Age-matched Population Research Articles

Pacemaker Implants and Their Influence on the Daily Life of Patients with Dementia with Lewy Bodies: A Qualitative Case Study.

Dementia with Lewy bodies (DLB) is an incurable form of dementia associated with detriments to the daily life of patients and carers from their family. Symptoms of orthostatic hypotension, syncope, and falls are supportive of DLB diagnosis. These symptoms may also be present among people with sick sinus syndrome (SSS), and subsequent pacemaker treatment to manage bradyarrhythmia is associated with improved cognitive function. The prevalence of SSS seems to be higher among people with underlying Lewy body pathology compared to the general age-matched population (5.2% vs. 0.17%). To our knowledge, how people with DLB and their family carers may experience pacemaker treatment to manage bradyarrhythmia has not been previously reported. Therefore, the aim of this study was to explore how people with DLB experience daily life following a pacemaker implant to manage associated symptoms of bradyarrhythmia. A qualitative case study design was used. Two men with DLB and their spouse carers were repeatedly interviewed as a dyad within 1year following implant of a dual-chamber rate-adaptive (DDD-CLS) pacemaker to manage SSS in the men. Content analysis was used to assess the qualitative interview data collected. Three categories emerged: (1) gaining control, (2) maintaining a social life, and (3) being influenced by concurrent diseases. Less syncope/falls and remote pacemaker monitoring increased a sense of control in everyday life, while perceived physical and/or cognitive improvements influenced social participation. The men were still affected by concurrent diseases, which continuously influenced each couple's daily life. Identifying and managing concurrent bradyarrhythmia through a pacemaker implant could improve well-being for people with DLB.

#2617 CHANGES IN PSYCHOSOCIAL HEALTH IN YOUNG ADULTS WITH KIDNEY FAILURE: A 5-YEAR FOLLOW-UP OF THE SPEAK STUDY

Abstract Background and Aims Young adulthood is a sensitive developmental period, and the psychosocial impact of kidney failure in this group is implicated in the observed high risk for transplant loss and death. In the Surveying People Experiencing young Adult Kidney failure (SPEAK) study we described differences in life-course outcomes, worse mental wellbeing and twice the likelihood of psychological disturbance among UK young adults with kidney failure (transplant or dialysis) compared to the general population. There have been no longitudinal studies investigating the natural history of these outcomes as young adults mature and get older. We undertook SPEAK-2 as a five-year follow-up study to address this. Method In this prospective observational study, respondents to SPEAK were invited to complete a revised online survey. PPI guided components of the original survey to amend. We analysed how psychosocial health had changed among respondents between studies using the paired t-test, Wilcoxon signed-rank test and McNemar's test for continues parametric and non-parametric data, and binary data respectively. We compared responses to age-matched respondents of the Health Survey for England 2012 using regression. Responses were weighted to increase generalisability. Results We had 158 survey responses. The analysis of psychological health change over time is presented in Table 1. A greater proportion of participants had evidence of psychological morbidity (45% versus 24% in the original SPEAK study; p<0.001). They had inferior mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale [WEMWBS] β, -1.76; 95% CI, -3.27 to -0.25; P = .02). No differences were identified in domains including quality of life (EQ5D). Key outcomes of the comparison to the age-matched general population are presented in Table 2. Respondents were less likely to be married or have children and were more likely to be living with their parents. They were almost 15 times more likely to report being unable to work due to health. Respondents had poorer quality of life and poorer mental wellbeing compared to the general population. They also five times greater odds of having psychological problems or mental ill health. Conclusion We report the first longitudinal study of the psychosocial health of a cohort of young adults with kidney failure as they age and mature. Over five years, we observed worse psychosocial health in terms of mental wellbeing and psychological morbidity. Respondents also lagged behind their peers in terms of life-course and psychosocial outcomes. Dedicated long-term follow-up is needed to clarify the extent and duration to which kidney failure in young adulthood impacts life participation and psychosocial health in the long term. Regardless, the degree of psychosocial ill health we have described warrants urgent increased support for this group.

Ulcerative colitis-associated carcinogenesis : An update

Ulcerative colitis (UC) is achronic inflammatory bowel disease beginning in the rectum and gradually extending to the right-sided colon and the terminal ileum (backwash-ileitis). Its causes are still not completely understood. Genetic susceptibility, changes in the microbiota and immune response, as well as environmental factors are thought to influence the disease course.Patients with UC are at increased risk of developing colorectal cancer (CRC) when compared to an age-matched normal population. Cancer risk increases with early onset, duration, and extent of the disease, with development of strictures, intraepithelial neoplasia, and concomitant primary sclerosing cholangitis.In contrast to the sporadic adenoma-carcinoma-sequence, UC-related CRC develops through an inflammation-intraepithelial neoplasia-carcinoma-sequence, in which genetic alterations already occur in the inflamed epithelium before the development of intraepithelial neoplasia.This article summarizes the current state of knowledge regarding UC-related carcinogenesis and its possible impact on prevention and therapy.

