Longitudinal Follow-up Research Articles

Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival

Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing, which is limited in its ability to detect copy number aberrations and other genomic changes beyond coding regions. Furthermore, many of these studies lack sufficient clinical follow-up data, making it difficult to draw meaningful associations between genetic variants and patient outcomes. Our study aimed to characterize the mutational landscape of cDLBCL using whole-genome sequencing of matched tumor-normal samples obtained from a cohort of 43 dogs previously enrolled in a clinical trial for which longitudinal follow-up was available. We focused on identifying genes that were significantly or recurrently mutated with coding point mutations, copy number aberrations, and their associations with patient outcomes. We identified 26 recurrently mutated genes, 18 copy number gains, and 8 copy number losses. Consistent with prior studies, the most commonly mutated genes included TRAF3, FBXW7, POT1, TP53, SETD2, DDX3X and TBL1XR1. The most prominent copy number gain occurred on chromosome 13, overlapping key oncogenes such as MYC and KIT, while the most frequent deletion was a focal loss on chromosome 26, encompassing IGL, PRAME, GNAZ, RAB36, RSPH14, and ZNF280B. Notably, our set of recurrently mutated genes was significantly enriched with genes involved in epigenetic regulation. In particular, we identified hotspot mutations in two histone genes, H3C8, and LOC119877878, resulting in H3K27M alterations predicted to dysregulate gene expression. Finally, a survival analysis revealed that H3K27M mutations in H3C8 were associated with increased hazard ratios for progression-free survival. No copy number aberrations were associated with survival. These findings underscore the critical role of epigenetic dysregulation in cDLBCL and affirm the dog as a relevant large animal model for interrogating the biological activity of novel histone-modifying treatment strategies.

A case control analysis of pattern and risk factors for pulmonary dysfunction amongst childhood cancer survivors: a single centre study from a low-middle income setting.

Pulmonary toxicity is one of the most common morbidities experienced by childhood cancer survivors (CCS). The aim of this study was to identify prevalence, pattern of dysfunction, and risk factors among CCS and compare with age and sex matched controls. Details of demographic and pulmonary-toxic treatment of CCS at least 2 years off-treatment were collected and a cross-sectional analysis of pulmonary function test (PFT) and risk factors was performed. Spirometry findings were categorized as normal, restrictive, or obstructive and diffusing capacity of carbon monoxide (DLCO) as normal or abnormal. PFT data of 192 CCS and 50 controls was analyzed. One or more abnormalities inspirometry or DLCO were observed among 112 (58.3%) CCS and 8 (16%) controls (p value <0.01). Abnormal PFT was more likely to be associated with older age at evaluation, longer follow-up, and use of chest-directed radiotherapy (p value 0.002, 0.02, 0.03). DLCO was the most common abnormality observed in 85 (44%) patients. Obstructive and restrictive patterns were observed in 66 (34.3%) and 42 (21.8%) survivors respectively. There was no correlation between any risk factor and specific pattern of pulmonary dysfunction. On univariate analysis age at evaluation >20 years, follow-up >10 years, cumulative bleomycin more than 120 mg/m2, chest-directed radiotherapy, surgery, and female gender were found to be predictive for abnormal PFT. On multivariable analysis first four factors retained significance. High subclinical prevalence among CCS especially in older patients with longer follow-up mandates longitudinal follow-up to assess long-term pulmonary outcome and plan intervention strategies for this subset.

Binaural Fusion Sharpens on a Scale of Octaves During Pre-adolescence in Children with Normal Hearing, Hearing Aids, and Bimodal Cochlear Implants, but not Bilateral Cochlear Implants.

