Marginal Structural Cox Model Research Articles

Investigating the causal association of generalized and abdominal obesity with microvascular complications in patients with type 2 diabetes: A community-based prospective study.

The paradoxical protective association between overweight/obesity and diabetic microvascular complications (DMC), a phenomenon well-known as the obesity paradox, has been considered a non-causal association based on methodological influences. We aimed to investigate the association of generalized and abdominal obesity, as measured by body mass index (BMI) and waist circumference (WC), respectively, with DMC in patients with type 2 diabetes (T2D), using a causal inference approach. We enrolled 1436 patients with clinically diagnosed T2D but not DMC at baseline in a community-based prospective cohort in China between 2017 and 2019 and followed them annually until 2022 with new-onset DMC recorded. Marginal structural Cox models with inverse probability weighting were constructed to determine the causal association. Subgroup analyses were performed to identify potential effect modifiers. We observed 360 incident DMC cases, including 109 cases of diabetic nephropathy (DN) and 277 cases of diabetic retinopathy (DR) during four follow-up visits. Multivariable-adjusted hazard ratios (95% confidence intervals) for overall DMC, DN and DR were 1.037 (1.005-1.071), 1.117 (1.062-1.175) and 1.018 (0.980-1.059) for 1 kg/m2 increase in BMI, and 1.005 (0.994-1.017), 1.034 (1.018-1.051) and 1.000 (0.987-1.014) for 1 cm increase in WC, respectively. Similar patterns were observed across the BMI and WC categories, while the positive association appeared to be more pronounced in women. Generalized but not abdominal obesity was associated with an increased risk for the overall DMC, whereas both obesities were causally related to DN, albeit not DR, in T2D. Routine weight management should not be neglected in diabetes care, particularly in women.

Adjustment for duration of employment in occupational epidemiology

PurposeIn occupational epidemiology, the healthy worker survivor effect can manifest as a time-dependent confounder because healthier workers can accrue greater amounts of exposure over longer periods of employment. For example, in occupational studies of radiation exposure that focus on cumulative annualized radiation dose, workers can accrue greater amounts of cumulative radiation exposure over longer periods of employment, while workers with longer periods of employment can transition into jobs with a reduced potential for annualized radiation exposure. The extent to which confounding arising from the healthy worker survivor effect impacts radiation risk estimates is unknown. MethodsWe assessed the impact of the healthy worker survivor effect on estimates of radiation risk among nuclear workers in a Million Person Study cohort. In simulation studies, we contrasted the ability of marginal structural Cox models with inverse probability weighting and Cox proportional hazards models to account for time-dependent confounding arising from the healthy worker survivor effect. ResultsMarginal structural Cox models and Cox proportional hazards models with flexible functional forms for duration of employment provided reliable results. ConclusionsIt is crucial to flexibly adjust for duration of employment to account for confounding arising from the healthy worker survivor effect in occupational epidemiology.

Long-term PM1 exposure and hypertension hospitalization: A causal inference study on a large community-based cohort in South China

Limited evidence exists on the effect of submicronic particulate matter (PM1) on hypertension hospitalization. Evidence based on causal inference and large cohorts is even more scarce. In 2015, 36,271 participants were enrolled in South China and followed up through 2020. Each participant was assigned single-year, lag0–1, and lag0–2 moving average concentration of PM1 and fine inhalable particulate matter (PM2.5) simulated based on satellite data at a 1-km resolution. We used an inverse probability weighting approach to balance confounders and utilized a marginal structural Cox model to evaluate the underlying causal links between PM1 exposure and hypertension hospitalization, with PM2.5-hypertension association for comparison. Several sensitivity studies and the analyses of effect modification were also conducted. We found that a higher hospitalization risk from both overall (HR: 1.13, 95% CI: 1.05–1.22) and essential hypertension (HR: 1.15, 95% CI: 1.06–1.25) was linked to each 1 µg/m3 increase in the yearly average PM1 concentration. At lag0–1 and lag0–2, we observed a 17%–21% higher risk of hypertension associated with PM1. The effect of PM1 was 6%–11% higher compared with PM2.5. Linear concentration-exposure associations between PM1 exposure and hypertension were identified, without safety thresholds. Women and participants that engaged in physical exercise exhibited higher susceptibility, with 4%–22% greater risk than their counterparts. This large cohort study identified a detrimental relationship between chronic PM1 exposure and hypertension hospitalization, which was more pronounced compared with PM2.5 and among certain groups.

