Cumulative Incidence Function Research Articles

Leaving the Patella Unresurfaced Does Not Increase the Risk of Short-Term Revision Following Total Knee Arthroplasty: An Analysis from the American Joint Replacement Registry.

The benefit of patellar resurfacing in total knee arthroplasty (TKA) remains uncertain, with conflicting evidence regarding associated revision rates and clinical outcomes. Although initial studies have reported higher revision rates associated with unresurfaced patellae, recent evidence questions the necessity of routine patellar resurfacing. This study aimed to evaluate the risk of revision following TKA performed with and without patellar resurfacing using data from the American Joint Replacement Registry (AJRR).The AJRR was queried for all patients aged 65 years and older undergoing elective TKA between January 2012 and March 2020 with a minimum 2-year follow-up. Cases were linked using supplemental Centers for Medicare and Medicaid data. Cases with hybrid fixation, highly constrained implants, and revision components were excluded. Patients were categorized into two groups: those with a resurfaced patella and those without. Cumulative incidence function (CIF) curves and cause-specific Cox models were utilized to assess all-cause revision risk, adjusting for sex, age, femoral design (cruciate retaining vs. posterior stabilized), fixation type (cemented vs. cementless), and Charlson Comorbidity Index.Of the 390,304 TKAs with minimum 2-year follow-up in our cohort, 22,829 had no patellar resurfacing performed. Adjusted hazard ratios (HRs) revealed no significant difference in all-cause revision (HR = 0.96, 95% confidence interval [CI]: 0.81-1.13, p = 0.656), revision for mechanical loosening (HR = 1.61 [0.88, 2.93], p = 0.122), or revision for infection (HR = 1.02 [0.79, 1.33], p = 0.860) associated with patellar resurfacing status.Our study found that patients with an unresurfaced patella do not face an increased short-term revision risk following TKA. These findings challenge the necessity of routine patellar resurfacing and underscore the importance of considering other factors, such as femoral design, patient comorbidities, and implant-related variables in revision risk stratification.

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.

International collaboration of neoadjuvant stereotactic radiosurgery for brain metastases: The INTERNEO individual patient data pooled analysis

Background and PurposeNeoadjuvant stereotactic radiosurgery (NaSRS) is an emerging treatment option for brain metastases (BrM) planned for resection. The aim of this study was to report on the efficacy and safety of NaSRS in an individual patient data pooled analysis. Materials and MethodsPatients undergoing single- and multi-fraction NaSRS for BrM at nine institutions in five countries (Australia, Canada, South Korea, Switzerland and USA) were included. Eligibility criteria included BrM from any primary malignancy and no prior local therapy. The primary endpoint was a composite of local recurrence (LR), any grade radionecrosis (RN), and/or nodular leptomeningeal disease (nLMD). Secondary endpoints included these endpoints and Grade ≥ 2 RN. Endpoints were evaluated using cumulative incidence functions. ResultsNaSRS was delivered to 179 patients with 189 BrM. Median follow-up was 28.4 months. Primary malignancies included non-small cell lung carcinoma (44 %) and melanoma (17 %). The median BrM diameter was 29 mm (IQR 21–36 mm). Single- and multi-fraction NaSRS was utilised in 100 (53 %) and 89 BrM (47 %) respectively. The median single-fraction dose was 18 Gy (IQR 16–20 Gy). Multi-fraction doses included 24 Gy in three fractions (55 %) and 27 Gy in three fractions (25 %). The 12-month incidence for the composite endpoint was 8.0 %. The 12-month incidence of LR was 4.6 %, any grade RN was 3.6 %, Grade ≥ 2 RN was 1.8 % and nLMD was 1.2 %. ConclusionNeoadjuvant SRS results in favourable rates of LR, RN and nLMD. We provide a global experience of this treatment approach with long-term data and the largest cohort of patients undergoing multi-fraction SRS.

DySurv: dynamic deep learning model for survival analysis with conditional variational inference.

