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Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8+ T cells following cure of human hepatitis C virus (HCV) infection. CD8+ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

Introduction Understanding the costs to increase vaccination demand among under-vaccinated populations, as well as costs incurred by beneficiaries and caregivers for reaching vaccination sites, is essential to improving vaccination coverage. However, there have not been systematic analyses documenting such costs for beneficiaries and caregivers seeking vaccination. Methods We searched PubMed, Scopus, and the Immunization Delivery Cost Catalogue (IDCC) in 2019 for the costs for beneficiaries and caregivers to 1) seek and know how to access vaccination (i.e., costs to immunization programs for social mobilization and interventions to increase vaccination demand), 2) take time off from work, chores, or school for vaccination (i.e., productivity costs), and 3) travel to vaccination sites. We assessed if these costs were specific to populations that faced other non-cost barriers, based on a framework for defining hard-to-reach and hard-to-vaccinate populations for vaccination. Results We found 57 studies describing information, education, and communication (IEC) costs, social mobilization costs, and the costs of interventions to increase vaccination demand, with mean costs per dose at $0.41 (standard deviation (SD) $0.83), $18.86 (SD $50.65) and $28.23 (SD $76.09) in low-, middle-, and high-income countries, respectively. Five studies described productivity losses incurred by beneficiaries and caregivers seeking vaccination ($38.33 per person; SD $14.72; n = 3). We identified six studies on travel costs incurred by beneficiaries and caregivers attending vaccination sites ($11.25 per person; SD $9.54; n = 4). Two studies reported social mobilization costs per dose specific to hard-to-reach populations, which were 2–3.5 times higher than costs for the general population. Eight studies described barriers to vaccination among hard-to-reach populations. Conclusion Social mobilization/IEC costs are well-characterized, but evidence is limited on costs incurred by beneficiaries and caregivers getting to vaccination sites. Understanding the potential incremental costs for populations facing barriers to reach vaccination sites is essential to improving vaccine program financing and planning.

Introduction Economic evidence on how much it may cost for vaccinators to reach populations is important to plan vaccination programs. Moreover, knowing the incremental costs to reach populations that have traditionally been undervaccinated, especially those hard-to-reach who are facing supply-side barriers to vaccination, is essential to expanding immunization coverage to these populations. Methods We conducted a systematic review to identify estimates of costs associated with getting vaccinators to all vaccination sites. We searched PubMed and the Immunization Delivery Cost Catalogue (IDCC) in 2019 for the following costs to vaccinators: (1) training costs; (2) labor costs, per diems, and incentives; (3) identification of vaccine beneficiary location; and (4) travel costs. We assessed if any of these costs were specific to populations that are hard-to-reach for vaccination, based on a framework for examining supply-side barriers to vaccination. Results We found 19 studies describing average vaccinator training costs at $0.67/person vaccinated or targeted (SD $0.94) and $0.10/dose delivered (SD $0.07). The average cost for vaccinator labor and incentive costs across 29 studies was $2.15/dose (SD $2.08). We identified 13 studies describing intervention costs for a vaccinator to know the location of a beneficiary, with an average cost of $19.69/person (SD $26.65), and six studies describing vaccinator travel costs, with an average cost of $0.07/dose (SD $0.03). Only eight of these studies described hard-to-reach populations for vaccination; two studies examined incremental costs per dose to reach hard-to-reach populations, which were 1.3–2 times higher than the regular costs. The incremental cost to train vaccinators was $0.02/dose, and incremental labor costs for targeting hard-to-reach populations were $0.16–$1.17/dose. Conclusion Additional comparative costing studies are needed to understand the potential differential costs for vaccinators reaching the vaccination sites that serve hard-to-reach populations. This will help immunization program planners and decision-makers better allocate resources to extend vaccination programs.

Introduction During a pandemic, there are many situations in which the first available vaccines may not have as high effectiveness as vaccines that are still under development or vaccines that are not yet ready for distribution, raising the question of whether it is better to go with what is available now or wait. Methods In 2020, the team developed a computational model that represents the U.S. population, COVID-19 coronavirus spread, and vaccines with different possible efficacies (to prevent infection or to reduce severe disease) and vaccination timings to estimate the clinical and economic value of vaccination. Results Except for a limited number of situations, mainly early on in a pandemic and for a vaccine that prevents infection, when an initial vaccine is available, waiting for a vaccine with a higher efficacy results in additional hospitalizations and costs over the course of the pandemic. For example, if a vaccine with a 50% efficacy in preventing infection becomes available when 10% of the population has already been infected, waiting until 40% of the population are infected for a vaccine with 80% efficacy in preventing infection results in 15.6 million additional cases and 1.5 million additional hospitalizations, costing $20.6 billion more in direct medical costs and $12.4 billion more in productivity losses. Conclusions This study shows that there are relatively few situations in which it is worth foregoing the first COVID-19 vaccine available in favor of a vaccine that becomes available later on in the pandemic even if the latter vaccine has a substantially higher efficacy.

BACKGROUND Teaching caregivers to respond to normal infant night awakenings in ways other than feeding is a common obesity prevention effort. Models can simulate caregiver feeding behavior while controlling for variables that are difficult to manipulate or measure in real life. METHODS We developed a virtual infant model representing an infant with an embedded metabolism and his/her daily sleep, awakenings, and feeds from their caregiver each day as the infant aged from 6 to 12 months (recommended age to introduce solids). We then simulated different night feeding interventions and their impact on infant body mass index (BMI). RESULTS Reducing the likelihood of feeding during normal night wakings from 79% to 50% to 10% lowered infant BMI from the 84th to the 75th to the 62nd percentile by 12 months, respectively, among caregivers who did not adaptively feed (e.g., adjust portion sizes of solid foods with infant growth). Among caregivers who adaptively feed, all scenarios resulted in relatively stable BMI percentiles, and progressively reducing feeding probability by 10% each month showed the least fluctuations. CONCLUSIONS Reducing night feeding has the potential to impact infant BMI, (e.g., 10% lower probability can reduce BMI by 20 percentile points) especially among caregivers who do not adaptively feed. IMPACT Teaching caregivers to respond to infant night waking with other soothing behaviors besides feeding has the potential to reduce infant BMI. When reducing the likelihood of feeding during night wakings from 79% to 50% to 10%, infants dropped from the 84th BMI percentile to the 75th to the 62nd by 12 months, respectively, among caregivers who do not adaptively feed. Night-feeding interventions have a greater impact when caregivers do not adaptively feed their infant based on their growth compared to caregivers who do adaptively feed. Night-feeding interventions should be one of the several tools in a multi-component intervention for childhood obesity prevention.

Introduction: With norovirus vaccine candidates currently under development, now is the time to identify the vaccine characteristics and implementation thresholds at which vaccination becomes cost effective and cost saving in a community setting. Methods: In 2020, a norovirus transmission, clinical, and economics computational simulation model representing different U.S. population segments was developed to simulate the spread of norovirus and the potential impact of vaccinating children aged

Background: Opsonization, is the molecular mechanism by which target molecules promote interactions with phagocyte cell surface receptors to remove unwanted cells by induced phagocytosis. We designed an in vitro system to demonstrate that this procedure could be driven to eliminate adipocytes, using peptides mimicking regions of the complement protein C3b to promote opsonization and enhance phagocytosis. Two cell lines were used: (1) THP-1 monocytes differentiated to macrophages, expressing the C3b opsonin receptor CR1 in charge of the removal of unwanted coated complexes; (2) 3T3-L1 fibroblasts differentiated to adipocytes, expressing AQP7, to evaluate the potential of peptides to stimulate opsonization. (3) A co-culture of the two cell lines to demonstrate that phagocytosis could be driven to cell withdrawal with high efficiency and specificity. Results: An array of peptides were designed and chemically synthesized p3691 and p3931 joined bound to the CR1 receptor activating phagocytosis (p

With the coronavirus disease 2019 (COVID-19) pandemic, one of the major concerns is the direct medical cost and resource use burden imposed on the US health care system. We developed a Monte Carlo simulation model that represented the US population and what could happen to each person who got infected. We estimated resource use and direct medical costs per symptomatic infection and at the national level, with various "attack rates" (infection rates), to understand the potential economic benefits of reducing the burden of the disease. A single symptomatic COVID-19 case could incur a median direct medical cost of $3,045 during the course of the infection alone. If 80 percent of the US population were to get infected, the result could be a median of 44.6 million hospitalizations, 10.7 million intensive care unit (ICU) admissions, 6.5 million patients requiring a ventilator, 249.5 million hospital bed days, and $654.0 billion in direct medical costs over the course of the pandemic. If 20 percent of the US population were to get infected, there could be a median of 11.2 million hospitalizations, 2.7 million ICU admissions, 1.6 million patients requiring a ventilator, 62.3 million hospital bed days, and $163.4 billion in direct medical costs over the course of the pandemic.

