Author Correction: EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.

We wish to correct two mutations in Supplementary Table 4 of this Letter. The NCI-H460 cell line was annotated as being mutant for TP53. NCI-H460 has been verified to be TP53 wild type by several sources1. The NCI-H2009 cell line was annotated as being mutant for PIK3CA. As annotated by COSMIC (ref. 24 of the original Letter) and CCLE (ref. 25 of the original Letter), the NCI-H2009 cell line has a mutation in PIK3C3, rather than PIK3CA. The cell line is wild type for PIK3CA. The Supplementary Information of this Amendment contains the corrected Supplementary Table 4. These errors do not affect our conclusions. The original Letter has not been corrected.

Who needs what (features) when? Personalizing engagement with data-driven self-management to improve health equity.

OBJECTIVES: To examine the feasibility of promoting engagement with data-driven self-management of health among individuals from minoritized medically underserved communities by tailoring the design of self-management interventions to individuals' type of motivation and regulation in accordance with the Self-Determination Theory. METHODS: Fifty-three individuals with type 2 diabetes from an impoverished minority community were randomly assigned to four different versions of an mHealth app for data-driven self-management with the focus on nutrition, Platano; each version was tailored to a specific type of motivation and regulation within the SDT self-determination continuum. These versions included financial rewards (external regulation), feedback from expert registered dietitians (RDF, introjected regulation), self-assessment of attainment of one's nutritional goals (SA, identified regulation), and personalized meal-time nutrition decision support with post-meal blood glucose forecasts (FORC, integrated regulation). We used qualitative interviews to examine interaction between participants' experiences with the app and their motivation type (internal-external). RESULTS: As hypothesized, we found a clear interaction between the type of motivation and Platano features that users responded to and benefited from. For example, those with more internal motivation reported more positive experience with SA and FORC than those with more external motivation. However, we also found that Platano features that aimed to specifically address the needs of individuals with external regulation did not create the desired experience. We attribute this to a mismatch in emphasis on informational versus emotional support, particularly evident in RDF. In addition, we found that for participants recruited from an economically disadvantaged community, internal factors, such as motivation and regulation, interacted with external factors, most notably with limited health literacy and limited access to resources. CONCLUSIONS: The study suggests feasibility of using SDT to tailor design of mHealth interventions for promoting data-driven self-management to individuals' motivation and regulation. However, further research is needed to better align design solutions with different levels of self-determination continuum, to incorporate stronger emphasis on emotional support for individuals with external regulation, and to address unique needs and challenges of underserved communities, with particular attention to limited health literacy and access to resources.

Etelcalcetide Utilization, Dosing Titration, and Chronic Kidney Disease-Mineral and Bone Disease (CKD-MBD) Marker Responses in US Hemodialysis Patients.

RATIONALE & OBJECTIVE: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017. STUDY DESIGN: New-user design within prospective cohort. SETTING & PARTICIPANTS: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS). PREDICTORS: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose. OUTCOME: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation. ANALYTICAL APPROACH: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses. RESULTS: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation. LIMITATIONS: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation. CONCLUSIONS: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.

The rate, cost and outcomes of parathyroidectomy in the united states dialysis population from 2016-2018.

