Cumulative Incidence Research Articles

Transjugular intrahepatic portosystemic shunt (TIPS) with variceal embolization reduces rebleeding risk for patients with portal pressure gradient over 12 mmHg: A long-term follow-up study

ObjectiveThe consensus on whether Transjugular intrahepatic portosystemic shunt (TIPS) should be combined with variceal embolization in the treatment of portal hypertension-induced bleeding has not yet been reached. This study aimed to compare the difference in rebleeding incidence between TIPS and TIPS combined with variceal embolization and to analyze the optimal population for variceal embolization. MethodsClinical data of 721 patients undergoing TIPS were retrospectively collected. Patients were divided into two groups: TIPS alone (n = 155) and TIPS with embolization (TIPS+E, n = 251). Kaplan-Meier (KM) curves were used to analyze prognostic differences between the two groups, and subgroup analysis was conducted based on post-TIPS portal pressure gradient (PPG) exceeding 12 mmHg. ResultsAfter TIPS placement, the mean PPG significantly decreased for all patients. A total of 51 patients (12.6 %) experienced rebleeding, with 24 cases (15.9 %) in the TIPS group and 27 cases (10.6 %) in the TIPS+E group. There was no significant difference in cumulative rebleeding incidence between the TIPS+E and TIPS groups. In the subgroup with post-TIPS PPG greater than 12 mmHg, the cumulative rebleeding incidence was significantly lower in the TIPS+E group compared to the TIPS group (HR = 0.47, 95 %CI = 0.24–0.93, Log rank P = 0.026). No significant difference was found in patients with a post-TIPS PPG less than 12 mmHg. ConclusionFor patients with post-TIPS PPG exceeding 12 mmHg, simultaneous variceal embolization with TIPS placement significantly reduces the risk of rebleeding.

Landmarking for Left-Truncated Competing Risk Data.

Landmarking is an alternative to complex multistate models when the aim is to calculate dynamic predictions. We develop the concept of landmarking for the case of left truncation and competing risks from the application background of drug safety assessment in pregnancy. The method is illustrated with a cohort study of the German Embryotox Pharmacovigilance Institute in Berlin to assess if the risk or the cumulative incidence of adverse pregnancy outcomes, like spontaneous abortions (SABs), is increased in fluoroquinolone-exposed women. Furthermore, we conduct an extensive simulation study to compare the dynamic predictions and coefficient estimates obtained by landmarking to those from nonparametric multistate models and classical time-dependent covariate Cox regression. The results from the simulation study indicate that attenuation of the effects is present in the landmark estimates, also in the complex setting considered here, but the estimates are still close to those from the multistate models. Regarding the Berlin fluoroquinolone data, the fluoroquinolone exposure of a pregnant woman in the first trimester seems to increase her cumulative incidence of elective termination of pregnancy over women never exposed before, but there is no evidence of a significantly increased risk or cumulative incidence in exposed women for SABs. This supports previous results on the same data, which were driven from an analysis without landmarkingmethods.

Modification of the association between cold spells and cardiovascular disease by changes in natural gas prices: A nationwide time-series study

BackgroundAlthough the association between low ambient temperature and cardiovascular disease (CVD) is well-established, the effect of winter energy prices on this association remains unknown. AimThis ecological study aimed to investigate whether changes in natural gas prices (NGP), which account for a significant portion of winter energy prices in Korea, affect the association of cold spells with hospital admissions and mortality due to CVD. MethodsData from the National Health Insurance Service and Statistics Korea were used to determine the daily number of hospital admissions and mortality rates associated with CVD. From January 2012 to February 2017, the NGP continually increased by 24.1%. From January 2012 to December 2014 the NGP continually decreased by 32.6% owing to the Korea Gas Corporation’s management decisions, independent of external socioeconomic factors. We investigated the differences in the associations between cold spells and CVD-related outcomes in price-increasing and price-decreasing periods using a Poisson regression with a distributed lag nonlinear model. Cold spells were assessed on two consecutive days at the 5th percentile of the temperature for each region. ResultsThe meteorological factors and air pollution levels were similar between the two periods. The association between cold spells and hospital admissions due to CVD was stronger during the price-increasing period than during the price-decreasing period [ratio of cumulative relative risk (RRR) = 1.71, 95% confidence interval (CI): 1.31–2.22]. The difference in the association with mortality due to CVD between the two periods was not significant, although the point estimate remained >1 (RRR = 1.11, 95% CI: 0.90–1.38). ConclusionsChanges in energy prices may modify the cold spell-related CVD risk, possibly by inducing behavioral changes to manage energy expenditure. Policymakers should take into account the potential public health implications of changes in energy prices, alongside their economic effects.

