Disease-specific Approach Research Articles

Abstract 4137833: The plasma cell-free transcriptome non-invasively profiles the immune response and myocardial damage in immune checkpoint inhibitor-induced myocarditis.

Introduction: Immune checkpoint inhibitor-induced myocarditis (ICI-m) is a severe complication of cancer immunotherapy, marked by cardiac inflammation. Despite its high mortality rate, diagnosing ICI-m remains challenging due to the lack of sensitive and non-invasive diagnostic modalities. Plasma cell-free mRNA (cf-mRNA) has recently been highlighted as a promising tool for non-invasive tissue profiling. Hypothesis: The plasma cf-mRNA profile contains disease-specific immune and tissue transcriptomic signatures of ICI-m that can be leveraged for disease-specific precision diagnostics. Aims: To establish and validate a novel cf-mRNA bench and bioinformatic pipeline for noninvasive profiling of the immune and tissue landscape of patients with ICI-m. Methods: We isolated, DNase-treated, and sequenced bulk cfRNA from frozen plasma of patients with ICI-treated cancer patients with no autoimmunity (group A, n=5), extracardiac autoimmunity (group B, n=7), and ICI-m with or without extracardiac autoimmunity (group C, n=10). Publicly available healthy control cfRNA was downloaded (n=30) as external controls. We used cell type-specific gene panels curated from single-cell RNA-sequencing datasets of circulating immune cells and cardiac cells for cellular deconvolution of the cf-mRNA. Signature scores of the sum of the counts of each cell type-specific gene were used to compare cell type contributions between patient groups. Results: Cancer and inflammatory gene pathways were significantly enriched in the cf-mRNA of all ICI-treated cancer patients. Cardiac pathways and conduction genes were significantly enriched in group C vs. A and B patients. Signature scores of Temra CD8+ T cells and cardiomyocytes, and gene expression of CCL5 and MYH6 were elevated in group C patients. Our custom ICI-m classifier containing 3 cardiac- and 3 immune cell-specific genes differentiated group C from A (AUC 0.903, 95% CI 0.858-0.903) and B patients (AUC 0.983, 95% CI 0.970-0.983) effectively, outperforming a diagnostic classifier obtained from unsupervised feature selection from all differentially expressed genes. Conclusions: Using our novel plasma cf-mRNA platform, we developed a diagnostic classifier that captures the disease-specific immune and tissue transcriptomic signatures of ICI-m, highlighting the advantages of this disease-specific approach over conventional biomarker discovery, and demonstrating the broader implications of the platform for the field of precision diagnostics.

A protocol for an open-label randomized parallel group clinical study on non-alcoholic fatty liver disease (NAFLD)

The primary objective of this study is to evaluate the efficacy of the combined effect of Agnideepan and Vyadhipratyaneek Chikitsa on the Fatty Liver Index (FLI) score in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). Secondary objectives include assessing the impact of combined chikitsa on Agni, lipid profile, body weight, waist circumference, and BMI. The study also aims to evaluate the effects of Vyadhi Pratyaneekachikitsa on changes in the FLI, lipid profile, body weight, waist circumference, BMI, and Agni, as well as the impact of Agni Deepanchikitsa on these parameters. Additionally, the quality of life of NAFLD patients will be evaluated using the SF36 questionnaire. Patients diagnosed with NAFLD will be selected from the outpatient department of CARICD, now renamed the Central Ayurveda Research Institute in New Delhi. Patient information sheets and consent forms will be provided to all willing participants. Screening will be conducted, and suitable patients will be randomized using a computer-generated chart. Trial formulations will be prescribed according to a set schedule, and patients will be called for follow-up visits accordingly. It is expected that the combined treatment of Agnideepan and Vyadhipratyaneek Chikitsa will be more effective than Vyadhipratyaneek Chikitsa alone in managing NAFLD. This study aims to explore the effectiveness of Ayurveda interventions in managing NAFLD through a disease-specific approach to precisely correct RaktavahaSrotodushti with Yakrt involvement and a general approach aimed at correcting metabolism. This dual approach highlights the role of multiple therapeutic targets in disease management tailored to patient-specific factor.

Liver transplantation for Wilson disease: Current knowledge and future perspectives.

