Time-dependent Cox Proportional Hazards Models Research Articles

Anemia Treatment, Hemoglobin Variability, and Clinical Events in Patients With Nondialysis-Dependent CKD in Japan.

Anemia management in patients with non-dialysis-dependent chronic kidney disease has attracted attention with the introduction of novel therapeutic agents; however, few studies have provided comprehensive epidemiologic information. A retrospective cohort study was conducted in adult patients with stage ≥3a non-dialysis-dependent chronic kidney disease and hemoglobin <11 g/dL (January 2013-November 2021; N=26,626) to assess longitudinal treatment patterns, hemoglobin, and iron parameters (ferritin and transferrin saturation) for anemia management. Time-dependent Cox proportional hazard models were applied to assess the risk of clinical events, including death, cardiovascular events, dialysis introduction, and red-blood-cell transfusion, associated with temporal fluctuation patterns of hemoglobin levels. The cumulative incidence of anemia treatment initiation within 12 months was 37.1%, including erythropoiesis-stimulating agents 26.5%, iron oral 16.8%, iron intravenous 5.1%, and hypoxia-inducible factor prolyl hydroxylase inhibitor 0.2%. The mean (±standard deviation) hemoglobin levels were improved from 9.9±1.2 g/dL to 10.9±1.6 g/dL at 12 months. Despite erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitor therapy, 30.1% of patients remained hemoglobin <10 g/dL. The risks of premature death, cardiovascular events, dialysis introduction, and red-blood-cell transfusion were significantly higher in groups with consistently low hemoglobin or low-amplitude hemoglobin fluctuation around the lower limit of target hemoglobin range than in patients with target hemoglobin range (p <0.05). Likewise, significantly higher risks for dialysis introduction and red-blood-cell transfusion were associated with high-amplitude hemoglobin fluctuation across target hemoglobin range were observed. The findings underscore the importance of stable hemoglobin control within the target range to reduce the mortality and morbidity risks in patients with non-dialysis-dependent chronic kidney disease while highlighting the suboptimal and heterogeneous treatment of anemia in clinical practice.

Insulin use and gout risk among patients with type 2 diabetes mellitus: a real-world cohort study in Shanghai, China.

The effect of insulin use on gout risk remains unknown. This study aimed to investigate the association between insulin use and gout risk among patients with type 2 diabetes mellitus (T2DM). Based on the Shanghai Link Healthcare Database, patients with newly diagnosed T2DM, with or without insulin exposure, were identified from January 1, 2014 to December 31, 2020, and followed until December 31, 2021. Apart from the original cohort, we also established a 1:2 propensity score-matched cohort. A time-dependent Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for gout incidence associated with insulin exposure. A total of 414,258 patients with T2DM, including 142,505 insulin users and 271,753 insulin non-users, were enrolled in this study. After a median follow-up of 4.08years (interquartile range, 2.46-5.90years), the incidence of gout was significantly higher in insulin users than in insulin non-users (319.35 versus 302.20 cases per 100,000 person-years; HR 1.09, 95% CI 1.03-1.16). The results were robust in propensity score-matched cohort, sensitivity analyses, and stratified analysis of aspirin. In other stratified analyses, the association between insulin use and increased gout risk was found only in patients who were female, or aged 40-69years, or without hypertension, dyslipidemia, ischemic heart disease, chronic lung disease, kidney disease, or not using diuretic. Insulin use is associated with a significantly increased risk of gout among patients with T2DM. Key Points • The first real-world study to investigate the effect of insulin use on gout risk. • Insulin use is associated with a significantly increased risk of gout among patients with type 2 diabetes mellitus.

Association between serum total cholesterol and chronic kidney disease progression in children: results from the KNOW-PedCKD.

Dyslipidemia can cause cardiovascular disease and increase the fatality rate among children with chronic kidney disease (CKD); this makes early screening and treatment of dyslipidemia crucial. This study aimed to assess the association between the changes in serum total cholesterol levels over time and the degree of CKD progression in children. From April 2011 to August 2021, 379 of the 432 participants enrolled in the KoreaN cohort study for Outcomes in patients With Pediatric CKD (KNOW-PedCKD) were included and divided into 4 categories based on total cholesterol levels (< 170mg/dL, acceptable; 170-199, borderline; 200-239, high; and ≥ 240, very high). Survival analysis using conventional and time-dependent Cox proportional hazards model were performed for a composite event of CKD progression (≥ 50% decrease in estimated glomerular filtration rate from baseline, a twofold increase in creatinine, or the occurrence of dialysis or kidney transplantation). The incidence of composite event of CKD progression was 96.3, 90.4, 87.3, and 270.6 cases per 1000 person-years in the acceptable, borderline, high, and very high categories, respectively. On using the time-dependent Cox proportional hazards model, the hazard ratio of the very high category was significantly higher than that of the acceptable category by 3.13 times as per univariate analysis and 2.37 times as per multivariate analysis. Very high serum total cholesterol is a significant risk factor for CKD progression in children. Lowering total cholesterol levels below the very high category in children with CKD may delay the progression of CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association between treatment of hepatitis C virus and risk of cardiovascular disease among insured patients with the virus in the United States.

