Structure of a tripartite protein complex that targets toxins to the type VII secretion system.

Type VII secretion systems are membrane-embedded nanomachines used by Gram-positive bacteria to export effector proteins from the cytoplasm to the extracellular environment. Many of these effectors are polymorphic toxins comprised of an N-terminal Leu-x-Gly (LXG) domain of unknown function and a C-terminal toxin domain that inhibits the growth of bacterial competitors. In recent work, it was shown that LXG effectors require two cognate Lap proteins for T7SS-dependent export. Here, we present the 2.6 Å structure of the LXG domain of the TelA toxin from the opportunistic pathogen Streptococcus intermedius in complex with both of its cognate Lap targeting factors. The structure reveals an elongated α-helical bundle within which each Lap protein makes extensive hydrophobic contacts with either end of the LXG domain. Remarkably, despite low overall sequence identity, we identify striking structural similarity between our LXG complex and PE-PPE heterodimers exported by the distantly related ESX type VII secretion systems of Mycobacteria implying a conserved mechanism of effector export among diverse Gram-positive bacteria. Overall, our findings demonstrate that LXG domains, in conjunction with their cognate Lap targeting factors, represent a tripartite secretion signal for a widespread family of T7SS toxins.

Component Costs of CAR-T Therapy in Addition to Treatment Acquisition Costs in Patients with Multiple Myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), is a B-cell maturation antigen-directed, genetically modified autologous chimeric antigen receptor T-cell (CAR-T) immunotherapy. It is indicated for treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The objective of this study was to estimate the per-patient US commercial healthcare costs related to cilta-cel (CARVYKTI®) CAR-T therapy (i.e., costs separate from cilta-cel therapy acquisition) for patients with RRMM. METHODS: US prescribing information for cilta-cel, publicly available data, and published literature were used with clinician input to identify the cost components and unit costs associated with administration of cilta-cel. Cost components included apheresis, bridging therapy, conditioning therapy, administration, and postinfusion monitoring for 1 year of follow-up. Adverse event (AE) management costs for all grades of cytokine release syndrome and neurologic toxicities, and additional AEs grade ≥ 3 occurring in > 5% of patients were included in the analysis. RESULTS: The estimated per-patient average costs of cilta-cel CAR-T therapy administered exclusively in an inpatient setting, excluding cilta-cel therapy acquisition costs, totaled US$160,933 over a 12 month period. Costs assuming different proportions of inpatient/outpatient administration (85%/15% and 70%/30%) were US$158,095 and US$155,257, respectively. CONCLUSION: Cost estimates from this analysis, which disaggregates CAR-T therapy costs, provide a comprehensive view of the cost components of CAR-T therapy that can help healthcare decision-makers make informed choices regarding the use of cilta-cel. Real-world costs may differ with improved AE prevention and mitigation strategies.

Assessing the Cost-effectiveness of a Hypothetical Disease-modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease.

PURPOSE: Clinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer's disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD. METHODS: We developed a Markov state-transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained. FINDINGS: From the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively. IMPLICATIONS: Under a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.

Dual Targeting Factors Are Required for LXG Toxin Export by the Bacterial Type VIIb Secretion System.