Electrophysiological trajectories of concussion recovery: From acute to prolonged stages in late teenagers.

Numerous studies have reported electrophysiological differences between concussed and non-concussed groups, but few studies have systematically explored recovery trajectories from acute concussion to symptom recovery and the transition from acute concussion to prolonged phases. Questions remain about recovery prognosis and the extent to which symptom resolution coincides with injury resolution. This study therefore investigated the electrophysiological differences in recoveries between simple and complex concussion. Student athletes with acute concussion from a previous study (19(2) years old) were tracked from pre-injury baseline, 24-48 hours after concussion, and through in-season recovery. The electroencephalography (EEG) with P300 evoked response trajectories from this acute study were compared to an age-matched population of 71 patients (18(2) years old) with prolonged post-concussive symptoms (PPCS), 61 (SD 31) days after concussion. Acute, return-to-play, and PPCS groups all experienced a significant deficit in P300 amplitude compared to the pre-injury baseline group. The PPCS group, however, had significantly different EEG spectral and coherence patterns from every other group. These data suggest that while the evoked response potentials deficits of simple concussion may persist in more prolonged stages, there are certain EEG measures unique to PPCS. These metrics are readily accessible to clinicians and may provide useful parameters to help predict trajectories, characterize injury (phenotype), and track the course of injury.

Evaluation of Psychological Resources of Young Adults With Type 1 Diabetes Mellitus During the Transition From Pediatric to Adult Diabetes Clinics: Multicenter Cross-sectional Study.

The transition period of patients with type 1 diabetes from pediatric to adult-oriented health care is associated with poorer glycemic control and less frequent clinic attendance. Fears and anxiety about the unknown, care approach differences in adult settings, and sadness about leaving the pediatric provider all contribute to a patient's reluctance to transition. This study aimed to evaluate the psychological parameters of young patients with type 1 diabetes transitioning to an adult outpatient clinic during the first visit. We examined 50 consecutive patients (n=28, 56% female) transitioning from March 2, 2021, to November 21, 2022, into adult care (3 diabetes centers from 3 regions in southern Poland: A, n=16; B, n=21; and C, n=13) and their basic demographic information. They completed the following psychological questionnaires: State-Trait Anxiety Inventory (STAI), Generalized Self-Efficacy Scale, Perceived Stress Scale, Satisfaction with Life Scale, Acceptance of Illness Scale, Multidimensional Health Locus of Control Scale Form C, Courtauld Emotional Control Scale, and Quality of Life Questionnaire Diabetes. We compared their data with those for the general healthy population and patients with diabetes from Polish Test Laboratory validation studies. During the first adult outpatient visit, patients' mean age was 19.2 (SD 1.4) years, with a diabetes duration of 9.8 (SD 4.3) years and BMI of 23.5 (SD 3.1) kg/m2. Patients came from diverse socioeconomic backgrounds: 36% (n=18) live in villages, 26% (n=13) live in towns with ≤100,000 inhabitants, and 38% (n=19) live in bigger cities. Regarding therapy type, 68% (n=34) were treated with insulin pump therapy, whereas 32% (n=16) were treated with multiple daily injections. Patients from center A had a mean glycated hemoglobin level of 7.5% (SD 1.2%). There was no difference regarding the level of life satisfaction, perceived level of stress, and state anxiety between the patients and reference populations. Patients had similar health locus of control and negative emotions control to the general population of patients with diabetes. Most patients (n=31, 62%) believe that control over their health depends on themselves, whereas 52% (n=26) believe that it depends mostly on others. Patients had higher levels of suppression of negative emotions-anger, depression, and anxiety-than the age-matched general population. Additionally, the patients were characterized by a higher acceptance of illness and higher level of self-efficacy compared to the reference populations: 64% (n=32) had a high level of self-efficacy and 26% (n=13) had a high level of life satisfaction. This study indicated that young patients transitioning to adult outpatient clinics have good psychological resources and coping mechanisms, which might result in adequate adaptation and adult life satisfaction including future metabolic control. These result also disprove the stereotypes that young people with chronic disease have worse life perspectives when entering adulthood.

0301 Associations between sleep and cognitive function in patients with Neurological post-acute sequelae of SARS-CoV-2 infection

