Target Patient Population Research Articles

Translational and clinical pharmacology considerations in drug repurposing for X-linked adrenoleukodystrophy-A rare peroxisomal disorder.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early-stage clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

95 Assessment of Social Determinants of Health and Linkage to Care Within the UMassMemorial Medical Center Emergency Department

The contribution of social determinants of health (SDOH) to poor health outcomes is well established, and the emergency department (ED) is the most common site of contact between socially vulnerable patients and the healthcare system. The ED is thus uniquely well positioned to screen patients for social determinants of health and connect those identified as having social needs with appropriate community resources. Before such programs are developed, more information regarding the needs and characteristics of the target patient population is required. Our objective was to characterize the prevalence of common social determinants of health among adult patients presenting to a high volume, urban ED at an academic medical center in New England. During April 2021, four research assistants (RAs) administered a SDOH survey based on Boston Medical Center’s THRIVE Social Determinants of Health Screening and Referral Program. Patients were screened during 8-hr shifts over 16 days, corresponding to 24-hr coverage over 7 days. Exclusion criteria included patients with age under 18 yr, medical or cognitive inability to participate, or currently in state or federal custody. Patients were verbally consented in their preferred language and survey responses were entered into a dedicated REDCap database; interpreter services were used for all low-English proficiency patients. All patients were offered referrals to local community resources via text or email through the CommunityHELP.org platform at the conclusion of the survey. Patients were considered to have a positive screen for social risk factors if they responded “Sometimes true” or “Often true” to Likert scale questions regarding the frequency of risk, or “Yes” to binary risk questions. A total of 650 patients were approached by RAs, of whom 343 were eligible to participate in the survey; 122 eligible patients (35.6%) were identified as screen positive for SDOH risk factors. Patients screening positive were significantly more likely to be of Hispanic ethnicity (23.0% v. 9.1%, p<0.001), nonwhite race (30.3% v. 16.9%, p=0.004), and income < $40, 000/yr (51.0% v. 23.7%, p<0.001). Among patients with positive screens, the most common risks identified were concerns regarding food insecurity (n=59, 48.4%), access to transportation for medical appointments (n=36, 29.5%), cost of medications (n=34, 27.9%), and heat or electricity bills (n=34, 27.9%). A significantly greater proportion of patients with positive SDOH screens reported an increase in their needs during the COVID-19 pandemic (55.9% v. 21.0%, p<0.001). This SDOH screening study indicates that our ED population has significant unmet social risks and needs. More research on ED-based solutions will be necessary address this growing need in our population, and thereby improve health outcomes.

Leveraging real-world evidence for determining performance goals for medical device studies.

Performance goals are numerical target values pertaining to effectiveness or safety endpoints in single-arm medical device clinical studies. Typically, performance goals are determined at the planning stage of the investigational study under consideration based on summarized outcome information from existing relevant clinical trials. In recent years, there is a growing interest in leveraging real-world evidence in medical product development. In this article, we introduce a new method for proposing performance goals by leveraging real-world evidence. The method applies entropy balancing to address possible patient dissimilarities between the study's target patient population and existing real-world patients, and can take into account operation differences between clinical studies and real-world clinical practice. An illustrative example is provided to demonstrate how to implement the proposed method for performance goal determination while leveraging real-world evidence.

Ibrutinib in Steroid-Refractory Chronic Graft-versus-Host Disease, a Single-Center Experience