Bacterial type VIIb secretion systems (T7SSb) are multisubunit integral membrane protein complexes found in Firmicutes that play a role in both bacterial competition and virulence by secreting toxic effector proteins. The majority of characterized T7SSb effectors adopt a polymorphic domain architecture consisting of a conserved N-terminal Leu-X-Gly (LXG) domain and a variable C-terminal toxin domain. Recent work has started to reveal the diversity of toxic activities exhibited by LXG effectors; however, little is known about how these proteins are recruited to the T7SSb apparatus. In this work, we sought to characterize genes encoding domains of unknown function (DUFs) 3130 and 3958, which frequently cooccur with LXG effector-encoding genes. Using coimmunoprecipitation-mass spectrometry analyses, in vitro copurification experiments, and T7SSb secretion assays, we found that representative members of these protein families form heteromeric complexes with their cognate LXG domain and in doing so, function as targeting factors that promote effector export. Additionally, an X-ray crystal structure of a representative DUF3958 protein, combined with predictive modeling of DUF3130 using AlphaFold2, revealed structural similarity between these protein families and the ubiquitous WXG100 family of T7SS effectors. Interestingly, we identified a conserved FxxxD motif within DUF3130 that is reminiscent of the YxxxD/E "export arm" found in mycobacterial T7SSa substrates and mutation of this motif abrogates LXG effector secretion. Overall, our data experimentally link previously uncharacterized bacterial DUFs to type VIIb secretion and reveal a molecular signature required for LXG effector export. IMPORTANCE Type VIIb secretion systems (T7SSb) are protein secretion machines used by an array of Gram-positive bacterial genera, including Staphylococcus, Streptococcus, Bacillus, and Enterococcus. These bacteria use the T7SSb to facilitate interbacterial killing and pathogenesis through the secretion of toxins. Although the modes of toxicity for a number of these toxins have been investigated, the mechanisms by which they are recognized and secreted by T7SSb remains poorly understood. The significance of this work is the discovery of two new protein families, termed Lap1 and Lap2, that directly interact with these toxins and are required for their secretion. Overall, Lap1 and Lap2 represent two widespread families of proteins that function as targeting factors that participate in T7SSb-dependent toxin release from Gram-positive bacteria.

Cost-effectiveness of vibegron for the treatment of overactive bladder in the United States.

AIMS: To evaluate the cost-effectiveness of vibegron compared with other oral pharmacologic therapies as treatment for overactive bladder (OAB). METHODS: A semi-Markov model with monthly cycles was developed to support a lifetime horizon of vibegron 75 mg from a US commercial payor or Medicare perspective. The model incorporated efficacy (reductions in daily micturitions and urinary incontinence episodes), adverse events, OAB-related comorbidities, drug-drug interactions, anticholinergic burden, and treatment persistence. Direct costs and quality-adjusted life years (QALY) were accumulated over time. The primary outcome was the cost per QALY incremental cost-effectiveness ratio (ICER). One-way (OWSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: For commercial payors, vibegron was cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $9,311) and at a WTP threshold of $150,000/QALY versus mirabegron 25 mg (ICER, $141,957) and versus an anticholinergic basket based on market share (ICER, $118,121). For Medicare, vibegron was cost-effective at a WTP threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $12,154) and at a WTP threshold of $100,000/QALY versus mirabegron 25 mg (ICER, $99,150) and versus an anticholinergic market basket (ICER, $60,756). For commercial payors and Medicare, OWSAs for vibegron versus mirabegron indicated cost-effectiveness was most sensitive to vibegron persistence at 1 and 12 months. PSAs indicated that vibegron was cost-effective versus mirabegron 50 mg 98.6% and 100% of the time at $50,000/QALY for commercial payors and Medicare payors, respectively. LIMITATIONS: Due to lack of real-world data available on persistence, vibegron was assumed to have the same persistence as mirabegron 50 mg. Long-term efficacy was assumed to be sustained beyond 52 weeks in the absence of clinical trials longer than 52 weeks. CONCLUSIONS: Vibegron is cost-effective from a commercial payor (WTP threshold $150,000/QALY) and Medicare (WTP threshold $100,000/QALY) perspective when compared with other oral pharmacologic treatments for OAB.