Liver transplantation currently represents a therapeutic option for patients with Wilson disease presenting with end-stage liver disease or acute liver failure. Indeed, it has been associated with excellent postoperative survival curves in view of young age at transplant and absence of recurrence. Attention has shifted over the past decades to a wise expansion of indications for liver transplantation. Evidence has emerged supporting the transplantation of carefully selected patients with primarily neuropsychiatric symptoms and compensated cirrhosis. The rationale behind this approach is the potential for surgery to improve copper homeostasis and consequently ameliorate neuropsychiatric symptoms. However, several questions remain unanswered, such as how to establish thresholds for assessing pretransplant neuropsychiatric impairment, how to standardize preoperative neurological assessments, and how to define postoperative outcomes for patients meeting these specific criteria. Furthermore, a disease-specific approach will be proposed both for the liver transplant evaluation of candidates with Wilson disease and for patient care during the transplant waiting period, highlighting the peculiarities of this systemic disease.

Prognostic enrichment for early-stage Huntington’s disease: An explainable machine learning approach for clinical trial

BackgroundIn Huntington’s disease clinical trials, recruitment and stratification approaches primarily rely on genetic load, cognitive and motor assessment scores. They focus less on in vivo brain imaging markers, which reflect neuropathology well before clinical diagnosis. Machine learning methods offer a degree of sophistication which could significantly improve prognosis and stratification by leveraging multimodal biomarkers from large datasets. Such models specifically tailored to HD gene expansion carriers could further enhance the efficacy of the stratification process. ObjectivesTo improve stratification of Huntington’s disease individuals for clinical trials. MethodsWe used data from 451 gene positive individuals with Huntington’s disease (both premanifest and diagnosed) from previously published cohorts (PREDICT, TRACK, TrackON, and IMAGE). We applied whole-brain parcellation to longitudinal brain scans and measured the rate of lateral ventricular enlargement, over 3 years, which was used as the target variable for our prognostic random forest regression models. The models were trained on various combinations of features at baseline, including genetic load, cognitive and motor assessment score biomarkers, as well as brain imaging-derived features. Furthermore, a simplified stratification model was developed to classify individuals into two homogenous groups (low risk and high risk) based on their anticipated rate of ventricular enlargement. ResultsThe predictive accuracy of the prognostic models substantially improved by integrating brain imaging features alongside genetic load, cognitive and motor biomarkers: a 24 % reduction in the cross-validated mean absolute error, yielding an error of 530 mm3/year. The stratification model had a cross-validated accuracy of 81 % in differentiating between moderate and fast progressors (precision = 83 %, recall = 80 %). ConclusionsThis study validated the effectiveness of machine learning in differentiating between low- and high-risk individuals based on the rate of ventricular enlargement. The models were exclusively trained using features from HD individuals, which offers a more disease-specific, simplified, and accurate approach for prognostic enrichment compared to relying on features extracted from healthy control groups, as done in previous studies. The proposed method has the potential to enhance clinical utility by: i) enabling more targeted recruitment of individuals for clinical trials, ii) improving post-hoc evaluation of individuals, and iii) ultimately leading to better outcomes for individuals through personalized treatment selection.

Using the Project ECHO Model to Increase Pediatric Primary Care Provider Confidence to Independently Treat Adolescent Depression.

The model for the Extension for Community Healthcare Outcomes (Project ECHO®) was used to extend specialist support to the pediatric medical home for the treatment of adolescent depression by taking a comprehensive, disease-specific approach. Child and adolescent psychiatrists constructed a course to train community pediatric primary care providers (PCPs) to screen patients for depression, initiate evidence-based interventions, and provide ongoing management. Participants were assessed for changes in clinical knowledge and self-efficacy. Secondary measures included self-reported practice change and emergency department (ED) mental health referrals 12months pre- and post-course completion. Sixteen out of 18 participants in cohort 1 and 21 out of 23 participants in cohort 2 completed the pre- and post-assessments. Clinical knowledge and self-efficacy showed statistically significant improvement pre- and post-course completion. ED mental health referrals from participant PCPs decreased by 34% (cohort 1) and 17% (cohort 2) after course completion. These findings indicate that utilizing the Project ECHO format to provide subspecialist support and education on the treatment of depression can improve pediatric PCPs' clinical knowledge and confidence in their ability to independently treat depression. Secondary measures suggest that this can translate into practice change and improved treatment access with decreased ED referrals for mental health assessments by participant PCPs. Future directions include more robust outcomes measurement and developing more courses with an in-depth approach to a single or similar cluster of mental health diagnoses such as anxiety disorders.