BACKGROUND: In end-stage kidney disease, patients may undergo parathyroidectomy if secondary hyperparathyroidism cannot be managed medically. This study was designed to estimate the parathyroidectomy rate in the United States (US) and to quantify changes in costs and other outcomes after parathyroidectomy. METHODS: This was a retrospective observational cohort study using US Renal Data System data for 2015-2018. Parathyroidectomy rates were estimated for adult hemodialysis and peritoneal dialysis patients alive at the beginning of 2016, 2017, and 2018 who were followed for a year or until parathyroidectomy, death, or transplant. Incremental differences in economic and clinical outcomes were compared before and after parathyroidectomy in adult hemodialysis and peritoneal dialysis patients who received a parathyroidectomy in 2016 and 2017. RESULTS: The rate of parathyroidectomy per 1,000 person-years decreased from 6.5 (95% CI 6.2-6.8) in 2016 to 5.3 (95% CI 5.0-5.6) in 2018. The incremental increase in 12-month cost after versus before parathyroidectomy was $25,314 (95% CI $23,777-$27,078). By the second month after parathyroidectomy, 58% of patients had a corrected calcium level < 8.5 mg/dL. In the year after parathyroidectomy (versus before), hospitalizations increased by 1.4 per person-year (95% CI 1.3-1.5), hospital days increased by 12.1 per person-year (95% CI 11.2-13.0), dialysis visits decreased by 5.2 per person-year (95% CI 4.4-5.9), and office visits declined by 1.3 per person-year (95% CI 1.0-1.5). The incremental rate per 1,000 person years for hematoma/bleed was 224.4 (95% CI 152.5-303.1), for vocal cord paralysis was 124.6 (95% CI 59.1-232.1), and for seroma was 27.4 (95% CI 0.4-59.0). CONCLUSIONS: Parathyroidectomy was a relatively uncommon event in the hemodialysis and peritoneal dialysis populations. The incremental cost of parathyroidectomy was mostly attributable to the cost of the parathyroidectomy hospitalization. Hypocalcemia occurred in over half of patients, and calcium and phosphate levels were reduced. Clinicians, payers, and patients should understand the potential clinical and economic outcomes when considering parathyroidectomy.

Severe asthma exacerbations in the United States:: Incidence, characteristics, predictors, and effects of biologic treatments.

BACKGROUND: Patients with severe asthma (SA) have a heightened risk of exacerbations including hospitalization. The real-world, specialist-verified incidence and characteristics of exacerbations among patients with SA in the United States have not been described. OBJECTIVE: To describe the real-world incidence, characteristics, and predictors of exacerbations among patients with SA in the United States. METHODS: The CHRONICLE study is an ongoing observational study of specialist-treated adults with SA in the United States receiving biologic treatment or maintenance systemic corticosteroids or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled from February 2018 to February 2020, annualized rates and characteristics of exacerbation-related events were summarized by treatment category for 12 months before enrollment and after enrollment through the latest data collection. Results were further analyzed for subgroups of interest. RESULTS: Among 1884 enrolled patients, 53.5% and 12.3% experienced an exacerbation and asthma hospitalization, respectively (0.81 and 0.14 per person-year). Of all exacerbations, 36%, 9%, and 15% required an unscheduled health care provider visit, emergency department visit without hospitalization, and hospitalization, respectively. Among patients not receiving biologics or systemic corticosteroids, higher blood eosinophil count, higher fractional exhaled nitric oxide, and lower total immunoglobulin E level were associated with higher exacerbation rates. Exacerbation rates decreased after starting or switching biologics (n = 1299). Multivariate analyses of enrolled patients revealed previous-year exacerbations or hospitalizations, lack of asthma control, and the geographic region also predicted event risk. CONCLUSION: In this real-world cohort of specialist-treated adults with SA in the United States, there was a substantial burden of exacerbations and associated health care resource utilization. Patients receiving biologics had a lower exacerbation burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Clinical and economic burden of severe asthma among US patients treated with biologic therapies.

BACKGROUND: Patients with severe asthma may remain uncontrolled despite biologic therapy in addition to standard therapy, but this disease burden has not been quantified. OBJECTIVE: To estimate the clinical and economic burden in a US national sample. METHODS: Patients who have severe asthma with indicated biologic treatment (earliest use = index date) were selected from the MarketScan database between January 1, 2013, and June 30, 2018. Inclusion criteria were continuous enrollment for 12 months postindex with a minimum of 2 biologic fills, greater than or equal to 12 years of age, evidence of medium- to high-dose inhaled corticosteroids and long-acting ß-agonist combination before the index, and absence of other respiratory diagnoses and malignancies. Disease exacerbations (used to classify asthma control), health care costs, and treatment characteristics were reported during the 12-month postindex period. RESULTS: The sample included 3262 biologic patients; 88% with anti-immunoglobulin E therapy (omalizumab) and 12% non-anti-immunoglobulin E (reslizumab, mepolizumab, benralizumab). The mean age was 49 (±15) years; 64% were women. Prescriptions included inhaled corticosteroids and long-acting ß-agonist (82%), systemic corticosteroids (76%), and leukotriene receptor antagonists (68%). Notably, 63% of patients presented greater than or equal to 1 asthma exacerbation (mean 1.3 per patient/year). Furthermore, 35% of patients were categorized as having controlled asthma, whereas 28% were suboptimally controlled and 29% were uncontrolled. Patients with uncontrolled disease had higher all-cause and asthma-related costs ($69,206 and $45,693, respectively) than patients with suboptimally controlled ($59,407 and $40,793, respectively) or controlled disease ($53,083 and $38,393, respectively). Furthermore, 62% of newly treated patients were persistent with their index biologic. CONCLUSION: Biologic therapies are effective in reducing exacerbations, but a substantial proportion of patients with severe asthma treated with current biologics continue to experience uncontrolled disease, highlighting a remaining unmet need for patients with severe uncontrolled asthma.

