Clinical Sequelae Research Articles

Pediatric SARS-CoV-2 long term outcomes study (PECOS): cross sectional analysis at baseline.

PECOS is an ongoing study aimed to characterize long-term outcomes following pediatric SARS-CoV-2 infection. This is a cross-sectional analysis of infected and uninfected cohorts at baseline. Participants (0-21 years) with laboratory-confirmed SARS-CoV-2 infection were enrolled as infected. Uninfected were defined as individuals without history or laboratory evidence of SARS-CoV-2 infection. Outcome measures included demographics, medical history, review of symptoms, physical exam, cardiopulmonary evaluation and validated psychological and developmental surveys. Primary outcomes were cohort comparisons for abnormalities on all measures. 654 participants (541 infected, 113 uninfected) completed baseline visits by June 30, 2023. Infected participants were more likely to report constitutional (OR: 2.24), HEENT (OR: 3.74); respiratory (OR: 2.41), or gastrointestinal (OR: 2.58) symptoms. Infected had worse scores in domains of Pain, Fatigue, Global Health, Physical and Cognitive functioning, Mobility and Sleep disturbances when compared to uninfected controls using Patient Reported Outcomes. Cardiopulmonary findings were similar among cohorts. The first report of this ongoing longitudinal study demonstrates that infected participants were more likely to report symptoms compared to uninfected controls, which may affect performance and quality of life of these individuals. Longitudinal data will increase understanding of long-term effects of SARS-CoV-2 infection in children. gov Identifier: NCT04830852 IMPACT: This study establishes a large, diverse, prospective, longitudinal, multi-center cohort of children with history of SARS-CoV-2 infection compared to an uninfected cohort to be followed for 3 years. Cross-sectional cohort analysis at study entry showed infected participants were more likely to report constitutional, respiratory, and GI symptoms compared to uninfected controls. Infected participants were more likely to have significantly worse parent-reported performance in 6 of 10 Patient Reported Outcome Measures domains. Continued study of this cohort will help identify clinical sequelae of COVID-19, characterize the immune response to SARS-CoV-2 infection, and identify potential genetic/immunologic factors associated with long-term outcomes.

Endothelial Cell Aging and Autophagy Dysregulation.

Entropy is a natural process that affects all living cells, including senescence, an irreversible physiological process that impairs cell homeostasis. Age is a significant factor in disease development, and the pathogenesis of endothelial cell aging is multifactorial. Autophagy dysfunction accelerates endothelial cell aging and cell death, while autophagy preserves endothelial cell youthfulness through intracellular homeostasis and gene expression regulation. Sirt, mTORC1, and AMPK are youthfulness genes that induce autophagy by inhibiting mTOR and upregulating FIP200/Atg13/ULK1. Aged endothelial cells have decreased levels of Lamin B1, γH2AX, Ki67, BrdU, PCNA, and SA β-Gal. Maintaining healthy young endothelial cells can prevent most cardiovascular diseases. Autophagy targeting is a potential future therapeutic strategy to modify endothelial cell age and potentially slow or reverse the aging process. This article provides state-of-the-art research on the role of autophagy in endothelial cell aging. Hypothesizing that autophagy dysregulation is associated with early endothelial cell dysfunction and further clinical sequelae, including atherosclerosis formation, leading to various cardiovascular diseases.

