Identification and management of pediatric venous thromboembolism in the emergency department.

Although the incidence of pediatric venous thromboembolism is increasing, it is often overlooked in children due to the overall low incidence. This issue reviews the epidemiology of pediatric venous thromboembolism, including the factors that have led to its increasing prevalence, and discusses the physiology of hemostasis and coagulation. Key features of the history and physical examination, as well as identification of risk factors, are reviewed, as these have the most diagnostic value for venous thromboembolism in pediatric patients. Recommendations are also provided for diagnostic testing and management in the emergency department.

Differences in Home Health Services and Outcomes Between Traditional Medicare and Medicare Advantage.

Importance: Private Medicare Advantage (MA) plans recently surpassed traditional Medicare (TM) in enrollment. However, MA plans are facing scrutiny for burdensome prior authorization and potential rationing of care, including home health. MA beneficiaries are less likely to receive home health, but recent evidence on differences in service intensity and outcomes among home health patients is lacking. Objective: To examine differences in home health service intensity and patient outcomes between MA and TM. Design, Setting, and Participants: This cross-sectional study was conducted from January 2019 to December 2022 in 102 home health locations in 19 states and included 178 195 TM and 107 102 MA patients 65 years or older with 2 or fewer 60-day home health episodes. It included a secondary analysis of standardized assessment and visit data. Inverse probability of treatment weighting regression compared service intensity and patient outcomes between MA and TM episodes, accounting for differences in demographic characteristics, medical complexity, functional and cognitive impairments, social environment, caregiver support, and local community factors. Models included office location, year, and reimbursement policy fixed effects. Data were analyzed between September 2023 and July 2024. Exposure: TM vs MA plan. Main Outcomes and Measures: Home health length of stay and number of visits from nursing, physical, occupational, and speech therapy, social work, and home health aides. Patient outcomes included improvement in self-care and mobility function, discharge to the community, and transfer to an inpatient facility during home health. Results: Of 285 297 total patients, 180 283 (63.2%) were female; 586 (0.2%) were American Indian/Alaska Native, 8957 (3.1%) Asian, 28 694 (10.1%) Black, 7406 (2.6%) Hispanic, 1959 (0.7%) Native Hawaiian/Pacific Islander, 237 017 (83.1%) non-Hispanic White, and 678 (0.2%) multiracial individuals. MA patients had shorter home health length of stay by 1.62 days (95% CI, -1.82 to 1.42) and received fewer visits from all disciplines except social work. There were no differences in inpatient transfers. MA patients had 3% and 4% lower adjusted odds of improving in mobility and self-care, respectively (mobility odds ratio [OR], 0.97; 95% CI, 0.94-0.99; self-care OR, 0.96; 95% CI, 0.92-0.99). MA patients were 5% more likely to discharge to the community compared with TM (OR, 1.05; 95% CI, 1.01-1.08). Conclusions and Relevance: The results of this cross-sectional study suggest that MA patients receive shorter and less intensive home health care vs TM patients with similar needs. Differences may be due to the administrative burden and cost-limiting incentives of MA plans. MA patients experienced slightly worse functional outcomes but were more likely to discharge to the community, which may have negative implications for MA patients, including reduced functional independence or increased caregiver burden.

Palbociclib Adherence and Persistence in Patients with Hormone Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Metastatic Breast Cancer.

