Real-world Prospective Cohort Research Articles

Safety of beta-blocker discontinuation after acute coronary syndromes with preserved or mildly reduced left ventricular ejection fraction: a target trial emulation from a real-world cohort.

The benefit of long-term beta-blocker therapy after acute coronary syndromes (ACS) without heart failure in the reperfusion era is uncertain. Two recent randomized trials found conflicting results. The present study assessed the safety of beta-blocker discontinuation within 12 months following ACS with LVEF ≥40%. In a multicentre prospective real-world cohort (N=3,762) of patients hospitalized for ACS, patients with LVEF ≥40% and beta-blockers at discharge were included. Patients who continued beta-blockers at one year were compared with those who discontinued beta-blockers within 12 months post-ACS using target trial emulation and inverse probability weighting over an additional four-year follow-up. The primary endpoint was major adverse cardiovascular events (MACE), a composite of four-year cardiovascular death, myocardial infarction, stroke, transient ischemic attack, unplanned coronary revascularization, or unstable angina hospitalization. Of 2,077 patients, 1,758 (85%) continued beta-blockers and 319 (15%) had discontinued beta-blockers at one year. The risk of primary endpoint was similar in both groups (14.1% versus 14.3% with beta-blocker discontinuation versus continuation; adjusted hazard ratio [aHR]=0.98; 95% confidence interval, 0.72-1.34, P=0.91). Subgroup analysis suggested a higher risk of primary endpoint with beta-blocker discontinuation after STEMI (aHR=1.46 [0.99-2.16]) compared to NSTEMI (aHR=0.70 [0.40-1.22], Pinteraction=0.033), whereas there was no interaction with LVEF (Pinteraction=0.68). Beta-blocker discontinuation within 12 months following ACS with LVEF ≥40% was not associated with an increased risk of MACE compared to long-term beta-blocker therapy. Subgroup analysis suggested potential risk in STEMI patients. Discontinuing beta-blockers 12 months after ACS appears safe in patients with LVEF ≥40%, particularly after NSTEMI.

Frailty and in-hospital mortality in older patients with acute exacerbation of COPD: A real-world prospective cohort study

BackgroundFew evidence exists for the effect of frailty on the patients admitted with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). ObjectiveWe explored the link between frailty and in-hospital death in AECOPD, and whether laboratory indicators mediate this association. MethodsThis was a real-world prospective cohort study including older patients with AECOPD, consisting of two cohorts: a training set (n = 1356) and a validation set (n = 478). The independent prognostic factors, including frail status, were determined by multivariate logistic regression analysis. The relationship between frailty and in-hospital mortality was estimated by multivariable Cox regression. A nomogram was developed to provide clinicians with a quantitative tool to predict the risk of in-hospital death. Mediation analyses for frailty and in-hospital death were conducted. ResultsThe training set included 1356 patients (aged 86.7 ± 6.6 years), and 25.0 % of them were frail. A nomogram model was created, including ten independent variables: age, sex, frailty, COPD grades, severity of exacerbation, mean arterial pressure (MAP), Charlson Comorbidity Index (CCI), Interleukin-6 (IL-6), albumin, and troponin T (TPN-T). The area under the receiver operating characteristic curve (ROCs) was 0.862 and 0.845 for the training set and validation set, respectively. Patients with frailty had a higher risk of in-hospital death than those without frailty (HR,1.83, 95%CI: 1.14, 2.94; p = 0.013). Furthermore, CRP and albumin mediated the associations between frailty and in-hospital death. ConclusionsFrailty may be an adverse prognostic factor for older patients admitted with AECOPD. CRP and albumin may be part of the immunoinflammatory mechanism between frailty and in-hospital death.

Comparison of the disease presentation of early- vs. later-onset colorectal cancer within the prospective ColoCare study.

