Advance Care Planning (ACP) in Medicare Beneficiaries with Heart Failure.

BACKGROUND: Heart failure is a leading cause of death in the USA, contributing to high expenditures near the end of life. Evidence remains lacking on whether billed advance care planning changes patterns of end-of-life healthcare utilization among patients with heart failure. Large-scale claims evaluation assessing billed advance care planning and end-of-life hospitalizations among patients with heart failure can fill evidence gaps to inform health policy and clinical practice. OBJECTIVE: Assess the association between billed advance care planning delivered and Medicare beneficiaries with heart failure upon the type and quantity of healthcare utilization in the last 30 days of life. DESIGN: This retrospective cross-sectional cohort study used Medicare fee-for-service claims from 2016 to 2020. PARTICIPANTS: A total of 48,466 deceased patients diagnosed with heart failure on Medicare. MAIN MEASURES: Billed advance care planning services between the last 12 months and last 30 days of life will serve as the exposure. The outcomes are end-of-life healthcare utilization and total expenditure in inpatient, outpatient, hospice, skilled nursing facility, and home healthcare services. KEY RESULTS: In the final cohort of 48,466 patients (median [IQR] age, 83 [76-89] years; 24,838 [51.2%] women; median [IQR] Charlson Comorbidity Index score, 4 [2-5]), 4406 patients had an advance care planning encounter. Total end-of-life expenditure among patients with billed advance care planning encounters was 19% lower (95% CI, 0.77-0.84) compared to patients without. Patients with billed advance care planning encounters had 2.65 times higher odds (95% CI, 2.47-2.83) of end-of-life outpatient utilization with a 33% higher expected total outpatient expenditure (95% CI, 1.24-1.42) compared with patients without a billed advance care planning encounter. CONCLUSIONS: Billed advance care planning delivery to individuals with heart failure occurs infrequently. Prioritizing billed advance care planning delivery to these individuals may reduce total end-of-life expenditures and end-of-life inpatient expenditures through promoting use of outpatient end-of-life services, including home healthcare and hospice.

How Ohio public library systems respond to opioid-related substance use: a descriptive analysis of survey results.

BACKGROUND: Public libraries in the United States have experienced increases in opioid-related substance use in their communities and on their premises. This includes fatal and non-fatal overdose events. Some libraries have adopted response measures in their branches to deter substance use or prevent overdose. A small number of libraries around the nation have decided to stock the opioid antagonist naloxone (Narcan) for staff to administer to patrons who experience overdose. This response measure has generated extensive media attention. Although Ohio ranks fourth in age-adjusted drug mortality rate in the United States, there has been no investigation of whether Ohio libraries are observing opioid-related transactions, consumption, and/or overdose events, or which measures they have adopted in response to these activities. We conducted a multimethod survey with Ohio public library directors to identify the response measures they have adopted. We present descriptive findings from the quantitative and qualitative items in our survey. METHODS: We conducted a cross-sectional 54-item multimethod survey of public library system directors (one per system) in Ohio. Directors of each of Ohio's public library systems were invited to participate via email. RESULTS: Of 251 library systems, 56 responded (22.3% response rate), with 34 respondents (60.7%) indicating awareness of opioid-related transactions, consumption, and/or overdose on their premises. Most (n = 43, 76.8%) did not stock naloxone in their buildings. Over half (n = 34, 60.7%) reported implementing one or more non-naloxone response measures. These measures focus on improving security for staff and patrons, deterring opioid-related transactions (purchases and exchanges) and consumption, and providing educational events on substance use. Nearly half (n = 25, 47.2%) partner with community organizations to provide opioid response measures. A similar proportion reported adequate funding to respond to opioid-related substance use (n = 23, 45.1%), and most (n = 38, 74.5%) reported adequate support from their boards and communities. Few respondents have implemented evaluations of their response measures. CONCLUSIONS: Ohio public libraries are responding to evidence of opioid-related transactions, consumption, and/or overdose on their premises with a range of measures that focus on substance use prevention and deterrence. Most Ohio library systems do not stock naloxone. Respondents indicated they prefer to call 911 and let first responders handle overdose events. The majority of respondents indicated their library systems have political capacity to respond to evidence of opioid-related substance use on their premises, but have limited operational and functional capacity. Findings suggest the need to revisit assumptions that public libraries are willing to stock naloxone to respond to overdose events, and that libraries have the resources to respond robustly to opioid-related transactions, consumption, and/or overdose on their premises.