The breadth of binaural pitch fusion, the integration of sounds differing in frequency across the two ears, can limit the ability to segregate and understand speech in background noise. Binaural pitch fusion is one type of central auditory processing that may still be developing in the pre-adolescent age range. In addition, children with hearing loss potentially have different trajectories of development of central auditory processing compared to their normal-hearing (NH) peers, due to disruption of auditory input and/or abnormal stimulation from hearing devices. The goal of this study was to measure and compare binaural pitch fusion changes during development in children with NH versus hearing loss and different hearing device combinations. Interaural pitch discrimination abilities were also measured to control for pitch discrimination as a potential limiting factor for fusion that may also change during development. Baseline measurements of binaural pitch fusion and interaural pitch discrimination were conducted in a total of 62 (22 female) children with NH (n = 25), bilateral hearing aids (HA; n = 10, bimodal cochlear implants (CI; n = 9), and bilateral CIs (n = 18), with longitudinal follow-up for a subset of participants (18 NH, 9 HA, 8 bimodal CI, and 15 bilateral CI). Age at the start of testing ranged from 6 to 10years old, with a goal of repeated measurements over 3-6years. Binaural pitch fusion ranges were measured as the range of acoustic frequencies (electrodes) presented to one ear that was perceptually fused with a single reference frequency (electrode) presented simultaneously to the other ear. Similarly, interaural pitch discrimination was measured as the range of frequencies (electrodes) that could not be consistently ranked in pitch compared to a single reference frequency (electrode) under sequential presentation to opposite ears. Children with NH and HAs initially had broad binaural pitch fusion ranges compared to adults. With increasing age, the binaural fusion range narrowed by 1-3 octaves for children with NH, bilateral HAs, and bimodal CIs, but not for children with bilateral CIs. Interaural pitch discrimination showed no changes with age, though differences in discrimination ability were seen across groups. Binaural fusion sharpens significantly on the scale of octaves in the age range from 6 to 14years. The lack of change in interaural pitch discrimination with increasing age rules out discrimination changes as an explanation for the binaural fusion range changes. The differences in the trajectory of binaural fusion changes across groups indicate the importance of hearing device combination for the development of binaural processing abilities in children with hearing loss, with implications for addressing challenges with speech perception in noise. Together, the results suggest that pruning of binaural connections is still occurring and likely guided by hearing experience during childhood development.

Quality matters: chronic kidney disease progression is associated to reduced muscle strength independently of changes in skeletal muscle mass: an observational study

Abstract Background and hypothesis Chronic kidney disease (CKD) is commonly associated with multifactorial neuromuscular impairments. Few studies have investigated CKD-induced changes in maximal voluntary force (MVF), and even fewer have longitudinal follow-up. The aim of this study is to investigate whether CKD progression modifies the relationship between skeletal muscle mass and force and the prevalence of sarcopenia and sarcopenic obesity. Methods The data used were prospectively collected during routine check-ups in a network of nutritional centres in Mexico and retrospectively analysed. From a dataset of 5430 patients, we selected 1098 patients with available anthropometric, kidney function, handgrip and bioimpedance data. The relationship between appendicular skeletal muscle mass (ASM) and MVF was investigated using mixed models and adjusted for age, sex, BMI, physical activity level and CKD aetiology. Sarcopenia prevalence were tested across period of follow-up using the Cochran-Mantel-Haenzen for repeated measures and across CKD stages using the Chi-2 test. Results After normalization with ASM, MVF was higher in CKD G1-G3 compared to G4 and G5 (p ≤ 0.001, Cohen's d = 0.270–0.576). Slopes between MVF and ASM were lower in CKD G3, G4 and G5 than in CKD G1-G2 (-2.268 [-3.927,-0.609], p = 0.008; -2.694 [-4.593,-0.794], p = 0.006; -3.675 [-5.326,-1.725], p &amp;lt; 0.001, respectively). The prevalence of sarcopenia and sarcopenic obesity did not differ across CKD stages, but recovery was most commonly observed in CKD G1-G2. Slope analysis showed an independent interaction between the slopes of kidney function and ASM on MVF evolution over time. Conclusions CKD negatively, progressively and independently affects the neuromuscular system, and force production is reduced for any given muscle mass as CKD progresses. While no association was found between CKD stage and prevalence of sarcopenia, recovery was more frequent in the early CKD stages. These results suggest the importance of early rehabilitation programs to improve musculoskeletal health, quality of life and survival in CKD patients.

COVID-19 in discharged patients with diabetes and chronic kidney disease: one-year follow-up and evaluation

PurposeTo evaluate the all-cause mortality rate and renal outcomes in patients with diabetes and chronic kidney disease (CKD) following hospital discharge for COVID-19.MethodsThis single-center prospective observational study included 187 discharged COVID-19 patients with diabetes and CKD, admitted between December 2022 and January 2023 at West China Hospital, Sichuan University. Cox regression analysis was used to assess mortality risk, and logistic regression was applied to identify risk factors for rapid CKD progression after discharge.ResultsDuring the one-year follow-up, the all-cause mortality rate was 26.7%, with a COVID-19-related acute kidney injury (AKI) incidence of 35.3%, and 35.8% of patients experienced rapid CKD progression after discharge. Cox proportional hazards regression indicated that sepsis and mechanical ventilation were major risk factors for post-discharge all-cause mortality. Logistic regression identified baseline eGFR &amp;lt; 60 mL/min/1.73 m² as an independent risk factor for rapid CKD progression.ConclusionsDuring the one-year follow-up period, we observed that patients with diabetes and CKD exhibited higher all-cause mortality and experienced rapid deterioration of kidney function after acute infection with COVID-19. This underscores the importance of ongoing longitudinal follow-up to more accurately track the long-term health effects of COVID-19 on patients with diabetes and CKD.