Hepatitis C virus (HCV) infection has been associated with increased risk of cardiovascular disease (CVD). It is unclear whether HCV treatment affects risk of CVD among patients infected with HCV. We assessed the incidence and risk of CVD among insured patients with HCV infection and evaluated if HCV treatment was associated with reduced CVD risk. This retrospective cohort study used MarketScan Commercial and Medicare Supplement databases. Patients newly diagnosed with HCV (vs. patients without HCV) between January 2008 and August 2015 were categorized by treatment (none, insufficient, or minimum effective) based on receipt and duration of anti-HCV treatments. After propensity score matching, time-dependent Cox proportional hazards models were used to compare CVD risk between patients with HCV versus without and between patients with HCV by treatment type and duration. HCV was associated with 13% increased risk of developing CVD overall (adjusted hazard ratio [aHR] 95% CI 1.26-1.35) and with 13% (aHR 1.07-1,18), 9% (aHR 1.03-1.15), and 32% (aHR 1.24-1.40) significantly increased risks of developing coronary artery disease, cerebrovascular disease, and peripheral vascular disease, respectively. Among patients with HCV, compared with no treatment, receipt of minimum effective treatment was associated with 24% decreased risk of CVD, and receipt of insufficient treatment was associated with 14% decreased risk of CVD. Individuals chronically infected with HCV had a higher incidence of CVD. Among patients with HCV, receipt of antiviral treatment for HCV was associated with decreased risk of CVD.

Baveno VII criteria for recompensation predict transplant-free survival in patients with hepatitis B-related decompensated cirrhosis

The latest Baveno VII consensus has provided guidance for identifying patients who have truly recompensated from those with hepatic decompensation. This study aimed to evaluate patients' transplant-free survival in three different stages of cirrhosis. All patients with chronic HBV infection and liver cirrhosis treated with oral nucleos(t)ide analogues from March 2006 to December 2022 were identified from a territory-wide database in Hong Kong. Patients with follow-up duration of <1 year were excluded. Participants were classified into three mutually exclusive groups: (1) no decompensated events (i.e. compensated group); (2) decompensated events occurred (i.e. decompensated group); or (3) decompensated events occurred followed by recompensation according to Baveno VII criteria (i.e. recompensated group). A time-dependent Cox proportional hazard model was adopted for evaluation. The follow-up period was 5 years. A total of 4,701 patients with cirrhosis and HBV who were treated with entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) were identified. During a median follow-up of 5 years (interquartile range 3.7, 5 years), 3,327 (70.8%), 1,347 (29.2%), and 265 (5.6%) patients had compensated, decompensated, and recompensated cirrhosis, respectively, at least once before the end of the study. In the time-dependent multivariable model, the recompensated grouphad similar transplant-free survival compared with the compensated group (adjusted hazard ratio 1.16; 95% CI 0.72-1.86; p= 0.536). The 5-year transplant-free survival rate was 89.3% for the compensated group, whereas it was 76.0% for the recompensated group, reflecting a minimal difference between the two groups. The clinical significance of recompensation of cirrhosis in improving patient outcomes for individuals with CHB infection was highlighted in this study. Early identification and treatment with nucleos(t)ide analogues might promote hepatic recompensation and thus reduce mortality in patients with CHB. The latest Baveno VII consensus introduces the new concept of hepatic recompensation, which refers to the reversal of the structural and functional changes of cirrhosis after removal, cure, or suppression of the aetiologyof cirrhosis. It is essential to investigate the transplant-free survival rates of patients who are able to achieve hepatic recompensation, as this has significant implications for the medical resources required to manage liver failure and transplantation. This study features the clinical significance of hepatic recompensation by comparing patient outcomes of those who achieve it to those who do not. The early identification and use of antiviral treatment with nucleos(t)ide analogues is a pivotal strategy to promote hepatic recompensation, which has the potential to significantly reduce mortality rates in patients with chronic HBV infection and ultimately aid in the elimination of hepatitis.