Retrospective cohort study of scalp cooling in breast cancer patients.

For patients with cancer, alopecia is a common side effect that negatively impacts personal identity, body image, self-esteem, quality of life, and medical decision-making. Scalp cooling is a technique used to prevent alopecia in patients undergoing chemotherapy in which patients wear a cooled cap during chemotherapy infusions, causing localized vasoconstriction of blood vessels on the scalp. Because of the recent emergence of scalp cooling, there is a need to explore further the reasons why patients pursue this treatment. A retrospective chart review of women with breast cancer treated at The Ohio State University was conducted to investigate how factors such as patient age, race, ethnicity, insurance status, stage of cancer, and chemotherapy regimen influenced patients' decisions to incorporate scalp cooling into their treatment plan as compared to those who did not. Findings revealed that patient age, race, insurance status, and chemotherapy regimen were predictors of a patient's likelihood to undergo scalp cooling. Patients diagnosed at younger age and those with private insurance were more likely to utilize scalp cooling. In comparison to White patients, non-White patients were less likely to choose scalp cooling. Furthermore, patients placed on the chemotherapy regimen of AC or AC-T were less likely to pursue scalp cooling than patients on PTCH or TC regimens. These findings provide background for the development of educational resources for both patients interested in this therapy and healthcare providers discussing this treatment option in dermatology and oncology settings.

Controlling the false-discovery rate when identifying the subgroup benefiting from treatment.

One common goal of subgroup analyses is to determine which (if any) types of patients-sets of patients sharing a vector of baseline covariates-benefit from a particular treatment. Many approaches involve testing, implicitly or explicitly, hypotheses about many patient types which are nonexchangeable. Methods of controlling family-wise Type I error rate inflation in such approaches are available. Such methods are designed to control the rate of erroneously declaring at least one type of patient as benefiting and are, therefore, quite conservative. We present a method for instead controlling a weighted false discovery rate in the sense of controlling the expected proportion of patient types declared benefiting, weighted by their population prevalence, which do not in fact benefit from treatment. Such population-weighted false discovery rate control is analogous to maintaining the positive predictive value of a diagnostic test for expected benefit. We minimize power loss by using a resampling approach that accounts for correlation among test statistics corresponding to similar patient types. Simulation studies demonstrate successful control of the weighted false discovery rate by the proposed method, as well as anti-conservativeness in the absence of multiplicity corrections and conservativeness by methods controlling the false discovery rate without accounting for dependent test statistics or controlling the family-wise error rate. An analysis of a clinical trial of an Alzheimer's disease treatment illustrates the approach on real data. Resampling-based methods allow weighted false discovery rate control without unnecessarily sacrificing power when treatment effect estimates are correlated among patient types, and admit useful interpretations in terms of bounding sets and positive predictive value.

The Evolution of Primary Care Telehealth Disparities During COVID-19: Retrospective Cohort Study.

