Affected Organ Systems Research Articles

Determining the Feasibility of a Cadmium Exposure Model to Activate the Inflammatory Arm of PANoptosis in Murine Monocytes.

A prevalence of cigarette smoking can cause the accumulation of cadmium (Cd2+) in the lungs, kidneys, and blood. The effects of exposure can cause multiple chronic disease types to emerge in the affected organ systems. The only moderately effective therapeutic option is chelation therapy; the health risks associated with this therapy have caused much criticism. The disease types associated with Cd2+ toxicity have inflammatory components and greatly impact innate immunity. These factors are affected at the cellular level and cause pathways like apoptosis, pyroptosis, and necroptosis. A development in understanding these pathways stipulates that these three pathways act as one complex of pathways, known together as PANoptosis. The inflammatory mechanisms of PANoptosis are particularly interesting in Cd2+ toxicity due to its inflammatory effects. Proteins in the gasdermin family act to release inflammatory cytokines, like interleukin-1β, into the extracellular environment. Cytokines cause inflammatory disease pathologies like fibrosis and cancer. RAW 264.7 monocytes are key in the murine immune system and provide an excellent model to investigate Cd2+ toxicity. Exposure of 0-15 µM CdCl2 was sufficient to increase expression of cleaved gasdermin D (GSDMD) and gasdermin E (GSDME) in this cell type. Cd2+ also exhibits a dose-dependent cytotoxicity in this cell type.

Clozapine-associated adverse drug reactions in 38,349 psychiatric inpatients: drug surveillance data from the AMSP project between 1993 and 2016

Clozapine is a second-generation antipsychotic drug that offers superior treatment results in patients with schizophrenia but is also associated with significant risks. This study analyzes data on pharmacotherapy with clozapine and the associated adverse drug reactions (ADRs) in an inpatient setting including 38,349 patients. Data about the use of clozapine and reports of severe ADRs within the period 1993–2016 were obtained from the multicentered observational pharmacovigilance program “Arzneimittelsicherheit in der Psychiatrie” (AMSP). In total, 586 severe clozapine-associated ADRs were documented (1.53% of all patients exposed). Patients aged ≥65 years had a higher risk of ADRs than patients aged <65 years (1.96 vs. 1.48%; p = 0.021). Significantly more ADRs were attributed to clozapine alone (396; 67.6% of all 586 ADRs) than to a combination with other drugs. The most frequent ADRs were grand mal seizures (0.183% of all 38,349 patients exposed), delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%). We detected 24 cases (0.063%) of clozapine-induced extrapyramidal symptoms, of which 8 (0.021%) were attributed to clozapine alone. Five ADRs resulted in death (0.013%): 2 due to agranulocytosis (41 cases total) (mortality = 4.88%) and 3 due to paralytic (sub)ileus (16 cases) (mortality = 18.75%). The median dose of clozapine in all patients treated was 300 mg/day, in patients who developed ADRs 250 mg/day. The main risk factor for an ADR was pre-existing damage of the affected organ system. Overall, the results of this study highlight the importance of alertness—especially of frequently overlooked symptoms—and appropriate monitoring during treatment with clozapine, even at low doses.

A Multi-Dimensional Approach to Map Disease Relationships Challenges Classical Disease Views.

The categorization of human diseases is mainly based on the affected organ system and phenotypic characteristics. This is limiting the view to the pathological manifestations, while it neglects mechanistic relationships that are crucial to develop therapeutic strategies. This work aims to advance the understanding of diseases and their relatedness beyond traditional phenotypic views. Hence, the similarity among 502 diseases is mapped using six different data dimensions encompassing molecular, clinical, and pharmacological information retrieved from public sources. Multiple distance measures and multi-view clustering are used to assess the patterns of disease relatedness. The integration of all six dimensions into a consensus map of disease relationships reveals a divergent disease view from the International Classification of Diseases (ICD), emphasizing novel insights offered by a multi-view disease map. Disease features such as genes, pathways, and chemicals that are enriched in distinct disease groups are identified. Finally, an evaluation of the top similar diseases of three candidate diseases common in the Western population shows concordance with known epidemiological associations and reveals rare features shared between Type 2 diabetes (T2D) and Alzheimer's disease. A revision of disease relationships holds promise for facilitating the reconstruction of comorbidity patterns, repurposing drugs, and advancing drug discovery in the future.

Positive health: An integrated quantitative approach in patients with chronic gastrointestinal and hepato-pancreatico-biliary disorders.

The concept of positive health (PH) supports an integrated approach for patients by taking into account six dimensions of health. This approach is especially relevant for patients with chronic disorders. Chronic gastrointestinal and hepato-pancreatico-biliary (GI-HPB) disorders are among the top-6 of the most prevalent chronically affected organ systems. The impact of chronic GI-HPB disorders on individuals may be disproportionally high because: (1) The affected organ system frequently contributes to a malnourished state; and (2) persons with chronic GI-HPB disorders are often younger than persons with chronic diseases in other organ systems. To describe and quantify the dimensions of PH in patients with chronic GI-HPB disorders. Prospective, observational questionnaire study performed between 2019 and 2021 in 235 patients with a chronic GI-HPB disorder attending the Outpatient Department of the Maastricht University Medical Center. Validated questionnaires and data from patient files were used to quantify the six dimensions of PH. Internal consistency was tested with McDonald's Omega. Zero-order Pearson correlations and t-tests were used to assess associations and differences. A P value < 0.05 was considered significant. The GI-HPB patients scored significantly worse in all dimensions of PH compared to control data or norm scores from the general population. Regarding quality of life, participation and daily functioning, GI-HPB patients scored in the same range as patients with chronic disorders in other organ systems, but depressive symptoms (in 35%) and malnutrition (in 45%) were more frequent in patients with chronic GI-HPB disorders. Intercorrelation scores between the six dimensions were only very weak to weak, forcing us to quantify each domain separately. All six dimensions of PH are impaired in the GI-HPB patients. Malnutrition and depressive symptoms are more prevalent compared to patients with chronic disorders in other organ systems.

An in vitro model system for testing chemical effects on microbiome-immune interactions - examples with BPX and PFAS mixtures.

More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly understood. Manufacturers are required to carry out toxicological studies, for example on the reproductive or nervous systems, before putting a new substance on the market. However, toxicological safety does not exclude effects resulting from chronic exposure to low doses or effects on other potentially affected organ systems. This is the case for the microbiome-immune interaction, which is not yet included in any safety studies. A high-throughput in vitro model was used to elucidate the potential effects of environmental chemicals and chemical mixtures on microbiome-immune interactions. Therefore, a simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species was cultured in vitro in a bioreactor that partially mimics intestinal conditions. The bacteria were continuously exposed to mixtures of representative and widely distributed environmental chemicals, i.e. bisphenols (BPX) and/or per- and polyfluoroalkyl substances (PFAS) at concentrations of 22 µM and 4 µM, respectively. Furthermore, changes in the immunostimulatory potential of exposed microbes were investigated using a co-culture system with human peripheral blood mononuclear cells (PBMCs). The exposure to BPX, PFAS or their mixture did not influence the community structure and the riboflavin production of SIHUMIx in vitro. However, it altered the potential of the consortium to stimulate human immune cells: in particular, activation of CD8+ MAIT cells was affected by the exposure to BPX- and PFAS mixtures-treated bacteria. The present study provides a model to investigate how environmental chemicals can indirectly affect immune cells via exposed microbes. It contributes to the much-needed knowledge on the effects of EDCs on an organ system that has been little explored in this context, especially from the perspective of cumulative exposure.

Real-world incidences and risk factors of immune-related adverse events in patients treated with immune checkpoint inhibitors: A nationwide retrospective cohort study

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are rare but fatal, requiring systemic steroid use. Therefore, to examine the outcomes, incidence, timing, and risk factors of ICI-associated steroid-requiring severe irAEs, we conducted a nationwide, retrospective, cohort study utilizing the Korean Health Insurance and Review Assessment database. We identified 357,010 patients with lung cancer, bladder cancer, or skin melanoma, eligible for ICI reimbursement in Korea between January 2012 to June 2020. Steroid-requiring severe irAEs following ICI treatment or treatment-emergent AEs following cytotoxic chemotherapy were defined as moderate- or high-dose steroid administration for over 2 consecutive days, along with corresponding ICD-10 codes indicating affected organ systems. The ICI-exposed group (N = 10,118) was compared to a matched cohort of 55,436 ICI-unexposed patients treated with cytotoxic chemotherapy. Incidences of acute severe irAEs requiring moderate- and high-dose steroids were higher in the ICI-exposed group (1.95% and 6.42%, respectively). The ICI-exposed group also had a higher risk of developing delayed severe irAEs requiring moderate- and high-dose steroid use (3.89% and 7.39%). Male sex, high comorbidity index, or previously diagnosed autoimmune diseases were associated with an increased risk of severe irAEs. Notably, 27.4–38.8% of the patients experienced recurrent severe irAEs after re-challenge with ICIs following moderate- or high-dose steroid use, with the severity matching the initial episode. Steroid-requiring severe irAEs were significantly more prevalent among patients exposed to ICIs than among those treated with chemotherapy in acute and delayed periods.

Analysis of healthcare provider management of immune-related adverse events and concordance with NCCN Guidelines.

11136 Background: Immune checkpoint inhibitors (ICIs) are a mainstay of treatment for many cancers but can cause immune-related adverse events (irAEs) that require prompt recognition and management. In 2017, we developed an online interactive decision support tool [www.clinicaloptions.com/immuneAEtool] for healthcare providers (HCPs) with case-specific recommendations for managing irAEs from a medical oncology expert. In 2019 and 2023, we updated the tool to offer recommendations from the latest National Comprehensive Cancer Network (NCCN) Guidelines. Here, we report a comparison of self-reported irAE management from HCPs using the 2023 tool vs NCCN recommendations and a comparison of practice patterns between the 2023 and 2019 tools. Methods: To use the online tool, HCPs entered the affected organ system, symptom grade/severity, and their planned management strategy. The tool showed the NCCN management recommendation for that irAE and then asked if the recommendation changed their intended management approach. Results: From July to December 2023, 172 HCPs entered 241 case scenarios into the tool; 53% treated &lt;10 patients/month with ICIs, and 38% of HCPs practiced in the United States. The most common irAEs involved the gastrointestinal (GI)/hepatobiliary (hep)/pancreatic (29% of cases) or dermatologic/oral (19%) systems. Overall, the planned irAE management strategy of HCPs matched the NCCN recommendations in 55% of cases, an increase from the 49% concordance rate in our 2019 analysis. In the current analysis, the lowest concordance was observed for infusion-related reactions (20%), musculoskeletal irAEs (46%), and dermatologic/oral mucosa irAEs (46%; Table). Furthermore, US HCPs had a lower overall concordance rate (46%) than non-US HCPs (66%). Approximately one half (56%) of all HCPs indicated that the NCCN recommendations in the tool changed their management plan. Conclusions: These data suggest that many HCPs are challenged to optimally manage irAEs and are not managing their patients in concordance with NCCN guidelines. A detailed analysis of HCP irAE management vs NCCN recommendations, including by organ system and severity, along with a comparison of 2023 vs 2019 practice patterns, will be presented. [Table: see text]

#664 Childhood Takayasu arteritis: a multicentre retrospective study

Abstract Background and Aims Takayasu arteritis (TA) is a rare, large vessel vasculitis affecting mainly the aorta and its major branches. Data on paediatric TA (pTA) is very scarce. The aim of this study was to characterize clinical presentation, therapy and outcome of pTA in a global study population. Method We conducted an international multicentre retrospective observational study of children diagnosed with pTA. Inclusion criteria were an age of less than 18 years at initial presentation in the year 2000 or more recently. Clinical data were collected from patients’ charts by the treating paediatric rheumatologist or nephrologist; data were fully anonymised for analysis purposes. Follow-up data was collected up to 2 years after diagnosis. Results 198 patients from 20 countries were included (76% female). The median age at disease onset was 12 years. Arterial hypertension (67%), a difference in pulses between limbs (65%) and fatigue (66%) were the most common symptoms at presentation. The gastrointestinal system was the second most affected organ system. The median eGFR (estimated glomerular filtration rate) at baseline was 105 ml/min/1.73 m2. Renal artery stenosis was documented in 58% of all patients and in 37% there was need for an invasive renovascular procedure. In 25 of 32 (78%) patients who had either a positron emission tomography–magnetic resonance imaging (PET-MRI) or PET-computed tomography (CT) there was evidence of active inflammation mainly of the aorta. 67% of all patients showed thickened wall abnormalities and 31% had arterial dilatations in a major vessel on any one or more anatomical imaging modality such as ultrasound, CT or MRI. Immunosuppressive treatment was primarily steroids, cyclophosphamide and methotrexate, 37% of all patients were treated with monoclonal antibodies of which 65% received an anti-tumor necrosis factor (TNF) antibody, 31% an anti-Interleukin 6 (IL-6) antibody and 4% an anti-B-cell antibody. Dialysis was necessary in 7% and one patient underwent kidney transplantation. Seven patient deaths (4%) were documented at the most recent follow-up. The renal function after two years was median eGFR 102 ml/min/1.73 m2, with 67% showing normal function, 31% presenting with chronic kidney disease (CKD) stage 1, 1% with stage 2, 1% with stage 3 and no patients showed stages 4 and 5. A quarter of the patients (27%) were still symptomatic at the 2-year follow-up. The median systolic blood pressure was 117 (interquartile range 107–125) mmHg. 64% of all patients still had antihypertensive treatment, and 87% were still on immunosuppressive therapy. Conclusion Our study represents the largest paediatric cohort of children diagnosed with Takayasu arteritis. Several organ systems were involved at onset and the clinical spectrum was highly variable. We will in our further analyses in more detail describe the outcome in relation to presenting symptoms and treatment.

The Scope of Mendelian Cardiomyopaties Genes

The review is devoted to the analysis of the scope of the genes of Mendelian cardiomyopathies (CM), specifically hypertrophic, dilatational, arrhythmogenic, and restrictive cardiomyopathy. According to Simple ClinVar, pathogenic/probably pathogenic variants of 75 genes lead to the development of one or more types of CM. At the same time, these genes are characterized by their expression in various tissues and organs (not only in the heart and blood vessels, but also in various parts of the brain, gastrointestinal tract, etc.), as well as by their involvement in a variety of metabolic pathways and biological processes. These data are generally consistent with the results of genome-wide association studies (GWAS). Polymorphisms of the CM genes are associated with various types of CM and other cardiovascular diseases, as well as obesity, various diseases of the musculoskeletal and nervous systems, mental, oncological, infectious diseases, and others. In addition to pathological conditions, common variants of the CM genes contributed to the variability of a wide range of quantitative traits, including pathogenetically significant for various multifactorial diseases. The non-randomness of the identified associations of CM genes with a wide range of diseases is evidenced by: comorbidity of CM with GWAS-associated diseases or the involvement of the latter as a symptom, a risk factor for the development of myocardial pathology, a modifier of the clinical presentation; overlapping of the affected organ systems and the spectrum of pathologies associated with common variants (according to GWAS) and to which rare pathogenic variants (according to OMIM) of the CM genes lead; confirmation of the involvement of CM genes in the pathogenesis of pathologies of other organ systems at the molecular level. Thus, the data presented in the review indicate the wide scope of the genes of primary CM, which goes beyond the cardiovascular system. That indicates the relevance of conducting comprehensive studies aimed at determining the cause-and-effect relationships between the CM and pathologies of other organs, including with the involvement of molecular genetic data.

Diagnostic accuracy of ultrasound screening for fetal structural abnormalities during the first and second trimester of pregnancy in low-risk and unselected populations.

Prenatal ultrasound is widely used to screen for structural anomalies before birth. While this is traditionally done in the second trimester, there is an increasing use of first-trimester ultrasound for early detection of lethal and certain severe structural anomalies. To evaluate the diagnostic accuracy of ultrasound in detecting fetal structural anomalies before 14 and 24 weeks' gestation in low-risk and unselected pregnant women and to compare the current two main prenatal screening approaches: a single second-trimester scan (single-stage screening) and a first- and second-trimester scan combined (two-stage screening) in terms of anomaly detection before 24 weeks' gestation. We searched MEDLINE, EMBASE, Science Citation Index Expanded (Web of Science), Social Sciences Citation Index (Web of Science), Arts & Humanities Citation Index and Emerging Sources Citation Index (Web of Science) from 1 January 1997 to 22 July 2022. We limited our search to studies published after 1997 and excluded animal studies, reviews and case reports. No further restrictions were applied. We also screened reference lists and citing articles of each of the included studies. Studies were eligible if they included low-risk or unselected pregnant women undergoing a first- and/or second-trimester fetal anomaly scan, conducted at 11 to 14 or 18 to 24 weeks' gestation, respectively. The reference standard was detection of anomalies at birth or postmortem. Two review authors independently undertook study selection, quality assessment (QUADAS-2), data extraction and evaluation of the certainty of evidence (GRADE approach). We used univariate random-effects logistic regression models for the meta-analysis of sensitivity and specificity. Eighty-seven studies covering 7,057,859 fetuses (including 25,202 with structural anomalies) were included. No study was deemed low risk across all QUADAS-2 domains. Main methodological concerns included risk of bias in the reference standard domain and risk of partial verification. Applicability concerns were common in studies evaluating first-trimester scans and two-stage screening in terms of patient selection due to frequent recruitment from single tertiary centres without exclusion of referrals. We reported ultrasound accuracy for fetal structural anomalies overall, by severity, affected organ system and for 46 specific anomalies. Detection rates varied widely across categories, with the highest estimates of sensitivity for thoracic and abdominal wall anomalies and the lowest for gastrointestinal anomalies across all tests. The summary sensitivity of a first-trimester scan was 37.5% for detection of structural anomalies overall (95% confidence interval (CI) 31.1 to 44.3; low-certainty evidence) and 91.3% for lethal anomalies (95% CI 83.9 to 95.5; moderate-certainty evidence), with an overall specificity of 99.9% (95% CI 99.9 to 100; low-certainty evidence). Two-stage screening had a combined sensitivity of 83.8% (95% CI 74.7 to 90.1; low-certainty evidence), while single-stage screening had a sensitivity of 50.5% (95% CI 38.5 to 62.4; very low-certainty evidence). The specificity of two-stage screening was 99.9% (95% CI 99.7 to 100; low-certainty evidence) and for single-stage screening, it was 99.8% (95% CI 99.2 to 100; moderate-certainty evidence). Indirect comparisons suggested superiority of two-stage screening across all analyses regarding sensitivity, with no significant difference in specificity. However, the certainty of the evidence is very low due to the absence of direct comparisons. A first-trimester scan has the potential to detect lethal and certain severe anomalies with high accuracy before 14 weeks' gestation, despite its limited overall sensitivity. Conversely, two-stage screening shows high accuracy in detecting most fetal structural anomalies before 24 weeks' gestation with high sensitivity and specificity. In a hypothetical cohort of 100,000 fetuses, the first-trimester scan is expected to correctly identify 113 out of 124 fetuses with lethal anomalies (91.3%) and 665 out of 1776 fetuses with any anomaly (37.5%). However, 79 false-positive diagnoses are anticipated among 98,224 fetuses (0.08%). Two-stage screening is expected to correctly identify 1448 out of 1776 cases of structural anomalies overall (83.8%), with 118 false positives (0.1%). In contrast, single-stage screening is expected to correctly identify 896 out of 1776 cases before 24 weeks' gestation (50.5%), with 205 false-positive diagnoses (0.2%). This represents a difference of 592 fewer correct identifications and 88 more false positives compared to two-stage screening. However, it is crucial to acknowledge the uncertainty surrounding the additional benefits of two-stage versus single-stage screening, as there are no studies directly comparing them. Moreover, the evidence supporting the accuracy of first-trimester ultrasound and two-stage screening approaches primarily originates from studies conducted in single tertiary care facilities, which restricts the generalisability of the results of this meta-analysis to the broader population.

Incidence, Risk Factors, and Outcomes of De Novo Malignancy following Kidney Transplantation.

Introduction: Post-transplant malignancy is a significant cause of morbidity and mortality following kidney transplantation often emerging after medium- to long-term follow-up. To understand the risk factors for the development of de novo post-transplant malignancy (DPTM), this study aimed to assess the incidence, risk factors, and outcomes of DPTM at a single nephrology centre over two decades. Methods: This retrospective cohort study included 963 kidney transplant recipients who underwent kidney transplantation between January 2000 and December 2020 and followed up over a median follow-up of 7.1 years (IQR 3.9-11.4). Cox regression models were used to identify the significant risk factors of DPTM development, the association of DPTM with graft survival, and mortality with a functioning graft. Results: In total, 8.1% of transplant recipients developed DPTM, and the DPTM incidence rate was 14.7 per 100 patient-years. There was a higher mean age observed in the DPTM group (53 vs. 47 years, p < 0.001). The most affected organ systems were genitourinary (32.1%), gastrointestinal (24.4%), and lymphoproliferative (20.5%). Multivariate Cox analysis identified older age at transplant (aHR 9.51, 95%CI: 2.60-34.87, p < 0.001) and pre-existing glomerulonephritis (aHR 3.27, 95%CI: 1.10-9.77, p = 0.03) as significant risk factors for DPTM. Older age was significantly associated with poorer graft survival (aHR 8.71, 95%CI: 3.77-20.20, p < 0.001). When age was excluded from the multivariate Cox model, DPTM emerged as a significant risk factor for poor survival (aHR 1.76, 95%CI: 1.17-2.63, p = 0.006). Conclusion: These findings underscore the need for tailored screening, prevention, and management strategies to address DPTM in an aging and immunosuppressed kidney transplant population.

Abstract 1167: Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity

Abstract Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, significantly improving outcomes. Nevertheless, too many melanoma patients undergoing ICI treatment experience severe and often debilitating immune-related adverse events (irAEs). In a retrospective melanoma cohort treated with ICIs, we previously found that elevated baseline levels of circulating CD4 effector memory T (TEM) cells were associated with the development of severe irAEs, irrespective of the affected organ system (Lozano et al., Nature Medicine, 2022). Here, we present data from an extended prospective validation cohort from 47 patients across two academic medical centers. Methods: Of 47 patients, 26 received combination anti-PD1/anti-CTLA4 ICIs, 3 combination anti-PD1/anti-LAG3 ICIs, 17 anti-PD1 ICI, and 1 anti-CTLA4 ICI. Peripheral blood mononuclear cells (PBMCs) were prepared from pretreatment (Cycle 1 Day 1) blood samples obtained from all patients. We performed mass cytometry (CyTOF) on PBMCs using a 38-marker panel to deeply profile immune subsets. We further leveraged bulk RNA-seq from 24 patients to (i) deconvolve CD4 memory T cell abundance using CIBERSORTx and (ii) determine T cell receptor (TCR) diversity using Shannon entropy following MiXCR clonotype assembly. irAEs were graded on a 5-point scale using the Common Terminology Criteria for Adverse Events v5. Results: After treatment initiation, 14 patients experienced severe irAEs (grade 3+) at a median of 12.1 weeks (range 4-54), including 4 with life-threatening (grade 4) irAEs. CyTOF revealed elevated circulating CD4 TEM cells in patients that developed severe irAEs (P&amp;lt;0.0001; AUC=0.87), including those treated with combination ICIs (P=0.0001; AUC=0.89). We further observed a continuous relationship between increasing CD4 TEM levels and irAE grade (P=3e-6, Jonckheere-Terpstra test). We then combined CD4 memory T cell abundance and TCR diversity derived from bulk RNA-seq on 24 of these patients using logistic regression (trained on data from Lozano et al.) to yield a composite model score. The pretreatment composite model score was strongly associated with severe irAE development (P=0.0009, AUC=0.88), and in a median split, identified patients with shorter time to severe irAE development (3 months vs. not reached; P=0.006; HR=10.5). Notably, composite model features and the overall score had no significant association with immunotherapy benefit. Conclusion: In this prospective study, both circulating CD4 TEM levels determined by CyTOF and a composite model score measured by RNA-seq were strongly associated with severe irAE development, independent of response status. These findings hold promise for future pretreatment risk stratification of ICI therapy. Citation Format: Abul Usmani, Noah Earland, Wubing Zhang, Peter K. Harris, Antonietta Bacchiocchi, Chloe M. Sachs, Aishwarya Nene, David Y. Chen, Mario Sznol, Ruth Halaban, Aaron M. Newman, Aadel A. Chaudhuri. Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1167.

Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?

Genetic high-resolution analyses and improved diagnostic imaging have impacted the ability to detect fetal disorders. It is unknown if this resulted in an alteration in the number of terminations of pregnancy due to fetal anomalies (TOPFA). The objective was to describe the incidence and indication of TOPFA. A descriptive study based on records from the Regional Abortion Council in the Central Denmark Region from 2008 to 2021 consisting of 1895 TOPFA. A consistent incidence of TOPFA was observed, accounting for 0.96% of the total births during that period. When examining fetal indications, there was a small increase in the occurrence of genetic aberrations, primarily caused by deletions, duplications, and single nucleotide variations, whereas the number of chromosomal aberrations remained stable. Of 35.5% of the cases with malformations, the central nervous system was the most affected organ system, followed by malformations of the heart 29.6%. Overall, the total number of cases remained stable. Unexpectedly, despite the development of new diagnostic tools, the incidence of TOPFA from 2008 to 2021 remained stable. However, the number of cases with genetic aberrations increased. This may be attributed to increased genetic testing for fetuses with identified malformations, resulting in more accurate diagnoses.

Prediction Models for Adverse Drug Reactions During Tuberculosis Treatment in Brazil.

Tuberculosis (TB) treatment-related adverse drug reactions (TB-ADRs) can negatively affect adherence and treatment success rates. We developed prediction models for TB-ADRs, considering participants with drug-susceptible pulmonary TB who initiated standard TB therapy. TB-ADRs were determined by the physician attending the participant, assessing causality to TB drugs, the affected organ system, and grade. Potential baseline predictors of TB-ADR included concomitant medication (CM) use, human immunodeficiency virus (HIV) status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (NAT2 acetylator profiles). The models were developed through bootstrapped backward selection. Cox regression was used to evaluate TB-ADR risk. There were 156 TB-ADRs among 102 of the 945 (11%) participants included. Most TB-ADRs were hepatic (n = 82 [53%]), of moderate severity (grade 2; n = 121 [78%]), and occurred in NAT2 slow acetylators (n = 62 [61%]). The main prediction model included CM use, HbA1c, alcohol use, HIV seropositivity, BMI, and age, with robust performance (c-statistic = 0.79 [95% confidence interval {CI}, .74-.83) and fit (optimism-corrected slope and intercept of -0.09 and 0.94, respectively). An alternative model replacing BMI with NAT2 had similar performance. HIV seropositivity (hazard ratio [HR], 2.68 [95% CI, 1.75-4.09]) and CM use (HR, 5.26 [95% CI, 2.63-10.52]) increased TB-ADR risk. The models, with clinical variables and with NAT2, were highly predictive of TB-ADRs.

Evaluation of adverse drug reactions to off-label use of drugs in children from spontaneously reported cases at a tertiary care hospital

Background: Off-label use of drugs (OLUDs) is relatively common in pediatric and this may be associated with adverse drug reactions (ADRs). The studies about the safety of drugs used in children cannot be applied to safety of drugs during OLUDs as drug is used in way that is different from that described in regulatory body. Hence, it is worthwhile to evaluate the off-label status of the suspected drugs causing ADRs. Aims and Objectives: The aim of the study was to analyze the pattern of ADRs occurring during OLUDs in pediatric patients from the spontaneously reported ADRs cases at the pharmacovigilance unit of a tertiary care hospital. Materials and Methods: Single center, retrospective, observational study was conducted in the department of pharmacology. ADRs spontaneously reported from January 2016 to December 2017, which occurred during OLUDs in children, where causality is certain, probable and possible. Results: A total of 46 ADRs occurred during OLUDs in 44 patients, these patients received 174 medicines among which 66 were off-labeled drugs. Off-label drugs mainly belonged to anti-infectives for systemic use (70.31%) and it is associated with 30 ADRs (68.18%). The most commonly affected organ system is skin and subcutaneous tissue (43.18%). Conclusion: OLUDs is associated with ADR, so caution should be taken while prescribing a drug in off-label manner in children.

Understanding patient, caregiver, and healthcare provider perspectives of the management of long-chain fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of rare, inherited, metabolic disorders that can lead to a wide range of symptoms that predominantly affect organ systems with high energy needs, such as the heart, liver, skeletal muscle, and nervous system. Clinical management primarily consists of close attention to and monitoring of diet and activity and avoidance of prolonged fasting. In addition, patients and caregivers must be alert for signs of life-threatening metabolic decompensation. As a result, LC-FAODs can have significant and wide-ranging impacts on the lives of patients and their caregivers. This article describes the effects of LC-FAODs at different life stages and in the context of the North American healthcare system from the perspective of a group of patients, caregivers, and healthcare providers (n = 6). We explain how challenges and needs change throughout life. Following an early diagnosis, an adjustment phase occurs during which caregivers may feel overwhelmed by their new roles and deeply concerned for their children's futures. As children grow, they become more aware of the differences between themselves and their peers, and with increasing independence comes more responsibility for managing their own condition. Major life events, such as new employment and moving house, pose challenges for people of all ages. In addition, it may be difficult to find and connect with qualified and experienced healthcare providers; navigate the health insurance system; and educate and align primary, specialist, and emergency care providers. We propose several strategies to improve the care of patients with LC-FAODs, such as educating local healthcare teams, improving trust between patients/caregivers and healthcare providers, and raising awareness of the challenges faced by patients and caregivers across the different life stages.

MitoHOPE: Embryological Aspects

Mitochondrial diseases are a group of rare genetic disorders that affect the function of mitochondria, the energy-producing structures within cells. These disorders result from mutations in either nuclear DNA or mitochondrial DNA (mtDNA), disrupting normal energy production process, with vital organs such as the brain, heart, muscles, and nervous system suffering from insufficient energy supply. Symptoms of mitochondrial disease are diverse however commonly include muscle weakness, fatigue, neurological issues, developmental delays, and organ dysfunction. Treatment options for mitochondrial disease are limited and primarily focus on managing symptoms and supporting affected organ systems. Currently, no cure exists, making early detection crucial to better manage the condition’s progression. Research efforts and advances in genetic technology offer hope for improved diagnostic methods and potential therapies in the future and for patients where the disease is caused by mutations in mtDNA, mitochondrial donation technology has also been developed in the hope of providing patients a means of having a family, with a reduced likelihood of passing on mtDNA disease to their offspring. Mitochondrial donation technology, also known as mitochondrial replacement therapy (MRT), is a ground-breaking medical technique designed to prevent the transmission of mitochondrial diseases from mother to child. This cutting-edge procedure involves replacing defective mitochondria in a woman’s egg with healthy mitochondria/cytoplasm from an egg donor using primarily either miotic spindle transfer (MST) or pro-nuclear transfer (PNT). Recently in Australia a MRFF grant has been awarded to facilitate bringing MRT to patients in Australia who have mtDNA disease and offering it as part of a clinical trial (mitoHOPE). As part of this, considerations must be given to how this technology is applied in a clinical IVF lab setting, specifically the equipment used, the technology that is selected (MST vs PNT) and optomised, the training of the clinical embryologists and the management of the oocyte donor program, all of which are crucial to ensure optimal clinical trial and technology provision.

A Pilot Study for the Kidney Effects of Voxelotor in Sickle Cell Anemia

The kidneys are among the most commonly affected organ systems in sickle cell anemia (SCA) and an estimated 15% of deaths in patients with SCA are attributed to kidney failure (PMID 7993409). Angiotensin converting enzyme-inhibitors and angiotensin receptor blockers have been adopted to treat SCA-related chronic kidney disease (CKD) from the non-SCA literature, although demonstrated efficacy in SCA CKD has been marginal in a limited number of small, short-term studies (PMID 28589652). Therapies that directly target the pathophysiology of SCA-related kidney disease may stabilize or improve kidney function. Both the rate of hemolysis and the degree of anemia are associated with the development and progression of CKD in SCA (PMID 24329963, 21523807). Voxelotor inhibits hemoglobin polymerization in SCA red blood cells in the deoxygenated state, leading to a reduction in the rate of hemolysis and an increase in hemoglobin concentration. We conducted a pilot study to determine whether voxelotor can improve kidney function in adults with SCA (NCT 04335721). SCA (HbSS or HbSβ 0-thalassemia) patients ≥ 18 years old and with urine dipstick-defined hemoglobinuria (+ for blood &amp; ≤ 2 red blood cells/high power field), CKD stage 1 or 2 (urine albumin-to-creatinine ratio [ACR] ≥ 30 mg/g &amp; estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73m 2), and hemoglobin concentrations of 5.5 - 10.5 g/dL were eligible. The eGFR was calculated using the CKD-EPI 2009 creatinine-based equation without the race coefficient and the 2012 cystatin C-based equation. Patients were randomized to voxelotor 1,500mg/day for 48 weeks or standard of care, as defined by their primary SCA provider. First or second void urines were collected for urine ACR measurements. The primary endpoint was the change in urine ACR from the mean values at baseline and screening versus the mean values at 47 and 48 week visits. One patient randomized to standard of care was started on voxelotor at week 24 by his provider to improve his hemoglobin concentration. This patient is included in the voxelotor treatment group in combined analysis; the change in laboratory measures in this patient is based upon changes from the mean of values at week 12 and 24 to week 47 and 48 visits. Median and range values are provided. Between 3/2021 and 6/2022, 8 SCA patients with hemoglobinuria and urine ACR &amp;gt; 30mg/g crt observed during routine clinic visits were screened and 6 met the inclusion criteria. The median age of the enrolled cohort was 36 (27 - 63) years, 4 were male, 4 were on stable doses of hydroxyurea (median dose 1000mg/day; 500 - 1500mg/day) and 2 were on stable doses of lisinopril (5, 20mg/day) for at least 90 days before screening. Two other patients had been on lisinopril in the past but developed hyperkalemia prior to enrollment. The median values of kidney function measures at screening and baseline study visits were as follows: urine ACR, 251 (32 - 3132) and 392 (80 - 3101) mg/g crt; creatinine-based eGFR, 109 (93 - 136) and 115 (88 - 137) mL/min/1.73m 2; and cystatin C-based eGFR, 82 (61 - 141) and 85 (61 - 128) mL/min/1.73m 2, respectively. SCA patients who received voxelotor (n = 4) had a median increase in hemoglobin concentration of +0.9 g/dL (-0.4 - +2.6 g/dL) and reductions in indirect bilirubin concentration of -2.2 mg/dL (0 - -4 mg/dL) and reticulocyte % of -2.7% (-1.2 - -4.9%). Urine ACR (-59%, -21% - -100%) improved in SCA patients treated with voxelotor but worsened in those who received standard of care without voxelotor (n = 2) (+86.3%, 64 - 108%) (P=0.009) (Figure 1A). 24-hour urine protein concentrations also improved in those that received voxelotor (-45%, -25% - -100%) but increased in those who did not receive voxelotor (+122%, 113 - 131%) (P = 0.002) (Figure 1B). Changes in creatinine- and cystatin-C based eGFR from baseline were not significantly different between patients who received voxelotor and those who did not. This pilot study demonstrates that SCA patients with hemoglobinuria and early stages of CKD treated with voxelotor may have significant improvements in urine ACR and proteinuria after 24 - 48 weeks of therapy. These preliminary results support the concept that improving hemolytic anemia could be a targeted therapeutic approach to reduce biomarkers of kidney dysfunction, and they warrant larger, prospective clinical studies.

Treatment of 95 post-Covid patients with SSRIs

After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response. Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia. Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge. Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.

A rare case of high risk multisystem Langerhans Cell Histiocytosis in infant

Objective: Langerhans cell histiocytosis (LCH) stands as the most common histiocytic disorder. It is categorized into single-system single site, single-system multi-site, and multisystem types, with or without involvement of risk organs. Clinical presentation exhibits considerable variability, contingent upon the affected organ systems. Given its rarity, diverse locations, and varying severity, there are currently no established treatment guidelines for LCH. Case Presentation: We documented the case of a 5-month-old male diagnosed with Langerhans cell histiocytosis (LCH), presenting with high-risk multisystem organ involvement and concurrent unifocal bone involvement. Bone marrow aspiration revealed infiltration by multinucleated giant cells within the marrow. Skin biopsy demonstrated Langerhans cell proliferation with epidermotrophism and the characteristic reniform nucleus resembling a coffee bean. The patient was treated following the histiocytosis protocol, which included daily oral prednisone and 6-mercaptopurine, in addition to weekly intravenous vinblastine and methotrexate administered every two weeks. Unfortunately, the patient displayed limited response during the initial phase of treatment and, tragically, passed away during the eighth week of therapy. Conclusion: Langerhans cell histiocytosis (LCH) is a rare disease characterized by variable disease presentations and is associated with significant morbidity and mortality. Timely recognition of clinical manifestations and risk factors, coupled with appropriate treatment, is crucial to reduce mortality and long-term complications associated with the condition.