Machine learning applications for longitudinal electronic health records often forecast the risk of events at fixed time points, whereas survival analysis achieves dynamic risk prediction by estimating time-to-event distributions. Here, we propose a novel conditional variational autoencoder-based method, DySurv, which uses a combination of static and longitudinal measurements from electronic health records to estimate the individual risk of death dynamically. DySurv directly estimates the cumulative risk incidence function without making any parametric assumptions on the underlying stochastic process of the time-to-event. We evaluate DySurv on 6 time-to-event benchmark datasets in healthcare, as well as 2 real-world intensive care unit (ICU) electronic health records (EHR) datasets extracted from the eICU Collaborative Research (eICU) and the Medical Information Mart for Intensive Care database (MIMIC-IV). DySurv outperforms other existing statistical and deep learning approaches to time-to-event analysis across concordance and other metrics. It achieves time-dependent concordance of over 60% in the eICU case. It is also over 12% more accurate and 22% more sensitive than in-use ICU scores like Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ Failure Assessment (SOFA) scores. The predictive capacity of DySurv is consistent and the survival estimates remain disentangled across different datasets. Our interdisciplinary framework successfully incorporates deep learning, survival analysis, and intensive care to create a novel method for time-to-event prediction from longitudinal health records. We test our method on several held-out test sets from a variety of healthcare datasets and compare it to existing in-use clinical risk scoring benchmarks. While our method leverages non-parametric extensions to deep learning-guided estimations of the survival distribution, further deep learning paradigms could be explored.

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 incidence of symptomatic CSF viral escape in patients on antiretroviral therapy in western India: a retrospective cohort study.

Antiretroviral treatment (ART) effectively suppresses viral loads in both plasma and cerebrospinal fluid (CSF). Patients with discordant plasma and CSF viral loads may experience chronic-progressive or fluctuating neurocognitive dysfunctions. This study examined the incidence of symptomatic CSF viral escape (CSFVE) in patients receiving ART. This retrospective cohort study was conducted between 2000 and 2023. The primary outcome measure was the incidence of symptomatic CSFVE. Nonparametric Mann-Whitney U and Fisher exact/χ 2 tests were applied for continuous and categorical variables, respectively. The cumulative incidence function with Gray's test was used to compare the incidence of CSFVE across the treatment regimens. During the study period, 52 of the 8415 patients were diagnosed with CSFVE. The median duration of HIV diagnosis in patients with CSF VE was 150 (12-288) months, with a median nadir CD4 + T-cell count 96.5 (13-601 cells/L)], and 75% of the patients were on a ritonavir-boosted protease inhibitor (PI/r) regimen. The cumulative incidence of symptomatic CSFVE at a follow-up of 14 years was 1% (95% CI, 0-1%). PI/r (HR 34.73; 95% CI 13.5 to 89.4; p < 0.001) and integrase strand transfer inhibitor (INSTI) (HR 3.42; 95% CI 1.94 to 6.02; p < 0.001) regimens were significantly more likely to be associated with CSFVE than the Non-nucleoside reverse transcriptase inhibitors (NNRTIs) regimens. NNRTIs had the lowest risk of CSFVE compared to the PI/r and INSTI regimens. A rapid and complete recovery is possible with symptomatic CSFVE if it is diagnosed and treated early.

Abstract 4136846: Sex Differences in Hypertension Diagnosis among Young Adults

Background: Young adults, especially men, may experience delays in diagnosis of hypertension, which subsequently affect timely treatment and control of high blood pressure (BP). Question: Compared with young adult women, how soon are young adult men diagnosed with hypertension after having high BPs during clinical encounters? Aim: To estimate the time to first diagnosis of hypertension in young adult men and women, and to identify factors associated with a delayed diagnosis of hypertension. Methods: Using electronic health records, we identified adults aged 18-39 years with systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, based on average of three consecutive separate outpatient BPs within two years of each other, between 2009-2016 from Kaiser Permanente Southern California. We followed them from the third qualifying BP until hypertension diagnosis, membership disenrollment, end of study (12/31/2019), or death, whichever occurred first. We used the cumulative incidence function and Cox proportional hazards models to estimate the time to first diagnosis of hypertension and identify factors associated with diagnosis. Results: Among 2,443 young adults (mean age 31 years, 57% men) with high BP, 37% were diagnosed with hypertension during a median of 5.9 years. Compared with women, a lower percentage of men were diagnosed with hypertension (30% vs 47%) and men received their diagnoses later (median time to diagnosis: 2.3 vs 1.4 years) ( Figure ). Among the total population, 19% of men and 12% of women did not have follow-up BP measures within one year following their third qualifying high BP. Among those diagnosed, 80% initiated with antihypertensive medications within one year following their diagnosis. Factors associated with a delayed diagnosis of hypertension included being male, younger, having lower systolic or diastolic BP, a lower body mass index, and the absence of dyslipidemia or (pre)diabetes. Conclusion: This study highlights that young adult men are at a higher risk of delayed hypertension diagnosis, emphasizing the need for healthcare system level interventions to improve the recognition, diagnosis, and treatment of hypertension in this population.

