Lifetime risk of comorbidity in patients with simple congenital heart disease: a Danish nationwide study.

AIMS: In a continuously ageing population of patients with congenital heart disease (CHD), understanding the long-term risk of morbidity is crucial. The aim of this study was to compare the lifetime risks of developing comorbidities in patients with simple CHD and matched controls. METHODS AND RESULTS: Using the Danish nationwide registers spanning from 1977 to 2018, simple CHD cases were defined as isolated atrial septal defect (ASD), ventricular septal defect (VSD), pulmonary stenosis, or patent ductus arteriosus in patients surviving until at least 5 years of age. There were 10 controls identified per case. Reported were absolute lifetime risks and lifetime risk differences (between patients with simple CHD and controls) of incident comorbidities stratified by groups and specific cardiovascular comorbidities. Of the included 17 157 individuals with simple CHD, the largest subgroups were ASD (37.7%) and VSD (33.9%), and 52% were females. The median follow-up time for patients with CHD was 21.2 years (interquartile range: 9.4-39.0) and for controls, 19.8 years (9.0-37.0). The lifetime risks for the investigated comorbidities were higher and appeared overall at younger ages for simple CHD compared with controls, except for neoplasms and chronic kidney disease. The lifetime risk difference among the comorbidity groups was highest for neurological disease (male: 15.2%, female: 11.3%), pulmonary disease (male: 9.1%, female: 11.7%), and among the specific comorbidities for stroke (male: 18.9%, female: 11.4%). The overall risk of stroke in patients with simple CHD was mainly driven by ASD (male: 28.9%, female: 17.5%), while the risks of myocardial infarction and heart failure were driven by VSD. The associated lifetime risks of stroke, myocardial infarction, and heart failure in both sexes were smaller in invasively treated patients compared with untreated patients with simple CHD. CONCLUSION: Patients with simple CHD had increased lifetime risks of all comorbidities compared with matched controls, except for neoplasms and chronic kidney disease. These findings highlight the need for increased attention towards early management of comorbidity risk factors.

Risk of ankylosis of avulsed teeth immediately replanted or stored under favorable storage conditions before replantation: A long-term clinical study.

BACKGROUND/AIM: There are few long-term clinical follow-up studies on human teeth replanted immediately or after storage in a suitable storage medium prior to replantation. This study aimed to assess the risk of ankylosis in avulsed human teeth replanted immediately or after storage in physiological media for a short time. MATERIAL: Data from 116 patients with 145 replanted avulsed permanent teeth were selected from a comprehensive dental trauma database in Copenhagen University Hospital. The following teeth were selected: Group 1 comprised 36 teeth replanted immediately (dry time <6 min; wet time <6 min). Group 2 comprised 61 teeth replanted after physiologic storage media (saliva and saline) (dry time <6 min; wet time >5 min; wet time ranged from 7 to 170 min, and mean wet time was 59 min). Group 3 (control) included 48 teeth replanted after dry storage (dry time > 60 min). METHOD: Clinical and radiographic registrations were carried out according to a standardized protocol; follow-up ranged from 7 months to 23 years. Ankylosis was diagnosed by percussion test and radiographs and related to the conditions prior to replantation and stage of root development. RESULTS: The overall risk of ankylosis was 17.2% [95% CI: 4.61; 29.79] for immediately replanted teeth, 55.3% [95% CI: 42.54; 68.00] for teeth stored in physiologic media before replantation, and 85.7% [95% CI: 75.70; 95.73] for teeth stored dry more than 1 h. Mature teeth showed a significantly higher risk of ankylosis than immature teeth. CONCLUSION: This clinical long-term study has verified earlier experimental studies showing that immediate reimplantation has the lowest risk of ankylosis. Physiologic storage media are good alternatives that also reduce the risk of ankylosis compared to dry storage, where ankylosis is more likely although not always seen. Mature teeth are significantly more likely to develop ankylosis.

Estimation of separable direct and indirect effects in a continuous-time illness-death model.

