Disease Outcome Research Articles

Immuno-therapeutic and prophylactic potential of Trichinella spiralis antigens for inflammatory bowel diseases

Ulcerative colitis (UC), a severe chronic inflammatory disorder of the colon, is one of the inflammatory bowel diseases (IBD) that affects humans and several domestic animal species, including cats and dogs. Helminth infections and autoimmune diseases are inversely correlated, as explained by the hygiene hypothesis, which suggests that IBD is infrequent in countries where helminth infections are common but more prevalent in developed nations. This study investigated the therapeutic and prophylactic potential of Trichinella spiralis (T. spiralis) antigens in an experimental colitis model for IBD. Mice were divided into eight groups: normal model, colitis model, larval antigen prophylaxis, adult antigen prophylaxis, larval antigen therapeutic, adult antigen therapeutic, larval antigen prophylaxis and therapeutic, and adult antigen prophylaxis and therapeutic. Colitis was induced intrarectally by administering a single dose of 0.2 ml of acetic acid, except in the healthy group, which received PBS (0.2 ml). The mice were euthanized 12 days after colitis induction. The therapeutic and prophylactic potential of T. spiralis antigens were assessed through colitis severity and histopathological, immunological, and immunohistochemical examinations. The results showed a significant reduction in Disease Activity Index (DAI), an increase in goblet cells' acidic mucin levels, reduced iNOS and TNF-α expression, and decreased serum levels of IFN-γ and IL-10 cytokines in Groups IV-VIII compared to the colitis model, particularly in the group that received adult worm antigen both prophylactically and therapeutically. This study demonstrated that T. spiralis antigens, especially from adult worms, had protective and therapeutic effects on experimental colitis, with a superior effect when administered both before and after colitis induction by reducing inflammation and modulating the immune response. Thus, T. spiralis antigens may improve disease outcomes and provide a novel treatment approach for ulcerative colitis.

Exploring cyclic vomiting syndrome (CVS) worldwide: Current epidemiological insights and recent developments.

Cyclic vomiting syndrome (CVS), a disorder of gut-brain interaction, presents with recurrent episodes of severe nausea and vomiting. It is often associated with missed or delayed diagnoses and substantial healthcare utilization. Despite historical recognition dating back to the 19th century, epidemiological insights remain limited, with research predominantly originating from specific regions, such as the US. CVS prevalence and incidence rates vary widely and are hindered by inconsistent methodologies and disease recognition. This review aims to provide a comprehensive overview of CVS prevalence and incidence rates. It reviews the currently available data and identifies gaps in knowledge. Understanding the global epidemiology of CVS, increasing awareness of the disease, and fostering global collaboration are crucial. Other pertinent issues include disparities in outcomes, particularly among African Americans and Hispanics in the United States, underscoring the need to understand the social determinants of health that drive disease outcomes. This understanding can inform targeted interventions to address these barriers and achieve equitable healthcare both in the United States and globally.

9218 Highly Multiplexed Mapping of the Ductal Carcinoma In Situ Ecosystem to Predict Disease Outcome

Abstract Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None. Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment. Presentation: 6/3/2024

9218 Highly Multiplexed Mapping Of The Ductal Carcinoma In Situ Ecosystem To Predict Disease Outcome

Abstract Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None. Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment. Presentation: 6/3/2024

8770 Highly Multiplexed Mapping of the Ductal Carcinoma In Situ Ecosystem to Predict Disease Outcome

Abstract Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None. Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment. Presentation: 6/3/2024

8770 Highly Multiplexed Mapping Of The Ductal Carcinoma In Situ Ecosystem To Predict Disease Outcome

Abstract Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None. Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment. Presentation: 6/3/2024

12362 Pathophysiology From Oxidative Stress Effectively Monitored In A Pre-clinical Model Of Type 2 Diabetes (T2D) With Point-of-care Microscale Magnetic Resonance (µNMR)