Risk of recurrence in early-onset versus late-onset non-metastatic colorectal cancer, 2004–2019: a nationwide cohort study

The incidence of colorectal cancer (CRC) in individuals younger than 50 years of age (early-onset CRC) is increasing. Early-onset CRC often present at advanced stage, suggesting a more aggressive cancer course compared to late-onset CRC (age 50-79). This nationwide cohort study estimates the incidence of recurrence following early-onset CRC and late-onset CRC. The study included all Danish patients <80 years old operated for first-time Union for International Cancer Control (UICC) stage I-III CRC between January 2004 and December 2019. Recurrence status was determined by applying a validated algorithm to individual-level data from nationwide health registries. The 5-year cumulative incidence functions (CIF) of recurrence were reported for early-onset versus late-onset CRC. The difference in time to recurrence was estimated as a time ratio (TR) using an accelerated failure time model. Among 25,729 CRC patients, 1441 (5.6%) had early-onset CRC. Compared to late-onset CRC, early-onset was associated with advanced disease stages and higher treatment intensity. The 5-year CIF of recurrence was 29% (95% CI: 26%-31%) in early-onset versus 21% (95% CI: 21%-22%) in late-onset CRC. The higher CIF of recurrence for early-onset patients persisted in stage-stratified analysis. Time to recurrence was shorter in early-onset versus late-onset patients with TR=0.76 (95% CI: 0.67-0.85). The 5-year CIF of recurrence decreased from 2004 to 2019 for both early- and late-onset patients-most prominent for early-onset patients. Early-onset CRC was associated with higher incidence of recurrence at all disease stages. Indicating that the increased risk is not explained by delayed diagnosis. The excess risk diminished from 2004 to 2019, suggesting that early-onset CRC may achieve a similar recurrence risk as late-onset CRC in a contemporary setting. Aarhus University, Novo Nordisk Foundation, Innovation Fund Denmark, and the Danish Cancer Society.

The Therapeutic Potency of Silver/Chitosan, Silver/Saponin and Chitosan/ Saponin Nanocomposites on Ethanol-induced Gastric Ulcers in Wistar Rats.

The annual incidence of peptic ulcer disease is estimated to be four million cases worldwide, with an average lifetime risk of 7.5% in individuals of all ages. Polymer nanocomposites have novel prospects in the field of modern medicine. The present research endeavors to assess the therapeutic efficacy of nanoparticles composed of silver/chitosan, silver/saponin, and chitosan/saponin against gastric ulcers induced by ethanol in Wistar rats. Forty-eight rats were randomly split into eight groups of the same size. Oral ethanol (5 ml/kg of body weight) was given to all rat groups except the control one for 1 hour before treatment. Control and ulcer groups of rats were given distilled water orally. The rats in the other groups were given orally 1/10 LD50 of each treatment as follows: AgNPs, chitosan NPs, Saponin, AgNPs-Chitosan NPs, AgNP-Saponin, and chitosan-Saponin NPs. NP-treated groups showed a significant increase in the gastric juice pH, glutathione reduced, catalase, and nitric oxide while gastric juice volume, ulcer index, and malondialdehyde levels decreased compared with the ulcer group. Histopathological investigation of stomach showed improvement in NPs groups specially in the chitosan-Saponin NPs group. The current study revealed that silver-chitosan, silver-saponin and chitosansaponin nanocomposites effectively treat gastric ulcers. Chitosan-Saponin nanoparticles showed high therapeutic effectiveness against gastric ulcer in rats.