Testosterone replacement therapy in men on active surveillance for prostate cancer.

While the use of testosterone replacement therapy (TRT) in men undergoing active surveillance (AS) for prostate cancer (PCa) has been historically contraindicated, recent studies have contributed to a paradigm shift to this approach. To examine the impact of testosterone on prostate-specific antigen (PSA) levels and prostate biopsy progression in men with low testosterone on AS for PCa. A retrospective single-center analysis was conducted on men undergoing AS for PCa who subsequently underwent TRT. Men previously treated for PCa were excluded. PSA and testosterone levels were recorded at regular intervals one year before and after the initiation of testosterone. ANOVA was used to analyze variance in PSA and testosterone levels, and paired t-tests and linear regression analysis were performed. Baseline and surveillance biopsies were documented. The primary outcomes were changes in PSA levels and biopsy progression following initiation of testosterone therapy. Forty-three men met the inclusion criteria. Median (IQR) testosterone level before testosterone therapy was 272 (221.5-333.5) ng/dL and 578.5 (354.5-846.5) ng/dL after therapy (P < 0.01). No significant variation in mean PSA levels was observed (P = 0.87). Baseline biopsies were available for 27 patients, showing Gleason 3 + 3 = 6 in no more than three cores. Fifteen (55.6%) patients had one or more surveillance biopsies after starting testosterone therapy. Of these, 12 (80.0%) had no disease progression in biopsies over a mean of 44.3months on testosterone. Three patients (20.0%) had a Gleason score 7 on biopsy after a mean of 79.5months on testosterone therapy. No patients developed metastatic disease. Testosterone therapy did not result in statistically significant changes in PSA levels in men with low testosterone on AS. Pathology changes were inconclusive, but the available data showed no apparent increase in PCa progression or disease worsening in the cohort. The study's strengths include a longitudinal follow-up design and use of multiple statistical analyses. Limitations include the retrospective design, small sample size which may limit generalizability, and lack of control group. No significant change in PSA level was observed after initiating testosterone therapy, despite an increase in testosterone levels. Despite limited biopsy data, our findings suggest similar rates of disease progression compared to the general AS population.

Abstract TP161: Machine Learning to Glean Characteristics of Quantitative Susceptibility Maps in Cerebral Cavernous Angiomas with Symptomatic Hemorrhage

Introduction and Hypothesis: New bleeding in cerebral cavernous malformations (CCM) heralds increased risk of future hemorrhage for several years, yet conventional imaging only detects new bleeding that occurred in the prior weeks. A biomarker of hemorrhage could help identifying high risk lesions. An increase of mean lesional quantitative susceptibility mapping (QSM) ≥6% on MRI has been adjudicated as reflecting new bleeding in CCM during longitudinal follow-up. However, mean lesional QSM from a single acquisition could not diagnose or prognosticate a bleed. We hypothesize that machine learning (ML) may identify diagnostic and prognostic features of bleeding within QSM maps at a single point in time. Material and Methods: Two hundred and sixty-five QSM maps of CCM lesions were acquired in 120 patients enrolled in National Institute of Health (NIH) multisite trial readiness project (NCT03652181). Each map was classified (Yes/No) in association with symptomatic hemorrhage (SH) and/or biomarker event with QSM increase ≥6% in the prior (diagnostic association) and subsequent (prognostic association) year. Twenty-eight features were extracted including 14 texture, 5 first-order statistical, as well as 3 size, shape, and morphological. Five-fold cross-validation was conducted on a support-vector machine (SVM) with linear stepwise kernel for both diagnostic and prognostic associations. Performance of individual features and composite classifiers was evaluated using student t-test ( p &lt;0.05) with Bonferroni-correction and receiver operating characteristic (ROC) analysis, area under the curve (AUC). Results: Lesions with SH in the prior year had lower average values for sum variance (AUC=0.79, p&lt;0.001), variance (AUC=0.79, p&lt;0.001), and correlation (AUC=0.71, p=0.004) as compared to lesions without SH. The SVM classification method tasked with distinguishing lesions with mean QSM increase ≥6% in the prior year included recurrent selection of sum average, mean, sphericity and margin sharpness, yielding an AUC of 0.61 (p=0.02). In the prognostic cohort, no individual feature nor any SVM classification model was able to distinguish cases with a subsequent clinical bleed or biomarker event. Conclusion: This proof-of-concept suggests that ML may assist in deriving features on QSM maps acquired at a single timepoint, which reflect prior hemorrhagic activity in CCM. Further investigation is planned in larger cohorts and in conjunction with clinical trials of bleeding in CCM.

Efficacy of a group-based 8-week multicomponent cognitive training on cognition, mood and activities of daily living among healthy older adults: A two-year follow-up of a randomized controlled trial.