Overactive bladder (OAB) affects more than 30 million adults in the United States. OAB is a condition associated with frequent and sudden urges to urinate. Drugs for treating OAB may improve symptoms for patients. Anticholinergic drugs are one type of drug available for treating OAB. Anticholinergic drugs may cause side effects such as dry mouth and constipation. Newer types of drugs called ß₃-adrenergic receptor agonists are available for treating OAB symptoms. Vibegron is a member of the ß₃-adrenergic receptor agonist class of drugs. Vibegron does not cause the same side effects related to anticholinergic drugs such as dry mouth and constipation. ß₃-adrenergic receptor agonists work well for OAB symptoms but may be more expensive than anticholinergic drugs. It is important to choose drugs that work well and that are a reasonable price. This study assessed if vibegron is cost-effective for people enrolled in US private insurance and Medicare plans. Compared with other common drugs such as anticholinergic drugs for OAB, vibegron is cost-effective for people enrolled in private insurance and Medicare plans. This was in part because vibegron works better for longer and causes fewer adverse effects than other drugs. Vibegron may be considered "good value for money" for patients with OAB.

Cultivation of ammonia-oxidising archaea on solid medium.

Ammonia-oxidising archaea (AOA) are environmentally important microorganisms involved in the biogeochemical cycling of nitrogen. Routine cultivation of AOA is exclusively performed in liquid cultures and reports on their growth on solid medium are scarce. The ability to grow AOA on solid medium would be beneficial for not only the purification of enrichment cultures but also for developing genetic tools. The aim of this study was to develop a reliable method for growing individual colonies from AOA cultures on solid medium. Three phylogenetically distinct AOA strains were tested: 'Candidatus Nitrosocosmicus franklandus C13', Nitrososphaera viennensis EN76 and 'Candidatus Nitrosotalea sinensis Nd2'. Of the gelling agents tested, agar and Bacto-agar severely inhibited growth of all three strains. In contrast, both 'Ca. N. franklandus C13' and N. viennensis EN76 tolerated Phytagel™ while the acidophilic 'Ca. N. sinensis Nd2' was completely inhibited. Based on these observations, we developed a Liquid-Solid (LS) method that involves immobilising cells in Phytagel™ and overlaying with liquid medium. This approach resulted in the development of visible distinct colonies from 'Ca. N. franklandus C13' and N. viennensis EN76 cultures and lays the groundwork for the genetic manipulation of this group of microorganisms.

Bacterial type VII secretion: An important player in host-microbe and microbe-microbe interactions.

Type VII secretion systems (T7SSs) are poorly understood protein export apparatuses found in mycobacteria and many species of Gram-positive bacteria. To date, this pathway has predominantly been studied in Mycobacterium tuberculosis, where it has been shown to play an essential role in virulence; however, much less studied is an evolutionarily divergent subfamily of T7SSs referred to as the T7SSb. The T7SSb is found in the major Gram-positive phylum Firmicutes where it was recently shown to target both eukaryotic and prokaryotic cells, suggesting a dual role for this pathway in host-microbe and microbe-microbe interactions. In this review, we compare the current understanding of the molecular architectures and substrate repertoires of the well-studied mycobacterial T7SSa systems to that of recently characterized T7SSb pathways and highlight how these differences may explain the observed biological functions of this understudied protein export machine.

MPOWER: The Impact of a Purpose Program on Adolescents' Intrinsic and Extrinsic Motivations.

Purpose has been defined as an active engagement toward goals that are meaningful to the self (i.e., personal meaningfulness) and contribute to the world beyond the self (BTS). These BTS contributions may reflect the intention to meet a wide range of needs from family financial needs to more macro-level concerns, including social injustices. This study investigates the efficacy of a school-based program called MPOWER expressly designed by the authors to cultivate the BTS aspect of purpose. Previous research suggests that the BTS aspect of purpose has beneficial effects on school engagement, goal-setting abilities and orientations, and ultimately school performance. Ninety-four students participated in this study that utilized a randomized, pre-test-post-test between-subjects design to evaluate MPOWER (52 in MPOWER and 42 in the control group). The ANCOVA results indicated a significant increase in the BTS aspect of purpose among program participants, compared to controls. Moreover, participants had higher post-test levels of general self-efficacy and grade point averages, and decreased performance-approach (e.g., playing to be the best, comparing self to others) and performance-avoidance (e.g., avoiding risks of failure, fear of social consequences) goal orientations. Findings can be used to design programs that aim to cultivate students' intentions to contribute to the world beyond themselves, as well as associated personal benefits (i.e., goal orientations, self-efficacy, academic performance).