BACKGROUND: Currently, there are no solutions to prevent congenital transmission of Chagas disease during pregnancy, which affects 1–40% of pregnant women in Latin America and is associated with a 5% transmission risk. With therapeutic vaccines under development, now is the right time to determine the economic value of such a vaccine to prevent congenital transmission. METHODS: We developed a computational decision model that represented the clinical outcomes and diagnostic testing strategies for an infant born to a Chagas-positive woman in Mexico and evaluated the impact of vaccination. RESULTS: Compared to no vaccination, a 25% efficacious vaccine averted 125 [95% uncertainty interval (UI): 122–128] congenital cases, 1.9 (95% UI: 1.6–2.2) infant deaths, and 78 (95% UI: 66–91) DALYs per 10,000 infected pregnant women; a 50% efficacious vaccine averted 251 (95% UI: 248–254) cases, 3.8 (95% UI: 3.6–4.2) deaths, and 160 (95% UI: 148–171) DALYs; and a 75% efficacious vaccine averted 376 (95% UI: 374–378) cases, 5.8 (95% UI: 5.5–6.1) deaths, and 238 (95% UI: 227–249) DALYs. A 25% efficacious vaccine was cost-effective (incremental cost-effectiveness ratio

Introduction With Zika vaccine candidates under development and women of childbearing age being the primary target population, now is the time to map the vaccine (e.g., efficacy and duration of protection) and vaccination (e.g., cost) characteristic thresholds at which vaccination becomes cost effective, highly cost effective, and cost saving. Methods A Markov model was developed (to represent 2019 circumstances, US$ and INT$, Region of the Americas) to simulate a woman of childbearing age and the potential risk and clinical course of a Zika infection. Results Compared with no vaccination, vaccination was cost effective (incremental cost–effectiveness ratio: US$1,254–$82,900/disability-adjusted life years averted) when the risk of infection was ≥0.05%–0.08% (varying with country income), vaccine efficacy was ≥25%, and vaccination cost was US$1–$7,500 (INT$5–$10,000 depending on country income level). Vaccination was dominant (i.e., saved costs and provided beneficial health effects) when the infection risk was ≥0.1% for a vaccine efficacy ≥75% and when the infection risk was ≥0.5% for a vaccine efficacy ≥25%, for scenarios where vaccination conferred a 1-year duration of protection and cost ≤$200. In some cases, the vaccine was cost effective when the risk was as low as 0.015%, the cost was as high as $7,500 (INT$10,000), the efficacy was as low as 25%, and the duration of protection was 1 year. Conclusions The thresholds at which vaccination becomes cost effective and cost saving can provide targets for Zika vaccine development and implementation.

Background When trying to control regional spread of antibiotic-resistant pathogens such as carbapenem-resistant Enterobacteriaceae (CRE), decision makers must choose the highest-yield facilities to target for interventions. The question is, with limited resources, how best to choose these facilities. Methods Using our Regional Healthcare Ecosystem Analyst–generated agent-based model of all Chicago metropolitan area inpatient facilities, we simulated the spread of CRE and different ways of choosing facilities to apply a prevention bundle (screening, chlorhexidine gluconate bathing, hand hygiene, geographic separation, and patient registry) to a resource-limited 1686 inpatient beds. Results Randomly selecting facilities did not impact prevalence, but averted 620 new carriers and 175 infections, saving $6.3 million in total costs compared to no intervention. Selecting facilities by type (eg, long-term acute care hospitals) yielded a 16.1% relative prevalence decrease, preventing 1960 cases and 558 infections, saving $62.4 million more than random selection. Choosing the largest facilities was better than random selection, but not better than by type. Selecting by considering connections to other facilities (ie, highest volume of discharge patients) yielded a 9.5% relative prevalence decrease, preventing 1580 cases and 470 infections, and saving $51.6 million more than random selection. Selecting facilities using a combination of these metrics yielded the greatest reduction (19.0% relative prevalence decrease, preventing 1840 cases and 554 infections, saving $59.6 million compared with random selection). Conclusions While choosing target facilities based on single metrics (eg, most inpatient beds, most connections to other facilities) achieved better control than randomly choosing facilities, more effective targeting occurred when considering how these and other factors (eg, patient length of stay, care for higher-risk patients) interacted as a system.

BACKGROUND: Since special efforts are necessary to vaccinate people living far from fixed vaccination posts, decision makers are interested in knowing the economic value of such efforts. METHODS: Using our immunization geospatial information system platform and a measles compartment model, we quantified the health and economic value of a 2-dose measles immunization outreach strategy for children

Background With multiple coronavirus disease 2019 (COVID-19) vaccines available, understanding the epidemiologic, clinical, and economic value of increasing coverage levels and expediting vaccination is important. Methods We developed a computational model (transmission and age-stratified clinical and economics outcome model) representing the United States population, COVID-19 coronavirus spread (February 2020–December 2022), and vaccination to determine the impact of increasing coverage and expediting time to achieve coverage. Results When achieving a given vaccination coverage in 270 days (70% vaccine efficacy), every 1% increase in coverage can avert an average of 876 800 (217 000–2 398 000) cases, varying with the number of people already vaccinated. For example, each 1% increase between 40% and 50% coverage can prevent 1.5 million cases, 56 240 hospitalizations, and 6660 deaths; gain 77 590 quality-adjusted life-years (QALYs); and save $602.8 million in direct medical costs and $1.3 billion in productivity losses. Expediting to 180 days could save an additional 5.8 million cases, 215 790 hospitalizations, 26 370 deaths, 206 520 QALYs, $3.5 billion in direct medical costs, and $4.3 billion in productivity losses. Conclusions Our study quantifies the potential value of decreasing vaccine hesitancy and increasing vaccination coverage and how this value may decrease with the time it takes to achieve coverage, emphasizing the need to reach high coverage levels as soon as possible, especially before the fall/winter.

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 [treating 25% of symptomatic cases, reducing by 0.5 days, reproductive number (R0) 3.5, and starting treatment when 15% of the population has been exposed] to 44.4 million SARS-CoV-2 cases (treating 75% of all infected cases, reducing by 3.5 days, R0 2.0). With R0 2.5, reducing the average infectious period duration by 0.5 days for 25% of symptomatic cases averted 1.4 million cases and 99,398 hospitalizations; increasing to 75% of symptomatic cases averted 2.8 million cases. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R0 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study quantifies the potential effects of reducing the SARS-CoV-2 infectious period duration., Author summary Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Our simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 to 44.4 million SARS-CoV-2 cases, varying the proportion of cases treated, average duration of the infectious period, and the reproductive rate. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective, R0 2.5). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R0 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study suggests that finding ways to reduce the infectious period of SARS-CoV-2 could help decrease its spread and impact.