Abstract Disclosure: A.T. Alves: ; Co-Founder. ; Self. ; LarmorBio. S.S. Thamarath: ; Co-Founder. ; Self. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-Founder. ; Self. ; LarmorBio. J. Han: None. L. Bouchard: Advisory Board Member; Self; LarmorBio. R. Rohr, BS.EE: ; Co-Founder, CEO. ; Self. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. The declining age of onset of T2D is a vital factor influencing its prospective burden. An early manifestation of the disease leads to an extended duration, which amplifies and accelerates the risk of micro and macrovascular complications. Oxidative stress is a major driver in the pathogenesis of T2D. Early detection and prevention of oxidative stress overload can improve and potentially modify the long-term harmful outcomes of metabolic diseases, including chronic hyperglycaemia.A novel µNMR assay was developed to monitor oxidative stress from minimally invasive plasma samples at the point of care. This approach is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation, and lipid peroxidation[1]. We hypothesized that oxidative stress would increase significantly faster in the disease group, enabling disease progression monitoring throughout the study and near real-time subject risk stratification based on the core pathophysiology of the diabetic phenotype.This 15-week longitudinal study (6th - 21st week of age) quantified oxidative stress in db/db and db/+ mice (n = 15 per group), accompanied by HbA1c, blood glucose (BG), and body weight (BW). The assay detailed separation (P ≤ 0.01) between the db/db and db/+ mice from the onset of the diabetic phenotype of db/db at 10 weeks of age (mean HbA1c = 6.5%). The oxidative stress monitored continued to increase in the subsequent weeks, where the HbA1c of db/db mice reached maximum (mean HbA1c = 8.8%). The definition of good (HbA1c ≤ 8) and poor (HbA1c > 8) glycaemic control was defined where sub-stratification (P ≤ 0.05) was achieved. Furthermore, the assay highlights a positive correlation with BW (ρ+/db = 0.52, P ≤ 0.0001, ρdb/db = 0.57, P ≤ 0.0001). In the two groups of mice, a positive correlation of oxidative stress with HbA1c (ρ = 0.58, P ≤ 0.0001) and BG (ρ = 0.47, P ≤ 0.0001) was reported. During the 15-week study, the control db/+ group exhibited a 13% mean increase in oxidative stress. In contrast, the db/db group demonstrated a cumulative 20% increase. Notably, considering the diabetic phenotype of the db/db mice, we quantified oxidative stress attributed to aging at 13%.In view of changing diabetes demographics, a multimodal approach of targeted sub-phenotype treatment combined with advanced metabolic monitoring may provide holistic, clinically relevant information to reduce the micro and macrovascular burden of diabetes. In summary, the µNMR assay is an effective method for real-time monitoring of oxidative stress assessment in metabolic disease research and opens new possibilities for cardiometabolic risk assessment and targeted interventions.(1) Peng, W.K. et.al., npj Aging Mech Dis 2020, 6, 11 Presentation: 6/1/2024

8772 Impact of Stress Hyperglycemia on Individuals Hospitalized for COVID-19 with and without Diabetes

Abstract Disclosure: E. Burguera-Couce: None. V.O. Cheng: None. J.G. Monteiro: None. G. Gopalakrishnan: None. Background: Stress hyperglycemia (SH), the physiologic increase in blood glucose during severe illness, has been linked with poor outcomes in certain disease states1. Hyperglycemia in the setting of diabetes (DM) has been well established as a predictor of poor outcomes in Coronavirus disease 2019 (COVID-19) infection2-4. The impact of SH on health outcomes for individuals without DM (NoDM) hospitalized with COVID-19 infection is less clear with studies reporting variable outcomes in this population4-6. Objective: To evaluate the impact of SH on health outcomes among hospitalized individuals with COVID-19Methods: Data from 1001 individuals with SH (defined as ≥ 2 instances of BG above 180 mg/dL) admitted in Rhode Island with COVID-19 infection during the first-wave (March 1-June 30, 2020) and second-wave (July 1, 2020-February 28, 2021) was analyzed. Multivariate logistic regression was conducted to compare DM status for length of stay (LOS), ICU admission, mechanical ventilation (MV) and in-hospital mortality, and was adjusted for age, race/ethnicity, gender, insurance, and wave. Model investigating risk factors associated with poor outcomes (ICU admission, MV or in-hospital mortality) in hospitalized individuals with SH was additionally adjusted to include BMI, Chronic kidney disease (CKD), hypertension (HTN), pulmonary disease, and cardiovascular diseases. Results: 17.0% (170) of the cohort had NoDM. Average age (67.6±13.9), gender (57.1% male) and race/ethnicity (Caucasian/White 48.9%, Hispanic 28.0%, Black 13.2% and Other 10.0%) noted in the overall cohort. Individuals with NoDM were more likely to be Caucasian/White (57.7 vs 47.1%, p-value=0.0122), and more likely to require LOS ≥1-week (OR 2.32[1.57-3.44]), ICU admission (2.26[1.60-3.20]) and MV (3.39[2.35-4.89]). NoDM was also associated with higher in-hospital mortality (3.44[2.39-4.96]). The risk of poor outcomes was significantly higher in NoDM compared to DM (ICU admission 47.7 vs 28.6%, MV 45.3 vs 20.1%, Mortality 41.8 vs. 18.2%). In multivariate analysis, Caucasians/Whites (0.50[0.29-0.87]) were less likely to have poor outcomes than the other races. NoDM (3.55[2.40-5.25]), male gender (1.57[1.16-2.13]), CKD stage 5 (1.94[1.40-2.68]), and admission during the first-wave (2.64[1.89-3.70]) were identified as independent risk factors for poor outcomes in SH associated with COVID-19. Conclusion: Our study showed that individuals without a known diagnosis of diabetes hospitalized with COVID-19 who experienced SH during their hospital course had worse outcomes when compared to individuals with diabetes and hyperglycemia. NoDM, male gender, nonwhite race/ethnicity, CKD stage 5 and admission during the first wave were identified as independent risk factors for poor outcomes in COVID-19 hospitalizations with hyperglycemia. Presentation: 6/1/2024

