Propensity weighting plus adjustment in proportional hazards model is not doubly robust.

Recently, it has become common for applied works to combine commonly used survival analysis modeling methods, such as the multivariable Cox model and propensity score weighting, with the intention of forming a doubly robust estimator of an exposure effect hazard ratio that is unbiased in large samples when either the Cox model or the propensity score model is correctly specified. This combination does not, in general, produce a doubly robust estimator, even after regression standardization, when there is truly a causal effect. We demonstrate via simulation this lack of double robustness for the semiparametric Cox model, the Weibull proportional hazards model, and a simple proportional hazards flexible parametric model, with both the latter models fit via maximum likelihood. We provide a novel proof that the combination of propensity score weighting and a proportional hazards survival model, fit either via full or partial likelihood, is consistent under the null of no causal effect of the exposure on the outcome under particular censoring mechanisms if either the propensity score or the outcome model is correctly specified and contains all confounders. Given our results suggesting that double robustness only exists under the null, we outline 2 simple alternative estimators that are doubly robust for the survival difference at a given time point (in the above sense), provided the censoring mechanism can be correctly modeled, and one doubly robust method of estimation for the full survival curve. We provide R code to use these estimators for estimation and inference in the supporting information.

Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark.

BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Efficacy and safety of oral anticoagulants according to kidney function among patients with atrial fibrillation.

BACKGROUND AND AIMS: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on the safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate the safety and efficacy of the DOACs across subgroups of kidney function. METHODS: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding. RESULTS: Among 26 686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73 m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73 m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (P-value interaction >0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to vitamin K antagonists (VKA) [hazard ratio 0.79, 95% confidence interval (CI) 0.67-0.93], and the risk difference was significantly larger among patients with reduced kidney function (P-value interaction 0.018). Rivaroxaban was associated with a higher risk of bleeding compared to apixaban (hazard ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73 m2. CONCLUSIONS: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban to VKA among patients with eGFR 15-30 mL/min/1.73 m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73 m2.

Exploring the potential use of platelet rich plasma (PRP) from adult and umbilical cord blood in murine follicle culture.

Ovarian follicle culture is a powerful tool to study follicular physiology and has potential applications in clinical and commercial settings. Despite remarkable progress, recreating folliculogenesis in vitro remains challenging for many mammalian species. This study investigates the impact of platelet-rich plasma (PRP) derived from adult blood (human platelet lysate, hPL) and umbilical cord blood (Umbilical cord plasma, UCP) on murine pre-antral follicle culture and oocyte maturation. Pre-antral follicles were cultured individually for 10 days with fetal bovine serum (FBS) serving as the control and two PRP sources (hPL and UCP) and their activated forms (Ac-hPL and Ac-UCP). The results suggest that neither hPL nor UCP, regardless of activation status, improved follicle culture outcomes compared to FBS. Interestingly, activation did not significantly impact the main functional outcomes such as maturation rates, survival, and growth. Oestradiol secretion and oocyte diameter, often considered hallmarks of follicle quality, did not show significant differences between matured and non-matured oocytes across the treatment groups. However, gene expression analysis revealed a significant upregulation of Gdf-9 and Bmp-15 mRNA levels in oocytes from the Ac-UCP group, regardless of maturation stage, suggesting that the accumulation of the mRNA could be due to potential challenges in translation in the Ac-UCP group. In conclusion, this study challenges the hypothesis that PRP, as a serum source, could improve follicle culture outcomes compared to FBS, the gold standard in murine follicle culture. Further research is needed to understand the species-specific effects of PRP and explore other potential factors affecting follicle culture and oocyte quality.

Incidence of depression in patients with cardiovascular disease and type 2 diabetes: a nationwide cohort study.

BACKGROUND: Estimating how type 2 diabetes (T2D) affects the rate of depression in cardiovascular disease (CVD) can help identify high-risk patients. The aim is to investigate how T2D affects the rate of depression according to specific subtypes of CVD. METHODS: Incident CVD patients, free of psychiatric disease, with and without T2D, were included from nationwide registries between 2010 and 2020. We followed patients from CVD diagnosis until the first occurrence of depression, emigration, death, 5 years, or end of study (December 31, 2021). We used time-dependent Poisson regression to estimate the incidence rates and rate ratios (IRR) of depression following subtypes of CVD with and without T2D. The model included age, sex, comorbidities, calendar year, T2D duration, educational level, and living situation as covariates. RESULTS: A total of 165,096 patients were included; 45,845 had a myocardial infarction (MI), 63,691 had a stroke, 19,959 had peripheral artery disease (PAD), 35,568 had heart failure (HF), and 979 were diagnosed with 2 or more CVD subtypes (= > 2 CVD's). Baseline T2D in each CVD subtype ranged from 11 to 17%. The crude incidence rate of depression per 1000 person-years (95% confidence intervals) was: MI + T2D: 131.1 (109.6;155.6), MI: 82.1 (65.3;101.9), stroke + T2D: 287.4 (255.1;322.6), stroke: 222.4(194.1;253.6), PAD + T2D: 173.6 (148.7;201.4), PAD:137.5 (115.5;162.5), HF + T2D: 244.3 (214.6;276.9), HF: 199.2 (172.5;228.9), = > 2 CVD's + T2D: 427.7 (388.1;470.2), = > 2 CVD's: 372.1 (335.2;411.9). The adjusted IRR of depression in MI, stroke, PAD, HF, and = > 2 CVD's with T2D compared to those free of T2D was: 1.29 (1.23;1.35), 1.09 (1.06;1.12), 1.18 (1.13;1.24), 1.05 (1.02;1.09), and 1.04 (0.85;1.27) (p-value for interaction < 0.001). CONCLUSION: The presence of T2D increased the rate of depression differently among CVD subtypes, most notable in patients with MI and PAD.

