Journey to anticoagulant access following payer rejection of apixaban.

OBJECTIVES: To investigate the journey to oral anticoagulant (OAC) access following formulary-related rejection of apixaban (Eliquis) and evaluate characteristics associated with failure to achieve OAC access among patients with atrial fibrillation (AF). STUDY DESIGN: Retrospective study using the Optum Market Clarity Data from January 2016 through February 2020. METHODS: Patients had at least 1 claim rejection for apixaban due to prior authorization (PA), formulary exclusion (FE), or quantity limit (QL) and at least 1 AF diagnosis on or before the rejected claim. Descriptive statistics summarized transaction journeys by type of formulary restriction. Multivariable regression assessed patient characteristics associated with not receiving an OAC within 60 days after initial rejection. RESULTS: Among 18,434 patients in the analytic sample, QL was the most common reason for rejection (68.7%), followed by PA (21.2%) and FE (10.2%). Most patients received a paid OAC claim within 60 days after rejection (82.2%-85.5% across restriction types). Mean time from rejection to paid claim ranged from 5.2 to 10.7 days among patients with a paid OAC claim and 12.4 to 17.6 days among those with multiple attempts before OAC receipt. Characteristics associated with higher odds of not receiving OAC treatment included being male, beingAfrican American, having Medicaid coverage, possessing a high stroke risk score, exhibiting no evidence of prior apixaban treatment, and being prescribed a low dose of apixaban on the initial rejected claim. CONCLUSIONS: Most patients with a claim rejection for apixaban received approval for apixaban within 60 days, suggesting that initial rejection merely created a delay in treatment. Vulnerable populations were at greater risk of not receiving a paid OAC claim.

Associations between clinical and social factors and anticoagulant prescription among patients with atrial fibrillation: A retrospective cohort study from a large healthcare system.

BACKGROUND: Patient clinical factors and social determinants of health (SDOH) are associated with an increased risk of stroke for patients with atrial fibrillation (AF); however, the association between these factors and the management of AF is not well characterized, particularly among those factors commonly collected in electronic health records (EHRs). This study used EHR data to evaluate the associations between patient clinical factors and SDOH and prescribing of an oral anticoagulant (OAC) for stroke prevention in AF. METHODS: This analysis included adult patients with newly diagnosed AF who had ≥2 encounters in the Advocate Aurora Health system in Wisconsin between May 2016 and May 2021. Patient-level demographics, comorbidities, medications, and SDOH were retrospectively extracted from EHRs. Area deprivation index (ADI) was linked to patient records as a measure of socioeconomic status. RESULTS: Of 16,656 patients with AF, 10,898 (65.4%) were prescribed an OAC within the first year of diagnosis. Patients were less likely to be prescribed an OAC (relative risk [95% CI]) if they were widowed (0.98 [0.96-0.99] vs single) or had a history of alcoholism (0.86 [0.79-0.95] vs no history). Most patients (53.3%) received prescriptions from a primary care provider. A linear relationship was found between worsening ADI and increased prescriptions for warfarin vs those for direct-acting OACs. CONCLUSIONS: Although guideline-concordant anticoagulant use remained suboptimal, clinical characteristics were strongly associated for whether a patient with AF would be prescribed an OAC. Disparities in patient care regarding the prescribing of OACs due to SDOH and associated behaviors were small but present, particularly for national ADI.

A Real-World Evaluation of Primary Medication Nonadherence in Patients with Nonvalvular Atrial Fibrillation Prescribed Oral Anticoagulants in the United States.