Purpose: To assess adherence and persistence with palbociclib therapy in patients with HR+/HER2- metastatic breast cancer (mBC) in a US real-world setting. Methods: This retrospective study evaluated palbociclib dosing, adherence, and persistence using commercial and Medicare Advantage with Part D claims data from the Optum Research Database. Adult patients with mBC who had continuous enrollment 12 months prior to mBC diagnosis and initiated first-line palbociclib with aromatase inhibitor (AI) or fulvestrant between 02/03/2015 and 12/31/2019 were included. Demographic and clinical characteristics, palbociclib dosing and dose changes, adherence (medication possession ratio [MPR]), and persistence were measured. Adjusted logistic and Cox regression models were used to examine demographic and clinical factors associated with adherence and discontinuation. Results: Patients (n = 1066) with a mean age of 66 years were included; 76.1% received first-line palbociclib+AI and 23.9% palbociclib+fulvestrant. Most patients (85.7%) initiated palbociclib at 125 mg/day. Of the 34.0% of patients with a dose reduction, 82.6% reduced from 125 to 100 mg/day. Overall, 80.0% of patients were adherent (MPR), and 38.3% discontinued palbociclib during a mean (SD) follow-up of 16.0 (11.2) and 17.4 (13.4) months, for palbociclib+fulvestrant and palbociclib+AI, respectively. Annual income below $75,000 was significantly associated with poor adherence. Older age (age 65-74 years (hazard ratio [HR] 1.57, 95% CI, 1.06, 2.33), age ≥75 years (HR 1.61, 95% CI: 1.08, 2.41)) and bone-only metastatic disease (HR 1.37, 95% CI, 1.06, 1.76) were significantly associated with palbociclib discontinuation. Conclusion: In this real-world study, >85% of patients started palbociclib at 125 mg/day and 1 in 3 had dose reductions during the follow-up. Patients were generally adherent and persistent with palbociclib. Older age, bone-only disease, and low-income levels were associated with early discontinuation or non-adherence. Further studies are needed to understand the associations of clinical and economic outcomes with palbociclib adherence and persistence.

Types of Partner Violence in Couples Affected by Incarceration: Applying Johnson's Typology to Understand the Couple-level Context for Violence.

In prior research, samples of incarcerated and reentering men and their partners report partner violence at roughly 10 times the frequency found in the general population. The relationship dynamics underlying these experiences remain poorly understood. Addressing this gap and expanding prior applications of Johnson's typology in other populations-which typically rely on survey data alone and include reports from just one member of a couple-we applied latent class analysis with dyadic survey data from 1,112 couples to identify types of partner violence in couples affected by incarceration. We assessed congruence between quantitative types and couples' qualitative accounts and compared the two major types using two-sample t-tests.In some couples, one partner used various tactics to systematically dominate and control the other, as in Johnson's coercive controlling violence. In others, physical violence arose in the context of jealousy but no other controlling behavior. This type resembled Johnson's situational couple violence. Qualitative data suggested that jealousy represented a common, situational response to periods of prolonged separation, relationship instability, status insecurity, and partnership concurrence and not a tactic of control per se. Victims of coercive controlling violence experienced more PTSD symptoms and felt less safe in their relationships than victims of jealous-only violence. Perpetrators of coercive controlling violence were more likely to use severe physical violence against their partners than perpetrators of jealous-only violence. Findings indicate that broader context is critical for interpreting the presence of jealousy (and whether it constitutes a control tactic). They indicate that prevention and response strategies tailored to these types could help couples cope safely with the extreme relationship stressors of incarceration and reentry. Finally, they suggest a need to move from an exclusive focus on individual accountability and services toward a model that also incorporates institutional accountability and change.

Medicaid Expansion and Racial and Ethnic Disparities in Access to Health Care: Applying the National Academy of Medicine Definition of Health Care Disparities.

Since 2014, 32 states implemented Medicaid expansion by removing the categorical criteria for childless adults and by expanding income eligibility to 138% of the federal poverty level (FPL) for all non-elderly adults. Previous studies found that the Affordable Care Act (ACA) Medicaid expansion improved rates of being insured, unmet needs for care due to cost, number of physician visits, and health status among low-income adults. However, a few recent studies focused on the expansion's effect on racial/ethnic disparities and used the National Academy of Medicine (NAM) disparity approach with a limited set of access measures. This quasi-experimental study examined the effect of Medicaid expansion on racial/ethnic disparities in access to health care for U.S. citizens aged 19 to 64 with income below 138% of the federal poverty line. The difference-in-differences model compared changes over time in 2 measures of insurance coverage and 8 measures of access to health care, using National Health Interview Survey (NHIS) data from 2010 to 2016. Analyses used the NAM definition of disparities. Medicaid expansion was associated with significant decreases in uninsured rates and increases in Medicaid coverage among all racial/ethnic groups. There were differences across racial/ethnic groups regarding which specific access measures improved. For delayed care and unmet need for care, decreases in racial/ethnic disparities were observed. After the ACA Medicaid expansion, most access outcomes improved for disadvantaged groups, but also for others, with the result that disparities were not significantly reduced.

