The Impact of Market Factors on Meaningful Use of Electronic Health Records Among Primary Care Providers: Evidence From Florida Using Resource Dependence Theory and Information Uncertainty Perspective.

BACKGROUND: Using federal funds from the 2009 Health Information Technology for Economic and Clinical Health Act, the Centers for Medicare and Medicaid Services funded the 2011-2021 Medicaid electronic health record (EHR) incentive programs throughout the country. OBJECTIVE: Identify the market factors associated with Meaningful Use (MU) of EHRs after primary care providers (PCPs) enrolled in the Florida-EHR incentives program through Adopting, Improving, or Upgrading (AIU) an EHR technology. RESEARCH DESIGN: Retrospective cohort study using 2011-2018 program records for 8464 Medicaid providers. MAIN OUTCOME: MU achievement after first-year incentives. INDEPENDENT VARIABLES: The resource dependence theory and the information uncertainty perspective were used to generate key-independent variables, including the county's rurality, educational attainment, poverty, health maintenance organization penetration, and number of PCPs per capita. ANALYTICAL APPROACH: All the county rates were converted into 3 dichotomous measures corresponding to high, medium, and low terciles. Descriptive and bivariate statistics were calculated. A generalized hierarchical linear model was used because MU data were clustered at the county level (level 2) and measured at the practice level (level 1). RESULTS: Overall, 41.9% of Florida Medicaid providers achieved MU after receiving first-year incentives. Rurality was positively associated with MU ( P <0.001). Significant differences in MU achievements were obtained when we compared the "high" terciles with the "low" terciles for poverty rates ( P =0.002), health maintenance organization penetration rates ( P =0.02), and number of PCPs per capita ( P =0.01). These relationships were negative. CONCLUSIONS: Policy makers and health care managers should not ignore the contribution of market factors in EHR adoption.

First-trimester cavum veli interpositi: prevalence and natural history.

OBJECTIVE: To confirm the identity and assess the prevalence and evolution of the fluid-filled interhemispheric midline structure, thought to be the cavum veli interpositi (CVI), in fetuses at 11-14 weeks' gestation. METHODS: This was a retrospective study of first-trimester ultrasound scans performed at a single center over 3 months. Inclusion criteria were singleton pregnancies at 11-14 weeks' gestation with known neonatal outcome. Five experts reviewed the images. Mixed-effects logistic regression and generalized estimating equations (GEE) were conducted to analyze the associations between the presence of the structure and variables including ultrasound approach (transabdominal vs transvaginal), maternal body mass index (BMI), gestational age, fetal crown-rump length (CRL) and biparietal diameter (BPD). Second-trimester ultrasound scans of the fetal central nervous system at 18-24 weeks' gestation were evaluated for the persistence of the CVI in fetuses in which the structure was observed in the first trimester. RESULTS: Of the 223 cases reviewed, 104 were included, among which the CVI was observed in 25 (24%) cases. There was no statistically significant difference in CVI visualization between transabdominal and transvaginal ultrasound examinations. GEE showed significant associations between the presence of the fetal structure and CRL (odds ratio (OR) per 10-unit increase, 1.32; P < 0.0001) and BPD (OR per 10-unit increase, 1.88; P = 0.0011). Maternal BMI and gestational age showed no significant effect on the presence of the CVI. At second-trimester follow-up of the 25 fetuses in which the CVI was observed initially, 44% still showed a CVI, 32% exhibited a cavum vergae, 4% had both structures and 20% had neither. CONCLUSIONS: Based on its anatomical location and, in some fetuses, its visualization as a distinct entity from the third ventricle, the identity of the interhemispheric midline structure in the suprathalamic region of the fetal brain between 11-14 weeks' gestation was confirmed as the CVI. The CVI and/or cavum vergae persisted into the second trimester in 80% of fetuses identified initially as having a CVI. Its presence is not linked to pathology, offering reassurance to practitioners and parents. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Long-read genome sequencing resolves a complex 13q structural variant associated with syndromic anophthalmia.