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogenic hematopoietic stem cell transplantation. Corticosteroid-based therapies are a mainstay of its initial treatment but there is no consensus in how to treat steroid-refractory cGVHD. Ibrutinib is a Bruton tyrosine kinase and IL-2-inducible kinase inhibitor thought to affect pathways driving cGVHD, and it was approved for the treatment of refractory cGVHD by the Food and Drug Administration (FDA) in August 2017 after a landmark phase 1b/2 study. It was the first medication approved for this indication, but how to best treat refractory cGVHD remains an open question, and there has been limited literature on ibrutinib after the FDA approval. This study sought to characterize the utilization and outcomes associated with ibrutinib use in cGVHD via a retrospective single-center study. Fifty-three patients were identified as having been treated with ibrutinib for cGVHD following FDA approval between September 1, 2017, and December 31, 2020, using an institutional data repository. Their records were reviewed for demographics, cGVHD characteristics, and outcomes. For the entire cohort, two-year overall survival was 76% (95% confidence interval [CI], 60% to 86%), with a median follow-up among survivors of 26 months (range, 1.3 to 39.5 months). However, the 2-year failure-free survival (FFS) after initiation of ibrutinib was 9% (95% CI, 2.6% to 20%), and the median FFS was 4.5 months (95% CI, 2.8 to 7.1 months). Events of FFS included treatment change due to lack of response or toxicity, malignant relapse, or non-treatment related mortality. At the time of this report, 11 patients (21%) remained on ibrutinib. At the time of the FFS event or last follow-up, 6 patients (12%) had a complete or partial response, 34 (64%) had stable disease, and 13 (25%) had progressive disease. Ibrutinib use was associated with no reduction in corticosteroid dose between ibrutinib initiation and FFS event or last follow-up (mean difference, 0.00; P=.98). The most frequently used noncorticosteroid cGVHD therapy after ibrutinib was ruxolitinib (n=14; 33%). The most common adverse events associated with treatment discontinuation were infection (lung, skin, enterocolitis; n=6), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleed; n=5), and muscle aches (n=2). In a real-world setting, ibrutinib is associated with a modest response rate and FFS and its use in a narrower, more targeted patient population may be indicated.

Model-Informed Repurposing of Medicines for SARS-CoV-2: Extrapolation of Antiviral Activity and Dose Rationale for Paediatric Patients.

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in the target patient population, which includes not only adults but also children. Here we show how paediatric regimens can be identified using pharmacokinetic-pharmacodynamic (PKPD) principles to establish the target exposure and evaluate the implications of dose selection for early and late intervention. Using in vitro data describing the antiviral activity and published pharmacokinetic data for the agents of interest, we apply a model-based approach to assess the exposure range required for adequate viral clearance and eradication. Pharmacokinetic parameter estimates were subsequently used with clinical trial simulations to characterise the probability target attainment (PTA) associated with enhanced antiviral activity in the lungs. Our analysis shows that neither remdesivir, nor anti-malarial drugs can achieve the desirable target exposure range based on a mg/kg dosing regimen, due to a limited safety margin and high concentrations needed to ensure the required PTA. To date, there has been limited focus on suitable interventions for children affected by COVID-19. Most clinical trials have defined doses selection criteria empirically, without thorough evaluation of the PTA. The current results illustrate how model-based approaches can be used for the integration of clinical and nonclinical data, providing a robust framework for assessing the probability of pharmacological success and consequently the dose rationale for antiviral drugs for the treatment of SARS-CoV-2 infection in children.

Referral of adults with obstructive sleep apnea for surgical consultation: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

This systematic review provides supporting evidence for the accompanying clinical practice guideline on the referral of adults with obstructive sleep apnea (OSA) for surgical consultation. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of upper airway sleep apnea surgery or bariatric surgery to no treatment as well as studies that reported on patient-important and physiologic outcomes pre- and postoperatively. Statistical analyses were performed to determine the clinical significance of using surgery to treat obstructive sleep apnea in adults. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search resulted in 274 studies that provided data suitable for statistical analyses. The analyses demonstrated that surgery as a rescue therapy results in a clinically significant reduction in excessive sleepiness, snoring, blood pressure (BP), apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxygen desaturation index (ODI); an increase in lowest oxygen saturation (LSAT) and sleep quality; and an improvement in quality of life in adults with OSA who are intolerant or unaccepting of positive airway pressure (PAP) therapy. The analyses demonstrated that surgery as an adjunctive therapy results in a clinically significant reduction in optimal PAP pressure and improvement in PAP adherence in adults with OSA who are intolerant or unaccepting of PAP due to side effects associated with high pressure requirements. The analyses also demonstrated that surgery as an initial treatment results in a clinically significant reduction in AHI/RDI, sleepiness, snoring, BP, and ODI and an increase in LSAT in adults with OSA and major anatomical obstruction. Analysis of bariatric surgery data showed a clinically significant reduction in BP, AHI/RDI, sleepiness, snoring, optimal PAP level, BMI, and ODI and an increase in LSAT in adults with OSA and obesity. Analyses of very limited evidence suggested that upper airway surgery does not result in a clinically significant increase in risk of serious persistent adverse events and suggested that bariatric surgery may result in a clinically significant risk of iron malabsorption that may be managed with iron supplements. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. Kent D, Stanley J, Aurora RN, etal. Referral of adults with obstructive sleep apnea for surgical consultation: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(12):2507-2531.

