Time-dependent Cox Regression Research Articles

Association of Right Bundle Branch Block with Ischemic Stroke Incidence: A UK Biobank Cohort Study.

Right bundle branch block (RBBB) is often considered benign; however, its association with ischemic stroke (IS) remains unclear. We aimed to investigate the relationship between RBBB and the incidence of IS. We conducted a retrospective cohort study using the UK Biobank database (2004-2021), which included 3,634 participants with new-onset RBBB and 3,643 matched controls. The primary outcome was the incidence of IS, while the secondary outcomes included atrial fibrillation (AF) and all-cause mortality. We applied a propensity score matching with variables such as age, sex, presence of hypertension, diabetes, dyslipidemia, and the Charlson Comorbidity Index. Subsequently, time-dependent Cox regression analyses were performed to assess the association between RBBB and the outcomes. The cumulative incidence of IS was higher in the RBBB group. RBBB was independently associated with an increased risk of IS (adjusted hazard ratio [aHR], 3.57; 95% confidence interval [CI], 2.12-6.03; p < 0.001), as well as AF (aHR, 4.58; 95% CI, 3.86-5.43; p < 0.001) and all-cause mortality (aHR, 2.66; 95% CI, 2.35-3.02; p < 0.001). RBBB was associated with an increased risk of IS, independent of age, sex, and other comorbidities. These findings emphasize the need for careful monitoring and management of patients with RBBB to mitigate the risk of IS and other adverse outcomes. Further research is needed to elucidate the underlying mechanisms and better inform clinical management strategies for patients with RBBB.

The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study.

To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery. Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC. International multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). Primary endpoint is OS from diagnosis. Time-dependent Cox regression analysis was performed to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at time of diagnosis. Adjusted OS probabilities were calculated. Overall, 2,282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared to upfront surgery (adjusted HR=0.69 [95%CI 0.58-0.83]) with an adjusted median OS of 53 vs. 37 months (P=0.0003) and adjusted 5-year OS rates of 47% vs. 35% (P=0.0001) compared to upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction=0.003) and higher serum CA19-9 (Pinteraction=0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction=0.43), splenic vein (Pinteraction=0.30), retroperitoneal (Pinteraction=0.84), and multivisceral (Pinteraction=0.96) involvement. Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared to upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.

Partial-linear single-index Cox regression models with multiple time-dependent covariates

BackgroundIn cohort studies with time-to-event outcomes, covariates of interest often have values that change over time. The classical Cox regression model can handle time-dependent covariates but assumes linear effects on the log hazard function, which can be limiting in practice. Furthermore, when multiple correlated covariates are studied, it is of great interest to model their joint effects by allowing a flexible functional form and to delineate their relative contributions to survival risk.MethodsMotivated by the World Trade Center (WTC)-exposed Fire Department of New York cohort study, we proposed a partial-linear single-index Cox (PLSI-Cox) model to investigate the effects of repeatedly measured metabolic syndrome indicators on the risk of developing WTC lung injury associated with particulate matter exposure. The PLSI-Cox model reduces the dimensionality of covariates while providing interpretable estimates of their effects. The model’s flexible link function accommodates nonlinear effects on the log hazard function. We developed an iterative estimation algorithm using spline techniques to model the nonparametric single-index component for potential nonlinear effects, followed by maximum partial likelihood estimation of the parameters.ResultsExtensive simulations showed that the proposed PLSI-Cox model outperformed the classical time-dependent Cox regression model when the true relationship was nonlinear. When the relationship was linear, both the PLSI-Cox model and classical time-dependent Cox regression model performed similarly. In the data application, we found a possible nonlinear joint effect of metabolic syndrome indicators on survival risk. Among the different indicators, BMI had the largest positive effect on the risk of developing lung injury, followed by triglycerides.ConclusionThe PLSI-Cox models allow for the evaluation of nonlinear effects of covariates and offer insights into their relative importance and direction. These methods provide a powerful set of tools for analyzing data with multiple time-dependent covariates and survival outcomes, potentially offering valuable insights for both current and future studies.

Transurethral resection of the prostate (TUR-P) and associated risk of infective endocarditis.

