Higher Risk Of Adverse Events Research Articles

Bayesian safety surveillance with adaptive bias correction.

Postmarket safety surveillance is an integral part of mass vaccination programs. Typically relying on sequential analysis of real-world health data as they accrue, safety surveillance is challenged by sequential multiple testing and by biases induced by residual confounding in observational data. The current standard approach based on the maximized sequential probability ratio test (MaxSPRT) fails to satisfactorily address these practical challenges and it remains a rigid framework that requires prespecification of the surveillance schedule. We develop an alternative Bayesian surveillance procedure that addresses both aforementioned challenges using a more flexible framework. To mitigate bias, we jointly analyze a large set of negative control outcomes that are adverse events with no known association with the vaccines in order to inform an empirical bias distribution, which we then incorporate into estimating the effect of vaccine exposure on the adverse event of interest through a Bayesian hierarchical model. To address multiple testing and improve on flexibility, at each analysis timepoint, we update a posterior probability in favor of the alternative hypothesis that vaccination induces higher risks of adverse events, and then use it for sequential detection of safety signals. Through an empirical evaluation using six US observational healthcare databases covering more than 360 million patients, we benchmark the proposed procedure against MaxSPRT on testing errors and estimation accuracy, under two epidemiological designs, the historical comparator and the self-controlled case series. We demonstrate that our procedure substantially reduces Type 1 error rates, maintains high statistical power and fast signal detection, and provides considerably more accurate estimation than MaxSPRT. Given the extensiveness of the empirical study which yields more than 7 million sets of results, we present all results in a public R ShinyApp. As an effort to promote open science, we provide full implementation of our method in the open-source R package EvidenceSynthesis.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Diagnostic standard: assessing glomerular filtration rate

ABSTRACT Creatinine-based estimated glomerular filtration rate (eGFR) is imprecise at individual level, due to non-GFR-related serum creatinine determinants, including atypical muscle mass. Cystatin C has the advantage of being independent of muscle mass, a feature that led to the development of race- and sex-free equations. Yet, cystatin C–based equations do not perform better than creatinine-based equations for estimating GFR unless both variables are included together. The new race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation had slight opposite biases between Black and non-Black subjects in the USA, but has poorer performance than that the previous version in European populations. The European Kidney Function Consortium (EKFC) equation developed in 2021 can be used in both children and adults, is more accurate in young and old adults, and is applicable to non-white European populations, by rescaling the Q factor, i.e. population median creatinine, in a potentially universal way. A sex- and race-free cystatin C–based EKFC, with the same mathematical design, has also be defined. New developments in the field of GFR estimation would be standardization of cystatin C assays, development of creatinine-based eGFR equations that incorporate muscle mass data, implementation of new endogenous biomarkers and the use of artificial intelligence. Standardization of different GFR measurement methods would also be a future challenge, as well as new technologies for measuring GFR. Future research is also needed into discrepancies between cystatin C and creatinine, which is associated with high risk of adverse events: we need to standardize the definition of discrepancy and understand its determinants.

Influence of background therapy on efficacy of dapagliflozin in patients with heart failure and improved ejection fraction

