Longitudinal Clinical Studies Research Articles

CODI: Enhancing machine learning-based molecular profiling through contextual out-of-distribution integration

Abstract Molecular analytics increasingly utilize machine learning (ML) for predictive modeling based on data acquired through molecular profiling technologies. However, developing robust models that accurately capture physiological phenotypes is challenged by the dynamics inherent to biological systems, variability stemming from analytical procedures, and the resource-intensive nature of obtaining sufficiently representative datasets. Here, we propose and evaluate a new method: Contextual Out-of-Distribution Integration (CODI). Based on experimental observations, CODI generates synthetic data that integrate unrepresented sources of variation encountered in real-world applications into a given molecular fingerprint dataset. By augmenting a dataset with out-of-distribution variance, CODI enables an ML model to better generalize to samples beyond the seed training data, reducing the need for extensive experimental data collection. Using three independent longitudinal clinical studies and a case-control study, we demonstrate CODI's application to several classification tasks involving vibrational spectroscopy of human blood. We showcase our approach's ability to enable personalized fingerprinting for multi-year longitudinal molecular monitoring and enhance the robustness of trained ML models for improved disease detection. Our comparative analyses reveal that incorporating CODI into the classification workflow consistently leads to increased robustness against data variability and improved predictive accuracy.

SDMA as a marker and mediator in cerebrovascular disease.

Symmetric dimethylarginine (SDMA) is a methylated derivative of arginine, generated by all cells as a by-product of cellular metabolism and eliminated via the kidney. For many years SDMA has been considered inert and of little biological significance. However, a growing body of evidence now suggests this view is outdated and that circulating SDMA levels may, in fact, be intricately linked to endothelial dysfunction and vascular risk. In this review, we specifically examine SDMA within the context of cerebrovascular disease, with a particular focus on ischaemic stroke. We first discuss pre-clinical evidence supporting the notion that SDMA has effects on nitric oxide signalling, inflammation, oxidative stress, and HDL function. We then appraise the most recent clinical studies that explore the relationship between circulating SDMA and cerebrovascular risk factors, such as chronic kidney disease, hypertension, atrial fibrillation, and atherosclerosis, exploring whether any associations may arise due to the existence of shared risk factors. Finally, we consider the evidence that elevated circulating SDMA is linked to poor outcomes following ischaemic and haemorrhagic stroke. We draw upon pre-clinical insights into SDMA function to speculate how SDMA may not only be a marker of cerebrovascular disease but could also directly influence cerebrovascular pathology, and we highlight the pressing need for more mechanistic pre-clinical studies alongside adequately powered, longitudinal clinical studies to fully evaluate SDMA as a marker/mediator of disease.

Regional/ethnic differences in ocular axial elongation and refractive error progression in myopic and non-myopic children.

To determine the regional and ethnic differences in ocular axial elongation and refractive error progression in myopic and non-myopic children. A retrospective analysis of 15 longitudinal clinical and population-based studies was conducted in the UK, Sweden, Australia (classified as European), China, and Vietnam (classified as East Asian) between 2005 and 2021. A total of 14,593 data points from 6208 participants aged 6-16 years with spherical equivalent from +6 to -6 D were analysed. Progression was annualised from longitudinal axial length and cycloplegic spherical equivalent (SE) refraction. Generalised estimating equation models including main effects and interactions were used for model building. Age and region-specific estimates for myopes and non-myopes and confidence intervals are reported. Factors affecting axial elongation and SE progression in children included being myopic, followed by age, region/ethnicity and sex. The magnitude of regional/ethnic differences was dependent on myopia and age. Axial elongation and SE progression were lower in European compared with East Asian children, but differences were reduced with increasing age and differences in axial elongation were larger in myopes than non-myopes. Age-specific regional/ethnic differences indicated that axial elongation for a 6-year-old East Asian myopic child was greater than a European child by 0.15 mm/year (0.58 vs. 0.43 mm/year) and by 0.09 mm/year (0.35 vs. 0.26 mm/year) for a 10-year-old myope. SE progression was lower in a 6-year-old European myope by 0.48 D/year and at 10 years of age by 0.34 D/year compared with an East Asian myope. There are regional/ethnic differences in age-specific refractive and axial growth patterns in both myopic and non-myopic eyes, with more marked differences in younger East Asian children who demonstrated a higher axial growth and greater negative SE shift than their non-Asian peers. Regional/ethnic differences in progression reflect environmental and ethnic variations. Age and region/ethnicity-specific estimates could contribute as a reference for future comparisons.