Diagnosis of Incident Cancer After Cryptogenic Stroke: An Exploratory Analysis of the ARCADIA Randomized Trial.

The objective of this study was to estimate the incidence, timing, and type of new cancer diagnosis among patients with cryptogenic stroke. We used data from the ARCADIA trial, which enrolled patients with cryptogenic stroke and atrial cardiopathy. Participants were prospectively followed, and serious adverse events were assessed every 3 months or sooner if investigators were alerted between visits to an event. Kaplan-Meier statistics were used to estimate the cumulative incidence of a cancer diagnosis within the first year after randomization. Among 878 participants without baseline history of cancer, 13 (1.5%) were diagnosed with incident cancer in the year after randomization, comprising 12 solid cancers (3 prostate, 2 breast, 2 gastrointestinal, and 5 other primary sites) and 1 hematologic cancer (non-Hodgkin lymphoma). The cumulative incidences of a cancer diagnosis were 0% at 3 months, 0.6% (95% CI 0.2%-1.5%) at 6 months, and 2.0% (95 CI 1.1%-3.4%) at 1 year. The median time from index stroke to cancer diagnosis was 261 days (interquartile range 183-358). In a multicenter cryptogenic stroke cohort with prospective follow-up, the 1-year cumulative incidence of a cancer diagnosis was 2%. This rate may be an underestimation because of the clinical trial population and exclusion of cancers diagnosed immediately after stroke. ClinicalTrials.gov Identifier: NCT03192215. Registered June 20, 2017. First patient enrolled February 1, 2018.

Nonparametric estimation of the cumulative incidence function for doubly-truncated and interval-censored competing risks data.

Interval sampling is widely used for collection of disease registry data, which typically report incident cases during a certain time period. Such sampling scheme induces doubly truncated data if the failure time can be observed exactly and doubly truncated and interval censored (DTIC) data if the failure time is known only to lie within an interval. In this article, we consider nonparametric estimation of the cumulative incidence functions (CIF) using doubly-truncated and interval-censored competing risks (DTIC-C) data obtained from interval sampling scheme. Using the approach of Shen (Stat Methods Med Res 31:1157-1170, 2022b), we first obtain the nonparametric maximum likelihood estimator (NPMLE) of the distribution function of failure time ignoring failure types. Using the NPMLE, we proposed nonparametric estimators of the CIF with DTIC-C data and establish consistency of the proposed estimators. Simulation studies show that the proposed estimator performs well for finite sample size.

The Implementation of the Food Quality Protection Act (FQPA) in Increasing the Safety Standards for New Pesticides Used on Foods

This paper examines the Food Quality Protection Act (FQPA) and its impact on enhancing safety standards for pesticides used on food in the United States. Initially, the study explores the Delaney Clause—a strict standard prohibiting carcinogenic food additives—which FQPA replaced with a more flexible "reasonable certainty of no harm" criterion. This shift allows the Environmental Protection Agency (EPA) to assess pesticide risk with consideration of potential benefits, even if a substance is carcinogenic at high doses. The paper also critiques the EPA's implementation challenges, including reliance on quantitative risk assessment (QRA) and cumulative risk assessment, which quantify risks of multiple chemical exposures but face informational and regulatory limitations. Recommendations focus on refining judicial review and integrating cumulative risk assessment to strengthen the FQPA’s capacity to safeguard public health, especially for vulnerable populations such as children. This study underscores the importance of regulatory clarity and rigorous assessment methods in pesticide management.

Pretransplantation risk factors for positive MRD after allogeneic stem cell transplantation in AML patients: a prospective study.