Abstract Introduction Fatigue and sleep disturbance are among the most common neurological post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). We tested the hypothesis that impaired sleep and disrupted rest-activity rhythms are associated with impaired cognitive performance and greater burden of self-reported Neuro-PASC symptoms. Methods Forty adults (mean age 45 years, 69% female, 15% hospitalized post COVID) recruited from the Neuro-COVID-19 Clinic at Northwestern Memorial Hospital. Patients were evaluated via clinical assessment/history, chart review, patient reported outcomes for symptom severity (PROMIS cognitive function, fatigue, sleep disturbance, anxiety, depression), cognitive performance tests (NIH Toolbox modules for processing speed, attention, executive function, working memory), and 7 days of wrist actigraphy with a sleep log. We tested associations between objective and subjective measures using Pearson’s correlation and difference from population normative data using Student’s t test. Results 39 participants provided sufficient data for analysis. The median number of discrete neurologic symptoms attributed to PASC was 6 with 87% reporting ≥4 neurologic symptoms. Fatigue, insomnia, and depression were common (~70% reporting each). Participants reported significant symptom burden in all PROMIS domains, and had measurably worse attention function along with borderline executive function, compared to population normative data (all p< 0.001 except executive cognition p=0.056). Actigraphy showed Neuro-PASC patients had lower sleep efficiency and greater sleep latency (both p< 0.001) but similar wakefulness after sleep onset (WASO) compared to age-matched population controls. Self-reported cognitive symptoms were correlated with severity of fatigue (p< 0.001), anxiety (p=0.05), and depression (p< 0.01), but not subjective sleep disturbance. There were no associations between actigraphy-measured sleep or rest-activity characteristics and self-reported symptoms. Patients with abnormal sleep characteristics (WASO, sleep efficiency, sleep latency) demonstrated impaired objective attention and executive function. Conclusion Neuro-PASC patients presenting to a post-COVID clinic have a significant burden of subjective mental health, sleep, fatigue and cognitive impairment symptoms, along with objectively abnormal cognitive performance and sleep, compared to population controls. Interventions to improve sleep could benefit cognitive performance. Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep/circadian rhythm disruption on the cognitive function and quality of life in patients with PASC. Support (if any) Center for Circadian and Sleep Medicine

A Pragmatic Approach to Managing Long-Term Adverse Effects in Chronic Myeloid Leukemia Treatment.

Long-term outcomes have significantly improved with treatment of chronic myeloid leukemia. With proper treatment, most patients will achieve similar survival rates compared to an age-matched population. Treatment-free remission is not attainable for over half of patients and chronic treatment carries with it unique challenges. We provide a pragmatic approach to the monitoring and management of chronic adverse effects (AEs). In the presence of severe or intolerable AEs, switching tyrosine kinase inhibitors (TKIs) is reasonable but is not without risk. Dose reductions can be attempted when response is stable to reduce AE intensity. More frequent molecular monitoring with any change is essential. Treatment strategies must adapt to the personalized treatment goal of each patient. Long-term survival remains good even when response is less than a complete molecular response. Consider risks of new AEs when changing therapy and evaluate for dose reductions when appropriate.

Family structure and living arrangements as indicators of social isolation, and prostate cancer risk

Social isolation has been linked to a poorer prostate cancer prognosis. Little is known about how it could also influence its incidence. We investigated the association between family structure and living arrangements as potential indicators of social isolation, and prostate cancer risk, globally and according to disease aggressiveness.Data from the Prostate Cancer & Environment Study (PROtEuS), a case-control population-based study conducted between 2005 and 2012 in Montreal, Canada, were used. The study population comprised 1931 incident cases of prostate cancer, aged ≤75 years, and 1994 age-matched (±5 years) population controls. In-person interviews collected information on family composition and living arrangements recently and at age 40. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders.Single men had an increased risk of high-grade prostate cancer at diagnosis (OR 1.80; 95% CI 1.29–2.51), compared to men currently married or with a partner. Having at least one daughter was associated with a lower risk of aggressive cancer (OR 0.76; 95% CI 0.61–0.96) while no association was found with having son(s). An inverse dose-response relationship was observed between the number of people living with the subject 2 years before diagnosis/interview and prostate cancer risk (p-trend<0.001).These results suggest a protective role of a rich personal environment on the risk of developing prostate cancer. As several of the associations studied here are novel, replication is required.

The Very Low IgE Producer: Allergology, Genetics, Immunodeficiencies, and Oncology.

Opposite to other immunoglobulin (Ig) classes and subclasses, there is no consensus on the definition of normal levels of serum total IgE. However, longitudinal studies on birth cohorts produced growth charts of total IgE levels in helminth-free and never atopic children and defining the normal ranges of total serum IgE concentration at the individual, rather than population, level. Accordingly, very 'low IgE producers' (i.e., children whose tIgE level belong to the lowest percentiles) became atopic while keeping their total IgE levels in a range considered 'normal' if compared to the general age-matched population but 'abnormally high' if projected on the tIgE growth chart against the trajectory of that child's own percentile levels. In 'low IgE producers', the IgE-specific activity, i.e., the ratio between allergen-specific and total IgE, is more important than the absolute specific IgE levels to confirm causality between allergen exposure and allergic symptoms. Patients with allergic rhinitis or peanut anaphylaxis but low or undetectable allergen-specific IgE levels must therefore be reconsidered considering their total IgE levels. Low IgE producers have been also associated with common variable immunodeficiency, lung diseases, and malignancies. A few epidemiological studies have shown a higher risk of malignancies in very low IgE producers, leading to a debated hypothesis proposing a novel, evolutionistic-relevant function for IgE antibodies for antitumor immune surveillance.

Poor Sit-to-Stand Performance in Adolescent and Young Adult Patients with Sarcoma.