English Translation and Cultural Adaptation of the Knee Numeric-Entity Evaluation Score (KNEES-ACL): A Condition-Specific Patient-Reported Outcome Measure for Anterior Cruciate Ligament Injuries

Background: The Knee Numeric-Entity Evaluation Score (KNEES-ACL) is a 41-item condition-specific patient-reported outcome measure (PROM) that was developed for patients with an anterior cruciate ligament (ACL) deficiency and patients after ACL reconstruction. This measure is intended to be used for longitudinal clinical studies. The KNEES-ACL has demonstrated face and content validity and superior responsiveness compared with other PROMs commonly used in patients with an ACL injury. However, this PROM was developed in Danish and has not been appropriately translated and culturally adapted into North American English. Purpose: To translate and culturally adapt the KNEES-ACL from Danish to North American English. Study Design: Cross-sectional study. Methods: Translation from Danish to English and cultural adaptation to a North American context were performed according to the dual panel method. First, the Danish KNEES-ACL was translated by a bilingual panel, which provided multiple English wording options for each item. Second, an English lay panel focus group was formed to determine the wording for each item that best reflected everyday spoken language. Finally, individual think-aloud cognitive interviews were conducted with patients after an ACL injury to evaluate the relevance, comprehensiveness, and comprehensibility of the PROM content and questions. Repeated modifications and testing were performed until a final English version of the KNEES-ACL was constructed. Results: Participants in the lay panel focus group were able to reach unanimous decisions for each of the 41 items. Further changes to 17 items were made after 8 think-aloud interviews with patients with ACL injuries at various time points to ensure that items were relevant and being interpreted consistently among different types of patients. The final KNEES-ACL consisted of 6 domains: Problems with Daily Activities, Mental Impact, Stability, Strength and Control, Pain, and Sport and Physical Activity. Conclusion: The English KNEES-ACL for patients with ACL injuries has undergone appropriate translation and cultural adaptation using established dual panel and cognitive interviewing methods in the population of interest. The psychometric properties of the English KNEES-ACL will likely mirror those established with the Danish version. However, direct validation of the psychometric properties of the English version would be beneficial before widespread use.

Optimization of handheld spectrally encoded coherence tomography and reflectometry for point-of-care ophthalmic diagnostic imaging.

Handheld optical coherence tomography (HH-OCT) systems enable point-of-care ophthalmic imaging in bedridden, uncooperative, and pediatric patients. Handheld spectrally encoded coherence tomography and reflectometry (HH-SECTR) combines OCT and spectrally encoded reflectometry (SER) to address critical clinical challenges in HH-OCT imaging with real-time en face retinal aiming for OCT volume alignment and volumetric correction of motion artifacts that occur during HH-OCT imaging. We aim to enable robust clinical translation of HH-SECTR and improve clinical ergonomics during point-of-care OCT imaging for ophthalmic diagnostics. HH-SECTR is redesigned with (1)optimized SER optical imaging for en face retinal aiming and retinal tracking for motion correction, (2)a modular aluminum form factor for sustained alignment and probe stability for longitudinal clinical studies, and (3)one-handed photographer-ergonomic motorized focus adjustment. We demonstrate an HH-SECTR imaging probe with micron-scale optical-optomechanical stability and use it for in vivo human retinal imaging and volumetric motion correction. This research will benefit the clinical translation of HH-SECTR for point-of-care ophthalmic diagnostics.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression

There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Cohort-specific plasma lipoprotein(a) concentration tertiles. Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Paediatric gender medicine: Longitudinal studies have not consistently shown improvement in depression or suicidality.