Typically, long-term acute care hospitals (LTACHs) have less experience in and incentives to implementing aggressive infection control for drug-resistant organisms such as carbapenem-resistant Enterobacteriaceae (CRE) than acute care hospitals. Decision makers need to understand how implementing control measures in LTACHs can impact CRE spread regionwide. Using our Chicago metropolitan region agent-based model to simulate CRE spread and control, we estimated that a prevention bundle in only LTACHs decreased prevalence by a relative 4.6%–17.1%, averted 1,090–2,795 new carriers, 273–722 infections and 37–87 deaths over 3 years and saved $30.5–$69.1 million, compared with no CRE control measures. When LTACHs and intensive care units intervened, prevalence decreased by a relative 21.2%. Adding LTACHs averted an additional 1,995 carriers, 513 infections, and 62 deaths, and saved $47.6 million beyond implementation in intensive care units alone. Thus, LTACHs may be more important than other acute care settings for controlling CRE, and regional efforts to control drug-resistant organisms should start with LTACHs as a centerpiece.

T cells play an important role to build up an effective immune response and are essential in the eradication of pathogens. To establish a long-lasting protection even after a re-challenge with the same pathogen, some T cells differentiate into memory T cells. Recently, a certain subpopulation of memory T cells at different tissue-sites of infection was detected—tissue-resident memory T cells (TRM cells). These cells can patrol in the tissue in order to encounter their cognate antigen to establish an effective protection against secondary infection. The liver as an immunogenic organ is exposed to a variety of pathogens entering the liver through the systemic blood circulation or via the portal vein from the gut. It could be shown that intrahepatic TRM cells can reside within the liver tissue for several years. Interestingly, hepatic TRM cell differentiation requires a distinct cytokine milieu. In addition, TRM cells express specific surface markers and transcription factors, which allow their identification delimited from their circulating counterparts. It could be demonstrated that liver TRM cells play a particular role in many liver diseases such as hepatitis B and C infection, non-alcoholic fatty liver disease and even play a role in the development of hepatocellular carcinoma and in building long-lasting immune responses after vaccination. A better understanding of intrahepatic TRM cells is critical to understand the pathophysiology of many liver diseases and to identify new potential drug targets for the development of novel treatment strategies.

Both acute and chronic hepatic inflammation likely result from an imbalance in the TH1/TH2 cell response and can lead to liver fibrosis and end-stage liver disease. More recently, a novel CD4+ T helper cell subset was described, characterized by the production of IL-17 and IL-22. These TH17 cells 50were predominantly implicated in host defense against infections and in autoimmune diseases. Interestingly, studies over the last 10 years revealed that the development of TH17 cells favors pro-inflammatory responses in almost all tissues and there is a reciprocal relationship between TH17 and TReg cells. The balance between TH17and TReg cells is critical for immune reactions, especially in injured liver tissue and the return to immune homeostasis. The pathogenic contribution of TH17 and TReg cells in autoimmunity, acute infection, and chronic liver injury is diverse and varies among disease etiologies. Understanding the mechanisms underlying TH17 cell development, recruitment, and maintenance, along with the suppression of TReg cells, will inform the development of new therapeutic strategies in liver diseases. Active manipulation of the balance between pathogenic and regulatory processes in the liver may assist in the restoration of homeostasis, especially in hepatic inflammation.

Background Although norovirus outbreaks periodically make headlines, it is unclear how much attention norovirus may receive otherwise. A better understanding of the burden could help determine how to prioritize norovirus prevention and control. Methods We developed a computational simulation model to quantify the clinical and economic burden of norovirus in the United States. Results A symptomatic case generated $48 in direct medical costs, $416 in productivity losses ($464 total). The median yearly cost of outbreaks was $7.6 million (range across years, $7.5–$8.2 million) in direct medical costs, and $165.3 million ($161.1–$176.4 million) in productivity losses ($173.5 million total). Sporadic illnesses in the community (incidence, 10–150/1000 population) resulted in 14 118–211 705 hospitalizations, 8.2–122.9 million missed school/work days, $0.2–$2.3 billion in direct medical costs, and $1.4–$20.7 billion in productivity losses ($1.5–$23.1 billion total). The total cost was $10.6 billion based on the current incidence estimate (68.9/1000). Conclusion Our study quantified norovirus’ burden. Of the total burden, sporadic cases constituted >90% (thus, annual burden may vary depending on incidence) and productivity losses represented 89%. More than half the economic burden is in adults ≥45, more than half occurs in winter months, and >90% of outbreak costs are due to person-to-person transmission, offering insights into where and when prevention/control efforts may yield returns.

BackgroundGiven the continuing coronavirus disease 2019 (COVID-19) pandemic and much of the U.S. implementing social distancing due to the lack of alternatives, there has been a push to develop a vaccine to eliminate the need for social distancing.MethodsIn 2020, we developed a computational model of the U.S. simulating the spread of COVID-19 coronavirus and vaccination.ResultsSimulation experiments revealed that when vaccine efficacy exceeded 70%, coverage exceeded 60%, and vaccination occurred on day 1, the attack rate dropped to 22% with daily cases not exceeding 3.2 million (reproductive rate, R0, 2.5). When R0 was 3.5, the attack rate dropped to 41% with daily cases not exceeding 14.4 million. Increasing coverage to 75% when vaccination occurred by day 90 resulted in 5% attack rate and daily cases not exceeding 258,029when R0 was 2.5 and a 26% attack rate and maximum daily cases of 22.6 million when R0 was 3.5. When vaccination did not occur until day 180, coverage (i.e., those vaccinated plus those otherwise immune) had to reach 100%. A vaccine with an efficacy between 40% and 70% could still obviate the need for other measures under certain circumstances such as much higher, and in some cases, potentially unachievable, vaccination coverages.ConclusionOur study found that to either prevent or largely extinguish an epidemic without any other measures (e.g., social distancing), the vaccine has to have an efficacy of at least 70%.

Introduction Given the continuing COVID-19 pandemic and much of the U.S. implementing social distancing owing to the lack of alternatives, there has been a push to develop a vaccine to eliminate the need for social distancing. Methods In 2020, the team developed a computational model of the U.S. simulating the spread of COVID-19 coronavirus and vaccination. Results Simulation experiments revealed that to prevent an epidemic (reduce the peak by >99%), the vaccine efficacy has to be at least 60% when vaccination coverage is 100% (reproduction number=2.5–3.5). This vaccine efficacy threshold rises to 70% when coverage drops to 75% and up to 80% when coverage drops to 60% when reproduction number is 2.5, rising to 80% when coverage drops to 75% when the reproduction number is 3.5. To extinguish an ongoing epidemic, the vaccine efficacy has to be at least 60% when coverage is 100% and at least 80% when coverage drops to 75% to reduce the peak by 85%–86%, 61%–62%, and 32% when vaccination occurs after 5%, 15%, and 30% of the population, respectively, have already been exposed to COVID-19 coronavirus. A vaccine with an efficacy between 60% and 80% could still obviate the need for other measures under certain circumstances such as much higher, and in some cases, potentially unachievable, vaccination coverages. Conclusions This study found that the vaccine has to have an efficacy of at least 70% to prevent an epidemic and of at least 80% to largely extinguish an epidemic without any other measures (e.g., social distancing).

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.

Introduction During an influenza epidemic, where early vaccination is crucial, pharmacies may be a resource to increase vaccine distribution reach and capacity. Methods We utilized an agent-based model of the US and a clinical and economics outcomes model to simulate the impact of different influenza epidemics and the impact of utilizing pharmacies in addition to traditional (hospitals, clinic/physician offices, and urgent care centers) locations for vaccination for the year 2017. Results For an epidemic with a reproductive rate (R0) of 1.30, adding pharmacies with typical business hours averted 11.9 million symptomatic influenza cases, 23,577 to 94,307 deaths, $1.0 billion in direct (vaccine administration and healthcare) costs, $4.2–44.4 billion in productivity losses, and $5.2–45.3 billion in overall costs (varying with mortality rate). Increasing the epidemic severity (R0 of 1.63), averted 16.0 million symptomatic influenza cases, 35,407 to 141,625 deaths, $1.9 billion in direct costs, $6.0–65.5 billion in productivity losses, and $7.8–67.3 billion in overall costs (varying with mortality rate). Extending pharmacy hours averted up to 16.5 million symptomatic influenza cases, 145,278 deaths, $1.9 billion direct costs, $4.1 billion in productivity loss, and $69.5 billion in overall costs. Adding pharmacies resulted in a cost-benefit of $4.1 to $11.5 billion, varying epidemic severity, mortality rate, pharmacy hours, location vaccination rate, and delay in the availability of the vaccine. Conclusions Administering vaccines through pharmacies in addition to traditional locations in the event of an epidemic can increase vaccination coverage, mitigating up to 23.7 million symptomatic influenza cases, providing cost-savings up to $2.8 billion to third-party payers and $99.8 billion to society. Pharmacies should be considered as points of dispensing epidemic vaccines in addition to traditional settings as soon as vaccines become available.