Abstract 4137781: Relationship between Race, Predelivery Cardiology Care and Cardiovascular Outcomes in Pre-eclampsia/Eclampsia among a Commercially Insured Population

Background: Inequities in Preeclampsia/Eclampsia (PrE/E) persist. It is unknown if the receipt of cardiology care relates to future risk of major adverse cardiovascular events (MACE) in Black and White patients with PrE/E. We sought to determine the cumulative incidence of MACE by race and whether predelivery cardiology care was associated with the hazard of MACE up to 1-year post-delivery for Black and White patients with PrE/E. Methods: Using Optum’s Clinformatics® Data Mart Database (CDM), we identified Black and White patients with PrE/E who had a delivery between 2008 to 2019. MACE was defined as the composite of heart failure, acute myocardial infarction, stroke, and death. Cumulative incidence functions were used to compare the incidence of MACE by race. Cox regression models were used to assess the hazard of MACE by cardiology care for Black and White patients. Results: Among 29,336 patients (83.4% White, 16.6% Black, mean age of 30.9 years) with PrE/E, 11.2% received cardiology care (10.9% White, 13.0% Black). Black patients had a higher incidence of MACE than White patients at 1-yr post-delivery (2.7% vs 1.4%). After adjusting for age and clinical comorbidities, receipt of cardiology care was associated with lower hazard of MACE for White patients (HR= 0.68, 95%CI: 0.50-0.92 p=0.013) but not Black patients (HR: 1.22, 95% CI: 0.82-1.81; p= 0.328). The interaction effect between race and cardiology care was statistically significant (p=0.013) Conclusions: Among a well-insured population of patients with PrE/E, Black patients had a higher cumulative incidence of MACE up to a year post-delivery. However, cardiology care significantly lowered the hazard of MACE for only White women. This observation does not suggest that cardiology care is detrimental to Black individuals but underscores the necessity to investigate why outcomes are disparate among these racial groups.

Abstract 4134572: Assessing Sex Differences in the Relationship Between Social Isolation and Incident Atherosclerotic Cardiovascular Disease and Death Using Data from the U.S. Health and Retirement Study

Background: Inadequate social connection has been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and mortality. There are insufficient and conflicting data on whether sex differences play a role in this relationship. Therefore, we sought to further examine the relationship between sex, social isolation, and these subsequent events. Methods: We analyzed Health and Retirement Study (HRS) and RAND data collected biennially from 8,987 individuals enrolled from 2004-2020 who completed at least 1 Leave Behind Questionnaire (LBQ). Social isolation was determined from LBQ data using a previously validated 6-item scale where scores of 3 or greater indicated social isolation. Development of ASCVD was classified as new self-reported myocardial infarction or stroke at any follow-up assessment. Mortality was determined with RAND longitudinal data, which was available for all individuals. We examined the incidence of ASCVD in socially isolated and not socially isolated individuals using a cumulative incidence function accounting for the competing risk of death. Results: Mean age at baseline LBQ survey was 55.7 years and 43% of the sample were male. In the sample, 23% identified as Black, 63% identified as White, and 13% identified as Other. Social isolation was present in 1,653 (18%) individuals at their baseline survey. ASCVD developed in 484 (5%) participants, and 593 (7%) participants died over the study’s follow-up period. Cumulative incidence analysis showed no significant difference in ASCVD incidence between socially isolated and non-socially isolated groups for either sex (male p-value: 0.15; female: 0.09) (Figure). However, the incidence of death was significantly increased for both socially isolated sexes (male p-value: &lt;0.001; female: &lt;0.001). Conclusion: While socially isolated participants were not at significantly increased risk of incident ASCVD, they were at significantly increased risk of mortality, irrespective of sex. This highlights the need for continued public health initiatives that foster social connection to enhance the well-being of the general population. The study is limited by reliance on self-report for ASCVD, which may underestimate disease incidence.