Unveiling sex differences in valvular disease care and outcomes.

Unveiling sex differences in valvular disease care and outcomes.

8091 Clinical Features Associated with ICU Admission and Mortality in Thyroid Storm and Impending Thyroid Storm

Abstract Disclosure: E.D. Zhang: None. I. Hussain: None. Introduction: Thyroid storm is a rare, life-threatening manifestation of thyrotoxicosis characterized by a clinical syndrome of acute multi-organ failure, which can result in significant morbidity and mortality. Impending thyroid storm is a stage of thyrotoxicosis that may progress to thyroid storm if untreated. The aim of this study was to evaluate the demographics and outcomes of patients with thyroid storm at our institution and determine the clinical features associated with severe complications and mortality. We also evaluated the differences in clinical features and outcomes in patients diagnosed with impending thyroid storm versus thyroid storm. Methods: This was a retrospective single-center cohort study evaluating patients aged 18 years or older who were clinically diagnosed with thyroid storm or impending storm at two affiliated tertiary academic centers from 2008-2021. A search of the electronic medical record system using ICD-10 codes for thyroid storm identified patient charts which were reviewed for eligibility. Results: This study included 121 admissions, with 75 (62.0%) patients with thyroid storm and 46 (38.0%) patients with impending thyroid storm. Our study cohort was notably more racially and ethnically diverse than prior U.S. studies with 5.0% non-Hispanic White, 52.9% Black, 33.9% Hispanic, and 8.3% Asian patients. The mortality rate was 4.7%, with all patient deaths occurring in the thyroid storm group. Multivariable logistic regression analysis showed atrial fibrillation (OR 4.09, 95% CI 1.21, 13.85, p=0.02) and acute respiratory failure (OR 22.18, 95% CI 2.29, 215.19, p=0.008) to be significantly associated with a composite outcome of intensive care unit (ICU) admission or death. Comparison of impending storm and thyroid storm groups showed fever (p=0.02), acute respiratory failure (p=0.03), and ICU admission (p=0.02) to be significantly different between groups. Conclusions: This study describes the largest published single-center cohort of patients treated for thyroid storm in the United States. Furthermore, our study contributes importantly to the data for racial/ethnic minorities who are under-represented in prior studies. The mortality rate in this study is lower than most recent studies. The presence of atrial fibrillation and acute respiratory failure were noted to be significantly associated with a composite outcome of ICU admission or death, and the five fatal cases had high rates of cardiac arrest and shock. These findings suggest that complications involving cardiopulmonary compromise are clinically important in predicting severe disease and poor outcomes. Acute respiratory failure was also noted to be significantly different between impending storm and thyroid storm groups indicating that while not currently included in existing diagnostic systems, it is an important complication of thyroid storm that may have prognostic value. Presentation: 6/2/2024

PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency

The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis.Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to 18F-FDG (7 days post-SE), 18F-GE180 (15 days post-SE) and 18F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (18F-FDG), volume of distribution (18F-GE180) and binding potential (18F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed.Fluoxetine treatment did not alter brain glucose metabolism. 18F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (−22.6%, p = 0.042), but no differences were found in GABAA receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = −0.58; p = 0.015).Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase.