Unsuccessful Progression of Sacral Neuromodulation From the Evaluation to the Implantation Stage: A Single-Center Experience.

IntroductionOver the years, sacral neuromodulation (SNM) has become an established and effective treatment for chronic urinary system retention and incontinence. The process of SNM is performed in two stages, the first is an evaluation phase and the second an implant phase. This study aimed to assess the rate of failure of progression from the evaluation to the implantation stage and the factors predicting the outcome of this commonplace procedure.Materials and methodsThis retrospective cross-sectional study took place at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. All the patients who underwent SNM implantation from January 1, 2016 to January 1, 2021 were included. Patients younger than 14 years and patients who had the SNM implantation in a different hospital and were only followed-up at KAMC were excluded. Patient-related information were extracted from the BESTCare system. Frequency and percentage were used for the categorical variables, and the mean, median, and standard deviation to display the continuous variables. Chi-square test and Mann-Whitney U test were used to test for the association of the categorical variables.ResultsAmong 28 patients, 46.4% (n=13) failed to progress from the evaluation phase to the implantation phase. Gender, age, having a co-morbidity, and SNM indication were not significant factors for predicting the outcome of the SNM evaluation phase.ConclusionThe observed failure rate was marginally higher than the ones detected in other studies. Although no significant association was detected between evaluation stage failure and the assigned predictors, the results need to be interpreted with caution due to the small population size. Larger multicenter studies need to be done in order to investigate the link between patient characteristics and the efficacy of SNM. Establishing a concrete evidence would further refine the targeted patient population and indications for SNM.

Implications of Age on Social Media Utilization in Health Care Practice Development: Cross-sectional Survey Study.

BackgroundMedical practices, which are businesses through which one or more physicians treat patients, have likely not yet taken full advantage of the reach of social media. This study analyzed data collected using an anonymous survey to assess the potential utilization of large, established social media platforms in health care. The survey collected data from a diverse population of health care professional students, faculty, and physicians affiliated with the Texas Tech University Health Sciences Center (TTUHSC). This study provides significant, actionable data to more efficiently implement a social media strategy focused on age to help developing private practices and outpatient clinics from the perspective of those with experience in the field of medicine.ObjectiveThis cross-sectional, exploratory, descriptive study aims to explore the most effective strategies to use social media based on patient age to bring further success to a medical practice.MethodsData were gathered from an anonymous, peer-validated Qualtrics survey created by the corresponding authors based on the recommendations from a panel of experts including executive leadership at TTUHSC. The survey used a variety of question styles to measure differences between social media platforms, including frequency of use, current and future implications in medicine, and comfort in a health care setting. The sample population included students, interns, faculty, and physicians affiliated with the TTUHSC located throughout West Texas.ResultsThe anonymous survey included 673 individuals from several different age groups predetermined at the beginning of the study. There were 154 respondents aged between 18 and 25 years, 171 aged between 26 and 35 years, 133 aged between 36 and 45 years, 104 aged between 46 and 55 years, and 111 aged between 56 and 89 years. The sample population also has a variety of educational achievements. The respondents were grouped based on the highest level of education attained, and this included 23.5% (n=158) of respondents who earned a high school diploma, 42% (n=283) who earned a bachelor’s degree, 17.1% (n=115) who earned a master’s degree, and 17.4% (n=117) who earned a doctorate degree.ConclusionsAs social media continues to gain momentum, efficient utilization of the available platforms can help medical practices achieve larger patient populations and deliver more personalized care. However, privacy and security concerns should be considered while using social media in health care settings. Although this study demonstrated overwhelming interest in using social media in the medical field across all age groups, adoption willingness appears to be higher in younger respondents than in older respondents. Facebook was the most widely accepted social media platform in health care settings among all age groups. Nonetheless, other social media platforms could potentially be used more effectively depending on the age range of the targeted patient population.