Structure of the Extracellular Region of the Bacterial Type VIIb Secretion System Subunit EsaA.

Gram-positive bacteria use type VII secretion systems (T7SSs) to export effector proteins that manipulate the physiology of nearby prokaryotic and eukaryotic cells. Several mycobacterial T7SSs have established roles in virulence. By contrast, the genetically distinct T7SSb pathway found in Firmicutes bacteria more often functions to mediate bacterial competition. A lack of structural information on the T7SSb has limited the understanding of effector export by this protein secretion apparatus. Here, we present the 2.4 Å crystal structure of the extracellular region of the T7SSb subunit EsaA from Streptococcus gallolyticus. Our structure reveals that homodimeric EsaA is an elongated, arrow-shaped protein with a surface-accessible "tip", which in some species of bacteria serves as a receptor for lytic bacteriophages. Because it is the only T7SSb subunit large enough to traverse the peptidoglycan layer of Firmicutes, we propose that EsaA plays a critical role in transporting effectors across the entirety of the Gram-positive cell envelope.

Contact-Dependent Interbacterial Antagonism Mediated by Protein Secretion Machines.

To establish and maintain an ecological niche, bacteria employ a wide range of pathways to inhibit the growth of their microbial competitors. Some of these pathways, such as those that produce antibiotics or bacteriocins, exert toxicity on nearby cells in a cell contact-independent manner. More recently, however, several mechanisms of interbacterial antagonism requiring cell-to-cell contact have been identified. This form of microbial competition is mediated by antibacterial protein toxins whose delivery to target bacteria uses protein secretion apparatuses embedded within the cell envelope of toxin-producing bacteria. In this review, we discuss recent work implicating the bacterial Type I, IV, VI, and VII secretion systems in the export of antibacterial 'effector' proteins that mediate contact-dependent interbacterial antagonism.

Molecular Basis for Immunity Protein Recognition of a Type VII Secretion System Exported Antibacterial Toxin.

Gram-positive bacteria deploy the type VII secretion system (T7SS) to facilitate interactions between eukaryotic and prokaryotic cells. In recent work, we identified the TelC protein from Streptococcus intermedius as a T7SS-exported lipid II phosphatase that mediates interbacterial competition. TelC exerts toxicity in the inner wall zone of Gram-positive bacteria; however, intercellular intoxication of sister cells does not occur because they express the TipC immunity protein. In the present study, we sought to characterize the molecular basis of self-protection by TipC. Using sub-cellular localization and protease protection assays, we show that TipC is a membrane protein with an N-terminal transmembrane segment and a C-terminal TelC-inhibitory domain that protrudes into the inner wall zone. The 1.9-Å X-ray crystal structure of a non-protective TipC paralogue reveals that the soluble domain of TipC proteins adopts a crescent-shaped fold that is composed of three α-helices and a seven-stranded ß-sheet. Subsequent homology-guided mutagenesis demonstrates that a concave surface formed by the predicted ß-sheet of TipC is required for both its interaction with TelC and its TelC-inhibitory activity. S. intermedius cells lacking the tipC gene are susceptible to growth inhibition by TelC delivered between cells; however, we find that the growth of this strain is unaffected by endogenous or overexpressed TelC, although the toxin accumulates in culture supernatants. Together, these data indicate that the TelC-inhibitory activity of TipC is only required for intercellularly transferred TelC and that the T7SS apparatus transports TelC across the cell envelope in a single step, bypassing the cellular compartment in which it exerts toxicity en route.

Estimated Budget Impact of Increased Use of Mirabegron, A Novel Treatment for Overactive Bladder.

