Patient-reported Symptoms Research Articles

Novel CHATogether family-centered mental health care in the post-pandemic era: a pilot case and evaluation

BackgroundThe COVID-19 pandemic impacted children, adolescents, and their families, with significant psychosocial consequences. The prevalence of anxiety, depression, and self-injurious behaviors increased in our youth, as well as the number of suicide attempts and hospitalizations related to suicidal ideation. Additionally, parents’ mental health saw increasing rates of depression, irritability, and alcohol use combined with worsening family function, child-parent connectedness, positive family expressiveness, and increases in family conflict. In light of these statistics, we created CHATogether (Compassionate Home, Action Together), a pilot family-centered intervention using multi-faceted psychotherapeutic approaches to improve familial communication and relational health between adolescents and their parents. This paper discusses the implementation of the CHATogether intervention at the Adolescent Intensive Outpatient Program (IOP), providing an example of the intervention through an in-depth pilot case, and evaluation of the program’s acceptability and feasibility.MethodsThis paper describes a case in detail and evaluation from a total of 30 families that completed CHATogether in the initial pilot. Each family had 4–6 one-hour CHATogether sessions during their 6-week treatment course at the IOP. Before and after CHATogether, adolescents and their parents separately completed a questionnaire designed to explore their perceived family conflicts. After completion of the program, participants completed a brief quality improvement survey to assess their overall experience with CHATogether. In the reported case, the family completed Patient-Reported Outcomes Measurement Information System (PROMIS) depressive and anxiety symptoms scales, Conflict Behavior Questionnaires (CBQ), 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9), and help-seeking attitude from adults during distress and suicide concerns.ResultsThe pilot case showed a trend of improvement in reported depressive and anxiety symptoms, child-parent conflicts, subfactors of suicide risk including pessimism, helplessness, and despair, help-seeking acceptability from parents for suicide concerns, and the establishment of individualized family relationship goals. Preliminary feedback from participating families demonstrated positive effects on intra-family communication and improvement in the overall family dynamic. Adolescents (n = 30/30) and their parents (n = 30/30) rated “strongly agree” or “agree” that their families had benefited from CHATogether and welcomed participation in future program development.ConclusionThis study presents CHATogether as a novel family-centered intervention to address post-pandemic family mental health stress, especially when a family system was disrupted and negatively affected the mental health of children and adolescents. The intervention facilitated positive child-parent communication on a variety of topics, through tools such as emotional expression and help-seeking behavior. The reported pilot case and evaluation suggested CHATogether’s acceptability and feasibility in a clinical context. We also provided quality improvement feedback to guide future studies in establishing the efficacy of CHATogether and other similar models of clinical family interventions.

Long-Term Patient Symptoms and Quality of Life in Adults After COVID-19: A Real Life Study

ObjectiveTo characterize long-term patient-reported symptoms and quality of life, in adults after COVID-19. Material and methodsCross-sectional study in Cantabria (Northern Spain) including adults with PCR-confirmed SARS-CoV-2 infection (n=694) with a time period between 4.7 and 24 month post-SARS-CoV-2 diagnosis, and their close contacts (n=663) (PCR negative and without suspected infection) obtained from simple random sampling of a total of 47,773 cases and 94,301 close contacts. The ISARIC survey was used as screening tool with self-reported “non-feeling fully recovery (NFFR)” defined as primary outcome. Results16.57% (n=115/694) reported NFFR. Most prevalent symptoms were in order of frequency: Fatigue (54.8%); Loss of smell (40.9%); Problems speaking or communicating (29.6%); Loss of taste (28.7%); Confusion/lack of concentration (27.8%); Persistent muscle pain (24.3%) and Shortness of breath/breathlessness (23.5%). When comparing the three ordinal groups (Close contacts, COVID-19 feeling recovered, and COVID-19 NFFR) the prevalence of these symptoms was increasingly higher among each ordinal group (p<0.001). Female gender was significantly associated with NFFR: (adjusted odds ratio (aOR)=1.56); as well as older age: aOR per 10 year increment=1.15. Lastly, they scored on average 9.63 points less in Euroquol. ConclusionsMore than 15% of patients in our real-life population-based study, reported NFFR, being female sex and older age independent predictors of this condition. Most symptoms in these patients were in accordance with WHO definition of post COVID-19 condition in adults, and were less prevalent in COVID-19 feeling recovered and close contact respectively, with a statistically significant dose-response pattern, and with a large decrease in quality of life according to Euroquol.

Pamrevlumab for Idiopathic Pulmonary Fibrosis

Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events. To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis. Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023. Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks. The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported. Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group). Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48. ClinicalTrials.gov Identifier: NCT03955146.