Background: Adolescents and young adult (AYA) patients with sarcoma are at heightened risk of reduced physical capacity and disease-related weakness. Sit-to-stand (STS) performance correlates with lower extremity functionality and activities of daily living; however, little is known regarding the relationship between muscular status and STS performance in patients with sarcoma. This study assessed STS performance in patients with sarcoma and the association between STS performance and the skeletal muscle index (SMI) and skeletal muscle density (SMD). Methods: This study included 30 patients with sarcoma (15-39 years old) treated with high-dose doxorubicin. Patients performed the five-times-STS test before starting treatment and 1 year after the baseline test. STS performance was correlated with SMI and SMD. SMI and SMD were quantified using computed tomography scans taken at the level of the 4th thoracic vertebra (T4). Results: Mean performance on the STS test at baseline and 1 year was 2.2-fold and 1.8-fold slower than the age-matched general population, respectively. A lower SMI was associated with worse performance on the STS test (p = 0.01). Similarly, lower SMD at baseline was also associated with poorer STS performance (p < 0.01). Conclusion: Patients with sarcoma have very poor STS performance at baseline and 1 year, which was accompanied by low SMI and SMD at T4.The inability for AYAs to return to healthy age normative STS standards by 1 year may indicate a need for early interventions to enhance skeletal muscle recovery and promote physical activity during and after treatment.

The Impact of Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies with and without Apheresis on Platelet Aggregation in Familial Hypercholesterolemia

Background and aimsIt is well known that elevated cholesterol is associated with enhanced platelet aggregation and patients suffering from familial hypercholesterolemia (FH) have a high risk of thrombotic cardiovascular events. Although decreasing cholesterol level is associated with attenuation of platelet hyperactivity, there are currently no data on the effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) on platelet reactivity in FH. The aim of the study was to analyse the impact of different therapies including PCSK9ab on platelet aggregation in FH.MethodsThis study enrolled all 15 patients treated in the University Hospital Hradec Králové for FH. PCSK9ab have been administered in 12 of 15 patients while 8 patients were also undergoing lipid apheresis. Blood samples from all patients including pre- and post-apheresis period were tested for platelet aggregation triggered by 7 inducers, and the effect of 3 clinically used drugs (acetylsalicylic acid, ticagrelor and vorapaxar) was compared as well.ResultsAlthough apheresis decreased the reactivity of platelets in general, platelet responses were not different between non-apheresis patients treated with PCSK9ab and apheresis patients (post-apheresis values) with the exception of ristocetin. However, when compared to age-matched healthy population, FH patients had significantly lower platelet aggregation responses to 4 out of 7 used inducers and higher profit from 2 out of 3 used antiplatelet drugs even after exclusion of FH patients regularly receiving conventional antiplatelet treatment.ConclusionThis study showed for the first time the suitability of PCSK9ab treatment for reduction of platelet reactivity in FH patients.

Three decades of reimplantation of the aortic valve-the Brussels experience.

Over the last three decades, the importance of native valve preservation has increasingly become evident. Valve-sparing root replacement procedures, such as the reimplantation or remodeling technique, are therefore being progressively used for aortic root replacement and/or aortic valve repair. Herein, we are summarizing our single-center experience with the reimplantation technique. We queried our prospective database for aortic valve repair and recruited all adult (≥18 years) patients who have undergone valve-sparing root replacement with the reimplantation technique between March 1998 and January 2022. We subcategorized the patients into three distinct groups: root aneurysm without aortic regurgitation (AR) (grade ≤1+), root aneurysm with AR (grade >1+) and isolated chronic AR (root <45 mm). Univariable logistic regression analysis was performed to identify variables of interest, which were further analyzed by multivariable Cox-regression analysis. Survival, freedom from valve reintervention, and freedom from recurrent regurgitation, were analyzed with the Kaplan-Meier method. A total of 652 patients were recruited for this study; 213 patients underwent reimplantation for aortic aneurysm without AR, 289 patients for aortic aneurysm with AR, and 150 patients with isolated AR. Cumulative survival was 95.4% (95% CI: 92.9-97.0%) after 5 years, 84.8% (80.0-88.5%) after 10 years, and 79.5% (73.3-84.5%) after 12 years, which was comparable to the age-matched Belgian population. Older age (HR 1.06, P≤0.001) and male gender (HR 2.1, P=0.02) were associated with late mortality. Freedom from reoperation on the aortic valve at 5 years was 96.2% (95% CI: 93.8-97.7%), and 90.4% (95% CI: 87.4-94.2%) at 12 years. Age (P=0.001) and preoperative left ventricular end-diastolic dimension (LVEDD) (P=0.03) were associated with late reoperation. Our long-term data supports our reimplantation approach as a viable option for aortic root aneurysms and/or aortic regurgitation, with long-term survival that mirrors that of the general population.

The Long-Term Risk of Knee Arthroplasty in Patients with Arthroscopically Verified Focal Cartilage Lesions: A Linkage Study with the Norwegian Arthroplasty Register, 1999 to 2020.

