounding results regarding subtypes of PS-positive EVs, and knowledge of PS exposure on the EV surface requires further elucidation. In this study, we enriched small EVs (sEVs) and medium/large EVs (m/lEVs) from conditioned media of breast cancer cells (MDA-MB-231, MDA-MB-468) and non-cancerous cells (keratinocytes, fibroblasts). Since several PS-binding molecules are available to date, we compared recombinant proteins of annexin A5 and the carboxylated glutamic acid domain of Protein S (GlaS), also specific for PS, to detect PS-exposing EVs. Firstly, PS externalization in each EV fraction was analyzed using a bead-based EV assay, which combines EV capture using microbeads and analysis of PS-exposing EVs by flow cytometry. The bulk EV assay showed higher PS externalization in m/lEVs derived from MDA-MB-468 cells but not from MDA-MB-231 cells, while higher binding of GlaS was also observed in m/lEVs from fibroblasts. Second, using single EV flow cytometry, PS externalization was also analyzed on individual sEVs and m/lEVs. Significantly higher PS externalization was detected in m/lEVs (annexin A1+) derived from cancer cells compared to m/lEVs (annexin A1+) from non-cancerous cells. These results emphasize the significance of PS-exposing m/lEVs (annexin A1+) as an undervalued EV subtype for early cancer detection and provide a better understanding of PS externalization in disease-associated EV subtypes.

Evaluation of the Efficacy and Safety of Antiplatelet Therapeutics in Rabbits.

Hemostasis is a multifactorial process that involves vasoconstriction of blood vessels, activation of the coagulation cascade, and platelet aggregation. Inappropriate activation of hemostatic processes can result in thrombosis and tissue ischemia. In patients at risk for thrombotic events, antiplatelet therapeutic agents inhibit platelet activation, thereby reducing the incidence of pathologic clot formation. Platelets are activated by several endogenous chemical mediators, including adenosine diphosphate, thrombin, and thromboxane. These activation pathways serve as attractive drug targets. The protocols described in this article are designed to evaluate the preclinical efficacy and safety of novel antiplatelet therapeutics in rabbits. Here, we provide two protocols for blood collection, two for determining platelet activation, and one for assessing bleeding safety. Together, these protocols can be used to characterize the efficacy and safety of antiplatelet agents for hemostasis. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Blood collection via the central ear artery Alternative Protocol 1: Blood collection via the jugular vein Basic Protocol 2: Platelet aggregation assessment via light transmission aggregometry Alternative Protocol 2: Platelet activation assessment via flow cytometry Basic Protocol 3: Determination of tongue bleeding time.

Clinician Adoption of an Artificial Intelligence Algorithm to Detect Left Ventricular Systolic Dysfunction in Primary Care.

OBJECTIVE: To compare the clinicians' characteristics of "high adopters" and "low adopters" of an artificial intelligence (AI)-enabled electrocardiogram (ECG) algorithm that alerted for possible low left ventricular ejection fraction (EF) and the subsequent effectiveness of detecting patients with low EF. METHODS: Clinicians in 48 practice sites of a US Midwest health system were cluster-randomized by the care team to usual care or to receive a notification that suggested ordering an echocardiogram in patients flagged as potentially having low EF based on an AI-ECG algorithm. Enrollment was between June 26, 2019, and July 30, 2019; participation concluded on March 31, 2020. This report is focused on those clinicians randomized to receive the notification of the AI-ECG algorithm. At the patient level, data were analyzed for the proportion of patients with positive AI-ECG results. Adoption was defined as the clinician order of an echocardiogram after prompted by the alert. RESULTS: A total of 165 clinicians and 11,573 patients were included in this analysis. Among patients with positive AI-ECG, high adopters (n=41) were twice as likely to diagnose patients with low EF (33.9%) vs low adopters, n=124, (16.9%); odds ratio, 1.62; 95% CI, 1.21 to 2.17). High adopters were more often advanced practice providers (eg, nurse practitioners and physician assistants) vs physicians, Family Medicine vs Internal Medicine specialty, and tended to have less complex patients. CONCLUSION: Clinicians who most frequently followed the recommendations of an AI tool were twice as likely to diagnose low EF. Those clinicians with less complex patients were more likely to be high adopters. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04000087.

Aerosol capture and coronavirus spike protein deactivation by enzyme functionalized antiviral membranes.