Abstract PO1-11-06: Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms

Abstract Background: Although treatment with an aromatase inhibitor (AI) for 5-10 years decreases 10-year breast cancer mortality by about 40%, up to 25% of patients will stop treatment early because of treatment-related, intolerable joint and muscular pain and stiffness, called aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). We previously identified that nociplastic pain, or chronic pain in the absence of tissue damage or inflammation, is associated with increased likelihood of developing AIMSS. Other studies have found that symptom clusters, such as the SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy/fatigue) are prevalent and co-occur in patients with cancer. Here we examine the prevalence of SPPADE symptoms for patients experiencing AIMSS and willing to enroll on a clinical trial examining use of cannabidiol (CBD) to treat their symptoms. Methods: Patients with stage 0-3 hormone receptor-positive breast cancer experiencing AIMSS (defined as worst joint pain ≥4/10 during prior 7 days that developed or worsened since starting AI therapy) were eligible for enrollment in this single arm, single center phase 2 open label clinical trial (NCT04754399). Enrolled patients completed validated questionnaires at baseline and then received CBD (Epidiolex) for 15 weeks. Patient-reported outcomes (PRO) data was collected serially, including the following questionnaires which addressed SPPADE symptoms: Brief Pain Inventory (BPI) to assess pain, PROMIS Profile 29+2 v2.1 to assess multiple symptoms, and Fibromyalgia Survey (FMS) to assess nociplastic pain. Results: 39 patients enrolled on this clinical trial. The median age at enrollment was 57 (range 37-59) and 21% of patients were over age 70. The majority of patients were white (92%) and average BMI was 31 (SD 6.6). Anastrozole was the most used aromatase inhibitor (74%), followed by exemestane (18%), and letrozole (8%). 5 patients (13%) required concomitant GnRHa therapy. Baseline PRO data was obtained from 37 patients. BPI average pain score over the week prior to enrollment was 5.1 (SD 1.5) and worst pain score was 7.2 (SD 1.3). Pain interference reported on the BPI was 4.1 (SD 2.1). Compared to the general population, enrolled patients reported better physical function (T-score 60.2, SE 3.7), less depression (T-score 45.5, SE 4.7) and fatigue (T-score 46.7, SE 5.1), and similar levels of anxiety (T-score 51, SE 7.1) and sleep disturbance (T-score 49.5, SE 5.9) on the PROMIS Profile. On the FMS, 62% of patients had evidence of nociplastic pain, with average score 13.3 (SD 5.7). The median number of sites of pain in the body reported by patients was 8 (range 1-16). Conclusions: While patients enrolling on an AIMSS clinical trial reported a high degree of daily pain that regularly interferes with their activities, for most patients these symptoms did not appear to have a negative impact on mood, affect, or other symptoms that typically cluster with pain. Though it is difficult to extrapolate results from a small population, the unexpected absence of co-occurring symptoms in this population raises additional questions about the interplay of AIMSS and other symptoms commonly reported in interventional AIMSS studies. Follow-up PRO data will be obtained in this clinical trial, allowing us to examine the impact of CBD use on pain, pain interference, and other patient-reported symptoms, as well as to explore which patients are more likely to obtain benefit from CBD treatment. Funding support provided by Conquer Cancer, the ASCO Foundation and the Rising Tide Foundation for Clinical Cancer Research. Citation Format: Fleege Nicole, N. Lynn Henry. Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-06.

Abstract PO5-11-11: Risk Assessment, Prevention and Early Detection of Breast Cancer Related Lymphedema – Objective Measurements and Patient Reported Outcomes

Abstract Background Breast cancer-related lymphedema (BCRL) affects the quality of life, but there is no consensus regarding early detection and monitoring. Patient-reported outcomes (PROs) are important in assessing cancer survivor outcomes, and different questionnaires have been developed. LYMPHA (Lymphatic Microsurgical Preventive Healing Approach) and S-LYMPHA (Simplified LYMPHA) have reduced BCRL rates. This study aims to identify the most reliable PRO in a South Florida multi-ethnic population and to study correlations between PROs and objective measurements in the first 6 months after axillary surgery. Methods Patients undergoing axillary lymph node dissection (ALND) or axillary radiation were included. L-Dex score (Bioimpedance Spectroscopy) and three validated questionnaires (LyQLI, Lymphedema Quality of Life Inventory; LyQOL, Lymphedema Quality of Life and FACT-B4+ Functional Assessment of Cancer Therapy – Lymphedema) were recorded at baseline, and 6 months post-surgery to assess the agreement between patient-reported symptoms and BCRL. L-Dex score outside the normal range or a 10 unit increase above baseline was considered lymphedema. Additional variables such as demographics, tumor characteristics, and treatment modalities were recorded. Results Out of 40 recruited patients, 39 were analyzed (excluding one deceased patient). Patient and treatment characteristics are described in Table 1. Patients were divided into three cohorts (Figure 1) for analysis: ALND with no axillary radiation (7.69%; n=33), Sentinel Lymph Node Biopsy (SLNB) with axillary radiation (7.69 %; n=3), and ALND with axillary radiation (85%; n=3). In the first cohort, LYMPHA or S-LYMPHA were associated with lower rates of lymphedema (19% vs, 50%) (p=0.116). No patients in the second or third cohort developed lymphedema. There were 4 out of 20 (20%) patients with lymphedema with scores above the median for FACT B4+ (p= 0.480) and a lower score (higher quality of life) correlated with lower L-Dex (p=0.76). The higher value in the physical domain of LyQLI showed higher L-Dex (p=0.826). There was a significant inter-domain correlation in LyQLI and LyQOL (p= &amp;lt; 0.001). Conclusion These results validate the use of PROs alongside objective measurements to assess BCRL. In addition, LYMPHA and S-LYMPHA significantly reduce lymphedema rates. Larger numbers will be necessary to reach statistical significance and to identify the best PRO. Figure 1 Division of patient population into three cohorts Table 1 Demographic and Treatment Summary Citation Format: Anshumi Desai, Orli-Friedman Eldar, Gili Halfteck, Mecker Moller, Susan Kesmodel, Dido Franceschi, Neha Goel, Jessica Crystal, Laura Huang, Jennifer Hu, Koru-Sengal Tulay, Wei Zhao, Alexis Narvaez-Rojas, Eli Avisar. Risk Assessment, Prevention and Early Detection of Breast Cancer Related Lymphedema – Objective Measurements and Patient Reported Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-11-11.