Trends in COA Use and Regulatory Acceptance for Epileptic Encephalopathy and Developmental Epileptic Encephalopathy Indications (P13-1.006)

<h3>Objective:</h3> To investigate the landscape of clinical outcome assessments (COAs) used in epileptic encephalopathies (EEs) and developmental epileptic encephalopathies (DEEs). <h3>Background:</h3> EEs and DEEs are rare conditions characterized by difficult-to-treat seizures and intellectual or developmental disability. The heterogeneity of these conditions creates unique challenges for outcome measurement, particularly in clinical trials. To assess trends in the COA landscape, a targeted literature review was conducted to identify COAs used in EE and DEE clinical trials. <h3>Design/Methods:</h3> A search was conducted in ClinicalTrials.gov to identify interventional studies in EEs and DEEs. Findings were supplemented by searches in PubMed (titles/abstracts only), PROLABELS, and Food and Drug Administration (FDA) COA guidance materials, pairing EE/DEE and COA search terms when applicable. No limits on year of publication were applied. All results were reviewed, and relevant data were extracted and analyzed to identify trends in COA use. <h3>Results:</h3> The search identified 153 trials (ClinicalTrials.gov), 405 articles (PubMed), and 92 FDA drug labels (PROLABELS). Following screening, 105 trials, 26 article abstracts, and 19 labels met the criteria for data extraction. Excluding safety measures, 113 COAs were identified. Consistent with FDA guidance, seizure assessments and diaries were utilized most frequently, followed by clinician- or caregiver-rated global impression measures. Observer-reported outcomes and clinician-reported outcomes were more common than patient-reported outcomes. Approximately 25% of COAs were disease-specific. Additionally, common domains in COAs reviewed included cognition (n=22), motor functioning (n=14), multi-domains or quality of life (n=14), or communication (n=6). Several COAs utilized a global impression approach to assess within-patient change in domains, such as seizure severity or non-seizure concepts. <h3>Conclusions:</h3> Importantly, disease-specific measures, including global impression items intended to capture change in multiple domains, were identified. These findings may suggest that a disease-specific global impression approach is becoming increasingly common in these heterogeneous conditions to accompany seizure assessments and diaries. <b>Disclosure:</b> Ms. Graham has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of IQVIA. Dr. Batchelder has received personal compensation for serving as an employee of IQVIA. Dr. Gleeson has nothing to disclose. Ms. Buenfil has received personal compensation for serving as an employee of IQVIA. Ms. Kim has received personal compensation for serving as an employee of IQVIA. Dr. Meyers has received personal compensation for serving as an employee of IQVIA. Dr. Williams has received personal compensation for serving as an employee of IQVIA.

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses.

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures.

Advance care planning in chronic kidney disease: A national Danish survey of knowledge and attitudes among clinicians.

Patients with chronic kidney disease and their families strongly request advance care planning. They want it to start early-before treatment decisions are made-and to be an ongoing process during their illness trajectory. Previous international studies show that health care professionals find there to be significant barriers that impact the extent of involvement in advance care planning. To identify Danish nephrology health care professionals' knowledge and attitudes to advance care planning and the status of current advance care planning practice in Denmark. An anonymous, cross-sectional survey was administrated online. The questionnaire was developed in Australia and translated and culturally adapted into Danish. Health care professionals were recruited via email lists. In descriptive statistics and multiple ordinal regression, the influence of the respondents' attributes on the extent of involvement in advance care planning was explored, along with the involvement of family, and skills, comfort, barriers and facilitators in relation to advance care planning. The 207 respondents comprised nephrologists (23%), other physicians (8%), nurses (62%) and other HCPs (7%), of whom 27% had participated in advance care planning training. In total, 66% indicated that they lacked access to material about advance care planning for patients with chronic kidney disease and 46% indicated that the conversations were performed ad hoc. A total of 47% reported that advance care planning was performed well at their workplace. Reported barriers were time, lack of experience and procedure. Training in advance care planning could facilitate the involvement. Nurses were less likely to feel skilled and comfortable in engaging advance care planning, while those with more than 10 years of experience were more likely to feel skilled and comfortable. Training in advance care planning with patients with chronic kidney disease and their families on both a theoretical and clinical level is important to ensure comfort among health care professionals and to facilitate the extent of involvement. A systematic chronic kidney disease-specific approach is significant, in order to guide the conversations and ensure that advance care planning is conducted to a set standard.

