Some records only list UMB authors. Go to the publication website to see the full list of authors and authorship order.

Collections in this community

Recent Submissions

  • Comparative Genomics Identifies Features Associated with Methicillin-Resistant Staphylococcus aureus (MRSA) Transmission in Hospital Settings.

    Adedrian, Timileyin; Hitchcock, Stephanie; O'Hara, Lyndsay M; Michalski, Jane M; Johnson, J Kristie; Calfee, David P; Miller, Loren G; Hazen, Tracy H; Harris, Anthony D; Rasko, David A (American Society for Microbiology, 2022-05-17)
    Methicillin-resistant Staphylococcus aureus (MRSA) is a serious public health concern in the United States. Patients colonized and/or infected can transmit MRSA to healthcare workers and subsequent patients However, the components of this transmission chain are just becoming evident, including certain patient factors, specific patient-healthcare worker interactions, and microbial factors. We conducted a comparative genomic analysis of 388 isolates from four hospitals in three states: Maryland, California, and New York. Isolates from nasal surveillance or clinical cultures were categorized as high, moderate, or low transmission surrogate outcomes based on the number of times the species was identified on the gloves or gowns of healthcare providers. The comparative analyses included a single gene, multigene, and core genome phylogenetic analysis, as well as a genome-wide association analysis to identify molecular signatures associated with the observed transmission surrogate outcomes, geographic origin, or sample source of isolation. Based on the phylogenetic analysis, 95% (n = 372) of the MRSA isolates were from four well-described genomic clades, with most of the isolates being part of the USA300 containing clade (n = 187; 48%). Genome-wide association studies also identified genes that were exclusive or prevalent among specific geographic locations. The identified genes provide insights into the transmission dynamics of MRSA isolates providing additional insights into the basis of the geographical differences of MRSA for molecular diagnostics. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) is considered a serious threat to public health and contributes to the dissemination of S. aureus in both the healthcare and community setting. Transmission of MRSA between patients via healthcare worker (HCW) has been described. However, what is not understood are the genetic determinants that contribute to the transmission of MRSA from patients to HCWs. In this study, we demonstrated that certain genes may be associated with transmission in the hospital setting.
  • A decade of GigaScience: 10 years of the evolving genomic and biomedical standards landscape.

    Schriml, Lynn M
    Standardization of omics data drives FAIR data practices through community-built genomic data standards and biomedical ontologies. Use of standards has progressed from a foreign concept to a sought-after solution, moving from efforts to coordinate data within individual research projects to research communities coming together to identify solutions to common challenges. Today we are seeing the benefits of this multidecade groundswell to coordinate, exchange, and reuse data; to compare data across studies; and to integrate data across previously siloed resources.
  • Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in heart failure patients.

    Samuel, T Jake; Lai, Shenghan; Schär, Michael; Wu, Katherine C; Steinberg, Angela M; Wei, An-Chi; Anderson, Mark; Tomaselli, Gordon F; Gerstenblith, Gary; Bottomley, Paul A; et al. (American Society for Clinical Investigation, 2022-05-17)
    Background: Sudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies such as implantable cardioverter defibrillators (ICDs) are based on left ventricular ejection fraction (LVEF), but these are imprecise with fewer than 5% of ICDs delivering life-saving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor the potential for metabolically predicting clinical SCD risk. Methods: We prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%). Results: By two different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over ~10 years. Life-threatening arrhythmia risk was ~3-fold higher in low ATP patients and independent of established risk factors including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings. Conclusion: These first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people suggest an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald non-invasive metabolic imaging as a complementary SCD risk stratification tool. Trial registration: NCT00181233.
  • Targeting CAR-Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.

    Stern, Sydney; Liang, Dongdong; Li, Linhao; Kurian, Ritika; Lynch, Caitlin; Sakamuru, Srilatha; Heyward, Scott; Zhang, Junran; Kareem, Kafayat Ajoke; Chun, Young Wook; et al. (American Society for Clinical Investigation, 2022-05-17)
    Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC) although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side-effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular co-culture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Further, CN06 preserves the viability and function of human iPSC-derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy:toxicity ratio of CPA/DOX-containing chemotherapy.
  • Pregnancy and the Risk of In-Hospital Coronavirus Disease 2019 (COVID-19) Mortality.