Colorectal cancer screening and surveillance strategy for patients with Diamond Blackfan anemia: Preliminary recommendations from the Diamond Blackfan Anemia Registry.

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red cell failure, congenital anomalies, poor linear growth, and cancer predisposition. Two previous analyses from the Diamond Blackfan Anemia Registry have quantified DBA as a cancer predisposition syndrome of moderate cancer penetrance. Patients with DBA have a 4.8-fold higher relative risk of developing cancer with an overall cumulative incidence of 13.7% by age 45 years. The two most prevalent solid tumors are colorectal cancer (CRC) and osteogenic sarcoma. Current and evolving data support the institution of cancer screening and surveillance strategies for CRC in DBA.

EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.

Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing. Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.

Socioeconomic factors, stress, hair cortisol, and white matter microstructure in children.

Socioeconomic disadvantage has been linked to increased stress exposure in children and adults. Exposure to stress in childhood has been associated with deleterious effects on cognitive development and well-being throughout the lifespan. Further, exposure to stress has been associated with differences in brain development in children, both in cortical and subcortical gray matter. However, less is known about the associations among socioeconomic disadvantage, stress, and children's white matter development. In this study, we investigated whether socioeconomic disparities would be associated with differences in white matter microstructure in the cingulum bundle, as has been previously reported. We additionally investigated whether any such differences could be explained by differences in stress exposure and/or physiological stress levels. White matter tracts were measured via diffusion tensor imaging in 58 children aged 5-9 years. Results indicated that greater exposure to stressful life events was associated with higher child hair cortisol concentrations. Further, physiological stress, as indexed by hair cortisol concentrations, were associated with higher fractional anisotropy in the cingulum bundle. These results have implications for better understanding how perceived and physiological stress may alter neural development during childhood.

Material hardship, prefrontal cortex-amygdala structure, and internalizing symptoms in children.

Material hardship, or difficulty affording basic resources such as food, housing, utilities, and health care, increases children's risk for internalizing problems. The uncinate fasciculus (UNC) and two of the gray matter regions it connects-the orbitofrontal cortex (OFC) and amygdala-may play important roles in the neural mechanisms underlying these associations. We investigated associations among material hardship, UNC microstructure, OFC and amygdala structure, and internalizing symptoms in children. Participants were 5-9-year-old children (N = 94, 61% female) from socioeconomically diverse families. Parents completed questionnaires assessing material hardship and children's internalizing symptoms. High-resolution, T1-weighted magnetic resonance imaging (n = 51), and diffusion tensor imaging (n = 58) data were acquired. UNC fractional anisotropy (FA), medial OFC surface area, and amygdala gray matter volume were extracted. Greater material hardship was significantly associated with lower UNC FA, smaller amygdala volume, and higher internalizing symptoms in children, after controlling for age, sex, and family income-to-needs ratio. Lower UNC FA significantly mediated the association between material hardship and internalizing symptoms in girls but not boys. These findings are consistent with the notion that material hardship may lead to altered white matter microstructure and gray matter structure in neural networks critical to emotion processing and regulation.

Real World Use and Effects of Calcimimetics in Treating Mineral and Bone Disorder in Hemodialysis Patients.