In this article we study the effect of a baseline exposure on a terminal time-to-event outcome either directly or mediated by the illness state of a continuous-time illness-death process with baseline covariates. We propose a definition of the corresponding direct and indirect effects using the concept of separable (interventionist) effects (Robins and Richardson in Causality and psychopathology: finding the determinants of disorders and their cures, Oxford University Press, 2011; Robins et al. in arXiv:2008.06019 , 2021; Stensrud et al. in J Am Stat Assoc 117:175-183, 2022). Our proposal generalizes Martinussen and Stensrud (Biometrics 79:127-139, 2023) who consider similar causal estimands for disentangling the causal treatment effects on the event of interest and competing events in the standard continuous-time competing risk model. Unlike natural direct and indirect effects (Robins and Greenland in Epidemiology 3:143-155, 1992; Pearl in Proceedings of the seventeenth conference on uncertainty in artificial intelligence, Morgan Kaufmann, 2001) which are usually defined through manipulations of the mediator independently of the exposure (so-called cross-world interventions), separable direct and indirect effects are defined through interventions on different components of the exposure that exert their effects through distinct causal mechanisms. This approach allows us to define meaningful mediation targets even though the mediating event is truncated by the terminal event. We present the conditions for identifiability, which include some arguably restrictive structural assumptions on the treatment mechanism, and discuss when such assumptions are valid. The identifying functionals are used to construct plug-in estimators for the separable direct and indirect effects. We also present multiply robust and asymptotically efficient estimators based on the efficient influence functions. We verify the theoretical properties of the estimators in a simulation study, and we demonstrate the use of the estimators using data from a Danish registry study.

Ranking of average treatment effects with generalized random forests for time-to-event outcomes.

Linkage between drug claims data and clinical outcome allows a data-driven experimental approach to drug repurposing. We develop an estimation procedure based on generalized random forests for estimation of time-point specific average treatment effects in a time-to-event setting with competing risks. To handle right-censoring, we propose a two-step procedure for estimation, applying inverse probability weighting to construct time-point specific weighted outcomes as input for the generalized random forest. The generalized random forests adaptively handle covariate effects on the treatment assignment by applying a splitting rule that targets a causal parameter. Using simulated data we demonstrate that the method is effective for a causal search through a list of treatments to be ranked according to the magnitude of their effect on clinical outcome. We illustrate the method using the Danish national health registries where it is of interest to discover drugs with an unexpected protective effect against relapse of severe depression.

Glycated haemoglobin levels among 3295 hospitalized COVID-19 patients, with and without diabetes, and risk of severe infection, admission to an intensive care unit and all-cause mortality.

AIM: To determine the risk of adverse outcomes across the spectrum of glycated haemoglobin (HbA1c) levels among hospitalized COVID-19 patients with and without diabetes. MATERIALS AND METHODS: Danish nationwide registries were used to study the association between HbA1c levels and 30-day risk of all-cause mortality and the composite of severe COVID-19 infection, intensive care unit (ICU) admission and all-cause mortality. The study population comprised patients hospitalized with COVID-19 (3 March 2020 to 31 December 2020) with a positive polymerase chain reaction (PCR) test and an available HbA1c ≤ 6 months before the first positive PCR test. All patients had at least 30 days of follow-up. Among patients with diabetes, HbA1c was categorized as <48 mmol/mol, 48 to 53 mmol/mol, 54 to 58 mmol/mol, 59 to 64 mmol/mol (reference) and >64 mmol/mol. Among patients without diabetes, HbA1c was stratified into <31 mmol/mol, 31 to 36 mmol/mol (reference), 37 to 41 mmol/mol and 42 to 47 mmol/mol. Thirty-day standardized absolute risks and standardized absolute risk differences are reported. RESULTS: We identified 3295 hospitalized COVID-19 patients with an available HbA1c (56.2% male, median age 73.9 years), of whom 35.8% had diabetes. The median HbA1c was 54 and 37 mmol/mol among patients with and without diabetes, respectively. Among patients with diabetes, the standardized absolute risk difference of the composite outcome was higher with HbA1c < 48 mmol/mol (12.0% [95% confidence interval {CI} 3.3% to 20.8%]) and HbA1c > 64 mmol/mol (15.1% [95% CI 6.2% to 24.0%]), compared with HbA1c 59 to 64 mmol/mol (reference). Among patients without diabetes, the standardized absolute risk difference of the composite outcome was greater with HbA1c < 31 mmol/mol (8.5% [95% CI 0.5% to 16.5%]) and HbA1c 42 to 47 mmol/mol (6.7% [95% CI 1.3% to 12.1%]), compared with HbA1c 31 to 36 mmol/mol (reference). CONCLUSIONS: Patients with COVID-19 and HbA1c < 48 mmol/mol or HbA1c > 64 mmol/mol had a higher associated risk of the composite outcome. Similarly, among patients without diabetes, varying HbA1c levels were associated with higher risk of the composite outcome.