Immune cell profiling in atherosclerosis: role in research and precision medicine.

Inflammation is intimately involved at all stages of atherosclerosis and remains a substantial residual cardiovascular risk factor in optimally treated patients. The proof of concept that targeting inflammation reduces cardiovascular events in patients with a history of myocardial infarction has highlighted the urgent need to identify new immunotherapies to treat patients with atherosclerotic cardiovascular disease. Importantly, emerging data from new clinical trials show that successful immunotherapies for atherosclerosis need to be tailored to the specific immune alterations in distinct groups of patients. In this Review, we discuss how single-cell technologies — such as single-cell mass cytometry, single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing — are ideal for mapping the cellular and molecular composition of human atherosclerotic plaques and how these data can aid in the discovery of new precise immunotherapies. We also argue that single-cell data from studies in humans need to be rigorously validated in relevant experimental models, including rapidly emerging single-cell CRISPR screening technologies and mouse models of atherosclerosis. Finally, we discuss the importance of implementing single-cell immune monitoring tools in early phases of drug development to aid in the precise selection of the target patient population for data-driven translation into randomized clinical trials and the successful translation of new immunotherapies into the clinic.

A Health eLearning Ontology and Procedural Reasoning Approach for Developing Personalized Courses to Teach Patients about Their Medical Condition and Treatment.

We propose a methodological framework to support the development of personalized courses that improve patients’ understanding of their condition and prescribed treatment. Inspired by Intelligent Tutoring Systems (ITSs), the framework uses an eLearning ontology to express domain and learner models and to create a course. We combine the ontology with a procedural reasoning approach and precompiled plans to operationalize a design across disease conditions. The resulting courses generated by the framework are personalized across four patient axes—condition and treatment, comprehension level, learning style based on the VARK (Visual, Aural, Read/write, Kinesthetic) presentation model, and the level of understanding of specific course content according to Bloom’s taxonomy. Customizing educational materials along these learning axes stimulates and sustains patients’ attention when learning about their conditions or treatment options. Our proposed framework creates a personalized course that prepares patients for their meetings with specialists and educates them about their prescribed treatment. We posit that the improvement in patients’ understanding of prescribed care will result in better outcomes and we validate that the constructs of our framework are appropriate for representing content and deriving personalized courses for two use cases: anticoagulation treatment of an atrial fibrillation patient and lower back pain management to treat a lumbar degenerative disc condition. We conduct a mostly qualitative study supported by a quantitative questionnaire to investigate the acceptability of the framework among the target patient population and medical practitioners.

Frequency of Helicobacter pylori in patients hemodialysis its correlation with demographic and biochemical factors; a single center study

Introduction: Hemodialysis is one of the most common methods of treating chronic kidney disease (CKD). The start time of dialysis is determined depending on the clinical findings and subjective and objective parameters. However, factors such as patient perception and anxiety related to starting dialysis can modify these parameters. Patients on hemodialysis often have gastrointestinal complications; however, it is unclear whether Helicobacter pylori infection is more prevalent in these patients. Objectives: The aim of this study was to investigate the relative frequency of levels of H. pylori antibody in hemodialysis patients and its relationship with demographic and biochemical factors of hemodialysis patients in a hemodialysis center. Patients and Methods: The present study is a cross-sectional and the target population of patients is the hemodialysis center of Amin hospital in 2019. The sampling method was a non-probabilistic sampling. The sample size in the present study was 85 people. The collected information was entered into SPSS software version 22 and analyzed with appropriate statistical tests. The significance level in the present study was less than 0.05. Results: In total, 85 patients participated in the present study, of which 68% were men and the rest were women. The cut-off point and the positive and negative border of laboratory results for H. pylori were 18.8 U/mL. The mean level of H. pylori antibody was 87.353 ± 104.17 U/mL. In this study, significant relationship between the level of H. pylori antibody and Parathyroid hormone (PTH) was detected. PTH level was lower in patients with a positive result for H. pylori. No further relationship was detected between H. pylori infection and biochemical parameters and blood indices, as well as Kt/V and urea reduction rate (URR) was detected. Additionally, there was no significant difference in the mean level of H. pylori antibody between men and women. Accordingly, there was no significant correlation between H. pylori antibody level and age of patients, duration and number of dialysis sessions and body mass index. Conclusion: Based on the findings of the present study, mean level of PTH was significantly lower in patients with a positive result for H. pylori. No significant relationship was observed between H. pylori infection with other demographic and biochemical factors.