BACKGROUND: Telehealth has become widely used as a novel way to provide outpatient care during the COVID-19 pandemic, but data about telehealth use in primary care remain limited. Studies in other specialties raise concerns that telehealth may be widening existing health care disparities, requiring further scrutiny of trends in telehealth use. OBJECTIVE: Our study aims to further characterize sociodemographic differences in primary care via telehealth compared to in-person office visits before and during the COVID-19 pandemic and determine if these disparities changed throughout 2020. METHODS: We conducted a retrospective cohort study in a large US academic center with 46 primary care practices from April-December 2019 to April-December 2020. Data were subdivided into calendar quarters and compared to determine evolving disparities throughout the year. We queried and compared billed outpatient encounters in General Internal Medicine and Family Medicine via binary logic mixed effects regression model and estimated odds ratios (ORs) with 95% CIs. We used sex, race, and ethnicity of the patient attending each encounter as fixed effects. We analyzed socioeconomic status of patients in the institution's primary county based on the patient's residence zip code. RESULTS: A total of 81,822 encounters in the pre-COVID-19 time frame and 47,994 encounters in the intra-COVID-19 time frame were analyzed; in the intra-COVID-19 time frame, a total of 5322 (11.1%) of encounters were telehealth encounters. Patients living in zip code areas with high utilization rate of supplemental nutrition assistance were less likely to use primary care in the intra-COVID-19 time frame (OR 0.94, 95% CI 0.90-0.98; P=.006). Encounters with the following patients were less likely to be via telehealth compared to in-person office visits: patients who self-identified as Asian (OR 0.74, 95% CI 0.63-0.86) and Nepali (OR 0.37, 95% CI 0.19-0.72), patients insured by Medicare (OR 0.77, 95% CI 0.68-0.88), and patients living in zip code areas with high utilization rate of supplemental nutrition assistance (OR 0.84, 95% CI 0.71-0.99). Many of these disparities persisted throughout the year. Although there was no statistically significant difference in telehealth use for patients insured by Medicaid throughout the whole year, subanalysis of quarter 4 found encounters with patients insured by Medicaid were less likely to be via telehealth (OR 0.73, 95% CI 0.55-0.97; P=.03). CONCLUSIONS: Telehealth was not used equally by all patients within primary care throughout the first year of the COVID-19 pandemic, specifically by patients who self-identified as Asian and Nepali, insured by Medicare, and living in zip code areas with low socioeconomic status. As the COVID-19 pandemic and telehealth infrastructure change, it is critical we continue to reassess the use of telehealth. Institutions should continue to monitor disparities in telehealth access and advocate for policy changes that may improve equity.

Multiplicity-adjusted semiparametric benefiting subgroup identification in clinical trials.

Background A recent focus in the health sciences has been the development of personalized medicine, which includes determining the population for which a given treatment is effective. Due to limited data, identifying the true benefiting population is a challenging task. To tackle this difficulty, the credible subgroups approach provides a pair of bounding subgroups for the true benefiting subgroup, constructed so that one is contained by the benefiting subgroup while the other contains the benefiting subgroup with high probability. However, the method has so far only been developed for parametric linear models. Methods In this article, we develop the details required to follow the credible subgroups approach in more realistic settings by considering nonlinear and semiparametric regression models, supported for regulatory science by conditional power simulations. We also present an improved multiple testing approach using a step-down procedure. We evaluate our approach via simulations and apply it to data from four trials of Alzheimer's disease treatments carried out by AbbVie. Results Semiparametric modeling yields credible subgroups that are more robust to violations of linear treatment effect assumptions, and careful choice of the population of interest as well as the step-down multiple testing procedure result in a higher rate of detection of benefiting types of patients. The approach allows us to identify types of patients that benefit from treatment in the Alzheimer's disease trials. Conclusion Attempts to identify benefiting subgroups of patients in clinical trials are often met with skepticism due to a lack of multiplicity control and unrealistically restrictive assumptions. Our proposed approach merges two techniques, credible subgroups, and semiparametric regression, which avoids these problems and makes benefiting subgroup identification practical and reliable.

A Bayesian credible subgroups approach to identifying patient subgroups with positive treatment effects.