Bacteremia is a well-known complication to surgery and may result in infective endocarditis (IE). Transurethral resection of the prostate (TUR-P) may give rise to bacteremia, but the associated risk of IE is not well described. We aimed to examine risk of infective endocarditis following TUR-P. We examined risk of IE following TUR-P between 2010 and 2020 in comparison with an age-matched (match-ratio 1:1) cohort from the background population. Patients were considered exposed to TUR-P related IE 6months after TUR-P. Comparisons were estimated using cumulative incidences and multivariable time-dependent Cox regression models. A total of 25,781 males underwent TUR-P (11.4% diagnosed with prostate cancer). Median age was 70.7years (25-75 percentiles, 64.9-76.3years). In the TUR-P group, 901 (3.5%) patients had bacteremia and 44 (0.2%) patients developed IE within 6months following index. The most common microorganism in IE-cases was Enterococcus faecalis (72.7%). The incidence of IE was higher < 6months after TUR-P (34.64 (25.78-46.55)) IEs per 10,000 person years) than 6-12months after TUR-P (8.37 (5.46-12.84) IEs per 10,000 person years). TUR-P was associated with a higher hazard ratio of IE within 6months (age-adjusted HR 8.16, 95% CI 3.06-21.79), but not 6-12months after TUR-P (adj. HR 2.15 (0.91-5.07)). TUR-P was associated with an eight-fold higher risk of IE compared with age-matched controls within 6months after surgery. Although the absolute risk was low, TUR-P seems to be a significant risk factor for IE and this warrant consideration for development of better prophylactic interventions.

Predictive value analysis of albumin-related inflammatory markers for short-term outcomes in patients with In-hospital cardiac arrest

ABSTRACT Objective This study investigated the predictive value of albumin-related inflammatory markers for short-term outcomes in in-hospital cardiac arrest (IHCA) patients. Methods A linear mixed model investigated the dynamic changes of markers within 72 hours after return of spontaneous circulation (ROSC). Time-Dependent COX regression explored the predictive value. Mediation analysis quantified the association of markers with organ dysfunctions and adverse outcomes. Results Prognostic Nutritional Index (PNI) and RDW-Albumin Ratio (RAR) slightly changed (p > 0.05). Procalcitonin-Albumin Ratio (PAR1) initially increased and then slowly decreased. Neutrophil-Albumin Ratio (NAR) and Platelet-Albumin Ratio (PAR2) decreased slightly during 24-48 hours (all p＜0.05). PNI (HR = 1.646, 95%CI (1.033,2.623)), PAR1(HR = 1.69, 95%CI (1.057,2.701)), RAR (HR = 1.752,95%CI (1.103,2.783)) and NAR (HR = 1.724,95%CI (1.078,2.759)) were independently associated with in-hospital mortality. PNI (PM = 45.64%, 95%CI (17.05%,87.02%)), RAR (PM = 45.07%,95%CI (14.59%,93.70%)) and NAR (PM = 46.23%,95%CI (14.59%,93.70%)) indirectly influenced in-hospital mortality by increasing SOFA (central) scores. PNI (PM = 21.75%, 95%CI(0.67%,67.75%)) may also indirectly influenced outcome by increasing SOFA (renal) scores (all p＜0.05). Conclusions Within 72 hours after ROSC, albumin-related inflammatory markers (PNI, PAR1, RAR, and NAR) were identified as potential predictors of short-term prognosis in IHCA patients. They may mediate the adverse outcomes of patients by causing damages to the central nervous system and renal function.

Time between pancreatic cancer diagnosis and treatment initiation and survival in the U.S. Military Health System.

Pancreatic cancer has a high case fatality and treatment is known to improve survival. It is unknown whether the time between diagnosis and treatment initiation (time-to-treatment) is related to survival. Access to medical care may influence both treatment receipt and timing. We examined the relationship between time-to-treatment and survival among patients with pancreatic adenocarcinoma treated in the equal access Military Health System. We used the MilCanEpi database to study a cohort of 806 men and women who were diagnosed with stage I-IV pancreatic adenocarcinoma between 1998 and 2014 and received either surgery or chemotherapy as primary treatment. Time-to-treatment in relation to overall survival was examined in multivariable time-dependent Cox regression models. Overall, median time-to-treatment was 3 weeks and 95% of patients received treatment within 12 weeks. Time-to-treatment >6 weeks was associated with a statistically significant lower risk of death (AHR=0.77, 95% CI=0.61-0.98) compared to time-to-treatment <3 weeks. Analysis by the first treatment type showed that time-to-surgery was not associated with survival among those receiving upfront surgery. Time-to-chemotherapy of >6 weeks was associated with reduced risks of death compared to <3 weeks (AHR=0.62, 95% CI=0.48-0.80) for patients receiving primary chemotherapy. Our data suggests that longer time-to-treatment, especially among patients with chemotherapy, was associated with lower risk of death among patients with pancreatic adenocarcinoma who received treatment. Further research is needed to understand the association of intervals along the whole cancer spectrum (e.g., presentation, diagnosis, treatment) and longer treatment intervals (i.e., >12 weeks) with survival.