Focal cartilage lesions are common in the knee. The risk of later ipsilateral knee arthroplasty remains unknown. The purposes of the present study were to evaluate the long-term cumulative risk of knee arthroplasty after arthroscopic identification of focal cartilage lesions in the knee, to investigate the risk factors for subsequent knee arthroplasty, and to estimate the subsequent cumulative risk of knee arthroplasty compared with that in the general population. Patients who had undergone surgical treatment of focal cartilage lesions at 6 major Norwegian hospitals between 1999 and 2012 were identified. The inclusion criteria were an arthroscopically classified focal cartilage lesion in the knee, an age of ≥18 years at the time of surgery, and available preoperative patient-reported outcomes (PROMs). The exclusion criteria were osteoarthritis or "kissing lesions" at the time of surgery. Demographic data, later knee surgery, and PROMs were collected with use of a questionnaire. A Cox regression model was used to adjust for and investigate the impact of risk factors, and Kaplan-Meier analysis was performed to estimate cumulative risk. The risk of knee arthroplasty in the present cohort was compared with that in the age-matched general Norwegian population. Of the 516 patients who were eligible, 322 patients (328 knees) consented to participate. The mean age at the time of the index procedure was 36.8 years, and the mean duration of follow-up was 19.8 years. The 20-year cumulative risk of knee arthroplasty in the cartilage cohort was 19.1% (95% CI, 14.6% to 23.6%). Variables that had an impact on the risk of knee arthroplasty included an ICRS grade of 3 to 4 (hazard ratio [HR], 3.1; 95% CI, 1.1 to 8.7), an age of ≥40 years at time of cartilage surgery (HR, 3.7; 95% CI, 1.8 to 7.7), a BMI of 25 to 29 kg/m2 (HR, 3.9; 95% CI, 1.7 to 9.0), a BMI of ≥30 kg/m2 (HR, 5.9; 95% CI, 2.4 to 14.3) at the time of follow-up, autologous chondrocyte implantation (ACI) at the time of the index procedure (HR, 3.4; 95% CI, 1.0 to 11.4), >1 focal cartilage lesion (HR, 2.1; 95% CI, 1.1 to 3.7), and a high preoperative visual analog scale (VAS) score for pain at the time of the index procedure (HR, 1.1; 95% CI, 1.0 to 1.1). The risk ratio of later knee arthroplasty in the cartilage cohort as compared with the age-matched general Norwegian population was 415.7 (95% CI, 168.8 to 1,023.5) in the 30 to 39-year age group. In the present study, we found that the 20-year cumulative risk of knee arthroplasty after a focal cartilage lesion in the knee was 19%. Deep lesions, higher age at the time of cartilage surgery, high BMI at the time of follow-up, ACI, and >1 cartilage lesion were associated with a higher risk of knee arthroplasty. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Associations of Serum Neurofilament Light Chain with Outcomes in Children with Autoimmune Encephalitis (P4-5.009)

<h3>Objective:</h3> To examine associations between serum neurofilament light chain (sNfL) levels at disease onset with markers of clinical severity in children with autoimmune encephalitis (AE). <h3>Background:</h3> Despite significant advances in the diagnosis and treatment of AE, little is known about markers of disease severity and their associations with outcomes. sNfL, a marker of axonal destruction, may fill this gap. <h3>Design/Methods:</h3> This is a longitudinal prospective case-control study of children presenting to a single tertiary center with AE (n=48) vs. an age-matched healthy control population (HC) (n=88). Clinical data and modified Rankin Scale (mRS) scores were collected using a standard CRF at baseline and at follow-up, up to one year. sNfL levels in stored samples were measured by Single Molecule Array Immunoassay (SIMOA). Volumetric analyses of key anatomic structures of brain MRIs were performed using FreeSurfer. Diffusion weighted MRI was assessed for restricted diffusion. Following standard diagnostic criteria, children were classified into those with no biological marker (antibody or genetic) and those with. We further dichotomized children into high vs. low sNFL levels. Descriptive statistics, group differences, and correlational analyses were performed using JASP version 0.16.3. <h3>Results:</h3> Baseline sNfL levels were significantly higher in patients with AE (no Ab), AE (MOG), and ANEC vs. HCs (log₂ sNfL=4.3 AE(no Ab), 2.9 AE(NMDA), 5.6 AE(MOG), 6.3(ANEC), 2.4(HC), <i>p</i>&lt;0.001). AE patients in the high sNfL group were more likely to be admitted to the ICU (<i>p</i>=0.02) and had significantly higher mRS scores at nadir (<i>p</i>=0.04), compared to patients in the low sNfL group. However, there was no significant difference in mRS scores at follow-up between groups. Baseline sNfL correlated significantly with baseline restricted diffusion (r_s(43)=0.45, <i>p</i>=0.002) and thalamic volumes (r_s(31)=0.45, <i>p</i>=0.009). <h3>Conclusions:</h3> Baseline sNfL levels may serve as a marker of disease severity in patients with AE. Future studies are needed to evaluate their associations with long-term outcomes. <b>Disclosure:</b> Ms. Da Silva has nothing to disclose. Ms. Yea has nothing to disclose. Dr. AlYanbuaawy has nothing to disclose. Dr. Matt has nothing to disclose. Dr. Longoni has nothing to disclose. Helen Branson has nothing to disclose. Logi Vidarsson has nothing to disclose. An immediate family member of Dr. Ertl-Wagner has received personal compensation for serving as an employee of Siemens Healthineers. Dr. Yeh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Yeh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PRIME. Dr. Yeh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Yeh has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Yeh has received research support from Biogen. The institution of Dr. Yeh has received research support from Stem Cell Network. The institution of Dr. Yeh has received research support from CIHR. The institution of Dr. Yeh has received research support from Ontario Institute for Regenerative Medicine. The institution of Dr. Yeh has received research support from National MS Society. The institution of Dr. Yeh has received research support from NIH. The institution of Dr. Yeh has received research support from SickKids Foundation. The institution of Dr. Yeh has received research support from CMSC. The institution of Dr. Yeh has received research support from MSSC.