Systematic literature reviews have found the evidence for hormonal interventions in paediatric-age patients with gender dysphoria is of low certainty. Studies in this field have all been observational, and generally of low quality. Nevertheless, some experts assert that the observational studies in this field have consistently found improvement in mental health, and therefore constitute sufficient evidentiary basis for hormonal interventions. The present review sought to characterise results of the longitudinal clinical research studies that have reported depression and suicidality outcomes. The present review collated, from examination of six existing reviews, 14 longitudinal clinical research studies that have specifically investigated depression and/or suicidality outcomes. Significantly positive depression outcomes were reported in six studies, and significantly positive suicidality outcomes in two studies. Outcomes were negative in the largest study. Notably, some studies articulated positive conclusions about hormonal interventions even in the setting of insignificant, small or negative findings. Analysis of longitudinal clinical research in this field showed inconsistent demonstration of benefit with respect to depression and suicidality. This analysis suggests that, contrary to assertions of some experts and North American professional medical organisations, the impact of hormonal interventions on depression and suicidality in this population is unknown.

Abstract PO4-27-02: Pandemic Shifts: How did elective breast cancer care change?

Abstract Introduction: As the COVID-19 pandemic began, concerns arose that timely utilization of elective breast cancer care would decrease due to state moratoriums, travel restrictions, or fear, resulting in poorer long-term outcomes. Advances in telemedicine provided a new avenue for care; however, rapid implementation brought concerns about variable uptake and disparities. To support longitudinal clinical and epidemiological studies, this analysis described elective breast cancer care utilization during the first year of the pandemic, including patient, hospital, and geographic barriers and facilitators. Methods: The Multidisciplinary Breast Reconstruction Research Program team reviewed all breast cancer surgeries and procedures at The University of Texas MD Anderson Cancer Center during the pre-pandemic (March 1, 2019 to February 29, 2020) and pandemic (March 1, 2020 to February 28, 2021) periods. The team identified procedures that were deemed elective or preference-sensitive, and summarized the timeline of pandemic milestones and changes, including the implementation of telemedicine appointments. A data analyst summarized the distributions of completed, canceled, rescheduled, and never completed procedures. T tests and analyses of variance tested differences between the pre-pandemic and pandemic year. Generalized linear models assessed patient, hospital, and geographic factors that correlated with successful access to, and completion of, procedures. Two focus groups reviewed data and informed the interpretation of results. Results: During the first pandemic year, 30 breast care procedures were identified that were postponed during March-April, July-August, and December-January. Surprisingly, no decrease in overall utilization of elective care procedures was observed; in fact, 19% more elective breast cancer care surgeries and procedures were scheduled (4752 pre-pandemic vs 4003 pandemic) in 13% more episodes of care (2723 pre-pandemic vs 2415 pandemic). As expected, rescheduling of procedures increased 98% (from 14% pre-pandemic to 27% pandemic); however, the majority of procedures were able to be completed by the end of the year (72% pre-pandemic, 73% pandemic). Telemedicine did not significantly mediate successful completion, as the majority of procedures were prophylactic or reconstructive surgeries. However, extended hours (p = 0.03) and proximity to the hospital facilitated access and successful completion of care (p< 0.01). The most common procedures that were not able to be performed within the first year of the pandemic were autologous breast reconstruction, revision, and mastopexy. Notably, patients reported slightly improved rates of anxiety and depression during the initial pandemic year (11% vs 14%, p = 0.04), possibly due to relative privation or comparison bias. Clinicians and patients/survivors noted several “lessons learned” that may inform access and preference-sensitive care delivery. Conclusions: Despite three periods of state-mandated discontinuation of elective care procedures, the majority of patients were able to access and successfully complete elective breast cancer care during the first year of the COVID-19 pandemic. Future studies and initiatives may use this information to explore innovations in care delivery and short- and long-term effects on health outcomes. Citation Format: Haoqi Wang, Greg Reece, Mary Catherine Bordes, Mia Markey, Aubri Hoffman. Pandemic Shifts: How did elective breast cancer care change? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-02.