Pseudomonas aeruginosa kills Staphylococcus aureus in a polyphosphate-dependent manner.

Due to their frequent coexistence in many polymicrobial infections, including in patients with cystic fibrosis or burn/chronic wounds, many studies have investigated the mechanistic details of the interaction between the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus. P. aeruginosa rapidly outcompetes S. aureus under in vitro cocultivation conditions, which is mediated by several of P. aeruginosa's virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor in P. aeruginosa, plays a role in the pathogen's ability to inhibit and kill S. aureus in a contact-independent manner. We show that P. aeruginosa cells characterized by low polyP levels are less detrimental to S. aureus growth and survival while the Gram-positive pathogen is significantly more compromised by the presence of P. aeruginosa cells that produce high levels of polyP. The polyP-dependent phenotype of P. aeruginosa-mediated killing of S. aureus could at least in part be direct, as polyP was detected in the spent media and causes significant damage to the S. aureus cell envelope. However, more likely is that polyP's effects are indirect through modulating the production of one of P. aeruginosa's virulence factors, pyocyanin. We show that pyocyanin production in P. aeruginosa occurs polyP-dependently and harms S. aureus through membrane damage and potentially the generation of reactive oxygen species, resulting in the increased expression of antioxidant enzymes. In summary, our study adds a new component to the list of biomolecules that the Gram-negative pathogen P. aeruginosa generates to compete with S. aureus for resources.IMPORTANCEHow do interactions between microorganisms shape the course of polymicrobial infections? Previous studies have provided evidence that the two opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus generate molecules that modulate their interaction with potentially significant impact on disease outcomes. Our study identified the biopolymer polyphosphate (polyP) as a new effector molecule that impacts P. aeruginosa's interaction with S. aureus. We show that P. aeruginosa kills S. aureus in a polyP-dependent manner, which occurs primarily through the polyP-dependent production of the P. aeruginosa virulence factor pyocyanin. Our findings add a new role for polyP to an already extensive list of functions. A more in-depth understanding of how polyP influences interspecies interactions is critical, as targeting polyP synthesis in bacteria such as P. aeruginosa may have a significant impact on other microorganisms and potentially result in dynamic changes in the microbial composition.

Functional disability and disease activity are affected by social determinants ofhealth in patients with rheumatoid arthritis.

The relationship between social determinants of health (SDH) and disease outcomes in rheumatoid arthritis (RA) is not well documented. Data were extracted from the Ontario Best Practices Research Initiative (OBRI) registry for patients between January 2008 and April 2022. Adjusted mixed models analysis was used to investigate the effect of baseline SDH on disease activity (Clinical Disease Activity Index (CDAI)) and functional disability (Health Assessment Questionnaire-Disability Index (HAQ-DI)) 12months after enrollment. The analyses were completed on multiple imputed data. There were 2651 patients with a mean age of 58.1years (SD 12.9). The majority (77.8%) were female. Greater improvements in physical function were seen in patients who were full-time employed (difference = - 0.20; 95% CI - 0.28, - 0.11), part-time employed (difference = - 0.10; 95% CI - 0.19, - 0.02), or retired (difference = - 0.17; 95% CI - 0.25, - 0.08), compared to unemployed, those with highest income ($75,000 or more) (difference = - 0.23; 95% CI - 0.37, - 0.09). Caucasian was also associated with a positive impact on functional ability (difference = - 0.09; 95% CI - 0.17, - 0.02). In contrast, smokers had smaller improvements in physical function (difference = 0.07; 95% CI 0.002, 0.14). Interestingly, women had greater improvement in CDAI (difference = - 2.40; 95% CI - 3.29, - 1.51), while they reported less improving in their physical function (difference = 0.33; 95% CI 0.27-0.39). Achieving CDAI low disease activity/remission state was also more common in females. Our findings suggest that disease activity and functional disability are affected by different SDH factors. The effects of SDH should be better understood and addressed by rheumatologists to provide equitable healthcare for all patients with RA. Key points • This study explored a comprehensive panel of social determinants of health and their relationship to clinical outcomes. • Previously unreported factors such as employment status and income were found to influence clinical outcomes. • Our findings can help physicians to identify high-risk patients who may benefit from additional attention to their social background.

