Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Cancer: A Target Trial Emulation from SEER-Medicare Database.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin in patients with atrial fibrillation (AFib). However, their safety and effectiveness in patients with AFib and cancer are inconclusive. METHODS: We conducted a retrospective cohort study by emulating a target trial. Patients with a record of cancer (breast, prostate, or lung), newly diagnosed with AFib initiated DOACs or warfarin within 3 months after AFib diagnosis from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database were included. We compared the risk of ischemic stroke, major bleeding, and secondary outcomes (venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, and non-critical site bleeding) between patients who initiated DOACs and warfarin. Inverse probability treatment weights and inverse probability censoring weights were used to adjust imbalanced patient and disease characteristics and loss to follow-up between the two groups. Weighted pooled logistic regression were used to estimate treatment effect with hazard ratios (HRs) with 95% confidence interval (95% CIs). RESULTS: The incidence rates of stroke and major bleeding between DOAC and warfarin initiators were 9.97 vs. 9.91 and 7.74 vs. 9.24 cases per 1000 person-years, respectively. In adjusted intention-to-treat analysis, patients initiated DOACs had no statistically significant difference in risk of ischemic stroke (HR = 0.87, 95% CI 0.52-1.44) and major bleeding (HR = 1.14, 95% CI 0.77-1.68) compared to those initiated warfarin. In adjusted per-protocol analysis, there was no statistical difference in risk of ischemic stroke (HR = 1.81, 95% CI 0.75-4.36) and lower risk for major bleeding, but the 95% CI was wide (HR = 0.35, 95% CI 0.12-0.99) among DOAC initiators compared to warfarin initiators. The benefits in secondary outcomes were in favor of DOACs. The findings remained consistent across subgroups and sensitivity analyses. CONCLUSION: DOACs are safe and effective alternatives to warfarin in the management of patients with AFib and cancer.

Benefit and risk of oral anticoagulant initiation strategies in patients with atrial fibrillation and cancer: a target trial emulation using the SEER-Medicare database.

Oral anticoagulants (OACs) are recommended for patients with atrial fibrillation (AFib) having CHA2DS2-VASc score ≥ 2. However, the benefits of OAC initiation in patients with AFib and cancer at different levels of CHA2DS2-VASc is unknown. We included patients with new AFib diagnosis and a record of cancer (breast, prostate, or lung) from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database (n = 39,915). Risks of stroke and bleeding were compared between 5 treatment strategies: (1) initiated OAC when CHA2DS2-VASc ≥ 1 (n = 6008), (2) CHA2DS2-VASc ≥ 2 (n = 8694), (3) CHA2DS2-VASc ≥ 4 (n = 20,286), (4) CHA2DS2-VASc ≥ 6 (n = 30,944), and (5) never initiated OAC (reference group, n = 33,907). Confounders were adjusted using inverse probability weighting through cloning-censoring-weighting approach. Weighted pooled logistic regressions were used to estimate treatment effect [hazard ratios (HRs) and 95% confidence interval (95% CIs)]. We found that only patients who initiated OACs at CHA2DS2-VASc ≥ 6 had lower risk of stroke compared without OAC initiation (HR 0.64, 95% CI 0.54-0.75). All 4 active treatment strategies had reduced risk of bleeding compared to non-initiators, with OAC initiation at CHA2DS2-VASc ≥ 6 being the most beneficial strategy (HR = 0.49, 95% CI 0.44-0.55). In patients with lung cancer or regional/metastatic cancer, OAC initiation at any CHA2DS2-VASc level increased risk of stroke and did not reduce risk of bleeding (except for Regimen 4). In conclusion, among cancer patients with new AFib diagnosis, OAC initiation at higher risk of stroke (CHA2DS2-VASc score ≥ 6) is more beneficial in preventing ischemic stroke and bleeding. Patients with advanced cancer or low life-expectancy may initiate OACs when CHA2DS2-VASc score ≥ 6.

Screening for clinically relevant drug-drug interactions between direct oral anticoagulants and antineoplastic agents: a pharmacovigilance approach.