Microphthalmia, anophthalmia, and coloboma (MAC) are a heterogeneous spectrum of anomalous eye development and degeneration with genetic and environmental etiologies. Structural and copy number variants of chromosome 13 have been implicated in MAC; however, the specific loci involved in disease pathogenesis have not been well-defined. Herein we report a newborn with syndromic degenerative anophthalmia and a complex de novo rearrangement of chromosome 13q. Long-read genome sequencing improved the resolution and clinical interpretation of a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) and terminal deletion. Sequence features at the breakpoint junctions suggested microhomology-mediated break-induced replication (MMBIR) of the maternal chromosome as the origin. Comparing this rearrangement to previously reported copy number alterations in 13q, we refine a putative dosage-sensitive critical region for MAC that might provide new insights into its molecular etiology.

Synchronization in a multilevel network using the Hamilton-Jacobi-Bellman (HJB) technique.

This paper presents the optimal control and synchronization problem of a multilevel network of Rössler chaotic oscillators. Using the Hamilton-Jacobi-Bellman technique, the optimal control law with a three-state variable feedback is designed such that the trajectories of all the Rössler oscillators in the network are optimally synchronized at each level. Furthermore, we provide numerical simulations to demonstrate the effectiveness of the proposed approach for the cases of one and three networks. A perfect correlation between the MATLAB and PSpice results was obtained, thus allowing the experimental validation of our designed controller and shows the effectiveness of the theoretical results.

Oxygen Uptake During Exoskeletal-Assisted Walking in Persons With Paraplegia.

OBJECTIVE: To determine the cardiometabolic demands associated with exoskeletal-assisted walking (EAW) in persons with paraplegia. This study will further examine if training in the device for 60 sessions modifies cost of transport (CT). DESIGN: Prospective cohort study. Measurements over the course of a 60-session training program, approximately 20 sessions apart. SETTING: James J. Peters Bronx Veterans Affairs Medical Center, Center for the Medical Consequences of Spinal Cord Injury Research Center. PARTICIPANTS: The participants' demographics (N=5) were 37-61 years old, body mass index (calculated as weight in kilograms divided by height in meters squared) of 22.7-28.6, level of injury from T1-T11, and 2-14 years since injury. INTERVENTIONS: Powered EAW. MAIN OUTCOME MEASURES: Oxygen consumption per unit time (V˙O2, mL/min/kg), velocity (m/min), cost of transport (V˙O2/velocity), and rating of perceived exertion (RPE). RESULTS: With training: EAW velocity significantly improved (Pre: 51±51m; 0.14±0.14m/s vs Post: 99±42m; 0.28±0.12m/s, P=.023), RPE significantly decreased (Pre: 13±6 vs Post: 7±4, P=.001), V˙O2 significantly improved (Pre: 9.76±1.23 mL/kg/m vs Post: 12.73±2.30 mL/kg/m, P=.04), and CT was reduced from the early to the later stages of training (3.66±5.2 vs 0.87±0.85 mL/kg/m). CONCLUSIONS: The current study suggests that EAW training improves oxygen uptake efficiency and walking velocities, with a lower perception of exertion.

Changes in bowel function following exoskeletal-assisted walking in persons with spinal cord injury: an observational pilot study.

STUDY DESIGN: Prospective, observational study. OBJECTIVE: To explore the effects of exoskeletal-assisted walking (EAW) on bowel function in persons with spinal cord injury (SCI). SETTING: Ambulatory research facility located in a tertiary care hospital. METHODS: Individuals 18-65 years of age, with thoracic vertebrae one (T1) to T11 motor-complete paraplegia of at least 12 months duration were enrolled. Pre- and post-EAW training, participants were asked to report on various aspects of their bowel function as well as on their overall quality of life (QOL) as related to their bowel function. RESULTS: Ten participants completed 25-63 sessions of EAW over a period of 12-14 weeks, one participant was lost to follow up due to early withdrawal after ten sessions. Due to the small sample size, each participant's results were presented descriptively in a case series format. At least 5/10 participants reported improvements with frequency of bowel evacuations, less time spent on bowel management per bowel day, fewer bowel accidents per month, reduced laxative and/or stool softener use, and improved overall satisfaction with their bowel program post-EAW training. Furthermore, 8/10 reported improved stool consistency and 7/10 reported improved bowel function related QOL. One participant reported worsening of bowel function post-EAW. CONCLUSION: Between 50 and 80% of the participants studied reported improvements in bowel function and/or management post-EAW training. EAW training appeared to mitigate SCI-related bowel dysfunction and the potential benefits of EAW on bowel function after SCI is worthy or further study.