We aimed to prospectively explore the risk factors for measurable residual disease (MRD) positivity after allogeneic stem cell transplantation (allo-SCT) in AML patients (n = 478). The cumulative incidences (CIs) of post-SCT MRD positivity at 100 days, 360 days and 3 years were 4.6%, 12.1% and 18.3%, respectively. Positive pre-SCT MRD and pre-SCT active disease were risk factors for post-SCT MRD positivity at both 360 days and 3 years (P < 0.001). European LeukemiaNet (ELN) 2017 risk stratification was a risk factor for positive post-SCT MRD at 360 days (P = 0.044). A scoring system for predicting post-SCT MRD positivity at 360 days was established by using pre-SCT MRD, pre-SCT active disease and ELN 2017 risk stratification. The CI of positive post-SCT MRD at 3 years was 13.2%, 23.7%, and 43.9% for patients with scores of 0, 1, and 2, respectively (P < 0.001). Multivariate analysis demonstrated that the scoring system was associated with a higher CI of post-SCT MRD positivity, leukemia relapse and inferior survival. Our data indicate that positive pre-SCT MRD status, pre-SCT active disease, and ELN 2017 risk stratification are risk factors for positive post-SCT MRD status in AML patients.

Characteristics of patients with drug-resistant epilepsy in a tertiary hospital

Drug-resistant epilepsy has a cumulative incidence between 14 and 20% of patients with epilepsy. It is associated with more comorbidities and with higher healthcare expenditure and impact on quality of life. A retrospective longitudinal descriptive study was performed covering the period from 01/01/2010 to 02/28/2024. All patients with epilepsy seen in the Pediatric Neurology unit of our center were collected and a review of medical records was carried out to collect the characteristics and evolution during the study period. The classification and definitions used were those established by the International League Against Epilepsy. A total of 325 patients with epilepsy were identified, with a cumulative incidence of DRE of 29%. The most frequent etiology was structural both in all patients with epilepsy (22%), and in drug-resistant epilepsy (36%). A statistically significant association was established between refractoriness and genetic and structural causes, and between having status epilepticus and the development of drug-resistant epilepsy. Seventy-nine percent of patients with drug-resistant epilepsy developed epileptic encephalopathy. The most commonly used antiseizure drug was valproic acid (90%), 19% received a ketogenic diet and 4.2% received epilepsy surgery. In our setting the incidence of drug-resistant epilepsy is high, more so than previously described. Genetic and structural etiologies are associated with a higher incidence. Having suffered status epilepticus is associated with refractoriness. A higher incidence was observed in patients with defined electroclinical syndromes, probably influenced by epileptic and developmental encephalopathies.

Age of onset moderates the effects of Vascular Risk Factors on Neurodegeneration, Blood-Brain-Barrier permeability, and cognitive decline in Alzheimer's Disease.

The role of Vascular risk factors (VRFs) in the progression of Alzheimer's Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset (< 65, EOAD), classic late-onset (65-75, cLOAD) and very late-onset (> 75, vLOAD), to evaluate the moderating effect of age of onset. Moreover, we explored the effects of VRFs on cognitive decline at one year follow-up (ΔMMSE). For 368 patients with biologically confirmed AD, we computed eight risk factors in a composite measure of cumulative vascular risk (vascular score, VS). Stratifying patients according to age of onset, we regressed VS and main individual VRFs on p-tau/Aβ42, t-tau and Qalb, and used bootstrapped mediation analysis to test direct and indirect associations of VS with t-tau, using Qalb as mediator. In a subset of 105 patients, we performed multivariate backward regressions to assess the effects of sex, APOE, Qalb, VS, p-tau/Aβ42 and t-tau on ΔMMSE. VS was positively associated with CSF t-tau in more vulnerable groups burdened by more aggressive disease progression (EOAD: β = 0.256, p = 0.019) or aging (vLOAD: β = 0.007, p < 0.001). Conversely, in patients with classic age of onset VS was associated with higher BBB permeability (cLOAD: β = 0.173, p = 0.015), which simultaneously causes the decrease of CSF t-tau, as a possible resilience response. Cognitive decline was not associated with VS in any of the subgroups. Instead, it was affected by both higher CSF t-tau and increased Qalb values in those with very early or very late onset (EOAD and vLOAD), but by Qalb alone in patients with classic age of onset, where CSF t-tau levels might be buffered by BBB permeability. Our results show that age of onset weighs on the heterogeneous effects played by VRFs in AD, which do not seem to have direct impact on cognitive decline. These findings stress the importance of a tailored patient-centered approach to the application of vascular prevention strategies in AD.