Cognitive training (CT) has been one of the important non-pharmaceutical interventions that could delay cognitive decline. Currently, no definite CT methods are available. Furthermore, little attention has been paid to the effect of CT on mood and instrumental activities of daily living (IADL). To assess the effectiveness of a multicomponent CT using a training program of executive functions, attention, memory and visuospatial functions (TEAM-V Program) on cognition, mood and instrumental ADL. A randomized, single-blinded, treatment-as-usual controlled trial. Geriatric clinic in Bangkok, Thailand. 80 nondemented community-dwelling older adults (mean age 65.7 ± 4.3 years). The CT (TEAM-V) Program or the treatment-as-usual controlled group. The TEAM-V intervention was conducted over 5 sessions, with a 2-week interval between each session. A total of 80 participants were randomized (n = 40 the TEAM-V Program; n = 40 the control group). The Thai version of Montreal Cognitive Assessment (MoCA), The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Thai version of Hospital Anxiety and Depression Scale (HADS) and The Chula ADL were used to assess at baseline, 6 months, 1 year and 2 years. Compared with the control arm (n = 36), the TEAM-V Program (n = 39) was associated with significantly improved general cognition (MoCA, P = 0.02) at 2 years. Compared with baseline, participants receiving the TEAM-V Program were associated with significantly improved immediate recall (word recall task, P < 0.001), retrieval and retention of memory processes (word recognition task, P = 0.01) and attention (number cancellation part A, P = 0.01) at 2 years. No training effects on anxiety (P = 0.94), depression (P = 0.093) and IADL (P = 0.48) were detected. The TEAM-V Program was effective in improving global cognitive function. Even though, the program did not significantly improve anxiety, depression and IADL compared with the control group, memory and attention improved in the intervention group compared with baseline. Further studies incorporating a larger sample size, longitudinal follow-up and higher-intensity CT should be conducted.

Neurodevelopmental Outcomes in Children Vertically Exposed to Chikungunya Virus: A Two Years Follow-up Study.

To monitor by the first 24 months of life, children born to mothers with laboratory evidence of chikungunya virus (CHIKV) infection during pregnancy or up to 8 weeks before it, and to describe abnormalities in head circumference (HC), auditory and ophthalmological assessments and neuroimaging tests during the follow-up period. This is a observational, descriptive, longitudinal and prospective study of children born to mothers who had a rash and a positive test for CHIKV during pregnancy or up to 8 weeks before it. They were admitted between November 2015 and May 2019 in the outpatient multidisciplinary clinic to investigate acute exanthematous disease. The exposed children were followed up by a multidisciplinary team and underwent periodic measurements of the HC. The Denver II test was applied, in addition to transfontanellar ultrasound (TU) to evaluate neurodevelopmental outcomes during the study period. Ophthalmological and auditory examinations, echocardiography and laboratory tests were also included. We included in the study 27 children vertically exposed to CHIKV. All children had a negative polymerase chain reaction test for the virus collected at the first outpatient visit (mean age of 16.8 days and standard deviation of 8 days). No clinical condition compatible with congenital infection at birth was reported. A change in HC characterized by macrocephaly and mild global delay development was observed in a 1-year-old child whose mother was infected in the peripartum, but with normal TU. Changes in the TU were observed in 2 other children with nonspecific subependymal cystic malformation that was not evident by the cranial computed tomography. The other children monitored showed normal results in the Denver II test, in the HC and TU. No changes were identified on ocular ophthalmoscopy or auditory brainstem response test. Two children had an increase in serum ferritin levels during the first year of life, with the others' inflammatory disease markers normal. Our study added knowledge about the neurodevelopment of children exposed to CHIKV during pregnancy by a longitudinal and prospective follow-up, throughout their first 24 months of life. We did not observe a negative impact of exposure to the virus on the neurological examination, global developmental test or measurements of the HC of these children.

Characterising the lipid profile of paediatric patients with anomalous aortic origins of a coronary artery.