Somatic symptom disorder, psychiatric comorbidities, and suicide.

Multiple studies have indicated an association between somatic symptom disorder (SSD) and suicidal symptoms, particularly suicidal ideation. Nevertheless, whether SSD is associated with a risk of suicide mortality remains unclear. In addition, how SSD-related psychiatric comorbidities such as bipolar disorder and major depressive disorder influence the risk of suicide remains unknown. In this study, 38,483 patients with SSD and 153,932 age- and sex-matched non-SSD individuals were followed up from 2003 to 2017. Suicide was evaluated within this study period, and major psychiatric disorders such as schizophrenia, bipolar disorder, major depression, alcohol use disorder (AUD), and substance use disorder (SUD) were identified. After these major psychiatric comorbidities were adjusted for, time-dependent Cox regression models were used to determine the influence of SSD on the risk of suicide. Patients with SSD had a higher risk of suicide (hazard ratio [HR]=3.41) compared with their non-SSD counterparts, regardless of their psychiatric comorbidities. Patients with SSD and comorbidities such as schizophrenia (HR=5.55), bipolar disorder (HR=5.99), major depression (HR=10.24), AUD (HR=4.33), and SUD (HR=4.33) were at an increased risk of suicide. Comorbid anxiety disorders with SSD were not assessed for the suicide risk in the present study. SSD is an independent risk factor for suicide. Both SSD and its associated psychiatric comorbidities can be used to develop strategies aimed at suicide prevention.

Thirty-Day Mortality of Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Insights from a Retrospective Cohort Study.

Although glycopeptides remain the preferred treatment for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, the treatment of persistent MRSA bacteremia has been challenging. We investigated real-world treatment strategies for persistent MRSA bacteremia, with a specific emphasis on the use of antimicrobial agents and the frequency of changes during the treatment course. We retrospectively identified patients with persistent MRSA bacteremia in four university-affiliated hospitals between 2017 and 2021. The primary objective of this study was to investigate the patterns of antimicrobial uses for MRSA bacteremia. The secondary objectives were evaluating the associated factors with 1) overall 30-day mortality and 2) changing agents during the treatment course. Time-dependent Cox regression analysis was used to adjust for immortal time bias. Among 116 patients, 37.1% underwent antimicrobials switching, primarily prompted by persistent bacteremia. The 30-day mortality rates of groups with and without antimicrobial switching were 21.4% and 44.2%, respectively (p=0.010 by log-rank test); however, after adjustment for immortal time bias, there was no statistical significance between the two groups (adjusted hazard ratio 0.24, 95% confidence interval 0.03-2.17, p=0.238). Only the Pitt bacteremia score on day 4 and pneumonia were associated with 30-day mortality. Meanwhile, the factors associated with antimicrobial switching were the duration of bacteremia, the initial use of teicoplanin, echocardiogram, and Charlson comorbidity index. This study showed that while over one-third of persistent MRSA bacteremia patients experience changes in antimicrobial agents during treatment, this practice does not significantly improve the 30-day mortality. Our study suggests the need for more effective treatment strategies in managing persistent MRSA bacteremia.