Prevalence of Obstructive Sleep Apnea Risk According to the STOP-BANG Questionnaire in an Oral Surgery Office-Based Anesthesia Patient Population.

PURPOSE: Patients with obstructive sleep apnea (OSA) are at an increased risk for perioperative and postoperative complications after receiving intravenous (IV) sedation or postoperative analgesia. We previously showed that most oral and maxillofacial surgery (OMS) providers do not screen for OSA using a quantifiable method. The purpose of this study was to determine the prevalence of OSA risk in the OMS office-based anesthesia patient population using the snoring, tiredness, observed apnea, high blood pressure, body mass index, age, neck circumference, and gender (STOP-BANG) questionnaire. PATIENTS AND METHODS: After deeming patients (n = 153) suitable for outpatient IV sedation using our existing institutional ambulatory preanesthesia protocol, 2 OMS providers administered the STOP-BANG questionnaire to classify patient risk for OSA. The questionnaire is a concise, validated predictor for OSA risk and consists of 8 yes or no questions. RESULTS: Of the 153 patients, 141 (92.16%) were at a low risk for moderate to severe OSA, 11 (7.19%) were at a moderate risk, and 1 (0.65%) was at a high risk. Overall, 12 (7.84%) patients were shown to be at risk for OSA. We estimate with 95% confidence that between 5.7 and 10% of all OMS office-based anesthesia patients are at risk for OSA. The IV sedation plans for 4 (2.61%) patients were changed after including OSA risk with the existing preanesthesia protocol. CONCLUSIONS: A statistically significant proportion (95% confidence interval, 0.0567 to 0.100) of the OMS office-based anesthesia patient population is at an increased risk for moderate to severe OSA. These results outline the importance of screening for OSA before office-based anesthesia administration. OMS providers can easily use the STOP-BANG questionnaire to assess OSA risk, modify anesthesia management, and improve patient safety.

Real-World Costs of Adverse Events in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer in the United States. Immunotherapies and cytotoxic chemotherapies used to treat advanced NSCLC carry a substantial risk of adverse events (AEs), but real-world data on the incidence and costs associated with the unique AE profiles of these treatments are sparse. OBJECTIVE: To examine the AE incidence and costs among patients initiating non-driver mutation-targeted first-line therapy for metastatic NSCLC (mNSCLC) in clinical practice. METHODS: This was a retrospective administrative claims study conducted among commercial and Medicare Advantage health plan members who initiated first-line, nontargeted systemic anti-NSCLC therapy between January 1, 2008, and February 28, 2018. Patients were assigned to mutually exclusive treatment cohorts (cytotoxic chemotherapy [CHEM], immuno-oncology agents [IO], or immuno-oncology + cytotoxic chemotherapy [IO-CHEM]) and were observed from the index date (start of first-line therapy) through the earliest of health plan disenrollment, death, or March 31, 2018. AE incidence rates and associated health care costs were measured from the index date through the earliest of the start of a new therapy, 180 days after the end of first-line therapy, or the end of the study period. The factors influencing whether patients incurred high AE-related health care costs were assessed using multivariable models adjusted for patient demographic and clinical characteristics. RESULTS: The final study population (mean [SD] age 68.6 [9.5] years, 53.9% male) included 8,818 in the CHEM cohort, 482 in the IO cohort, and 412 in the IO-CHEM cohort. Overall, 74.4% had at least 1 AE during follow-up. The AE incidence rate was lowest for the IO cohort, with incidence rate ratios (95% CI) of 1.4 (1.3-1.6) for the CHEM cohort and 1.4 (1.2-1.6) for the IO-CHEM cohort. Mean AE-related costs were lowest for the IO cohort ($16,319) and highest for the CHEM cohort ($23,009; P < 0.001). In the multivariable analysis, the odds of incurring any AE costs were similar for the IO and IO-CHEM cohorts compared with the CHEM cohort (OR = 0.82; P = 0.135 and OR = 0.98; P = 0.888, respectively). Among patients who incurred AE costs, those in the IO cohort were less likely than those in the CHEM cohort to have high costs (OR = 0.60; P = 0.030); the difference between the IO-CHEM and CHEM cohorts was not statistically significant. CONCLUSIONS: Among real-world patients initiating nontargeted first-line therapy for mNSCLC, those receiving immunotherapy experienced fewer AEs and had lower total AE-related costs than those treated with cytotoxic chemotherapy. Immunotherapy-treated patients were no more likely than chemotherapy-treated patients to incur AE-related costs and were less likely to have high AE costs if they incurred any at all. These findings indicate that immunotherapy-related AEs are not a differentiating factor in cost of care for this patient population in clinical practice. DISCLOSURES: This study was sponsored by AstraZeneca. Ryan is an employee of AstraZeneca. Engel-Nitz, Johnson, and Bunner are employees of Optum, which was contracted by AstraZeneca to conduct this study, and shareholders in UnitedHealth Group. Engel-Nitz has also worked on cancer-related studies for which Optum received funding from Bayer AG, Clovis Oncology, Eli Lilly, EMD Serono, Exact Sciences, Janssen, and Novartis. Johnson worked on cancer-related studies for which Optum received funding from Eli Lilly, Medtronic, Sanofi, and UnitedHealthcare. Bunner has worked on cancer-related studies for which Optum received funding from Celgene and Incyte.