Relationship Between Race, Predelivery Cardiology Care and Cardiovascular Outcomes in Pre-Eclampsia/Eclampsia Among a Commercially Insured Population.

Background: It is unknown whether predelivery cardiology care is associated with future risk of major adverse cardiovascular events (MACE) in Preeclampsia/Eclampsia (PrE/E). We sought to determine the cumulative incidence of MACE by race and whether predelivery cardiology care was associated with the hazard of MACE up to 1-year post-delivery for Black and White patients with PrE/E. Methods: Using Optum's de-identified Clinformatics® Data Mart Database, we identified Black and White patients with PrE/E who had a delivery between 2008 and 2019. MACE was defined as the composite of heart failure, acute myocardial infarction, stroke, and death. Cumulative incidence functions were used to compare incidence of MACE by race. Regression models were used to assess hazard of MACE by cardiology care for each race. Separate hazards were calculated for the first 14 days and the remainder of the year. Results: Among 29,336 patients (83.4% White, 16.6% Black, 99.5% commercially insured, mean age 30.9 years) with PrE/E, 11.2% received cardiology care (10.9% White, 13.0% Black). Black patients had higher incidence of MACE than White patients at 1-yr post-delivery (2.7% vs 1.4%) with the majority within 14 days of delivery (Black: 58.7%; White: 67.8%). After adjusting for age and comorbidities, receipt of cardiology care was associated with lower hazard of MACE for White patients within 14 days following delivery (HR 0.31, 95%CI: 0.21-0.46, p<0.001) but not Black patients (HR 1.00, 95%CI: 0.60-1.67; p= 0.999). The effect of the interaction between race and cardiology care was significant in the first 14 days (p<0.001) but not the remainder of the year (p=0.56). Conclusions: Among a well-insured population of patients with PrE/E, Black patients had a higher cumulative incidence of MACE up to a year post-delivery. Cardiology care was associated with a lower hazard of MACE only for White patients during the first 14 days following delivery.

Lack of diversity in patients undergoing carotid artery stenting: Implications for the Distressed Community Index.

As the role of social determinants in carotid artery stenting (CAS) outcomes remains unclear, we investigated the association between the Distressed Community Index (DCI) (zip-code based) and post-CAS mortality/stroke outcomes. We analyzed patients undergoing CAS from 2015 to 2019 using the Medicare claims-linked Vascular Quality Initiative database. Patients were grouped based on high (DCI ⩾ 60) and low (DCI < 60) community distress. We analyzed 36-month mortality using Kaplan-Meier survival curves and hierarchical Cox regression, and 36-month stroke using cumulative incidence function curves and Fine-Gray models. The final cohort included 8717 patients (3032 DCI ⩾ 60), with a mean DCI score of 46.2 (± 28.5) and mean age of 74.7 (± 7.8) years. Most participants were men (64.3%), White (92.7%), and non-Hispanic/Latino (97.7%). There was no significant difference in the 36-month mortality incidence between high and low community distress groups (25.6% vs 23.5%, p = 0.22), and no significant association between high community distress and mortality (unadjusted HR: 1.04; 95% CI 0.90-1.21; adjusted HR: 1.02; 95% CI 0.89-1.17). The high community distress group experienced an elevated 36-month stroke incidence (26.8% vs 22.4%, p = 0.048), but no significant association with stroke was observed (unadjusted sub-HR: 1.12; 95% CI 1.00-1.24; adjusted sub-HR: 1.03; 95% CI 0.92-1.16). Our cohort showed underrepresentation in terms of sex, race, and ethnicity, with a skewed DCI distribution towards lower community distress. Contrary to what we know about community distress, no independent association between higher community distress and post-CAS stroke/mortality risk was found. Future work must examine whether accessibility barriers and selective CAS allocation explain our results.

Association between GLP-1RA use and progression of MGUS to Multiple Myeloma among diabetic patients.