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

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

Changes in psychosocial distress and the number and types of problems reported by patients with cancer when routine screening is integrated within cancer services

Abstract Background: The impact of patient-reported outcome measures on patient outcomes in longitudinal clinical studies is poorly understood. This observational study explored longitudinal changes in distress and problems reported by cancer patients screened and managed in accordance with a clinical pathway for anxiety and depression (ADAPT CP), implemented over 12 months. Methods: Patients reported distress using the Distress Thermometer and indicated reasons for distress using the 39-item Problem List across five domains: practical, social, emotional, spiritual/religious, and physical. Repeat screening occurred on average 3 monthly (quarterly). Results: Six hundred sixty patients from 10 participating services completed 1,256 screening events over 12 months, reporting 8,645 problems. On average, more emotional (27–34%) and physical (19–22%) issues were reported across all quarters than practical (7–9%) and social (8–9%) issues. Distress and emotional, physical, practical, and social problems reduced from initial to follow-up screens, although the decrease in emotional problems over time was not significantly different than that of the other problems. Worry, fatigue, sleep difficulties, health of family members, and insurance/finances were more persistent problems. Conclusions: Although distress and the change in the number of emotional concerns over time did not differ from other problems, rescreening is recommended within oncology settings to allow patients to indicate new or persistent problems and hospital staff to monitor and assess needs. Emotional concerns are high in oncology patients, suggesting the need for the prioritization of psychosocial care. These problems can persist over time due to their clinically challenging nature or because access to, or implementation of, evidence-based interventions are not yet widespread.

Chrononutrition in the Prevention and Management of Metabolic Disorders: A Literature Review.

The concept of time-restricted eating (TRE) or time-restricted feeding (TRF) promotes daily periods of feeding and fasting to determine whole-body physiology. Chronic misalignment of circadian rhythms or chrono-disruption is related to an increased risk of diverse metabolic disorders. The progression of non-communicable diseases seems to be affected by the timing of meals. As a result, intermittent fasting is a promising approach for their management. The aim of the present literature review is to examine and scrutinize the TRE protocols in the fields of prevention and management of metabolic disorders. This is a thorough literature review of the reported associations among circadian rhythm, metabolic disorders, diabetes mellitus, obesity, TRE, TRF, dietary habits, circadian disruption, cardiovascular diseases, atherosclerosis, and non-alcoholic fatty liver to find the already existing clinical studies from the last decade (2014-2024) in the most precise scientific online databases, using relevant specific keywords. Several inclusion and exclusion criteria were applied to scrutinize only longitudinal, cross-sectional, descriptive, and prospective clinical human studies. The currently available clinical findings remain scarce and suggest that chrononutrition behaviors such as TRE or TRF may promote several metabolic benefits, mainly in body weight control and fat loss. Improvements in glucose levels and lipid profiles are currently quite controversial since some clinical studies show little or no effect. As far as liver diseases are concerned, the efficacy of intermittent fasting seems to be stronger in the management of non-alcoholic fatty liver disease due to body weight decline and fat loss. Even if there has been a gradual increase in clinical studies in the last few years, providing promising perspectives, currently, there is no conclusive evidence for the role of chrononutrition in metabolic disorders. Future studies should be well-designed with longer duration and larger sample sizes. Moreover, it is important to examine the best timing of the eating window and its feasibility.

The long-term effects of topical latanoprost 0.005% treatment on pupillary functions: A 2-year longitudinal study.