Lumbar disc herniation

The most common cause of disc herniation is the degeneration of the intervertebral disc. Consequently, lumbar disc herniations are amongst the most common pathologies of the lumbar spine. Factors that can increase the risk of disc herniation include genetics, weight, occupational risk factors, smoking, as well as apredominantly sedentary profession. Pathognomonic symptoms of aherniated disc include sciatica, caused by the compression of one or more spinal nerve roots. The clinical sequelae of lumbar disc herniations range from mild low back and buttock pain to severe, immobilising cases of sciatica to cauda equina compression syndromes. In 1-1.5% of cases, acauda equina syndrome may occur. This cauda equina syndrome may be considered an emergency situation that requires immediate attention and surgical decompression. The same applies to significant and rapidly deteriorating neurological deficits (< 24 h). In all other cases, which represents the majority of all patients,substantial pain relief can be achieved with nonsurgical measures. If an adequate and intolerable pain relief cannot be achieved despite intense conservative treatment measures after an extended period of 6-12weeks, surgical removal of the disc herniation may be indicated. Lumbar disc herniations may be addressed surgically with minimally invasive techniques. The goal of the surgery is full and sufficient safe removal of the herniated disc fragments in order to decompress the spinal nerves as well as the cauda equina. The two most commonly used surgical techniques (endoscopic/microsurgical) entail fivedifferent approaches (endoscopic: interlaminar, transforaminal; microsurgical: interlaminar, translaminar, extraforaminal). Patients are generally fully mobilized within hours after the surgery without any further restrictions. Postoperative rehabilitation measures are often carried out, but have no scientifically proven influence on the outcome of the operation. This article sheds light on the diagnostic and therapeutic procedures, techniques and special features of this socio-medically very important clinical picture.

Prediction of vesicouterine adhesions by transvaginal sonographic sliding sign technique: validation study.

Adhesions between the uterus, bladder and anterior abdominal wall are associated with clinical sequelae, including chronic pelvic pain and dyspareunia, and can also yield complications during surgery. The transvaginal sonographic (TVS) sliding bladder sign is a minimally invasive diagnostic tool to evaluate the presence of vesicouterine adhesions. This study aimed to determine the predictive value and intra- and interobserver variation of the TVS sliding bladder sign in the assessment of vesicouterine adhesions. This was a prospective observational double-blind diagnostic accuracy study conducted at the Amsterdam University Medical Center. Patients scheduled for gynecological laparoscopic surgery for a benign disorder between January 2020 and December 2022 were included consecutively. All patients underwent preoperative TVS, including a dynamic sliding bladder sign examination in our outpatient clinic. Videoclips of the TVS scans were stored for offline assessment and used as an index test. The recordings of both TVS and laparoscopy were evaluated for diagnostic characteristics of vesicouterine adhesions by independent assessors, who were blinded to the clinical situation in addition to the laparoscopic findings when assessing recordings of TVS and vice versa. The presence of adhesions on laparoscopy was used as the reference standard. The positive predictive value (PPV), negative predictive value (NPV), specificity and sensitivity of the sliding bladder sign were calculated. In addition, inter- and intraobserver variability of the sliding bladder sign on TVS were assessed. Of 116 included women, 57 had a negative sliding bladder sign on TVS, while on laparoscopy, 51 women had mild and 28 had severe vesicouterine adhesions. A negative sliding bladder sign had a PPV of 94.7% (95% CI, 88.9-100%) for the presence of any vesicouterine adhesions, and a positive sliding bladder sign had a specificity of 91.9% (95% CI, 83.1-100%). For severe adhesions, the negative sliding bladder sign had a sensitivity of 89.3% (95% CI, 77.8-100%) and a positive sliding bladder sign had a NPV of 94.9% (95% CI, 89.3-100%). When using Cohen's kappa coefficient, inter- and intraobserver agreement between assessors was good. Sliding bladder sign evaluation using TVS is a reliable diagnostic tool for the prediction of vesicouterine adhesions on laparoscopy. A negative sliding bladder sign indicates the presence of vesicouterine adhesions, while a positive sliding bladder sign makes the presence of severe adhesions unlikely. Establishing vesicouterine adhesions by TVS may optimize preoperative planning, and can be used for future studies to evaluate the relationship between symptomatology and vesicouterine adhesions and, subsequently, the effect of adhesion-prevention interventions. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Luspatercept: a treatment for ineffective erythropoiesis in thalassemia.

Patients with β-thalassemia continue to have several unmet needs. In non-transfusion-dependent patients, untreated ineffective erythropoiesis and anemia have been associated with a variety of clinical sequelae, with no treatment currently available beyond supportive transfusions. In transfusion-dependent forms, lifelong transfusion and iron chelation therapy are associated with considerable clinical, psychological, and economic burden on the patient and health care system. Luspatercept is a novel disease-modifying agent targeting ineffective erythropoiesis that became recently available for patients with β-thalassemia. Data from randomized clinical trials confirmed its efficacy and safety in reducing transfusion burden in transfusion-dependent patients and increasing total hemoglobin level in non-transfusion-dependent patients. Secondary clinical benefits in patient-reported outcomes and iron overload were also observed on long-term therapy, and further data from real-world evidence studies are awaited.