In patients with diabetes mellitus (DM) and monoclonal gammopathy of undetermined significance (MGUS), the impact of GLP-1 receptor agonists (GLP-1RAs) on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1RA use in the progression of MGUS to multiple myeloma (MM) in patients with DM. This is a population-based cohort study of Veterans diagnosed with MGUS from 2006-2021 with a prior diagnosis of DM. A validated natural language processing-algorithm was used to confirm MGUS and progression to MM. Gray's test was performed to detect the difference in cumulative Incidence functions (CIFs) for progression by GLP-1RA use status. The association between time-varying GLP-1RA use and progression was estimated in the 1 (exposed):2 (unexposed) matched cohort via multivariable-adjusted hazard ratio (aHR) using stratified Fine-Gray distribution hazard model with death as a competing event and stratum for the matched patient triad. Our analytic cohort included 1,097 MGUS patients who ever used GLP-1RAs, and the matched 2,194 patients who never used GLP-1RAs. Overall, 2.55% progressed in the GLP-1RA ever use group, compared to 5.01% in the GLP-1RA never use group. CIFs were significantly different between the exposed and unexposed groups (P = .02). GLP-1RA use, compared to no-use, was associated with decreased progression to MM (aHR 0.45, 95% confidence interval 0.22 to 0.93, P = .03). For patients with DM and MGUS, GLP-1RA use is associated with a 55% reduction in risk of progression from MGUS to MM, compared to no use.

Development and validation of the competing risk nomogram and risk classification system for predicting cancer-specific mortality in patients with cervical adenosquamous carcinoma treated via radical hysterectomy.

In this study, we established and validated a competing risk nomogram for predicting the cumulative incidence of cervical adenosquamous carcinoma (ASC)-specific death in patients undergoing radical hysterectomy. Patients diagnosed with ASC between 2010 and 2019 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) for various variables influencing ASC-specific mortality was computed. A Fine-Gray competing risk model was used to identify independent predictors, formulating a competing risk nomogram. A multivariate Cox proportional hazards model was also applied for comparative analysis. The performance of the nomogram was assessed using metrics such as the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). A corresponding risk classification system was constructed based on nomogram-derived scores. Factors such as advanced age, racial background (Black race), higher tumor grade, increased tumor size, advanced TNM stage, and receipt of radiotherapy without chemotherapy were found to be positively associated with elevated ASC-specific mortality. Additionally, age, T stage, M stage, and chemotherapy were identified as independent predictors correlated with ASC-specific mortality. The established nomogram exhibited accurate discriminatory capabilities and superior net benefits compared to the traditional TNM staging system. Additionally, the high-risk group consistently demonstrated higher probabilities of ASC-specific death in both the training and validation sets. The developed nomogram proficiently quantified the incidence of ASC-specific death in patients subjected to radical hysterectomy for ASC. This tool could help clinicians in formulating personalized treatment strategies and devising follow-up protocols.

Changing Treatment and Metastatic Disease Patterns in Patients with EGFR Mutated NSCLC: An Academic Thoracic Medical Investigator’s Consortium Registry Analysis

IntroductionOsimertinib is now a standard first-line (1L) therapy for EGFR-mutated (EGFRm) advanced NSCLC. We aimed to characterize patterns of therapy and longitudinal risk of brain and liver metastasis in a cohort of EGFRm NSCLC. MethodsPatients with metastatic EGFRm NSCLC who received 1L systemic therapy at sites within the Academic Thoracic Medical Investigator’s Consortium were included; demographic and clinical data including treatment patterns were described. Analyses of overall survival, time to next treatment, and incident brain and liver metastasis were performed using the Kaplan-Meier method, Cox regression, and cumulative incidence functions on patients who started 1L therapy in 2015 or later. ResultsThe full cohort included 1132 patients and the mean age of the participants was 63.4 years; among the participants, 53% were White individuals, 68% were female individuals, and 67% were nonsmokers. Among the participants, 830 patients received 1L systemic therapy in 2015 or later. The predominant first EGFR–tyrosine kinase inhibitor was erlotinib (65%) before 2018 and osimertinib (81%) after 2018. The median time to the next treatment after the start of 1L therapy was 13.9 months overall and the longest in patients receiving 1L osimertinib (28 months). In the post-2015 cohort, the baseline prevalence of brain metastasis (BM) was 54% and among patients without baseline brain metastasis, the probability of incident BM at 12, 24, and 48 months was 8%, 22%, and 44%, respectively. Development of an on-treatment brain metastasis among patients without baseline brain metastasis was associated with a 3.2 times higher risk of death. ConclusionEven in a contemporary era with prevalent osimertinib use, the baseline and longitudinal risk of BM development was high. The ongoing risk of developing BM, together with the associated survival detriment, argues for routine surveillance of the brain through magnetic resonance imaging for patients with EGFRm NSCLC, which is not currently included in the guidelines.