Many new experimental treatments benefit only a subset of the population. Identifying the baseline covariate profiles of patients who benefit from such a treatment, rather than determining whether or not the treatment has a population-level effect, can substantially lessen the risk in undertaking a clinical trial and expose fewer patients to treatments that do not benefit them. The standard analyses for identifying patient subgroups that benefit from an experimental treatment either do not account for multiplicity, or focus on testing for the presence of treatment-covariate interactions rather than the resulting individualized treatment effects. We propose a Bayesian credible subgroups method to identify two bounding subgroups for the benefiting subgroup: one for which it is likely that all members simultaneously have a treatment effect exceeding a specified threshold, and another for which it is likely that no members do. We examine frequentist properties of the credible subgroups method via simulations and illustrate the approach using data from an Alzheimer's disease treatment trial. We conclude with a discussion of the advantages and limitations of this approach to identifying patients for whom the treatment is beneficial.

Partnered dance evokes greater intrinsic motivation than home exercise as therapeutic activity for chemotherapy-induced deficits: secondary results of a randomized, controlled clinical trial.

Introduction: Dance has been proposed to support superior intrinsic motivation over non-dance forms of therapeutic physical activity. However, this hypothesis has yet to be evaluated empirically, particularly among populations living with neuropathology such as survivors of cancer with neurologic complications from chemotherapy treatment. Questions about motivation are relevant to clinical outcomes because motivation mediates neuroplasticity. We conducted this secondary analysis of a randomized-controlled study to begin to investigate the relationships between personal motivation and neurophysiologic effects of dance-based intervention for healthy aging among populations with neurologic complications of cancer. Methods: We measured motivation using the Intrinsic Motivation Inventory, a validated patient-reported outcome from the psychological approach of Self Determination Theory. We assessed intrinsic motivation, extrinsic motivation, and satisfaction with intervention within a randomized controlled trial of dance versus exercise designed to alleviate symptoms of chemotherapy-induced impairment. Fifty-two survivors of breast cancer with chemotherapy-induced neuropathy diagnosis and associated sensorimotor functional deficits were randomized (1:1) to 8 weeks of partnered dance or home exercise, performed biweekly (NCT05114005; R21-AG068831). Results: While satisfaction did not differ between interventions, intrinsic motivation was higher among participants randomized to dance than those randomized to exercise (p < 0.0001 at all timepoints: 2 weeks, 4 weeks, 6 weeks, and 8 weeks of intervention), as was extrinsic motivation at 2 weeks (p = 0.04) and 8 weeks (p = 0.01). Discussion: These data provide evidence that social dance is more motivating than the type of home exercise generally recommended as therapeutic physical activity. The results inform directions for future study of the effect of dance-based therapeutics on embodied agency, neuroplastic changes, and clinically-relevant neuropathic improvement.

A feasibility randomized controlled trial of an mHealth app vs booklets for patient-facing guidelines in adults with SCD.

Despite the increased number of evidence-based guidelines for sickle cell disease (SCD), dissemination of evidence-based guidelines in lay language for individuals or families with SCD has not been evaluated. We conducted a feasibility randomized controlled trial to determine the acceptability of a mobile health (mHealth) app with patient-facing guidelines to improve the knowledge of individuals with SCD about SCD-specific knowledge and reduce hospitalizations. Primary outcome measures include recruitment, retention, and adherence rates. Adults with SCD were enrolled at 2 sickle cell centers between 2018 and 2022. Participants were randomized to receive either an mHealth app + booklet with patient-facing guidelines or a booklet with the guidelines alone. Participants completed surveys at baseline and a final 6-month visit. Approximately 67 of 74 (91%) agreed to participate and were randomized, with 50 of 67 (75%) completing all the study components. All participants who completed the study in the treatment arm used the app. Our results demonstrated high recruitment, retention, and adherence rate for the first randomized trial for an mHealth app with patient-facing guidelines in adults with SCD. This clinical trial was registered at https://www.clinicaltrials.gov/ as #NCT03629678.

Genetic counseling and testing for females at elevated risk for breast cancer: Protocol for the randomized controlled trial of the Know Your Risk intervention.