Treatment of cerebral radiation necrosis using hyperbaric oxygen therapy in a child: illustrative case.

Cerebral radiation necrosis (RN) is an uncommon sequela that occurs in up to 25% of irradiated patients. This can occur 6 months to several years after therapy and create symptoms of headaches, focal neurological deficits, seizures, or behavioral changes. Management can involve corticosteroids, antiplatelet drugs, surgery, and hyperbaric oxygen therapy (HBOT). Currently, there is a paucity of literature investigating these therapies for routine use in the pediatric population. A 5-year-old male with a right frontal atypical teratoid rhabdoid tumor previously underwent craniotomy for tumor resection, followed by chemotherapy, radiation, and autologous stem cell transplant therapy. Progressive radiographic changes surrounding the resection cavity were noted on routine surveillance imaging 20 months after the initial craniotomy and 11 months after the completion of radiation therapy. A biopsy ultimately confirmed RN. Due to the patient's previous complications with steroid use, the patient underwent HBOT. This achieved a significant improvement in clinical and radiographic sequelae of RN. HBOT was utilized successfully for the management of this patient's RN. HBOT should be considered for pediatric patients with cerebral RN as a potential treatment strategy. https://thejns.org/doi/10.3171/CASE24460.

Clinical outcomes of pediatric patients with congenital toxoplasmosis in a fourthlevel center Introduction. Congenital

Congenital toxoplasmosis is a highly prevalent parasitic disease worldwide, with a high burden of disease and neurodevelopmental involvement in pediatric patients. To describe the clinical sequelae and neurodevelopmental state of pediatric patients with congenital toxoplasmosis at the Hospital Militar Central during 2013 to 2020. We conducted an observational, descriptive, cross-sectional study with an analytical component, including pediatric patients diagnosed with congenital toxoplasmosis. Patients consulted the Hospital Militar Central from January 2013 to December 2020. The Ages and Stages Questionnaires 3 neurodevelopmental scale was applied to children under six years old. Forty-five patients with confirmed congenital toxoplasmosis were included, with a mean age of 5.9 years; 60% were male; 11.2 % were symptomatic at birth, and 33% presented chorioretinitis. During the follow-up, 73% presented ophthalmologic sequelae, 64% cerebral calcifications, 4.4% hydrocephalus, 11.2% cerebral palsy, and 13.4% focal epilepsy. In children under six years old, 58% presented neurodevelopmental compromise, and in those over six years old, 62% had cognitive deficits. In this cohort, 68% of the patients received posnatal treatment, with a statistically significant association between not receiving treatment and ophthalmological sequelae (OR = 5.2; p < 0.001). Congenital toxoplasmosis is associated with important long-term sequelae similar to those described in several Latin American series. These findings highlight the importance of early diagnosis, evaluation, treatment, and timely interdisciplinary follow-up of patients in our country to improve their prognosis.

RNA shielding of P65 is required to potentiate oncogenic inflammation in TET2 mutated clonal hematopoiesis.

TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis (CH). These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of this inflammatory circuit is unknown. To address this, we performed scRNA and scATAC-seq in COVID-19 patients with and without TET2-mutated CH reasoning that the inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified MALAT1, a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic pro-inflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and P65 which leads to RNA "shielding" from PP2A dephosphorylation thus preventing resolution of inflammatory signaling.