Risk of out-of-hospital cardiac arrest in antidepressant drug users.

Conflicting results have been reported regarding the association between antidepressant use and out-of-hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA. METHODS: We conducted a nationwide nested case-control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time-dependent exposure and time-dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately. RESULTS: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high-dose citalopram (>20 mg) and high-dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27-1.69], HR:1.43 [95% CI:1.16-1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high-dose mirtazapine (>30; HR:1.59 [95% CI:1.18-2.14]) among the serotonin-norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05-1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors. CONCLUSION: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues.

Do changes in frailty, physical functioning, and cognitive functioning predict mortality in old age? Results from the Longitudinal Aging Study Amsterdam.

BACKGROUND: The ability to accurately predict survival in older adults is crucial as it guides clinical decision making. The added value of using various health indicators as well as changes in these indicators for predicting mortality remains unclear. The aim of this study was to investigate whether changes in health indicators such as frailty and physical performance improve mortality predictions in old age. METHODS: This is a population based prospective cohort study on 995 community-dwelling people aged 68-92 years from the Longitudinal Aging Study Amsterdam. Two measurements at a three-year interval (1995/1996 and 1998/1999) were available for the frailty index, frailty phenotype, grip strength, walking speed, and Mini-Mental State Examination (MMSE). Cox regression was used to analyze mortality risks associated with the current health status and changes in health, with mortality data up to 2017. The extent to which these health indicators improved mortality predictions compared to models with age and sex only was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: The AUC of age and sex for five-year mortality was 72.8% (95% CI 69.0 - 76.5) and was the lowest in the oldest old (age > 80.5 years). The added AUC of the current status of health indicators ranged from 0.7 to 3.3%. The added AUC of the three-year change was lower, ranging from -0.0 to 1.1%, whereas the added AUC of three-year change and current status combined was similar to current status alone, ranging from 0.6 to 3.2%. Across age, the added AUC of current status was highest in the oldest old, however there was no such pattern using three-year change. Overall, the frailty index appeared to improve mortality predictions the most, followed by the frailty phenotype, MMSE, grip strength, and walking speed. CONCLUSIONS: Current health status improved mortality predictions better than changes in health. Its contribution was highest in the oldest old, but the added value to models with age and sex only was limited.

All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study.

BACKGROUND: On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures. METHODS AND RESULTS: Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87-0.95; IRR 0.95, 95% CI 0.89-1.02; and IRR 0.87, 95% CI 0.83-0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97-1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88-0.96; out-of-hospital, IRR 1.04, 95% CI1.01-1.08). These trends were consistent irrespective of sex and age. CONCLUSIONS: Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

Association Between Male Sex and Outcomes of Coronavirus Disease 2019 (COVID-19)-A Danish Nationwide, Register-based Study.

BACKGROUND AND OBJECTIVES: Male sex has been associated with severe coronavirus disease 2019 (COVID-19) infection. We examined the association between male sex and severe COVID-19 infection and if an increased risk remains after adjustment for age and comorbidities. METHODS: Nationwide register-based follow-up study of COVID-19 patients in Denmark until 16 May 2020. Average risk ratio comparing 30-day composite outcome of all-cause death, severe COVID-19 diagnosis or intensive care unit (ICU) admission for men versus women standardized to the age and comorbidity distribution of all patients were derived from multivariable Cox regression. Included covariates were age, hypertension, diagnoses including obesity, alcohol, sleep apnea, diabetes, chronic obstructive pulmonary disease, previous myocardial infarction (MI), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral artery disease, cancer, liver, rheumatic, and chronic kidney disease (CKD). RESULTS: Of 4842 COVID-19 patients, 2281 (47.1%) were men. Median age was 57 [25%-75% 43-73] for men versus 52 [38-71] for women (P < .001); however, octogenarians had equal sex distribution. Alcohol diagnosis, diabetes, hypertension, sleep apnea, prior MI and IHD (all P < .001) as well as AF, stroke, and HF (all P = .01) were more often seen in men, and so was CKD (P = .03). Obesity diagnosis (P < .001) were more often seen in women. Other comorbidity differences were insignificant (P > .05). The fully adjusted average risk ratio was 1.63 [95% CI, 1.44-1.84]. CONCLUSIONS: Men with COVID-19 infection have >50% higher risk of all-cause death, severe COVID-19 infection, or ICU admission than women. The excess risk was not explained by age and comorbidities.