BACKGROUND: Oral pharmacological treatment for overactive bladder (OAB) consists of antimuscarinics and the beta-3 adrenergic agonist mirabegron. Antimuscarinic adverse events (AEs) such as dry mouth, constipation, and blurry vision can result in frequent treatment discontinuation rates, leaving part of the OAB population untreated. Antimuscarinics also contribute to a patient's anticholinergic cognitive burden (ACB), so the Beers Criteria recommends cautious use of antimuscarinics in elderly patients who take multiple anticholinergic medications or have cognitive impairment. Since mirabegron does not affect the cholinergic pathways, it is unlikely to contribute to a patient's ACB. OBJECTIVE: To estimate the health care costs associated with the pharmacological treatment of OAB with mirabegron and antimuscarinics from U.S. commercial payer and Medicare Advantage perspectives, using a budget impact model. METHODS: For this budget impact model, 2 analyses were performed. The primary analysis estimated the budgetary impact of increasing the use of mirabegron in a closed patient cohort treated with oral pharmacological treatments. The secondary analysis modeled the economic impact in an open cohort by allowing untreated patients to begin treatment with mirabegron after potential contraindication, intolerance, or lack of effectiveness of antimuscarinics. The analyses were performed over a 3-year time horizon. The economic impact of increased mirabegron use was quantified using direct medical costs, including prescription costs and health resource utilization (HRU) costs. Costs of comorbidities included pharmacy and medical costs of treating OAB-related urinary tract infections (UTI), skin rashes, and depression. An analysis of a large single-site integrated health network database was commissioned to quantify ACB-related HRU in terms of the increases in yearly outpatient and emergency department visits. Based on this analysis, the model associated each unit increase in ACB score with increased HRU and probability of mild cognitive impairment. Clinical outcomes of increased use of mirabegron were presented as the number of AEs and comorbidity episodes that could be avoided. One-way sensitivity analyses were performed to quantify the expected budget impact over the range of uncertainty for the key input variables. RESULTS: Primary analysis calculated the impact of increasing the use of mirabegron from 4.5% to 5.3%, 7.1%, and 9.4% in years 1, 2, and 3, respectively, among oral pharmacological OAB treatments that included generic and branded antimuscarinics: oxybutynin, tolterodine, trospium, darifenacin, fesoterodine, and solifenacin. For a 1 million-member U.S. commercial payer plan, the total prescription costs increased, and the total medical costs decreased during the 3-year time horizon, yielding increases of $0.005, $0.016, and $0.031 from current per member per month (PMPM) costs and $0.90, $2.92, and $5.53 from current per treated member per month (PTMPM) costs, an average of less than 2% of current OAB treatment costs. For the Medicare Advantage plan, the resulting incremental PMPM costs were $0.010, $0.034, and $0.065, and the incremental PTMPM costs were $0.93, $3.04, and $5.76; all were less than 4% of the current cost. The secondary analysis estimated the budgetary effects of reducing the untreated population by 1% annually by initiating treatment with mirabegron. For a commercial payer, this resulted in PMPM cost increases of $0.156, $0.311, and $0.467 from the current value, while the incremental PTMPM cost increased by $6.17, $11.67, and $16.61. For the Medicare Advantage plan, the incremental increases in PMPM costs were $0.277, $0.553, and $0.830, and in PTMPM costs were $6.42, $12.15, and $17.29. Clinically, treating more OAB patients resulted in fewer OAB-related comorbidities from both health plan perspectives, since most events associated with nontreatment could be avoided. In the Medicare Advantage population of the secondary analysis, the total numbers of avoided events were predicted as 452 UTIs, 2,598 depression diagnoses, and 3,020 skin rashes during the time horizon of the model. CONCLUSIONS: Mirabegron addresses an unmet need for therapy for certain OAB patients, for whom antimuscarinics are not recommended because of a risk of cognitive impairment and who are intolerant to the anticholinergic AEs. Using mirabegron involves moderate additional economic cost to a commercial or Medicare Advantage health plan for which medical cost savings can offset a substantial part of increased pharmacy costs. DISCLOSURES: Funding for this study was provided by Astellas. Perk, Wielage, T. Klein, and R. Klein are employed by Medical Decision Modeling, a contract research company that was paid to perform the described outcomes research and build the model contained in this study. Campbell and Perkins are employed by the Regenstrief Institute, which conducted a database analysis for this research. Campbell reports consultancy fees from Astellas, as well as pending grants from Merck, Sharpe, and Dohme Corp. Posta, Yuran, and Ng are employed by Astellas Pharma Global Development, the developer of mirabegron. Study concept and design were contributed by Perk, Wielage, R. Klein, and Ng. Campbell, T. Klein, and Perkins took the lead in data collection, assisted by Perk, Wielage, and Ng. Data interpretation was performed by Posta and Yuran, along with Perk, Wielage, R. Klein, Ng, Campbell, and Perkins. The manuscript was written by Perk and R. Klein, along with Wielage, T. Klein, Posta, Yuran, and Ng, and revised by all the authors.