The airborne nature of coronavirus transmission makes it critical to develop new barrier technologies that can simultaneously reduce aerosol and viral spread. Here, we report nanostructured membranes with tunable thickness and porosity for filtering coronavirus-sized aerosols, combined with antiviral enzyme functionalization that can denature spike glycoproteins of the SARS-CoV-2 virus in low-hydration environments. Thin, asymmetric membranes with subtilisin enzyme and methacrylic functionalization show more than 98.90% filtration efficiency for 100-nm unfunctionalized and protein-functionalized polystyrene latex aerosol particles. Unfunctionalized membranes provided a protection factor of 540 ± 380 for coronavirus-sized particle, above the Occupational Safety and Health Administration's standard of 10 for N95 masks. SARS-CoV-2 spike glycoprotein on the surface of coronavirus-sized particles was denatured in 30 s by subtilisin enzyme-functionalized membranes with 0.02-0.2% water content on the membrane surface.

Isolation and characterization of uterine leukocytes collected using a uterine swab technique.

PROBLEM: Leukocytes from the maternal-fetal interface are a valuable tool to study local changes in immune function during pregnancy; however, sampling can be challenging due to inadequate tissue availability and the invasive nature of placental bed biopsy. Here, we aim to purify and characterize leukocytes from paired peripheral and uterine blood samples to assess whether a less invasive method of uterine blood collection could yield a population of enriched uterine leukocytes suitable for ex vivo and in vitro analyses. METHOD OF STUDY: Human peripheral blood mononuclear cells (PBMC) and uterine blood mononuclear cells (UBMC) expressed from surgical gauze post C-section were isolated, and immunophenotypic information was acquired by multi-parameter flow cytometry. PBMC and UBMC were stained for markers used to define T and B lymphocytes, macrophages, regulatory T (TReg ) cells, and natural killer (NK) cells. Prime flow was performed to check expression and analysis of CD16- CD56++ and CD16- CD56++ NK transcripts in PBMC and UBMC samples. RESULTS: Immunophenotyping revealed that over 95% of both live PBMC and UBMC consisted of CD45+ leukocytes. Higher percentages of CD16- CD56++ , characterized as uterine NK (uNK) cells, were observed in UBMC samples as compared to PBMC samples (18.41% of CD45+ CD3- vs. 2.73%, respectively), suggesting that CD16- CD56++ cells were enriched in these samples. In UBMC, 49.64% of CD3-negative cells were of peripheral NK phenotype (CD16+ CD56++ ), suggesting infiltration of maternal peripheral NK (pNK) cell in the uterine interface. CONCLUSION: Intrauterine leukocytes, especially CD16- CD56++ NK cells, can be collected in sufficient numbers with increased purity by sampling the uterine cavity postdelivery with surgical gauze. Our results suggest that this non-invasive protocol is a useful sampling technique for isolating CD16- CD56++ cells, however, due to peripheral blood contamination, the NK cell yield could be lower compared to actual decidual or endometrial samples post-partum which is more invasive.

EED is required for mouse primordial germ cell differentiation in the embryonic gonad.

Development of primordial germ cells (PGCs) is required for reproduction. During PGC development in mammals, major epigenetic remodeling occurs, which is hypothesized to establish an epigenetic landscape for sex-specific germ cell differentiation and gametogenesis. In order to address the role of embryonic ectoderm development (EED) and histone 3 lysine 27 trimethylation (H3K27me3) in this process, we created an EED conditional knockout mouse and show that EED is essential for regulating the timing of sex-specific PGC differentiation in both ovaries and testes, as well as X chromosome dosage decompensation in testes. Integrating chromatin and whole genome bisulfite sequencing of epiblast and PGCs, we identified a poised repressive signature of H3K27me3/DNA methylation that we propose is established in the epiblast where EED and DNMT1 interact. Thus, EED joins DNMT1 in regulating the timing of sex-specific PGC differentiation during the critical window when the gonadal niche cells specialize into an ovary or testis.

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.

The effect of primary care clinician type and care team characteristics on health care costs.

OBJECTIVE: To evaluate health care costs as a function of assigned primary care clinician type and care team characteristics. METHODS: Administrative data were collected for 68 family medicine clinicians (40 physicians and 28 nurse practitioners [NPs]/physician assistant [PAs]), on 11 care teams (variable MD, NP and PA on teams), caring for 77,141 patients. We performed a generalized linear mixed multivariable regression model of standardized per member per month (PMPM) median cost as the outcome, with four practice sites included as random effects. RESULTS: In bivariate analysis, cost was higher in physicians than NP/PAs, in more complex patients, and associated with emergency department (ED) visit rate. On multivariate analysis, patient complexity, ED visit rate and higher patient experience ratings were independently associated with greater PMPM cost. More time in practice was associated with lower PMPM cost. In the adjusted multivariate model, physicians had 8.3% lower median PMPM costs than NP/PAs (p = 0.046). CONCLUSIONS: The primary drivers of greater PMPM cost were patient complexity, ED visits and patient satisfaction.