PET ligands [18F]LSN3316612 and [11C]LSN3316612 quantify O-linked-ß-N-acetyl-glucosamine hydrolase in the brain.

We aimed to develop effective radioligands for quantifying brain O-linked-ß-N-acetyl-glucosamine (O-GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer's disease, by O-GlcNAc through the enzyme pair OGA and O-GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau O-GlcNAcylation by OGA inhibition is believed to reduce tau aggregation. LSN3316612, a highly selective and potent OGA ligand [half-maximal inhibitory concentration (IC50) = 1.9 nM], emerged as a lead ligand after in silico analysis and in vitro evaluations. [3H]LSN3316612 imaged and quantified OGA in postmortem brains of rat, monkey, and human. The presence of fluorine and carbonyl functionality in LSN3316612 enabled labeling with positron-emitting fluorine-18 or carbon-11. Both [18F]LSN3316612 and [11C]LSN3316612 bound reversibly to OGA in vivo, and such binding was blocked by pharmacological doses of thiamet G, an OGA inhibitor of different chemotype, in monkeys. [18F]LSN3316612 entered healthy human brain avidly (~4 SUV) without radiodefluorination or adverse effect from other radiometabolites, as evidenced by stable brain total volume of distribution (VT) values by 110 min of scanning. Overall, [18F]LSN3316612 is preferred over [11C]LSN3316612 for future human studies, whereas either may be an effective positron emission tomography radioligand for quantifying brain OGA in rodent and monkey.

Economic impact of cardiac implantable electronic device infections: cost analysis at one year in a large U.S. health insurer.

Aims: Cardiac device infections (CDIs) are serious adverse events associated with morbidity and mortality, significant costs and increased healthcare utilization. The objective of the current study was to characterize the CDI rate by device type, risk factors for infection and healthcare costs from a large U.S. health insurer perspective.Materials and Methods: A retrospective analysis of a large U.S. health insurer database identified commercial and Medicare Advantage with Part D (MAPD) members ≥18 years with ≥1 claim for a cardiac implantable electronic device (CIED) procedure between 01 October 2011 and 31 October 2015. CIEDs included pacemakers (IPG), implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy - pacemakers without (CRT-P) and with defibrillation (CRT-D). Probabilities of CDI through one-year post implant were estimated using the Kaplan-Meier method. A regression model with stepwise variable selection was used to select risk factors associated with CDIs.Results: A total of 63,406 patients were included with an overall CDI rate of 1.28% (1.0% de novo and 1.74% replacement devices), varying by device type: IPG = 0.91%; ICD = 1.63%; CRT-p = 1.50%; CRT-D = 2.22%. The average adjusted annual medical costs were 2.4 times greater [95% confidence interval (CI) = 2.1-2.7] for those with an infection compared to those without, and the incremental cost difference was estimated to be $57,322 [95% CI $46,572-$70,484]. Observed risk factors of CDIs included prior device infection [Odds ratio (OR) = 11.356; 95% CI = 7.923-16.276], undergoing a CIED replacement procedure (OR = 1.644; 95% CI = 1.361-1.987), implantation of a high-power device (OR = 1.354; 95% CI = 1.115-1.643), and younger age (age < 65) (OR = 1.607; 95% CI = 1.307-1.976).Conclusions: The CDI rate at one year ranged from 0.91%-2.22% depending on device type. Management of CDIs among commercial and MAPD members is associated with high healthcare expenditures.