Lipid levels in paediatric patients with anomalous aortic origin of a coronary artery (AAOCA) have not previously been explored. Patients with CHD have an increased risk of atherosclerotic cardiovascular disease later in life compared to the general population. We aim to characterise the lipid profiles in paediatric patients with AAOCA and explore its relation to diagnosis, race/ethnicity, and exercise. Single institution retrospective cohort of 180 AAOCA paediatric patients (median age 13.7 years interquartile range 9.7-15.6, 66% male). Total cholesterol, HDL, LDL, triglycerides, total cholesterol to HDL ratio, and non-HDL cholesterol were evaluated across race/ethnicity, sex, type of AAOCA, documented ischaemia on imaging, exercise level, and surgery status. Normality of the data distribution for each lipid parameter was evaluated using Kolmogorov-Smirnov testing. Accordingly, Mann-Whitney U and t-tests were used to compare variables. The proportion of abnormal lipid levels by sex and race/ethnicity was calculated. Total cholesterol was elevated in 29%, (51/177) of patients, HDL 37% (64/174), triglycerides 44% (72/165), LDL 16% (28/170), total cholesterol-HDL ratio 29%, (48/163), and non-HDL cholesterol 28% (47/165). Across subgroups categorised on the basis of surgery status, exercise level, AAOCA type, and sex, the mean and median levels for individual lipid parameters were normal. By race/ethnicity, Hispanic patients had significantly higher triglyceride (median 99, interquartile range 71-136.5, p = <0.001) and total cholesterol to HDL ratios (median 3.2, interquartile range 2.7-4.5, p = 0.014) versus non-Hispanic White and Black patients. Two-thirds of patients exercise recreationally. Hispanic patients have significantly elevated triglycerides and total cholesterol to HDL ratios compared to others. Longitudinal follow-up evaluating differences in long-term lipid status in patients with AAOCA and risk for cardiovascular events is warranted.

Functional connectome gradient of prefrontal cortex as biomarkers of high risk for internet gaming disorder.

Adolescents and young adults are considered a high-risk group for internet gaming disorder (IGD). Early screening for high-risk individuals with IGD and exploring the underlying neural mechanisms is an effective strategy to reduce the harm of IGD. We recruited 219 non-internet gaming addicted college students and evaluated them with magnetic resonance imaging, followed by a two-year longitudinal follow-up. We used functional connectome gradient (FCG) to capture the macroscopic hierarchical organization of human brain. Canonical correlation analysis was employed to identify components mapping relationships between FCG and behavioral scores. Consequently, K-means clustering was used to define distinct subtypes. The risk of developing IGD and FCG patterns were compared among the subtypes. Three subtypes were identified and subtype 3 exhibited the highest risk for developing IGD according to the occurrence rates of IGD two years later: (1) subtype 1 (5.3 %, 4 participants), (2) subtype 2 (10.8 %, 9 participants), (3) subtype 3 (20 %, 12 participants). The abnormal FCG in the inferior frontal gyrus and posterior cingulate cortex at baseline were observed in subtype 3, which were correlated with impulsivity. These findings advanced understanding of the biological and behavioral heterogeneity associated with developing of IGD, and represented a promising step toward the prediction of high-risk individuals.

Perceptions of healthcare professionals on the use of a risk prediction model to inform atrial fibrillation screening: qualitative interview study in English primary care.

There is increasing interest in guiding atrial fibrillation (AF) screening by risk rather than age. The perceptions of healthcare professionals (HCPs) towards the implementation of risk prediction models to target AF screening are unknown. We aimed to explore HCP perceptions about using risk prediction models for this purpose, and how models could be implemented. Semistructured interviews with HCPs engaged in the Future Innovations in Novel Detection of AF (FIND-AF) study. Data were thematically analysed and synthesised to understand barriers and facilitators to AF screening and guiding screening using risk assessment. Five primary care practices in England taking part in the FIND-AF study. 15 HCPs (doctors, nurses/nurse practitioners, healthcare assistants, receptionists and practice managers). Participants knew the health implications of AF and were supportive of the risk prediction models for AF screening. Four main themes developed: (1) health implications of AF, (2) positives and negatives of risk prediction in AF screening, (3) strategies to implement a risk prediction model and (4) barriers and facilitators to risk-guided AF screening. HCPs thought risk-guided AF screening would improve patient outcomes by reducing AF-related stroke, and this outweighed concerns over health anxiety and the impact on workload. Pop-up notifications and practice worklists were the main suggestions for risk-guided screening implementation and for this to be predominantly run by administrative staff. Many recommended the need for educating staff on AF and the prediction models to help aid the implementation of a clear protocol for longitudinal follow-up of high-risk patients and communication of risk. Overall, HCPs participating in the FIND-AF study were supportive of using risk prediction to guide AF screening and willing to take on extra workload to facilitate risk-guided AF screening. The best pathway design and the method of how risk is communicated to patients require further consideration. NCT05898165.

Hyperglycemia inhibits AAA expansion: examining the role of lysyl oxidase.

Abdominal aortic aneurysm (AAA) is a common, progressive, and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic patients with AAA. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of patients with AAA from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (∼30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and patients with AAA. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic smooth muscle cells (SMCs) but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth-inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rates in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.NEW & NOTEWORTHY AAA grows slower in patients affected by diabetes. This growth inhibition is lost when the enzyme lysyl oxidase (LOX) is blocked in diabetic mice. The predominant arterial isoform of LOX, LOX-like 2 (LOXL2), overlaps with type IV collagen in the outer media of murine aneurysm tissue. Circulating LOXL2 correlates inversely with AAA growth in patients. Type IV collagen cross-linking by LOXL2 may play a role in the AAA growth inhibition associated with diabetes.