BACKGROUND: Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due to the concern regarding potential drug-drug interactions (DDIs) with antineoplastic treatments. However, the clinical relevance of these DDIs is unknown. METHODS: We conducted a pharmacovigilance study of adverse event (AE) reports from the US Food and Drug Administration Adverse Event Reporting System from 1/1/2004 to 12/31/2021. AE reports containing DOACs and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity suggested by published pharmacokinetic studies were included (n = 36,066). The outcomes of interest were bleeding or stroke, identified by MedDRA dictionary version 25.0. We used disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) algorithms to identify the safety signal of DDIs. RESULTS: The highest bleeding reporting rates for each drug class were the combination of DOACs with neratinib (39.08%, n = 34), tamoxifen (21.22%, n = 104), irinotecan (20.54%, n = 83), and cyclosporine (19.17%, n = 227). The highest rate of stroke was found for prednisolone (2.43%, n = 113). In the primary analysis, no signal of DDIs by the antineoplastic therapeutic class was detected by MGPS, DPA, and LR approaches. By individual antineoplastic drug, DOACs-neratinib was the only signal detected [EBGM (EB05-EB95) = 2.71 (2.03-3.54)]. CONCLUSION: No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Most DDIs between DOACs and antineoplastic agents may not be clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.

Does the Timing of Eribulin Treatment for Advanced or Metastatic Breast Cancer Matter? Evidence from a Real-World Setting.

BACKGROUND: This study aimed to examine the effectiveness and safety of eribulin used as an early-line (EL, i.e., first-/second-line) versus late-line (LL, i.e., third-line and beyond) chemotherapy for recurrent advanced or metastatic breast cancer (A/MBC) patients. METHODS: This study conducted a retrospective observation of A/MBC patients initiating eribulin between January 1, 2015, and June 30, 2019, using medical database at a university-affiliated teaching hospital in Taiwan. Patients were assigned into either the EL or LL group based on the timing of respective eribulin treatments and were observed for at least 6 months up to December 2019 for progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), disease response, and occurrence of adverse events. The Kaplan-Meier and Cox proportional hazard regression survival analyses were performed. RESULTS: Of 127 patients, 23.6% (n = 30) and 76.4% (n = 97) were assigned to the EL and LL groups, respectively, between which no difference in patient characteristics was noted. Median PFS and TTF were 6.5 months and 5.0 months for the EL and 4.2 months and 3.4 months for the LL, respectively. Median OS could not be estimated in the EL group and was 20.5 months in the LL group. Eribulin as an EL treatment was the only factor associated with longer TTF and OS, whereas the number of metastatic sites was additionally associated with PFS in the multivariate analysis. No complete response was reported in either group, but a partial response was obtained in 6.7% in the EL group and 3.1% in the LL group. The common adverse events between two groups were similar, including leukopenia (80.0%), neutropenia (76.7%), and anemia (60.0%). CONCLUSIONS: The eribulin used as an EL of chemotherapy was effective for A/MBC patients with known toxicities in this study, while eribulin as the LL chemotherapy showed consistent results with previous reports.

Social determinants of health and preventable emergency department patient encounters among adults with hypertension.

Limited access to resources promoting optimal health outcomes can lead to increased emergency department utilization for conditions often manageable by primary care resulting in rising healthcare costs, overcrowding in emergency departments, and poor patient outcomes. Social determinants of health often affect an individual's ability to achieve optimal health. To examine the association between social determinants of health and hypertension-related patient encounters among adults, we analyzed data from a 340-bed community hospital in the southeast region of the United States. Gender, race, and geographic location were strongly associated with hypertension-related encounters. Hypertension-related encounters in the emergency department were highest in women, African Americans, and young adults. Insurance status and geographic location were also strongly associated. Public health nursing is positioned to prevent disease and increase access to care, considering hypertension-related encounters in the emergency department account for a significant number of overall visits.

Efficacy of Tafamidis in Patients with Ala97Ser Hereditary Transthyretin Cardiac Amyloidosis: A Six-Month Follow-Up Study.

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown. Objectives: This study aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM after 6 months of treatment. Methods: We retrospectively analyzed ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. Functional status, biochemistry and echocardiography were measured at baseline and after 6 months of tafamidis treatment. The outcome measure was to compare the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at baseline and after 6 months of tafamidis treatment. Results: Twenty patients were enrolled in this study. Their mean age was 63.0 ± 5.8 years and 75% were men. The baseline left ventricular (LV) mass index was 200.9 ± 63.9 g/m2, and the baseline LV ejection fraction was 58.9 ± 13.5%. After 6 months of treatment, the log NT-proBNP level significantly improved from 2.9 ± 0.6 to 2.7 ± 0.5 (p = 0.036). Subgroup analysis showed that the LV posterior wall thickness and left atrial diameter were significantly higher in the patients with improved NT-proBNP, suggesting the benefits of tafamidis for ATTR-CM patients with severe cardiac involvement. Conclusions: The patients with hereditary A97S ATTR-CM in this study had decreased levels of NT-proBNP after 6 months of tafamidis treatment, and this reduction was especially pronounced in those with more severe cardiac involvement.