Dynamics of multilayer networks with amplification.

We study the dynamics of a multilayer network of chaotic oscillators subject to amplification. Previous studies have proven that multilayer networks present phenomena such as synchronization, cluster, and chimera states. Here, we consider a network with two layers of Rössler chaotic oscillators as well as applications to multilayer networks of the chaotic jerk and Liénard oscillators. Intra-layer coupling is considered to be all to all in the case of Rössler oscillators, a ring for jerk oscillators and global mean field coupling in the case of Liénard, inter-layer coupling is unidirectional in all these three cases. The second layer has an amplification coefficient. An in-depth study on the case of a network of Rössler oscillators using a master stability function and order parameter leads to several phenomena such as complete synchronization, generalized, cluster, and phase synchronization with amplification. For the case of Rössler oscillators, we note that there are also certain values of coupling parameters and amplification where the synchronization does not exist or the synchronization can exist but without amplification. Using other systems with different topologies, we obtain some interesting results such as chimera state with amplification, cluster state with amplification, and complete synchronization with amplification.

More salt, please: global patterns, responses and impacts of foliar sodium in grasslands.

Sodium is unique among abundant elemental nutrients, because most plant species do not require it for growth or development, whereas animals physiologically require sodium. Foliar sodium influences consumption rates by animals and can structure herbivores across landscapes. We quantified foliar sodium in 201 locally abundant, herbaceous species representing 32 families and, at 26 sites on four continents, experimentally manipulated vertebrate herbivores and elemental nutrients to determine their effect on foliar sodium. Foliar sodium varied taxonomically and geographically, spanning five orders of magnitude. Site-level foliar sodium increased most strongly with site aridity and soil sodium; nutrient addition weakened the relationship between aridity and mean foliar sodium. Within sites, high sodium plants declined in abundance with fertilisation, whereas low sodium plants increased. Herbivory provided an explanation: herbivores selectively reduced high nutrient, high sodium plants. Thus, interactions among climate, nutrients and the resulting nutritional value for herbivores determine foliar sodium biogeography in herbaceous-dominated systems.

Drivers of Mercury Cycling in the Rapidly Changing Glacierized Watershed of the High Arctic's Largest Lake by Volume (Lake Hazen, Nunavut, Canada).

Across the Arctic, glaciers are melting and permafrost is thawing at unprecedented rates, releasing not only water to downstream aquatic systems, but also contaminants like mercury, archived in ice over centuries. Using concentrations from samples collected over 4 years and calibrated modeled hydrology, we calculated methylmercury (MeHg) and total mercury (THg) mass balances for Lake Hazen, the world's largest High Arctic lake by volume, for 2015 and 2016. Glacial rivers were the most important source of MeHg and THg to Lake Hazen, accounting for up to 53% and 94% of the inputs, respectively. However, due to the MeHg and THg being primarily particle-bound, Lake Hazen was an annual MeHg and THg sink. Exports of MeHg and THg out the Ruggles River outflow were consequently very low, but erosion and permafrost slumping downstream of the lake increased river MeHg and THg concentrations significantly before entering coastal waters in Chandler Fjord. Since 2001, glacial MeHg and THg inputs to Lake Hazen have increased by 0.01 and 0.400 kg yr-1, respectively, in step with dramatic increases in glacial melt. This study highlights the potential for increases in mercury inputs to arctic ecosystems downstream of glaciers despite recent reductions in global mercury emissions.