To investigate the long-term effects of topical latanoprost 0.005% treatment on pupillary functions in early-stage primary open-angle glaucoma (POAG) eyes using automated pupillometry. This prospective study involved 20 eyes of 20 treatment-naive subjects with early-stage POAG. After comprehensive ophthalmic examination, static and dynamic pupillometry measurements were performedbefore treatment, at the 1st follow-up visit (1.10 ± 0.30 months) and the 2nd follow-up visit (25.85 ± 10.26 months) after treatment initiation. Dynamic parameters included resting diameter (mm), amplitude (mm), latency (ms), duration (ms), and velocity (mm/s) of pupil contraction and dilation. Static pupillometry parameters were pupil diameter (PD, mm) in high-photopic, low-photopic, mesopic and scotopic conditions. The velocity of pupil dilation significantly decreased during the 1st visit (p = 0.008) and the 2nd visit (p = 0.0003) of treatment compared to the pre-treatment visit. The resting PD was also significantly higher after the 1st visit (p = 0.003) and the 2nd visit (p = 0.001) compared to the pre-treatment visit. However, the difference in resting PD measured between the 1st and 2nd visits did not reach statistical significance (p = 0.065). There were no significant changes in other dynamic parameters (p > 0.05 for all). Additionally, a mild, but not significant, mydriatic effect was observed in PD measurements under scotopic, mesopic and low photopic lighting conditions after follow-up. None of the static and dynamic parameters correlate with age, changes in intraocular pressure (IOP) or mean deviation (MD) values of visual field tests. The long-term topical latanoprost 0.005% treatment in early-stage POAG has a slight mydriatic effect on the pupil. Further longitudinal clinical studies with larger patient cohorts are necessary to better understand the effects of latanoprost on pupillary functions.

Double-Negative T (DNT) Cells in Patients with Systemic Lupus Erythematosus.

Double-negative T (DNT) cells are a rare and unconventional T-lymphocyte subpopulation lacking both CD4 and CD8 markers. Their immunopathological roles and clinical relevance have yet to be elucidated. Beyond autoimmune lymphoproliferative syndrome (ALPS), these cells may also play a role in rheumatic disorders, including systemic lupus erythematosus (SLE); indeed, these two diseases share several autoimmune manifestations (including nephritis). Moreover, one of the main experimental murine models used to investigate lupus, namely the MRL/lpr mouse, is characterized by an expansion of DNT cells, which can support the production of pathogenic autoantibodies and/or modulate the immune response in this context. However, lupus murine models are not completely consistent with their human SLE counterpart, of course. In this mini review, we summarize and analyze the most relevant clinical studies investigating the DNT cell population in SLE patients. Overall, based on the present literature review and analysis, DNT cell homeostasis seems to be altered in patients with SLE. Indeed, most of the available clinical studies (which include both adults and children) reported an increased DNT cell percentage in SLE patients, especially during the active phases, even though no clear correlation with disease activity and/or inflammatory parameters has been clearly established. Well-designed, standardized, and longitudinal clinical studies focused on DNT cell population are needed, in order to further elucidate the actual contribution of these cells in SLE pathogenesis and their interactions with other immune cells (also implicated and/or altered in SLE, such as basophils), and clarify whether their expansion and/or immunophenotypic aspects may have any immunopathological relevance (and, then, represent potential disease markers and, in perspective, even therapeutic targets) or are just an unspecific epiphenomenon of autoimmunity.

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease

BackgroundBrain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles.MethodsWe included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group.ResultsCross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01).ConclusionsImmune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

Recruitment and Retention Strategies Adopted in TATA Longitudinal Study of Aging Study: A prospective Cohort Study on Aging in Urban India