#2560 HEMOGLOBIN VARIABILITY AND ADVERSE CLINICAL EVENTS IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE AND ANEMIA IN CONTINUOUS CARE

Abstract Background and Aims Anemia management in non-dialysis dependent chronic kidney disease (NDD-CKD) patients has attracted attention with the introduction of new treatment options, such as prolyl hydroxylase domain enzyme inhibitors (HIF-PHI). However, studies reporting comprehensive information on anemia management in NDD-CKD patients are limited. While previous studies reported increased risks of adverse clinical events associated with hemoglobin (Hb) fluctuation in hemodialysis patients, limited information is available in NDD-CKD patients. Method A retrospective cohort study was performed using a Japanese nationwide electronic medical record-based hospital database. Patients with stage ≥3a NDD-CKD, aged ≥18 years, and at least one recorded Hb &amp;lt;11 g/dL between January 1st 2013 and April 30th 2021 were included. Patients already receiving any anemia treatment (erythropoiesis stimulating agent (ESA), iron, or HIF-PHI) were excluded. Hb levels were collected at the index date (the date of the first recorded Hb &amp;lt;11 g/dL) and during the follow-up period. Clinical events included all-cause death, cardiovascular (CV) events (myocardial infarction, unstable angina pectoris, stroke, or hospitalization for heart failure), dialysis introduction, and red-blood-cell transfusion. Time-dependent Cox proportional hazard models, adjusted by clinically relevant variables were applied to assess the risk of clinical events associated with transitioning Hb fluctuation patterns, categorized into six groups: within the target Hb range (11–13 g/dL); consistently below the target (low); consistently above the target (high); low-amplitude fluctuation around the upper limit of the target (LAH); low-amplitude fluctuation around the lower limit of the target (LAL); and, high amplitude fluctuation across the target (HA). Results Of 162,170 patients with CKD, 26,626 (16.4%) NDD-CKD patients with Hb &amp;lt;11 g/dL were identified (median follow-up length, 1.9 years). The mean age was 75.9 years, and 37.8% were female. In overall patients, the mean (±SD) Hb levels at index and at 3, 6, and 12 months of follow up were 9.9±1.2 g/dL, 10.6±1.5 g/dL, 10.8±1.6 g/dL, and 10.9±1.6 g/dL, respectively. The proportion of patients with Hb &amp;lt;10 g/dL at index and at 12 months were 34.3% and 23.9%, respectively. In the subgroup of patients treated with ESA or HIF-PHI (n = 8,876), the mean Hb (±SD) levels had increased from 9.3±1.3 g/dL to 10.3±1.5 g/dL at 3 months, 10.5±1.5 g/dL at 6 months, and 10.6±1.5 g/dL at 12 months after treatment initiation. In this subgroup, the proportion of patients with Hb &amp;lt;10 g/dL had decreased from 70.0% to 30.1% at 12 months. Fig. 1 shows the Hb levels and proportions of patients with Hb &amp;lt;10 g/dL by treatment type. During the follow-up period, 5,991 (22.5%) deaths, 3,545 (13.3%) CV events, 4,231 (15.9%) dialysis introductions, and 5,561 (20.9%) red-blood-cell transfusions were observed. The risks of clinical events were significantly higher in the low and LAL Hb groups than in the target Hb group (Fig. 2). The hazard ratios (95% CIs) for death, CV events, dialysis introduction, and red-blood-cell transfusion in the low Hb group, compared to the target Hb group were 1.35 (1.20–1.52), 1.90 (1.58–2.27), 1.75 (1.39–2.20), and 2.80 (2.28–3.43), respectively, and in the LAL Hb group were 1.28 (1.14–1.43), 1.71 (1.43–2.04), 1.85 (1.48–2.33), and 1.64 (1.33–2.02), respectively. In HA Hb group, significantly higher risks for dialysis introduction and red-blood-cell transfusion were observed. Conclusion This study reports comprehensive information on anemia management in NDD-CKD patients in clinical practice. Despite treatment for Hb correction, 20–30% of patients persistently remained at low Hb levels. The increased risk of adverse clinical events associated with Hb fluctuations suggest that stable Hb control within the target range is important to reduce the risk of mortality and morbidity in patients with NDD-CKD and anemia.