Unveiling causal connections: Long-term particulate matter exposure and type 2 diabetes mellitus mortality in Southern China

Evidence of the potential causal links between long-term exposure to particulate matters (PM, i.e., PM1, PM2.5, and PM1–2.5) and T2DM mortality based on large cohorts is limited. In contrast, the existing evidence usually suffers from inherent bias with the traditional association assessment.A prospective cohort of 580,757 participants in the southern region of China were recruited during 2009 and 2015 and followed up through December 2020. PM exposure at each residential address was estimated by linking to the well-established high-resolution simulation dataset. Hazard ratios (HRs) were calculated using time-varying marginal structural Cox models, an established causal inference approach, after adjusting for potential confounders.During follow-up, a total of 717 subjects died from T2DM. For every 1 μg/m3 increase in PM2.5, the adjusted HRs and 95% confidence interval (CI) for T2DM mortality was 1.036 (1.019–1.053). Similarly, for every 1 μg/m3 increase in PM1 and PM1–2.5, the adjusted HRs and 95% CIs were 1.032 (1.003–1.062) and 1.085 (1.054–1.116), respectively. Additionally, we observed a generally more pronounced impact among individuals with lower levels of education or lower residential greenness which as measured by the Normalized Difference Vegetation Index (NDVI). We identified substantial interactions between NDVI and PM1 (P-interaction = 0.003), NDVI and PM2.5 (P-interaction = 0.019), as well as education levels and PM1 (P-interaction = 0.049).The study emphasizes the need to consider environmental and socio-economic factors in strategies to reduce T2DM mortality. We found that PM1, PM2.5, and PM1–2.5 heighten the peril of T2DM mortality, with education and green space exposure roles in modifying it.

Adjuvant Ovarian Function Suppression in Premenopausal Hormone Receptor–Positive Breast Cancer

Few oncology studies have assessed the effectiveness of adjuvant ovarian function suppression (OFS) in observational settings for premenopausal hormone receptor-positive breast cancer. Target trial emulation is increasingly used for estimating treatment outcomes in observational cohorts. To describe hormone therapy and OFS treatment patterns (aim 1), examine the association between adding OFS to tamoxifen (TAM) or aromatase inhibitor (AI) and survival (aim 2), and examine the association between duration of hormone treatment (TAM or AI) plus OFS (H-OFS) and survival (aim 3). This population-based cohort study included all premenopausal, early-stage breast cancer diagnoses between 2010 and 2020 in Alberta, Canada. Target trial emulation was conducted. Eligibility criteria were directly modeled after the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Participants were followed up for a maximum of 5 years. Data were analyzed from July 2022 through March 2023. For aim 2, exposures were receiving the following baseline treatments for 2 years: AI + OFS (AI-OFS), TAM + OFS (T-OFS), and TAM alone. For aim 3, exposures were a 2-year or greater and a less than 2-year duration of H-OFS. Recurrence-free survival was the primary outcome of interest. Marginal structural Cox models with inverse probability treatment and censoring weights were used to estimate hazard ratios (HRs), adjusted for baseline and time-varying confounding variables. Among 3434 female patients with premenopausal, early-stage breast cancer diagnoses (median [IQR] age, 45 [40-48] years), 2647 individuals satisfied SOFT and TEXT eligibility criteria. There were 2260 patients who initiated TAM, 232 patients who initiated T-OFS, and 155 patients who initiated AI-OFS; 192 patients received H-OFS for 2 or more years, and 195 patients received H-OFS for less than 2 years. The 5-year recurrence risks were not significantly lower in AI-OFS vs TAM (HR, 0.76; 95% CI, 0.38-1.33) or T-OFS vs TAM (HR, 0.87; 95% CI, 0.50-1.45) groups. Patients receiving H-OFS for 2 or more years had significantly better 5-year recurrence-free survival compared with those receiving H-OFS for less than 2 years (HR, 0.69; 95% CI, 0.54-0.90). This study found no significant reductions in recurrence risk for AI-OFS and T-OFS compared with TAM alone. H-OFS duration for at least 2 years was associated with significantly improved recurrence-free survival.