BACKGROUND: Nonadherence to oral anticoagulants (OACs) is a challenge to stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data on primary medication nonadherence (PMN) in NVAF are lacking. OBJECTIVES: Our aim was to assess the rates and predictors of PMN among NVAF patients who were newly prescribed an OAC. METHODS: This was a retrospective database analysis of linked healthcare claims and electronic health record data. Adult NVAF patients with a prescription order for an OAC (apixaban, rivaroxaban, dabigatran, or warfarin) between January 2016 and June 2019 were identified (date of first prescription order = index date). Patients had a 1-year baseline and a 6-month post-index period to assess the rates of PMN, defined as having a prescription order but no paid claim for any OAC on or within 30 days after the index date. Sensitivity analyses explored 60-, 90- and 180-day PMN thresholds. Logistic regression models were used to examine the predictors of PMN. RESULTS: Among 20,393 patients, the overall 30-day PMN rate was 28.4%; PMN rates decreased to 17% with a 180-day threshold. PMN was numerically lowest for warfarin among OACs and numerically lowest for apixaban among direct OACs. A CHA2DS2-VASc score of ≥ 3, commercial insurance, and African American race were associated with higher odds of PMN. CONCLUSIONS: More than one-quarter of patients experienced PMN within 30 days of their initial prescription order. This rate decreased over a longer period, suggesting a delay in fills. Understanding the factors associated with PMN is warranted to develop effective interventions for improving OAC treatment rates in NVAF.

Contemporary prevalence estimates of undiagnosed and diagnosed atrial fibrillation in the United States.

BACKGROUND: Atrial fibrillation (AF) prevalence estimates vary and have been based on cohorts with clinically established or diagnosed disease. Undiagnosed AF prevalence estimates are less certain as they are based on nongeneralizable convenience samples. HYPOTHESIS: Because AF is often asymptomatic, it my remain undiagnosed until the development of complications such as stroke or heart failure. Consequently, the observed prevalence of diagnosed AF from the literature may underestimate total disease burden. We therefore sought to estimate the total prevalence of both diagnosed and undiagnosed AF. METHODS: We performed a retrospective cohort study from 2012 to 2017 using data from five US medical claims data sets. Undiagnosed AF prevalence was estimated based on the observed incidence of ischemic stroke, systemic embolism (SE), and AF incidence after a stroke/SE. The diagnosed AF cohort included AF patients between Q1 2014 and Q3 2015. The undiagnosed AF cohort were patients with assumed undiagnosed AF in the year before a stroke/SE and who were newly diagnosed with AF in the 3-month poststroke/SE. Stroke/SE incidence was calculated among all AF patients and the ratio of number of undiagnosed AF patients to stroke rate was created. Age- and sex-adjusted estimates were stratified by period of assumed undiagnosed AF before poststroke/SE AF diagnosis (1 or 2 years). RESULTS: The estimated US prevalence of AF (diagnosed and undiagnosed) in Q3 2015 was 5 628 000 cases, of which 591 000 cases (11%) were undiagnosed. The assumed 2-year undiagnosed AF prevalence was 23% (1 531 000) of the total prevalent patients with AF (6 568 000). Undiagnosed (vs. diagnosed) AF patients were older and had higher CHA2DS2-VASc scores. Of undiagnosed AF, 93% had CHA2DS2-VASc ≥2 and met OAC criteria. CONCLUSIONS: These contemporary estimates demonstrate the high prevalence of undiagnosed AF in the United States. Undiagnosed AF patients are composed of primarily elderly individuals who if diagnosed, would meet criteria for stroke prevention therapy.

Oral anticoagulant underutilization among elderly patients with atrial fibrillation: insights from the United States Medicare database.