Abstract PO2-11-04: Assessing quality of Life in breast cancer patients undergoing mHealth mobile monitoring: A descriptive Analysis

Abstract Background: Breast cancer (BC) can be associated with a significant symptom burden that can be related both to the disease and to administered therapies. In particular, protocol related toxicity has an extreme impact on patient quality of life (QoL), and can lead to lack of adherence and ultimately, compromise therapy success. There is increasing interest in adopting more effective approaches for active/continuous patient-reported symptom monitoring. Emerging evidence, (Denis et al. 2019), shows that this strategy can reduce toxicity, emergency room visits, and improve QoL. Objectives: We aimed to analyze the QoL of women with BC diagnosis who underwent mobile-based continuous monitoring, searching for possible trends and describing the population. Methods: We conducted a retrospective analysis using data from patients with BC undergoing systemic treatment and monitored by a mobile-based application between January 2022 and June 2023 at an outpatient clinic in Brazil. Thummi is a digital platform for remote monitoring of cancer patients which enables them to record symptoms, toxicities and lifestyle variables. Utilizes the data to generate personalized recommendations and advice. It is available in Brazil at no cost. Doctors indicate the use and can monitor their patients in real time. In addition to an algorithm that informs the user if there is a need to go to the emergency room or not, the medical team can exchange real-time messages with patients. Clinicians have access to patient data through a web tool, allowing them to visualize the information, address symptom alerts, and make informed clinical-therapeutic decisions. The evaluated sample is from patients who come from physicians who indicated the use, without control of their origin, indication of treatment or clinical stage. The data were extracted from the platform's total database. Participants were requested to complete the Quality of Life Questionnaire (EORTC EQ-5D) integrated into the app every month. Inclusion criteria comprised a BC diagnosis, age ≥18, and having responded to the QoL questionnaire with at least a one-month interval between scores. Patients who failed to meet these criteria were excluded from the analysis. A comparison of QoL scores was performed between two periods: T0 (the first recorded response) and T1 (the subsequent response with at least a one-month interval between scores). Descriptive statistical analyses were conducted to search for possible trends, describe the population, and comprehensively examine the differences in QoL scores between T0 and T1. Results: There were 134 active patients in the mobile-based platform with a BC diagnosis, but only 86 (64,17%) met the inclusion criteria for the final analysis. The median age of this group was 54 years old (range 22-78). The most common treatments administered were Cyclophosphamide-Doxorubicin (28 patients, 33%) and Trastuzumab-Deruxtecan (18 patients, 21%). The average QoL score in T0 was 0,70 (SD 0,1379) and 1,0 (SD 0,1560) at T1, representing an increase of 30% after using the app for one month. Conclusion: This study suggests that mobile-based monitoring has the potential to improve the QoL for women diagnosed with BC. The difference in average QoL scores between the initial and subsequent periods indicates a positive impact of utilizing the platform. Further research is needed to establish a better correlation and to explore the specific interventions that contribute to these improvements. Implementing mobile-based monitoring in clinical practice could enhance patient well-being, treatment adherence, and survival time and can potentially lessen both burden of disease and resource utilization in BC care. Citation Format: Alessandra Morelle, Carlos Barrios, Carlos Pereira, Vinicius Agibert, Pedhro Lennon Freitas, Matheus Rocha, Paulo Schulze. Assessing quality of Life in breast cancer patients undergoing mHealth mobile monitoring: A descriptive Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-04.

Abstract PO4-18-10: Randomized controlled trial of Young, Empowered &amp; Strong (YES), a web-based patient-reported symptom monitoring and self-management portal for adolescent and young adult (AYA) breast cancer (BC) survivors