Estimation of the causal effects of time-varying treatments in nested case-control studies using marginal structural Cox models.

When estimating the causal effects of time-varying treatments on survival in nested case-control (NCC) studies, marginal structural Cox models (Cox-MSMs) with inverse probability weights (IPWs) are a natural approach. However, calculating IPWs from the cases and controls is difficult because they are not random samples from the full cohort, and the number of subjects may be insufficient for calculation. To overcome these difficulties, we propose a method for calculating IPWs to fit Cox-MSMs to NCC sampling data. We estimate the IPWs using a pseudo-likelihood estimation method with an inverse probability of sampling weight using NCC samples, and additional samples of subjects who experience treatment changes and subjects whose follow-up is censored are required to calculate the weights. Our method only requires covariate histories for the samples. The confidence intervals are calculated from the robust variance estimator for the NCC sampling data. We also derive the asymptotic properties of the estimator of Cox-MSM under NCC sampling. The proposed methods will allow researchers to apply several case-control matching methods to improve statistical efficiency. A simulation study was conducted to evaluate the finite sample performance of the proposed method. We also applied our method to a motivating pharmacoepidemiological study examining the effect of statins on the incidence of coronary heart disease. The proposed method may be useful for estimating the causal effects of time-varying treatments in NCC studies.

Impact of early heparin therapy on mortality in critically ill patients with sepsis associated acute kidney injury: a retrospective study from the MIMIC-IV database.

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI. Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed. Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding. Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60years and AKI stage 3.

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Adverse Impact of Sodium Bicarbonate Administration on Multiple Outcomes in Acute Pancreatitis Patients With Hyperlactatemia.

Hyperlactatemia is likely to occur among patients with acute pancreatitis (AP). Sodium bicarbonate (SB) therapy could be applied to correct potential detrimental acidic disturbances, but the exact impact of SB treatment is unknown. This study aims to investigate the impact of SB on AP patients complicated with hyperlactatemia. The study was conducted based on the database named Medical Information Mart for Intensive Care-IV (MIMIC-IV). Propensity matching (PSM) and inverse probability weighting (IPTW) were used to balance the baseline differences. Multivariate regression and marginal structural Cox models were performed to investigate the association between SB and multiple outcomes. Three hundred fifty-three AP patients with hyperlactatemia (initial serum lactate, >2.0 mmol/L) were extracted from the MIMIC-IV database. We found that SB treatment was significantly associated with worse multi-outcomes of AP patients with hyperlactatemia (in-hospital mortality: hazard ratio, 2.46; 95% confidence interval, 1.38-4.39; P < 0.01). Further analysis through marginal structural Cox models showed that SB had adverse impact on in-hospital prognosis of patients with severe lactic acidosis (pH < 7.15,lactate > 2.0 mmol/L). Sodium bicarbonate might not be an appropriate treatment for AP patients with hyperlactatemia (lactate > 2.0 mmol/L) or with severe lactic acidosis (pH < 7.15, lactate > 2.0 mmol/L).

Effect of sodium bicarbonate infusion on hospital mortality in acute kidney injury patients with metabolic acidosis.