Prognostic impact of in-hospital hemoglobin decline in non-overt bleeding ICU patients with acute myocardial infarction

BackgroundThe prognostic value of in-hospital hemoglobin drop in non-overt bleeding patients with acute myocardial infarction (AMI) admitted to the intensive care unit (ICU) remains insufficiently investigated.MethodsA retrospective analysis was performed based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. 2,334 ICU-admitted non-overt bleeders diagnosed with AMI were included. In-hospital hemoglobin values (baseline value on admission and nadir value during hospitalization) were available. Hemoglobin drop was defined as a positive difference between admission and in-hospital nadir hemoglobin. The primary endpoint was 180-day all-cause mortality. The time-dependent Cox proportional hazard models were structured to analyze the connection between hemoglobin drop and mortality.Results2,063 patients (88.39%) experienced hemoglobin drop during hospitalization. We categorized patients based on the degree of hemoglobin drop: no hemoglobin drop (n = 271), minimal hemoglobin drop (< 3 g/dl; n = 1661), minor hemoglobin drop (≥ 3 g/dl & < 5 g/dl, n = 284) and major hemoglobin drop (≥ 5 g/dl; n = 118). Minor (adjusted hazard ratio [HR] = 12.68; 95% confidence interval [CI]: 5.13–31.33; P < 0.001) and major (adjusted HR = 13.87; 95% CI: 4.50-42.76; P < 0.001) hemoglobin drops were independently associated with increased 180-day mortality. After adjusting the baseline hemoglobin level, a robust nonlinear relationship was observed in the association between hemoglobin drop and 180-day mortality, with 1.34 g/dl as the lowest value (HR = 1.04; 95% CI: 1.00-1.08).ConclusionIn non-overt bleeding ICU-admitted patients with AMI, in-hospital hemoglobin drop is independently associated with higher 180-day all-cause mortality.

Duration of influenza vaccine effectiveness in the elderly in Japan: A retrospective cohort study using large-scale population-based registry data.

The immune response to influenza vaccination in the elderly is likely to be lower than that in young adults. Clinical protection may not persist year-round in the elderly. However, the effectiveness of influenza vaccine in the elderly has not been adequately studied, especially in terms of the duration of effectiveness. We used a linked database of healthcare administrative claims data and vaccination records maintained by the municipality of a city in Kanto region of Japan. We studied individuals who were aged 65years or older at baseline and were followed up between April 1, 2014 to March 31, 2020. The duration of influenza vaccine effectiveness by age category was analyzed using a time-dependent piecewise Cox proportional hazard model with time-dependent vaccine status, prior season vaccination and covariates confirmed in the baseline period (age, sex, cancer, diabetes, chronic obstructive pulmonary diseases, asthma, chronic kidney diseases, and cardiovascular diseases). We identified an analysis population of 83,146 individuals, of which 7,401 (8.9%) had experienced influenza and 270 (0.32%) underwent influenza-related hospitalization. Individuals who were vaccinated during the first season (n=47,338) were older than non-vaccinated individuals (n=35,808) (average age, 75.8 vs. 74.1years, respectively). The multivariable analysis showed a lower incidence of influenza in vaccinated individuals (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.43-0.51; P<0.001), while the incidence of hospitalization for influenza did not differ significantly by vaccination status (HR, 0.79; 95% CI, 0.53-1.18; P=0.249). Protective effectiveness against incidence was maintained for 4 or 5months after vaccination in those aged 65-69 and 80-years, 5months in 70-79years. Our study identified moderate vaccine effectiveness in preventing the incidence of influenza in the Japanese elderly. Vaccine effectiveness showed a trend of gradual attenuation. Clinicians should suspect influenza infection even in those vaccinated, especially in elderly individuals who had received vaccination more than 4 or 5months previously.

EXAcerbations of COPD and their OutcomeS on CardioVascular diseases (EXACOS-CV) Programme: protocol of multicountry observational cohort studies

IntroductionIn patients with chronic obstructive pulmonary disease (COPD), the risk of certain cardiovascular (CV) events is increased by threefold to fivefold in the year following acute exacerbation of COPD (AECOPD),...