P076 Beyond articular cartilage: a systematic review of the extracellular matrix in other components of the osteoarthritic joint

Abstract Background/Aims Traditionally viewed from the perspective of cartilage degeneration, osteoarthritis is increasingly seen as a disease of global joint dysfunction. Connective tissue extracellular matrix (ECM) is a crucial determinant of joint mechanobiology, providing cells with scaffolding, topographical cues, and a reservoir of soluble factors. While ECM dysregulation has been extensively studied in osteoarthritic cartilage, it remains poorly defined in other joint tissues. Here, we systematically review the composition, architecture, and remodelling of non-cartilage soft joint tissue ECM in human osteoarthritis and animal disease models. Methods A systematic search strategy was run through the MEDLINE, EMBASE and Scopus databases on 30 October 2020 and repeated on 1 October 2021. The search criteria included disease nomenclature, relevant tissues, as well as structural ECM components and architectural features. All papers were independently screened by two reviewers on the Covidence platform according to predefined eligibility criteria. Relevant clinical, demographic, and biological data were extracted from included studies, which were assessed for bias using the OHAT Risk of Bias Rating Tool for Human and Animal Studies. Results 148 of 8,156 identified studies met all eligibility criteria. 113 papers evaluated human osteoarthritis; of 35 animal studies, the most frequently used models involved surgical joint destabilisation in small mammals. ECM was best defined in menisci, ligaments, and synovium; fewer papers assessed skeletal muscles, tendons, and fat pads. Compared to the healthy joint, osteoarthritis is associated with qualitative and quantitative alterations in structural ECM components, most notably collagens and proteoglycans. In recent years, whole proteome sequencing has been employed to address these changes systematically. The mechanical properties of ECM change significantly in osteoarthritis in response to post-translational modifications, extensive calcification, and the marked loss of matrix organisation across the joint. Notably, some aspects of ECM remodelling in these tissues appear to precede discernible cartilage dysregulation. Similar ECM dysregulation is also observed in animal models, although inter-model variability in arthritogenic precipitant and the range of reported outcomes make comparisons difficult. Many studies are limited by significant bias, notably in the infrequent reporting of investigator blinding, and in the poor demographic matching of osteoarthritic and control patients. Encouragingly, the quality of methodology reporting and use of age-matched control populations have improved in recent years. Conclusion Current data provide compelling evidence of whole joint ECM changes in osteoarthritis and importantly suggest that these changes occur early in the disease process. How ECM dysfunction affects the behaviour of tissue-resident cells remains less well understood. Our work will support the design of disease-relevant biomaterials used to model osteoarthritis in vitro, helping to address this issue, by more accurately recreating the extracellular environment. Furthermore, the development of imaging modalities sensitive to connective tissue ECM changes warrants investigation from both diagnostic and prognostic perspectives. Disclosure J.Y. Mimpen: None. I.G.A. Raza: None. S.J.B. Snelling: None.

Outcomes at a Mean of 13 Years After Proximal Humeral Fracture During Adolescence

The long-term outcomes of a proximal humeral fracture during adolescence are not well known. We investigated the course of primary treatment for these injuries and the long-term outcomes in adulthood, comparing the outcomes with those from age-matched controls. We also compared outcomes after operative and nonoperative treatment via propensity score matching. We included children who sustained a proximal humeral fracture between the ages of 10.0 and 16.0 years and underwent treatment between 1995 and 2005. Data from primary treatment episodes were extracted from patient files. The patients were invited to a follow-up visit with outcome assessment and radiographs or to a telephone interview if unable to attend. The primary outcome was the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The secondary outcomes were the Simple Shoulder Test (SST), pain at rest and with strenuous use, shoulder range of motion, strength measurements, health-related quality of life (15D), and harms. Participant results were compared with the normal values of an age-matched population. The effect of operative treatment was assessed using propensity score matching and the average treatment effect was calculated. This study included 209 patients (210 fractures). The mean follow-up (and standard deviation) was 13.1 ± 3.2 years. Outcome data were obtained from 152 participants (153 fractures); 78 participants attended the follow-up visit. The primary treatment episodes were uneventful. The mean scores were 2.5 (95% confidence interval [CI], 1.8 to 3.3 [range, 0 to 13]) for the DASH and 11.7 (95% CI, 11.5 to 11.8 [range, 8 to 12]) for the SST. Other outcomes were similarly good. There were no differences in function compared with the normal population values. Propensity matching showed no treatment effect for operative treatment compared with nonoperative treatment. Proximal humeral fractures of adolescents heal well and rarely result in impairments whether treated operatively or nonoperatively. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Exploring different research questions via complex multi-state models when using registry-based repeated prescriptions of antidepressants in women with breast cancer and a matched population comparison group