BACKGROUND: Genetic counseling and testing have an important role in the care of patients at elevated risk for breast cancer. However, conventional pre- and post-test genetic counseling is labor and time intensive, less accessible for patients living outside major urban centers, and impractical on a large scale. A patient-driven approach to genetic counseling and testing may increase access, improve patients' experiences, affect efficiency of clinical practice, and help meet workforce demand. The objective of this 2-arm randomized controlled trial is to determine the efficacy of Know Your Risk (KYR), a genetic counseling patient preference intervention. METHODS: Females (n = 1000) at elevated risk (>20% lifetime) for breast cancer will be randomized to the KYR intervention or conventional genetic counseling. The study will provide comprehensive assessment of breast cancer risk by multigene panel testing and validated polygenic risk score. Primary outcome is adherence to National Comprehensive Cancer Network guidelines for a clinical encounter every 6-12 months and an annual mammogram (breast MRI if recommended) determined by medical record review. Secondary outcomes include adherence to other recommended cancer screening tests determined by medical record review and changes in breast cancer knowledge, perception of risk, post-test/counseling distress, and satisfaction with counseling by completion of three surveys during the study. Study aims will be evaluated for non-inferiority of the KYR intervention compared to conventional genetic counseling. CONCLUSION: If efficacious, the KYR intervention has the potential to improve patients' experience and may change how genetic counseling is delivered, inform best practices, and reduce workforce burden. TRIAL REGISTRATION: ClinicalTrials.govNCT05325151.

Development of a web-based, theory-guided narrative intervention for women at elevated risk for breast cancer.

OBJECTIVE: To describe the development of a web-based, theory-guided narrative intervention that replaces conventional pre-test genetic counseling for women at elevated breast cancer risk. METHODS: We used an iterative process that was guided by health behavior theory and feedback from multiple stakeholder groups including: 1) content input from genetic experts; 2) study team input; 3) review of video storyboards, video example, study logo, recruitment materials, post-test patient preference counseling survey, and additional study surveys; 4) video series development; and 5) intervention review and finalization of study-related materials. RESULTS: The intervention is patient-centered providing convenience and an opportunity for an individual's preferences for post-test counseling delivery. The intervention's efficacy is being determined in a randomized controlled trial compared to conventional genetic counseling for adherence to recommended guidelines and changes in knowledge, perception of breast cancer risk, breast cancer-specific worry, and satisfaction with counseling. CONCLUSION: If efficacious, the intervention may improve the delivery of the genetic testing and counseling process, inform best practices, and reduce the genetic counseling workforce burden. PRACTICE IMPLICATIONS: The developed intervention has the potential to improve the genetic testing and counseling experience for women at elevated risk for breast cancer, inform best practices, and reduce genetic counseling workforce burden.

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

The Immunomodulatory Effects of Dexamethasone on Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

INTRODUCTION: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. METHODS: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. RESULTS: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. CONCLUSION: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status.

Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19).

Resveratrol is a polyphenol that has been well studied and has demonstrated anti-viral and anti-inflammatory properties that might mitigate the effects of COVID-19. Outpatients (N = 105) were recruited from central Ohio in late 2020. Participants were randomly assigned to receive placebo or resveratrol. Both groups received a single dose of Vitamin D3 which was used as an adjunct. The primary outcome measure was hospitalization within 21 days of symptom onset; secondary measures were ER visits, incidence of pneumonia, and incidence of pulmonary embolism. Five patients chose not to participate after randomization. Twenty-one-day outcome was determined of all one hundred participants (mean [SD] age 55.6 [8.8] years; 61% female). There were no clinically significant adverse events attributed to resveratrol. Outpatients in this phase 2 study treated with resveratrol had a lower incidence compared to placebo of: hospitalization (2% vs. 6%, RR 0.33, 95% CI 0.04-3.10), COVID-19 related ER visits (8% vs. 14%, RR 0.57, 95% CI 0.18-1.83), and pneumonia (8% vs. 16%, RR 0.5, 95% CI 0.16-1.55). One patient (2%) in each group developed pulmonary embolism (RR 1.00, 95% CI: 0.06-15.55). This underpowered study was limited by small sample size and low incidence of primary adverse events consequently the results are statistically similar between treatment arms. A larger trial could determine efficacy.Trial Registrations: ClinicalTrials.gov NCT04400890 26/05/2020; FDA IND #150033 05/05/2020.