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF), defined as prior reduced left ventricular EF (LVEF) ≤40% with a subsequent measurement LVEF &amp;gt;40%, is growing in prevalence, in part because of effective guideline directed medical therapy (GDMT) initiated when LVEF was ≤40%. These patients have been largely excluded from major HF clinical trials. The DELIVER trial demonstrated dapagliflozin to be beneficial in patients with symptomatic HFimpEF; whether this benefit differs by background medical therapy is unclear. Purpose We investigated the efficacy and safety of dapagliflozin in patients with HFimpEF by background HF GDMT (beta-blocker [BB], mineralocorticoid receptor antagonist [MRA], and ACEi/ARB/ARNI at baseline). Methods The DELIVER trial randomized patients with symptomatic heart failure and LVEF&amp;gt;40% to dapagliflozin or placebo. Treatment effects on the primary endpoint, worsening heart failure or cardiovascular (CV) death, and its components were assessed by a GDMT composite score. We assigned 1 point each for baseline use of ACEi/ARB, evidence-based BB, or MRA, and 2 points for sacubitril/valsartan. The composite GDMT score could range from 0 (no GDMT) to 4 (triple therapy inclusive of sacubitril/valsartan). Results Among the 6,263 patients randomized, 1,151 (18%) had HFimpEF. Of those, 2% of patients were on no GDMT, 14% were on 1 GDMT, 47% were on 2 GDMT therapies, and 37% were on triple therapy at baseline (Figure 1). Patients treated with triple therapy, compared to those on less than 3 therapies, were younger, more likely male, have a history of myocardial infarction, less likely to have diabetes, had a lower baseline LVEF and systolic blood pressure, and higher eGFR. During 2.2 years of median follow-up, the incidence rate was 9.8 per 100 person-years among those on 1 or no medications at baseline compared with 8.6 per 100 person-years among those on 2 or 3 therapies. Relative benefits of dapagliflozin on the primary outcome were not significantly modified by baseline GDMT score (Pinteraction = 0.11), but absolute benefits appeared more pronounced in those receiving 1 or no medications at baseline (Figure 2). Serious adverse events were well-balanced between treatment arms in the HFimpEF cohort, including among those already treated with triple therapy. Conclusions In patients with HFimpEF, the benefits of dapagliflozin are similar irrespective of background GDMT. Dapagliflozin was safe and did not lead to higher risk of adverse events among those with HFimpEF, including those already treated with triple therapy.Figure 1Figure 2

Patient-level outcomes of patients undergoing resorbable magnesium scaffold (RMS) implantation stratified according to different subgroups: a post-hoc analysis of SHERPA MAGIC study

Abstract Background The SHERPA-MAGIC is an investigator-driven, multicenter, prospective, single-arm study that enrolled patients undergoing resorbable magnesium scaffold (RMS) implantation in 18 Italian centers. The results from the first 543 patients supported the safety and long-term performance of RMS in a real-world population. Purpose The present post-hoc analysis aimed to assess differences in adverse events at patient-level (patient-oriented composite endpoints, POCE, defined as the composite of all-cause death, myocardial infarction -MI- and ischemia-driven coronary revascularization) at the longest follow-up between different subgroups of the final study population (n=543). Methods We identified the subgroups according to different variables: age, sex, cardiovascular risk factors, clinical presentation, left ventricle ejection fraction, multivessel disease, multivessel PCI, and antiplatelet therapy. If the analysis highlighted a subgroup of patients at higher risk of adverse events, to understand if this finding is related to RMS implantation or to the characteristic itself, a propensity score matched analysis was conducted comparing patients of the SHERPA-MAGIC study with a matched cohort of patients receiving second generation drug eluting stent. The endpoint for the comparison between the two matched cohorts was POCE. Results The mean age of the final study population was 56±9 years. 433 (78%) patients were men, and the most common clinical presentation was MI (n=402, 74%). At the median follow-up of 3.5 [2.6-4.3] years, the cumulative occurrence of the primary endpoint (vessel-oriented composite endpoints, VOCE, including cardiac death, target vessel MI, and ischemia-driven target vessel revascularization) was 37 (5.8%, 95%CI 4.1%-7.9%) and 54 (9.9%, 95% CI 7.5%-12.7%) patients met criteria for POCE. There was no significant difference among POCE in the subgroup analysis (Figure 1), with the exception of patients with MI as clinical presentation. As compared to patients admitted for chronic coronary syndrome, MI patients showed a significantly higher POCE rate (11.4 vs 5.6%, CI 8.5-14.9, p=0.04). Therefore, a propensity score matched analysis was conducted comparing MI patients of the SHERPA-MAGIC study with a matched cohort of MI patients from the Acute coRonary sYndrOmes proSpective regisTry Of Ferrara (ARYOSTO) study (NCT02438085) treated with second-generation DES. We did not find significant differences in the cumulative occurrence of POCE between SHERPA MAGIC and ARYOSTO (11.4% vs. 12.5% respectively, p=0.71) (Figure 2). Conclusions The present analysis confirmed the safety and effectiveness of RMS across several subgroups of patients stratified by clinical and procedural characteristics. We found that MI patients had an higher occurrence of POCE, but this was not related to RMS implantation. Indeed, a similar MI population treated with second generation DES showed the same long-term outcome.Fig 1POCE difference between subgroupsFig 2Propensity matched MI populations