BACKGROUND: Oral anticoagulants (OACs) mitigate stroke risk in patients with atrial fibrillation (AF). The study aim was to analyze prevalence and predictors of OAC underutilization. METHODS: Newly diagnosed AF patients with a CHA2DS2-VASc score ≥ 2 were identified from the US CMS Database (January 1, 2013-December 31, 2017). Patients were stratified based on having an OAC prescription versus not and the OAC prescription group was stratified by direct OAC (DOACs) versus warfarin. Multivariable logistic regression models were used to examine predictors of OAC underutilization. RESULTS: Among 1,204,507 identified AF patients, 617,611 patients (51.3%) were not prescribed an OAC during follow-up (mean: 2.4 years), and 586,896 patients (48.7%) were prescribed an OAC during this period (DOAC: 388,629 [66.2%]; warfarin: 198,267 [33.8%]). Age ≥ 85 years (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.55-0.56), female sex (OR 0.96, 95% CI 0.95-0.96), Black race (OR 0.78, 95% CI 0.77-0.79) and comorbidities such as gastrointestinal (GI; OR 0.43, 95% CI 0.41-0.44) and intracranial bleeding (OR 0.29, 95% CI 0.28-0.31) were associated with lower utilization of OACs. Furthermore, age ≥ 85 years (OR 0.92, 95% CI 0.91-0.94), Black race (OR 0.78, 95% CI 0.76-0.80), ischemic stroke (OR 0.77, 95% CI 0.75-0.80), GI bleeding (OR 0.73, 95% CI 0.68-0.77), and intracranial bleeding (OR 0.72, 95% CI 0.65-0.80) predicted lower use of DOACs versus warfarin. CONCLUSIONS: Although OAC therapy prescription is the standard of care for stroke prevention in AF patients, its overall utilization is still low among Medicare patients ≥ 65 years old, with specific patient characteristics that predict underutilization.

Contemporary clinical and economic outcomes among oral anticoagulant treated and untreated elderly patients with atrial fibrillation: Insights from the United States Medicare database.

BACKGROUND: Oral anticoagulants (OACs) mitigate the risk of stroke in atrial fibrillation (AF) patients. OBJECTIVE: Elderly AF patients who were treated with OACs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) were compared against AF patients who were not treated with OACs with respect to their clinical and economic outcomes. METHODS: Newly diagnosed AF patients were identified between January 2013 and December 2017 in the Medicare database. Evidence of an OAC treatment claim on or after the first AF diagnosis was used to classify patients into treatment-defined cohorts, and these cohorts were further stratified based on the initial OAC prescribed. The risks of stroke/systemic embolism (SE), major bleeding (MB), and death were analyzed using inverse probability treatment weighted time-dependent Cox regression models, and costs were compared with marginal structural models. RESULTS: The two treatment groups were composed of 1,421,187 AF patients: OAC treated (N = 583,350, 41.0% [36.4% apixaban, 4.9% dabigatran, 0.1% edoxaban, 26.7% rivaroxaban, and 31.9% warfarin patients]) and untreated (N = 837,837, 59.0%). OAC-treated patients had a lower adjusted risk of stroke/SE compared to untreated patients (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.68-0.72). Additionally patients receiving OACs had a lower adjusted risk of death (HR: 0.56; 95% CI: 0.55-0.56) and a higher risk of MB (HR: 1.57; 95% CI: 1.54-1.59) and this trend was consistent across each OAC sub-group. The OAC-treated cohort had lower adjusted total healthcare costs per patient per month ($4,381 vs $7,172; p < .0001). CONCLUSION: For the OAC-treated cohort in this elderly US population, stroke/SE and all-cause death were lower, while risk of MB was higher. Among OAC treated patients, total healthcare costs were lower than those of the untreated cohort.

The burden of undertreatment and non-treatment among patients with non-valvular atrial fibrillation and elevated stroke risk: a systematic review.

OBJECTIVE: Global treatment guidelines recommend treatment with oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and an elevated stroke risk. However, not all patients with NVAF and an elevated stroke risk receive guideline-recommended therapy. A literature review and synthesis of observational studies were undertaken to identify the body of evidence on untreated and undertreated NVAF and the association with clinical and economic outcomes. METHODS: An extensive search (1/2010-4/2020) of MEDLINE, the Cochrane Library, conference proceedings, and health technology assessments (HTAs) was conducted. Studies must have evaluated rates of nontreatment or undertreatment in NVAF. Nontreatment was defined as absence of OACs (but with possible antiplatelet treatment), while undertreatment was defined as treatment with only antiplatelet agents. RESULTS: Sixteen studies met our inclusion criteria. Rates of nontreatment for patients with elevated stroke risk ranged from 2.0-51.1%, while rates of undertreatment ranged from 10.0-45.1%. The clinical benefits of anticoagulation were reported in the evaluated studies with reductions in stroke and mortality outcomes observed among patients treated with anticoagulants compared to untreated or undertreated patients. Adverse events associated with all bleeding types (i.e. hemorrhagic stroke, major bleeding or gastrointestinal hemorrhaging) were found to be higher for warfarin patients compared to untreated patients in real-world practice. Healthcare resource utilization was found to be lower among patients highly-adherent to warfarin compared to untreated patients. CONCLUSIONS: Rates of nontreatment and undertreatment among NVAF patients remain high and are associated with preventable cardiovascular events and death. Strategies to increase rates of treatment may improve clinical outcomes.