Carbonic anhydrase inhibitors in patients with respiratory failure and metabolic alkalosis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Metabolic alkalosis is common in patients with respiratory failure and may delay weaning in mechanically ventilated patients. Carbonic anhydrase inhibitors block renal bicarbonate reabsorption, and thus reverse metabolic alkalosis. The objective of this systematic review is to assess the benefits and harms of carbonic anhydrase inhibitor therapy in patients with respiratory failure and metabolic alkalosis. METHODS: We searched the following electronic sources from inception to August 2017: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and SCOPUS. Randomized clinical trials were included if they assessed at least one of the following outcomes: mortality, duration of hospital stay, duration of mechanical ventilation, adverse events, and blood gas parameters. Teams of two review authors worked in an independent and duplicate manner to select eligible trials, extract data, and assess risk of bias of the included trials. We used meta-analysis to synthesize statistical data and then assessed the certainty of evidence using the GRADE methodology. RESULTS: Six eligible studies were identified with a total of 564 participants. The synthesized data did not exclude a reduction or an increase in mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.57 to 1.56) or in duration of hospital stay (mean difference (MD) 0.42 days, 95% CI -4.82 to 5.66) with the use of carbonic anhydrase inhibitors. Carbonic anhydrase inhibitor therapy resulted in a decrease in the duration of mechanical ventilation of 27 h (95% CI -50 to -4). Also, it resulted in an increase in PaO2 (MD 11.37 mmHg, 95% CI 4.18 to 18.56) and a decrease in PaCO2 (MD -4.98 mmHg, 95% CI -9.66, -0.3), serum bicarbonate (MD -5.03 meq/L, 95% CI -6.52 to -3.54), and pH (MD -0.04, 95% CI -0.07 to -0.01). There was an increased risk of adverse events in the carbonic anhydrase inhibitor group (RR 1.71, 95% CI 0.98 to 2.99). Certainty of evidence was judged to be low for most outcomes. CONCLUSION: In patients with respiratory failure and metabolic alkalosis, carbonic anhydrase inhibitor therapy may have favorable effects on blood gas parameters. In mechanically ventilated patients, carbonic anhydrase inhibitor therapy may decrease the duration of mechanical ventilation. A major limitation of this finding was that only two trials assessed this clinically important outcome.

COSTS OF DEPRESSION FROM CLAIMS DATA FOR MEDICARE RECIPIENTS IN A POPULATION-BASED SAMPLE.

BACKGROUND: Many persons with depressive disorder are not treated and associated costs are not recorded. AIMS OF THE STUDY: To determine whether major depressive disorder (MDD) is associated with higher medical cost among Medicare recipients. METHODS: Four waves of the Baltimore-Epidemiologic Catchment Area (Baltimore ECA) Study conducted between 1981 and 2004 were linked to Medicare claims data for the years 1999 to 2004 from the Centers for Medicare and Medicaid Services (CMS). Generalized linear models specified with a gamma distribution and log link function were used to examine direct medical care costs associated with MDD. RESULTS: Medicare recipients with no history of MDD in either the ECA or CMS data had mean six-year medical costs of US $40,670, compared to $87,445 for Medicare recipients with MDD as recorded in CMS data and $43,583 for those with MDD as recorded in Baltimore-ECA data. Multivariable regressions found that compared to Medicare recipients with no history of depression, those with depression identified in the CMS data had significantly higher medical costs; about 1.87 times (95% confidence interval (CI) 1.32 to 2.67) higher. Medicare recipients with a history of depression identified in the ECA data were no more likely to have higher costs than were Medicare recipients with no history of depression (relative ratio 1.33, 95% CI 0.87 to 2.02). DISCUSSION: Medicare recipients with a history of depression identified in claims data had significantly higher medical costs than recipients with no history of depression. However, no significant differences were found between Medicare recipients with depression in the community-based Baltimore ECA data and those with no history of depression. The results show that the source of diagnosis, in treatment versus survey data, produces differences in results as regards costs. LIMITATIONS: This study involved only Medicare recipients with claims data over the six years 1999 to 2004. Many of the ECA respondents were too young to qualify for Medicare. IMPLICATIONS FOR HEALTH POLICY: Depressive disorder involves substantial medical care costs. The findings provide information on the economic burden of depression, an important but often omitted dimension and perspective of the burden of mental illnesses.