Building and experimenting with an agent-based model to study the population-level impact of CommunityRx, a clinic-based community resource referral intervention.

CommunityRx (CRx), an information technology intervention, provides patients with a personalized list of healthful community resources (HealtheRx). In repeated clinical studies, nearly half of those who received clinical "doses" of the HealtheRx shared their information with others ("social doses"). Clinical trial design cannot fully capture the impact of information diffusion, which can act as a force multiplier for the intervention. Furthermore, experimentation is needed to understand how intervention delivery can optimize social spread under varying circumstances. To study information diffusion from CRx under varying conditions, we built an agent-based model (ABM). This study describes the model building process and illustrates how an ABM provides insight about information diffusion through in silico experimentation. To build the ABM, we constructed a synthetic population ("agents") using publicly-available data sources. Using clinical trial data, we developed empirically-informed processes simulating agent activities, resource knowledge evolution and information sharing. Using RepastHPC and chiSIM software, we replicated the intervention in silico, simulated information diffusion processes, and generated emergent information diffusion networks. The CRx ABM was calibrated using empirical data to replicate the CRx intervention in silico. We used the ABM to quantify information spread via social versus clinical dosing then conducted information diffusion experiments, comparing the social dosing effect of the intervention when delivered by physicians, nurses or clinical clerks. The synthetic population (N = 802,191) exhibited diverse behavioral characteristics, including activity and knowledge evolution patterns. In silico delivery of the intervention was replicated with high fidelity. Large-scale information diffusion networks emerged among agents exchanging resource information. Varying the propensity for information exchange resulted in networks with different topological characteristics. Community resource information spread via social dosing was nearly 4 fold that from clinical dosing alone and did not vary by delivery mode. This study, using CRx as an example, demonstrates the process of building and experimenting with an ABM to study information diffusion from, and the population-level impact of, a clinical information-based intervention. While the focus of the CRx ABM is to recreate the CRx intervention in silico, the general process of model building, and computational experimentation presented is generalizable to other large-scale ABMs of information diffusion.

Can the LACE index help identify uninsured patients at risk of loss to follow-up during a pharmacist-led transitions of care program?

BACKGROUND: Uninsured patients are susceptible to being lost to follow-up (LTFU). In addition to being uninsured, follow-up is especially critical among this population during transitions of care when patients are discharged from the hospital setting back to home because follow-up care after discharge has been proven to prevent readmissions. The LACE tool has historically been used to predict readmissions, but the LACE tool has not been used to evaluate patients' risk of LTFU. OBJECTIVE: To understand the potential translation of the LACE tool for use in uninsured patients' follow-up care, we assessed the association between LACE index scores and patients' risk of LTFU during a pharmacist-led transitions of care program for uninsured patients. METHODS: Data were extracted from a randomized controlled trial implementing a pharmacist-led transitions of care program at an indigent care clinic. The study population included uninsured adult patients (>18 years old) who spoke English and attended a clinical visit with a pharmacist within 16 days after discharge from a community hospital. Analyses sought to determine factors associated with the patients' LTFU status. RESULTS: Among 88 enrolled participants, 29 participants (32.95%) were LTFU. Thirty-two patients (36.4%) had a high LACE index score at baseline, indicating an increased risk of 30-day readmission. Of the remaining 56 patients (63.6%) with low-to-moderate LACE index scores, 54 (61.4%) had a moderate LACE index score, and only 2 (2.3%) had a low LACE index score. Uninsured patients with high LACE index scores had 70% lower odds of being LTFU than uninsured patients with low-to-moderate LACE index scores (exact odds ratio 0.297 [95% CI 0.081-0.947]). CONCLUSION: The LACE index score was inversely related to the risk of LTFU during a pharmacist-led transitions of care program. Pharmacists may use the LACE tool to identify patients at high risk of LTFU.