Abstract 18216: NT-proBNP After Discharge in Patients With Decompensated Heart Failure and Preserved Left Ventricle Ejection Fraction: The NICE Study

Introduction: In hospitalized patients with heart failure (HF), the transition period after discharge is associated with high risk of adverse events. The impact of monitoring natriuretic peptides (NP) in patients with preserved LVEF (HFpEF) has not specifically studied. Methods: NICE trial (NCT02807168) is a randomized, open-label, blinded for events and multicenter study. The study population included hospitalized patients with HFpEF (LVEF&gt;50% and at least one additional criteria of diastolic dysfunction). Patients were randomized at discharge into intervention (NP group) or control group. Both groups received optimal therapy and scheduled clinical visits at 14 and 30 days, 3 and 6 months, and NT-proBNP results were available for the clinician only in the intervention group. Results: 157 patients (76±8 years, 61% female, LVEF 61±7%) were randomized into NP group (n=79) and control group (n=78). Baseline characteristics did not differ between groups. At 6 months, no differences were found in HF readmission in NP vs. control group (12.8% vs. 11.4%, HR 1.15, CI95% 0.47-2.81), or any episode of worsening HF (20.5% vs. 24.1%, HR 0.89, CI95% 0.44-1.82). NP group had a significantly lower mortality than the control group (1.3% vs. 10.1%, HR 0.12, IC95% 0.02-0.98, p=0.048), as well as a trend to lower risk of hospitalization for non-HF related causes (12.8% vs. 19.0%, HR 0.68, IC95% 0.39-1.18). Considering the composite end-point (death or worsening HF), the intervention with NT-proBNP was associated with a lower risk trend (20.5% vs. 30.4%, HR 0.65, IC95% 0.34-1.22, p=0.181). Regarding the use of medical therapies, diuretic and ACEI doses were higher in the intervention group during the follow-up. Conclusions: In hospitalized patients with HFpEF, NT-proBNP availability during the transition period did not reduce the risk of HF readmissions. Nevertheless, it was associated with a lower mortality. These results suggest a global impact in the disease, beyond readmissions.

Abstract 15170: Prognostic Implication of Left Atrial Reservoir Strain in Severe Mitral Stenosis With Low Transmitral Diastolic Pressure Gradient: Result From Long-Term Follow-Up Registry

Background: Prognosis of severe mitral stenosis (MS) with low transmitral mean diastolic pressure gradient (MDPG) has not been fully understood with lack of long-term follow-up study. Aims: We investigated the prognostic implication in severe MS with low MDPG. Methods: We included patients with severe rheumatic MS (mitral valve area [MVA] &lt; 1.5 cm 2 ) from the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry. Patients with severe MS were categorized into high (≥ 5 mmHg) or low (&lt; 5 mmHg) MDPG groups. The primary outcome was a composite of all-cause mortality and stroke. Among 1,248 patients with severe MS, 322 (25.8%) had low and 926 (74.2%) had high MDPG. Results: Their mean age was 59±13 years, 25% were men, and 74% had atrial fibrillation. Patients with low MDPG were older and had a higher prevalence of atrial fibrillation. During a mean follow-up of 6.8±5.9 years, 194 patients (15.5%) experienced composite events. Patients with severe MS and low MDPG had a higher risk of experiencing composite events compared to those with high MDPG (hazard ratio [HR]: 1.56, 95% CI: 1.15-2.12; p=0.004). Subgroup analysis with low MDPG revealed that decreased left atrial reservoir strain (LARs) was independently associated with poorer outcome (HR, 2.58, 95% CI: 1.08-6.20; p=0.034). Conclusion: Severe MS patients with low MDPG are at higher risk of adverse events compared to those with high MDPG. The assessment of LARs can be useful in identifying subgroups of low MDPG severe MS patients with poor prognosis.