Monte Carlo approaches to frequentist multiplicity-adjusted benefiting subgroup identification.

One common goal of subgroup analyses is to determine the subgroup of the population for which a given treatment is effective. Like most problems in subgroup analyses, this benefiting subgroup identification requires careful attention to multiple testing considerations, especially Type I error inflation. To partially address these concerns, the credible subgroups approach provides a pair of bounding subgroups for the benefiting subgroup, constructed so that with high posterior probability one is contained by the benefiting subgroup while the other contains the benefiting subgroup. To date, this approach has been presented within the Bayesian paradigm only, and requires sampling from the posterior of a Bayesian model. Additionally, in many cases, such as regulatory submission, guarantees of frequentist operating characteristics are helpful or necessary. We present Monte Carlo approaches to constructing confidence subgroups, frequentist analogues to credible subgroups that replace the posterior distribution with an estimate of the joint distribution of personalized treatment effect estimates, and yield frequentist interpretations and coverage guarantees. The estimated joint distribution is produced using either draws from asymptotic sampling distributions of estimated model parameters, or bootstrap resampling schemes. The approach is applied to a publicly available dataset from randomized trials of Alzheimer's disease treatments.

Randomized Double-blind Placebo-controlled Proof-of-concept Trial of Resveratrol for Outpatient Treatment of Mild Coronavirus Disease (COVID-19).

Resveratrol is a polyphenol that has been well studied and has demonstrated anti-viral and anti-inflammatory properties that might mitigate the effects of COVID-19. Outpatients (N=105) were recruited from central Ohio in late 2020. Participants were randomly assigned to receive placebo or resveratrol. Both groups received a single dose of Vitamin D3 which was used as an adjunct. The primary outcome measure was hospitalization within 21 days of symptom onset; secondary measures were ER visits, incidence of pneumonia and pulmonary embolism. Five patients chose not to participate after randomization. Twenty-one day outcome was determined of all one hundred participants (mean [SD] age 55.6 [8.8] years; 61% female) (or their surrogates). There were no clinically significant adverse events attributed to resveratrol. Outpatients in this phase 2 study treated with resveratrol had a lower incidence compared to placebo of: hospitalization (2% vs. 6%, RR 0.33, 95% CI 0.04-3.10), COVID-related ER visits (8% vs. 14%, RR 0.57, 95% CI 0.18-1.83), and pneumonia (8% vs. 16%, RR 0.5, 95% CI 0.16-1.55). One patient (2%) in each group developed pulmonary embolism (RR 1.00, 95% CI: 0.06-15.55). This underpowered study was limited by small sample size and low incidence of primary adverse events. A larger trial could determine efficacy. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT04400890 26/05/2020; FDA IND #150033 05/05/2020.

Adverse Events and Perception of Benefit From Duloxetine for Treating Aromatase Inhibitor-Associated Arthralgias.