Effectiveness and Safety of Apixaban Versus Warfarin in Obese Patients with Nonvalvular Atrial Fibrillation Enrolled in Medicare and Veteran Affairs.

Real-world studies have evaluated the use of anticoagulants in obese patients with nonvalvular atrial fibrillation (NVAF), but they have been limited by sample size or the use of diagnosis codes on claims to define obesity. This retrospective study used body weight data of ≥100 kg or a body mass index of ≥30 kg/m2 to identify elderly (aged ≥65 years) NVAF patients with obesity in dually enrolled Veterans Affairs and fee-for-service Medicare patients. It evaluated the risk of stroke/systemic embolism (SE) and major bleeding (MB) in patients that initiated apixaban versus warfarin. Stabilized inverse probability treatment weighting was used to balance the baseline characteristics between patients prescribed apixaban and warfarin in obese patients. Cox models were used to evaluate the relative risk of stroke/SE and MB. Overall, 35.9% (n = 26,522) of the NVAF population were obese, of which 13,604 apixaban and 12,918 warfarin patients were included. After inverse probability treatment weighting, patient characteristics were balanced. The mean age was 75 years, the mean CHA2DS2-VASc score (Congestive Heart Failure, Hypertension, Age ≥75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65-74, Female) was 3.8, the mean HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score was ∼2.6, and >98% of patients were males. Obese apixaban patients were associated with a similar risk of stroke/SE (hazard ratio: 0.82; 95% confidence interval: 0.66 to 1.03) and a significantly lower risk of MB (hazard ratio: 0.62; 95% confidence interval: 0.54 to 0.70) versus warfarin. No significant interaction was observed between treatment and obesity status (nonobese, obese/nonmorbid, obese/morbid) for stroke/SE (interaction p = 0.602) or MB (interaction p = 0.385). In obese patients with NVAF, apixaban was associated with a similar risk of stroke/SE and a significantly lower risk of MB versus warfarin.

The IMPact of untReated nOn-Valvular atrial fibrillation on short-tErm clinical and economic outcomes in the US Medicare population: the IMPROVE-AF model.

BACKGROUND: Despite treatment guidelines recommending the use of oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke (CHA2DS2-VASc score ≥1), many patients remain untreated. A study conducted among Medicare beneficiaries with AF and a CHA2DS2-VASc score of ≥2 found that 51% of patients were not prescribed an OAC despite being eligible for treatment. When left untreated, NVAF poses an enormous burden to society, as stroke events are estimated to cost the US healthcare system about $34 billion each year in both direct medical costs and indirect productivity losses. This research explored the short-term clinical implications and budget impact (BI) of increasing OAC use among Medicare beneficiaries with NVAF. METHODS: A decision-analytic model was developed from the payer and societal perspectives to estimate the impact of increasing treatment rates among Medicare-eligible NVAF patients with a moderate-to-high risk of stroke over 1 year. Results of the model compared (1) a base case scenario using literature-derived rates of OAC use, and (2) a hypothetical scenario assuming an absolute 5% increase in overall OAC use. Clinical outcomes included the incremental annual number of ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding events, and stroke-related deaths. Economic outcomes included incremental annual and per-member per-month (PMPM) direct medical costs for the payer perspective and the incremental sum of annual direct medical and indirect costs from productivity loss and caregiver burden for the societal perspective. RESULTS: In total, 1.95 million Medicare patients with NVAF were estimated to be treated with OACs in the base case (3.8% of beneficiaries). In the hypothetical scenario analysis, nearly 200,000 more patients were treated resulting in 3,705 fewer ischemic strokes, 14 fewer gastrointestinal bleeds, 141 more hemorrhagic strokes, and 175 fewer deaths. The total incremental BI was $399.16 million ($0.65 PMPM) from the payer perspective and $377.10 million from the societal perspective due to indirect cost savings ($22.06 million). CONCLUSION: Our findings suggest that increased overall OAC use has a positive clinical benefit on the annual number of ischemic stroke events and deaths avoided in the Medicare population, while maintaining a modest increase in the overall BI to the Medicare system.