BACKGROUND: Calcimimetics are used to treat mineral and bone disorder by reducing parathyroid hormone (PTH), calcium (Ca), and phosphorus (Phos). The study objectives were to assess the control of PTH, Ca, and Phos over time in patients receiving cinacalcet or etelcalcetide as well as dosing and time to discontinuation for etelcalcetide. METHODS: This was a retrospective cohort study using electronic medical records from small and independent dialysis centers. Adults ≥18 years of age were identified as cinacalcet or etelcalcetide users based on the first calcimimetic received in 2018 (index date). Patients were followed from the index date until parathyroidectomy, kidney transplant, death, or end of data (December 31, 2018). Analyses of mean PTH, Ca, and Phos, as well as target achievement of PTH, Ca, and Phos were conducted over a 9-month period. Discontinuation with etelcalcetide was measured with the Kaplan-Meier estimator. RESULTS: There were 1,346 cinacalcet patients (mean age 60.5 years, 43.5% female, and 47.1% Black) and 1,255 etelcalcetide patients (mean age 63.4 years, 46.6% female, and 38.5% Black). At baseline, the proportions in target were similar for etelcalcetide versus cinacalcet: 36 versus 38% for PTH, 79 versus 80% for Ca, and 43 versus 44% for Phos. Overall, 40-47% of cinacalcet users and 48-62% of etelcalcetide users were observed to be in target for PTH over 9 months. The proportion in target for Phos ranged from 41 to 46% for cinacalcet and 46-51% for etelcalcetide. The proportion in target for Ca ranged from 74 to 78% for cinacalcet and 60-73% for etelcalcetide. Etelcalcetide 12-month discontinuation was 37.4%. CONCLUSION: Both calcimimetics were effective in keeping PTH, Ca, and Phos levels within target. Patients receiving etelcalcetide tended to have lower laboratory values for PTH, Ca, and Phos over time, while patients receiving cinacalcet tended to be more likely to be in target for Ca over time.

Infants of mothers with higher physiological stress show alterations in brain function.

Chronic stress has been increasingly linked with aberrations in children's behavioral, cognitive, and social development, yet the effect of chronic physiological stress on neural development during the first year of life is largely unknown. The present study aims to link a physiological index of chronic stress (maternal hair cortisol concentration) to maturational differences in infant functional brain development during the first year of life. Participants were 94 mother-infant dyads. To index chronic physiological stress, maternal hair samples were assayed for the previous three months' cortisol output. To examine the development of brain function during the first year of life, six-to-twelve-month-old infants (N = 94) completed a resting electroencephalography (EEG) recording. Infants of mothers with evidence of higher physiological stress showed increased relative low-frequency (theta) power and reduced relative high-frequency (alpha, high-gamma) power, compared to infants of mothers with evidence of low physiological stress. This pattern of findings is consistent with other studies suggesting that early life stress may lead to alterations in patterns of infant brain development. These findings are important given that maturational lags in brain development can be long-lasting and are associated with deficits in cognitive and emotional development. The present research also suggests that reducing maternal physiological stress may be a useful target for future interventions aiming to foster neurodevelopment during the first year of life.

Adapting the stage-based model of personal informatics for low-resource communities in the context of type 2 diabetes.

Growing availability of self-monitoring technologies creates new opportunities for collection of personal health data and their use in personalized health informatics interventions. However, much of the previous empirical research and existing theories of individuals' engagement with personal data focused on early adopters and data enthusiasts. Less is understood regarding ways individuals from medically underserved low-income communities who live with chronic diseases engage with self-monitoring in health. In this research, we adapted a widely used theoretical framework, the stage-based model of personal informatics, to the unique attitudes, needs, and constraints of low-income communities. We conducted a qualitative study of attitudes and perceptions regarding tracking and planning in health and other contexts (e.g., finances) among low-income adults living with type 2 diabetes. This study showed distinct differences in participants' attitudes and behaviors around tracking and planning, as well as wide variability in their sense of being in charge of different areas of one's life. Ultimately, we found a strong connection between these two: perceptions of being in charge seems to be strongly connected to an individual's proactive or reactive tracking and planning in that area. Whereas individuals with a greater sense of being in charge of their health were more proactive, meaning they were likely to engage with all the stages of personal informatics model on their own, those with less of a sense of being in charge were more likely to be reactive-relying on their healthcare providers for several critical stages of self-monitoring (deciding what data to collect, integrating data from multiple sources, reflecting over patterns in collected data, and arriving at conclusions and implications for action). Perhaps as a result, these individuals were less likely to experience increases in self-awareness and self-knowledge, common motivating factors to engaging in self-monitoring in the future. We argue that adapting this framework in a way that highlights gaps in individuals' engagement has a number of important implications for future research in biomedical informatics and for the design of new interventions that promote engagement with self-monitoring, and that are robust in light of fragmented engagement.