Human platelet lysate improves the growth and survival of cultured human pre-antral follicles.

RESEARCH QUESTION: How do platelet-rich plasma products like human platelet lysate (HPL) and umbilical cord plasma (UCP) affect the growth and survival of isolated human pre-antral follicles in vitro? DESIGN: Human pre-antral follicles (n = 724; mean diameter: 75 µm; range: 46-237 µm) were isolated from ovarian medulla donated by 14 patients undergoing unilateral oophorectomy for ovarian tissue cryopreservation. Follicles were encapsulated in 0.5% alginate and cultured for 8 days in media supplemented with 5% fetal bovine serum (FBS) (n = 171), 2.5% human serum albumin (HSA) (n = 159), 5% HPL (n = 223) or 5% UCP (n = 171). RESULTS: The survival probability was significantly higher in the group supplemented with HPL (80%) compared with the other three groups: FBS (54%, P < 0.001); HSA (63%, P = 0.004) and UCP (29%, P < 0.001). Surviving follicles in the UCP group had less defined follicular membranes and decompacted granulosa cell layers. The median growth of surviving follicles was significantly (P < 0.001) larger in the HPL group (73 µm) compared with any of the other three groups: HSA (43 µm); FBS (40 µm) UCP (54 µm). A descriptive analysis of follicular secretion of anti-Müllerian hormone and oestradiol did not reveal any difference between the groups. The detectability of follicular genes was high for AR (100%), AMHR2 (100%) and FSHR (76%), whereas few follicles expressed LHR (20%). CONCLUSION: Human platelet lysate significantly improved survival and growth of cultured human pre-antral follicles compared with FBS, HSA and UCP. The use of HPL is a valuable improvement to culture human pre-antral follicles but further studies will have to prove whether the superiority of HPL translates into better quality oocytes.

Post-prandial secretion of glucagon-like peptide-2 (GLP-2) after carbohydrate-, fat- or protein enriched meals in healthy subjects.

Glucagon-like peptide 2 (GLP-2) is an important regulator of intestinal growth and function. In adherable mixed meals the macronutrient composition with the best potential for stimulating GLP-2 secretion is not known. We compared the effect of 3 iso-energetic meals, where approximately 60 % of the energy ratio was provided as either carbohydrate, fat, or protein, respectively, on the post-prandial endogenous GLP-2 secretion. The responses were compared to secretion profiles of peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP). Ten healthy subjects were admitted on three occasions, at least a week apart, after a night of fasting. In an open-label, crossover design, they were randomized to receive a high carbohydrate (HC), high fat (HF) or high protein (HP) meal. The meals were approximately ∼3.9 MJ. Venous blood was collected for 240 min, and plasma concentrations of GLP-2, GIP and PYY were measured with specific radioimmunoassays. Mean GLP-2 levels peaked already at 30 min for the HC meal, however the HP meal induced the highest mean GLP-2 peaking levels, resulting in significantly higher mean GLP-2 area under the curve (AUC) from baseline of 7279 pmol*min/L, 95 %-CI [6081;8477] compared to the HC meal: 4764 pmol*min/L, 95 %-CI [3498;6029], p = 0.020 and the HF meal: 4796 pmol*min/L, [3385;6207], p = 0.011. Findings were similar for the PYY. The HC meal provided a greater AUC for GIP compared to the HP- and HF meals. The HP meal was most effective with respect to stimulation of the postprandial GLP-2 and PYY secretion, whereas the HC meal was more effective for GIP.

Treated periodontitis and recurrent events after first-time myocardial infarction: A Danish nationwide cohort study.

AIM: To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI). MATERIALS AND METHODS: From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE). RESULTS: A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92-1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42-1.52]), cardiovascular death (OR 1.71 [95% CI 1.64-1.78]) and heart failure (OR 1.13 [95% CI 1.07-1.20]) compared with patients presumed periodontally healthy. CONCLUSIONS: Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events.