Abstract 14817: Influence of Timing of Mechanical Thrombectomy in Treatment of Intermediate-Risk Pulmonary Embolism

Background: Acute pulmonary embolism (PE) is associated with significant morality. Patients with signs of right ventricular (RV) dysfunction are at a high risk of adverse events. Mechanical thrombectomy reduces RV strain and therefore is often performed in intermediate-risk PE. The optimal timing of the procedure is uncertain. We aimed to assess the influence of timing of mechanical thrombectomy on outcomes in patients with intermediate-risk PE. Methods: A single-center, retrospective study collected patient data between 7/2020 and 1/2023. Adults presenting with an intermediate-risk PE who were treated with mechanical thrombectomy were included. Patients with high risk PE were excluded. We compared patient outcomes between individuals receiving intervention within 12 hours of diagnosis (early treatment; ET) to those receiving intervention after 12 hours of diagnosis (delayed treatment, DT). Our primary outcome was change in pulmonary artery pressures. Secondary outcomes included length of stay, intubation rates, vasopressor need and mortality. Results: 69 patients (52% male) were included for analysis. Of these, 37 were included in the ET group and 32 in the DT group. Presenting WHO class was higher in the ET group. Other baseline demographics, presenting vital signs, and echocardiographic parameters were similar between groups (Table). Patients in the ET group had a greater reduction in their pulmonary artery systolic pressure (PASP) after intervention compared to the DT group (-14.8 mm Hg vs. -8.3 mm Hg, p = 0.05; Fig). There were no differences in mortality, intubation rate, vasopressor or inotrope use between groups. There was no significant difference in overall hospital length of stay (LOS), though there was a trend towards shorter ICU LOS in the ET group (1.92 d vs. 4.2 d, p = 0.056). Conclusions: When performed for intermediate-risk PE ET is associated with greater reductions in PASP compared to DT.

Abstract 17281: Outcome of Stress-Induced Cardiomyopathy in Patients With Covid-19 Infection: A US Cohort Propensity-Matched Study

Introduction: COVID-19 has affected millions of people worldwide and is associated with cardiovascular complications like myocarditis, MI, pericarditis &amp; stress-induced cardiomyopathy (Takotsubo cardiomyopathy). Hypothesis and aim: The aim of our study was to examine the outcomes of stress-induced cardiomyopathy in patients with COVID-19. Methods: Using TriNetX, which aggregates &gt;100 million patients' charts, we identified adults (&gt;18) between Jan. 2020 &amp; Apr. 2023. We identified 2 groups: stress induced cardiomyopathy in the setting of COVID-19, &amp; stress-induced cardiomyopathy without COVID-19. We performed 1:1 propensity score matching for demographics and co-morbidities like DM, HTN, HLD, IHD, CKD, obesity, PVD, COPD, liver cirrhosis, smoking &amp; alcohol abuse. We conducted Kaplan-Meier survival analysis to assess all-cause mortality. Adjusted odds ratios (aOR) with 95% confidence interval (CI) were calculated to express the risk of each outcome. Results: We identified 1990 cases of stress-induced cardiomyopathy with COVID-19, and 27,702 patients with stress-induced cardiomyopathy without COVID-19. The majority were female gender and white race across the groups. Table 1 summarizes the demographics and characteristics of cohorts. After matching, stress-induced cardiomyopathy with COVID-19 were more likely to develop LV thrombus (aOR 1.41 [1.02-1.61]), cerebral infarction (aOR 1.25 [1.05-1.47]), acute respiratory failure (aOR 1.72 [1.53-1.94]), cardiogenic shock (aOR 1.37 [1.09-1.72]), and VTE (aOR 1.86 [1.61-2.14]). No difference was found in VT (aOR 0.89 [0.72-1.10]), or cardiac arrest (aOR [1.13 (0.88-1.45]), figure 1. All cause-mortality was worse in COVID-19 associated stress-induced cardiomyopathy (HR 1.17 [1.007-1.35]). Conclusions: Stress induced cardiomyopathy in the setting of COVID-19 was associated with a higher risk of adverse events and increased mortality compared to stress induced cardiomyopathy without COVID-19.