Prediction of cardiovascular outcomes by subtle changes in the peripheral immune cell landscape - insights from the LURIC single cell RNA-sequencing study (LuRNA)

Abstract Background and Aims Atherosclerosis and its clinical sequelae, myocardial infarction and stroke, represent the main causes of death worldwide. Although preclinical evidence has suggested the existence of an inflammatory response driving disease, the extend of cellular alterations in human atherosclerosis remains enigmatic. Here, we employ single cell RNA-sequencing (scRNA-seq) on peripheral blood mononucleated cells (PBMCs) in a well-defined cardiovascular risk cohort from the "Ludwigshafen Risk and Cardiovascular Health (LURIC) trial" to define changes in the immune cell landscape in atherosclerotic patients. Methods and Results Of 3317 patients enrolled in the LURIC trial between 1997 and 2000, we selected individuals with stable coronary-artery disease (CAD) (n=31) and healthy patients (no CAD) (n=16) by propensity score matching, adjusted for CRP, NTproBNP, Troponin T, LDL-C, and Cystatin-C, in a case-control design. scRNA-seq was performed by droplet sequencing on PBMCs stored in liquid nitrogen. Individual data sets were integrated and changes between healthy individuals and patients with CAD were evaluated on numeric and transcriptional level. Single cell transcriptomes were annotated using an established CITE-seq reference atlas. While bulk RNA-sequencing of PBMC preparations revealed only minor changes between both conditions, we identified several leukocyte populations on a single cell level with specific transcriptomes that were differentially regulated between both conditions. Interestingly, we found that several subsets of Natural Killer (NK) cells, T cells with an enrichment of proliferation-associated pathways, and a population resembling hematopoietic stem cells were more frequent in patients with CAD, while naïve phenotypes of B and T cells were overrepresented in the absence of CAD. Consistently, most T and B cell populations in patients with CAD were enriched in pathways associated with cell activation, immune receptor signalling, and differentiation. In addition, we detected restricted repertoires of T cell receptor sequences in several adaptive immune cell subtypes from patients with CAD, suggestive of increased cellular clonality and antigen-specificity. Finally, in a comparison of cellular frequencies with cardiovascular outcomes over more than 15 years, several immune cell subsets and cell-type specific transcriptional programs predicted cardiovascular death in this case-control scenario in multi-variate adjusted regression analysis. Notably, addition of scRNA-seq derived parameters was superior to traditional risk prediction with clinical characteristics and soluble biomarkers alone. Conclusion Employing scRNAseq, we demonstrate that atherosclerosis is associated with a profound change in the circulating immune cell landscape even in the absence of measurable differences in inflammatory biomarkers. These findings propose the usage of scRNAseq for the discovery of outcome-relevant cellular biomarkers in the future.

Substantial morbidity and mortality due to cardiovascular diseases in hospitalized vaccinated and un-vaccinated patients with COVID-19 from 16 countries: the WHF COVID-19 Long-term study

Abstract Background Long-term adverse consequences of the COVID-19 affect many organ systems, and this requires the identification and appropriate care of diverse symptoms. Purpose The World Heart Federation (WHF) international study describes the burden of clinical sequelae of COVID-19 up to 1 year after hospitalization, including patients from low- middle-and high-income countries. Methods We prospectively recruited patients hospitalized due to COVID-19 from 16 countries between January 2022 and June 2023. Patients were followed up at 1, 3, 6, and 9-12 months after hospital discharge. A standardized questionnaire administered by telephone collected data on long COVID symptoms, quality of life using the EuroQol 5 Dimension scale (EQ-5D), and disease outcomes including new onset diabetes and hypertension, major adverse cardiovascular events (MACE), and mortality. We report a descriptive analysis including demographic characteristics and outcomes up to one year after initial hospitalization. Results Of 2504 patients, the majority were Asian (78%), and male (56%). Mean age was 59.2 years (SD 19.9). Low- and lower-middle-income country participants constituted 65% of the cohort, with upper middle-income and high-income representing 20% and 15%, respectively. Follow-up rate was complete for 86%. 55% had received at least two doses of COVID-19 vaccination. At 1 month, 63% reported at least one persistent symptom, which decreased to 28% at 9-12 months. Fatigue was reported by 45% at 1-month and 17% at final follow-up. Anxiety occurred in 20% and 9% at these respective timepoints, and breathlessness in 12% and 6%. At 9-12 months, moderate to severe impairment of usual activities as measured by EQ-5D occurred in 19%, anxiety/depression in 10%, and mobility problems in 10%. The most frequent post-discharge new-onset illnesses were pulmonary embolism (7%), kidney problems (4%), and hypertension (3%). In-hospital mortality was 4% (n=102), and a further 12% (265 patients) died by one-year. The most common cause was sudden cardiac death (59%), respiratory disease including pulmonary embolism (13%), and stroke (6%). Conclusions We observed a significant burden of post-COVID-19 complications with one fifth of patients with persistent difficulties in usual activities at one year. This underscores the urgent need to understand the underlying mechanisms for organ damage and death, and for targeted preventive strategies and proactive management approaches to reduce them.