A prophylactic tyrosine kinase inhibitor strategy based on measurable residual disease pre-transplantation for Ph+ acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A prospective multicenter cohort study.

Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph+ ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%-41.0%) and 20.3% (11.6%-30.7%; HR = 1.272, 95% CI: 0.551-2.940, p = .549), and non-relapse mortality was 10.5% (3.3%-22.7%) and 9.7% (4.2%-17.9%; HR = 1.094, 95% CI: 0.320-3.738, p = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%-84.1%) and 84.1% (72.9%-90.9%; HR = 1.746, 95% CI: 0.741-4.112, p = .196), and leukemia-free survival was 64.1% (45.8%-77.7%) and 70.0% (57.6%-79.4%; HR = 1.212, 95% CI: 0.607-2.421, p = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.

Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

Trends in Peripheral Artery Disease, Lower Extremity Revascularization, and Lower Extremity Amputation in Incident Type 2 Diabetes: A Danish Population-Based Cohort Study.

To examine trends in peripheral artery disease (PAD), lower-extremity (LE) revascularization, and LE amputation in patients with incident type 2 diabetes. This cohort study included patients in Denmark diagnosed with type 2 diabetes in 1996-2015 and followed until 2020. Patients were age and sex matched with as many as three general population individuals. Outcomes comprised 5-year cumulative incidences of first-time PAD, LE revascularization, and LE amputation. Age- and sex-adjusted hazard ratios (aHRs) were computed using Cox regression. The cohort comprised 349,454 patients with incident type 2 diabetes (53% male; median age 62 years) and 1,025,054 general population individuals. Among patients with diabetes, decreases in 5-year cumulative incidence of PAD (from 6.2 to 3.4%; aHR 0.55 [95% CI 0.52-0.57]), LE revascularization (from 0.8 to 0.6%; aHR 0.80 [95% CI 0.71-0.90]), and LE amputation (from 1.0 to 0.4%; aHR 0.45 [95% CI 0.40-0.51]) occurred from 1996-2000 to 2011-2015. LE amputation decreased at all amputation levels (hip/thigh, knee/lower leg, and ankle/foot/toe) during the study period. In the general population, 5-year cumulative incidence remained stable (1.2-1.5% for PAD, ∼0.4% for LE revascularization, and ∼0.2% for LE amputation). However, the relative rates of all outcomes were two- to threefold higher in patients with diabetes than matched individuals in 2011-2015. In recent decades, the cumulative incidence of LE complications substantially decreased in patients with incident type 2 diabetes while remaining stable in the general population.

Complications on the feeding artery after an arterio-venous fistula closure in patients after kidney transplantation - a national cohort study

Abstract Background Arteriovenous fistulas (AVFs) in kidney transplant recipients are sometimes closed, either as a policy or due to complications. We collected data on the incidence of complications after AVF closure in a national cohort of transplanted patients. Methods Patients who received a kidney transplant between 2000-2015 and had a functional AVF that was later ligated or extirpated were included. Medical records were searched for arterial complications on the arm with the closed AVF. Furthermore, all patients who were still alive in January 2023 were invited for a follow-up arterial ultrasound examination. Results Sixty patients were included; mean follow-up was 9.3±3.8 years. There were 5 (8% cumulative incidence) patients with symptomatic arterial thrombosis and 3 (5% incidence) with symptomatic feeding artery aneurysm. Prospective ultrasound exam was performed in 50 patients; mean diameter of brachial artery was almost doubled on the arm with closed AVF (8.1±3.2 vs. 4.7±0.7 mm, p &amp;lt; 0.001). Additional asymptomatic complications were found in 9 patients (18% incidence): 7 cases (14% incidence) of arterial thrombosis, some extending up to the axillary artery, and 3 (6% incidence) brachial artery aneurysms. All patients in whom the thrombosis spread to the brachial artery had large brachial arteries (&amp;gt; 10 mm) or an aneurysm. Conclusion We observed a high cumulative incidence of arterial thrombosis (20%) and brachial artery aneurysms (10%), sometimes developing several years after AVF closure. These complications should be taken into account when contemplating closure of a well-developed AVF and an AVF preserving approach with flow-reduction surgery might be preferred in some cases.