Healthcare resource utilization and costs in patients with HIV-1 who switched first-line antiretroviral therapy.

Objectives: This study compared healthcare utilization and costs associated with switching the first-line protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) based antiretroviral (ARV) regimen due to reasons other than virologic failure among patients with HIV-1. Methods: This was a retrospective analysis of commercial and Medicare Advantage with Part D enrollees in two US administrative claims databases. The study population comprised adults with HIV-1 infection initiating antiretroviral therapy (ART) on PI- or NNRTI-containing regimens from 1 January 2006 to 31 December 2015. Patients with a subsequent change in anchor agent were assigned to the switch cohort; the non-switch cohort was constructed using propensity score matching of three non-switching patients for each patient in the switch cohort. Patient characteristics and per patient per month healthcare resource utilization and costs were compared between the cohorts during the pre-switch, switch (15 days before and after switching) and post-switch periods. Costs during the switch period were also estimated with a multivariable-adjusted model. Results: The matched study population consisted of 1204 patients who switched their first-line PI- or NNRTI-based regimen and 3612 patients who did not. Compared with the non-switch cohort, patients who switched had higher healthcare resource utilization during the pre-switch, switch and post-switch periods. Mean unadjusted non-ART costs in the switch cohort were nearly double ($2944 versus $1530, p < .001), more than double ($2562 versus $1215, p < .001) and 1.5 times higher ($1473 versus $968, p < .001) than costs in the non-switch cohort in the pre-switch, switch and post-switch periods, respectively. Conclusions: Patients with HIV-1 who initiated PI- or NNRTI-based regimens and switched ARTs for reasons other than virologic failure used more healthcare resources and incurred greater costs relative to patients in the non-switch cohort. This study highlights the importance of initiating patients on appropriate first-line ART to avoid the need to switch due to reasons other than virologic failure.

Peripheral and central nervous system distribution of the CGRP neutralizing antibody [125I] galcanezumab in male rats.

OBJECTIVE: The objective of this investigation was to examine the distribution of galcanezumab and a control immunoglobulin 4 antibody containing the same constant regions as galcanezumab, into peripheral and central tissues. METHODS: Galcanezumab and a control immunoglobulin 4 antibody were radioiodinated with Iodine-125 to specific activities of 0.11 mCi/mg and 0.16 mCi/mg, respectively. At 24, 72, and 168 hours following subcutaneous injection of either antibody (4 mg/kg), cerebrospinal fluid and plasma were obtained followed by saline perfusion to remove residual blood and collection of selected tissues for determination of Iodine-125 content by gamma counting. RESULTS: The peak plasma levels of Iodine-125 galcanezumab and Iodine-125 control immunoglobulin 4 were observed at 72 hours and remained high at 168 hours post-dose. The rank order of tissue levels was dura mater = spleen > trigeminal ganglia ≫hypothalamus = spinal cord = prefrontal cortex = cerebellum. Iodine-125 galcanezumab levels in peripheral tissue (dura mater, spleen, and trigeminal ganglia) averaged 5% to 11% of plasma, whereas all of the central nervous system (CNS) tissue levels and the cerebrospinal fluid levels were < 0.4% of plasma. Distribution of the antibodies into the dura mater and the trigeminal ganglia was similar to that observed in the spleen and significantly greater than exposure in the brain or spinal cord. CONCLUSIONS: The central levels of galcanezumab were relatively low, which would favor the dura mater and trigeminal ganglia as sites of action for its observed clinical efficacy. However, a central site of action cannot be excluded.