Overnight Stay in the Emergency Department and Mortality in Older Patients

Patients in the emergency department (ED) who are waiting for hospital admission on a wheeled cot may be subject to harm. However, mortality and morbidity among older patients who spend the night in the ED while waiting for a bed in a medical ward are unknown. To assess whether older adults who spend a night in the ED waiting for admission to a hospital ward are at increased risk of in-hospital mortality. This was a prospective cohort study of older patients (≥75 years) who visited the ED and were admitted to the hospital on December 12 to 14, 2022, at 97 EDs across France. Two groups were defined and compared: those who stayed in the ED from midnight until 8:00 am (ED group) and those who were admitted to a ward before midnight (ward group). The primary end point was in-hospital mortality, truncated at 30 days. Secondary outcomes included in-hospital adverse events (ie, falls, infection, bleeding, myocardial infarction, stroke, thrombosis, bedsores, and dysnatremia) and hospital length of stay. A generalized linear-regression mixed model was used to compare end points between groups. The total sample comprised 1598 patients (median [IQR] age, 86 [80-90] years; 880 [55%] female and 718 [45%] male), with 707 (44%) in the ED group and 891 (56%) in the ward group. Patients who spent the night in the ED had a higher in-hospital mortality rate of 15.7% vs 11.1% (adjusted risk ratio [aRR], 1.39; 95% CI, 1.07-1.81). They also had a higher risk of adverse events compared with the ward group (aRR, 1.24; 95% CI, 1.04-1.49) and increased median length of stay (9 vs 8 days; rate ratio, 1.20; 95% CI, 1.11-1.31). In a prespecified subgroup analysis of patients who required assistance with the activities of daily living, spending the night in the ED was associated with a higher in-hospital mortality rate (aRR, 1.81; 95% CI, 1.25-2.61). The findings of this prospective cohort study indicate that for older patients, waiting overnight in the ED for admission to a ward was associated with increased in-hospital mortality and morbidity, particularly in patients with limited autonomy. Older adults should be prioritized for admission to a ward.

Association Between Same-Day Discharge Shoulder Arthroplasty and Risk of Adverse Events in Patients with American Society of Anesthesiologists Classification ≥ 3: A Cohort Study.

Same-day discharge for shoulder arthroplasty (SA) is well-supported in the literature, however, most studies have focused on healthier patients. Indications for same-day discharge SA have expanded to include patients with more comorbidities, but safety of same-day discharge in this population remains unknown. We sought to compare outcomes following same-day discharge versus inpatient SA in a cohort of patients considered higher-risk for adverse events, defined as an American Society of Anesthesiologists (ASA) classification of ≥3. Data from a US-based healthcare system's SA registry were utilized to conduct a retrospective cohort study. All patients with an ASA classification of ≥3 who underwent primary elective anatomic or reverse SA in a hospital from 2018-2020 were included. The exposure of interest was in-hospital length of stay: same-day discharge versus ≥1-night hospital inpatient stay. The likelihood of 90-day post-discharge events, including emergency department (ED) visit, readmission, cardiac complication, venous thromboembolism (VTE), and mortality, was evaluated using propensity score-weighted logistic regression with noninferiority testing using a margin of 1.10. The cohort included a total of 1,814 SA patients, of whom 1,005 (55.4%) had same-day discharge. In propensity score-weighted models, same-day discharge was not inferior to an inpatient stay SA regarding 90-day readmission (odds ratio [OR]=0.64, one-sided 95% upper bound [UB]=0.89) and overall complications (OR=0.67, 95% UB=1.00). We lacked evidence in support of non-inferiority for 90-day ED visit (OR=0.96, 95% UB=1.18), cardiac event (OR=0.68, 95% UB=1.11), or VTE (OR=0.91, 95% UB=2.15). Infections, revisions for instability, and mortality were too rare to evaluate using regression analysis. In a cohort of over 1,800 patients with an ASA of ≥3, we found same-day discharge SA did not increase the likelihood of ED visits, readmissions, or complications compared with an inpatient stay and same-day discharge was not inferior to an inpatient stay with regard to readmissions and overall complications. These findings suggest that it is possible to expand indications for same-day discharge SA in the hospital setting.

Review finds antidepressants effective for depression comorbid with medical illness

A systematic review of 52 meta‐analyses has concluded that antidepressants improve symptoms of depression relative to placebo in patients with comorbid depression and medical illness. Antidepressants were shown to be safe overall but were associated with a higher risk of adverse events compared with placebo.