Bleeding risk using non-steroidal anti-inflammatory drugs with anticoagulants after venous thromboembolism: a nationwide Danish study

Abstract Background and Aims The bleeding risk of using non-steroidal anti-inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants for venous thromboembolism (VTE) remains unclear. Methods A nationwide cohort study of 51 794 VTE patients initiating oral anticoagulants between 1 January 2012 and 31 December 2022 was conducted. Time-dependent multivariate cause-specific Cox regression was used to compute adjusted hazard ratios between NSAID use and hospital-diagnosed bleeding episodes. Results Event rates for any bleeding per 100 person-years were 3.5 [95% confidence interval (CI), 3.4–3.7] during periods without NSAID use and 6.3 (95% CI, 5.1–7.9) during periods with NSAID use (number needed to harm = 36 patients treated for 1 year). Compared with non-use, the adjusted hazard ratios for any bleeding associated with NSAID use were 2.09 (95% CI, 1.67–2.62) overall, 1.79 (95% CI, 1.36–2.36) for ibuprofen, 3.30 (95% CI, 1.82–5.97) for diclofenac, and 4.10 (95% CI, 2.13–7.91) for naproxen. Compared with non-use, the adjusted hazard ratios associated with NSAID use were 2.24 (95% CI, 1.61–3.11) for gastrointestinal bleeding, 3.22 (95% CI, 1.69–6.14) for intracranial bleeding, 1.36 (95% CI, .67–2.77) for thoracic and respiratory tract bleeding, 1.57 (95% CI, .98–2.51) for urinary tract bleeding, and 2.99 (95% CI, 1.45–6.18) for anaemia caused by bleeding. Results were consistent for anticoagulant and VTE subtypes. Conclusions Patients treated with oral anticoagulants for VTE had a more than two-fold increased bleeding rate when using NSAIDs. This increased bleeding rate was not restricted to the gastrointestinal tract.

Associations of Clinical Characteristics With Sudden Cardiac Arrest in People With Type 2 Diabetes With and Without Cardiovascular Disease: A Longitudinal Case-Control Study Using Routine Primary Care Data.

To assess longitudinal associations with sudden cardiac arrest (SCA) of clinical characteristics recorded in primary care in people with type 2 diabetes (T2D), both with and without cardiovascular disease (CVD). We performed a case-control study, with SCA case subjects with T2D from the Amsterdam Resuscitation Studies (ARREST) registry of out-of-hospital resuscitation attempts in the Dutch Noord-Holland region (2010-2020) and up to five matched (age, sex, T2D, general practitioner [GP] practice) non-SCA control subjects. We collected relevant clinical measurements, medication use, and medical history from GPs' electronic health care records. We analyzed the associations of clinical characteristics and medication use with SCA in the total sample and in subgroups with or without CVD using multivariable time-dependent Cox regression (hazard ratios, 95% confidence intervals). We included 689 SCA case subjects and 3,230 non-SCA control subjects. In multivariable models, low fasting glucose (<4.5 mmol/mol: 1.91 [1.00-3.64]), antihypertensive (1.80 [1.39-2.33]), glucose lowering (oral only: 1.32 [1.06-1.63]; insulin only: 2.31 [1.71-3.12]; oral and insulin: 1.64 [1.21-2.22]), heart failure (1.91 [1.55-2.35]), and QTc-prolonging prokinetic (1.78 [1.27-2.50]), antibiotic (1.35 [1.05-1.73]), and antipsychotic (2.10 [1.42-3.09]) medication were associated with SCA in the total sample. In subgroup effect modification analyses, QTc-prolonging antibiotic (1.82 [1.26-2.63]) and antipsychotic (3.10 [2.09-4.59]) medication use were associated with SCA only in those without CVD. In people with T2D, low fasting glucose and QTc-prolonging prokinetic, antibiotic, or antipsychotic medication use and a history of heart failure are associated with SCA risk. Subgroup analyses indicate antibiotic and antipsychotic medication use increases SCA risk specifically in those without CVD.

Effect of choline alfoscerate in older adult patients with dementia: an observational study from the claims data of national health insurance