The Relation of Diabetes Complications to a New Interpretation of Glycaemic Variability from Continuous Glucose Monitoring in People with Type 1 Diabetes.

Microvascular and macrovascular complications in type 1 diabetes (T1D) may be linked to endothelial stress due to glycaemic variability. Continuous glucose monitoring systems (CGMs) provide new opportunities to quantify this variability, utilising the amplitude of glucose change summated over time. The aim of this study was to examine whether this determination of glucose variability (GV) is associated with microvascular clinical sequelae. Continuous glucose monitoring values were downloaded for 89 type 1 diabetes mellitus (T1D) individuals for up to 18 months from 2021 to 2023. Data for patient demographics was also taken from the patient record which included Sex, Date of Birth, and Date of Diagnosis. The recorded laboratory glycated haemoglobin (HbA1c) test results were also recorded. The glucose management index (GMI) was calculated from average glucose readings for 18 months using the formula GMI (%) = (0.82-(Average glucose/100)). This was then adjusted to give GMI (mmol/mol) = 10.929 * (GMI (%) - 2.15). Average Glucose Fluctuation (AGF) was calculated by adding up the total absolute change value between all recorded results over 18 months and dividing by the number of results minus one. The % Above Critical Threshold (ACT) was calculated by summing the total number of occurrences for each result value. A cumulative 95% limit was then applied to identify the glucose value that only 5% of results exceeded in the overall population. Using this value, we estimated the percentage of total tests that were above the Critical Threshold (ACT). Results for the 89 individuals (44 men and 45 women) were analysed over 18months. The mean age of participants was 43 years and the mean duration of diabetes was 18years. A total of 3.22 million readings were analysed, giving an average of 10.3mmol/L blood glucose. Those with the largest change in glucose from reading to reading, summated over time, showed the greatest change in eGFR of 3.12ml/min/1.73 m2 (p = 0.007). People with a higher proportion of glucose readings > 18mmol/L showed a fall in eGFR of 2.8ml/min/1.73 m2 (p = 0.009) and experienced higher rates of sight-threatening retinopathy (44% of these individuals) (p = 0.01) as did 39% of individuals in the highest tertile of glucose levels (p = 0.008). Those individuals with T1D in the highest tertile of reading-to-reading glucose change showed the greatest change in eGFR. Those with a higher proportion of glucose readings > 18mmol/L also showed a fall in eGFR and experienced higher rates of sight-threatening retinopathy, as did people with higher mean glucose. Discussions with T1D individuals could reflect on how the percentage recorded glucose above a critical level and degree of change in glucose are important in avoiding future tissue complications.

Interleukin-1 Beta rs16944 and rs1143634 and Interleukin-6 Receptor rs12083537 Single Nucleotide Polymorphisms as Potential Predictors of COVID-19 Severity.

Host genetic variation has been recognized as a key predictor of diverse clinical sequelae among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. Insights into the link between the Interleukin-6 receptor (IL-6R) and Interleukin-1 beta (IL-1β) genetic variation and severe coronavirus disease 2019 (COVID-19) are crucial for developing new predictors and therapeutic targets. We aimed to investigate the association of IL-6R rs12083537, IL-1β rs16944, and IL-1β rs1143634 SNPs with the severity of COVID-19. Our study was conducted on 300 COVID-19-negative individuals (control group) and 299 COVID-19-positive cases, classified into mild, moderate, and severe subgroups. Analyses of IL-1β (rs16944, rs1143634) and IL-6R (rs12083537) SNPs' genotypes were performed using qPCR genotyping assays. The IL-1β (rs16944) CC genotype and IL-6R (rs12083537) GG genotype were substantially related to COVID-19 severity, which was also associated with comorbidities and some laboratory parameters (p < 0.001). The IL-1β (rs1143634) TT genotype was found to be protective. Likewise, the IL-1β (rs16944) CC genotype was associated with increased mortality. IL-1β rs16944 and IL-6R rs12083537 SNPs are promising potential predictors of SARS-CoV-2 disease severity. Meanwhile, the rs1143634 SNP T allele was protective against severity and mortality risk.