Transplantation of initially rejected donor lungs using ex vivo lung perfusion: A 5-year experience.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a method for the evaluation and reconditioning of high-risk donor lungs to increase the pool of potential donor lungs. METHODS: We reviewed all consecutive patients who received lung transplants from May 2012 to May 2017 with follow-up until July 2021. EVLP was used in lungs initially rejected due to inadequate oxygenation but without other contraindications. Lungs with improved oxygenation levels above the threshold were transplanted. The primary endpoint was the time to graft failure, which was defined as the time from surgery to death or re-transplantation, whichever occurred first. The secondary outcome was freedom from chronic lung allograft dysfunction. RESULTS: A total of 157 patients underwent transplantation during the study period. Thirty-nine patients received EVLP-treated donor lungs. Restricted mean graft survival time up to 7 years is 5.14 years for non-EVLP and 4.19 for EVLP, the difference being -0.95 (confidence interval [CI]-1.93 to 0.04, p = .059). The hazard ratio is 1.66 (CI 1.00-2.75, p = .046). Chronic lung allograft dysfunction was the highest contributor to mortality in both groups. There were significant differences in freedom from chronic lung allograft dysfunction at 12 and 24 months of follow-up (p = .005 and p = .030, respectively). Subgroup analyses revealed that the first patients who received EVLP in 2012-2013 had a substantially worse 5-year graft survival than those who received EVLP more recently in 2016-2017 (14.3% vs. 60.0%). For the latter, the 5-year graft survival was observed to be remarkably close to the non-EVLP group (60.8%). CONCLUSION: Long-term survival was significantly lower, and lung function was poorer among recipients in the EVLP group than in the non-EVLP group. However, the outcome of patients who received EVLP-treated lungs was observed to improve steadily after the first 2 years after EVLP was introduced in Denmark.

Clinical cardiovascular phenotypes and the pattern of future events in patients with type 2 diabetes.

IMPORTANCE: Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events. OBJECTIVE: We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease. DESIGN, SETTING AND PARTICIPANTS: Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death. MAIN OUTCOMES AND MEASURES: The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and  new-onset cardiovascular disease. RESULTS: Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4). CONCLUSIONS: In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events.

On logistic regression with right censored data, with or without competing risks, and its use for estimating treatment effects.

Simple logistic regression can be adapted to deal with right-censoring by inverse probability of censoring weighting (IPCW). We here compare two such IPCW approaches, one based on weighting the outcome, the other based on weighting the estimating equations. We study the large sample properties of the two approaches and show that which of the two weighting methods is the most efficient depends on the censoring distribution. We show by theoretical computations that the methods can be surprisingly different in realistic settings. We further show how to use the two weighting approaches for logistic regression to estimate causal treatment effects, for both observational studies and randomized clinical trials (RCT). Several estimators for observational studies are compared and we present an application to registry data. We also revisit interesting robustness properties of logistic regression in the context of RCTs, with a particular focus on the IPCW weighting. We find that these robustness properties still hold when the censoring weights are correctly specified, but not necessarily otherwise.

Acute kidney injury and risk of cardiovascular outcomes: A nationwide cohort study.

BACKGROUND: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI. METHODS: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age <50 years, estimated glomerular filtration rate (eGFR) <15ml/min/1.73m2, renal transplantation, index-admission due to cardiovascular disease or death during index-admission. The primary outcome was cardiovascular risk within one year from discharge, which was a composite of the secondary outcomes ischemic heart disease, heart failure or stroke. To estimate risks, we applied multiple logistic regression fitted by inverse probability of censoring weighting and stratified estimations by eGFR and age. We adjusted for proteinuria in the subcohort with measurements available. RESULTS: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m2, respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria. CONCLUSION: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not only due to heart failure, independent of age and eGFR.

Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease : A Case-Crossover Study.

BACKGROUND: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. OBJECTIVE: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors. DESIGN: Case-crossover design. SETTING: Nationwide study of Danish patients from 2000 to 2018. PATIENTS: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors. MEASUREMENTS: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event. RESULTS: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome). LIMITATION: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use. CONCLUSION: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified. PRIMARY FUNDING SOURCE: Ib Mogens Kristiansens Almene Fond and Helsefonden.

Derivation and validation of the Rapid Assessment of Dementia Risk (RADaR) for older adults.