Abstract Background: BC is the most common malignancy diagnosed in AYAs. AYAs develop more biologically aggressive BC and present at more advanced stages, necessitating more intensive therapy with curative intent. While acute physical sequelae often resolve following initial treatment, the long-term physical and psychosocial impact of BC on a survivor’s life may worsen or emerge in survivorship. This impact includes symptoms (e.g., sexual problems, anxiety, fatigue, stress, sleep issues, hot flashes) as well as concerns unique to, or accentuated by, being young (e.g., fertility, genetics, childrearing, educational/work attainment). With provider attention to these issues often sub-optimal, strategies that empower patients have the potential to improve their well-being. To engage and activate AYA BC survivors, we developed YES, a web-based portal that leverages electronic patient-reported outcomes (ePROs) to facilitate self-monitoring and management of symptoms/AYA concerns. In contrast to ePRO models dependent on clinician interaction, our approach emphasizes self-management of chronic survivorship concerns outside of the clinic environment. This model is grounded in the reality that most clinicians have limited bandwidth to address these needs and considers that AYAs can have competing demands (e.g., missing work, child-care) that may make accessing in-person support challenging. Methods: The YES study is a randomized controlled trial of the YES intervention vs. usual care. YES supports participants to 1) self-monitor needs/symptoms; and 2) provides a repository for information and resources on self-management of symptoms/AYA concerns. Eligibility criteria include: female, age 15-39 years at diagnosis, stage 0-III BC, within 3 years of diagnosis, no recurrent/second primary BC, no other malignancy since BC diagnosis, and English speaking. Participants randomized to the YES arm are prompted through a monthly text or email to complete an ePRO assessment regarding current symptoms/AYA concerns. For each symptom/concern endorsed, information/resources to address the symptom/concern is automatically provided via the YES portal. The portal is monitored, and providers are contacted if participants report severe distress or suicidality. YES also provides peer support via a chat room and self-support through a journaling platform in the portal. Participants in the usual care group are offered access to YES for up to 3 months at the end of their 9-month study participation. All participants complete a REDCap survey with validated measures of quality of life (QOL), symptoms, and other PROs at baseline, 3, 6, and 9 months after randomization and provide a dried blood spot specimen via a self-administration kit at baseline and 6 months. The primary study aim is to determine the efficacy of YES vs. usual care in improving life quality measured by the QOL in Adult Cancer Survivors [QLACS] scale at 6 months post-randomization. With a planned sample size of 360 participants, the study will have ≥90% power to detect a 6-point mean change (6 months vs. baseline) in the cancer-specific QLACS score between arms. Secondary outcomes include efficacy of YES in reducing symptoms/AYA concerns at 6 months and sustainability of the effects of YES at 9 months. Repeated measures regression will be used with link functions selected based on the type of outcome data analyzed. Exploratory aims will evaluate moderators and mediators of intervention efficacy and the effects of YES on inflammatory biomarkers. At study completion, a subset of 30 participants diverse in age, race, ethnicity, and gender identity are invited to participate in an interview to understand their survivorship preferences/concerns and to understand how the portal supported their self-management. The YES trial opened to enrollment in 9/2021. As of 6/2023, 245 participants are enrolled. Clinical Trials Information: NCT04906200 Citation Format: Shoshana Rosenberg, Yue Zheng, Dawn Hershman, Craig Snow, Kate Dibble, Magnolia Contreras, Noel Roma, Nabihah Tayob, Michelle Naughton, Ann Partridge. Randomized controlled trial of Young, Empowered &amp; Strong (YES), a web-based patient-reported symptom monitoring and self-management portal for adolescent and young adult (AYA) breast cancer (BC) survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-10.

Time to re-define ‘normal’ in the context of Post-Acute COVID-19 biomarkers in the assessment of patient outcomes?

Introduction: Post-acute COVID-19 or Long COVID (LC) is a threat to health and well-being, and 1 in 10 infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop persistent symptoms. LC is associated with &gt;200 symptoms that impact quality of life and functional status. Many LC patients are being dismissed from care due to returning ‘normal’ results on ‘routine’ clinical investigations. Accordingly, the objective of the study was to explore the relationship between potential diagnostic biomarkers, symptom profile severity and functional status. Method: Participants with a confirmed history of COVID-19 were recruited from Long COVID clinics in the United Kingdom, as part of a 16-week cohort observation study. Venous blood samples were taken from 35 individuals [24 female] and assessed for standard clinical chemistry markers of inflammatory and metabolic status, including full blood count (white blood cells [WBC], red blood cells [RBC], platelets, haemoglobin, hematocrit, ferritin, mean corpuscular volume [MCV] mean corpuscular haemoglobin [MCH], mean corpuscular haemoglobin concentration [MCHC], red cell distribution width [RDW], basophils, neutrophils, lymphocytes, eosinophils, monocytes), CRP, d dimers, interleukin 6 (IL-6), and lactate dehydrogenase [LDH]. Patient-reported outcomes and symptoms were assessed by validated self-report methods including fatigue, dyspnoea, cognitive deficit, quality of life and symptom frequency and severity. Functional status was assessed via 6-Minute-Walk (6MWT). Results: Sixty-three percent of participants [17 female] had one or more values outside of expected reference ranges (WBC n=3, RBC n=6, haemoglobin n=3, haematocrit n=2, MCV n=3, MCH n=3, MCHC n= 1, RDW n=4, neutrophils n=3, lymphocytes n=5, monocytes n=1, basophils n=2, CRP n=3, ferritin n=3, d-dimer n=9). These changes were not linked to changes in function status or patient-reported outcomes ( p=&gt;0.05), but there was a significant between-group difference with those outside of expected reference ranges completing less on the 6MWT on their final visit ( p=&lt;0.05). Discussion: The pathophysiology of LC is complex and patients report broad symptoms across multiple organ systems, such as respiratory, gastrointestinal, cardiovascular, and the autonomic nervous system. Routine clinical investigations of biomarkers are vital, but assessments often return results within a pre-determined ‘normal’ range. Whilst routine testing is important, condition-specific investigations should also be explored. Further inspection of the data in reference to the symptom profile and reduced functional status demonstrates a need for more holistic approaches. Conclusion: The complex pathophysiology of LC requires further understanding and development of investigative approaches to LC diagnoses and treatment. Routine investigations of people with LC demonstrate abnormal responses, and even those that return ‘normal’ results experience debilitating symptom profiles and reduced quality of life. Due to the complex underlying mechanistic issues of LC, more specific biochemical profiling is required during clinical investigations. This study was supported by an unrestricted investigator-sponsored research grant from Gilead Sciences (#IN-UK-983-6080). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Special issue PRO] A demonstration of estimands and sensitivity analyses for time-to-deterioration of patient reported outcomes