Depression, anxiety, and quality of life as predictors of rehospitalization in patients with chronic heart failure

BackgroundChronic heart failure (CHF) is a severe condition, often co-occurring with depression and anxiety, that strongly affects the quality of life (QoL) in some patients. Conversely, depressive and anxiety symptoms are associated with a 2–3 fold increase in mortality risk and were shown to act independently of typical risk factors in CHF progression. The aim of this study was to examine the impact of depression, anxiety, and QoL on the occurrence of rehospitalization within one year after discharge in CHF patients.Methods148 CHF patients were enrolled in a 10-center, prospective, observational study. All patients completed two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Questionnaire Short Form Health Survey 36 (SF-36) at discharge timepoint.ResultsIt was found that demographic and clinical characteristics are not associated with rehospitalization. Still, the levels of depression correlated with gender (p ≤ 0.027) and marital status (p ≤ 0.001), while the anxiety values ​​were dependent on the occurrence of chronic obstructive pulmonary disease (COPD). However, levels of depression (HADS-Depression) and anxiety (HADS-Anxiety) did not correlate with the risk of rehospitalization. Univariate logistic regression analysis results showed that rehospitalized patients had significantly lower levels of Bodily pain (BP, p = 0.014), Vitality (VT, p = 0.005), Social Functioning (SF, p = 0.007), and General Health (GH, p = 0.002). In the multivariate model, poor GH (OR 0.966, p = 0.005) remained a significant risk factor for rehospitalization, and poor General Health is singled out as the most reliable prognostic parameter for rehospitalization (AUC = 0.665, P = 0.002).ConclusionTaken together, our results suggest that QoL assessment complements clinical prognostic markers to identify CHF patients at high risk for adverse events. Clinical Trial Registration: The study is registered under http://clinicaltrials.gov (NCT01501981, first posted on 30/12/2011), sponsored by Charité – Universitätsmedizin Berlin.

MGAT5/TMEM163 variant is associated with prognosis in ursodeoxycholic acid-treated patients with primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.3 and prognosis of PBC patients. We performed a retrospective analysis of 347 PBC patients treated with ursodeoxycholic acid (UDCA) for at least 1 year. We collected clinical data at diagnosis and 1 year after UDCA treatment. SNPs within 200kb upstream and downstream of the lead variant were genotyped and screened. We identified that rs661899 near MGAT5 and TMEM163 showed the strongest association with prognosis in PBC patients. Patients carrying the rs661899 T allele tended to respond incompletely to UDCA treatment and had worse performances in laboratory values including aspartate aminotransferase (53.5 vs 32 vs 28.5 U/L, p = 0.001), alkaline phosphate (157.25 vs 125 vs 113 U/L, p = 0.001), albumin (41.5 vs 42.3 vs 43.7g/L, p = 0.008) and bilirubin (19.2 vs 14.9 vs 12.85μmol/L, p = 0.001). GLOBE scores (p = 4.8 × 10-5) and UK-PBC risk scores (p = 4.6 × 10-4) were strongly correlated with rs661899 genotype. Patients with TT genotype had a higher risk for adverse events compared with CC genotype (p = 0.039) during the 1-year follow-up. Results were also verified in an independent cohort. PBC patients carrying the rs661899 T allele are associated with poor prognosis and adverse outcomes after 1-year UDCA therapy.

Large common bile duct stones in high-risk elderly patients: Immediate endoscopic stone removal or elective stone removal? A single-center retrospective study