Physicians usually consider that sodium bicarbonate (SB) infusion can be used for metabolic acidosis; however, there is little evidence available to assess its effect on hospital mortality in large AKI cohorts. Here, we investigated the effect of SB infusion in patients with AKI complicated by metabolic acidosis. Patients with AKI complicated by metabolic acidosis were screened from the MIMIC-IV database. A propensity score analysis (PSA) was used to decrease baseline differences in the probability of receiving SB. The marginal structural Cox model (MSCM) was employed to adjust for both baseline and time-varying confounding factors. A total of 1853 patients with AKI complicated with metabolic acidosis were included in our study. A total of 390 pairs of patients were divided into an SB infusion group and a non-SB infusion group. The SB infusion group had more serious and worse laboratory indicators, including lower pH [7.19 (0.11) vs. 7.26 (0.07)] and bicarbonate concentration (BC) [12.36 (4.26) vs. 15.96 (3.25) mmol/l]. While there was no significant effect on overall hospital mortality in AKI patients complicated with metabolic acidosis (p = 0.056), SB infusion was observed to have beneficial correlation on hospital mortality in patients with high AG acidosis (AG > 18 mmol/L) (p = 0.012). Similar results were replicated with the MSCM. We found that SB infusion in AKI patients with metabolic acidosis is not beneficial for hospital mortality. However, SB infusion for AKI patients and high AG metabolic acidosis significantly improved hospital mortality. Further larger randomized controlled trials are needed to confirm these results.

Long-term particulate matter exposure and the risk of neurological hospitalization: Evidence from causal inference of a large longitudinal cohort in South China

With limited evidence on the neurological impact of particulate matter (PM) exposure in China, particularly for PM1 which is smaller but more toxic, we conducted a large Chinese cohort study using causal inference approaches to comprehensively clarify such impact. A total of 36,271 participants in southern China were recruited in 2015 and followed up through 2020. We obtained the neurological hospitalizations records by linking the cohort data to the electronic reports from 418 medical institutions across the study area. By using high-resolution PM concentrations from satellite-based spatiotemporal models and the cohort data, we performed marginal structural Cox models under causal assumptions to assess the potential causal links between time-varying PM exposure and neurological hospitalizations. Our findings indicated that increasing PM1, PM2.5, and PM10 concentrations by 1 μg/m³ were associated with higher overall neurological hospitalization risks, with hazard ratios (HRs) of 1.10 (95% confidence interval (CI) 1.04–1.16), 1.09 (95% CI 1.04–1.14), and 1.03 (95% CI 1.00–1.06), respectively. PM1 appeared to have a stronger effect on neurological hospitalization, with a 1% and 7% higher impact compared to PM2.5 and PM10, respectively. Additionally, each 1-μg/m3 increase in the annual PM1 concentration was associated with an elevated risk of hospitalizations for ischemic stroke (HR: 1.15; 95% CI, 1.06–1.26), which tended to be larger than the estimates for PM2.5 (HR: 1.13, 95% CI, 1.04–1.23) and PM10 (HR: 1.05, 95% CI, 1.00–1.09). Furthermore, never-married or female individuals tended be at a greater risk compared with their counterparts. Our study provides important insights into the health impact of particles, particularly smaller particles, on neurological hospitalization risk and highlights the need for clean-air policies that specifically target these particles.

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events

The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Kidney function estimators for drug dose adjustment of direct oral anticoagulants in older adults with atrial fibrillation.

The Cockcroft-Gault equation (CrClC-G) is recommended for dose adjustment of direct oral anticoagulant drugs (DOACs) to kidney function. We aimed to assess whether defining DOAC dose appropriateness according to various kidney function estimators changed the associations between dose appropriateness and adverse events in older adults with atrial fibrillation (AF). Participants of the Berlin Initiative Study with AF and treated with DOACs were included. We investigated CrClC-G and estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration and European Kidney Function Consortium equations based on creatinine and/or cystatin C. Marginal structural Cox models yielded confounder-adjusted hazard ratios for the risk of mortality, thromboembolism and bleeding associated with dose status. A total of 224 patients were included in the analysis (median age 87years). Using CrClC-G, 154 (69%) had an appropriate dose of DOACs, 52 (23%) were underdosed and 18 (8%) were overdosed. During a 39-month median follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced thromboembolism and 60 (9.8/100 person-years) experienced bleeding. Dose status was not associated with mortality and thromboembolism, independent of the equation. Underdose status was associated with a lower risk of bleeding with all the equations compared with the appropriate dose group. In participants with discrepancies in dose status using CrClC-G and eGFR equations, the occurrence of endpoints did not differ between participants having an appropriate dose using CrClC-G or eGFR. In older adults with AF, the association of DOAC dose status with adverse events did not differ when using CrClC-G or eGFR. Our results suggest that eGFR equations are not inferior to CrClC-G within this context.