    Pineles, Beth L; Goodman, Katherine E; Pineles, Lisa; O'Hara, Lyndsay M; Nadimpalli, Gita; Magder, Laurence S; Baghdadi, Jonathan D; Parchem, Jacqueline G; Harris, Anthony D (Wolters Kluwer Health, 2022-04-05)
    Objective: To evaluate whether pregnancy is an independent risk factor for in-hospital mortality among patients of reproductive age hospitalized with coronavirus disease 2019 (COVID-19) viral pneumonia. Methods: We conducted a retrospective cohort study (April 2020-May 2021) of 23,574 female inpatients aged 15-45 years with an International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code for COVID-19 discharged from 749 U.S. hospitals in the Premier Healthcare Database. We used a viral pneumonia diagnosis to select for patients with symptomatic COVID-19. The associations between pregnancy and in-hospital mortality, intensive care unit (ICU) admission, and mechanical ventilation were analyzed using propensity score-matched conditional logistic regression. Models were matched for age, marital status, race and ethnicity, Elixhauser comorbidity score, payer, hospital number of beds, season of discharge, hospital region, obesity, hypertension, diabetes mellitus, chronic pulmonary disease, deficiency anemias, depression, hypothyroidism, and liver disease. Results: In-hospital mortality occurred in 1.1% of pregnant patients and 3.5% of nonpregnant patients hospitalized with COVID-19 and viral pneumonia (propensity score-matched odds ratio [OR] 0.39, 95% CI 0.25-0.63). The frequency of ICU admission for pregnant and nonpregnant patients was 22.0% and 17.7%, respectively (OR 1.34, 95% CI 1.15-1.55). Mechanical ventilation was used in 8.7% of both pregnant and nonpregnant patients (OR 1.05, 95% CI 0.86-1.29). Among patients who were admitted to an ICU, mortality was lower for pregnant compared with nonpregnant patients (OR 0.33, 95% CI 0.20-0.57), though mechanical ventilation rates were similar (35.7% vs 38.3%, OR 0.90, 95% CI 0.70-1.16). Among patients with mechanical ventilation, pregnant patients had a reduced risk of in-hospital mortality compared with nonpregnant patients (0.26, 95% CI 0.15-0.46). Conclusion: Despite a higher frequency of ICU admission, in-hospital mortality was lower among pregnant patients compared with nonpregnant patients with COVID-19 viral pneumonia, and these findings persisted after propensity score matching.
  • Exacerbation of COVID-19 mortality by the fragmented United States healthcare system: A retrospective observational study.

    Campbell, Travis; Galvani, Alison P; Friedman, Gerald; Fitzpatrick, Meagan C (Elsevier, 2022-05-12)
    Background Before widespread vaccination, the United States was disproportionately affected by COVID-19 with a mortality rate several times that of other affluent societies. Comparing regions with different rates of health insurance, we assess how much of this excess mortality may be due to the relatively large population without health insurance. Methods We use daily surveillance data from the US Centers for Disease Control and Prevention (CDC) stratified by region, age group, gender, and race in regression analysis of daily COVID-19 cases, hospitalization, and mortality. COVID-19 data have been matched with structural characteristics of the region including average proportion with health insurance. As checks, we have estimated regressions for different time periods, different groups of states, and by comparing adjacent counties between states with and without Medicaid expansion. Findings Groups with lower health insurance coverage had significantly higher mortality as well as greater case counts and hospitalization. Early in the pandemic, they were also less likely to be tested for COVID-19. Applying our regression estimates, we estimate that had there been full health insurance coverage of the population, there would have been 60,000 fewer deaths, 26% of the total death toll in the period of this analysis. Interpretation Our study demonstrates that a significant share of COVID-19 mortality in the United States, and much of the excess mortality in the United States compared with other countries, is due to our reliance on a system of market-driven healthcare. Providing universal insurance coverage should be part of our campaign to reduce COVID-19 mortality. It also suggests that these concerns should not be restricted to COVID-19 but apply across all diseases, contributing to many unnecessary deaths in the United States each year even apart from the COVID-19 pandemic.
  • Ensuring a high-quality and resilient supply chain of essential medications means paying more.

    Mattingly, T Joseph; Conti, Rena M (Academy of Managed Care Pharmacy (AMCP), 2022-05)
    DISCLOSURES: Dr Mattingly reports consulting fees from Arnold Ventures, Pharmaceutical Research and Manufacturers of America, and research support from the US Food and Drug Administration unrelated to this article.
  • The Economic Burden of Multiple Sclerosis in the United States: Estimate of Direct and Indirect Costs.