A life course approach to asthma and wheezing among young children caused by ozone: A prospective birth cohort in northern China

BackgroundGiven differences in vulnerability of children in early life, a life course approach to asthma and wheezing (AW) in young children caused by ozone (O3) is not fully understood. MethodsWe conducted a birth cohort in Jinan, China from 2018 to 2021 to elucidate the onset model of childhood AW due to O3 exposure. An inverse distance weighted model was used for individual exposure assessment. The time-dependent Cox proportional-hazard model and logistic model were used to investigate the effects of O3 exposure on AW. Principal component analysis, interaction analysis, and distributed lag model were used to analyze the life course approach. ResultsThe cumulative incidence rate for AW among 6501 children aged 2 was 1.4%. A high level of O3 was related to AW (HR: 2.10, 95% CI: 1.31, 3.37). Only O3 exposure after birth was associated with AW, with an OR of 1.82 (1.08, 3.12), after adjusting for the effect before birth. Furthermore, adjusting for other air pollutants, the HR for the individual effect of high O3 exposure on AW was 2.44 (1.53, 3.89). Interestingly, P values for interactions for O3 and the principal components of other pollutants, as well as the characteristic variable of open windows were less than 0.1. Moreover, an increase in the IQR of O3 exposure at the 31st to 37th weeks before birth and the 1st to 105th weeks after birth was associated with an increase in the HRs for AW. ConclusionsHigh-level of O3 exposure after birth could lead to AW among young children. Importantly, the AW onset model may include the risk factors accumulation and the sensitive period model. Specifically, there are two sensitive windows in early life, and the correlated insults between the high level of O3 and other pollutants as well as open windows in the asthma-inducing effect.

Type and timing of antiretroviral therapy during pregnancy: Impact on risk of preterm delivery and small-for-gestational age births in Canada, a retrospective cohort study.

To evaluate the impact of type and timing of antiretroviral therapy (ART) on the risk of preterm delivery (PTD) and small-for-gestational age (SGA) birth among pregnant women and people living with HIV in Canada. Data for this retrospective cohort study were analyzed from the Canadian Perinatal HIV Surveillance Program from 1990 to 2020. The association between ART and risk of PTD (<37 weeks) and SGA birth(<10th percentile)was explored using mixed effects logistic regression and time-dependent Cox proportional hazards models. Overall, there were 14.9% (654 of 4379) PTD and 18.5% (732 of 3947) SGA cases. A higher risk of PTD was observed with nonnucleoside reverse transcriptase inhibitor-(adjusted hazard ratio [aHR], 1.73; P=0.019) and boosted protease inhibitor-(aHR,186;P=0.007)based regimenscompared with integrase strand transfer inhibitor (INSTI)-based regimens. ART initiation prior to conception was associated with a lower risk of SGA birthcompared with ART initiation after conception at 1 to 14 weeks (adjusted odds ratio [aOR], 0.69; P=0.024) and > 14 weeks (aOR, 0.70; P=0.005). INSTI-based ART regimens were associated with lower risk of PTD compared with other regimens, and ART initiation before conception was associated with a lower risk of SGAbirth. These findings, with overall safety data, should be considered when providing pregnancy counseling to people living with HIV.

Health effects of air pollution on maternal preeclampsia in a rural area of China: A population-based cohort study

Few studies have focused on the effects of air pollutants on maternal preeclampsia and sub-types in rural areas. In this study, a time-dependent Cox proportional hazards model was used to explore trimester-specific and entire pregnancy concentrations of pollutants and preeclampsia in Liuyang rural area of China from 2017 to 2019, and to examine whether season and parity could modify the effects. 36,776 participants were included, of whom 968 (2.63%) were diagnosed with preeclampsia (mild 448; severe 520). Exposure to PM2.5 was significantly associated with mild preeclampsia (HR 1.12–1.90) in the adjusted models for the overall pregnancy. Exposure to ozone had the opposite effect. SO2 exposure in the third trimester was positively associated with mild preeclampsia (HR 1.14–1.35). Exposure to PM10 was associated with a 2% risk of severe preeclampsia in the adjusted models for the first trimester. Mild preeclampsia was positively associated with exposure to NO2 and SO2 in the third trimester in the summer conception, and both sizes of particulate matter in the first trimester in the winter. The risk of preeclampsia was increased by exposure to SO2 in the third trimester for nulliparous women (HR 1.30, 95% CI: 1.12–1.52), PM10 in the first trimester for primiparous women (HR 1.03, 95% CI: 1.01–1.04), and both sizes of particulate matter in the second trimester for multiparous women (HR 1.09, 95% CI: 1.02–1.17; HR 1.07, 95% CI: 1.02–1.13). The study adds to evidence on the association between maternal exposure to air pollutants and different types of preeclampsia.