Evaluating the Psychometric Properties of the Migraine Functional Impact Questionnaire (MFIQ).

BACKGROUND: Migraine is a chronic neurologic disease that can be associated with significant migraine-related impact, disability, and burden. Patient-reported outcome measures (PRO) are included in clinical trials of migraine interventions to capture treatment effects from a patient perspective. Clinical and regulatory guidelines also encourage use of PROs in trials. The Migraine Functional Impact Questionnaire (MFIQ) is a novel PRO measure, assessing the impact of migraine on Physical Function (PF), Usual Activities (UA), Social Function (SF), and Emotional Function (EF), in the past 7 days. Scientific methods recommended to meet the requirements of the U.S. Food and Drug Administration were followed, to ensure that the MFIQ content included outcomes that were relevant to adults with migraine and were clinically relevant, specifically to evaluate preventive treatments for migraine. OBJECTIVE: The objective of this study was to conduct item analyses informing item reduction and scoring, and to evaluate the psychometric properties of the MFIQ. METHODS: In a prospective, observational study, adults with migraine completed the MFIQ as well as additional clinical and PRO instruments, including the Headache Impact Test (HIT-6TM ), Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS-PF), Migraine-Specific Quality-of-Life Questionnaire (MSQ), and Patient Global Rating of Change (PGIC). Item-level evaluation, item response theory (IRT), and factor analysis were used to select final MFIQ items, identify domains, and inform scoring. Psychometric properties of the MFIQ were evaluated to assess reliability (internal consistency and test-retest), validity (construct and known-groups), and responsiveness. RESULTS: The study enrolled 569 adults with migraine. Subjects had an average age of 39.9 years (SD 12.0), 87.2% were female, and 80.8% were white. Five items were dropped from the draft version based on results of item-level analyses reviewed in the context of previous qualitative research to produce the final 26-item MFIQ (v.2). Four domain scores (PF, UA, SF, and EF) and a global item score for impact on UA were identified. Higher scores on a 0-100 scale represent greater impact. All scores exhibited high internal consistency (α ≥ 0.89) and moderate test-retest reliability among stable subjects (ICCs ≥ 0.47). Construct validity was demonstrated by significant correlations (all P < .0001) between MFIQ domain scores, related PRO scores, and the frequency of migraine days and headache days. All domain scores differentiated between subgroups ("known groups") defined based on established levels of clinical severity: number of monthly migraine and headache days, migraine interference levels and scores on other PRO instruments (P < .05). Improvements in MFIQ scores corresponded with clinical improvement (percent reduction in monthly migraine days), improvement in migraine interference with daily activities, and related improvements in PRO scores (P < .05), demonstrating that the MFIQ was responsive to changes in migraine impact. CONCLUSIONS: The MFIQ is a reliable and valid measure that can be used to collect data about migraine impact. The MFIQ is being used to evaluate outcomes of migraine interventions in clinical trials and observational studies. It could potentially also be used in clinical practice both for initial and ongoing assessments for monitoring outcomes and to enhance communication between patients and healthcare professionals for the management of migraine.

The functions of store-operated calcium channels.

Store-operated calcium channels provide calcium signals to the cytoplasm of a wide variety of cell types. The basic components of this signaling mechanism include a mechanism for discharging Ca2+ stores (commonly but not exclusively phospholipase C and inositol 1,4,5-trisphosphate), a sensor in the endoplasmic reticulum that also serves as an activator of the plasma membrane channel (STIM1 and STIM2), and the store-operated channel (Orai1, 2 or 3). The advent of mice genetically altered to reduce store-operated calcium entry globally or in specific cell types has provided important tools to understand the functions of these widely encountered channels in specific and clinically important physiological systems. This review briefly discusses the history and cellular properties of store-operated calcium channels, and summarizes selected studies of their physiological functions in specific physiological or pathological contexts. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

Synthesis and Evaluation of a Novel 64Cu- and 67Ga-Labeled Neurokinin 1 Receptor Antagonist for in Vivo Targeting of NK1R-Positive Tumor Xenografts.