OBJECTIVES: Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Several new MRSA-active antibiotics have been developed, including semisynthetic glycopeptides (telavancin, dalbavancin and oritavancin). Of these, dalbavancin and oritavancin offer extended dosing intervals. METHODS: We performed a systematic review, network meta-analysis and cost analysis to compare the newer glycopeptides to standard care and each other for the treatment of complicated SSTIs (cSSTI). A search for randomized controlled trials (RCTs) was conducted in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We also developed a model to evaluate the costs associated with dalbavancin and oritavancin from the third-party payer perspective. RESULTS: Seven RCTs met inclusion criteria. Network meta-analyses suggested that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.90-1.33; OR 0.78, CI 0.52-1.18; and OR 1.06, CI 0.85-1.33, respectively). Head-to-head comparisons showed no difference in clinical response between oritavancin and dalbavancin (OR 1.36; CI 0.85-2.18), oritavancin and telavancin (OR 0.98; CI 0.72-1.31) or dalbavancin and telavancin (OR 0.72; CI 0.45-1.13). Telavancin had a higher incidence of overall adverse events compared to standard care (OR 1.33; CI 1.10-1.61). Compared to telavancin, there were fewer overall adverse events with dalbavancin (OR 0.58; CI 0.45-0.76) and oritavancin (OR 0.71; CI 0.55-0.92). Studies were of high quality overall. Our cost analyses demonstrated that dalbavancin and oritavancin were less costly compared to standard care under baseline assumptions and many scenarios evaluated. The use of dalbavancin could save third-party payers $1,442 to $4,803 per cSSTI, while the use of oritavancin could save $3,571 to $6,932 per cSSTI. CONCLUSIONS: Dalbavancin and oritavancin demonstrate efficacy and safety comparable to standard care in well-designed RCTs and result in cost savings when standard care is treatment that covers MRSA.

Background: Obesity is a state of relative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) deficiency, and the GH/IGF-1 axis has been implicated in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and the progression to steatohepatitis (NASH) in preclinical models and human studies. GH has both lipolytic and anti-inflammatory properties while IGF-1 has been implicated in reducing hepatic fibrosis and promoting hepatic regeneration. The GH/IGF-1 axis may be a therapeutic target in NAFLD/NASH, however, IGF-1, IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult human hepatic tissue has not been studied across the spectrum of disease severity. Methods: We quantified IGF-1, IGF-1R, and GHR gene expression in hepatic tissue from 318 adults with obesity using the Nanostring nCounter assay. Subjects were classified into four categories of disease severity based on histopathology: normal liver histology (NLH) (n=76, 24%), steatosis only (Steatosis) (n=88, 28%), NASH without fibrosis (NASH F0) (n=72, 23%), and NASH with fibrosis (NASH F1-F4) (n=82, 26%). Gene expression analysis is presented as normalized gene counts by group with p-value of the generalized linear model controlled for age, sex and BMI. Results: Mean (±SD) age (whole cohort 44.0±12 years) and BMI (whole cohort 46.8±7.2 kg/m2) did not differ across groups (p=0.2 for both). ALT was higher with increasing disease severity (NLH 30.1±26.7, Steatosis 31.9±15.7, NASH F0 35.7±16.5, NASH F1-4 48.4±34.9, p0.05 between any disease state; GHR NLH 6382±2366, Steatosis 6544±2699, NASH F0 7220±2542 and NASH F1-4 5997±2352, p>0.05 between any disease state). Conclusion: We demonstrated that IGF-1 gene expression was lower in liver tissue from patients with NAFLD and NASH than healthy controls. This is consistent with our prior finding that histologic NASH and fibrosis are associated with lower serum IGF-1 levels. Moreover, we demonstrated that hepatic IGF-1R and GHR gene expression is not lower in liver tissue from patients with NAFLD and does not decline across disease severity. This reinforces our prior finding that GHR staining intensity and zonality by immunohistochemistry does not change with increasing disease severity in NAFLD/NASH. These data demonstrate that the GH axis is relatively suppressed but that expression of GHR and IGF-1R receptors is stable with worsening disease severity in NAFLD/NASH, suggesting that GH augmentation may be a viable therapeutic target in NAFLD.

Key Points Question Which multidrug-resistant organism (MDRO) intervention is best to implement in a set of health care facilities to reduce the spread of MDROs regionwide? Findings In this computational simulation modeling study of 102 facilities in Orange County, California, the use of an agent-based model indicated that, after 3 years, increasing contact precaution effectiveness and implementing decolonization procedures in 42 target facilities would yield countywide relative decreases in the prevalence of methicillin-resistant Staphylococcus aureus of 1% and 24% and countywide relative decreases in the prevalence of carbapenem-resistant Enterobacteriaceae of 2% and 40%, respectively, but varied with effectiveness. Increasing interfacility communication produced no changes in prevalence or transmission. Meaning This study’s findings suggest that modeling can inform the design of real-world regional interventions to control MDROs when intervening in a set of health care facilities., Importance Multidrug-resistant organisms (MDROs) can spread across health care facilities in a region. Because of limited resources, certain interventions can be implemented in only some facilities; thus, decision-makers need to evaluate which interventions may be best to implement. Objective To identify a group of target facilities and assess which MDRO intervention would be best to implement in the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County, a large regional public health collaborative in Orange County, California. Design, Setting, and Participants An agent-based model of health care facilities was developed in 2016 to simulate the spread of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae (CRE) for 10 years starting in 2010 and to simulate the use of various MDRO interventions for 3 years starting in 2017. All health care facilities (23 hospitals, 5 long-term acute care hospitals, and 74 nursing homes) serving adult inpatients in Orange County, California, were included, and 42 target facilities were identified via network analyses. Exposures Increasing contact precaution effectiveness, increasing interfacility communication about patients’ MDRO status, and performing decolonization using antiseptic bathing soap and a nasal product in a specific group of target facilities. Main Outcomes and Measures MRSA and CRE prevalence and number of new carriers (ie, transmission events). Results Compared with continuing infection control measures used in Orange County as of 2017, increasing contact precaution effectiveness from 40% to 64% in 42 target facilities yielded relative reductions of 0.8% (range, 0.5%-1.1%) in MRSA prevalence and 2.4% (range, 0.8%-4.6%) in CRE prevalence in health care facilities countywide after 3 years, averting 761 new MRSA transmission events (95% CI, 756-765 events) and 166 new CRE transmission events (95% CI, 158-174 events). Increasing interfacility communication of patients’ MDRO status to 80% in these target facilities produced no changes in the prevalence or transmission of MRDOs. Implementing decolonization procedures (clearance probability: 39% in hospitals, 27% in long-term acute care facilities, and 3% in nursing homes) yielded a relative reduction of 23.7% (range, 23.5%-23.9%) in MRSA prevalence, averting 3515 new transmission events (95% CI, 3509-3521 events). Increasing the effectiveness of antiseptic bathing soap to 48% yielded a relative reduction of 39.9% (range, 38.5%-41.5%) in CRE prevalence, averting 1435 new transmission events (95% CI, 1427-1442 events). Conclusions and Relevance The findings of this study highlight the ways in which modeling can inform design of regional interventions and suggested that decolonization would be the best strategy for the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County., This computational simulation modeling study uses an agent-based model to identify target facilities and assess the optimal intervention to reduce the regional spread of multidrug-resistant organisms across health care facilities in Orange County, California.