BackgroundMulti-state models are used to study several clinically meaningful research questions. Depending on the research question of interest and the information contained in the data, different multi-state structures and modelling choices can be applied. We aim to explore different research questions using a series of multi-state models of increasing complexity when studying repeated prescriptions data, while also evaluating different modelling choices.MethodsWe develop a series of research questions regarding the probability of being under antidepressant medication across time using multi-state models, among Swedish women diagnosed with breast cancer (n = 18,313) and an age-matched population comparison group of cancer-free women (n = 92,454) using a register-based database (Breast Cancer Data Base Sweden 2.0). Research questions were formulated ranging from simple to more composite ones. Depending on the research question, multi-state models were built with structures ranging from simpler ones, like single-event survival analysis and competing risks, up to complex bidirectional and recurrent multi-state structures that take into account the recurring start and stop of medication. We also investigate modelling choices, such as choosing a time-scale for the transition rates and borrowing information across transitions.ResultsEach structure has its own utility and answers a specific research question. However, the more complex structures (bidirectional, recurrent) enable accounting for the intermittent nature of prescribed medication data. These structures deliver estimates of the probability of being under medication and total time spent under medication over the follow-up period. Sensitivity analyses over different definitions of the medication cycle and different choices of timescale when modelling the transition intensity rates show that the estimates of total probabilities of being in a medication cycle over follow-up derived from the complex structures are quite stable.ConclusionsEach research question requires the definition of an appropriate multi-state structure, with more composite ones requiring such an increase in the complexity of the multi-state structure. When a research question is related with an outcome of interest that repeatedly changes over time, such as the medication status based on prescribed medication, the use of novel multi-state models of adequate complexity coupled with sensible modelling choices can successfully address composite, more realistic research questions.

Abstract 2577: Pre-cancerous ovarian cells harboring a familial SMARCA4 mutation acquire in vitro phenotypes associated with transformation in SSCOHT

Abstract Introduction: Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) is an extremely rare but deadly ovarian cancer associated with mutations in the SMARCA4 gene. Using a unique population of ovarian cells derived from a familial carrier of an SCCOHT-associated SMARCA4 mutation, we sought to determine if non-cancerous cells would spontaneously transform during in vitro culture, thereby providing a model system for studying formation of SCCOHT. Methods: Ovarian cells derived from a familial carrier of a SMARCA4 mutation (P590, SMARCA4. c.3081+1G&amp;gt;T) were serially passaged in vitro and interrogated for acquisition of phenotypes consistent with cellular transformation. Loss of contact-dependent inhibition was interrogated with focus-forming assays in confluent monolayers. The ability of cells to escape anoikis and grow independently as spheroids was tested in attachment-free growth conditions using both single and aggregate spheroid growth assays. Senescence-associated β-galactosidase (SA-β-gal), cellular necrosis, and cellular apoptosis was also measured. All experiments were conducted in parallel with an age-matched cell population derived from a benign ovarian surgery (P583). In experiments to determine if these differences could be attributed to loss of functional SMARCA4, non-mutant P583 cells were cultured in the presence of the SWI/SNF inhibitor BRM014 and interrogated in focus-forming and attachment-free growth assays. Results: P590 cells passaged over 12 twelve times (approx. 40 cell divisions) continued to proliferate in culture. In contrast, non-mutant P583 cells failed to grow beyond 11-12 passages. With prolonged culture, P590 cells lost expression of SMARCA4 protein, while P583 cells retained SMARCA4 expression. P590 cells grown to confluency spontaneously formed foci of multicellular aggregates, while P583 cells did not. In attachment-free culture conditions, P590 cells readily formed spheroids from both early-passage and late-passage cells. In contrast, P583 formed small spheroids that failed to expand in culture. Surprisingly, both P590 and P583 cells displayed elevated SA-β-gal staining, with neither cell populations showing elevated necrosis or apoptosis markers. Treating P583 cells with BRM014 increased focus formation and spheroid growth similar to that of mutant cells. Conclusions: SCCOHT is extremely rare, with very few representative samples useful for developing early-stage markers or improved therapeutics. Long-term culture of ovarian cells harboring inactivated forms of SMARCA4 result in the acquisition of several phenotypes consistent with early stages of cellular transformation. Our data suggest that mutating or inactivating SMARCA4 in non-transformed ovarian cells may be a way to create novel research tools for studying formation of SCCOHT. This work was supported by DoD award W81XWH-21-1-0512 Citation Format: Sonali Joshi, Shawn Campbell, Yukie Bean, Tanja Pejovic, Adam Krieg. Pre-cancerous ovarian cells harboring a familial SMARCA4 mutation acquire in vitro phenotypes associated with transformation in SSCOHT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2577.