Safety of hepatitis E vaccine in pregnancy: an emulated target trial following a mass reactive vaccination campaign in Bentiu internally displaced persons camp, South Sudan

Epidemic forms of hepatitis E cause high mortality among pregnant people, with case fatality risks over 30% and adverse fetal outcomes. In 2022, the first mass reactive vaccination campaign against hepatitis E was conducted in South Sudan with the HEV239 vaccine. We aimed to assess whether vaccination against hepatitis E in pregnancy increases the risk of fetal loss in a cohort of vaccinated and unvaccinated pregnant people. In this emulated target trial, an exhaustive pregnancy census was conducted in Bentiu internally displaced persons camp after the second of three vaccination rounds. Women and girls aged 14-45 years with no current jaundice or acute illness were eligible for participation. Individuals who consented were revisited 28 days after their delivery date to document the pregnancy outcome. We used an emulated target trial framework to address biases inherent in observational studies. We matched vaccinated to unvaccinated participants on age, gestational age, and vaccination propensity score and estimated cumulative incidence functions for fetal loss in vaccinated compared to unvaccinated women in a competing risks framework using the Aalen-Johansen estimator. Between May 16 and June 30, 2022, 3421 participants were enrolled and followed up for inclusion in analysis. Among 2741 women who had a pregnancy outcome after the start of the vaccination campaign, 67 (2·4%) were vaccinated before conception, 2036 (74·3%) were vaccinated during pregnancy, and 638 (23·2%) were not vaccinated. Among the 2407 women retained in the matched analyses, the cumulative risk of fetal loss among individuals vaccinated during pregnancy was 7·2% (95% CI 5·6-8·7) compared with 6·1% (3·7-9·2) among unvaccinated individuals, implying a risk ratio of 1·2 (95% CI 0·7-1·9). No evidence of increased risk of fetal loss was found among individuals vaccinated during pregnancy. Médecins Sans Frontières.

Estimands and Cumulative Incidence Function Regression in Clinical Trials: Some New Results on Interpretability and Robustness.

Regression analyses based on transformations of cumulative incidence functions are often adopted when modeling and testing for treatment effects in clinical trial settings involving competing and semi-competing risks. Common frameworks include the Fine-Gray model and models based on direct binomial regression. Using large sample theory we derive the limiting values of treatment effect estimators based on such models when the data are generated according to multiplicative intensity-based models, and show that the estimand is sensitive to several process features. The rejection rates of hypothesis tests based on cumulative incidence function regression models are also examined for null hypotheses of different types, based on which a robustness property is established. In such settings supportive secondary analyses of treatment effects are essential to ensure a full understanding of the nature of treatment effects. An application to a palliative study of individuals with breast cancer metastatic to bone is provided for illustration.

Bacteremia after transcatheter aortic valve implantation: a nationwide cohort study

Abstract Background Bacteremia and infective endocarditis (IE) are rare but severe complications to transcatheter aortic valve implantation (TAVI). However, data on early bacteremia and microbiological etiological profile are scarce. Purpose The study aimed to investigate the incidence of bacteremia and IE within six months after TAVI. Methods Using Danish nationwide registries, we identified all patients who underwent TAVI from 2012 to 2021. These patients were matched 1:1 by age, sex, and index-year with individuals who underwent elective coronary angiography (CAG). The primary outcomes were bacteremia and IE within six months. Outcomes were compared with cumulative incidence functions and adjusted hazard ratios (HR). All patients were followed six months from the index date until the outcome of interest, death, emigration, or end of study (December 31st, 2021), whichever came first. Results We identified 5,990 patients undergoing first-time TAVI, of whom 56 % were men, and the median age was 81 years [IQR 77–85]. All patients were matched with controls undergoing CAG (56% men, median age 81 [IQR 77-85]). Patients undergoing TAVI had more comorbidities than controls. The six-month cumulative incidence of bacteremia was 4.2% [95% CI 3.7-4.7] and 2.6% [95% CI 2.2-3.0] after TAVI and CAG, respectively, corresponding to an adjusted HR of 1.57 (95% CI 1.27-1.96) (Figure 1). The common bacterial etiologies for bacteremia after TAVI were Streptococci (20%), Coagulase-negative staphylococci (CoNS) (19%), and Enterococci (18%). After CAG, CoNS (22%) and Staphylococcus aureus (16%) were the most frequent. By six months, 1.1% [95% CI 0.9-1.4] and 0.2% [95% CI 0.1-0.3] developed IE after TAVI and CAG, respectively, with an adjusted HR of 20.01 (95% CI 5.97-67.48). Conclusion In this nationwide cohort study, the risks of bacteremia and infective endocarditis within six months post-TAVI were significantly higher than in the matched coronary angiography population. Bacteremia post-TAVI was characterized by significantly more Enterococci spp. These results could have implications in the selection of peri-procedural antibiotics, as commonly used antibiotic regimens do not cover Enterococci spp.Cumulative incidence of bacteremia