Malaria-endemic countries have to decide how much of their limited resources for vector control to allocate toward implementing long-lasting insecticidal nets (LLINs) versus indoor residual spraying (IRS). To help the Mozambique Ministry of Health use an evidence-based approach to determine funding allocation toward various malaria control strategies, the Global Fund convened the Mozambique Modeling Working Group which then used JANUS, a software platform that includes integrated computational economic, operational, and clinical outcome models that can link with different transmission models (in this case, OpenMalaria) to determine the economic value of vector control strategies. Any increase in LLINs (from 80% baseline coverage) or IRS (from 80% baseline coverage) would be cost-effective (incremental cost-effectiveness ratios ≤ $114/disability-adjusted life year averted). However, LLIN coverage increases tend to be more cost-effective than similar IRS coverage increases, except where both pyrethroid resistance is high and LLIN usage is low. In high-transmission northern regions, increasing LLIN coverage would be more cost-effective than increasing IRS coverage. In medium-transmission central regions, changing from LLINs to IRS would be more costly and less effective. In low-transmission southern regions, LLINs were more costly and less effective than IRS, due to low LLIN usage. In regions where LLINs are more cost-effective than IRS, it is worth considering prioritizing LLIN coverage and use. However, IRS may have an important role in insecticide resistance management and epidemic control. Malaria intervention campaigns are not a one-size-fits-all solution, and tailored approaches are necessary to account for the heterogeneity of malaria epidemiology.

Background: Mathematical models can help aid public health responses to Chagas disease. Models are typically developed to fulfill a particular need, and comparing outputs from different models addressing the same question can help identify the strengths and weaknesses of the models in answering particular questions, such as those for achieving the 2020 goals for Chagas disease. Methods: Using two separately developed models (PHICOR/CIDMA model and Princeton model), we simulated dynamics for domestic transmission of Trypanosoma cruzi (T. cruzi). We compared how well the models targeted the last 9 years and last 19 years of the 1968–1998 historical seroprevalence data from Venezuela. Results: Both models were able to generate the T. cruzi seroprevalence for the next time period within reason to the historical data. The PHICOR/CIDMA model estimates of the total population seroprevalence more closely followed the trends seen in the historic data, while the Princeton model estimates of the age-specific seroprevalence more closely followed historic trends when simulating over 9 years. Additionally, results from both models overestimated T. cruzi seroprevalence among younger age groups, while underestimating the seroprevalence of T. cruzi in older age groups. Conclusion: The PHICOR/CIDMA and Princeton models differ in level of detail and included features, yet both were able to generate the historical changes in T. cruzi seroprevalence in Venezuela over 9 and 19-year time periods. Our model comparison has demonstrated that different model structures can be useful in evaluating disease transmission dynamics and intervention strategies.

Obesity has become a truly global epidemic, affecting all age groups, all populations, and countries of all income levels. To date, existing policies and interventions have not reversed these trends, suggesting that innovative approaches are needed to transform obesity prevention and control. There are a number of indications that the obesity epidemic is a systems problem, as opposed to a simple problem with a linear cause-and-effect relationship. What may be needed to successfully address obesity is an approach that considers the entire system when making any important decision, observation, or change. A systems approach to obesity prevention and control has many benefits, including the potential to further understand indirect effects or to test policies virtually before implementing them in the real world. Discussed here are 5 key efforts to implement a systems approach for obesity prevention: 1) utilize more global approaches; 2) bring new experts from disciplines that do not traditionally work with obesity to share experiences and ideas with obesity experts; 3) utilize systems methods, such as systems mapping and modeling; 4) modify and combine traditional approaches to achieve a stronger systems orientation; and 5) bridge existing gaps between research, education, policy, and action. This article also provides an example of how a systems approach has been used to convene a multidisciplinary team and conduct systems mapping and modeling as part of an obesity prevention program in Baltimore, Maryland.

Background: Carbapenem-resistant Enterobacteriaceae (CRE) are endemic in the Chicago region. We assessed the regional impact of a CRE control intervention targeting high-prevalence facilities; that is, long-term acute-care hospitals (LTACHs) and ventilator-capable skilled nursing facilities (vSNFs). Methods: In July 2017, an academic–public health partnership launched a regional CRE prevention bundle: (1) identifying patient CRE status by querying Illinois’ XDRO registry and periodic point-prevalence surveys reported to public health, (2) cohorting or private rooms with contact precautions for CRE patients, (3) combining hand hygiene adherence, monitoring with general infection control education, and guidance by project coordinators and public health, and (4) daily chlorhexidine gluconate (CHG) bathing. Informed by epidemiology and modeling, we targeted LTACHs and vSNFs in a 13-mile radius from the coordinating center. Illinois mandates CRE reporting to the XDRO registry, which can also be manually queried or generate automated alerts to facilitate interfacility communication. The regional intervention promoted increased automation of alerts to hospitals. The prespecified primary outcome was incident clinical CRE culture reported to the XDRO registry in Cook County by month, analyzed by segmented regression modeling. A secondary outcome was colonization prevalence measured by serial point-prevalence surveys for carbapenemase-producing organism colonization in LTACHs and vSNFs. Results: All eligible LTACHs (n = 6) and vSNFs (n = 9) participated in the intervention. One vSNF declined CHG bathing. vSNFs that implemented CHG bathing typically bathed residents 2–3 times per week instead of daily. Overall, there were significant gaps in infection control practices, especially in vSNFs. Also, 75 Illinois hospitals adopted automated alerts (56 during the intervention period). Mean CRE incidence in Cook County decreased from 59.0 cases per month during baseline to 40.6 cases per month during intervention (P < .001). In a segmented regression model, there was an average reduction of 10.56 cases per month during the 24-month intervention period (P = .02) (Fig. 1), and an estimated 253 incident CRE cases were averted. Mean CRE incidence also decreased among the stratum of vSNF/LTACH intervention facilities (P = .03). However, evidence of ongoing CRE transmission, particularly in vSNFs, persisted, and CRE colonization prevalence remained high at intervention facilities (Table 1). Conclusions: A resource-intensive public health regional CRE intervention was implemented that included enhanced interfacility communication and targeted infection prevention. There was a significant decline in incident CRE clinical cases in Cook County, despite high persistent CRE colonization prevalence in intervention facilities. vSNFs, where understaffing or underresourcing were common and lengths of stay range from months to years, had a major prevalence challenge, underscoring the need for aggressive infection control improvements in these facilities.Funding: The Centers for Disease Control and Prevention (SHEPheRD Contract No. 200-2011-42037)Disclosures: M.Y.L. has received research support in the form of contributed product from OpGen and Sage Products (now part of Stryker Corporation), and has received an investigator-initiated grant from CareFusion Foundation (now part of BD).