Importance of open marine waters to the enrichment of total mercury and monomethylmercury in lichens in the Canadian High Arctic.

Caribou, which rely on lichens as forage, are a dietary source of monomethylmercury (MMHg) to many of Canada's Arctic Aboriginal people. However, little is understood about the sources of MMHg to lichens in the High Arctic. We quantified MMHg, total mercury (THg) and other chemical parameters (e.g., marine and crustal elements, δ(13)C, δ(15)N, organic carbon, calcium carbonate) in lichen and soil samples collected along transects extending from the coast on Bathurst and Devon islands, Nunavut, to determine factors driving lichen MMHg and THg concentrations in the High Arctic. Lichen MMHg and THg concentrations ranged from 1.41 to 17.1 ng g(-1) and from 36.0 to 361 ng g(-1), respectively. Both were highly enriched over concentrations in underlying soils, indicating a predominately atmospheric source of Hg in lichens. However, MMHg and THg enrichment at coastal sites on Bathurst Island was far greater than on Devon Island. We suggest that this variability can be explained by the proximity of the Bathurst Island transect to several polynyas, which promote enhanced Hg deposition to adjacent landscapes through various biogeochemical processes. This study is the first to clearly show a strong marine influence on MMHg inputs to coastal terrestrial food webs with implications for MMHg accumulation in caribou and the health of the people who depend on them as part of a traditional diet.

Temperature and the sulfur cycle control monomethylmercury cycling in high Arctic coastal marine sediments from Allen Bay, Nunavut, Canada.

Monomethylmercury (MMHg) is a neurotoxin of concern in the Canadian Arctic due to its tendency to bioaccumulate and the importance of fish and wildlife in the Inuit diet. In lakes and wetlands, microbial sediment communities are integral to the cycling of MMHg; however, the role of Arctic marine sediments is poorly understood. With projected warming, the effect of temperature on the production and degradation of MMHg in Arctic environments also remains unclear. We examined MMHg dynamics across a temperature gradient (4, 12, 24 °C) in marine sediments collected in Allen Bay, Nunavut. Slurries were spiked with stable mercury isotopes and amended with specific microbial stimulants and inhibitors, and subsampled over 12 days. Maximal methylation and demethylation potentials were low, ranging from below detection to 1.13 pmol g(-1) h(-1) and 0.02 pmol g(-1) h(-1), respectively, suggesting that sediments are likely not an important source of MMHg to overlying water. Our results suggest that warming may result in an increase in Hg methylation - controlled by temperature-dependent sulfate reduction, without a compensatory increase in demethylation. This study highlights the need for further research into the role of high Arctic marine sediments and climate on the Arctic marine MMHg budget.

The influence of religious attendance on smoking.

UNLABELLED: Generalized linear models were used to assess the relationship between religious attendance and lifetime smoking status among middle-aged adults (n = 666) sampled from waves three (1993 to 1996) and four (2004 to 2005) of the Baltimore Epidemiologic Catchment Area (ECA) study. Religious attendance once per week or greater as compared to never was inversely associated with smoking status. Future research should explore potential mediating factors of the association between religious attendance and smoking among middle-aged adults in order to gain a greater understanding of the mechanisms underlying this relationship. FUNDING: NIMH grant DA026652; NIDA grant T32DA007292.

The impact of county-level factors on meaningful use of electronic health records (EHRs) among primary care providers.