BackgroundCholine alfoscerate, a cholinergic precursor with limited evidence of efficacy in dementia management, has been used for various cognitive impairments in Korea. Partly due to its insurance coverage, this agent appears to incur significant expense for the insurance system. Thus, we aimed to describe choline alfoscerate prescription patterns and analyze their long-term effects in an older adult cohort with dementia.MethodsThis observational study used the National Health Insurance Service Senior Cohort Dataset. Choline alfoscerate -naïve patients who were diagnosed with dementia between 2003 and 2014 with at least 12 months of follow-up were selected. Time-dependent Cox regression was employed to estimate the association between drug exposure and the risk of treatment failure events.ResultsThere were 11,463 eligible participants, of whom approximately 73% were female, and 19% had been exposed to choline alfoscerate. According to the main regression survival analysis, the association between longitudinal choline alfoscerate use and the risk of progression events related to treatment failure was unclear. However, a significant decrease of nearly 20% in the risk of all-cause mortality was associated with choline alfoscerate exposure, and a slight reduction in progression regarding treatment failure was observed with CA use only during the early stages of diagnosis. Age, sex, insurance premiums, several comorbidities and concurrent medications were significantly associated with the probability of the events according to the multivariate models.ConclusionsFurther analyses are needed to confirm the early-stage and long-term effectiveness of choline alfoscerate in specific populations, which will help in considering its reimbursement.Graphical abstract

Abstract 4136755: Associations of Pulmonary Hypertension and Lung Cancer: A Prospective Cohort Study of Half a Million UK Biobank Participants

Background: Pulmonary hypertension (PH) and lung cancer (LC) are both significant public health issues with substantial morbidity and mortality. Recent studies suggest potential associations between pulmonary vascular diseases and LC due to shared risk factors and pathophysiological mechanisms, yet comprehensive research in large populations is scarce. Methods: This prospective cohort study utilized data from the UK Biobank, with baseline assessment between 2006 and 2010 and follow-up until November 30, 2023, for England and Scotland, and May 31, 2022, for Wales. We included 6,425 participants with LC, identified using linked cancer registry data, and followed them for the incidence of PH over a period of 10 years. We adjusted for potential confounders including age, ethnics, sex, smoking status, BMI, and histologic subtypes of LC. Statistical analyses were performed using Time-dependent Cox proportional hazards models to estimate the associations between PH and LC. Results: Of 502,173 participants in this prospective cohort, 6,425 were diagnosed with LC, while 494,451 did not receive the LC diagnosis. The prevalence of PH in the LC cohort and the no-LC cohort were 0.64% (1,494 of 3,142 women [47.55%]) and 2.40% (59 of 154 women [38.31%]), respectively, with significant difference between the two groups (p&lt;0.001). In the LC cohort, the mortality rates of patients without PH and with PH were 69.18% and 77.92% (p=0.020). Among the patients diagnosed with LC and PH, 33.12% were diagnosed with LC after PH (PH-LC), while 66.88% were diagnosed with LC before PH (LC-PH). And the mortality rates of the PH-LC group and the LC-PH group were 78.43% and 77.67%, respectively, with no significant difference between the two groups (p=0.915). Time-dependent Cox regression analysis showed that PH shows an increasing trend in risk (5th year HR: 3.22, 95% CI: 2.09-4.99, p-value &lt; 0.001), highlighting its significant impact on LC long-term prognosis. Conclusion: To conclude, the presence of PH significantly increased the risk of mortality in participants with LC, especially for the long-term LC survivors. And certain percentage of patients were diagnosed with LC before PH, but they had no significant difference between the patients with LC after PH.

Chronic kidney disease in patients with psoriatic arthritis: a cohort study

ObjectivesChronic kidney disease (CKD) is a comorbidity in psoriatic arthritis (PsA). We aimed to define the prevalence of CKD in patients with PsA, describe their long-term renal outcomes and identify...

Landmarking for Left-Truncated Competing Risk Data.

Landmarking is an alternative to complex multistate models when the aim is to calculate dynamic predictions. We develop the concept of landmarking for the case of left truncation and competing risks from the application background of drug safety assessment in pregnancy. The method is illustrated with a cohort study of the German Embryotox Pharmacovigilance Institute in Berlin to assess if the risk or the cumulative incidence of adverse pregnancy outcomes, like spontaneous abortions (SABs), is increased in fluoroquinolone-exposed women. Furthermore, we conduct an extensive simulation study to compare the dynamic predictions and coefficient estimates obtained by landmarking to those from nonparametric multistate models and classical time-dependent covariate Cox regression. The results from the simulation study indicate that attenuation of the effects is present in the landmark estimates, also in the complex setting considered here, but the estimates are still close to those from the multistate models. Regarding the Berlin fluoroquinolone data, the fluoroquinolone exposure of a pregnant woman in the first trimester seems to increase her cumulative incidence of elective termination of pregnancy over women never exposed before, but there is no evidence of a significantly increased risk or cumulative incidence in exposed women for SABs. This supports previous results on the same data, which were driven from an analysis without landmarkingmethods.