Boosting of tau protein aggregation by CD40 and CD48 gene expression in Alzheimer's disease.

Neurodegenerative diseases result from the interplay of abnormal gene expression and various pathological factors. Therefore, a disease-specific integrative genetic approach is required to understand the complexities and causes of target diseases. Recent studies have identified the correlation between genes encoding several transmembrane proteins, such as the cluster of differentiation (CD) and Alzheimer's disease (AD) pathogenesis. In this study, CD48 and CD40 gene expression in AD, a neurodegenerative disease, was analyzed to infer this link. Total RNA sequencing was performed using an Alzheimer's disease mouse model brain and blood, and gene expression was determined using a genome-wide association study (GWAS). We observed a marked elevation of CD48 and CD40 genes in Alzheimer's disease. Indeed, the upregulation of both CD48 and CD40 genes was significantly increased in the severe Alzheimer's disease group. With the elevation of CD48 and CD40 genes in Alzheimer's disease, associations of protein levels were also markedly increased in tissues. In addition, overexpression of CD48 and CD40 genes triggered tau aggregation, and co-expression of these genes accelerated aggregation. The nuclear factor kappa B (NF-ĸB) signaling pathway was enriched by CD48 and CD40 gene expression: it was also associated with tau pathology. Our data suggested that the CD48 and CD40 genes are novel AD-related genes, and this approach may be useful as a diagnostic or therapeutic target for the disease.

Patterns and Determinants of Multimorbidity in Older Adults: Study in Health-Ecological Perspective.

(1) Background: Multimorbidity has become one of the key issues in the public health sector. This study aims to explore the patterns and health-ecological factors of multimorbidity in China to propose policy recommendations for the management of chronic diseases in the elderly. (2) Methods: A multi-stage random sampling method was used to conduct a questionnaire survey on 3637 older adults aged 60 and older in Shanxi, China. Association rule mining analysis (ARM) and network analysis were applied to analyze the patterns of multimorbidity. The health-ecological model was adopted to explore the potential associated factors of multimorbidity in a multidimensional perspective. A hierarchical multiple logistic model was employed to investigate the association strengths reflected by adjusted odds ratios and 95% confidence. (3) Results: Multimorbidity occurred in 20.95% of the respondents. The graph of network analysis showed that there were 6 combinations of chronic diseases with strong association strengths and 14 with moderate association strengths. The results of the ARM were similar to the network analysis; six dyadic chronic disease combinations and six triadic ones were obtained. Hierarchical multiple logistic regression indicated that innate personal traits (age, history of genetics, and body mass index), behavioral lifestyle (physical activity levels and medication adherence), interpersonal network (marital status), and socioeconomic status (educational level) were the common predictors of multimorbidity for older adults, among which, having no family history was found to be a relative determinant as a protective factor for multimorbidity after controlling the other covariates. (4) Conclusions: multimorbidity was prevalent in older adults and most disease combinations are associated with hypertension, followed by diabetes. This shows that diabetes and hypertension have a high prevalence among older adults and have a wide range of associations with other chronic diseases. Exploring the patterns and associated factors of multimorbidity will help the country prevent complications and avoid the unnecessary use of the health service, adopting an integrated approach to managing multimorbidity rather than an individual disease-specific approach and implementing different strategies according to the location of residence.

Direct medical and indirect absenteeism costs among working adult ADHD patients in the United States

Objective: This study investigated the direct medical and indirect (i.e., absenteeism) costs among working adult ADHD patients in the United States. Methods: This study utilized 2017-2018 Medical Expenditure Panel Survey data. Attribution and regression-based incremental cost approaches were utilized to estimate direct medical costs, i.e., prescription drug costs and total costs. The regression-based approach was utilized to estimate absenteeism cost. Results: The study sample consisted of 32,222 observations (weighted: 187,207,896). Of these, 459 (weighted: 3,175,033) had ADHD. The mean annual per person ADHD-attributable prescription drug cost was 2018 US $1,248 (standard error (SE): 97) and the ADHD-attributable total cost was $2,031 (SE: 371). This contributed to a mean overall annual spending of $3.96 (SE: 0.42) billion on ADHD-attributable prescription drugs and $6.45 (SE: 1.26) billion on ADHD-attributable total direct medical costs among adult ADHD patients. Based on the regression-based approach, the mean annual incremental cost for ADHD was $1,641 (SE: 164) and $4,328 (SE: 862) per person for prescription medication costs and total costs, respectively. The mean indirect cost of ADHD was estimated at $512 (SE: 91) per year, per person among working adults with ADHD in the United States. Conclusions: There is significant direct and indirect economic burden on working adults with ADHD.