The association of continuity of care and risk of mortality in breast cancer patients with cardiometabolic comorbidities.

OBJECTIVE: The association of continuity of care (COC) among providers and mortality risk for breast cancer patients with comorbidities is not sufficiently studied. DESIGN: A retrospective cohort study using the 2006-2014 Surveillance, Epidemiology and End Results (SEER)-Medicare data. PARTICIPANTS: Newly diagnosed female breast cancer patients (n = 57,578) with comorbidities (hypertension, hyperlipidemia, and/or diabetes). METHODS: All-cause mortality was assessed annually for up to 5 years. COC was estimated using the Bice-Boxerman index, which included: 1) specialty COC capturing continuity of visits to the same provider type (Primary Care Physicians, Oncologists, and Other specialists) and 2) individual COC capturing continuous care to the same provider regardless of provider specialty. Cox proportional hazards models estimated the hazard ratio (HR) of all-cause mortality across quartile of the COC index. RESULTS: Mortality was positively associated with advanced tumor stages and number of comorbidities (p < 0.05). Patients with high specialty COC (4th vs. 1st quartile, HR 1.34, 95%CI 1.29-1.40) had higher risks of mortality compared with those with low specialty COC. However, patients with high individual COC (4th vs. 1st quartile, HR 0.53, 95%CI 0.51-0.54) had lower risks of mortality compared to those with low individual COC. CONCLUSION: Receiving care from fewer providers is associated with lower mortality and from fewer types of provider is associated with higher mortality. The results might be confounded by uncontrolled factors and provoke the need for alternative patient care models that recognize the balance between appropriate subspecialties and minimizing the fragmentation of care within and across subspecialties.

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model.

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.

Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy.

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.

Implementation of a pharmacist-led transitions of care program in an indigent care clinic: A randomized controlled trial.

OBJECTIVES: Pharmacists' involvement in the transitions of care has shown the potential to decrease readmissions and increase access to care in many populations; however, the uninsured patient populations have not been studied. The evidence for the feasibility of implementing transitions of care services in indigent care clinics with limited resources also remains limited. The objectives were to implement a pharmacist-led transitions of care program in an indigent care clinic, to demonstrate the feasibility of its implementation, and to evaluate its impact on readmissions and emergency department (ED) visit rates among an uninsured population. METHODS: The study was a single-blind, parallel, randomized controlled trial implemented in an indigent care clinic in the Southeast region of the United States from October 2018 to July 2019. Eligible patients were those older than 18 years, uninsured, English-speaking, diagnosed with any condition, and recently discharged from a local community hospital within the past 16 days. The primary outcome was the hospital readmission rate at 30 days after discharge. The secondary outcomes included 60- and 90-day readmission rates in addition to 30-, 60-, and 90-day ED visit rates. RESULTS: A total of 88 participants were recruited. The intervention was successfully implemented in the clinic, but patient-level barriers to follow-ups included transportation, accessibility, financial burdens, inconsistent telephone communication, and a lack of knowledge about the importance of follow-ups. At 30 days postdischarge, 13.64% of the patients in the usual care group experienced readmissions compared with 9.30% of the patients in the intervention group. The relative change in the 30-day readmission rates between the usual care and the intervention groups was 1.7 (rate ratio [RR] 1.69 [95% CI 0.47-6.08]). The RRs were insignificant for the 30-, 60-, and 90-day readmission and ED visit rates. CONCLUSION: This study demonstrated the feasibility of implementing transitions of care services in a clinic with limited resources by pharmacists. The intervention showed promising results by reducing readmission rates.

A classification algorithm to predict chronic pain using both regression and machine learning - A stepwise approach.

This secondary data analysis study aimed to (1) investigate the use of two sense-based parameters (movement and sleep hours) as predictors of chronic pain when controlling for patient demographics and depression, and (2) identify a classification model with accuracy in predicting chronic pain. Data collected by Oregon Health & Science University between March 2018 and December 2019 under the Collaborative Aging Research Using Technology Initiative were analyzed in two stages. Data were collected by sensor technologies and questionnaires from older adults living independently or with a partner in the community. In Stage 1, regression models were employed to determine unique sensor-based behavioral predictors of pain. These sensor-based parameters were used to create a classification model to predict the weekly recalled pain intensity and interference level using a deep neural network model, a machine learning approach, in Stage 2. Daily step count was a unique predictor for both pain intensity (75% Accuracy, F1 = 0.58) and pain interference (82% Accuracy, F1 = 0.59). The developed classification model performed well in this dataset with acceptable accuracy scores. This study demonstrated that machine learning technique can be used to identify the relationship between patients' pain and the risk factors.