Changes in length of hospital stay for infective endocarditis - data from before and after the POET trial

Abstract Background The results from the Partial Oral Treatment of left-sided Endocarditis (POET) trial was published in August 2018 and established non-inferiority of a switch to oral step-down antibiotic treatment in stabilized patients with infective endocarditis (IE). However, data on length of hospital stay and safety following the POET trial are warranted. Purpose To examine the changes in length of hospital stay before and after POET publication. Further, to assess safety (relapse of bacteremia and 180 days of mortality) before and after POET publication. Methods By cross-linkage of Danish nationwide registries, patients with first-time IE caused by Streptococcus spp., Enterococcus faecalis, Staphylococcus aureus, or coagulase negative staphylococci from 2012-2021 were identified. Immediately following the publication of the POET trial, the POET criteria was implemented and used in Denmark. The study period was categorized according to publication date (before and after September 2018). Median length of hospital stay was examined according to calendar period. Mortality (from admission date) and relapse of bacteremia (after discharge) at 180 days of follow-up were examined with the Kaplan-Meier estimator and the Cumulative Incidence Function, respectively. Results We identified 3,008 patients before publication of the POET trial (median age 72.8 years) and 1,740 after the publication (median age 75.2 years) (p&amp;lt;0.0001). The burden of comorbidities was comparable between groups. The median length of hospital stay decreased by 8 days: 41 days (IQR: 29-49) before POET publication and 33 days (IQR: 21-44) after POET publication (p&amp;lt;0.0001 for difference), Figure 1. Similar reductions in length of hospital stay were seen across different microbiological etiologies and age groups. The reduction in length of hospital stay was most pronounced in non-surgically treated patients. The mortality from IE admission with a maximum of 180 days follow-up was 27.5% before POET publication and 28.3% after POET publication (p-value=0.41 for difference). The bacteremia relapse rate within 180 days was 3.5% before POET publication and 1.6% after POET publication (p-value=0.0002 for difference), Figure 2. Conclusion Following the POET trial, we found an 8 days reduction in median length of hospital stay with no change in mortality and an associated lower rate of relapse of bacteremia.