Author(s): McKinnell, James A; Singh, Raveena D; Miller, Loren G; Kleinman, Ken; Gussin, Gabrielle; He, Jiayi; Saavedra, Raheeb; Dutciuc, Tabitha D; Estevez, Marlene; Chang, Justin; Heim, Lauren; Yamaguchi, Stacey; Custodio, Harold; Gohil, Shruti K; Park, Steven; Tam, Steven; Robinson, Philip A; Tjoa, Thomas; Nguyen, Jenny; Evans, Kaye D; Bittencourt, Cassiana E; Lee, Bruce Y; Mueller, Leslie E; Bartsch, Sarah M; Jernigan, John A; Slayton, Rachel B; Stone, Nimalie D; Zahn, Matthew; Mor, Vincent; McConeghy, Kevin; Baier, Rosa R; Janssen, Lynn; O'Donnell, Kathleen; Weinstein, Robert A; Hayden, Mary K; Coady, Micaela H; Bhattarai, Megha; Peterson, Ellena M; Huang, Susan S | Abstract: BackgroundMultidrug-resistant organisms (MDROs) spread between hospitals, nursing homes (NHs), and long-term acute care facilities (LTACs) via patient transfers. The Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County is a regional public health collaborative involving decolonization at 38 healthcare facilities selected based on their high degree of patient sharing. We report baseline MDRO prevalence in 21 NHs/LTACs.MethodsA random sample of 50 adults for 21 NHs/LTACs (18 NHs, 3 LTACs) were screened for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), extended-spectrum β-lactamase-producing organisms (ESBL), and carbapenem-resistant Enterobacteriaceae (CRE) using nares, skin (axilla/groin), and peri-rectal swabs. Facility and resident characteristics associated with MDRO carriage were assessed using multivariable models clustering by person and facility.ResultsPrevalence of MDROs was 65% in NHs and 80% in LTACs. The most common MDROs in NHs were MRSA (42%) and ESBL (34%); in LTACs they were VRE (55%) and ESBL (38%). CRE prevalence was higher in facilities that manage ventilated LTAC patients and NH residents (8% vs l1%, P l .001). MDRO status was known for 18% of NH residents and 49% of LTAC patients. MDRO-colonized adults commonly harbored additional MDROs (54% MDRO+ NH residents and 62% MDRO+ LTACs patients). History of MRSA (odds ratio [OR] = 1.7; confidence interval [CI]: 1.2, 2.4; P = .004), VRE (OR = 2.1; CI: 1.2, 3.8; P = .01), ESBL (OR = 1.6; CI: 1.1, 2.3; P = .03), and diabetes (OR = 1.3; CI: 1.0, 1.7; P = .03) were associated with any MDRO carriage.ConclusionsThe majority of NH residents and LTAC patients harbor MDROs. MDRO status is frequently unknown to the facility. The high MDRO prevalence highlights the need for prevention efforts in NHs/LTACs as part of regional efforts to control MDRO spread.

Background Clinical testing detects a fraction of carbapenem-resistant Enterobacteriaceae (CRE) carriers. Detecting a greater proportion could lead to increased use of infection prevention and control measures but requires resources. Therefore, it is important to understand the impact of detecting increasing proportions of CRE carriers. Methods We used our Regional Healthcare Ecosystem Analyst–generated agent-based model of adult inpatient healthcare facilities in Orange County, California, to explore the impact that detecting greater proportions of carriers has on the spread of CRE. Results Detecting and placing 1 in 9 carriers on contact precautions increased the prevalence of CRE from 0% to 8.0% countywide over 10 years. Increasing the proportion of detected carriers from 1 in 9 up to 1 in 5 yielded linear reductions in transmission; at proportions >1 in 5, reductions were greater than linear. Transmission reductions did not occur for 1, 4, or 5 years, varying by facility type. With a contact precautions effectiveness of ≤70%, the detection level yielding nonlinear reductions remained unchanged; with an effectiveness of >80%, detecting only 1 in 5 carriers garnered large reductions in the number of new CRE carriers. Trends held when CRE was already present in the region. Conclusion Although detection of all carriers provided the most benefits for preventing new CRE carriers, if this is not feasible, it may be worthwhile to aim for detecting >1 in 5 carriers.

BACKGROUND Therapeutic vaccines to prevent Chagas disease progression to cardiomyopathy are under development because the only available medications (benznidazole and nifurtimox) are limited by their efficacy, long treatment course, and side effects. Better understanding the potential clinical and economic value of such vaccines can help guide development and implementation. METHODS We developed a computational Chagas Markov model to evaluate the clinical and economic value of a therapeutic vaccine given in conjunction with benznidazole in indeterminate and chronic Chagas patients. Scenarios explored the vaccine's impact on reducing drug treatment dosage, duration, and adverse events, and risk of disease progression. RESULTS When administering standard-of-care benznidazole to 1000 indeterminate patients, 148 discontinued treatment and 219 progressed to chronic disease, resulting in 119 Chagas-related deaths and 2293 DALYs, costing $18.9 million in lifetime societal costs. Compared to benznidazole-only, therapeutic vaccination administered with benznidazole (25-75% reduction in standard dose and duration), resulted in 37-111 more patients (of 1000) completing treatment, preventing 11-219 patients from progressing, 6-120 deaths, and 108-2229 DALYs (5-100% progression risk reduction), saving ≤$16,171 per patient. When vaccinating determinate Kuschnir class 1 Chagas patients, 10-197 fewer patients further progressed compared to benznidazole-only, averting 11-228 deaths and 144-3037 DALYs (5-100% progression risk reduction), saving ≤$34,059 per person. When vaccinating Kuschnir class 2 patients, 13-279 fewer progressed (279 with benznidazole-only), averting 13-692 deaths and 283-10,785 DALYs (5-100% progression risk reduction), saving ≤$89,759. Therapeutic vaccination was dominant (saved costs and provided health benefits) with ≥ 5% progression risk reduction, except when only reducing drug treatment regimen and adverse events, but remained cost-effective when costing

Carbapenem-resistant Enterobacteriaceae (CRE), a group of pathogens resistant to most antibiotics and associated with high mortality, are a rising emerging public health threat. Current approaches to infection control and prevention have not been adequate to prevent spread. An important but unproven approach is to have hospitals in a region coordinate surveillance and infection control measures. Using our Regional Healthcare Ecosystem Analyst (RHEA) simulation model and detailed Orange County, California, patient-level data on adult inpatient hospital and nursing home admissions (2011-2012), we simulated the spread of CRE throughout Orange County health-care facilities under 3 scenarios: no specific control measures, facility-level infection control efforts (uncoordinated control measures), and a coordinated regional effort. Aggressive uncoordinated and coordinated approaches were highly similar, averting 2,976 and 2,789 CRE transmission events, respectively (72.2% and 77.0% of transmission events), by year 5. With moderate control measures, coordinated regional control resulted in 21.3% more averted cases (n = 408) than did uncoordinated control at year 5. Our model suggests that without increased infection control approaches, CRE would become endemic in nearly all Orange County health-care facilities within 10 years. While implementing the interventions in the Centers for Disease Control and Prevention's CRE toolkit would not completely stop the spread of CRE, it would cut its spread substantially, by half.

Background Regions are considering the use of electronic registries to track patients who carry antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). Implementing such a registry can be challenging and requires time, effort, and resources; therefore, there is a need to better understand the potential impact. Methods We developed an agent-based model of all inpatient healthcare facilities (90 acute care hospitals, 9 long-term acute care hospitals, 351 skilled nursing facilities, and 12 ventilator-capable skilled nursing facilities) in the Chicago metropolitan area, surrounding communities, and patient flow using our Regional Healthcare Ecosystem Analyst software platform. Scenarios explored the impact of a registry that tracked patients carrying CRE to help guide infection prevention and control. Results When all Illinois facilities participated (n = 402), the registry reduced the number of new carriers by 11.7% and CRE prevalence by 7.6% over a 3-year period. When 75% of the largest Illinois facilities participated (n = 304), registry use resulted in a 11.6% relative reduction in new carriers (16.9% and 1.2% in participating and nonparticipating facilities, respectively) and 5.0% relative reduction in prevalence. When 50% participated (n = 201), there were 10.7% and 5.6% relative reductions in incident carriers and prevalence, respectively. When 25% participated (n = 101), there was a 9.1% relative reduction in incident carriers (20.4% and 1.6% in participating and nonparticipating facilities, respectively) and 2.8% relative reduction in prevalence. Conclusions Implementing an extensively drug-resistant organism registry reduced CRE spread, even when only 25% of the largest Illinois facilities participated due to patient sharing. Nonparticipating facilities garnered benefits, with reductions in new carriers.