This study examines the impact of county-level factors on "meaningful use" (MU) of electronic health records (EHRs) for 8415 primary care providers (PCPs) that enrolled in the Florida Medicaid EHR Incentive Program through adopting, improving, or upgrading (AIU) a certified EHR technology. PCPs received incentive payments at enrollment and if they used their EHRs in meaningful ways; ways that benefit patients and providers alike they received additional payments. We conducted a retrospective cohort study of these providers over the 2011-2018 period while linking their records to other state data. We used the core constructs of the resource dependence theory (RDT), a well-established organization theory in business management, to operationalize the county-level variables. These variables were rurality, poverty, educational attainment, managed care penetration, changes in population, and number of PCPs per capita. The unit of analysis was provider-years. For practical and computational purposes, all the county variables were dichotomized. We used analysis of variance (ANOVA) to test for differences in MU attestation rates across each county variable. Odds ratios and corresponding 95% confidence intervals were derived from pooled logistic regressions using generalized estimated equations (GEE) with the binomial family and logit link functions. Clustered standard errors were used. Approximately 42% of these providers attested to MU after receiving first-year incentives. Rurality and poverty were significantly associated with MU. To some degree, managed care penetration, change in population size, and number of PCPs per capita were also associated with MU. Policy makers and healthcare managers should not ignore the contribution of county-level factors in the diffusion of EHRs among physician practices. These county-level findings provide important insights about EHR diffusion in places where traditionally underserved populations live. This county-perspective is particularly important because of the potential for health IT to enable public health monitoring and population health management that might benefit individuals beyond the patients treated by the Medicaid providers.

Eliciting patients' preferences for outpatient treatment of febrile neutropenia: a discrete choice experiment.

BACKGROUND: Studies have demonstrated that patients at low risk for febrile neutropenia (FN) complications can be treated safely and effectively at home. Information on patient preferences for outpatient treatment of this condition will help to optimize health care delivery to these patients. The purpose of this study was to elicit non-Hodgkin lymphoma patients' preferences on attributes related to outpatient treatment of FN. METHODS: We used a self-administered discrete choice experiment questionnaire based on the attributes of out-of-pocket costs, unpaid caregiver time required daily, and probability of return to the hospital. Ten paired scenarios in which levels of the attributes were varied were presented to study patients. For each pair, patients indicated the scenario they preferred. Adjusted odds ratios (ORs) of accepting a scenario that described outpatient care for FN were estimated. RESULTS: Eighty-eight patients completed the questionnaire. Adjusted ORs [95 % confidence intervals] of accepting outpatient care for FN were 0.84 [0.75, 0.95] for each $10 increase in out-of-pocket cost; 0.82 [0.68, 0.99] for each 1 h increase in daily unpaid caregiver time; and 0.53 [0.50, 0.57] for each 5 % increase in probability of return to the hospital. CONCLUSIONS: Probability of return to the hospital was the most important attribute to patients when considering home-based care for FN. Patients considered out-of-pocket costs and unpaid caregiver time to be less important than probability of return to the hospital. This study identifies factors that could be incorporated into outpatient delivery systems for FN care to ensure adequate patient uptake and satisfaction with such programs.

Adaptation of computerized posturography to assess seated balance in persons with spinal cord injury.

BACKGROUND: The ability to retain or improve seated balance function after spinal cord injury (SCI) may mean the difference between independence and requiring assistance for basic activities of daily living. Compared with assessments of standing and walking balance, seated balance assessments remain relatively underemphasized and under-utilized. OBJECTIVE: To optimize tools for assessing seated balance deficits and recovery in SCI. DESIGN: Cross-sectional observational study of different methods for assessing seated balance function. SETTING: Veterans Affairs Center of Excellence for the Medical Consequences of Spinal Cord Injury. PARTICIPANTS: Seven able-bodied volunteers, seven participants with chronic motor-complete thoracic SCI. INTERVENTIONS: A computerized pressure-plate apparatus designed for testing standing balance was adapted into a seated balance assessment system. OUTCOME MEASURES: Seated section of Berg Balance Scale; modified functional reach test; and two posturography tests: limits of stability and clinical test of sensory integration on balance. RESULTS: Seated posturography demonstrated improved correlation with neurological level of lesion compared to that of routinely applied subjective clinical tests. CONCLUSION: Seated posturography represents an appealing outcome measure that may be applied toward the measurement of functional changes in response to various rehabilitation interventions in individuals with paralysis.