An Examination of Prescribing Responsibilities between Psychiatrists and Primary Care Providers.

Patients with comorbid mental health and chronic conditions often receive care from both psychiatrists and primary care physicians (PCPs). The introduction of multiple providers into the care process introduces opportunities for disruptions in care continuity. The purpose of this study was to explore psychiatrists' and PCPs' comfort prescribing, along with their comfort having other physician specialties prescribe medications for cardiometabolic, psychiatric, and neurological/behavioral conditions. This cross-sectional study utilized an online, validated, pilot-tested, anonymous survey to examine prescribing practices of psychiatrists and PCPs. Eligible participants included physicians with medical degrees, U.S. prescribing authority, and active patient care for ≥2 days/week. Outcomes of interest were physicians' self-comfort and cross-specialty comfort (other specialists prescribing mutual patients' medications) prescribing cardiometabolic, psychiatric, and neurological/behavioral medications. Comfort prescribing was measured using 7-point Likert scales. Discrepancies in comfort were analyzed using student's, one-sample, and paired t-tests. Multiple linear regressions examined associations between physician practice characteristics and physicians' comfort-level prescribing cardiometabolic and psychiatric medication categories. Among 50 psychiatrists and 50 PCPs, psychiatrists reported significantly lower self-comfort prescribing cardiometabolic medications (mean ± SD = 2.99 ± 1.63 vs. 6.77 ± 0.39, p < 0.001), but significantly higher self-comfort prescribing psychiatric medications (mean ± SD = 6.79 ± 0.41 vs. 6.00 ± 0.88, p < 0.001) and neurological/behavioral medications (mean ± SD = 6.48 ± 0.74 vs. 5.56 ± 1.68, p < 0.001) than PCPs. After adjusting for covariates, physician specialty was strongly associated with self-comfort prescribing cardiometabolic and psychiatric medication categories (both p < 0.001). Differences between self-comfort and cross-specialty comfort were identified. Because comfort prescribing medications differed by physician type, incorporating psychiatrists through collaborative methods with PCPs could potentially ensure comfort among physicians when initiating medications.

Impact of a Low-Intensity Resource Referral Intervention on Patients' Knowledge, Beliefs, and Use of Community Resources: Results from the CommunityRx Trial.

BACKGROUND: Connecting patients to community-based resources is now a cornerstone of modern healthcare that supports self-management of health. The mechanisms that link resource information to behavior change, however, remain poorly understood. OBJECTIVE: To evaluate the impact of CommunityRx, an automated, low-intensity resource referral intervention, on patients' knowledge, beliefs, and use of community resources. DESIGN: Real-world controlled clinical trial at an urban academic medical center in 2015-2016; participants were assigned by alternating week to receive the CommunityRx intervention or usual care. Surveys were administered at baseline, 1 week, 1 month, and 3 months. PARTICIPANTS: Publicly insured adults, ages 45-74 years. INTERVENTION: CommunityRx generated an automated, personalized list of resources, known as HealtheRx, near each participant's home using condition-specific, evidence-based algorithms. Algorithms used patient demographic and health characteristics documented in the electronic health record to identify relevant resources from a comprehensive, regularly updated database of health-related resources in the study area. MAIN MEASURES: Using intent-to-treat analysis, we examined the impact of HealtheRx referrals on (1) knowledge of the most commonly referred resource types, including healthy eating classes, individual counseling, mortgage assistance, smoking cessation, stress management, and weight loss classes or groups, and (2) beliefs about having resources in the community to manage health. KEY RESULTS: In a real-world controlled trial of 374 adults, intervention recipients improved knowledge (AOR = 2.15; 95% CI, 1.29-3.58) and beliefs (AOR = 1.68; 95% CI, 1.07-2.64) about common resources in the community to manage health, specifically gaining knowledge about smoking cessation (AOR = 2.76; 95% CI, 1.07-7.12) and weight loss resources (AOR = 2.26; 95% CI 1.05-4.84). Positive changes in both knowledge and beliefs about community resources were associated with higher resource use (P = 0.02). CONCLUSIONS: In a middle-age and older population with high morbidity, a low-intensity health IT intervention to deliver resource referrals promoted behavior change by increasing knowledge and positive beliefs about community resources for self-management of health. NIH TRIAL REGISTRY: NCT02435511.