Objective Despite numerous studies, the clinical value of sputum cultures in the management of pneumonia remains controversial; therefore, understanding the economic value of sputum cultures may help decision makers determine their appropriate use in patient management. Methods We developed a decision model to determine the economic and clinical value of using sputum cultures in the treatment of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) from the hospital perspective under various conditions. Results For both CAP and HCAP patients, obtaining sputum cultures resulted in similar costs compared to no culture, even if cultures cost $0. Given current clinical practices, obtaining cultures cost $539–631 more per CAP patient and $13–170 per HCAP patient compared to no culture use. However, cultures saved $8–202 per HCAP patient with a 40% probability the pathogen was the true cause (75% reduction in adverse outcomes, greater length of hospital stay (LOS) increase) to a 70% probability the pathogen was the true cause (25% reduction in outcomes and greater LOS increase and a 75% reduction in outcomes and all LOS increases). Additionally, obtaining sputum cultures had no impact on the number of adverse outcomes (i.e., adverse drug events, Clostridium difficile infection, pneumonia readmissions, additional hospitalization days). When all patients were treated with antibiotics empirically, obtaining cultures saved $4–342. Conclusions Overall, obtaining sputum cultures does not provide significant clinical or economic benefits for CAP or HCAP patients; however, it can reduce costs and shorten overall LOS under some circumstances. Clinicians should consider their local conditions when making decisions about sputum culture use.

OBJECTIVEWhile previous work showed that the Centers for Disease Control and Prevention toolkit for carbapenem-resistant Enterobacteriaceae (CRE) can reduce spread regionally, these interventions are costly, and decisions makers want to know whether and when economic benefits occur.DESIGNEconomic analysisSETTINGOrange County, CaliforniaMETHODSUsing our Regional Healthcare Ecosystem Analyst (RHEA)-generated agent-based model of all inpatient healthcare facilities, we simulated the implementation of the CRE toolkit (active screening of interfacility transfers) in different ways and estimated their economic impacts under various circumstances.RESULTSCompared to routine control measures, screening generated cost savings by year 1 when hospitals implemented screening after identifying ≤20 CRE cases (saving $2,000–$9,000) and by year 7 if all hospitals implemented in a regional coordinated manner after 1 hospital identified a CRE case (hospital perspective). Cost savings was achieved only if hospitals independently screened after identifying 10 cases (year 1, third-party payer perspective). Cost savings was achieved by year 1 if hospitals independently screened after identifying 1 CRE case and by year 3 if all hospitals coordinated and screened after 1 hospital identified 1 case (societal perspective). After a few years, all strategies cost less and have positive health effects compared to routine control measures; most strategies generate a positive cost-benefit each year.CONCLUSIONSActive screening of interfacility transfers garnered cost savings in year 1 of implementation when hospitals acted independently and by year 3 if all hospitals collectively implemented the toolkit in a coordinated manner. Despite taking longer to manifest, coordinated regional control resulted in greater savings over time.Infect Control Hosp Epidemiol 2018;39:516–524

The long head of biceps tendon (LHB) score was designed to clinically assess LHB pathologies. Purpose of this study was to prospectively assess patients with LHB pathologies preoperatively and after LHB surgery using the LHB score. Fifty-seven patients (29 f/28 m, O age 61.0 years), showing clinical signs of LHB pathologies, were prospectively included into this study. In 43 patients LHB pathologies could be confirmed intraoperatively. Among these, in 26 patients a biceps tenodesis (group I; 8 f/18 m, O age 61.2 years), and in 17 patients a biceps tenotomy was performed (group II; 12 f/5 m, O age 64.2 years). In 14 patients no intraoperative correlate concerning the biceps symptoms could be found (group III; 9 f/5m, O age 56.8 years). In these patients no further LHB treatment was carried out. The clinical evaluation contained the Constant score (CS) as well as the LHB score preoperatively and 2 years postoperatively. The CS improved significantly in all the three groups [group I: 41.7 (20–70) to 81.3 (62–100); group II: 42.2 (18–66) to 75.3 (41–84); group III: 45.7 (22–77) to 72.9 (48–85)] (p

Background New vaccine technologies may improve the acceptability, delivery (potentially enabling self-administration), and product efficacy of influenza vaccines. One such technology is the microneedle patch (MNP), a skin delivery technology currently in development. Although MNPs hold promise in preclinical studies, their potential economic and epidemiologic impacts have not yet been evaluated. Methods We utilized a susceptible-exposed-infectious-recovered (SEIR) transmission model linked to an economic influenza outcomes model to assess the economic value of introducing the MNP into the current influenza vaccine market in the United States from the third-party payer and societal perspectives. We also explored the impact of different vaccination settings, self-administration, the MNP price, vaccine efficacy, compliance, and MNP market share. Outcomes included costs, quality-adjusted life years (QALYs), cases, and incremental cost-effectiveness ratios (ICERs; cost/QALY). Results With healthcare provider administration, MNP introduction would be cost-effective (ICERs ≤$23,347/QALY) at all MNP price points ($9.50–$30) and market shares (10–60%) assessed, except when compliance and efficacy were assumed to be the same as existing vaccines and the MNP occupied a 10% market share. If MNP self-administration were available (assuming the same efficacy as current technologies), MNP compliance or its efficacy would need to increase by ≥3% in order to be cost-effective (ICERs ≤$1401/QALY), assuming a 2% reduction in administration success with unsupervised self-administration. Under these conditions, MNP introduction would be cost-effective for all price points and market shares assessed. Conclusions When healthcare providers administered the MNP, its introduction would be cost-effective or dominant (i.e., less costly and more effective) in the majority of scenarios assessed. If self-administration were available, MNP introduction would be cost-effective if it increased compliance enough to overcome any decrease in self-administration success or if the MNP presentation afforded an increase in efficacy over current delivery methods for influenza vaccines.

Influenza vaccination is administered throughout the influenza disease season, even as late as March. Given such timing, what is the value of vaccinating the population earlier than currently being practiced?We used real data on when individuals were vaccinated in Allegheny County, Pennsylvania, and the following 2 models to determine the value of vaccinating individuals earlier (by the end of September, October, and November): Framework for Reconstructing Epidemiological Dynamics (FRED), an agent-based model (ABM), and FluEcon, our influenza economic model that translates cases from the ABM to outcomes and costs [health care and lost productivity costs and quality-adjusted life-years (QALYs)]. We varied the reproductive number (R0) from 1.2 to 1.6.Applying the current timing of vaccinations averted 223,761 influenza cases, $16.3 million in direct health care costs, $50.0 million in productivity losses, and 804 in QALYs, compared with no vaccination (February peak, R0 1.2). When the population does not have preexisting immunity and the influenza season peaks in February (R0 1.2-1.6), moving individuals who currently received the vaccine after September to the end of September could avert an additional 9634-17,794 influenza cases, $0.6-$1.4 million in direct costs, $2.1-$4.0 million in productivity losses, and 35-64 QALYs. Moving the vaccination of just children to September (R0 1.2-1.6) averted 11,366-1660 influenza cases, $0.6-$0.03 million in direct costs, $2.3-$0.2 million in productivity losses, and 42-8 QALYs. Moving the season peak to December increased these benefits, whereas increasing preexisting immunity reduced these benefits.Even though many people are vaccinated well after September/October, they likely are still vaccinated early enough to provide substantial cost-savings.

Increasing physical activity among children is a potentially important public health intervention. Quantifying the economic and health effects of the intervention would help decision makers understand its impact and priority. Using a computational simulation model that we developed to represent all US children ages 8-11 years, we estimated that maintaining the current physical activity levels (only 31.9 percent of children get twenty-five minutes of high-calorie-burning physical activity three times a week) would result each year in a net present value of $1.1 trillion in direct medical costs and $1.7 trillion in lost productivity over the course of their lifetimes. If 50 percent of children would exercise, the number of obese and overweight youth would decrease by 4.18 percent, averting $8.1 billion in direct medical costs and $13.8 billion in lost productivity. Increasing the proportion of children who exercised to 75 percent would avert $16.6 billion and $23.6 billion, respectively.