Abstract 1928: Erdafitinib in combination with BCLXL/BCL2 inhibitor induce apoptosis in urothelial carcinoma cells without FGFR mutation

Abstract Although Erdafitinib has recently emerged as a treatment for metastatic urothelial carcinoma, it has been shown to be effective against FGFR mutations, but the target patient population is small, and a new treatment for urothelial carcinoma without FGFR mutations is needed. We found that Erdafitinib degrades MCL1 in urothelial carcinoma cells. Furthermore, we found that in combination with Navitoclax, a BCLXL/BCL2 inhibitor, it induced potent apoptosis in urothelial carcinoma cell lines without FGFR mutation. This combination therapy may represent a new treatment for urothelial carcinoma without FGFR mutations. Citation Format: Akira ohtsu, Seiji Arai, Tatsuhiro Sawada, Kazuhiro Suzuki. Erdafitinib in combination with BCLXL/BCL2 inhibitor induce apoptosis in urothelial carcinoma cells without FGFR mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1928.

Monitoring established Crohn’s disease with pan-intestinal video capsule endoscopy in Europe: clinician consultation using the nominal group technique

Objective Monitoring established Crohn’s disease (CD) through a “treat-to-target” strategy aims to reduce and prevent long-term bowel damage and disability. Despite the availability of different monitoring techniques, there is a current lack of integrated evidence to guide optimal monitoring in terms of appropriate tools and timing. Pan-intestinal video capsule endoscopy (PCE) enables non-invasive and direct visualization of the entire intestinal tract with proven safety and efficacy. This study aims to generate insights on the value of PCE for monitoring established CD from the physician’s perspective. Methods The Nominal Group Technique (NGT) was used to create discussion around pre-defined research questions aimed at identifying target patient populations for PCE, benefits of PCE in terms of improving disease management, comparative benefits of PCE over standard of care, research priorities to ratify the use of PCE, and hurdles to PCE utilization. A NGT panel was held in Brussels, Belgium in October 2018 with 9 gastroenterology experts. Data were collected from multiple rankings of statements to the research questions and analyzed descriptively. Results Consensus indicated that PCE is differentiated from other diagnostic tools, allowing for non-invasive and direct visualization of the luminal intestinal tract in one single procedure. Participants agreed that PCE is beneficial for mapping and grading established CD in all patients, enabling individual and tailored treatment decision-making. Time required to read PCE results was identified as the main utilization hurdle by participants. Well-designed studies are needed to confirm improved outcomes amongst patients with CD managed through a PCE-guided approach. Conclusions This study, using the NGT, generated expert opinion on the value of PCE for monitoring established CD in terms of target patient populations and benefits compared to other diagnostic modalities. Participants perceived PCE to facilitate a “treat-to-target” strategy for CD management. Further research is needed to support this value perception.

Remote home monitoring (virtual wards) for confirmed or suspected COVID-19 patients: a rapid systematic review.

Backgroundthe aim of this review was to analyze the implementation and impact of remote home monitoring models (virtual wards) for confirmed or suspected COVID-19 patients, identifying their main components, processes of implementation, target patient populations, impact on outcomes, costs and lessons learnt.Methodswe carried out a rapid systematic review on models led by primary and secondary care across seven countries (US, Australia, Canada, The Netherlands, Ireland, China, UK). The main outcomes included in the review were: impact of remote home monitoring on virtual length of stay, escalation, emergency department attendance/reattendance, admission/readmission and mortality. The search was updated on February 2021. We used the PRISMA statement and the review was registered on PROSPERO (CRD: 42020202888).Findingsthe review included 27 articles. The aim of the models was to maintain patients safe in the appropriate setting. Most models were led by secondary care and confirmation of COVID-19 was not required (in most cases). Monitoring was carried via online platforms, paper-based systems with telephone calls or (less frequently) through wearable sensors. Models based on phone calls were considered more inclusive. Patient/career training was identified as a determining factor of success. We could not reach substantive conclusions regarding patient safety and the identification of early deterioration due to lack of standardized reporting and missing data. Economic analysis was not reported for most of the models and did not go beyond reporting resources used and the amount spent per patient monitored.Interpretationfuture research should focus on staff and patient experiences of care and inequalities in patients’ access to care. Attention needs to be paid to the cost-effectiveness of the models and their sustainability, evaluation of their impact on patient outcomes by using comparators, and the use of risk-stratification tools.