    Bebo, Bruce; Cintina, Inna; LaRocca, Nicholas; Ritter, Leslie; Talente, Bari; Hartung, Daniel; Ngorsuraches, Surachat; Wallin, Mitchell; Yang, Grace (Wolters Kluwer Health, 2022-04-13)
    BACKGROUND AND OBJECTIVES: A recent report estimated that approximately 1 million adults were living with multiple sclerosis (MS) in the United States. Although MS is rarely the direct cause of death, its debilitating effects on normal body functions can result in considerable disruption to daily living and life roles including work, physical independence, mobility, social interaction, and participation in leisure activities. This study estimated the total economic burden of MS in the United States in 2019. METHODS: This study used a prevalence-based approach to estimate the national economic burden of MS. Claims from 3 sources (Medicare Current Beneficiary Survey, Medicare Standard Analytical File, and Optum de-identified Normative Health Information System) were used to obtain direct costs and a survey was developed to collect indirect costs (e.g., labor market productivity losses, costs of paid and unpaid caregivers, home modification) from 946 patients with MS (PwMS). Direct medical costs reflected the difference in the total average annual amount paid for PwMS vs matched controls without MS. Future earnings loss due to premature death attributable to MS was calculated using Centers for Disease Control and Prevention mortality data and Medicare claims data. RESULTS: The estimated total economic burden was $85.4 billion, with a direct medical cost of $63.3 billion and indirect and nonmedical costs of $22.1 billion. Retail prescription medication (54%); clinic-administered drugs, medication, and administration (12%); and outpatient care (9%) were the 3 largest components of the direct costs. The average excess per-person annual medical costs for PwMS was $65,612; at $35,154 per person, disease-modifying therapies (DMTs) accounted for the largest proportion of this cost. The cost per DMT user ranged from $57,202 to $92,719, depending on sex-age strata. The average indirect and nonmedical costs were $18,542 per PwMS and $22,875 per PwMS if caregivers' costs were included. Lost earnings due to premature death, presenteeism, and absenteeism losses were the largest indirect cost components. DISCUSSION: MS is a costly chronic disease, with direct costs of prescription drugs and indirect productivity loss being important cost drivers. Our findings suggested that the burden of MS in the United States has been underestimated. Copyright © 2022 The Author(s).
  • Bone turnover markers as surrogates of fracture healing after intramedullary fixation of tibia and femur fractures.

    Stewart, Christopher C; O'Hara, Nathan N; Bzovsky, Sofia; Bahney, Chelsea S; Sprague, Sheila; Slobogean, Gerard P (British Editorial Society of Bone & Joint Surgery, 2022-04)
    A total of 102 participants aged 18 to 50 years (median 28 years (interquartile range 23 to 35)), receiving an intramedullary nail for a tibial or femoral shaft fracture, were enrolled in a randomized controlled trial comparing vitamin D3 supplementation to placebo. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and N-terminal propeptide of type I procollagen (P1NP; bone formation marker) were measured at baseline, six weeks, and 12 weeks post-injury. Clinical and radiological fracture healing was assessed at three months.
  • Gastrointestinal neoplasia: carcinogenic interaction between bile acids and Helicobacter pylori in the stomach.

    Alizadeh, Madeline; Raufman, Jean-Pierre (American Society for Clinical Investigation, 2022-05-16)
    Bile acids modulate cell functions in health and disease, however, the mechanisms underlying their actions on neoplastic cells in the gastrointestinal (GI) tract remain largely unknown. In this issue of the JCI, Noto et al. comprehensively analyzed how interactions between Helicobacter pylori infection, iron deficiency, and bile acids modulate gastric inflammation and carcinogenesis. The investigators used sophisticated models, including INS-GAS mice with elevated serum gastrin and gastric acid secretion, in which H. pylori infection mimics human disease progression, to show that selected bile acids potentiated the carcinogenic effects of H. pylori infection and iron depletion. This elegant work has broad translational implications for microbe-associated GI neoplasia. Importantly, bile acid sequestration robustly attenuated the combined effects of H. pylori infection and iron depletion on gastric inflammation and cancer.
  • Estimated Transmission Outcomes and Costs of SARS-CoV-2 Diagnostic Testing, Screening, and Surveillance Strategies among a Simulated Population of Primary School Students