Accrual of organ damage and one-year mortality in systemic sclerosis: A prospective observational study.

To determine cumulative organ damage in patients with systemic sclerosis (SSc) according to the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), assess 1-year mortality risk, and identify associated factors. A prospective, single-center study was conducted in a cohort of patients with SSc. A cross-sectional study and a 12-month longitudinal follow-up were carried out. The main outcomes were SCTC-DI and all-cause mortality at 12 months. Other variables included clinical-laboratory data, modified Rodnan Skin Score (mRSS), EuroQoL 5-D (EQ-5D), and Steinbrocker functional status. Multivariate models were used to study factors associated with SCTC-DI and mortality. The study population comprised 75 patients (97.3% females) with a mean age of 59.6 years. The median (IQR) of the SCTC-DI was 4(6), and only 4 (5.3%) patients had severe SCTC-DI (≥13). The factors associated with SCTC-DI were disease duration (β=0.276), mRSS (β=0.287), C-reactive protein (CRP) concentration (β=0.311), and EQ-5D (β= -0.207). After 1 year of follow-up, 4 patients had died. The factors associated with mortality at 12 months (OR [95% CI]) were baseline SCTC-DI ≥13 (44.5 [1.6-1237.9]; p = 0.025) and visual analog scale (VAS) of the EQ-5D (0.9 [0.8-0.9]; p = 0.018). The SCTC DI can prove useful in clinical practice for assessing disease progression and short-term mortality risk. Cumulative damage was associated with disease duration, mRSS, CRP concentration, and a decline in EQ-5D, while the risk of death at 12 months was primarily associated with high SCTC-DI and low EQ-5D VAS. New studies are needed to improve assessment tools in patients with SSc.

Characterizing Wellness Initiatives in Academic Radiation Oncology Departments

Burnout is prevalent in radiation oncology (RO), and an increased focus on promoting physician wellness and formalizing wellness-directed efforts has transpired in recent years. We aimed to characterize current wellness leadership positions and efforts within academic RO departments. Academic RO department chairs were contacted to inquire whether they had a departmental wellness leader with a request for leader contact information, if applicable. Wellness leaders were invited to complete an anonymous survey in January and February 2023 using Qualtrics. Questions assessed leader demographic characteristics, role structure and resources, current initiatives, and impacts to date. Descriptive statistics and summaries of free-text responses are reported. A total of 120 chairs were contacted. In total, 71 (59%) responded, with 43 (61%) having departmental wellness leaders, of which 17 (39.5%) responded, to the survey. A total of 70.6% were female, and 76.5% were physician faculty. Most respondents were early-career. The most common previously implemented initiatives included offering programming and education (33.3%) and improved access to mental health services (25%). The most common active initiatives include conducting studies to address root causes of burnout (41.7%), developing specific wellness goals (25%), performing a review of policies that encourage prolonged work hours (25%), and offering programming and education (25%). Challenges included limited bandwidth (66.7%), lack of funding (41.7%), and lack of departmental interest in organizing or attending events (33.3%). Leaders highlight the importance of a dedicated individual to tangibly implement changes and the unique opportunity of someone within RO to understand the specific challenges faced by those in our field. Wellness leadership roles exist in many RO departments. As evidenced by a limited number of fully implemented initiatives, these roles are new and evolving. A focus on wellness has the potential to bring positive change to departments; however, the impact of newly established wellness roles on culture and balance requires longitudinal followup.

Inflammation biomarkers and neurobehavioral performance in rural adolescents

Systemic inflammation has been associated with lower neurobehavioral performance in diverse populations, yet the evidence in adolescents remains lacking. Cytokines can alter neural network activity to induce neurocognitive changes. This work seeks to investigate the association between inflammation and neurobehavior in adolescents living in a rural region of Ecuador. We examined 535 adolescents in rural communities of Ecuador (ESPINA study), 508 of which had neurobehavioral assessments (NEPSY-II) and circulating plasma levels of inflammatory markers (CRP, IL-6, TNF-⍺, sICAM-1, sVCAM-1, SAA, and sCD14). Associations between inflammatory biomarker concentrations and neurobehavioral scores were examined using adjusted bivariate semi-parametric models with generalized estimating equations. A partial least squares regression approach was used to create composite variables from multiple inflammation biomarkers and model their association with cognitive outcomes. Higher sCD14 and TNF-α concentrations were significantly associated with lower social perception scores, by -0.465 units (95% CI: -0.80, -0.13) and -0.418 units (-0.72, -0.12) for every 50% increase in inflammatory marker concentration, respectively. Similarly, every 50% increase in the inflammation summary score was associated with a significantly lower Social Perception score by -0.112 units (-0.19, -0.03). A greater inflammatory composite variable from seven markers was associated with lower scores in language (β=-0.11, p=0.043), visuospatial processing (β=-0.15, p=0.086), and social perception (β=-0.22, p=0.005) domains. Higher levels of inflammation were associated with lower neurobehavioral performance in adolescents, especially with social perception. In addition, using a robust analytic method to examine an association between a composite inflammatory variable integrating seven markers led to additional findings, including the domains of language and visuospatial processing. A longitudinal follow-up of such investigations could unveil potential changes in inflammation-neurobehavior performance links through developmental stages and intervention opportunities.