AbstractBackgroundRecruitment and retention of participants is a crucial step in any longitudinal study. The TATA Longitudinal Study for Aging (TLSA) is an urban cohort study to gather long term data to identify risk and protective factors for dementia in India.MethodWe have recruited more than 1000 individuals with age ≥ 45 years for the study. Our recruitment strategies centered around existing urban community centers in Bangalore, India, where we have conducted more than 50 awareness programs to inform the participants about the healthy aging and our study. We maintain the periodic contact with participants through telephone, in person visits and mental health awareness programs. Though we do not offer any treatment the clinical team provides brief feedback on participants blood test reports, ECG and MRI and makes appropriate referrals to the health system if necessary. To emphasize participant convenience and reduce burden, our study team has a mobile unit that conducts clinical and cognitive sessions at the participant’s location. Transportation is also offered for each participant to attend the sessions at the study center. During the COVID 19 pandemic period, all participants were given special attention in terms of enquiring about their well‐being and using standard methods to assess their anxiety and depression. To keep the participants engaged during COVID 19 pandemic, we had shared the links for virtual museums, materials to read and offered psychosocial support.ResultWe have approached 2225 individuals out of which 52% consented and able to complete the baseline assessment for them. It is been observed that good support and willingness to contribute to the study with the notion of potentially helping their future generations. Currently up to 50% of the participants completed first follow‐up sessions.ConclusionThe recruitment and retention of participants in the longitudinal clinical studies is a challenging task. However, TLSA study provides the unique insights on recruitment approaches that can be tailored and adopted for increasing the study enrolment and retaining in the urban cohorts of developing countries like India.

Investigation of inflammation in Lewy body dementia: a scoping review

AbstractBackgroundInflammatory mechanisms are increasingly recognized as part of the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Advances in analytical techniques using in vivo and postmortem samples have been applied to address questions of key mechanisms and relevance to clinical manifestations. Our primary objective was to review methods used to investigate inflammation in LBD (dementia with Lewy bodies and Parkinson’s disease dementia), and how these are applied to conceptualise inflammation. Our secondary objective was to identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease, and compared to related neurodegenerative disease, in particular AD and PD.MethodA scoping review was performed by identifying relevant human studies that investigated inflammation in LBD. The major electronic databases MEDLINE, Embase, Web of Science, and PSYCHInfo were searched. Two authors performed abstract screening and full text review.ResultOf 1970 results screened, 65 studies were included. Twenty‐nine studies analysed postmortem brain tissue and 35 included living subjects. Largely cross‐sectional data were available, although 2 longitudinal clinical studies of prodromal Lewy body disease were noted. Analysis of biofluid (blood and cerebrospinal fluid) was the most common in vivo method used (n = 31) and 3 studies investigated LBD genetics. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, lymphocytes), and molecules linked to inflammation (e.g., cytokines). Results of included studies supported innate and adaptive immune system contribution to inflammation associated with Lewy body pathology and clinical features of the disease. Different signals in early and late‐stage disease, with possible late immune senescence including dystrophic microglia and altered adaptive immunity, were distinct from Alzheimer’s disease. The strength of these associations is limited by the varying methodologies, small study sizes and cross‐sectional nature of data.ConclusionCurrent investigation of inflammation in LBD utilises substrate collected from early to late‐stage disease. Strengths and limitations of the range of analytical techniques used must be considered when forming conclusions. Longitudinal data that informs associations with clinical and other biomarker outcomes is needed to improve understanding of inflammatory activity over the disease course of LBD. This could identify markers of disease activity and therapeutic targets.

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

Abstract 13421: Meta-Analysis of Penetrance in Genetic Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is clasically caused by pathogenic or likely pathogenic (P/LP) variants in genes encoding sarcomeric proteins (G+) leading to left ventricular hypertrophy (LVH). Aim: To contrast cross-sectional penetrance in clinical and population studies, and to determine the phenotypic conversion (% of G+ developing LVH during follow-up) in longitudinal studies ( Figure 1 ). Methods: A systematic literature search was performed. Pooled penetrance (with 95% confidence intervals [CIs]) and phenotypic conversion were calculated with random effects generalized linear mixed model meta-analyses. Calculations were made for each gene and across all genes. Meta-regression was employed to explore sex-related differences. Results: In cross-sectional clinical studies, after excluding probands, penetrance across all genes in relatives carrying P/LP variants identified during cascade screening was 58% (95% CI [53,64]). Penetrance varied from ~32% for myosin light chain 3 to ~65% for myosin heavy chain 7 ( MYH7 ) and troponin T ( TNNT2 ). The mean age of HCM onset was 38 years (95% CI [36, 40]) across all genes, but studies including a higher % of males reported a later age of onset. In contrast, penetrance in population studies was ~10-15%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in the UK Biobank. In longitudinal clinical studies, the pooled phenotypic conversion was 15% (95% CI [8,27]) over an average of ~7 years of follow up, starting from a mean age of ~16 years across all genes. However, it varied from ~12% for myosin binding protein C to ~23% for MYH7 . Conclusions: The penetrance is 5-7-fold higher in a clinical context compared to incidental identification in population studies, suggesting important but currently undefined factors that modify disease expression. More longitudinal studies are needed to improve understanding of penetrance and identify drivers of the transition from genetic susceptibility to overt HCM