Pharmacist-led motivational interviewing for diabetes medication adherence in a worksite wellness program.

OBJECTIVE: The primary objective was to evaluate the impact of a pharmacist-delivered motivational interviewing (MI) intervention for diabetes medication adherence; the secondary objectives were to assess the changes in clinical outcomes and health-related quality of life (HRQoL). METHODS: A quasi-experimental intervention study was conducted with baseline, postintervention, and follow-up data collections. The study duration was 6 months. Pharmacists trained in MI delivered 3 face-to-face encounters using MI-based semistructured conversation tools to address barriers or challenges to medication adherence. A diabetes worksite wellness program (WWP) at a 350-bed regional hospital in the southeastern United States was the setting, and the study participants were WWP employees or dependents (with type 1 diabetes or type 2 diabetes). The primary outcome was a change in self-reported diabetes medication adherence; the secondary outcomes included the changes in clinical indicators (glycated hemoglobin [HbA1c], blood pressure, and depressive symptoms), and HRQoL. The measures included the Medometer, Summary of Diabetes Self-Care Activities-Medication Subscale (SDSCA-MS), Audit of Diabetes-Dependent QoL (ADDQoL-19), and the Short Form-12 (SF-12) health survey. RESULTS: Fifty-three WWP participants enrolled, and 36 completed the full intervention protocol. Medication adherence (through the Medometer) demonstrated statistically significant improvement after the intervention (P = 0.010); the SDSCA-MS score improved, but was not statistically significant. The change in diastolic blood pressure was statistically significant (P = 0.034), but the changes in HbA1c, systolic blood pressure, presence of depressive symptoms, and ADDQoL-19 were not statistically significant. The SF-12 physical component summary (PCS) and mental component summary (MCS) scores were statistically significant: PCS, P = 0.003, and MCS, P = 0.025. CONCLUSION: The findings from this pilot study support the effectiveness of a pharmacist-delivered, semistructured MI-based intervention for medication adherence in persons with diabetes in a hospital-based WWP. Pharmacists can support patients' behavior change using MI communication skills to explore salient barriers to medication adherence and to facilitate goal setting to overcome these in encounters aimed at shared clinical and behavioral decision-making.

Intentional endometrial injury increases embryo implantation potentials through enhanced endometrial angiogenesis†.

Embryo implantation rates have been found to be enhanced by precedent endometrial injuries, but the underlying mechanism is not fully investigated. Endometrial inflammation occurs both at peri-implantation period and after endometrial injury, in which vascular reaction is a distinctive feature of inflammation. In this study, intentional endometrial injury was done with a 0.7-mm-diameter brush inserted into the left uterine horn of female ICR mice, then turned around 720° (group 2), and the right uterine horn served as the controls without endometrial injuries (group 1). Intraperitoneal equine chorionic gonadotropin 2.5 IU was injected, followed by human chorionic gonadotropin 10 IU injection, and the uterus was dissected 5 days later, roughly at the peri-implantation period. The peri-implantation endometrium was obtained, and angiogenesis protein array revealed that matrix metalloproteinase-3 (MMP-3), plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor binding protein 1 (IGFBP-1), and IL-1α were more strongly expressed in injured endometrium (group 2) than in the controls (group 1). Immunohistochemical CD34 staining was more prominently expressed in group 2 uterus, and the treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly decreased CD34 immunopositive cells. The capabilities of permeability, proliferation, tube formation, and migration of mouse endometrial endothelial cells were significantly enhanced in group 2 than in group 1. Our results demonstrate that enhanced endometrial angiogenesis is a possible mechanism accounting for the increased endometrial receptivity after endometrial injury.

CommunityRx: A Real-World Controlled Clinical Trial of a Scalable, Low-Intensity Community Resource Referral Intervention.