Potential causal links of long-term air pollution with lung cancer incidence: From the perspectives of mortality and hospital admission in a large cohort study in southern China.

Evidence on the potential causal links of long-term air pollution exposure with lung cancer incidence (reflected by mortality and hospital admission) was limited, especially based on large cohorts. We examined the relationship between lung cancer and long-term exposure to particulate matter (PM, including PM2.5 , PM10 and PM10-2.5 ) and nitrogen dioxide (NO2 ) among a large cohort of general Chinese adults using causal inference approaches. The study included 575 592 participants who were followed up for an average of 8.2 years. The yearly exposure of PM and NO2 was estimated through satellite-based random forest approaches and the ordinary kriging method, respectively. Marginal structural Cox models were used to examine hazard ratios (HRs) of mortality and hospital admission due to lung cancer following air pollution exposure, adjusting for potential confounders. The HRs of mortality due to lung cancer were 1.042 (95% confidence interval [CI]: 1.033-1.052), 1.032 (95% CI:1.024-1.041) and 1.052 (95% CI:1.041-1.063) for each 1 μg/m3 increase in PM2.5 , PM10 and NO2 , respectively. In addition, we observed statistically significant effects of PMs on hospital admission due to lung cancer. The HRs (95%CI) were 1.110 (1.027-1.201), 1.067 (1.020-1.115) and 1.079 (1.010-1.153) for every 1 μg/m3 increase in PM2.5 , PM10 , PM10-2.5 , respectively. Furthermore, we found larger effect estimates among the elderly and those who exercised more frequently. We provided the most comprehensive evidence of the potential causal links between two outcomes of lung cancer and long-term air pollution exposure. Relevant policies should be developed, with special attention to protecting the vulnerable groups of the population.

Early sodium bicarbonate infusion was associated with improved outcome in critically ill patients with acute moderate metabolic acidosis: a retrospective observational study

Abstract Background Sodium bicarbonate (SB) infusion is widely administered for severe metabolic acidosis (MA). However, evidence supporting its effect on mortality in patients with acute moderate MA (MMA) has not yet been established. This study investigated the effect of early SB administration on mortality in critically ill patients with acute MMA and in other subgroups. Methods We retrospectively analyzed a large intensive care unit (ICU) database, Medical Information Mart for Intensive Care (MIMIC)-IV. Patients with acute MMA were identified using MIMIC-IV. Propensity score analysis (PSA) was performed to explain baseline differences in the probability of receiving SB. The marginal structural Cox model (MSCM) was developed to adjust for both baseline and time-varying confounding variables. The primary outcome was ICU mortality, and the secondary outcome was hospital mortality. Results In total, 1738 patients with acute MMA were identified; 484 were enrolled in the SB group and 1254 in the non-SB group. In the PSA, early SB infusion was not associated with reduced ICU mortality (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.67–1.14; P = 0.33) in the overall cohort. However, it was associated with improved ICU survival in patients with sepsis (HR: 0.69; 95% CI: 0.48–0.99; P &lt; 0.05), sepsis shock (HR: 0.61; 95% CI: 0.40–0.93; P &lt; 0.05), and sepsis and lactic acidosis (lactate &gt;2.2 mmol/L; HR: 0.69; 95% CI: 0.48–0.99; P &lt; 0.05). The results from MSCM were similar to those obtained for PSA. Conclusion Early SB infusion was associated with improved ICU survival outcomes in critically ill adult patients with sepsis, septic shock, and sepsis and lactic acidosis and acute MMA. Further large randomized controlled trials are required to confirm these results.