Mirabegron for the treatment of overactive bladder: cost-effectiveness from US commercial health-plan and Medicare Advantage perspectives.

BACKGROUND AND OBJECTIVE: The first class of oral pharmacologic treatments for overactive bladder (OAB) are antimuscarinics that are associated with poor persistence, anticholinergic adverse events, and increased anticholinergic burden (ACB) with risk of cognitive impairment. Mirabegron, a ß3-adrenoceptor agonist, is an oral treatment that does not contribute to ACB and has early evidence of improved persistence. The objective of the analysis was to assess the cost-effectiveness of mirabegron for OAB vs six antimuscarinics in the US. METHODS: A Markov state-transition model assessed US commercial health-plan and Medicare Advantage perspectives over a 3-year time horizon in an OAB patient population. Transition probabilities between five micturition and five incontinence severity states were derived from a network meta-analysis of 44 trials of oral OAB treatments. Therapy beginning with an oral OAB agent could discontinue or switch to another oral agent and could be followed by tibial nerve stimulation, sacral neuromodulation, or onabotulinumtoxinA. The primary outcome was cost per quality-adjusted life year (QALY). Utilities were mapped from incontinence and micturition frequencies as well as demographics. Based on analysis of data from a large healthcare system, elevated ACB was associated with increased healthcare utilization and probability of cognitive impairment. RESULTS: From both commercial and Medicare Advantage perspectives, mirabegron was the most clinically effective treatment, while oxybutynin was the least expensive. Tolterodine immediate release (IR) was also on the cost-effectiveness frontier. The analysis estimated costs per QALY of $59,690 and $66,347 for mirabegron from commercial health plan and Medicare Advantage perspectives, respectively, compared to tolterodine IR. Other antimuscarinics were dominated. CONCLUSIONS: This analysis estimated that mirabegron is a cost-effective treatment for OAB from US commercial health plan and Medicare Advantage perspectives, due to fewer projected adverse events and comorbidities, and data suggesting better persistence.

Draft Genome Sequences of Three Bacillus Species from South African Marine Sponges.

The rise in antibiotic-resistant bacteria has spurred efforts to identify novel compounds with antimicrobial activity. This brief report describes the genome sequence of threeBacillusspecies isolates from South African marine sponges, which produce compounds with antimicrobial activity. A search for secondary metabolite clusters revealed several secondary metabolite pathways in these genomes, which may hold promise as novel antibiotics.

Using common random numbers in health care cost-effectiveness simulation modeling.