Assessment of Quadriceps Muscle Strength and Thickness in Adolescents with Polycystic Ovary Syndrome: A Case-control and Longitudinal Follow-up Study.

No studies have investigated muscle strength and thickness in adolescents with polycystic ovary syndrome (PCOS). We investigated whether there were changes in quadriceps muscle thickness and strength between adolescents with PCOS and controls. Secondly, we evaluated the effects of six months of combined oral contraceptive (COC) treatment on the quadriceps muscle. The study included 20 adolescents with PCOS and 20 healthy adolescents. The isokinetic dynamometer for the knee muscle strengths and hand dynamometer for grip strength, and ultrasound for quadriceps muscle thickness were used. These measurements were repeated after six months of COCs treatment in the patient group. Age, weight, height, pubertal stage, Physical Activity Questionnaire scores, quadriceps muscle thickness, grip strength and all isokinetic knee strength values were similar between patients and controls (all p>0.05). Compared to baseline, weight, height, quadriceps strength and lipid profile increased (all p<0.05). According to subgroup analyses, significant (and greater) increases in quadriceps muscle strength were found in COC-containing levonorgestrel users (n=6) than in cyproterone acetate users (n=13) (both p<0.05). Quadriceps muscle thickness and strength values were similar between PCOS patients and controls. Significant and greater increases were observed in quadriceps muscle strength in levonorgestrel users than cyproterone acetate users. Further longitudinal studies with larger samples evaluating the COCs with different androgenic capacity are awaited to confirm our preliminary findings.

516. Cytomegalovirus (CMV) Saliva Shedding Kinetics in Children with Congenital Cytomegalovirus Infection (cCMV)

Abstract Background CMV is the most common cause of congenital viral infection worldwide and the leading cause of non-genetic sensorineural hearing loss (SNHL). Children with congenital CMV infection (cCMV) shed the virus in urine and saliva for prolonged but variable durations. However, data on CMV saliva shedding kinetics in cCMV is limited because of the lack of longitudinal virological follow-up. The objective of this study is to describe CMV shedding kinetics in saliva during early childhood in a cohort of children with cCMV identified through universal newborn screening. Methods As part of the CMV and Hearing Multicenter Screening study (CHIMES), &amp;gt;100,000 newborns were screened for cCMV. Data from 211 children with ≥ 5 visits each with audiological follow-up and serial saliva samples collected every six months through four years of life was analyzed. Saliva CMV shedding duration and intermittent shedding according to presence of newborn symptoms, hearing status and antiviral treatment are described. Results Of the 211 children with cCMV, 14 received anti-viral treatment in early infancy. Most children shed CMV in saliva during infancy with a gradual decrease in frequency on follow-up (Figure 1). The median duration of shedding did not differ between children with asymptomatic and symptomatic cCMV (25 vs 26 months respectively; p = 0.61); children with SNHL and normal hearing (22 vs 26 months respectively; p = 0.26); and between those treated with antiviral agents and untreated children (23 vs 25 months; p = 0.9). Salivary CMV shedding was intermittent in about a third of the cohort (71/197 - 36%), mostly (91.5%) in those with asymptomatic cCMV. CMV shedding duration was significantly longer in children with intermittent shedding compared to those who did not (34 vs 17 months; p &amp;lt; 0.0001). Conclusion In this large cohort of children with cCMV identified through newborn screening, children shed CMV DNA in saliva for a median of two years, irrespective of newborn symptoms, hearing status, and receipt of anti-viral therapy. A third of the cohort shed CMV intermittently. Based on these observations, we conclude that a negative saliva CMV PCR result during infancy in newborns with findings consistent with cCMV but not tested in the newborn period likely excludes a diagnosis of cCMV. Disclosures Swetha Pinninti, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Karen Fowler, DrPH, Moderna: Advisor/Consultant Suresh Boppana, MD, GSK: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support