BackgroundWhile the persistence of high surgical site infection (SSI) rates has prompted the advent of more expensive sutures that are coated with antimicrobial agents to prevent SSIs, the economic value of such sutures has yet to be determined.MethodsUsing TreeAge Pro, we developed a decision analytic model to determine the cost-effectiveness of using antimicrobial sutures in abdominal incisions from the hospital, third-party payer, and societal perspectives. Sensitivity analyses systematically varied the risk of developing an SSI (range, 5%–20%), the cost of triclosan-coated sutures (range, $5–$25/inch), and triclosan-coated suture efficacy in preventing infection (range, 5%–50%) to highlight the range of costs associated with using such sutures.ResultsTriclosan-coated sutures saved $4,109–$13,975 (hospital perspective), $4,133–$14,297 (third-party payer perspective), and $40,127–$53,244 (societal perspective) per SSI prevented, when a surgery had a 15% SSI risk, depending on their efficacy. If the SSI risk was no more than 5% and the efficacy in preventing SSIs was no more than 10%, triclosan-coated sutures resulted in extra expenditure for hospitals and third-party payers (resulting in extra costs of $1,626 and $1,071 per SSI prevented for hospitals and third-party payers, respectively; SSI risk, 5%; efficacy, 10%).ConclusionsOur results suggest that switching to triclosan-coated sutures from the uncoated sutures can both prevent SSIs and save substantial costs for hospitals, third-party payers, and society, as long as efficacy in preventing SSIs is at least 10% and SSI risk is at least 10%.

Our objective was to model the cost-effectiveness and economic value of routine peri-operative Staphylococcus aureus screening and decolonization of lung and heart-lung transplant recipients from hospital and third-party payer perspectives. We used clinical data from 596 lung and heart-lung transplant recipients to develop a model in TreeAge Pro 2009 (Williamsport, MA, USA). Sensitivity analyses varied S. aureus colonization rate (5–15 %), probability of infection if colonized (10–30 %), and decolonization efficacy (25–90 %). Data were collected from the Cardiothoracic Transplant Program at the University of Pittsburgh Medical Center. Consecutive lung and heart-lung transplant recipients from January 2006 to December 2010 were enrolled retrospectively. Baseline rates of S. aureus colonization, infection and decolonization efficacy were 9.6 %, 36.7 %, and 31.9 %, respectively. Screening and decolonization was economically dominant for all scenarios tested, providing more cost savings and health benefits than no screening. Savings per case averted (2012 $US) ranged from $73,567 to $133,157 (hospital perspective) and $10,748 to $16,723 (third party payer perspective), varying with the probability of colonization, infection, and decolonization efficacy. Using our clinical data, screening and decolonization led to cost savings per case averted of $240,602 (hospital perspective) and averted 6.7 S. aureus infections (4.3 MRSA and 2.4 MSSA); 89 patients needed to be screened to prevent one S. aureus infection. Our data support routine S. aureus screening and decolonization of lung and heart-lung transplant patients. The economic value of screening and decolonization was greater than in previous models of other surgical populations.

The performance of a printable, ultraviolet (UV) photoconducting biopolymer is investigated for UV photodetectors of varying layer thicknesses. The biopolymer is formed from deoxyribonucleic acid (DNA) with the addition of the Clevios P formulation of poly(3,4-ethylenedioxythiophene)-poly(styrenesulphonate) (PEDOT:PSS) and hexadecyltrimethyl-ammonium chloride (CTMA); it is then combined with phenyl-C61-butyric acid methyl (PCBM) to make a printable, UV photoconducting material. The highest measured responsivity of the photodetectors is 1.2 mA/W at 20 V bias using a 260 nm source.

Background Surgical site infection (SSI) after total joint arthroplasty (TJA) is a rare but devastating complication. Various skin antiseptic applications are used preoperatively to prevent SSI. Recent literature suggests 2% chlorhexidine gluconate (CHG) wipes reduce microbial content at surgical sites, but it is unclear whether they reduce rates of SSI.

Background Because patients can remain colonized with vancomycin-resistant enterococci (VRE) for long periods of time, VRE may spread from one health care facility to another. Methods Using the Regional Healthcare Ecosystem Analyst, an agent-based model of patient flow among all Orange County, California, hospitals and communities, we quantified the degree and speed at which changes in VRE colonization prevalence in a hospital may affect prevalence in other Orange County hospitals. Results A sustained 10% increase in VRE colonization prevalence in any 1 hospital caused a 2.8% (none to 62%) average relative increase in VRE prevalence in all other hospitals. Effects took from 1.5 to >10 years to fully manifest. Larger hospitals tended to have greater affect on other hospitals. Conclusions When monitoring and controlling VRE, decision makers may want to account for regional effects. Knowing a hospital's connections with other health care facilities via patient sharing can help determine which hospitals to include in a surveillance or control program.

Clin Microbiol Infect The economic impact of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) remains unclear. We developed an economic simulation model to quantify the costs associated with CA-MRSA infection from the societal and third-party payer perspectives. A single CA-MRSA case costs third-party payers $2277-$3200 and society $7070-$20489, depending on patient age. In the United States (US), CA-MRSA imposes an annual burden of $478million to 2.2billion on third-party payers and $1.4-13.8billion on society, depending on the CA-MRSA definitions and incidences. The US jail system and Army may be experiencing annual total costs of $7-11million ($6-10million direct medical costs) and $15-36million ($14-32million direct costs), respectively. Hospitalization rates and mortality are important cost drivers. CA-MRSA confers a substantial economic burden on third-party payers and society, with CA-MRSA-attributable productivity losses being major contributors to the total societal economic burden. Although decreasing transmission and infection incidence would decrease costs, even if transmission were to continue at present levels, early identification and appropriate treatment of CA-MRSA infections before they progress could save considerable costs. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Clostridium difficile is a nosocomial infection that causes substantial morbidity, mortality, and healthcare costs [1–3]. Clostridium difficile infection (CDI) causes a wide range of clinical disease and is the leading cause of infectious diarrhea in hospitalized patients, particularly affecting elderly and frail patients [2, 3]. Treatment of CDI is challenging [2, 4, 5], even though several treatment strategies exist. Recurrences are of primary concern and add an additional complication to treatment of CDI [6]. In May 2011, the Food and Drug Administration (FDA) approved fidaxomicin, a new macrocyclic antibiotic, for the treatment of CDI [7]. Clinical studies have shown this drug to be just as efficacious as vancomycin in the clinical treatment of CDI [8, 9]. It has a similar cure rate but results in a lower incidence of recurrence when used in the treatment of the non–North American pulsed field type 1 and polymerase chain reaction ribotype 027 (NAP1/BI/027) strain [8, 9]. The NAP1/BI/027 strain is quite widespread and has been implicated in outbreaks worldwide; it accounts for approximately 50% of isolates and is prevalent in North America, having been identified in 40 states, several provinces in Canada, and throughout Europe [10–12]. The NAP1/BI/027 strain has increased production of toxins A and B, production of binary toxin, and fluoroquinolone resistance [2]. Although this strain is thought to cause more severe episodes of CDI, as opposed to nonsevere disease, debate remains as some studies show that severity is not different by strain [2, 10, 13]. Recurrent CDI is a difficult and increasingly common challenge associated with CDI management; up to 25% of patients have a recurrence and this rate may increase with the number of CDI episodes a patient experiences [4, 14]. Costs of CDI also increase with the number of CDI episodes [15–18]. The cost per episode to treat recurrent CDI is an estimated $4948, but varies on the basis of management (ie, inpatient vs outpatient treatment) [19, 20]. Thus, although comparative effectiveness studies have been performed on various C. difficile treatments, finding no antimicrobial agent to be superior for the initial cure of nonsevere CDI, treatment with fidaxomicin does result in fewer recurrences in non-NAP1/BI/027 strains [21]. This begs the question of whether the use of fidaxomicin might be a cost-effective treatment for CDI despite its higher drug costs when compared to metronidazole and, to a lesser extent, oral vancomycin. The cost-effectiveness of fidaxomicin for the treatment of CDI remains undetermined. In this study, we constructed a decision analytic simulation model to evaluate the economic value of fidaxomicin for the treatment of CDI (either first episode or first recurrence), comparing the cost-effectiveness of CDI treatment in these 3 cases: (1) no use of fidaxomicin, (2) only use of fidaxomicin, and (3) fidaxomicin use based on strain typing results. Our hope is that clinicians, policy makers, and third-party payers would be able to use the results of this model to determine the best treatment strategy and reimbursement rates.