Background and objectiveFor high-risk elderly patients with chronic diseases, endoscopic stone removal for large common bile duct stones is associated with a high risk of adverse events and incomplete stone removal. The aim of this study was to investigate whether the treatment strategy of short-term biliary plastic stent placement followed by elective endoscopic stone removal is more effective and safer than immediate endoscopic stone removal.MethodsThe data of 262 high-risk elderly patients who received endoscopic retrograde cholangiopancreatography (ERCP) for large common bile duct (CBD) stones from 2017 to 2022 were retrospectively analyzed. The patients were divided into group A (immediate stone removal) and group B (stent drainage + elective stone removal). The baseline data of the 2 groups were matched 1:1 by propensity score matching. The stone clearance rate, ERCP procedure time, total hospital stay, and procedure-related adverse events were compared between the matched groups. In group B, stone size before and after stent placement, hospital stay, procedure time and adverse events of two ERCPs were compared.ResultsA total of 57 pairs of patients were successfully matched between the 2 groups. The stone clearance rate in group B was higher than that in group A (89.5% vs. 75.3, P = 0.049). The total hospital stay in group B was longer than that in group A (11.86 ± 3.912 d vs. 19.14 ± 3.176 d, P<0.001). The total adverse event rate in group A was higher than that in group B (29.8% vs. 12.3%, P = 0.005). The incidence of cholangitis/cholecystitis after ERCP was significantly higher in group A than in group B (7.0% vs. 0.9% P = 0.029). There was no significant difference in the incidence of post-ERCP pancreatitis, bleeding, pneumonia, and cardio-cerebrovascular events between the 2 groups. There were no perforation cases in either group. After plastic biliary stent placement in group B, the stone size was significantly smaller than before stent placement (1.59 ± 0.544 cm vs. 1.95 ± 0.543 cm, P < 0.001), and there was no significant difference in the total adverse event incidence between the two ERCP procedures (18.8% vs. 10.9%, P = 0.214).ConclusionFor high-risk elderly patients with large CBD stones, the treatment strategy involving temporary placement of plastic stent and elective endoscopic stone removal is safer and more effective than immediate stone removal.

Machine learning-based biomarker profile derived from 4210 serially measured proteins predicts clinical outcome of patients with heart failure.

Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF. In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c-index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c-index of 0.85 upon internal validation and c-indices up to 0.80 upon external validation. The c-index was higher than that of a model containing established risk factors (P = 0.021). Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication. https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.

Regional biomechanical characterization of human ascending aortic aneurysms: Microstructure and biaxial mechanical response.

The ascending thoracic aortic aneurysm (ATAA) is a permanent dilatation of the vessel with a high risk of adverse events, and shows heterogeneous properties. To investigate regional differences in the biomechanical properties of ATAAs, tissue samples were collected from 10 patients with tricuspid aortic valve phenotype and specimens from minor, anterior, major, and posterior regions were subjected to multi-ratio planar biaxial extension tests and second-harmonic generation (SHG) imaging. Using the data, parameters of a microstructure-motivated constitutive model were obtained considering fiber dispersion. SHG imaging showed disruptions in the organization of the layers. Structural and material parameters did not differ significantly between regions. The non-symmetric fiber dispersion model proposed by Holzapfel etal. [25] was used to fit the data. The mean angle of collagen fibers was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. The experimental data collected in this study contribute to the biomechanical data available in the literature on human ATAAs. Region-specific parameters for the constitutive models are fundamental to improve the current risk stratification strategies, which are mainly based on aortic size. Such investigations can facilitate the development of more advanced finite element models capable of capturing the regional heterogeneity of pathological tissues. STATEMENT OF SIGNIFICANCE: Tissue samples of human ascending thoracic aortic aneurysms (ATAA) were collected. Samples from four regions underwent multi-ratio planar biaxial extension tests and second-harmonic generation imaging. Region-specific parameters of a microstructure-motivated model considering fiber dispersion were obtained. Structural and material parameters did not differ significantly between regions, however, the mean fiber angle was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. This study provides a unique set of mechanical and structural data, supporting the microstructural influence on the tissue response. It may facilitate the development of better finite element models capable of capturing the regional tissue heterogeneity.

Current and Emerging Therapies for Atopic Dermatitis in the Elderly.