OBJECTIVES: To identify the problem of separating statistical noise from treatment effects in health outcomes modeling and analysis. To demonstrate the implementation of one technique, common random numbers (CRNs), and to illustrate the value of CRNs to assess costs and outcomes under uncertainty. METHODS: A microsimulation model was designed to evaluate osteoporosis treatment, estimating cost and utility measures for patient cohorts at high risk of osteoporosis-related fractures. Incremental cost-effectiveness ratios (ICERs) were estimated using a full implementation of CRNs, a partial implementation of CRNs, and no CRNs. A modification to traditional probabilistic sensitivity analysis (PSA) was used to determine how variance reduction can impact a decision maker's view of treatment efficacy and costs. RESULTS: The full use of CRNs provided a 93.6 percent reduction in variance compared to simulations not using the technique. The use of partial CRNs provided a 5.6 percent reduction. The PSA results using full CRNs demonstrated a substantially tighter range of cost-benefit outcomes for teriparatide usage than the cost-benefits generated without the technique. CONCLUSIONS: CRNs provide substantial variance reduction for cost-effectiveness studies. By reducing variability not associated with the treatment being evaluated, CRNs provide a better understanding of treatment effects and risks.

Design and Evaluation of a Personal Diffusion Battery.

A four-stage personal diffusion battery (pDB) was designed and constructed to measure submicron particle size distributions. The pDB consisted of a screen-type diffusion battery, solenoid valve system, and electronic controller. A data inversion spreadsheet was created to solve for the number median diameter (NMD), geometric standard deviation (GSD), and particle number concentration of unimodal aerosols using stage number concentrations from the pDB combined with a handheld condensation particle counter (pDB+CPC). The inversion spreadsheet included particle entry losses, theoretical penetrations across screens, the detection efficiency of the CPC, and constraints so the spreadsheet solved to values within the pDB range. Size distribution parameters (NMD, GSD, and number concentration) measured with the pDB+CPC with inversion spreadsheet were within 25% of those measured with a scanning mobility particle sizer (SMPS) for 5 of 12 polydisperse combustion aerosols. For three tests conducted with propylene torch exhaust, the pDB+CPC with inversion spreadsheet successfully identified that the NMD was smaller than the constraint value of 16 nm. The ratio of the nanoparticle portion of the aerosol compared to the reference (Rnano) was calculated to determine the ability of pDB+CPC with inversion spreadsheet to measure the nanoparticle portion of the aerosols. The Rnano ranged from 0.87 to 1.01 when the inversion solved and from 0.06 to 2.01 when the inversion solved to a constraint. The pDB combined with CPC has limited use as a personal monitor but combining the pDB with a different detector would allow for the pDB to be used as a personal monitor.

The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden.

BACKGROUND: This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO) and glucocorticoid-induced osteoporosis (GIOP). The study's objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. METHODS: A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs) for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated.For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD) T-Score of -3.0. The GIOP cohorts simulated had an initial BMD T-Score of -2.5. RESULTS: The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were €36,995 per QALY and €19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were €20,826 per QALY and €15,155 per QALY, respectively. CONCLUSIONS: The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO and GIOP cohorts evaluated is justified at a cost per QALY threshold of €50,000.

Budget impact analysis of insulin therapies and associated delivery systems.

PURPOSE: A budget impact analysis of insulin therapies and associated delivery systems is presented. METHODS: Based on inputted procurement totals, per-item costs (based on 2011 average wholesale price), insulin distribution system (floor stock or individual patient supply), waste, and treatment protocols for a specified time frame, the budget impact model approximated the number of patients treated with subcutaneous insulin, costs, utilization, waste, and injection mechanism (pen safety needle or syringe) costs. To calculate net changes, results of one-year 3-mL vial use were subtracted from one-year 10-mL vial or 3-mL pen use. RESULTS: Switching from a 10-mL vial to a 3-mL vial was associated with reductions in both costs and waste. The net reductions in costs and waste ranged from $15,482 and 120,000 IU, respectively, for floor-stock 10-mL vial to floor-stock 3-mL vial conversion to $871,548 and 6,750,000 IU, respectively, for individual patient supply 10-mL vial to floor-stock 3-mL vial conversion. Switching from floor-stock 10-mL vials to individual patient supply 3-mL vials increased costs and waste by $164,659 and 1,275,000 IU, respectively. Converting from individual patient supply 3-mL pens to individual patient supply 3-mL vials reduced costs by $117,236 but did not decrease waste. CONCLUSION: A budget impact analysis of the conversion of either 10-mL insulin vials or 3-mL insulin pens to 3-mL insulin vials found reductions in both cost and waste, except when converting from floor-stock 10-mL vials to individual patient supply 3-mL vials.