Developing Hemodynamic Valve Deterioration and Mortality in Aortic Valve Replacement

BackgroundAs life span increases, in patients having a bioprosthetic valve, the development of hemodynamic valve deterioration (HVD) is an important concern. We evaluated the association of developing HVD to survival in patients undergoing surgical aortic valve replacement (SAVR). MethodsThe individuals undergoing isolated SAVR and serial echocardiography exams (interval >30 d) were included in this study. HVD was defined as mean pressure gradient ≥ 20 mmHg, mean pressure gradient ≥10 mmHg higher than in the baseline exam, or more than moderate regurgitation on Doppler echocardiography (moderate and severe grade). A time-dependent Cox proportional hazard model was used for this study. ResultsA total of 631 patients were included. The mean age was 71.8 ± 6.1 y old (female: 53.6%). HVD was found in 259 patients (41%) during echocardiographic follow-up (mean 3.3 ± 3.0 y). Patient-prosthetic mismatch was found in 174 patients. One hundred and twenty-six patients died during follow-up (median 62.1 mo, interquartile range 31.1-96.8). The development of HVD was an independent risk factor for death during follow-up (P = 0.038, hazard ratio 1.46, 95% confidential interval: 1.02-2.08). ConclusionsHVD was common after bioprosthetic SAVR during mid-term follow-up. Developing HVD, including moderate and severe grades, was associated with a poor survival rate compared with patients without HVD.

Bloodstream infection and ventilator-associated pneumonia in patients with coronavirus disease 2019 (COVID-19) supported by extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) has been widely used in the care of patients with respiratory failure from coronavirus disease 2019 (COVID-19). We characterized bloodstream infections (BSIs) and ventilator-associated pneumonias (VAPs) in COVID-19 patients supported with ECMO, and we investigated their impact on patient outcomes. Retrospective cohort study from March 1, 2020, to June 30, 2021. Academic tertiary-care referral center. Consecutive adult patients admitted for COVID-19 who received ECMO. We identified BSIs and VAPs and described their epidemiology and microbiology. Cumulative antimicrobial use and the specific management of BSIs were determined. Multivariate time-dependent Cox proportional hazards models were constructed to evaluate the impact of BSIs and VAPs on mortality, controlling for age, receipt of COVID-19-specific therapeutics, and new renal replacement therapy. We identified 136 patients who received ECMO for COVID-19 pneumonia during the study period. BSIs and VAPs occurred in 81 patients (59.6%) and 93 patients (68.4%), respectively. The incidence of BSIs was 29.5 per 1,000 ECMO days and increased with duration of ECMO cannulation. Enterococci, Enterobacterales, and Staphylococcus aureus were the most common causes of BSIs, whereas S. aureus, Klebsiella species, and Pseudomonas aeruginosa comprised the majority of VAPs. Mean antibiotic use comprised 1,031 days of therapy per 1,000 ECMO days (SD, 496). We did not detect an association between BSIs or VAPs and mortality. BSIs and VAPs are common in COVID-19 ECMO-supported patients. Efforts to optimize their diagnosis, prevention, and management should be prioritized.

Associations of Health-Related Quality of Life and Sleep Disturbance With Cardiovascular Disease Risk in Postmenopausal Breast Cancer Survivors.

Breast cancer (BC) survivors are at an increased risk of long-term cardiovascular disease (CVD), often attributed to cancer treatment. However, cancer treatment may also negatively impact health-related quality of life (HRQoL), a risk factor of CVD in the general population. We examined whether sleep disturbance, and physical or mental HRQoL were associated with CVD risk in BC survivors. We conducted a longitudinal analysis in the Women's Health Initiative of postmenopausal women given a diagnosis of invasive BC during follow-up through 2010 with no history of CVD before BC. The primary outcome was incident CVD, defined as physician-adjudicated coronary heart disease or stroke, after BC. Physical and mental HRQoL, measured by the Short-Form 36 Physical and Mental Component Summary scores, and sleep disturbance, measured by the Women's Health Initiative Insomnia Rating Scale, were recorded post BC. Time-dependent Cox proportional hazards models were used starting at BC diagnosis until 2010 or censoring and adjusted for relevant confounders. In 2884 BC survivors, 157 developed CVD during a median follow-up of 9.5 years. After adjustment, higher Physical Component Summary scores were significantly associated with a lower risk of CVD (hazard ratio, 0.90 [95% confidence interval, 0.81-0.99]; per 5-point increment in Physical Component Summary). No associations with CVD were found for Mental Component Summary or Insomnia Rating Scale. In BC survivors, poor physical HRQoL is a significant predictor of CVD. Our findings highlight the importance for nurses to assess and promote physical HRQoL as part of a holistic approach to mitigating the risk of CVD in BC survivors.