Assessment of Studies of Quality Improvement Strategies to Enhance Outcomes in Patients With Cardiovascular Disease

Clinical care quality improvement (QI) strategies are critical to prevent and control cardiovascular disease (CVD). However, there is limited evidence regarding which components of the health system-, clinician-, and patient-based QI strategies contribute to their impact on CVD. To identify, map, and organize evidence on the effectiveness and implementation of cardiovascular QI strategies that seek to improve outcomes in patients with CVD. Eight electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, the Cochrane Library, ProQuest, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform) were searched for studies published between January 1, 2009, and October 25, 2019. Eligible study designs included randomized trials and preintervention and postintervention evaluations. Descriptive findings of included studies were reported using several frameworks to map the intervention components stratified by target population, setting, outcomes, and overall results. From 8066 screened titles and abstracts, 456 unique studies with 150 148 unique patients (38.1% women and 61.9% men; mean [SD] age, 64.6 [7.1] years) were identified, including 427 randomized trials, 21 quasi-randomized studies, and 8 preintervention and postintervention studies. Of 336 studies from 45 countries that were classified, 255 (75.9%) were from high-income countries; 68 (20.2%), upper-middle-income countries; 13 (3.9%), lower-middle-income countries; and 0, low-income countries, with diverse clinical settings and target patient populations (post-myocardial infarction, stroke, heart failure). Patient support (311 studies), information communication technology (ICT) for health (78 studies), community support (18 studies), supervision (15 studies), and high-intensity training (14 studies) were the most commonly evaluated QI strategies. Other strategies were group problem-solving (7 studies), printed information (5 studies), strengthening infrastructure (4 studies), and financial incentives (3 studies). Patient support, ICT for health, training, and community support were strategies that had been evaluated the most for clinical end points and showed modest associations with several clinical outcomes. The other strategies did not have outcome-driven evaluations reported. Group problem-solving was associated with improved patient self-care and quality of life. Strengthening infrastructure was associated with improved treatment satisfaction. Printed information and financial incentives showed no meaningful effect. This systematic review found that substantial variations exist in the types, effectiveness, and implementation of QI strategies for patients with CVD. A comprehensive map of QI strategies created by this study would be useful for researchers to identify where new knowledge is needed to improve cardiovascular outcomes. Outcome-driven evaluations and long-term studies are needed, particularly in low-income settings, to better understand the effects of QI strategies on prevention and control of CVD.

Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events.

BackgroundElevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.ObjectiveThis analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.MethodsPhenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child–Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.ResultsPhenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child–Pugh C than in Child–Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.ConclusionsDose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01047-5.

The connected patient project: moving towards a population-based primary health care research registry

BackgroundThe NHS pledges to give all patients access to clinical research. In England, 32% of General Practices are research active and only 14% of patients engage in research. This project aimed to evaluate consent-for-contact and communication in primary care patients.MethodsAn explanatory mixed methods study of patients and staff within a single general practice. The study included all patients over the age of 18 years, and excluded those on the palliative care register and those unable to give informed consent. The questionnaire asked recipients to indicate their preferred contact method and data-sharing permissions with three organisations: NHS, Universities and Commercial Companies. Survey recipients and staff were invited to take part in a semi-structured interview. Interviews explored project acceptability, feasibility and reasoning behind choices made. Statistical data were triangulated with interview data.ResultsThe target patient population was 4678, 24% (n = 1148) responded. Seven hundred and three gave permission for at least one of the organisations to contact them. Older people were more likely to respond than young people, (p < 0.001). There was a trend for more women than men to give permissions however, in the 70 years plus age group this was reversed. Short message service was the preferred method of communication (48% n = 330), but those aged 70 years and over, preferred letter (p = 0.001). Interviews suggested patients felt the project was primarily about improving communication and secondly access to research. Patients trusted the NHS and university researchers. Staff interviewees found the project was less onerous than expected. Barriers to wider rollout included workload and the fragmented nature of NHS digital systems.ConclusionsA registry of patients was established; however, the response rate of 24% needs increasing before wider adoption. Health promotion and chronic disease-based research may recruit better when based in primary health care. Older demographics would be more likely to volunteer for research. NHS and academic researchers are trusted, commercial organisations less so. The move to digitalise communication methods has the potential to marginalise older women. Findings were used to drive forward two novel developments: a consent registry (Research+Me) and a federation-wide participant identification process.