Background: Duloxetine effectively treats aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) in women with breast cancer but causes low-grade toxicities. This secondary analysis examines the relationship between adverse events (AE) and patient-perceived benefit, based on patient self-report that the treatment received was beneficial despite side effects. We hypothesized that duloxetine had a favorable effect on patient-perceived benefit, even among duloxetine-treated patients who experienced AEs and who, had they been treated with placebo, would have experienced none. Methods: Principal stratification was used to estimate the effect of duloxetine vs placebo on patient-perceived benefit and Functional Assessment of Cancer Therapy-Endocrine Scale functional quality of life in the randomized, double-blind trial SWOG S1202 (n = 289). Subgroups of patients were defined by observed and counterfactual (what would have occurred had they been randomly assigned to the opposite study arm) experiences of AEs and the original primary outcome, reduction of average pain after 12 weeks of at least 2 points on the Brief Pain Inventory-Short Form. Results: Duloxetine caused an estimated 23.4% (95% credible interval [CI] = 13.4% to 33.7%) of patients to experience an AE even though they would have experienced none on placebo. Those patients remained more likely to report that their received treatment was beneficial than comparable patients assigned placebo (73.3% vs 41.8%, respectively; 95% CI for difference = 15.4 to 47.2 percentage points), although there was no statistically significant effect of duloxetine on functional quality of life (11.3 vs 9.0, 95% CI for difference = -2.2 to +6.7). Conclusion: Duloxetine resulted in higher patient-perceived benefit, even among those who would have an AE on duloxetine but none on placebo. Treatment of AIMSS with duloxetine should be considered for appropriate patients.

Palliative Care Referral Patterns for Adolescent and Young Adult Patients at a Comprehensive Cancer Center.

Palliative care (PC) serves a valuable role throughout the disease trajectory for adolescents and young adults (AYAs) living with cancer. A 3-year retrospective chart review was performed to characterize AYA PC referral patterns in patients aged 18-39 years to identify strategies for improving PC access. Despite known benefits, AYA referrals to PC during oncologic treatment occurred only for a small percentage of eligible patients (8.4%), largely occurred in the inpatient setting (73%), and were more likely in specific cancer types with high symptom burden and/or poor survival, with the greatest penetrance noted in lung cancer (51%).

A Framework for Safety Evaluation Throughout the Product Development Life-Cycle.

Evaluation of the safety profile of medicines is moving from a more reactive approach, where safety experts and statisticians have been primarily focusing on the review of clinical trial data and spontaneous reports, to a more proactive endeavor with cross-functional teams strategically evolving their understanding of the safety profile. They do this by anticipating the ultimate benefit-risk profile and its related risk management implications from the start of development. The proposed approach is based on assessments of integrated program-level safety data. These data stem from multiple sources such as preclinical information; clinical and spontaneous adverse event reports; epidemiological, real-world, and registry data; as well as, potentially, data from social media. Blended qualitative and quantitative evaluations allow integration of data from diverse sources. Adding to this, a collaborative multidisciplinary view, which is focused on continuous learning and decision-making via diverse safety management teams, ensures that companies look at their growing safety database and associated risk management implications from every relevant perspective. This multifaceted and iterative approach starts early in the development of a new medicine, continues into the post-marketing setting, and wanes as the product matures and the safety profile becomes more well understood. Not only does this satisfy regulatory requirements but, crucially, it provides the healthcare system and treated patients with a better understanding of the drug's safety profile.

Evaluation of a Rapid Assessment Questionnaire Using a Biomarker for Dietary Intake of n-3 Fatty Acids.

While there is considerable evidence supporting health benefits of consuming diets high in omega-3 (n-3) fatty acids, there is no quick and effective tool to measure n-3 intake. The objective of this study was to evaluate the accuracy of a rapid assessment questionnaire (the Omega-3 Checklist) used to quantify intake of n-3 fatty acids. This was done by comparing n-3 intakes to blood biomarkers of n-3 exposure in a population of healthy men and women. In addition, a separate analysis was run including covariates age, sex, and weight, which have been shown to affect n-3 biomarker levels. Reported intake of eicosapentaenoic acid (EPA), docoshexaenoic acid (DHA), and EPA + DHA was correlated with erythrocyte EPA (Spearman's rank correlation rs = 0.51, p < 0.001), DHA (rs = 0.54, p < 0.001), and the Omega-3 Index (rs = 0.57, p < 0.001). These associations remained significant when controlling for age, sex, and weight. Therefore, the Omega-3 Checklist can be a useful, rapid assessment tool to estimate individuals' EPA and DHA intake.