ABSTRACT In oncology trials, health-related quality of life (HRQoL), specifically patient-reported symptom burden and functional status, can support the interpretation of survival endpoints, such as progression-free survival. However, applying time-to-event endpoints to patient-reported outcomes (PRO) data is challenging. For example, in time-to-deterioration analyses clinical events such as disease progression are common in many settings and are often handled through censoring the patient at the time of occurrence; however, disease progression and HRQoL are often related leading to informative censoring. Special consideration to the definition of events and intercurrent events (ICEs) is necessary. In this work, we demonstrate time-to-deterioration of PRO estimands and sensitivity analyses to answer research questions using composite, hypothetical, and treatment policy strategies applied to a single endpoint of disease-related symptoms. Multiple imputation methods under both the missing-at-random and missing-not-at-random assumptions are used as sensitivity analyses of primary estimands. Hazard ratios ranged from 0.52 to 0.66 over all the estimands and sensitivity analyses modeling a robust treatment effect favoring the treatment in time to disease symptom deterioration or death. Differences in the estimands include how people who experience disease progression or discontinue the randomized treatment due to AEs are accounted for in the analysis. We use the estimand framework to define interpretable and principled approaches for different time-to-deterioration research questions and provide practical recommendations. Reporting the proportions of patient events and patient censoring by reason helps understand the mechanisms that drive the results, allowing for optimal interpretation.

Unmet needs in phenylketonuria: an exploratory Italian survey among patients and caregivers

Objective Patients with phenylketonuria (PKU) require a strict diet to maintain phenylalanine (Phe) levels within the desired range. However, the diet can be onerous, resulting in poor adherence. We carried out the first online national survey in Italy to better understand the perceptions, knowledge, and experiences of both patients with PKU and caregivers with the goal of improving patient outcomes. Methods An online survey of 35 questions to patients and 36 questions to caregivers was distributed in September 2022 through physicians and relevant Italian associations. The information collected included knowledge and impact of PKU, unmet needs, knowledge of available drugs, and satisfaction with therapy. Results Overall, 241 questionnaires were completed by 85 patients and 156 caregivers (96.0% were parents). Knowledge of the pathogenic basis of PKU was generally high. The most common patient-reported symptoms were agitation/anxiety (48.8%), fatigue (41.1%), mood disorders (39.8%), and difficulty concentrating (33.4%). Different perspectives on adherence to a low-Phe diet were observed (22.9% of patients reported strict adherence vs. 47.0% of caregivers). Drugs that allow more freedom were needed by 49.4% of patients and 61.7% of caregivers, along with a wider range of choices of non-dietary treatments (48.2% and 60.0%, respectively). Unmet informational needs of patients included PKU and pregnancy, complications, travel, sports, and transition into adult care. Conclusions Our data showed that patients with PKU and their caregivers reported difficulties in adherence to diet therapy and indicated interest in new therapeutic approaches. Apparent differences between patient and caregiver perspectives were identified. More informational resources on PKU are needed.

Longitudinal changes in adiposity following anterior cruciate ligament reconstruction and associations with knee symptoms and function

ObjectiveTo evaluate adiposity after anterior cruciate ligament reconstruction (ACLR): i) cross-sectionally (1-year post-ACLR) compared to uninjured controls; ii) longitudinally up to 5 years post-ACLR; and iii) associations with patient-reported symptoms and physical performance. MethodsIn 107 individuals post-ACLR and 19 controls, we assessed global (BMI), peripheral (subcutaneous adipose tissue thickness on the posteromedial side of knee MRI), and central (waist circumference in ACLR group) adiposity. Patient-reported symptoms (Knee injury and Osteoarthritis Outcome Score) and physical performance (hop for distance) were evaluated at 1 and 5 years post-ACLR. Linear regression models evaluated adiposity between groups. Paired t-tests evaluated changes in adiposity from 1- to 5 years post-ACLR. Linear regression models analyzed adiposity's associations with patient-reported symptoms and physical performance at 1-year post-ACLR, changes in symptoms and performance over 4 years post-ACLR, and longitudinal changes in adiposity and symptoms and performance, controlling for age, sex, and activity level. ResultsIndividuals 1-year post-ACLR were associated with higher average global (3 ​kg/m2) and peripheral adiposity (2.3 ​mm). From 1- to 5 years post-ACLR, higher average global (0.58 ​kg/m2) and central (5 ​cm) adiposity, and lower average peripheral adiposity (1.3 ​mm) were observed. In general, adiposity at one-year post-ACLR was negatively associated with patient-reported symptoms and physical performance, and changes from 1 to 5 years post-ACLR. Increases in adiposity were negatively associated with changes in patient-reported symptoms and physical performance over four years post-ACLR. ConclusionGreater global and central adiposity is a feature of young adults following ACLR and influences current and future patient-reported symptoms and physical performance.