Do Time-Dependent Repeated Measures of Anthropometric and Body Composition Indices Improve the Prediction of Incident Diabetes in the Cohort Study? Findings from a Community-Based Korean Genome and Epidemiology Study.

Cumulative evidence consistently shows that anthropometric and body composition measurements are strongly linked to the risk of incident diabetes, typically based on baseline measurements. This study aims to assess whether repeated measurements enhance the prediction of diabetes risk beyond baseline assessments alone. We utilized data from a 16-year population-based follow-up cohort within the Korean Genome and Epidemiology Study, comprising 6,030 individuals aged 40 to 69 years at baseline. We included eight indices: a body shape index (ABSI), body adiposity index (BAI), waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), weight-adjusted skeletal muscle index (SMI), percent body fat, and fat-to-muscle ratio. The effect of these measurements for incident diabetes was estimated using Harrell's C-indexes and hazard ratios with 95% confidence intervals, employing time-dependent Cox proportional hazard models. Over the 16-year follow-up, 939 new diabetes cases were identified (cumulative incidence, 15.6%). The median number of indicator measurements per participant was eight. The basic model, including 10 features (sex, age, education levels, physical activity, alcohol intake, current smoking, total energy intake, dietary diversity score, and log-transformed C-reactive protein levels, and quartiles of unweighted genetic risk score at baseline), yielded a Harrell's C-index of 0.610. The highest C-index in repeated measurements was for WC (0.668) across the general population, weight-adjusted SMI in men, and WHR in women. However, except for ABSI and BAI, the diabetes predictive power of the other indicators was comparable. Additionally, repeated measurements of WC, BMI, and WHR in women were found to contribute to improved discrimination compared to baseline measurements, but not in men. Utilizing repeated measurements of general and central adiposity to predict diabetes may be helpful in predicting hidden risks, especially in women.

Clinical Outcomes According to Aortic Stenosis Management: Insights From Real-World Practice.

Real-world data regarding clinical outcomes according to aortic stenosis (AS) management are scarce. Therefore, we aimed to investigate long-term management across the spectrum of outpatients with AS. Between May 2016 and December 2017, consecutive outpatients with mild (peak aortic velocity, 2.5-2.9 m/s), moderate (3-3.9 m/s), and severe AS (≥4 m/s) were included by 117 cardiologists in the VALVENOR (Follow-Up of a Cohort of Patients With Valvular Aortic Stenosis in the Nord-pas-de-Calais Region) study and followed-up for aortic valve replacement (AVR) and modes of death. Among 2704 patients included, 1156 (42.7%) had mild, 1121 (41.5%) moderate, and 427 (15.8%) severe AS. After a median follow-up of 5 years, 993 AVRs (488 surgical and 505 transcatheter) and 1098 deaths occurred. The 5-year cumulative incidence of AVR or of the composite of death or AVR was 13.3% and 45.2% in mild AS, 45.5% and 75.3% in moderate AS, and 62.8% and 90.6% in severe AS, respectively. Of the 292 patients who met the criteria for AVR but were not treated, AVR was considered futile in 137 patients and 155 patients refused AVR. Mortality rates after 3 years were high: 86% for anticipated futility and 72.3% for refusal. While patients at anticipated futility showed a well-balanced proportion of cardiovascular and noncardiovascular deaths, cardiovascular deaths predominated among those who refused AVR. At 5-year follow-up, only two thirds of patients with severe AS underwent AVR. Patients with untreated severe AS experienced high mortality rates, mostly cardiovascular for patients who declined AVR. This advocates for better patient education based on shared decision making and for optimizing AS quality of care, from diagnosis to treatment.