Preoperative Assessment of Obstructive Sleep Apnea in the Ambulatory Anesthesia Patient: A Survey of Oral and Maxillofacial Surgery Providers.

PURPOSE: Oral and maxillofacial surgeons often treat patients with both diagnosed and undiagnosed obstructive sleep apnea (OSA). Patients with OSA are at substantial risk of perioperative and postoperative complications after receiving intravenous sedation, general anesthesia, or postoperative opiate analgesia. The purpose of this study was to determine whether oral and maxillofacial surgery (OMS) providers are screening patients for perioperative and postoperative risks related to OSA before office-based ambulatory anesthesia. MATERIALS AND METHODS: SurveyMonkey software (SurveyMonkey, San Mateo, CA) was used to distribute a survey to 1,658 community- and hospital-based OMS providers in the United States. A response rate of 17.4% (n = 288) was achieved. The 27-question survey was created to obtain demographic information and to assess the preoperative anesthesia routine of the OMS providers. The questions were developed based on American Society of Anesthesiologists guidelines and the STOP-Bang questionnaire to determine the quality and rate of screening for OSA before office-based ambulatory anesthesia procedures. RESULTS: All incomplete survey responses were excluded from analysis. Demographic analysis showed that 73.61% of the 288 respondents were in private practice only, with no hospital affiliation. Of the respondents, 81.88% reported performing fewer than 50 hospital operating room procedures per year, 81.60% reported performing more than 200 office-based ambulatory anesthesia cases per year, and 96.19% reported performing their own office-based ambulatory anesthesia. In this cohort, only 34.7% of OMS providers stated that they asked patients OSA-specific screening questions, whereas 74.3% reported asking other preoperative anesthesia questions (χ2 = 91.0, df = 1, P < .0001). CONCLUSIONS: Most of the surveyed OMS providers are not screening pre-anesthesia patients for OSA with a quantifiable method such as the STOP-Bang questionnaire. These findings identify a need to investigate the rate of undiagnosed OSA syndrome in the OMS office-based ambulatory anesthesia patient population. The STOP-Bang questionnaire may be a useful tool to better assess for anesthesia risk and modify management accordingly.

Cross-sectional survey study to examine underuse of twice daily inhaled maintenance therapy among patients with asthma.

Objective: Anecdotal evidence suggests that some patients with asthma intentionally use their twice-daily (BID) inhaled controller therapy once daily (QD), thus not achieving optimal dosing levels. This study identified the prevalence of and factors associated with intentional QD use of BID-indicated controllers among adult patients with asthma. Methods: This was a cross-sectional survey study of adults using inhaled controllers intended for BID dosing for treatment of asthma and/or COPD. Survey responses were linked to administrative claims data for the prior 12 months (baseline). Results of patients indicating both an asthma diagnosis and current intentional QD or BID use of controllers are presented. Results: Of 1401 patients with asthma, 30.9% reported intentional QD use of their controller and 69.1% reported BID use. Intentional QD use was mostly a function of patients' lack of perceived need for BID treatment (44.1%) or physician orders to take their controller QD (34.0%). Patients reporting intentional QD use tended to be healthier (higher health status scores, and lower Charlson comorbidity scores, ambulatory and ER visits, and healthcare costs) with better asthma control (lower asthma-related ER and ambulatory visits and rescue medication use, and higher Asthma Control Test scores) compared with patients reporting BID use. Conclusions: Perceptions regarding health and the necessity of controller use to control or treat asthma were the main drivers of medication-taking behavior. Patients with less severe asthma were more likely to report once daily use of their inhaled controller, but still maintained asthma control.

Impact of a Health Management Program on Healthcare Outcomes among Patients on Augmentation Therapy for Alpha 1-Antitrypsin Deficiency: An Insurance Claims Analysis.

INTRODUCTION: Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct®; PD). OBJECTIVES: This study compared clinical and economic outcomes between patients with and without PD program participation. METHODS: This retrospective study included commercial and Medicare Advantage health insurance plan members with ≥ 1 claim with diagnosis codes for COPD and ≥ 1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin® or Prolastin®-C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts. RESULTS: The study sample comprised 445 patients (n = 213 in PD cohort; n = 232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations. CONCLUSIONS: These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy. FUNDING: Grifols Shared Services of North America, Inc.