Patient-reported outcomes after personalised dose-escalation for stage II-III non-small-cell lung cancer patients: Results from the randomised ARTFORCE PET-Boost trial

Background and purposeThe ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy. Materials and methodsThe international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0–5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes. ResultsBetween Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months. ConclusionIn patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue.

Intermediate-Term Clinical Outcomes of High-Density Autologous Chondrocyte Implantation in Patients with Concomitant Anterior Cruciate Ligament Reconstruction and Focal Chondral Lesions.

To investigate intermediate-term clinical results in patients with concomitant anterior cruciate ligament (ACL) reconstruction and chondral defect treated with high-density autologous chondrocyte implantation (HD-ACI) compared to patients without ACL tear but with a chondral lesion and HD-ACI treatment. Forty-eight patients with focal chondral lesions underwent HD-ACI (24 with ACL reconstruction after an ACL injury and 24 with an intact ACL). Follow-up assessments occurred at 6, 12, and 24 months. Patient-reported knee function and symptoms were assessed using the International Knee Documentation Committee (IKDC) questionnaire, pain was measured using the Visual Analog Scale (VAS), and adverse events were monitored. Physical activity was assessed using the Tegner Activity Level Scale, and cartilage healing was evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. No significant adverse events occurred during follow-up. Both groups showed significant improvements at 2 years compared to baseline (VAS: 8.0 ± 1.3 to 1.4 ± 2.0 [normal ACL]; 7.4 ± 2.3 to 2.1 ± 2.3 [ACL reconstruction]; IKDC: 39.2 ± 10.6 to 76.1 ± 22.0 [intact ACL]; 35.6 ± 12.1 to 74.6 ± 20.9 [ACL reconstruction]). Patients in both groups exceeded the minimal clinically important difference (MCID) for IKDC scores. The Tegner Activity Level Scale decreased immediately after surgery and increased after 2 years, with 70.6% (normal ACL) and 89.5% (ACL reconstruction) returning to their preinjury activity levels. No significant differences in the MOCART score were observed between the groups. ACL reconstruction does not appear to reduce the outcomes (at 2 years) of HD-ACI.

Impact of SARS-CoV-2 Infection on Long-Term Depression Symptoms among Veterans

BackgroundPrior research demonstrates that SARS-COV-2 infection can be associated with a broad range of mental health outcomes including depression symptoms. Veterans, in particular, may be at elevated risk of increased depression following SARS-COV-2 infection given their high rates of pre-existing mental and physical health comorbidities. However, few studies have tried to isolate SARS-COV-2 infection associations with long term, patient-reported depression symptoms from other factors (e.g., physical health comorbidities, pandemic-related stress).ObjectiveTo evaluate the association between SARS-COV-2 infection and subsequent depression symptoms among United States Military Veterans.DesignSurvey-based non-randomized cohort study with matched comparators.ParticipantsA matched-dyadic sample from a larger, stratified random sample of participants with and without known to SARS-COV-2 infection were invited to participate in a survey evaluating mental health and wellness 18-months after their index infection date. Sampled participants were stratified by infection severity of the participant infected with SARS-COV-2 (hospitalized or not) and by month of index date. A total of 186 participants in each group agreed to participate in the survey and had sufficient data for inclusion in analyses. Those in the uninfected group who were later infected were excluded from analyses.Main MeasuresParticipants were administered the Patient Health Questionnaire-9 as part of a phone interview survey. Demographics, physical and mental health comorbidities were extracted from VHA administrative data.Key ResultsVeterans infected with SARS-COV-2 had significantly higher depression symptoms scores compared with those uninfected. In particular, psychological symptoms (e.g., low mood, suicidal ideation) scores were elevated relative to the comparator group (MInfected = 3.16, 95%CI: 2.5, 3.8; MUninfected = 1.96, 95%CI: 1.4, 2.5). Findings were similar regardless of history of depression.ConclusionSARS-COV-2 infection was associated with more depression symptoms among Veterans at 18-months post-infection. Routine evaluation of depression symptoms over time following SARS-COV-2 infection is important to facilitate adequate assessment and treatment.