Serum Bicarbonate and Graft and Patient Outcomes Among Kidney Transplant Recipients: A Retrospective Cohort Study Evaluating Changes in Serum Bicarbonate Over Time

Identification of treatable risk factors for kidney allograft failure is necessary to improve graft longevity. Metabolic acidosis with either low serum bicarbonate or normal serum bicarbonate (eubicarbonatemic metabolic acidosis) is implicated in native kidney disease progression but its effects in kidney transplant recipients are unclear. Retrospective cohort study. An Integrated Claims-Clinical dataset of US patients with chronic kidney disease (estimated glomerular filtration rates<60mL/min/1.73m2) and serum bicarbonate data were used to generate a cohort of kidney transplant recipients with data from≥1 year before and after transplantation. The primary independent variable was a change in serum bicarbonate from baseline. The primary outcomes were graft failure and all-cause mortality. The secondary outcomes were major adverse cardiac events and all-cause hospitalization. We used adjusted time-dependent Cox proportional hazards models to assess the risk of graft failure, all-cause mortality, major adverse cardiac events, and time to first hospitalization. In this US community-based cohort of 1,915 kidney transplant recipients with a median follow-up of ∼2.5 years, each 1-mEq/L increase in serum bicarbonate was associated with significantly lower hazard of graft loss, death, major adverse cardiac events, and hospitalization by 10%, 8%, 4%, and 8%, respectively. Possible residual confounding. In a US community-based population of kidney transplant recipients, even small incremental increases in serum bicarbonate (1 mEq/L) were significantly associated with reduced hazard of graft loss, all-cause mortality, cardiovascular events, and hospitalization. Interventional trials evaluating the potential benefits of treating metabolic acidosis in kidney transplant recipients are warranted.

Target phosphate and calcium levels in patients undergoing hemodialysis: a post-hoc analysis of the LANDMARK study.

It is necessary to re-examine the optimal phosphate (P) and calcium (Ca) target values in the contemporary management of chronic kidney disease-mineral and bone disorder to reduce the risks of cardiovascular events in patients receiving hemodialysis. We performed a post-hoc analysis of the LANDMARK study. The outcomes were defined as cardiovascular events and all-cause death. Data from 2135 patients receiving hemodialysis at risk of vascular calcification were analyzed using a time-dependent Cox proportional hazard model adjusted for background factors. On the hazard ratio (HR) curve, the ranges where the lower 95% confidence interval (CI) were below the minimum of HR (= 1.00) were as follows: P = 3.5-5.5mg/dL; albumin-adjusted Ca < 9.1mg/dL for cardiovascular events; and P = 3.6-5.3mg/dL; albumin-adjusted Ca < 9.1mg/dL for all-cause mortality. In stratified analysis, the HRs for cardiovascular events in P < 3.5mg/dL and P ≥ 5.5mg/dL were similar to that of P = 3.5-5.5mg/dL (P ≥ 0.05), and albumin-adjusted Ca ≥ 9.1mg/dL had higher HR than values < 9.1mg/dL [1.30 (95% CI 1.00-1.68; P = 0.046)]. For all-cause mortality, the HR in P < 3.6mg/dL was higher than that in P = 3.6-5.3mg/dL [1.76 (95% CI 1.25-2.48; P = 0.001)], while the HRs between P ≥ 5.3mg/dL and P = 3.6-5.3mg/dL as well as those between albumin-adjusted Ca ≥ 9.1 and < 9.1mg/dL were not significantly different (P ≥ 0.05). Managing albumin-adjusted Ca < 9.1mg/dL may reduce the cardiovascular risk among patients undergoing hemodialysis. Hypophosphatemia < 3.6mg/dL may be associated with mortality.