Prevalence and Clinical Correlates of Endometriosis in Patients With IC/BPS.

Interstitial cystitis/bladder pain syndrome (IC/BPS) presents as a complex heterogeneous disorder that poses a significant clinical challenge both for diagnosis and treatment. The identification of patient subgroups with significant overlap in their nonurological associated symptoms, including endometriosis, may enable a more targeted therapeutic approach. This study investigated the prevalence, clinical correlates, and clinical sequelae associated with concurrent endometriosis in patients with IC/BPS. Demographic, clinical, surgical, and questionnaire data from female patients (n = 533) with a diagnosis of IC/BPS were evaluated in this retrospective cohort study. Surgical history was obtained from patient electronic medical records, using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes. Data from participants with and without concurrent endometriosis were compared using univariate analysis, followed by binary logistic regression to identify associated variables. Of 533 participants, 108 (20.3%) reported a history of endometriosis. Those with concurrent endometriosis were younger, had a larger bladder capacity, and had a higher number of nonurological associated symptoms. Patients with concurrent endometriosis were less likely to have a history of cystectomy (the surgical removal of the bladder) and report allergies but more prone to report comorbidities such as chronic pelvic pain, chronic fatigue, fibromyalgia, migraines, and pelvic floor dysfunction. Binary logistic regression identified a positive association between endometriosis and chronic pelvic pain, and a negative association between allergies and low bladder capacity for those with concurrent endometriosis. Endometriosis is common in younger female patients with IC/BPS and is associated with a non-bladder-centric (ie, systemic pain disorder) phenotype.

18F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis.

18F-sodium fluoride (NaF) positron-emission tomography (PET) is increasingly being used to measure microcalcification in atherosclerotic disease in vivo. Correlations have been drawn between sodium fluoride uptake and the presence of high-risk plaque features, as well as its association with clinical atherosclerotic sequelae. The aim of this study was to perform a meta-analysis of NaF uptake on PET imaging and its relation to symptomatic and asymptomatic disease. A systematic review was performed according to PRISMA guidelines, via searching the Ovid MEDLINE, Ovid Embase, Cochrane Library, PubMed, Scopus, and Web of Science Core Collection databases up to May 2024. The search strategy included the terms 'NaF', 'PET', and 'plaque', and all studies with data regarding the degree of microcalcification, as measured by 18F-NaF uptake in symptomatic and asymptomatic atherosclerotic plaques, were included. Analysis involved calculating mean differences between uptake values and comparison using a random-effects model. A total of 16 articles, involving 423 participants, were included in the meta-analysis (10 carotid artery studies, five coronary artery studies, and one in peripheral vascular disease). Comparing 18F-NaF uptake in symptomatic versus asymptomatic atherosclerotic plaques, a mean difference of 0.43 (95% CI 0.29 to 0.57; p < 0.0001, I2 = 65%) was noted in studies comparing symptomatic and asymptomatic plaques in the same participant, with a significant difference in effect based on arterial territory studied (χ2 = 12.68, p = 0.0018). In studies of participants with and without symptomatic disease, there was no significant difference between symptomatic and asymptomatic plaques (mean difference 0.27, 95% CI -0.26 to 0.80, p = 0.28, I2 = 85%). PET imaging using 18F-NaF can detect differences in microcalcification between symptomatic and asymptomatic atherosclerotic plaques within, but not between, individuals, and thus, is a marker of symptomatic disease. The standardization of 18F-NaF PET imaging protocols, and its future use as a risk stratification tool or outcome measure, requires further study. (PROSPERO Registration ID: CRD42023451363).

Genetic Heterogeneity Across Dimensions of Alcohol Use Behaviors.