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography.

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC50 2.4-7.0 nM, Emax 43%-73%), displaying binding selectivity for M1 mAChRs (Kd = 1.5 nM) that was conserved across species (native tissue Kd = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP).

Background Many patients with migraines suffer from allergies and vice versa, suggesting a relationship between biological mechanisms of allergy and migraine. It was proposed many years ago that mast cells may be involved in the pathophysiology of migraines. We set out to investigate the relationship between mast cell activation and known neurogenic peptides related to migraine. Methods Cultured human mast cells were assayed for the presence of neuropeptides and their receptors at the RNA and protein level. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. Mast cell degranulation assays were performed and pituitary adenylate cyclase-activating polypeptide (PACAP) activity was measured with a bioassay. Results We found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. We confirmed existing literature that mast cell degranulation can also be induced by several neurogenic peptides, which also resulted in PACAP release. Conclusion Our data provides a potential biological explanation for the association between allergy and migraine by demonstrating the release of biologically active PACAP from mast cells.

Management of a Rare Disease Population: A Model for Identifying a Patient Population With Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare genetic disorder affecting the brain and other vital organs with varying symptoms and severity among patients. This study developed and validated a risk model to identify patients with TSC using large databases of medical and pharmacy claims.

Patient Preference for Dosing Frequency Based on Prior Biologic Experience.

BACKGROUND: There is limited research exploring patient preferences regarding dosing frequency of biologic treatment of psoriasis. METHODS: Patients with moderate-to-severe plaque psoriasis identified in a healthcare claims database completed a survey regarding experience with psoriasis treatments and preferred dosing frequency. Survey questions regarding preferences were posed in two ways: (1) by likelihood of choosing once per week or 2 weeks, or 12 weeks; and (2) by choosing one option among once every 1-2 or 3-4 weeks or 1-2 or 2-3 months. Data were analyzed by prior biologic history (biologic-experienced vs biologic-naïve, and with one or two specific biologics). RESULTS: Overall, 426 patients completed the survey: 163 biologic-naïve patients and 263 biologic-experienced patients (159 had some experience with etanercept, 105 with adalimumab, and 49 with ustekinumab). Among patients who indicated experience with one or two biologics, data were available for 219 (30 with three biologics and 14 did not specify which biologic experience). The majority of biologic-naïve (68.8%) and overall biologic-experienced (69.4%) patients indicated that they were very likely to choose the least frequent dosing option of once every 12 weeks (Table 1). In contrast, fewer biologic-naïve (9.1% and 16.7%) and biologic-experienced (22.5% and 25.3%) patients indicated that they were very likely to choose the 1-week and 2-week dosing interval options, respectively. In each cohort grouped by experience with specific biologics, among those with no experience with ustekinumab, the most chosen option was 1-2 weeks. The most frequently chosen option was every 2-3 months, among patients with any experience with ustekinumab, regardless of their experience with other biologics. CONCLUSIONS: The least frequent dosing interval was preferred among biologic naïve patients and patients who had any experience with ustekinumab. Dosing interval may influence the shared decision-making process for psoriasis treatment with biologics.

J Drugs Dermatol. 2017;16(3):220-226.

Broad spectrum efficacy with LY2969822, an oral prodrug of metabotropic glutamate 2/3 receptor agonist LY2934747, in rodent pain models.

BACKGROUND AND PURPOSE: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. EXPERIMENTAL APPROACH: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioural assessments of allodynia, hyperalgesia and nocifensive behaviours were determined in preclinical pain models after administration of LY2969822 0.3-10 mg·kg-1 . In addition, the ability of i.v. LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed. KEY RESULTS: Following treatment with LY2934747, the spontaneous activity and electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia were suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviours induced by an intraplantar injection of formalin. The on-target nature of this effect was confirmed by blockade with an mGlu2/3 receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant - induced mechanical hyperalgesia. The mGlu2/3 receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially prevented the nocifensive behaviours in the mouse acetic acid writhing model. CONCLUSIONS AND IMPLICATIONS: Following oral administration of the prodrug LY2969822, the mGlu2/3 receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.

Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.