91 Background: Within the United States (US), colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related fatalities, with a median age at diagnosis of 66 years. While the incidence of sporadic CRC is decreasing, the incidence in those aged 18-49 years has steadily increased. Younger patients are not often screened for CRC, and they are often diagnosed at a later stage of disease. Herein, we compare the presenting symptoms and stage at diagnosis of early-onset CRC to disease in those aged 50 or greater. Methods: The ColoCare Study is a prospective cohort enrolling individuals diagnosed with primary CRC across six cancer centers in the US and one site in Germany. Serial questionnaires administered at baseline assessed demographic characteristics and symptoms experienced prior to diagnosis, while clinical data such as staging and pathology were abstracted from medical records. For this analysis, only patients who had available age and tumor stage were included. Patients diagnosed <50 years old were categorized as “early-onset” and ≥50 as “later-onset.” Fisher’s exact test was used to compare demographics, disease state characteristics, and symptoms experienced by age group. Statistical significance was based on a two-sided alpha level of 0.05. Results: 1,996 patients were included in this analysis. Of these, 1,508 (76%) were later-onset (mean diagnosis age 64, range: 50-94), while 488 (24%) were early-onset (mean age: 42, range: 21-49). Demographic data was similar between early- and later-onset patients in terms of gender and primary site. Disease stage at diagnosis was significantly associated with age (p < 0.001). A higher proportion of early-onset patients had advanced disease at the time of diagnosis compared to later-onset for both stage III (43% vs 37%) and stage IV disease (28% vs 17%). For patients with available histologic data, younger patients were more likely to have vascular (35% vs 28%, p=0.03) and perineural invasion (33% vs 21%, p <0.001) at diagnosis. Early-onset patients were also more likely to report symptoms prior to diagnosis (95% vs 83%, p <0.001). Specifically, younger patients reported higher rates of abdominal pain (46% vs 23%, p < 0.001), blood in stool (71% vs 54%, p <0.001), and changes in bowel habits (54% vs 40%, p <0.001). General weakness and vomiting were also statistically more likely to be noted at presentation in early-onset patients. Conclusions: In this prospective real-world cohort analysis, patients with early-onset CRC are more likely to be diagnosed with more advanced disease at presentation than later-onset patients. This analysis highlights key symptoms that should raise awareness as possible indicators of a new diagnosis of CRC, even in individuals <50 years old. Additional disease comparisons between age groups will be presented at the meeting.

Real-World Clinical Equivalence of Generic and Branded Tofacitinib: A Prospective Longitudinal Cohort Study in Patients With Rheumatoid Arthritis

ObjectivesTo explore the clinical efficacy and safety of generic tofacitinib vs brand name tofacitinib in patients with rheumatoid arthritis (RA) in a single-center comparative study based on a prospective real-world cohort. MethodsPatients with RA receiving tofacitinib, either generic (Kelejia) or branded (Xeljanz), from March 2017, to December 31, 2022, were enrolled. The primary outcome was the simplified disease activity index (SDAI)–defined remission rate at month 6. Secondary outcomes included the rates of remission and low disease activity defined by other composite scores; European Alliance of Associations for Rheumatology response rate, and ultrasonic synovitis scores at months 1, 3, 6, and 12. Cost-effectiveness was investigated. Propensity score–based inverse probability of treatment weighting was adopted to reduce selection bias. ResultsA total of 204 patients were enrolled: 59 in the generic group and 145 in the branded group. An SDAI-defined remission was achieved in 41.1% and 39.2% of patients in the generic and branded groups, respectively, at month 6 (P=.85). Rates of remission and low disease activity achievement, changes in clinical disease activity scores, and power Doppler and gray scale synovitis scores at months 1, 3, 6, and 12 were comparable between the 2 groups. Similar proportions of patients in the groups achieved moderate/good response at months 1, 3, 6, and 12. Rates of drug retention and adverse effects were also similar in the 2 groups. Both Kelejia and Xeljanz were cost-effective, but Kelejia had a lower average cost-effectiveness ratio. ConclusionGeneric tofacitinib (Keljia) had equivalent clinical efficacy and safety and better cost-effectiveness compared with its originator (Xeljanz).

Long-term efficacy and safety of dupilumab for moderate-to-severe atopic dermatitis: a prospective real-world cohort study in China.

Dupilumab has demonstrated remarkable efficacy and safety in clinical trials for moderate-to-severe atopic dermatitis (AD). However, long-term real-world evidence, especially in the Chinese population, remains limited. To investigate the long-term efficacy and safety of dupilumab for moderate-to-severe AD in a real-world clinical setting in China and analyze factors that may influence its long-term treatment outcomes. This prospective, observational real-world study included moderate-to-severe AD patients from the AD cohort of the dermatology department of Chongqing Hospital of Traditional Chinese Medicine who received dupilumab treatment for≥52 weeks. Efficacy and adverse events were assessed at baseline, weeks 4, 16, 24, and 52. Multivariate logistic regression analysis was used to identify predictive factors for achieving EASI 50 and EASI 75 at week 52. A total of 124 patients were included. At week 52, EASI, SCORAD, IGA, NRS, and DLQI scores were significantly improved compared to baseline. The proportions of patients achieving EASI-50/75 were 50.81%/29.84%, 72.58%/42.74%, 75%/53.23%, and 67.74%/41.94% at weeks 4, 16, 24 and 52, respectively. Female sex, absence of atopic comorbidities, higher baseline EASI, and medication compliance were positive predictive factors for 52-week EASI-50/75. Eosinophil elevation predicted lower EASI-50 attainment. Nineteen adverse events occurred during the 52-week period (incidence rate: 14.52%), mostly mild and manageable. Dupilumab demonstrated significant efficacy and a low incidence of adverse events over 52 weeks in Chinese patients with moderate-to-severe AD, making it an effective and safe long-term treatment option. Predictive factors were identified to guide treatment optimization.