Identification of indications for albumin administration in septic patients with liver cirrhosis

BackgroundAlbumin infusion is the primary therapeutic strategy for septic patients with liver cirrhosis. Although recent studies have investigated the efficacy of albumin in the resuscitation stage of septic patients with liver cirrhosis, it remains unclear whether daily albumin administration can improve outcomes. Furthermore, the indications for initiating albumin therapy are not well defined.MethodsSeptic patients with liver cirrhosis were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV 2.0) database. Marginal structural Cox models were employed to investigate the association between daily albumin infusion and 28-day mortality. We also aimed to explore under what circumstances enrolled patients could benefit most from albumin administration, based on the clinical parameters collected on the day of albumin infusion, including serum albumin concentration, serum lactate concentration, mean arterial pressure (MAP), and vasopressor dosage.ResultsA total of 2265 patients were included in the final analysis, of whom 1093 (48.3%) had received albumin treatment at least once. The overall 28-day mortality was 29.6%. After marginal structural modeling, daily albumin infusion was associated with a reduced risk of 28-day death (hazard ratio, 0.76; 95% CI 0.61–0.94). We found that patients benefit most from albumin infusion when initiated on the day of serum albumin concentration between 2.5 and 3.0 g/dL, serum lactate concentration greater than or equal to 2 mmol/L, MAP less than 60 mmHg, or vasopressor dosage between 0.2 and 0.3 mcg/kg/min (norepinephrine equivalent, NEE).ConclusionsAlbumin infusion is associated with a reduction in mortality in septic patients with liver cirrhosis under specific circumstances. Serum albumin concentration, serum lactate, MAP, and vasopressor dosage were found to be modifiers of treatment effectiveness and should be considered when deciding to initial albumin infusion.

Is COPD mortality in South China causally linked to the long-term PM1 exposure? Evidence from a large community-based cohort

BackgroundLong-term ambient particulate matter (PM) exposure has been found associated with chronic obstructive pulmonary disease (COPD) mortality in an increasing body of research. However, limited evidence was available on the potential causal links between PM1 and COPD mortality, especially in highly exposed areas. ObjectivesTo examine the COPD mortality risk following long-term ambient PM1 exposure in south China. MethodsThe cohort included 580,757 participants recruited during 2009–2015. Satellite-based annual concentrations of PM1 were estimated at a spatial resolution of 1 km × 1 km and assigned to each participant based on their residential addresses. We analyzed the potential causal links between time-varying PM1 exposure and COPD mortality using marginal structural cox models within causal frameworks. Stratified analyses were also performed to identify the potential susceptible groups. ResultsThe annual average PM1 concentration continuously decreased over time. After adjusting for confounders, each 1 μg/m3 increase in PM1 concentration corresponded to an 8.1 % (95% confidence interval: 6.4–9.9 %) increment in the risk of COPD mortality. The impact of PM1 was more pronounced among the elderly and those with low exercise frequency, with a 1.9–6.9 % higher risk than their counterparts. We further observed a 0.1–9.7 % greater risk among those who lived in lower greenness settings. Additionally, we observed higher effect estimates in participants with long-term low PM1 exposure compared to the general population. ConclusionsCOPD mortality risk significantly increased following long term ambient PM1 exposure, particularly among groups with certain demographics or long-term low exposure.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

BackgroundSimultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly...

#3207 KIDNEY FUNCTION ESTIMATORS FOR DRUG DOSE ADJUSTMENT OF DIRECT ORAL ANTICOAGULANTS IN OLDER ADULTS WITH ATRIAL FIBRILLATION