The Legacy of Redlining: Increasing Childhood Asthma Disparities through Neighborhood Poverty.

Rationale: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. Objectives: To determine whether the racist policy of redlining in the 1930s led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). Methods: We categorized census tracts at the birth address of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into categories A, B, C, and D as defined by the Home Owners Loan Corporation, with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract, including the percentage of low-income households, the CDC's Social Vulnerability Index, and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through tract-level mediators adjusting for individual-level covariates. Measurements and Main Results: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6%, and 13.2% resided in census tracts with a Home Owners Loan Corporation grade of D. In mediation analyses, residing in Grade-D tracts (adjusted odds ratio = 1.03 [95% confidence interval = 1.01, 1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for the Social Vulnerability Index and other tract-level variables. Conclusions: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Genetic Analysis of Asymptomatic Antinuclear Antibody Production.

Antinuclear antibodies (ANA) are detected in up to 14% of the population, and many individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity is limited. In this study, we aimed to perform a genome-wide association study of asymptomatic ANA positivity in multiple populations. Asymptomatic individuals who were either ANA positive or ANA negative from the All of Us Research Program were included in this study, selecting those with an ANA test performed by immunofluorescence and no evidence of autoimmune disease. Imputation was performed, and a multipopulation meta-analysis including approximately 6 million single-nucleotide polymorphisms (SNPs) was conducted. Genome-wide SNP-based heritability was estimated using the Genome-wide Complex Trait Analysissoftware. A cumulative genetic risk score for lupus was constructed using previously reported genome-wide significant loci. A total of 1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals across three populations were included. The multipopulation meta-analysis revealed SNPs with a suggestive association (P <1 × 10-5) across 8 different loci, but no genome-wide significant loci were identified. A gene variant upstream of HLA-DQB1, (rs17211748, P = 1.4 × 10-6, odds ratio 0.82, 95% confidence interval 0.76-0.89), showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Individuals who were asymptomatic and ANA positive did not exhibit increased cumulative genetic risk for lupus compared with individuals who were ANA negative. ANA production is not associated with significant genetic risk and is primarily determined by environmental factors.

Investigating Microperimetric Features in Bietti Crystalline Dystrophy Patients: A Cross-Sectional Longitudinal Study in a Large Cohort.

To assess the clinical and genetic characteristics of patients with Bietti crystalline dystrophy (BCD) with a focus on potential of microperimetry in monitoring macular function. A total of 208 genetically-confirmed BCD patients were enrolled in this retrospective study. The patients were categorized into subgroups based on their fundus characteristics (fovea sparing and fovea involved), optical coherence tomography (OCT) findings (presence/absence of retinal pigment epithelium [RPE] or ellipsoid zone [EZ] line at the fovea/parafovea), and genetic profiles (Mis/Mis, Tru/Mis, Tru/Tru). Fixation patterns were analyzed, and macular sensitivity (MS) parameters were compared among different groups. Longitudinal analysis was performed to calculate the annual changes in MS parameters. Correlation between genotype and phenotype were further investigated by analyzing cumulative incidence of vision impairment among different genotypic groups. Patients with well-preserved RPE or EZ at the foveal/parafoveal region exhibited higher MS. Notably, there was a decline in sensitivity parameters, with a decrease of -2.193dB/year (95% confidence interval [CI] -4.292 to -0.095, P = 0.041) at the fovea and -1.353dB/year (95% CI -2.047 to -0.659, P < 0.001) in average sensitivity. An age-adjusted comparison of sensitivity among genotypic groups and cumulative incidence analyses showed no association between genotypic groups and vision loss. Microperimetry proves to be one of a credible tool for detecting macular functional changes in BCD patients. BCD patients with different genotypes may have similar disease progression.