Correlates of accelerometry non-adherence in an economically disadvantaged minority urban adult population.

OBJECTIVES: The purpose of this study was to examine socio-demographic and psychosocial correlates of non-adherence to an accelerometry protocol in an economically disadvantaged urban population. DESIGN: Cross-sectional study. METHODS: We analyzed 985 New York City adult participants aged 18-81 years from the Physical Activity and Redesigned Community Spaces (PARCS) study. Participants were asked to wear a hip-worn ActiGraph GT3X-BT accelerometer for one week. Adherent accelerometer wear was defined as ≥3 days of ≥8 h/day of wear over a 7-day period and non-adherent accelerometry wear was defined as any wear less than adherent wear from returned accelerometers. Examined correlates of adherence included sociodemographic and psychosocial characteristics (e.g., general physical/mental health-related quality of life, self-efficacy for exercise, stress, sense of community/neighborhood well-being, and social cohesion). RESULTS: From the total sample, 636 (64.6%) participants provided adherent wear and 349 (35.4%) provided non-adherent wear. In multivariable analysis, younger age (odds ratio [OR] = 0.63, 95% confidence interval [CI]: 0.53-0.75), poorer health-related quality of life (OR = 0.80, 95% CI: 0.65-0.98 for physical health and OR = 0.77, 95% CI: 0.62-0.94 for mental health), lower sense of community (OR = 0.79, 95% CI: 0.62-1.00) and current smoking status (OR = 1.97, 95% CI: 1.35-2.86) were associated with non-adherent wear. CONCLUSIONS: Non-adherent wear was associated with younger age, smoking, and lower self-reported physical/mental functioning and sense of community. This information can inform targeted adherence strategies to improve physical activity and sedentary behavior estimates from accelerometry data in future studies involving an urban minority population.

Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction.

Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.

The association between coeliac disease and periodontitis: Results from NHANES 2009-2012.

AIM: To investigate whether coeliac disease (CD) was associated with periodontitis among a nationally representative sample of US adults. MATERIALS AND METHODS: The National Health and Nutrition Examination Survey (NHANES) 2009-2012 enrolled 6,661 subjects with full-mouth periodontal examination and serological testing for antitissue transglutaminase (tTg) and antiendomysial (EMA) antibodies. CD was defined as (i) self-reported physician diagnosis while on a gluten-free diet; or (ii) tTg levels >10.0 U/ml and positive EMA results. Positive serology without self-reported diagnosis was defined as undiagnosed CD (UdxCD). Periodontitis was defined according to the CDC/AAP definition. Multivariable linear and logistic models were used to regress the mean probing depth (PD) or attachment loss (AL) outcomes across CD categories (none, diagnosed and undiagnosed). RESULTS: The prevalence of moderate/severe periodontitis and diagnosed/undiagnosed CD was 40% and 0.74%, respectively. Mean AL was lower among those with CD although results were not statistically significant (p = .67). The odds of periodontitis among individuals with diagnosed and undiagnosed CD were: 0.5(0.22, 1.16) and 0.62(0.1, 3.75), respectively. Mean PD levels among those without CD or with diagnosed or undiagnosed CD were 1.49 ± 0.02, 1.36 ± 0.11 and 1.31 ± 0.11 (p = .03). CONCLUSION: CD is associated with modestly lower levels of mean PD but was not associated with mean AL or periodontitis. Larger studies are necessary to enhance precision and strengthen conclusions.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.