P-1983. A Longitudinal Study of COVID-19 Sequelae and Immunity: Effects of SARS-CoV-2 Reinfection

Abstract Background Post-acute sequelae of SARS-CoV-2 (PASC) affects approximately 10-30% of COVID-19 patients. Previous research suggests that reinfection with SARS-CoV-2 is associated with worsening PASC regardless of patients’ vaccination status and that reinfection contributes additional risks of pulmonary and other sequelae. The aims of this analysis are to describe rates of SARS-CoV-2 reinfection among patients followed on a longitudinal post-COVID-19 study with different vaccination statuses and compare the effect of reinfection on pulmonary symptoms and function and other PASC symptoms. Methods A sub-analysis of a NIAID clinical longitudinal study of COVID-19 was used with a convenience sample of 284 patients infected with SARS-CoV-2. Data was collected at enrollment and at six-month follow-up visits. Reinfection was documented by clinicians during follow-up visits and data on vaccination status was collected at baseline and follow-up visits. Pulmonary function tests including forced vital capacity (FVC), forced expiratory volume (FEV), FEV1/FVC ratio, and diffusing capacity of carbon monoxide (DLCO) were performed annually. Results Participants with SARS-CoV-2 reinfection, and those without reinfection, had similar vaccination rates. Among reinfected patients, nearly two thirds of participants reported an improvement in severity or resolution of their PASC symptoms following reinfection. Additionally, no patient without a history of PASC at enrollment developed PASC symptoms after their reinfection. In examining pulmonary function, there was no significant difference in FVC, FEV1, FEV1/FVC, and DLCO changes when comparing patients who were reinfected with SARS-CoV-2 to those who were not. Conclusion SARS-CoV-2 reinfection was not observed to be related with vaccine status, was not associated with new or worsening PASC symptoms, and there was no observed decline in pulmonary function when comparing reinfected and not reinfected patients. Continued longitudinal follow-up of this NIAID cohort will help clarify the effect of SARS-CoV-2 reinfection on the natural history of PASC and can inform overall clinical care when treating COVID-recovered patients. Disclosures All Authors: No reported disclosures

P-2207. HCV Reinfection is Associated with Cocaine Use and Ongoing Injection Drug Use in People with OUD: Outcomes from the ANCHOR and LOOP Studies

Abstract Background Despite achieving sustained virologic response (SVR), people with HCV, opioid use disorder (OUD) and ongoing injection drug use (IDU) remain at risk of reinfection. Identification and retreatment of reinfected individuals is critical to HCV elimination. We sought to evaluate the rate of HCV reinfection, factors associated with reinfection, and retreatment in a cohort of people who inject drugs (PWID).Table 1.Bivariate analysis of baseline sociodemographic characteristics. Methods The ANCHOR study provided HCV treatment for 198 people with chronic HCV, OUD, and recent opioid use. Those who achieved SVR underwent screening for HCV reinfection, with retreatment initiated per standard of care. At each visit, surveys were administered to evaluate ongoing risk behaviors and medication for OUD (MOUD) status. Patients were followed for 96 weeks with optional enrollment in a 2-year extension study (LOOP).Table 2.Bivariate (IRR) and multivariable (aIRR) analyses of factors associated with HCV reinfection. Results 158 individuals achieved SVR and were followed after treatment completion for 353 person-years, median 90 weeks (IQR 84-160 weeks). Subjects were predominantly male (69%), Black (84.2%), middle-aged (58 years), and HIV-negative (94.9%). Twenty individuals (12.7%) were reinfected a median of 77 weeks (IQR 60-105 weeks) after HCV treatment, at a rate of 5.7/100 person-years. Reinfection was associated with cocaine use (p&amp;lt; 0.001) and IDU in the past month (p=0.005). Of the 20 reinfected individuals, 16 (80%) initiated HCV re-treatment a median of 26 weeks after detection (IQR 4-64 weeks), with 12 (75%) achieving SVR, 1 currently on treatment, and 5 deaths.Figure 1.Kaplan-Meier reinfection free survival curve assessing associations of cocaine use with HCV reinfection. Conclusion In this cohort of people with OUD recently cured of HCV, we observed moderate rates of HCV reinfection associated with cocaine use and past month IDU, with high rates of retreatment uptake and SVR. These data highlight that in people with active drug use, longitudinal follow-up for retesting and retreatment is critical for HCV elimination. Enhanced accessibility to and engagement with harm-reduction services – such as syringe service programs - and interventions specifically addressing polysubstance use are crucial to reducing ongoing HCV transmission and reinfection. Disclosures Elana S. Rosenthal, MD, Gilead Sciences: Grant/Research Support|Merck: Grant/Research Support