BACKGROUND: There is no practical dementia risk score in the clinical setting. OBJECTIVE: To derive and validate a score obtained by a rapid and simple assessment, which guides primary care providers in predicting the risk of dementia among older adults. DESIGN: A total of 4178 participants from three longitudinal cohorts (mean age at baseline = 76.8 [SD = 7.6] years), without baseline dementia, followed annually for a median of 10 years (IQR: 5 to16 years, Reverse Kaplan-Meier). PARTICIPANTS: To derive the score, we used data from 1,780 participants from the Rush Memory and Aging Project (93% White). To validate the score, we used data from 1,299 participants from the Religious Order Study (92% White), and to assess generalizability, 679 participants from the Minority Aging Research Study (100% Black). MEASUREMENTS: Clinician-based dementia diagnosis at any time after baseline and predictive variables associated with dementia risk that can be collected in a primary care setting: demographics, clinical indicators, medical history, memory complaints, cognitive and motor tests, and questions to assess functional disability, depressive symptoms, sleep, social isolation, and genetics (APOE e4 and AD polygenic risk score). RESULTS: At baseline, age, memory complaint, the ability to handle finances, the recall of the month, recall of the room, and recall of three words, were associated with the cumulative incidence of dementia, in the derivation cohort. The discrimination of the RADaR (Rapid Risk Assessment of Dementia) was good for the derivation and external-validation cohorts (AUC3 years = 0.82-0.86), compared to the overall discrimination of age alone (AUC3 years = 0.73), a major risk factor for dementia. Adding genetic data did not increase discrimination. LIMITATIONS: Participants were volunteers, may not represent the general population. CONCLUSIONS: The RADaR, derived from community-dwelling older persons, is a brief and valid tool to predict dementia risk at 3 years in older White and Black persons.

The burden of cardiovascular outcomes in heart failure patients with new-onset, prevalent, and without type 2 diabetes.

BACKGROUND: The prognostic importance of new-onset type 2 diabetes (T2D) in heart failure (HF) remains unknown. We aimed to describe the cardiovascular outcome profile in HF patients with new-onset, no and prevalent T2D. METHODS: We constructed a cohort of patients with first HF admission between 1998 and 2016 from nationwide Danish registers. Outcomes were ischemic event, HF event, and death from other causes. The landmarking approach and the Aalen Johansen estimator were used together to estimate 5-year absolute and 5-year relative risk of the outcomes in HF patients with new-onset, no and prevalent T2D. Risk among subgroups were investigated by stratification. RESULTS: A total of 139 264 HF patients were included between 1998 and 2016, of which 29 078 patients had prevalent T2D. A total of 11 819 developed new-onset T2D. The 5-year risks of ischemic event in new-onset, no, and prevalent T2D were: 17.9% [17.2; 18.6], 18.8% [18.6; 19.0], and 26.1% [25.6; 26.7]. The 5-year risks of HF event were: 31.5% [30.6; 32.3], 30.7% [30.5; 31.0], and 33.6% [33.0; 34.2]. For other causes of death, the 5-year risks were: 20.9% [20.2; 21.7], 18.6% [18.4; 18.8], and 18.9% [18.4; 19.3]. The 5-year risk ratios of HF event or death from other causes versus ischemic event were: 2.9 [2.8; 3.1], 2.6 [2.6; 2.7], and 2.0 [2.0; 2.1] in patients with new-onset, no, and prevalent T2D. CONCLUSIONS: In patients with new-onset T2D, death from other causes were more likely to occur than an ischemic event, whereas in patients with prevalent T2D and no T2D, ischemic events were more common.

Bleeding Risk Following Systemic Fluconazole or Topical Azoles in Patients with Atrial Fibrillation on Apixaban, Rivaroxaban, or Dabigatran.

BACKGROUND: Bleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban, or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations. METHODS: Using nationwide Danish registers, we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban, or dabigatran from 2012-2018. We investigated associations between bleeding incidents and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We included 32,340 (36%), 32,409 (36%), and 24,940 (28%) patients initiated on apixaban, rivaroxaban, and dabigatran, respectively. Patients on apixaban were older (median age: 77 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively. CONCLUSION: In patients with atrial fibrillation on either apixaban, rivaroxaban, or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.

A closed max-t test for multiple comparisons of areas under the ROC curve.

Comparing areas under the ROC curve (AUCs) is a popular approach to compare prognostic biomarkers. The aim of this paper is to present an efficient method to control the family-wise error rate when multiple comparisons are performed. We suggest to combine the max-t test and the closed testing procedures. We build on previous work on asymptotic results for ROC curves and on general multiple testing methods to efficiently take into account both the correlations between the test statistics and the logical constraints between the null hypotheses. The proposed method results in an uniformly more powerful procedure than both the single-step max-t test procedure and popular stepwise extensions of the Bonferroni procedure, such as Bonferroni-Holm. As demonstrated in this paper, the method can be applied in most usual contexts, including the time-dependent context with right censored data. We show how the method works in practice through a motivating example where we compare several psychometric scores to predict the t-year risk of Alzheimer's disease. The example illustrates several multiple testing settings and demonstrates the advantage of using the proposed methods over common alternatives. R code has been made available to facilitate the use of the methods by others.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.