Spatiotemporal multilevel joint modeling of longitudinal and survival outcomes in end-stage kidney disease.

Individuals with end-stage kidney disease (ESKD) on dialysis experience high mortality and excessive burden of hospitalizations over time relative to comparable Medicare patient cohorts without kidney failure. A key interest in this population is to understand the time-dynamic effects of multilevel risk factors that contribute to the correlated outcomes of longitudinal hospitalization and mortality. For this we utilize multilevel data from the United States Renal Data System (USRDS), a national database that includes nearly all patients with ESKD, where repeated measurements/hospitalizations over time are nested in patients and patients are nested within (health service) regions across the contiguous U.S. We develop a novel spatiotemporal multilevel joint model (STM-JM) that accounts for the aforementioned hierarchical structure of the data while considering the spatiotemporal variations in both outcomes across regions. The proposed STM-JM includes time-varying effects of multilevel (patient- and region-level) risk factors on hospitalization trajectories and mortality and incorporates spatial correlations across the spatial regions via a multivariate conditional autoregressive correlation structure. Efficient estimation and inference are performed via a Bayesian framework, where multilevel varying coefficient functions are targeted via thin-plate splines. The finite sample performance of the proposed method is assessed through simulation studies. An application of the proposed method to the USRDS data highlights significant time-varying effects of patient- and region-level risk factors on hospitalization and mortality and identifies specific time periods on dialysis and spatial locations across the U.S. with elevated hospitalization and mortality risks.

Umbrella+ review on interventions to reduce risks and impacts on health of children and adolescents in Europe from environmental noise

The health burden from environmental noise underscores the need for interventions to reduce exposure and protect children and adolescents. This Umbrella+ review aims to present the latest knowledge on interventions minimizing the health impacts of environmental noise in this demographic. Initially, we conducted a scoping review anchored in the WHO's systematic review on transportation noise interventions and their impacts on health. The subsequent Umbrella+ review prioritizes recent high-quality systematic reviews and includes new, high-quality original studies from Europe published after 2014 to complement identified reviews. Study eligibility follows a PICOS (Population, Intervention, Comparator, Outcome, and Study) approach, focusing on interventions targeting children and adolescents up to age 18. We also consider broader population interventions and their potential effects on children. We consider intervention studies addressing noise exposure from road, rail, and aircraft. Potential health outcomes identified from the scoping process include changes in noise exposure and health outcomes, such as annoyance, sleep disturbance, cardiovascular disease, cognitive development, and birth outcomes. This Umbrella+ review is poised to contribute to the 2024 European Topic Centre on Human Health and the Environment report, offering insights to guide action plans, policies, and legislation related to noise intervention for the health of children and adolescents.

Hemophagocytic lymphohistiocytosis: pediatric hepatic perspective

BackgroundHepatic manifestations of hemophagocytic lymphohistiocytosis (HLH), an underrecognized primary presentation in pediatric age group, mandate high levels of suspicion for early diagnosis.AimThis is to study the frequencies of clinical and laboratory hepatic involvement in patients with familial/primary or secondary/acquired HLH in relation to disease reactivation and outcome.MethodsA 6-month retrospective cohort study recruited 35 patients with HLH. Detailed clinical, laboratory, and genetic characteristics of HLH were collected. Hepatic transaminases and synthetic liver functions were collected at presentation, weeks 2 and 8 after starting treatment, and at time of reactivation. Biochemical liver involvement was considered when alanine aminotransferase (ALT) lived three-times more than the upper normal level. Overall (OS) and reactivation free survival were analyzed according to liver involvement.ResultsTwenty patients (57%) had genetically confirmed HLH, 12 (34.3%) had MUNC13D mutations, 3 (8.5%) had STXBP2 mutations, and 5 (14.3%) had RAB27A mutations, while 9 (25.7%) had no genetic mutations with 4 of them had secondary HLH. Six patients (17.2%) patients had unknown genetics status. Median (IQR) age of the whole group was 18 months (6–36) with an age range of 2–108 months. Liver enlargement was detected at diagnosis in 29 (82.9%) and at reactivation in 18 (51.4%) patients. Eight (22.86%) patients had biochemical hepatic involvement at presentation with no significant difference in their demographic, initial clinical presentation, survival, or the type of mutant gene according to liver involvement.ConclusionVariable hepatic biochemical involvement might be the presenting manifestation of HLH at diagnosis and upon reactivation, yet it did not impact disease outcome.

Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome.

Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear. We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome. Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection. The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

Effect of methimazole treatment on Th1, Th17, and Th22 lymphocytes in pediatric Graves' disease patients.

Graves' disease is the leading cause of autoimmune hyperthyroidism. Thyroid hormones are an essential element of the endocrine system, playing a pivotal role in the body's development, especially important in children with intensified growth. Disturbance within thyroid tissue certainly affected the whole body. Nowadays, numerous research studies indicate different factors contributing to the onset of the disease; however, the exact pathomechanism of Graves' disease is still not fully understood, especially in the context of immune-related processes. Th1, Th17, and Th22 effector lymphocytes were found to be crucial participants in the disease outcome, as well as in autoimmune diseases. Here, our study aimed at assessing selected effector T lymphocytes, Th1, Th17, and Th22, in newly diagnosed pediatric Graves' disease patients, together with their association with thyroid-related parameters and the potential outcome of disease management. We indicated significant increases in the frequencies and absolute numbers of selected effector lymphocytes in Graves' disease patients. In addition, their mutual ratios, as well as Th1/Th17, Th/Th22, and Th17/Th22, seem to be significant in those diseases. Notably, low Th17/Th22 ratio values were distinguished as potential prognostic factors for normalizing TSH levels in response to methimazole treatment. To sum up, our research determines the crucial contribution of Th1, Th17, and Th22 cells in the pathogenesis of Graves' disease. Moreover, the mentioned subset of T cells is highly likely to play a substantial role in the potential prediction of therapy outcomes.

Admission and outcomes of COVID-19 among chronic obstructive pulmonary diseases patients in Africa: protocol for a systematic review and meta-analysis.

When the coronavirus case was originally reported in Wuhan, China, in December 2019, it quickly spread throughout the world and became a global public health problem. Evidence of the admission and outcomes of coronavirus disease among patients with chronic obstructive pulmonary disease (COPD) has not been reported in Africa. Consequently, this research protocol uses a systematic review and meta-analysis of the admission and outcomes of COVID-19 in patients with COPD in Africa. All observational studies published in the English language and reporting on the prevalence, admission and outcomes of COVID-19 among patients with COPD in Africa will be included. A search strategy will be implemented using electronic databases and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol recommendations. The findings of this review will be reported to health program designers, decision-makers and healthcare providers.

Lats-IN-1 protects cardiac function and promotes regeneration after myocardial infarction by targeting the hippo pathway.

Myocardial infarction (MI), a leading cause of heart failure, is characterized by the loss of cardiomyocytes, which severely limits the heart's regenerative capacity. The Hippo pathway, which regulates cell proliferation and apoptosis, presents a therapeutic target for cardiac regeneration. This study explores the efficacy of Lats-IN-1, a LATS1/2 kinase inhibitor targeting the Hippo pathway, as a novel treatment for MI. Using male C57BL/6 mice subjected to surgically induced MI, we administered Lats-IN-1 and evaluated the effects on cardiac function, infarct size, cardiomyocyte proliferation, and apoptosis through various assays and echocardiographic assessments. Our results demonstrate that Lats-IN-1 significantly improves cardiac function, as evidenced by enhanced ejection fraction and reduced ventricular dimensions. Additionally, Lats-IN-1 decreased infarct size and apoptosis rates while promoting cardiomyocyte proliferation. These findings suggest that Lats-IN-1 promotes cardiac repair and regeneration. By modulating the Hippo pathway and reducing apoptosis markers, Lats-IN-1 represents a promising therapeutic strategy for improving outcomes in heart diseases characterized by cardiomyocyte loss. This study highlights the critical role of the Hippo pathway in facilitating cardiac regeneration.