Imaging-based patient inclusion model for clinical trial performance optimization.

105 Background: In the era of precision medicine, development of new cancer therapies relies strongly on effective selection of target patient population. We hypothesize that computational analysis of imaging data can be used for development of a quantitative population enrichment strategy in clinical trials and thus we aim to establish an appropriate framework for this analysis. Methods: This hypothesis was tested among soft-tissue sarcoma (STS) patients accrued into a randomized Phase III clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its survival objective (PMC7771354). We tested whether an inclusion/exclusion model based on radiomic analysis and relevant clinical covariates could have been employed to result in a significant treatment benefit of the Evo+Dox combination compared to the standard Dox monotherapy. A total of 163 radiomics features were extracted from lung metastases of 303 patients from the SARC021 trial, divided into demographically matched training and test sets. Stability analysis identified the most reproducible features. Univariable and multivariable models were utilized to discriminate OS in the two treatment groups. Results: A bespoke enrichment framework was established for individualized patient selection, based on model-derived risk score threshold. A radiomic feature, Short Run Emphasis, was identified as the most informative. When combined with tumor histology and smoking history information, an enriched subset (42%) of patients had longer OS in Evo+Dox vs. Dox groups [p = 0.01, Hazard Ratio (HR) = 0.57 (0.36-0.90)], overperforming a clinical-only approach. Application of the same model and threshold value in an independent test set confirmed the significant survival difference (p = 0.002, HR = 0.29 (0.13-0.63), 38% patients included). The breakdown of Dox+Evo treatment benefit depending on proportion of patients included based on the model is shown in the Table. Notably, this process also identified patients most likely to benefit from doxorubicin alone. Conclusions: The study presents a first of its kind radiomic approach for patient enrichment in clinical trials based on a quantitative score. In particular, we have shown that had the novel model been used for selective patient inclusion into the SARC021 trial, it would have met its primary survival objective for patients with metastatic STS.[Table: see text]

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF)

BackgroundThe Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines. MethodsThe 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM. Score distribution, reliability, construct-related validity, sensitivity to change, and interpretation guidelines were evaluated for AdvSM-SAF items, gastrointestinal symptom score (GSS), skin symptom score (SSS), and total symptom score (TSS). ResultsThirty-one patients contributed to the analyses. At Baseline, the GSS, SSS, and TSS had adequate internal consistency (α > 0.7) and test-retest reliability (intraclass correlation coefficients >0.7). AdvSM-SAF scores were moderately to strongly correlated with variables as expected, and distinguished among clinically distinct groups. Observed relationships between change scores in the AdvSM-SAF and other assessments reflect evidence that AdvSM-SAF scores change in concert with other assessments designed to measure similar constructs. The magnitude of AdvSM-SAF weekly TSS mean change scores based on different anchor groupings was as expected (improvement > stable > worsening). Candidate clinically meaningful between-group difference estimates (GSS = 2–4, SSS = 2–3, and TSS = 4–7 points) and within-person change estimates (GSS = 6–9, SSS = 1–4, TSS = 9–14) for AdvSM-SAF weekly scores were generated. ConclusionThe AdvSM-SAF produced reliable, construct-valid, and sensitive scores when administered in the target patient population. These results, along with its strong development history and evidence of content validity, indicate that the AdvSM-SAF is fit for the purpose of measuring treatment benefit in individuals with AdvSM.