Integrated self-management support provided by primary care nurses to persons with chronic diseases and common mental disorders: a scoping review

AimTo map integrated and non-integrated self-management support interventions provided by primary care nurses to persons with chronic diseases and common mental disorders and describe their characteristics.DesignA scoping review.Data sourcesIn April 2020, we conducted searches in several databases (Academic Research Complete, AMED, CINAHL, ERIC, MEDLINE, PsycINFO, Scopus, Emcare, HealthSTAR, Proquest Central) using self-management support, nurse, primary care and their related terms. Of the resulting 4241 articles, 30 were included into the analysis.Review methodsWe used the Rainbow Model of Integrated Care to identify integrated self-management interventions and to analyze the data and the PRISMS taxonomy for the description of interventions. Study selection and data synthesis were performed by the team. Self-management support interventions were considered integrated if they were consistent with the Rainbow model’s definition of clinical integration and person-focused care.ResultsThe 30 selected articles related to 10 self-management support interventions. Among these, five interventions were considered integrated. The delivery of the interventions showed variability. Strategies used were education, problem-solving therapies, action planning, and goal setting. Integrated self-management support intervention characteristics were nurse-person relationship, engagement, and biopsychosocial approach. A framework for integrated self-management was proposed. The main characteristics of the non-integrated self-management support were disease-specific approach, protocol-driven, and lack of adaptability.ConclusionOur review synthesizes integrated and non-integrated self-management support interventions and their characteristics. We propose recommendations to improve its clinical integration. However, further theoretical clarification and qualitative research are needed.Implication for nursingSelf-management support is an important activity for primary care nurses and persons with chronic diseases and common mental disorders, who are increasingly present in primary care, and require an integrated approach.ImpactThis review addresses the paucity of details surrounding integrated self-management support for persons with chronic diseases and common mental disorders and provides a framework to better describe its characteristics. The findings could be used to design future research and improve the clinical integration of this activity by nurses.

Genetic Diagnosis in a Cohort of Adult Patients with Inherited Metabolic Diseases: A Single-Center Experience

Inherited metabolic diseases (IMDs) are genetic conditions that result in metabolism alterations. Although research-based Next Generation Sequencing (NGS) testing for IMD has been recently implemented, its application in a clinical diagnostic setting remains challenging. Thus, we aimed at investigating the genetic diagnostic approach in a cohort of adult patients with IMDs referred to our adult metabolic unit. A retrospective analysis was performed collecting demographic, clinical, and genetic data of patients referred to the Adult Metabolic Unit in Padua from November 2017 to March 2022. In total, 108 adult patients (mean age: 33 years ± 17, 55% women) were enrolled in the study, and 83 (77%) of the patients transitioned from the pediatric metabolic clinics. The most prevalent groups of IMDs were disorders of complex molecule degradation (32 patients) and disorders of amino acid metabolism (31) followed by disorders of carbohydrates (26). Molecular genetic diagnosis was reported by 69 (64%) patients, with the higher rate reported by patients referred from specialty other than pediatric (88% vs. 55%). Almost all the subjects (92%) with disorders of complex molecule degradation had a genetic diagnosis. Patients with disorders of amino acid metabolism and disorders of carbohydrates had almost the same rate of genetic test (39% and 38%, respectively). Among the patients without a genetic diagnosis that we tested, two novel mutations in disease-associated genes were detected. In our single-center cohort, a consistent proportion (36%) of subjects with IMDs reaches the adulthood without a genetic demonstration of the disease. This lack, even if in some cases could be related to disease-specific diagnostic approach or to different disease onset, could be detrimental to patient management and impact to some of the specific needs of adult subjects.

A phase I study of ADXS-504, a cancer type specific immunotherapy, for patients with biochemically recurrent prostate cancer.