Increasingly large samples in genome-wide association studies (GWASs) for alcohol use behaviors (AUBs) have led to an influx of implicated genes, yet the clinical and functional understanding of these associations remains low, in part because most GWASs do not account for the complex and varied manifestations of AUBs. This study applied a multidimensional framework to investigate the latent genetic structure underlying heterogeneous dimensions of AUBs. Multimodal assessments (self-report, interview, electronic health records) were obtained from approximately 400,000 UK Biobank participants. GWAS was conducted for 18 distinct AUBs, including consumption, drinking patterns, alcohol problems, and clinical sequelae. Latent genetic factors were identified and carried forward to GWAS using genomic structural equation modeling, followed by functional annotation, genetic correlation, and enrichment analyses to interpret the genetic associations. Four latent factors were identified: Problems, Consumption, BeerPref (declining alcohol consumption with a preference for drinking beer), and AtypicalPref (drinking fortified wine and spirits). The latent factors were moderately correlated (rg values, 0.12-0.57) and had distinct patterns of associations, with BeerPref in particular implicating many novel genomic regions. Patterns of regional and cell type-specific gene expression in the brain also differed between the latent factors. Deep phenotyping is an important next step to improve understanding of the genetic etiology of AUBs, in addition to increasing sample size. Further effort is required to uncover the genetic heterogeneity underlying AUBs using methods that account for their complex, multidimensional nature.

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Comparative analysis of COVID-19 responses in Japan and Africa: diet, phytochemicals, vitamin D, and gut microbiota in reducing mortality-A systematic review and meta-analysis.

As the novel coronavirus disease 2019 (COVID-19) pandemic subsides, the clinical sequelae are becoming more problematic. Interestingly, the statistical data indicate that Africa has experienced the lowest number of cases and deaths, with an unexpected phenomenon where the number of deaths from COVID-19 has not increased significantly. Several studies have investigated the relationship between diet and coronavirus. However, no systematic review/meta-analysis has conclusively linked diet (phytochemicals and vitamin D) and the gut microbiota in the context of COVID-19. This study examined the responses to COVID-19 in Japan and Africa, formulating the following hypotheses: (1) a healthy diet is effective against COVID-19, (2) blood vitamin D levels are associated with COVID-19 mortality, and (3) COVID-19 is associated with the gut microbiota. To investigate these hypotheses, a keyword search and meta-analysis were conducted using PubMed, and each hypothesis was tested. This study found that a healthy diet, particularly rich in phytochemicals such as polyphenols and flavonoids, is effective against COVID-19. An association was detected between blood vitamin D levels and COVID-19 mortality. The gut microbiota was linked to COVID-19 and its amelioration. These findings may have significant implications for not only understanding COVID-19 but also future prevention of pneumonia.

Light Chain (AL) Amyloidosis for Nephrologists - Treatment Standard.

Amyloidosis is a group of complex diseases caused by the misfolding and aggregation of proteins into amyloid fibrils. AL amyloidosis is one of the most prevalent forms of amyloidosis, characterized by the gradual proliferation of light chains from plasma cell clones. A growing body of evidence has contributed to our understanding of its pathogenesis, presentation, and clinical course. Increased recognition of its clinical sequelae has increased the prevalence of AL amyloidosis. Renal involvement, seen in up to 70% of cases, is particularly challenging due to its impact on quality of life and access to treatment options. Thus, early recognition of its unique sequelae, appropriate staging, and a comprehensive understanding of treatment options balanced by their organ toxicities are crucial to managing this disease. We review the current treatment standards and discuss novel developments in the pathophysiology, diagnosis, outcome prediction, and management of AL amyloidosis for the Nephrologist.

Atypical Presentation and Postoperative Management of Vagal Nerve Tumors.