Revascularisation after discharge in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Background Multivessel coronary artery disease frequently occurs in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS), which is associated with a higher mortality rate. Previous studies have focused on revascularisation during the initial admission. The need for revascularisation after discharge has not yet been well-studied. Purpose To determine the incidence of revascularisation after discharge in patients initially hospitalised with AMICS compared to ST-elevation myocardial infarction (STEMI) patients without CS. Methods Data from a cohort of individually validated AMICS patients admitted to two tertiary cardiac centres in Denmark between 2010 and 2017 - the RETROSHOCK cohort - were included (fig.1). Data were cross-linked with The National Patient Register, containing diagnostic and procedural codes for all hospital contacts for Danish citizens. For comparison, an age- and sex-matched cohort of STEMI patients (4:1 ratio) without CS treated at the same centres and within the same timeframe was established from The National Patient Register. The incidence of revascularisation (percutaneous coronary intervention (PCI) and/or coronary artery bypass grafting (CABG)) was assessed in patients surviving a "blanking period" of 60 days after discharge to take staged elective revascularisation into account and until a maximum follow-up of 5 years. The cumulative incidence function with death as a competing event was used. Gray’s test was used for comparison of incidence functions. Results A total of 1,716 AMICS patients were included, of whom 753 (44%) survived to 60 days after discharge – of those, 538 (71%) patients had STEMI. Revascularisation was performed during follow-up and after the 60-day ‘blanking period’ in 68 patients (9%) – median follow-up time was 3.4 years in the AMICS group and 3.5 years in the control group. Multivessel disease, out-of-hospital cardiac arrest and hyperlipidaemia at index hospitalisation were more prevalent in patients revascularised during the follow-up period (69% vs. 52% p=0.009, 62% vs. 47% p=0.018 and 42% vs. 27% p=0.014) for revascularised vs. not-revascularised). No significant differences in sex or age were present in revascularised vs. not-revascularised patients. The five-year cumulative incidence rate for revascularisation after discharge was 10.0% (95% Confidence Interval (CI) 7.9-12.7%), which was similar compared to the matched STEMI cohort without CS (11.5% 95% (CI) 10.7-12.4%), HR 0.88 95% (CI) 0.68-1.13, p=0.319) (fig.1a). The finding was similar in a subgroup analysis of STEMI-only patients with CS compared to the non-CS cohort. Conclusions The cumulative incidence of revascularisation after discharge for AMICS patients was comparable to STEMI patients without CS during five years follow-up. Multivessel disease, out-of-hospital cardiac arrest and hyperlipidaemia at index admission were more prevalent in patients who were revascularised during follow-up.

Drug-use-associated infective endocarditis in Denmark

Abstract Introduction Infective endocarditis (IE) has high mortality and the incidence is rising. Intravenous drug use is a risk factor for IE and poses challenges in clinical care. Amid the opioid crisis in many countries, rates of drug-use-associated IE (DU-IE) are increasing. While drug use in Denmark has remained stable the last decade, little is understood about the features and prognostic impact of DU-IE in developed nations not facing a current opioid crisis. Further, with multiple preventive measures deployed in local Danish regions, data on the evolution of DU-IE are warranted. Purpose To examine the temporal evolution, baseline characteristics, and long-term rates of all-cause mortality and IE recurrence in patients with DU-IE compared with patients with non-DU-IE. Methods This nationwide cohort study identified all first-time IE-patients (1999-2018) and categorized them in 1) patients with DU-IE, and 2) patients with non-DU-IE. Drug use was defined using ICD-8/10 codes or treatment for opioid use disorder. Patients were followed from the date of discharge, and absolute one-year rates of mortality and IE recurrence were examined with Kaplan-Meier estimates and the cumulative incidence function, respectively. Outcomes were compared with a multivariable adjusted Cox model. Results We identified 8,843 patients with IE: 407 (4.6%) with DU-IE (61% male, median age 44 years) and 8,436 (95.4%) with non-DU-IE (66% male, median age 72 years). While the absolute number of DU-IE increased, the proportion of DU-IE decreased from 5.9% in 1999-2003 (n=87) to 3.8% in 2014-2018 (n=114). Patients with DU-IE had a higher proportion of bloodstream infection with Staphylococcus aureus (49.4% vs 26.7%, p&amp;lt;0.001); conversely, they had a lower proportion of bloodstream infections with Streptococcusspecies (14.4% vs. 26.2%, p&amp;lt;0.011). Patient with DU-IE had lower in-hospital mortality compared with non-DU-IE (15.5% vs. 20.9%, p&amp;lt;0.001). Among those surviving admission, the one-year cumulative incidence of all-cause mortality was 16.9% in DU-IE and 17.3% in non-DU-IE (p=0.82), yet in adjusted analysis, DU-IE was associated with a higher one-year mortality rate (HR 1.64 [95% CI:1.23-2.21]) (Figure). The one-year cumulative incidence of IE recurrence was 12.8% in DU-IE and 4.3% in non-DU-IE, which corresponded to an adjusted HR of 3.39 (95% CI:2.35-4.88) in DU-IE. Conclusion While an increase in the absolute number of patients with DU-IE was observed, the proportion among all IE-patients was on the decline in Denmark until 2018—which contrasts with other countries where physicians currently battle collateral damage of the opioid crisis. Although drug use was associated with lower in-hospital mortality, it was striking that even though patient with DU-IE was almost 30 years younger, they still had higher rates of all-cause mortality and a more than three-fold increase in IE recurrence one year following discharge.