TPS5115 Background: Roughly 20%-30% of prostate cancer patients experience biochemical recurrence (BCR), rising prostate-specific antigen (PSA) levels, after definitive therapy with radical prostatectomy (RP) or radiation therapy (RT). The optimal therapy and timing of treatment for BCR is unknown, however, for patients who are not eligible for salvage radiation, androgen deprivation therapy (ADT) is the standard first-line treatment. ADT is an effective therapy but has many acute and long-term toxicities. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADXS-504 is a live attenuated Listeria monocytogenes (Lm)-based immunotherapy consisting of a truncated nonhemolytic fragment of listeriolysin O (tLLO) fused to a total of 24 tumor associated antigens (TAA). ADXS-504 was designed so that nearly 20% of patients with BCR cancer will express at least one of the targeted hotspot mutation peptide antigens and that &gt;90% will express at least one of the TAAs targeted by the sequence-optimized TAA peptide antigens. By combining these shared, commonly expressed antigen targets into a single Lm-based immunotherapy, ADXS-504 provides the potential for a potent, disease-specific approach to treating patients with prostate cancer. In addition to the generation of antigen-specific T cell responses, treatment with Lm-based immunotherapies has been shown to reprogram the tumor microenvironment (TME), by reducing the frequencies and function of immunosuppressive regulatory T cells and myeloid-derived suppressor cells within the TME. A pre-clinical murine model showed that a proto-type Lm-construct could reduce the number of metastases after removal of the primary tumor by eliminating residual tumor cells. We hypothesize that ADXS-504 is safe and promotes anti-tumor immune responses that may delay or prevent the use of ADT in castration sensitive prostate cancer. Methods: This is an open-label dose-escalation phase I trial of ADXS-504 in patients with BCR of prostate cancer previously treated with RP or RT. The study will enroll up to 18 subjects with BCR with a PSA ≥ 0.3 and a PSADT ≥ 4 months without evidence of metastatic disease on traditional CT imaging and bone scans. ADXS-504 will be given by IV every 4 weeks level for 6 study treatments, followed by maintenance therapy given every 12 weeks for 4 doses for overall total of 10 doses of study treatment. DLTs will be evaluated over the first 28 days of treatment. PSA response, PSADT, and adverse events will be summarized. The Kaplan- Meier method will be used to estimate time to PSA progression and rPFS. Immunologic activity will be evaluated by ELISpot analysis, flow cytometry, and multiplex assays and blood samples will be collected for gene sequencing analysis. The study is currently open to enrollment. Clinical trial information: NCT05077098.

Evaluating the Role of Probiotics in the Prevention and Management of Age-Related Diseases.

The human lifespan has been significantly increased due to scientific advancements in the management of disease; however, the health span of the aging population does not follow the same trend. Aging is the major risk factor for multimorbidity that is derived from the progressive loss of homeostasis, immunological and stem cell exhaustion, as well as exacerbated inflammation responses. Age-related diseases presenting with high frequencies include neurodegenerative, musculoskeletal, cardiovascular, metabolic diseases and cancer. These diseases can be co-morbid and are usually managed using a disease-specific approach that can eventually lead to polypharmacy, low medication adherence rates and undesired drug-drug interactions. Novel studies suggest targeting the shared biological basis of age-related diseases to retard the onset and manage their manifestations. Harvesting the anti-inflammatory and immunomodulatory capacity of probiotics to tackle the root cause of these diseases, could pose a viable alternative. In this article, a comprehensive review of the effects of probiotic supplementation on the molecular pathogenesis of age-related diseases, and the potential of probiotic treatments as preventative or alleviatory means is attempted. Furthermore, issues on the safety and efficiency of probiotic supplementation, as well as the pitfalls of current clinical studies are discussed, while new perspectives for systematic characterization of probiotic benefits on aged hosts are outlined.

Perioperative acute kidney injury: impact and recent update.

Acute kidney injury (AKI) is common in hospitalized patients and is a major risk factor for increased length of stay, morbidity, and mortality in postoperative patients. There are multiple barriers to reducing perioperative AKI - the etiology is multi-factorial and the diagnosis is fraught with issues. We review the recent literature on perioperative AKI and some considerations for anesthesiologists that examine the far-reaching effects of AKI on multiple organ systems. This review will discuss recent literature that addresses the epidemiology, use of novel biomarkers in risk stratification, and therapeutic modalities for AKI in burn, pediatrics, sepsis, trauma, cardiac, and liver disease, contrast-induced AKI, as well as the evidence assessing goal-directed fluid therapy. Recent studies address the use of risk stratification models and biomarkers, more sensitive than creatinine, in the preoperative identification of patients at risk for AKI. Although exciting, these scores and models need validation. There is a need for research assessing whether early AKI detection improves outcomes. Enhanced recovery after surgery utilizing goal-directed fluid therapy has not been shown to make an appreciable difference in the incidence of AKI. Reducing perioperative AKI requires a multi-pronged and possibly disease-specific approach.