Sorbets as Functional Food Products, Unexplored Food Matrices, Their Challenges, and Advancements

Functional foods and beverages are becoming one of the leading food products on the global market today. This is predominately due to the consumer, industry and research-related interests in the use of food-derived products for the management of several chronic conditions. The diversity of currently available functional food products also provides an opportunity for the use of fruit-based sorbets as a carrier of functional ingredients. Therefore, the aim of this literature review is to explore the use of sorbets as a functional food product, which is one commercial method that can be utilized to provide health benefits, extend the shelf life of foods, and preserve nutrients and improve taste. Firstly, we provide an overview of sorbets as a functional food matrix, their development and implications for the absorption of functional ingredients in humans. We discuss the developmental considerations of functional foods, such as the technical conditions and physicochemical and organoleptic properties through which functional foods can provide beneficial health effects. These include product stability, metabolism of the functional food ingredient, its interactions with the food matrix and limitations related to its production. There is a paucity of clinical data that investigate the long-term health effects of products claiming additional functional benefits. Given the extensive potential benefits of functional bioactive food compounds and their heavy prevalence in the market, extensive research and further regulation is needed to ensure health recommendations for large populations in longitudinal clinical studies warranting any functional claim.

Alteration of skeletal muscle energy metabolism assessed by phosphorus-31 magnetic resonance spectroscopy in clinical routine, part 1: Advanced quality control pipeline.

Implementing a standardized phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) dynamic acquisition protocol to evaluate skeletal muscle energy metabolism and monitor muscle fatigability, while being compatible with various longitudinal clinical studies on diversified patient cohorts, requires a high level of technicality and expertise. Furthermore, processing data to obtain reliable results also demands a great degree of expertise from the operator. In this two-part article, we present an advanced quality control approach for data acquired using a dynamic 31 P-MRS protocol. The aim is to provide decision support to the operator to assist in data processing and obtain reliable results based on objective criteria. We present here, in part 1, an advanced data quality control (QC) approach of a dynamic 31 P-MRS protocol. Part 2 is an impact study that will demonstrate the added value of the QC approach to explore data derived from two clinical populations that experience significant fatigue, patients with coronavirus disease 2019 and multiple sclerosis. In part 1, 31 P-MRS was performed using 3-T clinical MRI in 175 subjects from clinical and healthy control populations conducted in a University Hospital. An advanced data QC score (QCS) was developed using multiple objective criteria. The criteria were based on current recommendations from the literature enriched by new proposals based on clinical experience. The QCS was designed to indicate valid and corrupt data and guide necessary objective data editing to extract as much valid physiological data as possible. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Using QCS enabled rapid identification of subjects with data anomalies, allowing the user to correct the data series or reject them partially or entirely, as well as identify fully valid datasets. Overall, the use of the QCS resulted in the automatic classification of 45% of the subjects, including 58 participants who had data with no criterion violation and 21 participants with violations that resulted in the rejection of all dynamic data. The remaining datasets were inspected manually with guidance, allowing acceptance of full datasets from an additional 80 participants and recovery phase data from an additional 16 subjects. Overall, more anomalies occurred with patient data (35% of datasets) compared with healthy controls (15% of datasets). In conclusion, the QCS ensures a standardized data rejection procedure and rigorous objective analysis of dynamic 31 P-MRS data obtained from patients. This methodology contributes to efforts made to standardize 31 P-MRS practices that have been underway for a decade, with the goal of making it an empowered tool for clinical research.