Optimized Methods for the Production of High-Purity 203Pb Using Electroplated Thallium Targets.

203Pb is a surrogate imaging match for 212Pb. This elementally matched pair is emerging as a suitable pair for imaging and targeted radionuclide therapy in cancer care. Because of the half-life (51.9 h) and low-energy γ-rays emitted, 203Pb is suitable for the development of diagnostic radiopharmaceuticals. The aim of this work was to optimize the production and separation of high-specific-activity 203Pb using electroplated thallium targets. We further investigated the radiochemistry optimization using a suitable chelator, tetraazacyclododecane-1,4,7-triacetic acid (DO3A), and targeting vector, VMT-α-NET (lead-specific chelator conjugated to tyr3-octreotide via a polyethylene glycol linker). Methods: Targets were prepared by electroplating of natural or enriched (205Tl) thallium metal. Scanning electron microscopy was performed to determine the structure and elemental composition of electroplated targets. Targets were irradiated with 24-MeV protons with varying current and beam time to investigate target durability. 203Pb was purified from the thallium target material using an extraction resin (lead resin) column followed by a second column using a weak cation-exchange resin to elute the lead isotope as [203Pb]PbCl2 Inductively coupled plasma mass spectrometry studies were used to further characterize the separation for trace metal contaminants. Radiolabeling efficiency was also investigated for DO3A chelator and VMT-α-NET (a peptide-based targeting conjugate). Results: Electroplated targets were prepared at a high plating density of 76-114 mg/cm2 using a plating time of 5 h. A reproducible separation method was established with a final elution in HCl (400 µL, 1 M) suitable for radiolabeling. Greater than 90% recovery yields were achieved, with an average specific activity of 37.7 ± 5.4 GBq/µmol (1.1 ± 0.1 Ci/µmol). Conclusion: An efficient electroplating method was developed to prepare thallium targets suitable for cyclotron irradiation. A simple and fast separation method was developed for routine 203Pb production with high recovery yields and purity.

Guidelines for health technologies: specific guidance for oncology products in Canada.

OBJECTIVE: Specific methodological challenges are often encountered during cancer-related economic evaluations. The objective of this study was to provide specific guidance to analysts on the methods for the conduct of high-quality economic evaluations in oncology by building on the Canadian Agency for Drugs and Technologies in Health Guidelines for the Economic Evaluation of Health Technologies (third edition). METHODS: Fifteen oncologists, health economists, health services researchers, and decision makers from across Canada identified sections in Canadian Agency for Drugs and Technologies in Health guidelines that would benefit from oncology-specific guidance. Fifteen sections of the guidelines were reviewed to determine whether 1) Canadian Agency for Drugs and Technologies in Health guidelines were sufficient for the conduct of oncology economic evaluations without further guidance specific for oncology products or 2) additional guidance was necessary. A scoping review was conducted by using a comprehensive and replicable search to identify relevant literature to inform recommendations. Recommendations were reviewed by representatives of academia, government, and the pharmaceutical industry in an iterative and formal review of the recommendations. RESULTS: Major adaptations for guidance related to time horizon, effectiveness, modeling, costs, and resources were required. Recommendations around the use of final outcomes over intermediate outcomes to calculate quality-adjusted life-years and life-years gained, the type of evidence, the source of evidence, and the use of time horizon and modeling were made. CONCLUSIONS: This article summarizes key recommendations for the conduct of economic evaluations in oncology and describes methods required to ensure that economic assessments in oncology are conducted in a standardized manner.

Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell engager in multiple myeloma.

In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose-response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis-"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs.