Adult Disease Research Articles

In vivo perturb-seq of cancer and microenvironment cells dissects oncologic drivers and radiotherapy responses in glioblastoma.

Genetic perturbation screens with single-cell readouts have enabled rich phenotyping of gene function and regulatory networks. These approaches have been challenging in vivo, especially in adult disease models such as cancer, which include mixtures of malignant and microenvironment cells. Glioblastoma (GBM) is a fatal cancer, and methods of systematically interrogating gene function and therapeutic targets in vivo, especially in combination with standard of care treatment such as radiotherapy, are lacking. Here, we iteratively develop a multiplex in vivo perturb-seq CRISPRi platform for single-cell genetic screens in cancer and tumor microenvironment cells that leverages intracranial convection enhanced delivery of sgRNA libraries into mouse models of GBM. Our platform enables potent silencing of drivers of in vivo growth and tumor maintenance as well as genes that sensitize GBM to radiotherapy. We find radiotherapy rewires transcriptional responses to genetic perturbations in an in vivo-dependent manner, revealing heterogenous patterns of treatment sensitization or resistance in GBM. Furthermore, we demonstrate targeting of genes that function in the tumor microenvironment, enabling alterations of ligand-receptor interactions between immune and stromal cells following in vivo CRISPRi perturbations that can affect tumor cell phagocytosis. In sum, we demonstrate the utility of multiplexed perturb-seq for in vivo single-cell dissection of adult cancer and normal tissue biology across multiple cell types in the context of therapeutic intervention, a platform with potential for broad application.

Plasma Proteomic Biomarkers in Alzheimer's Disease and Cardiovascular Disease: A Longitudinal Study.

The co-occurrence of Alzheimer's disease (AD) and cardiovascular diseases (CVDs) in older adults highlights the necessity for the exploration of potential shared risk factors. A total of 566 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 111 individuals with AD, 383 with mild cognitive impairment (MCI), and 410 with CVD. The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD with longitudinal changes in 146 plasma proteomic biomarkers (measured at baseline and the 12-month follow-up). The LMM showed that 48 biomarkers were linked to AD and 46 to CVD (p < 0.05). Both AD and CVD were associated with longitudinal changes in 14 biomarkers (α1Micro, ApoH, β2M, BNP, complement C3, cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF), and both MCI and CVD were associated with 12 biomarkers (ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), suggesting intricate connections between cognitive decline and cardiovascular health. Among these, the Tamm Horsfall Protein (THP) was associated with AD, MCI, CVD, and APOE-ε4. This study provides valuable insights into shared and distinct biological markers and mechanisms underlying AD and CVD.

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

7119 Klinefelter Syndrome in a Tertiary Referral Clinic: A Case Series and Clinical Audit

Abstract Disclosure: J. Luo: None. S. Sarlos: None. R. Giri: None. I. Sim: None. R.I. McLachlan: None. C.A. Allan: None. R. Upreti: None. Background: Klinefelter syndrome, the most common chromosomal disorder in men, remains underdiagnosed in many of those affected. Klinefelter syndrome is associated with hypogonadism and infertility, as well as an increased risk for venous thromboembolism (VTE), cardiometabolic disease, osteoporosis and gynaecomastia in adults. We studied the clinical features and disease associations in a tertiary referral cohort, and audited the care provided. Methods: Following ethics approval, adult patients with Klinefelter syndrome attending a Clinical Andrology Service in a tertiary Australian institution since 1 January 2011 were recruited. A database was established and demographics, aspects of initial diagnosis, ongoing treatments and comorbidities were documented. We audited our care using the European Academy of Andrology 2021 Guidelines for Klinefelter Syndrome. Results: Of 94 patients eligible, 57 patients consented to participation. The median age of diagnosis was 28 years, with the most common karyotype being 47,XXY (74%), followed by mosaic (20%) and higher degree polysomy (6%). Infertility (44%) and hypogonadism (33%) were the most common reasons for diagnosis. Most patients (88%) were treated with testosterone. Five men (11%) had genetic children with seven (18%) having previously attempted surgical sperm extraction. VTE occurred in seven patients (12%), with five on long-term anticoagulation following VTE diagnosis. Cardiovascular risk factor prevalence assessed at a median age of 42 years included increased BMI (72%), hypertension (25%), dyslipidaemia (70%), tobacco use (26%), impaired fasting glucose (11%) and type 2 diabetes (22%), though only one patient had a previous cardiovascular event. Osteopenia and osteoporosis were present in 28% and 4% of patients respectively, though only two patients had minimal trauma fractures. The audit of longitudinal care showed that gynaecomastia status was underreported (42%) in our clinic, whilst assessment and management of other health domains were mostly in keeping with the current recommendations. Conclusions: Klinefelter syndrome diagnosis continues to be delayed until adulthood in many men, with presentations most commonly involving infertility and/or hypogonadism. Our tertiary cohort demonstrates low rates of fertility treatment and success, which is likely multifactorial. There is a high burden of VTE, cardiovascular risk factors and reduced bone density despite testosterone treatment. Low rates of cardiovascular events and fracture may be reflective of a younger cohort as well as more aggressive risk factor management in a sub-specialist service. Gynaecomastia identification, documentation and management are areas for potential improvement. Increased awareness of Klinefelter syndrome and research into its associated risks are essential for standardising care and improving long-term outcomes. Presentation: 6/1/2024

7190 Serum uric acid and serum uric acid-to-creatinine ratio and its association with metabolic syndrome in Korean adolescents: the nation-wide population-based study

Abstract Disclosure: S. Jung: None. J. Kim: None. S. Kim: None. Backgrounds: As the prevalence of obesity and metabolic syndrome (MetS) among the pediatric population continues to rise, it is crucial to identify the factors associated with cardiometabolic risk factors (CMRFs) to prevent the future development of diabetes and cardiovascular disease. Elevated serum uric acid (SUA) and SUA-to-creatine ratio (SUA/Cr) levels are associated with MetS, CMRFs, and non-alcoholic fatty liver disease (NAFLD) in adults. However, studies on the usefulness of SUA or SUA/Cr to predict MetS in adolescents were sparse. The aim of this study is to investigate the association between SUA or SUA/Cr level and MetS and CMRFs among Korean adolescents. Material/Methods: Data collected from the Korea National Health and Nutrition Examination Survey between 2016 and 2021, which was nationally representative cross-sectional data, were used. A total of 2,218 subjects (1,185 males, 54.0%) aged 13-18 years were included in this study. They were classified into tertiles of SUA or SUA/Cr levels (T1, lower tertile; T2, mid-tertile; and T3, upper tertile) according to sex. The prevalence of MetS and CMRFs, including alanine aminotransferase (ALT), was compared by tertiles of SUA. Results: The mean SUA and SUA/Cr was higher in males than females (6.37 ± 0.04 mg/dL and 4.66 ± 0.06 mg/dL, P &amp;lt; 0.001 for SUA; 7.90 ± 0.07 mg/dL and 7.30 ± 0.06 mg/dL, P &amp;lt; 0.001 for SUA/Cr). Z-scores of body mass index, waist circumference, waist-height ratio, levels of total cholesterol, triglyceride, and ALT were significantly higher in T3 of SUA and SUA/Cr in both sexes, while high-density lipoprotein cholesterol (HDL-C) was lower. In T3 of SUA and SUA/Cr, the prevalence and odds ratio (95% confidence interval) increased significantly in abdominal obesity [34.5%, 5.5 (4.0, 7.7) vs. 31.3%, 5.3 (3.7, 7.6)], elevated blood pressure [19.5%, 2.1 (1.5, 2.9) vs. 16.3% 1.6 (1.1, 2.2)], elevated triglyceride [29.5%, 2.1 (1.5, 2.8) vs. 27.9%, 2.1 (1.6, 2.8)], low HDL-C [22.5%, 3.4 (2.4, 5.0) vs. 20.2%, 2.6 (1.8, 3.9)], elevated ALT [31.5%, 5.7 (3.8, 8.6) vs. 19.1% 4.9 (3.2, 7.6)], obesity [33.6%, 7.6 (5.2, 11.2) vs. 25.9%, 6.0 (3.9, 9.1)] and MetS [13.7%, 7.4 (4.3, 13.0) vs. 10.8%, 6.8 (3.9, 9.1)], compared with T1 of SUA and SUA/Cr, respectively. In the receiver operating characteristic curve analysis, the area under the curve of predicting MetS was 0.681 for males and 0.823 for females using SUA and 0.653 for males and 0.840 for females using SUA/Cr. The proportion of participants with ≥ 3 CMRFs was 2.1% in T1, 3.5% in T2, and 13.7% in T3 in SUA (P &amp;lt; 0.001) and 2.1% in T1, 5.8% in T2, and 10.8% in T3 in SUA/Cr (P &amp;lt; 0.001). Conclusions: In this nationwide cross-sectional study, SUA and SUA/Cr levels are associated with MetS, its components, and the marker of NAFLD in Korean adolescents. SUA and SUA/Cr seem to be more specific in diagnosing MetS in female adolescents. Both SUA and SUA/Cr could be used as important markers to predict MetS in adolescents. Presentation: 6/1/2024

7119 Klinefelter Syndrome in a Tertiary Referral Clinic: A Case Series and Clinical Audit

Abstract Disclosure: J. Luo: None. S. Sarlos: None. R. Giri: None. I. Sim: None. R.I. McLachlan: None. C.A. Allan: None. R. Upreti: None. Background: Klinefelter syndrome, the most common chromosomal disorder in men, remains underdiagnosed in many of those affected. Klinefelter syndrome is associated with hypogonadism and infertility, as well as an increased risk for venous thromboembolism (VTE), cardiometabolic disease, osteoporosis and gynaecomastia in adults. We studied the clinical features and disease associations in a tertiary referral cohort, and audited the care provided. Methods: Following ethics approval, adult patients with Klinefelter syndrome attending a Clinical Andrology Service in a tertiary Australian institution since 1 January 2011 were recruited. A database was established and demographics, aspects of initial diagnosis, ongoing treatments and comorbidities were documented. We audited our care using the European Academy of Andrology 2021 Guidelines for Klinefelter Syndrome. Results: Of 94 patients eligible, 57 patients consented to participation. The median age of diagnosis was 28 years, with the most common karyotype being 47,XXY (74%), followed by mosaic (20%) and higher degree polysomy (6%). Infertility (44%) and hypogonadism (33%) were the most common reasons for diagnosis. Most patients (88%) were treated with testosterone. Five men (11%) had genetic children with seven (18%) having previously attempted surgical sperm extraction. VTE occurred in seven patients (12%), with five on long-term anticoagulation following VTE diagnosis. Cardiovascular risk factor prevalence assessed at a median age of 42 years included increased BMI (72%), hypertension (25%), dyslipidaemia (70%), tobacco use (26%), impaired fasting glucose (11%) and type 2 diabetes (22%), though only one patient had a previous cardiovascular event. Osteopenia and osteoporosis were present in 28% and 4% of patients respectively, though only two patients had minimal trauma fractures. The audit of longitudinal care showed that gynaecomastia status was underreported (42%) in our clinic, whilst assessment and management of other health domains were mostly in keeping with the current recommendations. Conclusions: Klinefelter syndrome diagnosis continues to be delayed until adulthood in many men, with presentations most commonly involving infertility and/or hypogonadism. Our tertiary cohort demonstrates low rates of fertility treatment and success, which is likely multifactorial. There is a high burden of VTE, cardiovascular risk factors and reduced bone density despite testosterone treatment. Low rates of cardiovascular events and fracture may be reflective of a younger cohort as well as more aggressive risk factor management in a sub-specialist service. Gynaecomastia identification, documentation and management are areas for potential improvement. Increased awareness of Klinefelter syndrome and research into its associated risks are essential for standardising care and improving long-term outcomes. Presentation: 6/1/2024

Monogenic Kidney Diseases in Adults With Chronic Kidney Disease (CKD).

According to current evidence, every 10th to 11th adult with chronic kidney disease (CKD) has a monogenic disease of the kidney. This review is based on reported studies in which molecular genetic diagnostic techniques were used to investigate monogenic kidney diseases in adults with CKD. The studies were identified by a selective literature search using predefined criteria. In 12 selected studies, diagnostic variants of 179 different genes were identified in 1467 out of 6607 study participants with CKD (22.2%). More than 60% of these variants affected 8 genes (PKD1, PKD2, COL4A3, COL4A4, COL4A5, UMOD, MUC1, HNF1B). Three diseases are associated with these genes: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, and autosomal dominant tubulo-interstitial kidney disease (ADTKD). Physicians treating patients with CKD should be alert to the presence of any red flags, such as onset at a young age, a positive family history, or hematuria of unknown cause. When a genetic etiology is suspected, a specialized work-up is indicated, often including a molecular genetic investigation. A positive genetic finding usually leads to a modification of the patient's specific diagnosis and/or treatment. Awareness of the high prevalence of monogenic kidney diseases in adults with CKD and alertness to their suggestive clinical features are crucial for the timely initiation of targeted diagnostic testing. The molecular genetic identification of these diseases is a prerequisite for appropriate patient management.

Placental Malaria Induces a Unique Methylation Profile Associated with Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malaria (PM), characterized by sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous space, is the leading global cause of FGR, but its impact on placental epigenetics is unknown. We hypothesized that placental methylomic profiling would reveal common and distinct mechanistic pathways of non-malarial and PM-associated FGR. We analyzed placentas from a US cohort with no malaria exposure (n = 12) and a cohort from eastern Uganda, a region with a high prevalence of malaria (n = 12). From each site, 8 cases of FGR (defined as birth weight <10%ile for gestational age by Intergrowth-21 standard curves) and 4 healthy controls with normal weight were analyzed. PM was diagnosed by placental histopathology. We compared the methylation levels of over 850K CpGs of the placentas using Infinium MethylationEPIC v1 microarray. Non-malarial FGR was associated with 65 differentially methylated CpGs (DMCs), whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls without FGR. One DMC (cg16389901, located in the promoter region of BMP4) was commonly hypomethylated in both groups. We identified 522 DMCs between non-malarial FGR vs. PM-FGR placentas, which was independent of differing geographic location or cellular composition. Placentas with PM-associated FGR have distinct methylation profiles as compared to placentas with non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. Larger cohort studies are needed to determine the distinct long-term health outcomes in PM-associated FGR pregnancies.

Macrovascular blood flow and microvascular cerebrovascular reactivity are regionally coupled in adolescence.

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n=12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Insonmia: cardiovascular risk factor in adult people

Introduction. Cardiovascular diseases (CVD) will be the cause of 24.2 million deaths in the world in 2030 and the poor quality and quantity of people's sleep are increasingly related to their risk factors, including insomnia. Objective. The main objective of this research work was to know the influence of chronic insomnia as a risk factor for cardiovascular diseases in adults. Methodology. The present study is based on an integrative review of the literature of articles published between the years 2012-2024, obtained from the journal portal Scientific Electronic Library Online (SCIELO) and the bibliographic databases SCOPUS, Web of Science (WOS), Library of Medicine National Institutes of Health (PubMed), ProQuest and Google Scholar, results that were organized according to the PRISMA methodology. Results. 11 articles were finally included, derived from primary research works, which describe the relationship and impact of chronic insomnia with cardiovascular diseases, their mortality and morbidity. Conclusions. Chronic insomnia is currently established as a modifiable cardiovascular risk factor; its effective treatment will in the future be a preventive measure that will reduce the incidence, mortality and morbidity rates of different cardiovascular diseases

Childhood Developmental Milestones and Risk of Adult Cerebrovascular Disease: The Northern Finland Birth Cohort 1966

Introduction: To the best of our knowledge, no previous studies have examined the relationship between childhood developmental milestones and risk of adulthood cerebrovascular disease (CeVD). We studied whether the risk of adult CeVD is associated with delayed attainment of motor and language milestones. Methods: Within the Northern Finland Birth Cohort 1966, a total of 11,688 persons were followed from birth to either death, moving abroad or 54 years of age. CeVD diagnoses, i.e., ischemic and hemorrhagic strokes and transient ischemic attacks, were extracted from national registers with diagnostic coding based on recommendations of the World Health Organization. Cox proportional hazard models stratified by sex were used to estimate associations of motor development and language milestones between ages 0 and 4 years and adult CeVD women-to-men relative hazard ratios (RHRs) were estimated for each developmental milestone. Analyses were adjusted for family socioeconomic status and birth weight for gestational age. Results: Altogether 498 (4.3%) CeVDs were recorded during follow-up. Among both sexes, later turning from back to tummy was associated with ischemic CeVD in adulthood with an adjusted hazard ratio (aHR) of 1.25 and 95% confidence interval (CI) 1.06–1.46 for men and an aHR: 1.20 (CI: 1.02–1.42) for women per 1 month delay in achievement. Delayed overall motor development, modeled by motor milestone principal component score, was related to increased risk of ischemic CeVD (aHR: 1.50; CI: 1.03–2.19) among men. Later achievement of making sounds was associated with any CeVD (aHR: 2.74; CI: 1.39–5.40) and especially ischemic CeVD (aHR: 3.41; CI: 1.65–7.06) among men with women-to-men RHR’s of 0.17 (95% CI: 0.04–0.81) for any CeVD and RHR 0.18 (95% CI: 0.04–0.89) for ischemic stroke indicating risk to be lower in women compared to men. Conclusions: These findings suggest that later achievement of childhood milestones could be a predictor for development of CeVD risk. The results point toward a common neurodevelopmental background and could in part explain lifetime CeVD risk accumulation.

Burden of Chronic Kidney Disease for Adults 70 Years and Older in Iran During 1990-2021

Objectives: To report the burden of chronic kidney disease (CKD) among those aged 70 and above in Iran by age, sex, and province from 1990 to 2021. Design: Systematic analysis. Outcome measures: Data were obtained from the Global Burden of Disease study 2021. All estimates were reported as counts and age-standardized rates per 100000 individuals, with their corresponding 95% uncertainty intervals (UIs). Results: In 2021, CKD recorded an age-standardized prevalence of approximately 44 thousand per 100000 population among adults 70 years and older in Iran (95% UI: 39807–47784.5 per 100000). This rate meant a 5% increase compared to 1990, which was statistically significant. CKD also accounted for 8,725 deaths in the elderly population of Iran in 2021. Furthermore, disability-adjusted life years (DALY) rates were 3697.7 per 100000 population and had a 28.2% increase in the span of 1990–2021. Fars and Chahar Mahaal and Bakhtiari had the highest and lowest point prevalence per 100000 at 50357.2 and 40453.9, respectively, in the elderly population. In 2021, the prevalence, deaths, and DALYs due to CKD did not differ significantly between the two sexes, although the numbers were slightly higher in the female population. Moreover, the age-standardized prevalence, deaths, and DALYs of CKD in the elderly of Iran in 2021 started to rise in the 70–74 and increased with aging. Conclusions: The burden of CKD in the elderly of Iran has increased over the past 30 years. This is in line with the increase in the elderly population and the rising of its related risk factors. Preemptive measures, public knowledge raising, and the implementation of risk management policies can brighten the future of Iran’s elderly population in terms of non-communicable diseases, especially CKD.

Clinical factors and predictors for spontaneous separation of epiretinal membranes.

To investigate the clinical characteristics, imaging features, and predictive factors for spontaneous separation in patients with idiopathic or secondary ERM. The overall cohort was divided into two subgroups: idiopathic ERM (28 eyes, 56%) and secondary ERM (22 eyes, 44%). Electronic records and multimodal imaging were reviewed. Among the 50 eyes included in this study, the self-separation of ERM occurred over a mean duration of 28.1 ± 25.3months (median: 25.4months). Compared with the secondary ERM group, the idiopathic group had a shorter interval to separation (idiopathic vs. secondary, 23.4 vs. 34.1months, respectively; P = .01) and better vision at diagnosis (logMAR 0.094 vs. 0.224; P = .009) and after separation (logMAR 0.097 vs. 0.188; P = .01). Overall, in both subgroups, spontaneous ERM separation appeared to have been induced by posterior vitreous detachment (PVD) (P < .001). Multivariate analysis revealed that the self-separation interval (odds ratio [OR] 0.936) and IRF (OR 0.049) were significantly associated with complete ERM separation (all P < .05). Additionally, secondary ERM (OR 15.224) and lower initial best-corrected visual acuity (OR 267.589) were significantly associated with improvements in vision after self-separation (all P < .05). The self-separation of ERM appears to be induced by PVD development in most eyes. Owing to the possibility of complete spontaneous separation, surgical membrane peeling may be delayed by up to 28months in eyes without PVD, regardless of whether the cause is idiopathic or secondary. Patients with secondary ERM may experience favorable visual improvement after self-separation despite having poor vision at diagnosis and IRF on OCT. What is known • An epiretinal membrane (ERM), the most prevalent retinal disease in adults, is less understood regarding clinical factors and the accurate mechanism of spontaneous separation. What is new • The separation of ERM appears to be induced by PVD development in most eyes. • Favorable vision outcomes were associated with secondary ERMs and lower initial visual acuity. • Complete ERM separation was associated with a shorter self-resolution interval and the absence of intraretinal fluid (IRF) in OCT imaging.

A-227 One Step Toward Implementation of Advanced Lipoprotien Testing in Children: A Pilot Study on Pediatric Reference Ranges

Abstract Background Abnormal serum lipid levels in childhood are associated with dyslipidemia and increased risk of cardiovascular disease in adulthood. High prevalence of childhood obesity in the US has increased concerns about the adverse effects of abnormal lipids in children, prompting recommendations for universal lipid screening in adolescents. While specialized analysis of lipoproteins by nuclear magnetic resonance (NMR) has been predominately used in adults with risk factors for CVD, our laboratory also receives pediatric samples for NMR testing, most commonly associated with diagnostic codes for hyperlipidemia and/or abnormal weight gain. Currently adult-based reference ranges for the NMR lipoprotein measurements are used in children. The objective of this pilot study was to compare lipoprotein profiles of healthy adults and children and to assess the impact of reference intervals for children on clinical interpretation of pediatric results. Methods Serum samples were collected from 60 healthy children, ages 1 - 17 years, and 148 self-identified healthy adults, ages 19 - 64 years old. NMR lipoprotein analysis was performed using the Axinon lipoFIT by NMR assay on a 600 MHz NMR (Bruker). Statistical analysis was conducted in Excel and Graph Pad Prism. Reference intervals (RIs) were determined in EP Evaluator as the central 95% interval. Results The levels of atherogenic low-density lipoprotein particle number (LDL-P) and small LDL-P (sLDL-P) were significantly lower in children compared to adults: 783±222 vs 1212±412 nmol/L and 302±142 vs 498±306 nmol/L, respectively (p&amp;lt;0.00001). Additionally, LDL size (LDL-s) was significantly larger in children than adults (21.23±0.29 vs 21.06±0.44 nm, p=0.006), reflecting prevalence of less dense LDL-P in the former group. Pediatric samples also had lower number of anti-atherogenic high-density lipoprotein particles (HDL-P) compared to adults: 29.4±4.6 vs 33.5±4.6 µmol/L, p&amp;lt;0.00001. The significant differences in the number and size of lipoprotein particles between adults and children implies that currently used adult reference intervals might not be appropriate for evaluating pediatric NMR samples. Therefore, we estimated RIs for our heathy pediatric and adult cohorts and applied these RIs to our retrospective data of 618 samples from children 1-17 years old, which were submitted for NMR lipoprotein testing in recent years. The analysis showed that using the adult RIs, 37% and 27% of pediatric samples would not flag for abnormally elevated LDL-P and sLDL-P, respectively; but they would be flagged based on the RI derived from our pediatric cohort. Moreover, 12% pediatric samples flagged for low HDL-P would have normal HDL-P levels if pediatric RIs are used instead of adult RIs. Conclusions Use of adult reference intervals in children may result in misclassification of lipid status and underestimation or overestimation of dyslipidemia and CVD risk in children. This pilot study highlights the need for pediatric reference intervals to guide interpretation of advanced lipid testing in children.

The epidemiology and microbiology of central venous catheter related bloodstream infections among hemodialysis patients in the Philippines: a retrospective cohort study

BackgroundDespite efforts to improve the management of catheter-related bloodstream infections (CRBSI) in literature, temporary CVCs continue to be used for maintenance hemodialysis outside of acute care settings, particularly in the Philippines.MethodsWe conducted a retrospective cohort study to investigate the incidence, outcomes, risk factors, and microbiological patterns of CRBSI among adult kidney disease patients undergoing hemodialysis at the Philippine General Hospital, the country's largest tertiary referral center. We included all adult patients who received a CVC for hemodialysis from January 1, 2018, to August 31, 2019, and followed them for six months to observe the occurrence of CRBSI and its outcomes.ResultsOur study documented a CRBSI incidence rate of 6.72 episodes per 1000 catheter days, with a relapse rate of 5.08%, a reinfection rate of 15.74%, and a mortality rate of 6.09%. On multivariable regression analysis, we identified autoimmune disease, dialysis frequency of > 3 × per week, use of CVC for either blood transfusion or IV medications, renal hypoperfusion, drug-induced nephropathy, and hypertensive kidney disease as significant risk factors for CRBSI. Gram-negative bacteria, including B. cepacia complex, Enterobacter, and Acinetobacter spp, were the most common organisms causing CRBSI. Multidrug-resistant organisms (MDROs) comprised almost half of the isolates (n = 89, 44.5%), with Coagulase-negative Staphylococcus species having the highest proportion among gram-positive organisms and Acinetobacter spp. among gram-negative isolates.ConclusionOur findings emphasize the need for more stringent measures and interventions to prevent the propagation of identified pathogens, such as a review of sterile technique and adequate hygiene practices, continued surveillance, and expedited placement and utilization of long-term access for patients on maintenance hemodialysis. Furthermore, CVC use outside of hemodialysis should be discouraged, and common antibiotic regimens such as piperacillin-tazobactam and fluoroquinolones should be reviewed for their low sensitivity patterns among gram-negative isolates. Addressing these issues can improve hemodialysis patients' outcomes and reduce the CRBSI burden in our institution.

Breastfeeding in infancy and cardiovascular disease in middle-aged and older adulthood: a prospective study of 0.36 million UK Biobank participants

BackgroundCardiovascular disease originates in early life. We aimed to investigate the association between breastfeeding in infancy and cardiovascular disease in adult life. MethodsWe followed 364,240 participants from UK Biobank aged 40–73 years from 2006 – 2010 to 2021. Information on breastfeeding in infancy was self-reported by questionnaire. Cox proportional hazard regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between breastfeeding and cardiovascular disease in middle-aged and older adulthood. The multivariable Cox models were used by adjusting for the age (used as the time scale), sex, ethnicity, assessment centre, birth weight, multiple birth status, maternal smoking during pregnancy, Townsend deprivation index, smoking status, alcohol drinker status, physical activity, and menopausal status for women. Binary and multinomial multivariable logistic regression models were used to explore the associations of breastfeeding in infancy with cardiovascular disease risk factors including obesity, body composition, metabolic and inflammatory disorders. ResultsDuring a median of 12.6 years of follow-up, we documented 29,796 new cases of cardiovascular disease, including 24,797 coronary heart disease and 6229 stroke. The multivariable adjusted HRs for breastfed versus non-breastfed were 0.94 (95% CI: 0.91, 0.96) for cardiovascular disease, 0.94 (95% CI: 0.91, 0.96) for coronary heart disease, and 0.95 (95% CI: 0.89, 1.01) for stroke. Furthermore, the strength of observed association between breastfeeding and cardiovascular disease seems to decrease with age (P for interaction <0.001), and increase with polygenic risk for cardiovascular disease (P for interaction <0.001). Consistently, breastfeeding in infancy was associated with cardiovascular disease risk factors including lower body mass index 0.92 (95% CI: 0.89, 0.95), body fat percentage 0.85 (95% CI: 0.83, 0.87), android to gynoid fat ratio 0.89 (95% CI: 0.83, 0.96), visceral adipose tissue 0.92 (95% CI: 0.84, 1.01), as well as lower C-reactive protein level 0.95 (95% CI: 0.94, 0.97) and a lower risk of metabolic syndrome 0.89 (95% CI: 0.85, 0.92). ConclusionsBreastfeeding in infancy was associated with a lower risk of cardiovascular disease in middle-aged and older adulthood. Promoting breastfeeding is vital not only for promoting child health, but also for halting the increasing trend of cardiovascular disease in adults.

Thyroglossal Duct Cyst Carcinoma: Our 12-year Experience in a Tertiary Care Centre.

Malignant transformation in thyroglossal duct cyst is an extremely rare occurrence, papillary carcinoma being the most common type of malignancy. In this study, we present our 12-years experience on this rare pathology. Records of all the patients with thyroglossal duct cyst and thyroid malignancies who were managed between January 2011 and December 2022 were reviewed retrospectively. The data was recorded and studies. Descriptive statistics were used to summarize the data. Out of 112 cases of thyroglossal duct cyst, 11 adult patients had associated carcinoma. Their age ranged from 20 to 68 years with a median age of 32 years. The most common presentation was anterior midline painless neck swelling. The diagnosis was made on final histopathological examination post-operatively. Alignant change is rare complication of the most common congenital thyroid anomaly. This study highlights the occurrence of this disease in adults and provides data on manifestation and management of this rare disease.

Phosphodiesterase4 inhibitors in dermatology : Role in the treatment of skin diseases

Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase4 (PDE4) inhibitors represent apossible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has afavorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as atopical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.

Effectiveness of Resting Transthoracic Echocardiography at Detecting Significant Coronary Artery Disease in Adults

Abstract Background: Detection of the regional wall motion abnormalities (RWMA) on the transthoracic echocardiography (TTE) is commonly used to correlate with coronary artery disease (CAD) and often prompts a further workup, including cardiac computed tomography or cardiac catheterization. However, the RWMA do not consistently predict obstructive CAD. This study investigates the accuracy and reliability of the presence of the RWMA on the TTE at detecting significant CAD (≥70% vessel stenosis). Materials and Methods: A retrospective chart review was conducted on the adults seen by the Baylor Scott and White Temple Echocardiography Laboratory who received a resting TTE followed by a cardiac catheterization within 30 days over 4 years. The exclusion criteria included catheterization without coronary angiography and a prior history of CAD, percutaneous coronary intervention, or coronary artery bypass graft. We analyzed the RWMA on the TTE and atherosclerotic CAD on the cardiac catheterization to assess correlation. Results: Four hundred and thirty-five patients were included in the study, and 198 patients received ultrasound-enhancing agent (UEA). The sensitivity and specificity of the RWMA on the TTE for detecting CAD in the adults were 49.5% and 78.8%, respectively. The positive and negative likelihood ratios were 2.33 and 0.641, respectively. The use of UEA made no significant difference in the sensitivity or specificity. Discussion: Our results show that the presence of the RWMA on the TTE has a high ability to rule in CAD, but the absence of the RWMA displays a much lower ability to rule out CAD than previously reported. Our results also show UEA did not enhance or detract from the sensitivity or specificity of TTE on CAD. The clinicians should be aware that the presence of the RWMA on the resting TTE has a high association with obstructive CAD, but the absence of the RWMA does not sufficiently exclude CAD.

Severe acute liver disease in adults: Contemporary role of histopathology.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).