Dabigatran and the Risk of Staphylococcus aureus Bacteremia: A Nationwide Cohort Study.

BACKGROUND: Treatment with dabigatran, an oral direct thrombin inhibitor, reduces the virulence of Staphylococcus aureus in in vitro and in vivo models. However, it remains to be determined whether dabigatran reduces the risk of S. aureus infections in humans. We investigated the incidence rate of S. aureus bacteremia (SAB) in patients with atrial fibrillation treated with the direct thrombin inhibitor dabigatran compared with patients treated with the factor Xa-inhibitors rivaroxaban, apixaban, and edoxaban. METHODS: In this observational cohort study, 112 537 patients with atrial fibrillation who initiated treatment with direct oral anticoagulants (August 2011-December 2017) were identified from Danish nationwide registries. The incidence rates of SAB in patients treated with dabigatran versus patients treated with the factor Xa-inhibitors were examined by multivariable Cox regression accounting for time-dynamic changes in exposure status during follow-up. RESULTS: A total of 112 537 patients were included. During a median follow-up of 2.0 years, 186 patients in the dabigatran group and 356 patients in the factor Xa-inhibitor group were admitted with SAB. The crude incidence rate of SAB was lower in the dabigatran group compared with the factor Xa-inhibitor group (22.8 [95% confidence interval [CI], 19.7-26.3] and 33.8 [95% CI, 30.5-37.6] events per 10 000 person-years, respectively). In adjusted analyses, dabigatran was associated with a significantly lower incidence rate of SAB compared with factor Xa-inhibitors (incidence rate ratio, .76; 95% CI, .63-.93). CONCLUSIONS: Treatment with dabigatran was associated with a significantly lower incidence rate of SAB compared with treatment with factor Xa-inhibitors.

Artificial intelligence grading of breast cancer: a promising method to refine prognostic classification for management precision.

AIM: Artificial intelligence (AI)-based breast cancer grading may help to overcome perceived limitations of human assessment. Here, the potential value of AI grade was evaluated at the molecular level and in predicting patient outcome. METHODS AND RESULTS: A supervised convolutional neural network (CNN) model was trained on images of 612 breast cancers from The Cancer Genome Atlas (TCGA). The test set, obtained from the Cooperative Human Tissue Network (CHTN), comprised 1058 cancers with corresponding survival data. Upon reversal, a CNN was trained from images of 1537 CHTN cancers and tested on 397 TCGA cancers. In TCGA, mRNA models were trained using AI grade and Nottingham grade (NG) as labels. Performance of mRNA models in predicting patient outcome was evaluated using data from 1807 cancers from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. In selecting images for training, nucleolar prominence determined high- versus low-grade cancer cells. In CHTN, NG corresponded to significant survival stratification in stages 1, 2 and 3 cancers, while AI grade showed significance in stages 1 and 2 and borderline in stage 3 tumours. In METABRIC, the mRNA model trained from AI grade was not significantly different to the NG-based model. The gene which best described AI grade was TRIP13, a gene involved with mitotic spindle assembly. CONCLUSION: An AI grade trained from the morphologically distinctive feature of nucleolar prominence could transmit significant patient outcome information across three independent patient cohorts. AI grade shows promise in gene discovery and for second opinions.

Smartphone interactions and mental well-being in young adults: A longitudinal study based on objective high-resolution smartphone data.

Aims: To investigate the effects of objectively measured smartphone interactions on indicators of mental well-being among men and women in a population of young adults. Methods: A total of 816 young adults (mean±SD age 21.6±2.6 years; 77% men) from the Copenhagen Network Study were followed with objective recordings of smartphone interactions from calls, texts and social media. Participants self-reported on loneliness, depressive symptoms and disturbed sleep at baseline and in a four-month (interquartile range 75-163 days) follow-up survey. Multiple linear regression was used to analyse the association between smartphone interactions and mental well-being separately for men and women. Results: A higher number of smartphone interactions was associated with lower levels of loneliness at baseline and the same pattern appeared for depressive symptoms, although this was less pronounced. A high level of smartphone interaction was associated with lower levels of disturbed sleep for men, but not for women. In follow-up analyses, a high versus low level of smartphone interaction was associated with an increase in loneliness and depressive symptoms over time for women, but not for men. Conclusions: Smartphone interactions are related to better mental well-being, which may be attributed to the beneficial effects of an underlying social network. Over time, accommodating a large network via smartphone communication might, however, have negative effects on mental well-being for women.