Tumors involving the vagus nerve are often clinically silent. We offer a case series with different clinical presentations and distinctive post-surgical sequelae that highlight some of the challenges associated with managing cervical vagal nerve tumors. Single-institution, retrospective review of patients with tumors involving the vagus nerve. We describe clinical presentations and postoperative sequelae of five patients who underwent surgical management of vagal nerve pathology with atypical presentation or subsequent clinical course. Here, we present five patients treated at our institution for vagal tumors. In four of the five patients, the presenting symptoms resolved after surgery. Two patients presented with intractable neurogenic cough, and another two presented with autonomic symptoms, one with syncope/palpitations and the other with intractable sweating. The final patient presented with a rapidly enlarging vagal paraganglioma and developed intractable cough after resection. We present two patients with novel approach to vagal paragangliomas that underwent ligation of feeding blood supply without removing the tumor, resulting in resolution of an intractable cough in one patient and resolution of severe nighttime sweating in the other. Management of tumors associated with the cervical vagus nerve that present with symptoms or rapid growth poses a clinical dilemma. Consideration of the tumor origin with either enucleation of schwannomas or ligation of feeding vessels may preserve function while addressing the presenting symptoms.

9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome During A Phase 1b/2a, Single Center, 10-day, Inpatient, Open-Label Study

Abstract Disclosure: H. Elenius: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. R. McGlotten: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. C. Moore: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. Y.B. Omotosho: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. L.K. Nieman: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc.. Atumelnant is a potent, once-daily oral, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R) antagonist that blocks ACTH-mediated G-protein activation and subsequent signaling. It is being developed for the treatment of ACTH-dependent Cushing Syndrome (ADCS) and classic congenital adrenal hyperplasia. We report preliminary data from the first-in-disease, dose-finding study of atumelnant in patients with ADCS (NCT05804669). Inpatient participants with active ADCS (24h urine free cortisol (UFC) &amp;gt;1.3xULN, ACTH &amp;gt;10 pg/mL) received atumelnant 80 mg once daily at 08.00 for 10 days (D1-10) followed by a 4-day washout. Endpoints included changes in UFC (upper limit of normal (ULN) 45 ug/d), early morning cortisol (EMC), and early morning ACTH (EMA, ULN 46 pg/mL). Daily questionnaires assessed adverse events (AEs) and signs and symptoms of adrenal insufficiency (AI) and ADCS. Data are shown as median (range). We report 5 participants (4 men; 4 Cushing disease, 1 ectopic ACTH; age 47 years (34-55)); each completed the study. All participants developed biochemical evidence of AI (EMC &amp;lt;5 mcg/dL) after 2 days (1-10) of atumelnant administration and then commenced physiologic hydrocortisone (HC) add-back. Compared to D1, biochemical disease control (normal UFC plus EMC &amp;lt;5 mcg/dL) was shown on D11 in all participants, while receiving HC replacement: UFC 252 mcg (99-293) vs 24 mcg (3.9-51); EMC 14 mcg/dL (10.7-18.1) vs 1.4 (1.0-4.7). This was associated with an increase in EMA: 52.1 pg/mL (33-1088) vs 78 pg/mL (48.8-4045). HC was discontinued when EMC was ≥7 mcg/dL, on D13 (D12-18). Many pre-existing features of ADCS improved during atumelnant administration, including poor concentration, insomnia (n=3 each); brain fog, anxiety, irritability (n=2 each); fatigue, poor memory, low libido, depression, edema and bloating (n=1 each). Low testosterone, neutrophilia (n=3 each) and leukocytosis (n=2) observed at baseline resolved during atumelnant administration. Anti-hypertensive therapy was paused or reduced in 3 subjects. New fatigue, headache, nausea, anorexia, edema (n=2 for each) all coincided with development of biochemical AI; most symptoms improved with HC add-back. Serious adverse events included AI and one non-treatment related transient GI bleed 19 days after the last dose. All other AEs were mild or moderate: transient increases of creatinine (n=2), and ALT (&amp;lt;3xULN, n=2). In conclusion, the first 5 patients with ADCS to receive once daily, oral atumelnant experienced rapid lowering of serum and urine cortisol and improvement or resolution of some signs and symptoms of ADCS. Atumelnant was generally well-tolerated. The observed compensatory increase in ACTH was not associated with loss of efficacy or clinical sequelae. This ongoing study will further explore the relationship between atumelnant dose, including lower doses, and therapeutic response. Presentation: 6/3/2024