Cost-effectiveness of several atypical antipsychotics in orally disintegrating tablets compared with standard oral tablets in the treatment of schizophrenia in the United States.

OBJECTIVE: Although the use of innovative drug delivery systems, like orally disintegrating antipsychotic tablets (ODT), may facilitate medication adherence and help reduce the risk of relapse and hospitalization, no information is available about the comparative cost-effectiveness of standard oral tablets (SOT) vs ODT formulations in the treatment of schizophrenia. This study compared the cost-effectiveness of olanzapine ODT and olanzapine SOT in the usual treatment of outpatients with schizophrenia from a US healthcare perspective. The study also compared olanzapine ODT with risperidone and aripiprazole, two other atypical antipsychotics available in both ODT and SOT formulations. METHODS: Published medical literature and a clinical expert panel were used to populate a 1-year Monte Carlo Micro-simulation model. The model captures clinical and cost parameters including adherence levels, treatment discontinuation by reason, relapse with and without inpatient hospitalization, quality-adjusted life years (QALYs), treatment-emergent adverse events, healthcare resource utilization, and associated costs. Key outcomes were total annual direct cost per treatment, QALY, and incremental cost-effectiveness (ICER) per 1 QALY gained. RESULTS: Based on model projections, olanzapine ODT therapy was more costly ($9808 vs $9533), but more effective in terms of a lower hospitalization rate (15% vs 16%) and better QALYs (0.747 vs 0.733) than olanzapine SOT therapy. Olanzapine ODT was more cost-effective than olanzapine SOT (ICER: $19,643), more cost-effective than risperidone SOT therapy (ICER: $39,966), and dominant (meaning less costly and more effective) than risperidone ODT and aripiprazole in ODT or SOT formulations. LIMITATIONS: Lack of head-to-head randomized studies comparing the three studied atypical antipsychotics required making input assumptions that need further study. CONCLUSIONS: This micro-simulation found that the utilization of olanzapine ODT for the treatment of schizophrenia is predicted to be more cost-effective than any other ODT or SOT formulations of the studied atypical antipsychotic medications.

Screening and treatment for Alzheimer's disease: predicting population-level outcomes.

BACKGROUND: Advances in screening and treatment are needed to mitigate increasing prevalence of dementia due to Alzheimer's disease (DAT). Current proposals to revise Alzheimer's disease (AD) diagnostic criteria incorporate diagnostic biomarkers. Such revisions would allow identification of persons with AD pathology before the onset of dementia. The population-level impact of screening for preclinical AD and treating with a disease-modifying agent is important when evaluating new biomarkers and medications. METHODS: A published computer simulation model assigned AD-related event times, such that delays in disease progression due to therapy effectiveness can be estimated for a preclinical AD cohort. Attributes such as screening sensitivity/specificity, treatment efficacy, age at first screening, and rescreening intervals were varied. Outcomes included incident mild cognitive impairment (MCI-AD), incident DAT, and number of patients recommended for treatment. RESULTS: One-time screening at age 65 years, 50% efficacy, and literature-based proxy persistence rates yielded 12.4% incidence of MCI-AD and 0.9% decrease in DAT incidence from base case of no screening/treatment. Modest reductions in incident MCI-AD and DAT were observed with more sensitive testing. Reducing specificity yielded greater reductions in MCI-AD and DAT cases, albeit by treating more patients. Probabilistic sensitivity analysis predicted that for a cohort of patients aged 65 years, the number that needed to be treated to avoid one AD case was 11.6 (range: 5.7-104). CONCLUSION: The reduction in MCI-AD and DAT depends on initial screening age, screening frequency, and specificity. When considering population-level impact of screening-treatment, the effect of these parameters on incidence would need to be weighed against the number of individuals screened and treated.