Association between vertebral endplate defects and patient-reported symptoms: an immunohistochemical study investigating the COX-2/PGE-2/EP-4 axis

Background ContextVertebral endplate defects are often implicated in degenerative disc disorders, yet their connection to patient-reported symptoms remains unclear. COX-2 and PGE-2 are known for their roles in inflammation and pain, with EP-4 receptor involvement in pain signaling. Examining their expression in vertebral endplate tissues may provide insights into pathomechanism of low back pain. PurposeTo investigate the association between endplate defects and patient-reported symptoms and to further clarify the role of the COX-2/PGE-2/EP-4 axis in the pathogenesis of chronic low back pain. Study Design/SettingRetrospective study. Patient SampleA total of 71 patients who had undergone single-level L4/5 or L5/S1 modified laminectomy decompression preserving proximal upper laminae and transforaminal lumbar interbody fusion surgery were included in this study, including 18 patients diagnosed with lumbar disc herniation, 19 with lumbar disc herniation accompanied by degenerative lumbar spinal stenosis, and 34 with degenerative spondylolisthesis. Outcome MeasuresDemographic data, Pfirrmann grade, Modic changes, endplate defect score, visual analog scale (VAS) for back and leg pain, and Oswestry Disability Index (ODI) before surgery, 3-month and 6-month follow-up, and the percentage of immune-positive cells (COX-2, PGE-2, and EP-4) in endplate tissue sections. MethodsPatients were divided into defect and nondefect groups according to endplate morphology on lumbar MR. All intraoperative endplate specimens were immediately fixed in 10% formaldehyde, and then embedded in paraffin 3 days later for tissue sections. The outcome measures were compared between the defect group and nondefect group. Data were analyzed using independent t-tests and χ² tests. Pearson's rank correlation test was used to assess correlations between patient-reported symptoms and the percentage of immune-positive cells in the groups. Multivariable logistic regression models using the forward stepwise likelihood ratio method were used to identify the factors that were independently associated with endplate defects. ResultsThe age of Defect group was significantly higher than that of nondefect group (52.5±7.7 vs 57.2±9.1. p=.024). There were no significant differences in gender, diagnosis, BMI, comorbidities, or surgical level between the two groups. Modic changes (Type Ⅱ/Type Ⅲ) were more common in patients of Defect group than nondefect group (38.5% vs 11.1%, p<.001), and so was disc degeneration (Pfirrmann grade Ⅳ/Ⅴ) (69.2% vs 33.3%, p<.001). Defect group had significantly higher VAS-Back (6.5±2.0 vs 4.9±1.6, p<.001) and ODI scores (62.9±10.7 vs 45.2±14.8, p<.001) than nondefect group, while there was no significant differences between the two groups during the 3 and 6-month follow-up after surgery. Histologically, Defect group was characterized by upregulation of COX-2, PGE-2, and EP-4 in endplate tissue sections. Both in defect and nondefect groups, VAS-Back showed moderate positive correlations with the expressions of COX-2 (r=0.643; r=0.558, p both<.001), PGE-2 (r=0.611; r=0.640, p both<.001), and EP-4 (r=0.643; r=0.563, p both<.001). Multivariate regression analyses reveled that percentage of COX-2-positive cells was associated with endplate defects (OR=1.509, 95%CI [1.048–2.171], p=.027), as well as percentage of PGE-2-positive (OR=1.291, 95%CI [1.106–1.508], p=.001) and EP-4-positive cells (OR=1.284, 95%CI [1.048∼2.171], p=.003). ConclusionsPatients with endplate defects had worse quality of life, more severe disc degeneration and Modic changes, and up-regulated COX-2/PGE-2/EP-4 axis expression in cartilage endplates in patients with defected endplates. Inflammatory factors may significantly contribute to the onset and progression of chronic low back pain in patients with endplate defects, consequently impacting patient-reported symptoms.

Patient-Reported Sinonasal Symptoms and Risk of Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Relapses are frequent and difficult to predict in antineutrophil cytoplasmic antibody-associated vasculitis (AAV), resulting in long-term use of immunosuppression. Although sinonasal disease is associated with relapse of AAV, detailed characterization of sinonasal symptoms is lacking. Using a patient-reported outcome, the 22-item SinoNasal Outcome Test (SNOT-22), we investigated the relationship between sinonasal symptoms and disease activity in AAV. This was a prospective, longitudinal study of individual with AAV and healthy individuals. Relapse was defined as a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis score >0. Higher SNOT-22 scores indicate worse symptoms. Generalized estimating equation and Cox proportional hazard models evaluated the association between SNOT-22 and relapse. There were 773 visits (106 active disease visits) from 168 patients with AAV and 51 controls. Median SNOT-22 at remission was higher in AAV versus controls (20 vs 5; P < 0.001) and higher during active disease versus remission (P < 0.001). In all AAV, and particularly within granulomatosis with polyangiitis, higher SNOT-22 scores were observed months to years before relapse and were associated with increased risk of relapse (hazard ratio 2.7, 95% confidence interval 1.2-6.2; P = 0.02). Similar findings were seen when examining patients with versus without sinonasal disease and after removing relapses limited to the ear, nose, and throat. A patient-reported outcome measure of sinonasal disease, the SNOT-22, not only changes with disease activity in AAV, but also is associated with a higher risk of relapse within two years. These findings support the possibility that the SNOT-22 score may enhance prediction of relapse and that persistent sinonasal disease may be important in the pathophysiology of relapse.