Glucose lowering drugs with proven cardiovascular benefit following acute coronary syndrome in type 2 diabetes: treatment gaps and outcomes

Abstract Background and Aims Real-world data on the implementation and prognostic impact of glucose-lowering drugs with proven cardiovascular benefits in patients with type 2 diabetes (T2D) following acute coronary syndromes (ACS) is limited. We investigated the utilization and treatment patterns of sodium-glucose contrasporter-2 inhibitors (SGLT2I) and glucagon-like peptide-1 receptor-agonists (GLP1RA) in T2D patients experiencing ACS, and analyzed their association with mortality and major adverse cardiovascular events (MACE) including recurrent ACS, acute revascularization, heart failure or ischemic stroke. Methods Retrospective analysis of 9,756 patients with T2D from a nationwide healthcare organization hospitalized with ACS between 01/2019 and 01/2022. Drug prescriptions were estimated pre-hospitalization, 90-days and 1-year following hospitalization. The association between SGLT2I and/or GLP1RA treatment with MACE and mortality was investigated using time-dependent Cox regression analysis with multivariable adjustment. Results Prescription rates (prehospitalization, 90-days and 1-year posthospitalization) of GLP1RA were 13%, 13.2%, and 18%, and of SGLT2I were 23.9%, 33.6% and 42.7%, respectively. At 1-year, 13.9% prescribed both therapeutic groups. The use of SGLT2I and/or GLP1RA was higher in younger age-groups, and increased from 2019 to 2021 (38.1% to 59.2%). The adjusted hazard ratio for the association of pre- or post-hospitalization SGLT2I and/or GLP1RA treatment with mortality and MACE was 0.724 (0.654-0.801) and 0.974 (0.909-1.043), respectively. Conclusions In real-world practice of patients with T2D experiencing ACS, implementation of SGLT2I and particularly GLP1RA was suboptimal, both early and 1-year following hospitalization, emphasizing the need to improve medical care. Treatment with SGLT2I and/or GLP1RA was associated with favorable impact on mortality but not MACE.Graphical Abstract

Association of serum testosterone levels with left atrial size, function, and risk of atrial fibrillation in adult men: observational and mendelian randomization analyses

Abstract Background Numerous studies have investigated the association between serum testosterone levels, testosterone replacement therapy (TRT), and cardiovascular risk. However, research examining the relationship between testosterone levels and atrial fibrillation (AF) risk remains limited. We comprehensively analyzed the association between total testosterone (TT) levels, intermediary phenotypes such as left atrium (LA) size and function, and the risk of AF in middle-aged and older men. Methods We utilized data from the UK Biobank, a population-based prospective cohort, focusing on 179,988 White men who had complete serum TT level data and no AF history. Observational associations between TT levels and LA imaging traits, as well as AF risk, were estimated using multivariable regression and time-dependent Cox regression models, treating TT levels as a time-varying variable. Genetic associations were examined by Mendelian randomization (MR), using both UK Biobank and external large consortia genome-wide association study data. Results During the median follow-up of 11.8 years (IQR 10.9–12.5), we observed 13,847 incident AF cases (7.7%). Participants with normal TT levels (≥ 300 ng/dL) showed a 15% reduced risk of AF (HR of 0.85 [95% CI, 0.82–0.89]) compared to those with low TT (&amp;lt; 300 ng/dL). Interestingly, participants undergoing TRT experienced a 51% higher risk of AF (1.51 [1.09–2.07]). Furthermore, each 1-standard deviation increase in TT levels was associated with a reduced AF risk (OR of 0.91 [0.89–0.93]) and an improved LA emptying fraction (1.29 [1.06–1.58]). Applying age-specific cutoff values for low TT levels highlighted a more pronounced AF risk reduction in participants with normal TT. MR analyses supported these observations, suggesting potential causal relationships between TT levels and both LA function and AF risk. Conclusions Our findings suggest that low TT levels are associated with reduced LA function and increased risk of AF, both observationally and genetically, indicating that serum TT could serve as a surrogate marker or even a potential causal mediator in the development of AF.Abstract tableAbstract figure