Neurokinin 1 receptor (NK1R) is expressed in gliomas and neuroendocrine malignancies and represents a promising target for molecular imaging and targeted radionuclide therapy. The goal of this study was to synthesize and evaluate a novel NK1R ligand (NK1R-NOTA) for targeting NK1R-expressing tumors. Using a carboxymethyl moiety linked to L-733060 as a starting reagent, NK1R-NOTA was synthesized in a three-step reaction and then labeled with 64Cu (or 67Ga for in vitro studies) in the presence of CH3COONH4 buffer. The radioligand affinity and cellular uptake were evaluated with NK1R-transduced HEK293 cells (HEK293-NK1R) and NK1R nontransduced HEK293 cells (HEK293-WT) and their xenografts. Radiolabeled NK1R-NOTA was obtained with a radiochemical purity of >95% and specific activities of >7.0 GBq/µmol for 64Cu and >5.0 GBq/µmol for 67Ga. Both 64Cu- and 67Ga-labeled NK1R-NOTA demonstrated high levels of uptake in HEK293-NK1R cells, whereas co-incubation with an excess of NK1R ligand L-733060 reduced the level of uptake by 90%. Positron emission tomography (PET) imaging showed that [64Cu]NK1R-NOTA had a accumulated rapidly in HEK293-NK1R xenografts and a 10-fold lower level of uptake in HEK293-WT xenografts. Radioactivity was cleared by gastrointestinal tract and urinary systems. Biodistribution studies confirmed that the tumor-to-organ ratios were ≥5 for all studied organs at 1 h p.i., except kidneys, liver, and intestine, and that the tumor-to-intestine and tumor-to-kidney ratios were also improved 4 and 20 h post-injection. [64Cu]NK1R-NOTA is a promising ligand for PET imaging of NK1R-expressing tumor xenografts. Delayed imaging with [64Cu]NK1R-NOTA improves image contrast because of the continuous clearance of radioactivity from normal organs.

Direct and Indirect Healthcare Resource Utilization and Costs Among Migraine Patients in the United States.