Ankle inversion proprioception measured during stair descent can identify chronic ankle instability

BackgroundIndividuals with chronic ankle instability (CAI) may experience recurrent ankle sprains and symptoms during daily activities such as stair descent, where the associated proprioceptive deficit is largely unevaluated. ObjectivesTo evaluate the reliability and validity of an ankle inversion discrimination apparatus for stair descent, and examine whether proprioceptive scores from this apparatus are associated with patient-reported symptoms. DesignCross-sectional study. MethodSixty-six participants volunteered in this study. The ankle inversion discrimination apparatus was purpose-built to assess ankle proprioception across four positions of ankle inversion (10°, 12°, 14°, and 16°) during stair descent. The Area Under the Receiver Operating Curve (AUC) was employed as the ankle proprioceptive discrimination score. ResultsTest-retest reliability ICC (3,1) for the whole group was 0.825, with 0.747 for the non-CAI group (95%CI = 0.331–0.920) and 0.701 for CAI (95%CI = 0.242–0.904). The CAI group performed at a significantly lower level than non-CAI on the ankle inversion discrimination apparatus for stair descent assessment (0.769 ± 0.034 vs. 0.830 ± 0.035, F = 33.786, p < 0.001). CAIT scores were strongly and significantly correlated with scores from this apparatus (Spearman's rho = 0.730, p < 0.001). ConclusionsThe ankle inversion discrimination apparatus for stair descent is reliable and valid for assessing task-specific ankle proprioceptive impairments in CAI. The strong and significant relationship found between ankle proprioception during stair descent and the severity of CAI suggests that rehabilitation programs focusing on deficits in ankle inversion proprioception during stair descent may improve self-reported instability in CAI.

Novel Approach for Detecting Respiratory Syncytial Virus in Pediatric Patients Using Machine Learning Models Based on Patient-Reported Symptoms: Model Development and Validation Study.

Respiratory syncytial virus (RSV) affects children, causing serious infections, particularly in high-risk groups. Given the seasonality of RSV and the importance of rapid isolation of infected individuals, there is an urgent need for more efficient diagnostic methods to expedite this process. This study aimed to investigate the performance of a machine learning model that leverages the temporal diversity of symptom onset for detecting RSV infections and elucidate its discriminatory ability. The study was conducted in pediatric and emergency outpatient settings in Japan. We developed a detection model that remotely confirms RSV infection based on patient-reported symptom information obtained using a structured electronic template incorporating the differential points of skilled pediatricians. An extreme gradient boosting-based machine learning model was developed using the data of 4174 patients aged ≤24 months who underwent RSV rapid antigen testing. These patients visited either the pediatric or emergency department of Yokohama City Municipal Hospital between January 1, 2009, and December 31, 2015. The primary outcome was the diagnostic accuracy of the machine learning model for RSV infection, as determined by rapid antigen testing, measured using the area under the receiver operating characteristic curve. The clinical efficacy was evaluated by calculating the discriminative performance based on the number of days elapsed since the onset of the first symptom and exclusion rates based on thresholds of reasonable sensitivity and specificity. Our model demonstrated an area under the receiver operating characteristic curve of 0.811 (95% CI 0.784-0.833) with good calibration and 0.746 (95% CI 0.694-0.794) for patients within 3 days of onset. It accurately captured the temporal evolution of symptoms; based on adjusted thresholds equivalent to those of a rapid antigen test, our model predicted that 6.9% (95% CI 5.4%-8.5%) of patients in the entire cohort would be positive and 68.7% (95% CI 65.4%-71.9%) would be negative. Our model could eliminate the need for additional testing in approximately three-quarters of all patients. Our model may facilitate the immediate detection of RSV infection in outpatient settings and, potentially, in home environments. This approach could streamline the diagnostic process, reduce discomfort caused by invasive tests in children, and allow rapid implementation of appropriate treatments and isolation at home. The findings underscore the potential of machine learning in augmenting clinical decision-making in the early detection of RSV infection.

Patient adherence and response time in electronic patient-reported outcomes: insights from three longitudinal clinical trials.

Patient-reported outcome measures (PROMs) are used to collect data on disease symptoms in support of clinical trial endpoints. Clinical studies can last a year or more, and the patients' adherence and response time to daily at-home questionnaires may vary significantly over time. The aim of this study was to understand patterns and changes in patients' completion of daily PROMs during longitudinal clinical studies. Data were collected from 1342 patients randomized into three respiratory clinical trials (NCT03401229, NCT03347279, and NCT03406078). PROMs were completed by patients using electronic handheld devices that collected the starting and completion times. A Bayesian generalized linear mixed-effects model was used to identify unbiased coefficients associated with PROM adherence and response time using patient, site, and calendar features as covariates. Adherence decreased over time after randomization, and the rate of decrease was higher in younger patients. The 14-day pre-randomization adherence was correlated with adherence throughout the study. Patients were also more adherent during working days compared to non-working days. Oldest patients took twice as long to complete PROMs throughout the study; however, the response time for all patients decreased during the first month of the study regardless of age. Response time increased 7days before and after the date of a scheduled clinic visit and when a patient-reported higher symptom burden. Detailed analyses of adherence and response time for daily PROMs in clinical trials can provide significant insights about trends of patient behavior in longitudinal clinical studies with high baseline adherence.

Patient-reported Symptoms of Mood, Fatigue, and Sleep Are Not Captured by Clinician-reported Outcomes in Patients with LGI1-IgG Autoimmune Encephalitis (S4.002)

Patient-reported Symptoms of Mood, Fatigue, and Sleep Are Not Captured by Clinician-reported Outcomes in Patients with LGI1-IgG Autoimmune Encephalitis (S4.002)