Atopic dermatitis (AD) in the elderly has recently emerged as a distinct subgroup of AD, garnering widespread concern due to its increasing global incidence rate. Epidermal barrier dysfunction, inflammatory response, and chronic pruritus interact with each other, contributing to the pathogenesis andpathophysiology of AD in the elderly. Although fundamental medications are essential for managing AD in the elderly, older adults often struggle with regular usage of moisturizing emollients, topical medications, and avoidance of environmental triggers, leading to recurrent or even exacerbated disease progression. Therefore, a systematic medication approach is necessary to control pruritus and skin lesions. Traditional systemic treatments may not adequately meet the treatment needs of moderate and severe AD in the elderly and may even pose certain safety risks. Biologics and Janus kinase (JAK) inhibitors, exhibiting excellent clinical efficacy, have made significant breakthroughs in AD treatment. Existing evidence suggests that dupilumab, a human monoclonal IgG4 antibody, has been confirmed as an effective and safe first-line systematic treatment for moderate to severe AD in the elderly, with no notable differences between adults and the elderly. However, the limited inclusion of elderly patients in related clinical studies hinders the generalizability of these findings. As older patients face a higher risk of adverse events with JAK inhibitors, JAK inhibitors are recommended when no other suitable treatment options are available. Obtaining population-specific data is crucial for making evidence-based treatment choices when managing AD in older adults with JAK inhibitors.

Quantitation of diffuse myocardial ischemia with mental stress and its association with cardiovascular events in individuals with recent myocardial infarction

Microcirculatory dysfunction during psychological stress may lead to diffuse myocardial ischemia. We developed a novel quantification method for diffuse ischemia during mental stress (dMSI) and examined its relationship with outcomes after a myocardial infarction (MI). We studied 300 patients ≤ 61 years of age (50% women) with a recent MI. Patients underwent myocardial perfusion imaging with mental stress and were followed for 5 years. dMSI was quantified from cumulative count distributions of rest and stress perfusion. Focal ischemia was defined in a conventional fashion. The main outcome was a composite outcome of recurrent MI, heart failure hospitalizations, and cardiovascular death. A dMSI increment of 1 standard deviation was associated with a 40% higher risk for adverse events (HR 1.4, 95% CI 1.2–1.5). Results were similar after adjustment for viability, demographic and clinical factors and focal ischemia. In sex-specific analysis, higher levels of dMSI (per standard deviation increment) were associated with 53% higher risk of adverse events in women (HR 1.5, 95% CI 1.2–2.0) but not in men (HR 0.9, 95% CI 0.5–1.4), P 0.001. A novel index of diffuse ischemia with mental stress was associated with recurrent events in women but not in men after MI.

Maternal and neonatal outcomes in pregnant women with heart disease with single evaluation vs. semi-structured evaluation by a cardio-obstetric team.

Cardiovascular diseases in pregnant women are challenging, with high maternal and perinatal morbidity and mortality, so a cardio-obstetric team is recommended for their care. Even so, little data evaluates the impact of these teams. Therefore, the present study aims to compare the obstetric, maternal, and neonatal outcomes of semi-structured follow-up (SSF) in a Cardio-obstetric clinic concerning regular or unstructured follow-up (USF) in pregnant women with heart disease. A prospective registry of pregnant women with heart disease was carried out. Patients with SSF by a cardio-obstetric team were compared with those with single evaluation or USF. The risk of events was calculated according to the modified World Health Organization (mWHO) classification and the CARPREG-II scale, and cardiac, obstetric, and neonatal outcomes were evaluated. One hundred sixty-eight patients were evaluated, 37 with SSF and 131 with single evaluation (USF). The primary diagnoses were congenital heart disease, arrhythmias, and valve disease. The average CARPREG-II in USF patients was 2.48 (SD 2.3); in SSF patients, it was 3.37 (SD 2.45; p = 0.041). The average of the mWHO in patients with USF was 2.1 (SD 1.6), and with SSF, it was 2.65 (SD 0.95; p = 0.0052). There were no significant differences in primary cardiac outcomes (13.8% in USF vs. 5.4% in SSF; p = 0.134), secondary cardiac (5.3% in USF vs. 2.7% in SSF; p = 0.410), obstetric (10% in USF vs. 16.2% in SSF; p = 0.253) and neonatal (35.9% in USF and 40.5% in SSF; p = 0.486) even though patients with SSF had a higher risk than patients with USF according to the mWHO and CARPREG-II scales. In pregnant women with heart disease, an SSF compared with a USF by a cardio-obstetric team did not show statistically significant differences in cardiovascular, obstetric, and neonatal outcomes. However, patients with SSF had a significantly higher risk of adverse outcomes due to the mWHO and CARPREG-II scales. This result suggests that the SSF achieves at least equal outcomes despite the higher risk of adverse events that patients in this group had.