Increased risk of infective endocarditis following transurethral resection of the prostate (TUR-P)

Abstract Background Transient bacteremia is a well-known complication of transurethral resection of the prostate (TUR-P). Still, the associated risk of bacteremia and subsequent infective endocarditis (endocarditis) after TUR-P has been sparsely examined. Purpose To examine the risk of bacteremia and infective endocarditis following TUR-P. Methods We identified all patients who underwent TUR-P between 2010-2020 with ICD-10 codes from Danish nationwide registries. Patients were compared to an age-matched cohort of males from the general population (1:1 match-ratio). We defined a 6-month exposure window following TUR-P and examined the risk of bacteremia and endocarditis within the first 6 months and compared with the following 6-12 months after TUR-P. Microbiology findings were based on complete data on blood culture results. Incidences of bacteremia and endocarditis were calculated, and groups were compared with cumulative incidences. To account for predisposing endocarditis risk factors, multivariable time-dependent Cox regression analyses were performed on the associated risk of bacteremia and endocarditis. Results In total, 25.781 patients underwent TUR-P. Median age was 70.7 years (IQR: 64.9-76.3). Incidence of bacteremia was higher in the TUR-P group than the control group (727.47 [681.49-776.56] per 10,000 person years vs 84.75 [95% CI: 70.19-102.35)] per 10,000 person years). Incidence of endocarditis was also higher in the TUR-P group than the control group (34.64 [95% CI: 25.78-46.55] per 10,000 person years vs 3.14 [95% CI: 1.18-8.35] per 10,000 person years). In 72.7% of endocarditis-cases, Enterococcus Faecalis was the disease-causing pathogen in the TUR-P group. As compared with an age-matched control group, we found an increased associated risk of bacteremia in patients undergoing TUR-P within the first 6 months from the procedure (adj. HR: 7.72 [95% CI: 6.25-9.53]) and the increased risk persisted within the following 6-12 months (adj. HR 2.31 [95% CI: 1.83-2.91]). TUR-P was also associated with endocarditis within 6 months from the procedure (8.16 [95% CI 3.06-21.79]), but not significantly the following 6-12 months after (2.15 [95% CI: 0.91-5.07]) as compared with the age-matched control group. Conclusion Transurethral resection of the prostate (TUR-P) is associated with an almost 8 times increased risk of bacteremia and an 8 times increased risk of infective endocarditis. Our findings emphasize the necessity for development of better preventive strategies against infective endocarditis after TUR-P.Risk of endocarditis post-TUR-P

Cardiovascular disease in pregnancy: Prevalence and obstetric outcomes in a Swedish population-based cohort study between 2000 and 2019.

The prevalence of cardiovascular disease during pregnancy (cardiovascular disease diagnosed before, during or up to 6 months after childbirth) and the risk of adverse outcomes associated with it have not been previously described in Sweden. This study examined trends in prevalence of cardiovascular disease and its association with maternal and perinatal outcomes, overall and by timing of diagnosis in relation to pregnancy. This population-based observational retrospective cohort study consisted of women aged 15-49 years who were registered in the Swedish Medical Birth Register 2000-2019. Prevalence was defined as annual diagnosis of cardiovascular disease per pregnant woman as numerator and all pregnant women per year as denominator. Adverse maternal and perinatal outcomes were analyzed using time-dependent Cox regression and Poisson regression models. Outcomes were obtained during and after childbirth up to 1 year postpartum, depending on the outcome. There were 2 069 107 births to 1 186 137 women (911 101 primiparous). The prevalence of cardiovascular disease among pregnant women in Sweden during 2000-2019 increased from 0.31% to 1.34%, for non-congenital cardiovascular disease, this was primarily driven by arrythmia (0.11%-0.58%). Primiparous women with cardiovascular disease had a higher risk of eclampsia over-all (aHR 4.50, 95% CI 2.01-10.05) and when diagnosed during pregnancy (aHR 3.22, 95% CI 1.21-8.61); admission to psychiatric ward overall (aHR 2.51, 95% CI 1.30-4.83), and when diagnosed during pregnancy (aHR 2.54, 95% CI 1.21-5.34); and one-year mortality when diagnosed before pregnancy (aHR 1.67, 95% CI 1.16-2.42) and when diagnosed postpartum (aHR 6.59, 95% CI 3.38-12.84), compared to those without cardiovascular disease. Children born to women with cardiovascular disease diagnosed both overall and in relation to timing of diagnosis had an increased risk of being born preterm and small for gestational age. Cardiovascular disease prevalence among pregnant women in Sweden increased during 2000-2019, primarily driven by arrhythmias. In primiparous women, the timing of diagnosis of cardiovascular disease is important for maternal and perinatal outcomes, including when diagnosed postpartum. This calls for awareness among all staff when planning pregnancy and monitoring women with cardiovascular disease throughout pregnancy and in the postpartum period.