    Bilinski, Alyssa; Ciaranello, Andrea; Fitzpatrick, Meagan C.; Giardina, John; Shah, Maunank; Salomon, Joshua A.; Kendall, Emily A. (American Medical Association, 2022-01-01)
    Importance: In addition to illness, the COVID-19 pandemic has led to historic educational disruptions. In March 2021, the federal government allocated $10 billion for COVID-19 testing in US schools. Objective: Costs and benefits of COVID-19 testing strategies were evaluated in the context of full-time, in-person kindergarten through eighth grade (K-8) education at different community incidence levels. Design, Setting, and Participants: An updated version of a previously published agent-based network model was used to simulate transmission in elementary and middle school communities in the United States. Assuming dominance of the delta SARS-CoV-2 variant, the model simulated an elementary school (638 students in grades K-5, 60 staff) and middle school (460 students grades 6-8, 51 staff). Exposures: Multiple strategies for testing students and faculty/staff, including expanded diagnostic testing (test to stay) designed to avoid symptom-based isolation and contact quarantine, screening (routinely testing asymptomatic individuals to identify infections and contain transmission), and surveillance (testing a random sample of students to identify undetected transmission and trigger additional investigation or interventions). Main Outcomes and Measures: Projections included 30-day cumulative incidence of SARS-CoV-2 infection, proportion of cases detected, proportion of planned and unplanned days out of school, cost of testing programs, and childcare costs associated with different strategies. For screening policies, the cost per SARS-CoV-2 infection averted in students and staff was estimated, and for surveillance, the probability of correctly or falsely triggering an outbreak response was estimated at different incidence and attack rates. Results: Compared with quarantine policies, test-to-stay policies are associated with similar model-projected transmission, with a mean of less than 0.25 student days per month of quarantine or isolation. Weekly universal screening is associated with approximately 50% less in-school transmission at one-seventh to one-half the societal cost of hybrid or remote schooling. The cost per infection averted in students and staff by weekly screening is lowest for schools with less vaccination, fewer other mitigation measures, and higher levels of community transmission. In settings where local student incidence is unknown or rapidly changing, surveillance testing may detect moderate to large in-school outbreaks with fewer resources compared with schoolwide screening. Conclusions and Relevance: In this modeling study of a simulated population of primary school students and simulated transmission of COVID-19, test-to-stay policies and/or screening tests facilitated consistent in-person school attendance with low transmission risk across a range of community incidence. Surveillance was a useful reduced-cost option for detecting outbreaks and identifying school environments that would benefit from increased mitigation. © 2022 American Medical Association. All rights reserved.
  • Frequency and Duration of, and Risk Factors for, Diagnostic Delays Associated with Histoplasmosis

    Miller, Aaron C.; Arakkal, Alan T.; Koeneman, Scott H.; Cavanaugh, Joseph E.; Thompson, George R.; Baddley, John W.; Polgreen, Philip M. (MDPI AG, 2022-05-01)
    Histoplasmosis is often confused with other diseases leading to diagnostic delays. We estimated the incidence, length of, and risk factors for, diagnostic delays associated with histoplasmosis. Using data from IBM Marketscan, 2001–2017, we found all patients with a histoplasmosis diagnosis. We calculated the number of visits that occurred prior to the histoplasmosis diagnosis and the number of visits with symptomatically similar diagnoses (SSDs). Next, we estimated the number of visits that represented a delay using a simulation-based approach. We also computed the number of potential opportunities for diagnosis that were missed for each patient and the length of time between the first opportunity and the diagnosis. Finally, we identified risk factors for diagnostic delays using a logistic regression model. The number of SSD-related visits increased significantly in the 97 days prior to the histoplasmosis diagnosis. During this period, 97.4% of patients had a visit, and 90.1% had at least one SSD visit. We estimate that 82.9% of patients with histoplasmosis experienced at least one missed diagnostic opportunity. The average delay was 39.5 days with an average of 4.0 missed opportunities. Risk factors for diagnostic delays included prior antibiotic use, history of other pulmonary diseases, and emergency department and outpatient visits, especially during weekends. New diagnostic approaches for histoplasmosis are needed. © 2022 by the authors.
  • Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX‐2