OBJECTIVE: The goal of this analysis was to provide a contemporary estimate of the burden of migraine, incorporating both direct and indirect costs, by comparing the costs of migraine patients to a matched group of patients without migraine in a large, nationally representative sample of commercially insured patients in the United States. BACKGROUND: Previous studies have shown that the economic burden of migraine in the United States is substantial for payers, patients, and employers. Despite the availability of multiple acute and preventive pharmacological treatment options and a relatively stable migraine prevalence in the United States, there has been a documented increase in migraine-related healthcare resource and pharmacy use. Given the frequently disabling nature of migraine and its high prevalence, especially during peak productive years, and the lack of recent estimates of the burden of migraine, there is a need to update the existing literature with more current data. METHODS: This retrospective, observational cohort study identified migraine patients in the Truven Health Market Scan Research Databases between January 2008 and June 2013. Adult patients had 12 months of continuous enrollment before (baseline period) and after (follow-up period) the day they received migraine diagnoses and/or medications (index) and no diagnosis of HIV or malignancy during the study period. The patients with migraine were matched 1:1 to a group of patients without migraine on demographic variables and index date. Direct healthcare utilization and costs and indirect (absenteeism, short-term disability, and long-term disability) costs were assessed during the 12-month follow-up period and differences between patients with vs without migraine were assessed. Two additional multivariable logistic regression analyses were conducted. First, an analysis was conducted comparing the odds of having a short-term disability claim between patients with and without migraine after controlling for patient demographic and clinical characteristics. A second analysis, conducted among the migraine patients only, compared the odds of having a short-term disability claim between (1) patients treated with acute or preventive migraine medications only during the baseline period and patients with no migraine treatment during baseline and (2) patients treated with both acute and preventive migraine medications during the baseline period and patients with no migraine treatment during baseline, after controlling for patient demographic and clinical characteristics. RESULTS: Migraine patients had total annual direct plus indirect costs that were $8924 (in 2014 United States dollars) higher than those of demographically similar individuals without evidence of migraine. Migraine patients' mean annual direct all-cause healthcare costs were $6575 higher than those of matched patients without migraine ($11,010 [standard deviation = $19,663] vs $4436 [standard deviation=$13,081]; P < .01). Total mean annual indirect costs were $2350 higher in the migraine cohort than in the matched no migraine patients ($11,294 vs $8945. Migraine patients were 2.0 times more likely as their nonmigraine counterparts to use opioids (45.5% vs 21.9%; P < .01) and among patients with opioid prescriptions, migraine patients had 1.8 times the number of opioid prescriptions per patient than did those without migraine (4.9 [standard deviation = 6.9] vs 2.7 [standard deviation = 4.0]; P < .01). After adjusting for baseline demographic and clinical characteristics, migraine patients treated with either acute or preventive migraine medications (odds ratio = 0.81 [95% confidence interval = 0.72-0.91]; P < .01) or both acute and preventive migraine medications during the baseline period (odds ratio = 0.93 [95% confidence interval = 0.89-0.98]; P < .01) were significantly less likely to have short-term disability claims than untreated patients during the follow-up period (Migraine patients with either acute or preventive medications only: 7290/45,632 [16.0%]; with both acute and preventive medications: 3085/14,941 [20.6%]; untreated patients: 1604/11,169 [14.4%] had a short-term disability claim.) However, overall, migraine patients had 1.94 times the odds of having a short-term disability claim than their matched counterparts (95% confidence interval = 1.83-2.05; P < .01; migraine patients: 11,979/71,742 [16.7%]; nonmigraine patients: 4801/71,742 [6.7%] had a short-term disability claim). CONCLUSIONS: Results from this real-world assessment of the economic burden of migraine suggest that migraine imposes a substantial direct and indirect cost burden in the United States. Compared to matched nonmigraine patients, migraine patients were more likely to have work loss and longer periods of work loss, leading to significantly higher indirect costs. Migraine patients also had higher levels of healthcare utilization, despite the relatively stable prevalence of migraine and the available acute and preventive treatment options for migraine management.

Development of a New Tool for Evaluating the Benefit of Preventive Treatments for Migraine on Functional Outcomes - The Migraine Functional Impact Questionnaire (MFIQ).

OBJECTIVE: The objective of this study was to develop a method for evaluating patient-relevant outcomes of interventions for preventing migraine attacks, followed by an assessment of the content validity of a new patient-reported outcome (PRO) instrument: the Migraine Functional Impact Questionnaire (MFIQ). BACKGROUND: The aim of preventive treatments for migraine is not only to reduce migraine frequency, but also to restore patients' ability to function and improve quality of life. METHODS: A multi-stage process based on best practice methods and regulatory guidelines for ensuring content validity of PRO instruments for evaluating treatment benefit was followed. Qualitative concept elicitation interviews conducted to understand the experiences of adults with migraine underpinned the development of the instrument. The initial stage included the development of a conceptual disease model (CDM) based on information from these interviews. This CDM was used to identify the concepts of interests (COI) to evaluate outcomes of preventive treatments. The results of the interviews were also used in stage 2, to develop a measurement framework for collecting data about these COI. In the third stage, existing instruments were reviewed for coverage of the concepts in the framework and evidence of concept elicitation to the point of saturation, to support content validity. In the fourth stage, an instrument was drafted to evaluate concepts in the framework, based on the qualitative data collected from the interviews. Following a review by clinical and translation experts, the new instrument was tested in adults with migraine in the fifth stage using 2 rounds of cognitive interviews, and was modified based on interview feedback. In the last stage, the instrument was linguistically adapted, using methods recommended for PRO instruments, to ensure conceptual equivalence of language versions for use in international studies. Each language version was tested in at least 5 native speakers using cognitive interviews. RESULTS: Results from the concept elicitation interviews suggested that migraine had an impact on various aspects of functioning. A conceptual framework for evaluating functional outcomes was developed for the concept selected based on a review of the CDM - physical and emotional functioning, every day activities, and social/leisure activities. Existing PROs lacked coverage of some concepts in the conceptual framework, had recall periods that were inappropriate for capturing the experience of COI or did not have evidence of content validity. A novel PRO instrument, the MFIQ, was developed to address these gaps. Cognitive interviews with 9 adults with migraine resulted in minor changes to the items of the MFIQ, and a final round of 8 interviews confirmed the changes were acceptable and supported its validity. The interviews conducted to test linguistic adaptations confirmed conceptual equivalence in the 25 countries evaluated. CONCLUSIONS: Development of the MFIQ followed best measurement practices to ensure content validity and followed regulatory guidelines for PRO instruments to evaluate benefits of treatments. The MFIQ was developed for use in clinical trials or clinical practice settings to track outcomes of preventive treatments that are most relevant to adults with migraine.