Time for an individualized approach to first-line management of follicular lymphoma.

Follicular lymphoma is a heterogeneous B-cell lymphoma both in presentation and at progression. For most patients it is a chronic, relapsing indolent disease with overall survival expectations now potentially beyond 20 years. However, in a significant minority (~20%) who experience early progression or histological transformation after treatment, the disease no longer has an indolent behavior. This review looks at the development of prognostic indices, staging and therapies for follicular lymphoma, identifying where the data can, and cannot, guide the multidisciplinary team to determine an individualized approach to first-line therapy. A nuanced patient- and disease-specific approach is necessary to maximize disease response and survival while minimizing therapeutic toxicity.

Identifying and delineating the type 2 diabetes population in the Netherlands using an all-payer claims database: characteristics, healthcare utilisation and expenditures

ObjectivesWe aimed to identify and delineate the Dutch type 2 diabetes population and the distribution of healthcare utilisation and expenditures across the health system from 2016 to 2018 using an...

A disease-specific screening-level modeling approach for assessing the cancer risks of pesticide mixtures

As humans are always exposed to multiple pesticides, it is necessary to conduct risk assessments for pesticide mixtures. Due to data limitations, in this study, we introduced a disease-specific screening-level modeling framework to simulate the cumulative cancer risk (CR) of carcinogenic pesticides, which was developed based on the lognormal dose-response (LDR) curve of chemicals with disease-specific modes of action (MOAs). The simulated results of a case study indicate that the cumulative CR can be at least two orders of magnitude higher than the simulated CRs of individual pesticides. The comparison between the LDR model and the linear extrapolation (or cancer slope factor, CSF) model indicates that the CSF model can greatly overestimate population cancer risks. In addition, we applied our model to evaluate current regulatory standards of carcinogenic pesticide mixtures, and the results indicate that current standards for the selected jurisdictions can control the cumulative cancer risks within the acceptable level. However, the CSF model suggests that all selected jurisdictions cannot protect population health against the carcinogenic pesticide mixture, which is due to the nature of the low-dose linear extrapolation that triggers an initial slope when the effect dose is close to zero. Thus, we concluded that although the MOAs of pesticides in human bodies must be evaluated in future studies, our disease-specific model can be a useful and practical tool for cancer risk assessment and regulatory management of pesticide mixtures.

Methodology for triage of urologic surgical cases in the setting of a pandemic

BackgroundThe first wave of the COVID-19 pandemic in March 2020 forced our healthcare system in the Bronx, New York to cancel nearly all scheduled surgeries. We developed a framework for prioritizing postponed urologic surgeries that was utilized once cases were permitted to be rescheduled. As many parts of our country experience first and second waves of this pandemic, our framework may serve as a resource for other centers experiencing restrictions on the scheduling of elective urologic surgeries.MethodsAs the COVID-19 pandemic started and peaked in New York, almost all of our scheduled urologic surgeries were cancelled. Each Urologist was asked to rank his/her cancelled surgeries by priority (Level 1—least urgent; Level 2—moderately urgent; Level 3—most urgent). A committee of Urologists assigned a subclass to Level 3 and 2 cases (3a—least urgent; 3b—moderately urgent; 3c—most urgent; 2a—lower priority; 2b—higher priority). The committee then reviewed cases by urgency to derive a final priority ranking.ResultsA total of 478 total urologic surgeries were canceled and categorized: 250 Level 1, 130 Level 2, 98 Level 3 (73 adult, 25 pediatric). Level 3c involved renal cell carcinoma ≥ T2b, high-grade bladder urothelial carcinoma, adrenal mass/cancer > 6 cm, testicular cancer requiring radical orchiectomy, and penile cancer. Level 3b involved T2a renal masses requiring nephrectomy, while high-risk prostate cancer and symptomatic nephrolithiasis were classified as 3a. Level 2 included testicular cancer requiring retroperitoneal lymph node dissection and complicated benign prostatic hyperplasia. Surgeries for urologic reconstruction, non-complicated nephrolithiasis, erectile dysfunction, and urinary incontinence were considered Level 1.ConclusionsOur disease-specific approach to surgical rescheduling offers appropriate guidance for triaging urologic surgeries. Our system can provide guidance to other institutions as COVID-19 cases surge in different regions and with the growing second wave.