Abstract 1001: Urinary metabolite diagnostic and prognostic liquid biopsy biomarkers of lung cancer - never smokers versus tobacco smokers

Abstract Introduction: Never smokers account for 10-13% of all lung cancer cases in the United States. The etiology is attributed to multiple causes including exposure to passive smoking, parental smoking, asbestos and radon. However, these lung cancer cases do not fit the current United States Government-funded criterion of low-dose computed tomography that identifies early stages of lung cancer with higher survival following surgical removal. Methods: The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified by liquid chromatography-mass spectrometry to determine if never smokers with non-small cell lung cancer (NSCLC) can also be identified alongside tobacco smoker NSCLC cases as compared with gender and age-matched non-cancer population controls. Results: These cancer biomarkers were significantly higher and comparable in never-smokers and tobacco smokers cases compared to population controls. Receiver Operating Characteristics (ROC) analysis in never smokers was equivalent for CR and NANA levels area under the curve (AUC) 0.91. In contrast, combined CR and NANA levels resulted in better predictive performance (AUC 0.94). Kaplan-Meier survival curves showed that high levels of CR and NANA were associated (p&amp;lt;0.05) with increased cancer-specific death in never-smokers and tobacco smokers. Therefore these metabolites are independent of Tobacco smoking. NANA metabolite category factor, histology and stage were independent predictors of survival (p&amp;lt;0.05) in multivariate analyses for never smokers as shown in Table 1. Conclusions: These results indicate that measuring CR and NANA in liquid biopsy urine could identify never-smoking lung cancer candidates for LDCT screening and warrant prospective studies of these biomarkers in high-risk environments. Table 1. Univariate and multivariate regression analysis for factors associated with survival in the never smokers population Univariate Analysis Multivariate analysis Factors Levels N HR 95%CI P-value HR 95%CI P-value Stage Early Stage (I &amp; II); Late Stage (III &amp; IV) 145 3.52 2.3, 5.3 &amp;lt;0.001 3.94 2.2, 6.8 &amp;lt;0.001 Histology Adenocarcinoma; Squamous cell carcinoma 114 1.62 0.7, 3.5 0.26 3.42 1.4, 7.9 0.01 CR Category Low; High 166 1.34 0.8-2.1 0.19 1.67 0.9, 3.0 0.08 NANA Category Low; High 166 2.11 1.1-3.9 0.009 2.31 1.0, 5.0 0.02 Age N=166 166 1.00 0.9, 1.0 0.50 0.99 0.9, 1.0 0.4 Sex Male; Female 166 0.87 0.5, 1.2 0.49 0.90 0.5, 1.5 0.7 Race African American; European American 166 0.82 0.2, 2.5 0.75 0.40 0.1, 1.3 0.2 Citation Format: Bhavik Dalal, Takeshi Tada, Daxesh P. Patel, Mohammed Khan, Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Leila Toulabi, Kristopher Krausz, Ana Robles, Elise Bowman, Frank Gonzalez, Curtis Harris. Urinary metabolite diagnostic and prognostic liquid biopsy biomarkers of lung cancer - never smokers versus tobacco smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1001.

Caregiver Burden and Quality of Life Across Alzheimer's Disease Severity Stages.

The objective is to estimate the caregiver burden in terms of informal care time, health-related quality of life (HRQoL), and societal costs by disease severity (mild, moderate, or severe) and living situation (community-dwelling or institutionalized) of persons with AD (PwAD); and PwAD HRQoL. Caregivers were recruited through an online panel provider in the Netherlands. The survey used validated instruments, including iMTA Valuation of Informal Care Questionnaire, CarerQoL, and EQ-5D-5L. One hundred two caregivers participated. PwADs received, on average, 26 hours of informal care per week. Informal care costs were higher for community-dwelling PwADs compared with institutionalized PwADs (€480 and €278, respectively). On the EQ-5D-5L, caregivers scored on average 0.797, reflecting a utility decrement of 0.065 compared with an age-matched population. Proxy-rated utility scores for PwADs decreased with increasing disease severity (0.455, 0.314, and 0.212 for mild, moderate, and severe AD, respectively). Institutionalised PwADs had lower utility scores than community-dwelling PwADs (0.590 vs. 0.421). There was no difference in informal care time, societal costs, CarerQol scores, and caregiver EQ-5D-5L scores between disease severities. The burden of AD extends to caregivers in terms of HRQoL and time investment, regardless of the disease severity of the target population. These impacts should be incorporated into the evaluation of new AD interventions.