New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people.

AIM: To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown. METHODS AND RESULTS: Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12). CONCLUSIONS: Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.

The risks of ankylosis of 89 avulsed human teeth stored in saliva prior to replantation-A re-evaluation of a long-term clinical study.

BACKGROUND/AIM: The survival of an avulsed tooth highly depends on the emergency management. The aim of this study was to evaluate the risk of ankylosis for avulsed human teeth stored in saliva preceded by various dry storage conditions prior to replantation. MATERIAL AND METHODS: Data include 74 patients (54 male and 20 female) with 89 avulsed and replanted teeth (16 immature teeth, 73 mature teeth). Patient ages ranged from 6 to 36 years (median: 13.0 years). All teeth were stored in saliva before replantation. Treatment and follow-up were performed according to a standardized procedure. Follow-up periods ranged from 7 months to 20 years (mean 5.3 years). The risk of ankylosis over time was estimated by the Aalen-Johansen method in relation to the length of dry storage and the stage of root development. The effect of risk factors (root development and length of dry time) on the risk of ankylosis was analysed by Cox regression analysis. RESULTS: For mature teeth, dry storage for 5 min or less before saliva storage resulted in a 47.4% (95% confidence interval (CI): 32.8-60.7) ankylosis rate. When dry storage was >5 min and <20 min, the risk of ankylosis was 76.8% (95% CI: 45.7-91.5). When dry storage exceeded 20 min prior to saliva storage, ankylosis increased to 89.3% (95% CI: 68.0-96.7). Ankylosis also increased with increasing saliva storage time. Specifically, one additional minute of wet time increased the ankylosis hazard rate (HR) by approximately 1% (CI = [0%, 2%], p = .052). Teeth with mature root development were significantly more frequently affected by ankylosis than teeth with immature root development (HR: 2.4 (95% CI: 1.0-5.5), p = .04). CONCLUSION: Temporary storage in saliva should be encouraged if an avulsed permanent tooth cannot be immediately replanted or a suitable storage medium such as milk or saline is not immediately available at the place of the accident.

Bystander Efforts and 1-Year Outcomes in Out-of-Hospital Cardiac Arrest.

BACKGROUND: The effect of bystander interventions on long-term functional outcomes among survivors of out-of-hospital cardiac arrest has not been extensively studied. METHODS: We linked nationwide data on out-of-hospital cardiac arrests in Denmark to functional outcome data and reported the 1-year risks of anoxic brain damage or nursing home admission and of death from any cause among patients who survived to day 30 after an out-of-hospital cardiac arrest. We analyzed risks according to whether bystander cardiopulmonary resuscitation (CPR) or defibrillation was performed and evaluated temporal changes in bystander interventions and outcomes. RESULTS: Among the 2855 patients who were 30-day survivors of an out-of-hospital cardiac arrest during the period from 2001 through 2012, a total of 10.5% had brain damage or were admitted to a nursing home and 9.7% died during the 1-year follow-up period. During the study period, among the 2084 patients who had cardiac arrests that were not witnessed by emergency medical services (EMS) personnel, the rate of bystander CPR increased from 66.7% to 80.6% (P<0.001), the rate of bystander defibrillation increased from 2.1% to 16.8% (P<0.001), the rate of brain damage or nursing home admission decreased from 10.0% to 7.6% (P<0.001), and all-cause mortality decreased from 18.0% to 7.9% (P=0.002). In adjusted analyses, bystander CPR was associated with a risk of brain damage or nursing home admission that was significantly lower than that associated with no bystander resuscitation (hazard ratio, 0.62; 95% confidence interval [CI], 0.47 to 0.82), as well as a lower risk of death from any cause (hazard ratio, 0.70; 95% CI, 0.50 to 0.99) and a lower risk of the composite end point of brain damage, nursing home admission, or death (hazard ratio, 0.67; 95% CI, 0.53 to 0.84). The risks of these outcomes were even lower among patients who received bystander defibrillation as compared with no bystander resuscitation. CONCLUSIONS: In our study, we found that bystander CPR and defibrillation were associated with risks of brain damage or nursing home admission and of death from any cause that were significantly lower than those associated with no bystander resuscitation. (Funded by TrygFonden and the Danish Heart Foundation.).

The c-index is not proper for the evaluation of $t$-year predicted risks.