Improving Medical Communication in Migraine Management: A Modified Delphi Study to Develop a Digital Migraine Tracker.

OBJECTIVE: This study aimed to identify the essential content and amount of information to be collected from people with migraine via a patient-facing smartphone-based migraine tracker for them to share with clinicians during live discussions to assist in optimizing migraine management. The proposed tracker is intended for use in non-interventional research to evaluate disease burden in episodic migraine and chronic migraine patients as assessed by demographic and clinical characteristics and health resource utilization in an integrated delivery network setting. The proposed tracker is not intended for commercial purposes. BACKGROUND: Epidemiological studies suggest migraine is underdiagnosed and undertreated. Studies of patient-clinician interactions suggest that effective medical communication may help address these issues. METHODS: Four migraine practice leaders, an epidemiologist with extensive migraine experience, and a measurement expert took part in a modified Delphi panel process to identify data elements that could be collected from people with migraine through a smartphone-based migraine tracker. Importantly, the proposed tracker would not be intended to replace the patient-clinician encounter but to support the encounter through enabling the patient to document migraine symptoms and experiences in a timely and accurate manner for sharing with a clinician as part of a broader face-to-face discussion. The panel reviewed questions derived from the existing migraine diaries in the public domain, those used in clinical trials, and patient-centric surveys assessing the impact of migraine on physical function and other related concepts. Key considerations included identification of the most clinically useful data elements for a shared communication tool for people with migraine under the care of a clinician. The panel also identified numerous functionality requirements for such a tool and provided recommendations on the most effective way to present results to a clinician. RESULTS: The expert panel opined that people with migraine may value the ability to capture a relatively broad range of information for their own migraine-tracking purposes, while clinicians will likely find greater value in a small set of data relevant to the management of migraine. The panel identified the 3 most essential concepts in categories of data for a clinician, for which they coined the term "The 3 Fs": Frequency of days with headache; Frequency of acute medication usage; and Functional impairment. Information on the frequency of days with headache was felt to combine with the information on the frequency of acute medication usage to provide essential insights into current migraine management strategy and its outcomes, and to assist considerations of preventive measures. Functional impairment was treated as an effective surrogate for headache severity and was assessed based on the following: degree of difficulty in performing activities of daily living, impact on absenteeism (taking leave from work or cancelling/avoiding other activities) and presenteeism (performing work or other daily activities, with reduced productivity/capability), and amount of rest required as a result of a migraine attack. The modified Delphi panel process resulted in the selection of 13 questions in 8 categories to elicit sufficient and meaningful data comprising headache occurrence, symptoms, daily/preventive and as-needed/acute medication usage, triggers, ability to concentrate, and functional impairment. The panel also agreed that the tracker should generate 2 distinct reports: one for people with migraine that would include a wider range of data about symptoms and perceived triggers, and a targeted report for the clinician that would place prime emphasis on the 3 Fs for aggregating the results of each headache occurrence and the trend over time. CONCLUSIONS: A system that easily captures critical data elements about migraine, with specific feedback displays for patients to share with clinicians during live discussions, may offer some benefit to people with migraine and their clinicians by facilitating more objective communication and optimizing management. The tracker's output may enable people with migraine to track a wide range of data for their own purposes, allowing them to better understand their condition, while a synthesized view of the selected data may support more informed clinical decision-making for the clinician and individualized, evidence-based discussion with the patient. As a result, this shared decision-making tool may enable patients to more accurately convey essential migraine information during live patient-clinician discussions to drive improved management and patient outcomes.