    Kavaliauskas, Povilas; Opazo, Felipe Stambuk; Acevedo, Waldo; Petraitiene, Ruta; Grybaitė, Birutė; Anusevičius, Kazimieras; Mickevičius, Vytautas; Belyakov, Sergey; Petraitis, Vidmantas (MDPI AG, 2022-05-01)
    Non‐small cell lung cancer (NSCLC) remains a leading cause of cancer‐associated mortal-ities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX‐2 mediated pathway. The biological evaluation of compounds 9–16 showed promising structure‐de-pendent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4‐hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non‐cancerous Vero cells. The in silico ADMET properties revealed promising drug‐like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX‐2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16. © 2022 by the authors.
  • A 41-year-old man with bilateral, painless loss of vision.

    Chang, Michael; Yee, Kin K (Massachusetts Eye and Ear Infirmary, 2021-11-05)
  • Segmental removal of infected frontalis sling.

    Maripudi, Snehaa; Grumbine, Francis Lawson; Merbs, Shannath; Alexander, Janet Leath (Massachusetts Eye and Ear Infirmary, 2021-11-14)
    Congenital ptosis is one of the most common oculoplastic diseases of infancy. Where there is poor levator function, a frontalis sling is the procedure of choice. Here, we describe 2 cases of frontalis sling extrusion that were managed by segmental sling removal, with favorable results. In case 1, an infant developed silicone extrusion 2 months after bilateral frontalis sling implantation. The exposed segment was excised, and the area healed quickly without recurrence of infection and lid height remained optimal. Case 2 developed recurrent brow abscesses during the 3 years following bilateral frontalis sling. Surgical revision involved excision of the involved sling segment for definitive control of the chronic recurrent infection. Adjustment at the time of segmental excision resulted in improved eyelid position. These cases demonstrate that postoperative infection with implant exposure can be managed by partial sling removal, which may be the preferred procedure in children in order to minimize the number of procedures and exposure to general anesthesia.
  • Digitally recorded and remotely classified lung auscultation compared with conventional stethoscope classifications among children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

    Park, Daniel E; Watson, Nora L; Focht, Christopher; Feikin, Daniel; Hammit, Laura; Brooks, W Abdullah; Howie, Stephen R C; Kotloff, Karen L; Levine, Orin S; Madhi, Shabir A; et al.
    We collected digitally recorded lung sounds, conventional auscultation classifications and clinical measures and samples from children with pneumonia (cases) in low-income and middle-income countries. Physicians remotely classified recordings as crackles, wheeze or uninterpretable. Conventional and digital auscultation concordance was evaluated among 383 pneumonia cases with concurrently (within 2 hours) collected conventional and digital auscultation classifications using prevalence-adjusted bias-adjusted kappa (PABAK). Using an expanded set of 737 cases that also incorporated the non-concurrently collected assessments, we evaluated whether associations between auscultation classifications and clinical or aetiological findings differed between conventional or digital auscultation using χ2 tests and logistic regression adjusted for age, sex and site.
  • Epigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma.

    Hurník, Pavel; Chyra, Zuzana; Ševčíková, Tereza; Štembírek, Jan; Trtková, Kateřina Smešný; Gaykalova, Daria A; Buchtová, Marcela; Hrubá, Eva (Frontiers Media S.A., 2022-04-27)
    Carcinomas of the oral cavity and oropharynx belong among the ten most common malignancies in the human population. The prognosis of head and neck squamous cell carcinoma (HNSCC) is determined by the degree of invasiveness of the primary tumor and by the extent of metastatic spread into regional and distant lymph nodes. Moreover, the level of the perineural invasion itself associates with tumor localization, invasion's extent, and the presence of nodal metastases. Here, we summarize the current knowledge about different aspects of epigenetic changes, which can be associated with HNSCC while focusing on perineural invasion (PNI). We review epigenetic modifications of the genes involved in the PNI process in HNSCC from the omics perspective and specific epigenetic modifications in OSCC or other neurotropic cancers associated with perineural invasion. Moreover, we summarize DNA methylation status of tumor-suppressor genes, methylation and demethylation enzymes and histone post-translational modifications associated with PNI. The influence of other epigenetic factors on the HNSCC incidence and perineural invasion such as tobacco, alcohol and oral microbiome is overviewed and HPV infection is discussed as an epigenetic factor associated with OSCC and related perineural invasion. Understanding epigenetic regulations of axon growth that lead to tumorous spread or uncovering the molecular control of axon interaction with cancer tissue can help to discover new therapeutic targets for these tumors.
  • Refining colorectal cancer classification and clinical stratification through a single-cell atlas.