Abstract Background and Aims The Food and Drug Administration and the European Medicines Agency (EMA) recommend using the Cockcroft-Gault equation (CG) for drug dose adjustment of direct oral anticoagulant drugs (DOACs) in non-valvular atrial fibrillation (NVAF), whereas Cardiology guidelines recommend using estimated glomerular filtration rate (eGFR). This issue is of great importance in older adults, which are more prone to adverse drug reactions and have higher prevalence of atrial fibrillation as compared to younger adults, and in whom CG has worse diagnostic performance than most eGFR equations. We aimed to assess if prognosis was similar according to drug dose status using different kidney function estimators based on creatinine and/or cystatin C in older adults with NVAF. Method We used data from the Berlin Initiative Study (BIS): a population-based prospective cohort study initiated in 2009, with five biennial study visits. Participants with a history of NVAF (based on ICD-10 codes) and a dispensed prescription of DOAC four months prior to baseline or a follow-up visit according to claims data were included. Drug dose status was defined according to the EMA guidelines. CG, deindexed (in ml/min) creatinine and/or cystatin C-based CKD-EPI, and deindexed BIS 1 (creatinine-based) and BIS 2 (creatinine and cystatin C-based) equations were included. Associations between dosing status and mortality, stroke or systemic embolism, and bleeding events were assessed using marginal structural Cox models with time-varying variables and taking account of various confounders. Subgroup analyses were performed in rivaroxaban and apixaban users, but not in dabigatran and edoxaban users because of too small sample sizes. Results Two hundred twenty four patients treated with DOACs were included in this analysis (median age 87 years, median eGFRCKD-EPIcr 56 ml/min/1.73m², median follow-up length 40 months for the mortality analysis). Of those, 99 (44%) were taking rivaroxaban, 86 (38%) apixaban, 21 (9%) edoxaban, and 18 (8%) dabigatran. Using CG, 154 (69%) had appropriate DOAC dose at baseline, 52 (23%) were underdosed, and 18 (8%) were overdosed. Discrepancies were found by comparing dosing status according to CG and eGFR equations (Figure 1). During the follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced a stroke or systemic embolism, and 60 (9.9/100 person-years) experienced a bleeding event. Drug dose status was not significantly associated with mortality and the occurrence of stroke or systemic embolism, whatever equation was used. Underdose status was associated with a significantly lower risk of bleeding events with all the equations but overdose status was not associated with a higher risk of bleeding events (Figure 2). In subgroup analyses, drug dose status was not associated with mortality and bleeding event in apixaban users, whatever equation was used. In rivaroxaban users, underdose status was associated with a significant higher risk of death by using CG, eGFRCKD-EPIcys, and BIS 2, and a lower risk of bleeding event by using eGFRCKD-EPIcr. Conclusion In this population of very old adults with NVAF, drug dose status of DOAC was not associated with mortality or the occurrence of stroke or systemic embolism for any of the studied equations. However, underdose status was associated with bleeding events occurrence regardless of the equation used. These associations differed according to the used drug, but this should be interpreted with cautious due to small sample sizes. Our results do not allow us to provide any guidance which equation to use in this context. A study including a larger group of patients with discrepancy in dose status according to the used equations would be of great interest.

Causal links between long-term exposure to NO2 and the risk of cardiovascular hospitalization

Objective: To determine the causal association between long-term Nitrogen dioxide (NO2) exposure and the risk of cardiovascular hospitalization. Methods: Based on a sub-cohort of a community-based prospective cohort study, a total of 36 271 participants were recruited from 35 communities randomly selected in Guangzhou in 2015. The annual average exposure of NO2, demographic characteristics, lifestyle factors, and information on the causes of hospitalization was collected. We applied marginal structural Cox models to investigate the effect of NO2 on cardiovascular hospitalization. Demographic and behavioral factors also stratified results. Results: The mean age of participants in the present study was (50.9±17.8) years, and the cardiovascular admission rate was 8.7%, with 203 822 person-years of follow-up. The annual mean NO2 concentration was 48.7 μg/m3 during 2015-2020. For each 10 μg/m3 increase in NO2 concentrations, the HRs (95%CIs) of total cardiovascular hospitalization, cardiovascular hospitalization, and cerebrovascular hospitalization were 1.33 (1.16-1.52), 1.36 (1.16-1.60) and 1.25 (1.00-1.55), respectively. Participants who were never married/married, with secondary education, high exercise frequency, or non-smokers/current smokers may be more susceptible than their counterparts. Conclusion: Long-term exposure to NO2 significantly increased hospitalization risk for cardiovascular disease.