Clinical significance of time-varying on-treatment platelet reactivity after percutaneous coronary intervention

Abstract Objectives This study aimed to determine the prognostic value of serial measurement of platelet reactivity (PR) using the VerifyNow, P2Y12 reaction unit (PRU) assay following percutaneous coronary intervention (PCI) during antiplatelet therapy. Background On-treatment PR changes over time, but the prognostic value of serial PR measurements has not been defined. Methods We enrolled 3204 patients who had PCI and who were measured at PCI and 1 month. We constructed regular and time-dependent Cox proportional hazard models to compare the prognostic value between baseline and serial FU of PR on a primary endpoint of cardiovascular death, myocardial infarction (MI) or stroke over a three-year period. Results Time-varying PR and baseline PR were both associated with an increased risk of the primary endpoint, but the duration of association with primary endpoint differed. The prognostic value of time-varying PR (adjusted hazard ratio (HR) 1.008, 95% confidence interval (CI) 1.005–1.011, p=0.001) was rapidly decreased until 3 month and no prognostic value of time-varying PR after 3 month (adjusted HR 0.999, 95% CI 0.997–1.002, p=0.683). Baseline PR was associated with an increased risk of primary endpoint upto 1 year (adjusted HR 1.005, 95% CI 1.003–1.008, p&amp;lt;0.001) and no prognostic value of baseline PR after 1 year (adjusted HR 0.999, 95% CI 0.997–1.002, p=0.827) was not noted, which showed more slow reduction of the prognostic value of baseline PR. Conclusions Time-varying on-treatment PR reflects more real-world clinical practice. The prognostic value of PR decreased rapidly after PCI and we have to be cautious to use of single time point for the prediction of clinical event using on-treatment PR. Funding Acknowledgement Type of funding sources: None.

Fractures and long-term mortality in cancer patients: a population-based cohort study.

Currently, there are no population-based data among cancer patients on post-fracture mortality risk across a broad range of cancer diagnoses. Our objective was to estimate the association of fracture with mortality in cancer survivors. Using Manitoba Cancer Registry data from the province of Manitoba, Canada, we identified all women and men with cancer diagnosed between January 1, 1987, and March 31, 2014. We then linked cancer data to provincial healthcare administrative data and ascertained fractures after cancer diagnosis and mortality to March 31, 2015. Hazard ratios for all-cause mortality in those with versus without fracture were estimated from time-dependent Cox proportional hazards models adjusted for multiple covariates. The study cohort consisted of 122,045 cancer patients (median age 68years, IQR 58-77, 49.2% female). During the median follow-up of 5.8years from cancer diagnosis, we ascertained 7120 (5.8%) major fractures. All fracture sites, except for the forearm, were associated with increased mortality risk, even after multivariable adjustment. Excess mortality risk associated with a major fracture was greatest in the first year after fracture (HR 2.42, 95% CI 2.30-2.54) and remained significant > 5years after fracture (HR 1.60, 95% CI 1.50-1.70) and for fractures occurring > 10years after cancer diagnosis (HR 1.93, 95% CI 1.79-2.07). Fractures among cancer patients are associated with increased all-cause mortality. This excess risk is greatest in the first year and persists more than 5years post-fracture; increased risk is also noted for fractures occurring up to and beyond 10years after cancer diagnosis.

Association of menopausal hormone therapy with gastric and colorectal cancer risks in Korean women: A nationwide population-based cohort study

BackgroundMenopausal hormone therapy (MHT) has been associated with a decreased risk of gastric cancer (GC) and colorectal cancer (CRC); however, few studies have been conducted in diverse ethnic groups, particularly in the Asian population. Therefore, the current study evaluated if MHT is inversely associated with GC and CRC in East Asia using a representative population-based study in Korea. MethodsThis retrospective cohort study was conducted using the National Health Insurance Service–National Sample Cohort 2.0 in South Korea from 2002 to 2015. A total of 196,095 women aged ≥40 years were included in the study. The numbers of participants who did and did not use MHT were 19,063 (9.7 %) and 177,032 (90.3 %), respectively. Hazard ratios (HRs) and the corresponding 95 % confidence intervals (CIs) were estimated using a time-dependent Cox proportional hazards model. Age was considered as a time scale, and other confounding factors, including income levels based on insurance premiums, region of residence, and comorbidities, were included in the multivariable-adjusted model. ResultsThe total number of incident cases of GC and CRC were 1339 (0.68 %) and 1428 (0.73 %), respectively. We observed an inverse association of the use of estrogen replacement therapy (ERT; estrogen-containing therapy regardless of other regimen types) with GC [HR (95 % CI):0.68 (0.51–0.90)], CRC [0.57 (0.42–0.78)] and gastrointestinal cancer [GI, 0.63 (0.51–0.77)]. In the analyses by CRC subsite, the risks of both colon and rectal cancers were associated with ERT. In addition, both estrogen and combined estrogen and progestogen regimens were significantly associated with CRC and GI cancer. ConclusionERT was associated with a decreased risk of GC and CRC. Our findings support the protective effect of estrogen against GC and CRC in Korean women.