    Khaliq, Ateeq M; Erdogan, Cihat; Kurt, Zeyneb; Turgut, Sultan Sevgi; Grunvald, Miles W; Rand, Tim; Khare, Sonal; Borgia, Jeffrey A; Hayden, Dana M; Pappas, Sam G; et al. (Springer Nature, 2022-05-11)
    Background: Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results: Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions: Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.
  • Patterns of opioid use in commercially insured patients with cancer.

    Le, Tham Thi; Fleming, Sean P; Simoni-Wastila, Linda (Intellisphere, 2022-05)
    Objectives: In an era of heightened opioid prescribing scrutiny, ensuring safe and adequate pain management is challenging. Understanding opioid use in patients with cancer can facilitate effective pain management regimens while minimizing safety concerns. This study characterized patterns of and factors associated with opioid use following a new cancer diagnosis. Study design: Retrospective cohort study. Methods: Our study included patients with a new cancer diagnosis aged 18 to 64 years in IQVIA PharMetrics Plus 2007-2013 who were continuously enrolled 12 months before receiving their cancer diagnosis and 24 months after. Study outcomes included opioid prevalence and measures of potentially high-risk opioid use (total days supplied, number of prescriptions, and morphine equivalent daily dose [MEDD]). Descriptive analyses and logistic regression were implemented. Results: Of 191,616 eligible individuals, 93,739 (48.9%) received opioid prescriptions; of these, 56,025 (59.8%) were new opioid users. Opioid users received 4.6 prescriptions on average, covering 65 total days with a mean MEDD of 31.8 mg. Only 2387 (2.5%) patients received higher than recommended (≥ 90 mg) MEDD. Predictors of opioid use post cancer included prior opioid use, select comorbidities, use of nonopioid pain treatment adjuvants (muscle relaxants, sedative/hypnotics, anticonvulsants, antidepressants, and steroids), cancer site, and metastatic cancer. Conclusions: Fewer than half of patients received opioids in the 2 years following cancer onset. Among users, we found a relatively small proportion of potentially problematic opioid use. Further research is warranted to assess the adequacy of cancer pain treatment and determinants of high-risk opioid use.
  • The cost-effectiveness of standalone HEPA filtration units for the prevention of airborne SARS CoV-2 transmission.

    Zafari, Zafar; de Oliveira, Pedro M; Gkantonas, Savvas; Ezeh, Chinenye; Muennig, Peter Alexander (Springer Nature, 2022-05-12)
    Objective: Airborne infection from aerosolized SARS-CoV-2 poses an economic challenge for businesses without existing heating, ventilation, and air conditioning (HVAC) systems. The Environmental Protection Agency notes that standalone units may be used in areas without existing HVAC systems, but the cost and effectiveness of standalone units has not been evaluated. Study design: Cost-effectiveness analysis with Monte Carlo simulation and aerosol transmission modeling. Methods: We built a probabilistic decision-analytic model in a Monte Carlo simulation that examines aerosol transmission of SARS-CoV-2 in an indoor space. As a base case study, we built a model that simulated a poorly ventilated indoor 1000 square foot restaurant and the range of Covid-19 prevalence of actively infectious cases (best-case: 0.1%, base-case: 2%, and worst-case: 3%) and vaccination rates (best-case: 90%, base-case: 70%, and worst-case: 0%) in New York City. We evaluated the cost-effectiveness of improving ventilation rate to 12 air changes per hour (ACH), the equivalent of hospital-grade filtration systems used in emergency departments. We also provide a customizable online tool that allows the user to change model parameters. Results: All 3 scenarios resulted in a net cost-savings and infections averted. For the base-case scenario, improving ventilation to 12 ACH was associated with 54 [95% Credible Interval (CrI): 29-86] aerosol infections averted over 1 year, producing an estimated cost savings of $152,701 (95% CrI: $80,663, $249,501) and 1.35 (95% CrI: 0.72, 2.24) quality-adjusted life years (QALYs) gained. Conclusions: It is cost-effective to improve indoor ventilation in small businesses in older buildings that lack HVAC systems during the pandemic.

View more