The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.

Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.

Gsk3 is a metabolic checkpoint regulator in B cells.

B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40. Gsk3 was required to prevent metabolic collapse and ROS-induced apoptosis after glucose became limiting, functioning in part by repressing growth dependent on the myelocytomatosis oncoprotein c-Myc. Notably, we found that Gsk3 was required for the generation and maintenance of germinal center B cells, which require high glycolytic activity to support growth and proliferation in a hypoxic microenvironment.

The Physical Activity and Redesigned Community Spaces (PARCS) Study: Protocol of a natural experiment to investigate the impact of citywide park redesign and renovation.

BACKGROUND: The built environment plays a critical role in promoting physical activity and health. The association between parks, as a key attribute of the built environment, and physical activity, however, remains inconclusive. This project leverages a natural experiment opportunity to assess the impact of the Community Parks Initiative (CPI), a citywide park redesign and renovation effort in New York City, on physical activity, park usage, psychosocial and mental health, and community wellbeing. METHODS: The project will use a longitudinal design with matched controls. Thirty intervention park neighborhoods are socio-demographically matched to 20 control park neighborhoods. The study will investigate whether improvements in physical activity, park usage, psychosocial and mental health, and community wellbeing are observed from baseline to 3 years post-renovation among residents in intervention vs. control neighborhoods. DISCUSSION: This study represents a rare opportunity to provide robust evidence to further our understanding of the complex relationship between parks and health. Findings will inform future investments in health-oriented urban design policies and offer evidence for addressing health disparities through built environment strategies.

Essential Role for Survivin in the Proliferative Expansion of Progenitor and Mature B Cells.

Survivin is a member of the inhibitor of apoptosis family of proteins and a biomarker of poor prognosis in aggressive B cell non-Hodgkin's lymphoma. In addition to its role in inhibition of apoptosis, survivin also regulates mitosis. In this article, we show that deletion of survivin during early B cell development results in a complete block at the cycling pre-B stage. In the periphery, B cell homeostasis is not affected, but survivin-deficient B cells are unable to mount humoral responses. Correspondingly, we show that survivin is required for cell division in response to mitogenic stimulation. Thus, survivin is essential for proliferation of B cell progenitors and activated mature B cells, but is dispensable for B cell survival. Moreover, a small-molecule inhibitor of survivin strongly impaired the growth of representative B lymphoma lines in vitro, supporting the validity of survivin as an attractive therapeutic target for high-grade B cell non-Hodgkin's lymphoma.

PDK1 regulates B cell differentiation and homeostasis.

Successful B cell differentiation and prevention of cell transformation depends on balanced and fine-tuned activation of cellular signaling pathways. The phosphatidyl inositol-3 kinase (PI3K) signaling pathway has emerged as a major regulator of B lymphocyte homeostasis and function. Phosphoinositide-dependent protein kinase-1 (PDK1) is the pivotal node in the PI3K pathway, regulating the stability and activity of downstream AGC kinases (including Akt, RSK, S6K, SGK, and PKC). Although the importance of PI3K activity in B cell differentiation is well documented, the role of PDK1 and other downstream effectors is underexplored. Here we used inducible and stage-specific gene targeting approaches to elucidate the role of PDK1 in early and peripheral B cell differentiation. PDK1 ablation enhanced cell cycle entry and apoptosis of IL-7-dependent pro-B cells, blocking Ig synthesis and B cell maturation. PDK1 also was essential for the survival and activation of peripheral B cells via regulation of PKC and Akt-dependent downstream effectors, such as GSK3α/ß and Foxo1. We found that PDK1 deletion strongly impaired B cell receptor (BCR) signaling, but IL-4 costimulation was sufficient to restore BCR-induced proliferation. IL-4 also normalized PKCß activation and hexokinase II expression in BCR-stimulated cells, suggesting that this signaling pathway can act independent of PDK1 to support B cell growth. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation.

Context-specific BAFF-R signaling by the NF-κB and PI3K pathways.

BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.