ERBB2 is a potential diagnostic and prognostic biomarker in renal clear cell carcinoma

Renal clear cell carcinoma (ccRCC) is a common parenchymal tumor of the kidney, and the discovery of biomarkers for early and effective diagnosis of ccRCC can improve the early diagnosis of patients and thus improve long-term survival. Erb-b2 receptor tyrosine kinase 2 (ERBB2) mediates the processes of cell proliferation, differentiation, and apoptosis inhibition. The purpose of this study was to investigate the diagnostic and prognostic role of ERBB2 in ccRCC. We analyzed the expression levels of ERBB2 in various cancers from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA-seq data were analyzed using R packages to identify differentially expressed genes between the high and low ERBB2 expression groups in the TCGA-KIRC dataset. Spearman correlation analysis was performed to determine the correlation between ERBB2 expression and immune cell infiltration, immune checkpoint expression, and PTEN expression. DNA methylation changes and genetic alterations in ERBB2 were assessed using the MethSurv and cBioPortal databases. Logistic regression analysis was performed to determine the correlation between ERBB2 expression and the clinicopathological characteristics of ccRCC patients. The diagnostic and prognostic value of ERBB2 was assessed using Kaplan‒Meier (K‒M) survival curves, diagnostic ROC curves, time-dependent ROC curves, nomogram models, and Cox regression models. The expression level of ERBB2 is lower in tumor tissues of ccRCC patients than in the corresponding control tissues. Differentially expressed genes associated with ERBB2 were significantly enriched in the pathways “BMP2WNT4FOXO1 pathway in primary endometrial stromal cell differentiation” and “AMAN pathway”. In ccRCC tissues, ERBB2 expression levels were associated with immune cell infiltration, immune checkpoints, and PTEN. The DNA methylation status of 10 CpG islands in the ERBB2 gene was associated with the prognosis of ccRCC. ERBB2 expression levels in ccRCC tissues were associated with race, sex, T stage, M stage, histological grade, and pathological stage. Cox regression analysis showed that ERBB2 was a potential independent predictor of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in ccRCC patients. ROC curve analysis showed that the expression level of ERBB2 could accurately distinguish between ccRCC tissue and adjacent normal renal tissue. Our study showed that ERBB2 expression in ccRCC tissues can be of clinical importance as a potential diagnostic and prognostic biomarker.

Barriers to clinical follow-up visits in multiple sclerosis: A nationwide register-based study.

In Denmark, specialized multiple sclerosis (MS) clinics offer free-of-charge treatment to people with MS. However, not all people with MS attend regular clinical follow-up. To identify people with MS who do not attend Danish MS clinics and identify barriers to treatment. The Danish Multiple Sclerosis Registry was linked to other national Danish registries with follow-up from 2000-2020. We used a time-dependent Cox regression to rank factors associated with low attendance to clinical follow-up visits based on the magnitude of hazard ratios (HRs). We included 10,175 adults with MS, of which 3862 (38%) had less than one visit annually. The five top-ranked factors that reduced the risk of visits occurring included never having received diseases modifying treatment (HR: 0.48; 95%CI: 0.46-0.49), been diagnosed with MS before 2009 (0.79; 0.78-0.81), association with MS center in an outer region of Denmark (0.82; 0.80-0.84), having progressive MS type (0.88; 0.86-0.91) and not having received symptomatic treatment at diagnosis (0.91; 0.89-0.93). Our results highlight disease-specific and geographic inequalities in the management of people with MS in Denmark. Strategies to prevent this inequality, especially for people with progressive phenotypes and those who need supportive and non-medical treatment and care, should be implemented.