We show that the widely used concordance index for time to event outcome is not proper when interest is in predicting a $t$-year risk of an event, for example 10-year mortality. In the situation with a fixed prediction horizon, the concordance index can be higher for a misspecified model than for a correctly specified model. Impropriety happens because the concordance index assesses the order of the event times and not the order of the event status at the prediction horizon. The time-dependent area under the receiver operating characteristic curve does not have this problem and is proper in this context.

Evaluating the predictive performance of malaria antibodies and FCGR3B gene polymorphisms on Plasmodium falciparum infection outcome: a prospective cohort study.

BACKGROUND: Malaria antigen-specific antibodies and polymorphisms in host receptors involved in antibody functionality have been associated with different outcomes of Plasmodium falciparum infections. Thus, to identify key prospective malaria antigens for vaccine development, there is the need to evaluate the associations between malaria antibodies and antibody dependent host factors with more rigorous statistical methods. In this study, different statistical models were used to evaluate the predictive performance of malaria-specific antibodies and host gene polymorphisms on P. falciparum infection in a longitudinal cohort study involving Ghanaian children. METHODS: Models with different functional forms were built using known predictors (age, sickle cell status, blood group status, parasite density, and mosquito bed net use) and malaria antigen-specific immunoglobulin (Ig) G and IgG subclasses and FCGR3B polymorphisms shown to mediate antibody-dependent cellular functions. Malaria antigens studied were Merozoite surface proteins (MSP-1 and MSP-3), Glutamate Rich Protein (GLURP)-R0, R2, and the Apical Membrane Antigen (AMA-1). The models were evaluated through visualization and assessment of differences between the Area Under the Receiver Operating Characteristic Curve and Brier Score estimated by suitable internal cross-validation designs. RESULTS: This study found that the FCGR3B-c.233C>A genotype and IgG against AMA1 were relatively better compared to the other antibodies and FCGR3B genotypes studied in classifying or predicting malaria risk among children. CONCLUSIONS: The data supports the P. falciparum, AMA1 as an important malaria vaccine antigen, while FCGR3B-c.233C>A under the additive and dominant models of inheritance could be an important modifier of the effect of malaria protective antibodies.

Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction.

AIMS: Guidelines differ in their recommendations on therapy to prevent gastrointestinal bleeding for patients treated with dual antiplatelet treatment (DAPT). We sought to investigate the effectiveness of proton pump inhibitors (PPIs) to prevent upper gastrointestinal (UGI) bleeding in patients using DAPT following myocardial infarction (MI) in relation to current European Society of Cardiology guidelines recommendations. METHODS AND RESULTS: We linked Danish nationwide registries to identify patients taking DAPT 7 days following hospital discharge for an acute MI, and excluded individuals on anticoagulation therapy. We used multiple Cox regression modelling, to compute average risk of UGI bleeding in relation to PPI use. The associated treatment efficacy was compared based on guideline risk assessment. We studied 46 301 patients on DAPT after MI. Only 35% of patients at higher risk of UGI bleeding received recommended treatment with a PPI based on the guideline criteria. The 1--year risk of UGI bleeding was 1.0% [95% confidence interval (CI) 0.9-1.1%] and 1.7% (CI 1.5-2.0%) for high-risk patients. Overall PPI compared with no therapy, was associated with a risk ratio for UGI bleeding of 0.62 (CI 0.48-0.77) corresponding to an absolute risk difference of 0.44% (CI 0.39-0.48%). Proton pump inhibitor therapy was associated with a similar absolute risk difference [0.47% (CI 0.43-0.51%)] for high-risk patients. CONCLUSION: Proton pump inhibitor therapy is used less than suggested by guidelines in patients treated with DAPT following MI and was generally associated with reduced risk of UGI bleeding. Considering the overall low risk of bleeding, more focus should be on identifying patients benefiting the most from PPI therapy.

Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality.

IMPORTANCE: It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2. OBJECTIVE: To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020. EXPOSURES: ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. MAIN OUTCOMES AND MEASURES: In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. RESULTS: In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). CONCLUSIONS AND RELEVANCE: Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

On the interpretation of the hazard ratio in Cox regression.

We argue that the term "relative risk" should not be used as a synonym for "hazard ratio" and encourage to use the probabilistic index as an alternative effect measure for Cox regression. The probabilistic index is the probability that the event time of an exposed or treated subject exceeds the event time of an unexposed or untreated subject conditional on the other covariates. It arises as a well known and simple transformation of the hazard ratio and nicely reveals the interpretational limitations. We demonstrate how the probabilistic index can be obtained using the R-package Publish.