OBJECTIVES: To test the effect of CommunityRx, a scalable, low-intensity intervention that matches patients to community resources, on mental health-related quality of life (HRQOL) (primary outcome), physical HRQOL, and confidence in finding resources. METHODS: A real-world trial assigned publicly insured residents of Chicago, Illinois, aged 45 to 74 years to an intervention (n = 209) or control (n = 202) group by alternating calendar week, December 2015 to August 2016. Intervention group participants received usual care and an electronic medical record-generated, personalized list of community resources. Surveys (baseline, 1-week, 1- and 3-months) measured HRQOL and confidence in finding community resources to manage health. RESULTS: At 3 months, there was no difference between groups in mental (-1.03; 95% confidence interval [CI] = -3.02, 0.96) or physical HRQOL (0.59; 95% CI = -0.98, 2.16). Confidence in finding resources was higher in the intervention group (odds ratio = 2.08; 95% CI = 1.18, 3.63); the effect increased at each successive time point. Among intervention group participants, 65% recalled receiving the intervention; 48% shared community resource information with others. CONCLUSIONS: CommunityRx did not increase HRQOL, but its positive effect on confidence in finding resources for self-care suggests that this low-intensity intervention may have a role in population health promotion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02435511.

Predicting the serum digoxin concentrations of infants in the neonatal intensive care unit through an artificial neural network.

BACKGROUND: Given its narrow therapeutic range, digoxin's pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age, especially for critically ill newborns. There is limited evidence to support the safety and dosage requirements of digoxin, let alone to predict its concentrations in infants. This study aimed to compare the concentrations of digoxin predicted by traditional regression modeling and artificial neural network (ANN) modeling for newborn infants given digoxin for clinically significant patent ductus arteriosus (PDA). METHODS: A retrospective chart review was conducted to obtain data on digoxin use for clinically significant PDA in a neonatal intensive care unit. Newborn infants who were given digoxin and had digoxin concentration(s) within the acceptable range were identified as subjects in the training model and validation datasets, accordingly. Their demographics, disease, and medication information, which were potentially associated with heart failure, were used for model training and analysis of digoxin concentration prediction. The models were generated using backward standard multivariable linear regressions (MLRs) and a standard backpropagation algorithm of ANN, respectively. The common goodness-of-fit estimates, receiver operating characteristic curves, and classification of sensitivity and specificity of the toxic concentrations in the validation dataset obtained from MLR or ANN models were compared to identify the final better predictive model. RESULTS: Given the weakness of correlations between actual observed digoxin concentrations and pre-specified variables in newborn infants, the performance of all ANN models was better than that of MLR models for digoxin concentration prediction. In particular, the nine-parameter ANN model has better forecasting accuracy and differentiation ability for toxic concentrations. CONCLUSION: The nine-parameter ANN model is the best alternative than the other models to predict serum digoxin concentrations whenever therapeutic drug monitoring is not available. Further cross-validations using diverse samples from different hospitals for newborn infants are needed.

Increased platelet factor 4 and aberrant permeability of follicular fluid in PCOS.

BACKGROUND/PURPOSE: Abnormal folliculogenesis is one of the cardinal presentations of polycystic ovarian syndrome (PCOS) and permeability of follicular wall has been proposed to be involved in the normal follicular growth. However, whether or not there is a change in intrafollicular permeability underlies PCOS is unknown. METHODS: This was a tertiary center-based case-control study. From 2014 to 2015, thirteen patients with PCOS who underwent in vitro fertilization-embryo transfer (IVF-ET) were enrolled. Eleven normo-ovulatory patients who underwent IVF-ET due to male factor and/or tubal factor infertility were enrolled as the control group. The influence of ovarian follicular fluid (FF) on endothelial cell permeability was evaluated using a human umbilical vein endothelial cell monolayer permeability assay. The intrafollicular expression profiles of angiogenesis-related proteins were analyzed using a Human Angiogenesis Protein Array Kit. RESULTS: The FF from PCOS patients caused significantly poorer endothelial cell permeability comparing with the effect of FF from the control group (46% ± 12% vs. 58% ± 9%, P = 0.023). Among the 55 angiogenesis-related proteins tested, there was a significantly higher level of intrafollicular platelet factor 4 (PF4) and PF4/IL-8 complex in the PCOS group (p = 0.004). The anti-permeability effect of PF4 was related to the decrease in the intercellular gaps and antagonistic binding with IL-8. CONCLUSION: Our study provides the first evidence of the pathophysiologic contribution of the well-known angiostatic protein, PF4, on human reproductive biology. The increase of the intrafollicular PF4 and its anti-permeability effect might affect the formation of FF and folliculogenesis in PCOS.