Safety, effectiveness, and usefulness of higher-dose tablets of generic pirfenidone in patients with IPF: a nationwide observational study in South Korea.

Pirfenidone is an antifibrotic medication approved for idiopathic pulmonary fibrosis (IPF). Fybro®, a generic version of pirfenidone developed in South Korea, gained approval and is available in 200mg and in higher-dose formulations of 400 and 600mg. This real-world prospective cohort study investigated the safety and effectiveness of Fybro®. A nationwide observational study was conducted in patients with IPF. Patients were followed up for 6 months, with a subset of patients being followed up for 12 months. Data on lung function and adverse events were collected. Patient adherence to fewer-pill (400 and/or 600mg tablets) and multiple-pill (200mg tablets) regimens were compared. Of the 359 enrolled patients, 352 received pirfenidone (Fybro®) at least once and were included in the analysis. The mean age was 69.0 years and 82.4% of patients were male. The median treatment duration was 186.0 days. A total of 253 patients (71.9%) experienced adverse events, with decreased appetite being the most common (16.5%). The adjusted decline rates in lung function were -1.5% and -2.2% predicted per year for forced vital capacity and diffusing capacity, respectively. No significant differences were observed based on the pirfenidone dose. For a daily intake of 1,200 or 1800mg of pirfenidone, a significantly longer duration of drug administration was observed with the fewer-pill regimen than with multiple-pill regimen. The safety and effectiveness of Fybro® observed in this real-world cohort study are consistent with previous studies. Using higher-strength tablets to reduce pill burden may improve medication adherence.

Efficacy and Safety of Methylphenidate and Atomoxetine in Medication-Naive Children with Attention-Deficit Hyperactivity Disorder in a Real-World Setting.

Methylphenidate (MPH) and atomoxetine (ATX) are the most common medications used to treat attention-deficit hyperactivity disorder (ADHD) in China; however, despite this, there is still a paucity of studies comparing their efficacy and safety, particularly for different characteristics. To address the lack of research, a real-world prospective cohort study was conducted to examine these properties of MPH and ATX, and to analyze correlations associated with age, sex, and different ADHD presentation. Children with ADHD meeting the eligibility criteria were recruited from January 2016 to July 2021. Study participants were treated with either MPH or ATX prescribed in the real-world setting, and were followed up for 26 weeks. Clinical efficacy response and adverse events (AEs) were recorded and measured. Subgroup analysis was performed to examine the efficacy response and AEs associated with age, sex, and different ADHD presentation. A total of 1050 children were recruited and 29 children were lost to follow-up. Of the 1021 children remaining, 533 were treated with MPH and 488 were treated with ATX. No significant differences were found in intelligence quotient, age, sex, or ADHD presentation between the MPH- and ATX-treated groups (p>0.05). The response rates were 84.6% in the MPH-treated group and 63.3% in the ATX-treated group. Subgroup analysis of response rate demonstrated that the treatment effect of MPH over ATX was consistent across subgroups except in the girls (odds ratio [OR] 2.09, 95% confidence interval [CI] 0.97-4.7) and the hyperactive/impulsive presentation group (OR 2.88, 95% CI 0.77-12.76). A total of 47.8% of children experienced AEs during MPH treatment, significantly lower than the rate of 56.8% during ATX treatment (p<0.05). The incidence of AEs in the MPH-treated group was higher in young children (<8years: 56.8%; 8-10 years: 47.2%) and lower in children over 10 years of age (29.0%). Overall, MPH was more effective and better tolerated than ATX. The incidence of AEs in children treated with MPH varied with age, and was higher in young children and lower in children over 10 years of age.

Impact of the infarct-related coronary artery on inflammatory profiles and outcomes in patients presenting with acute coronary syndromes: insights from a prospective multicenter real-world cohort

Abstract Background Patients with a total coronary occlusion (TCO) of the infarct-related artery (IRA) frequently present as ST-segment elevation myocardial infarction (STEMI). However, patients presenting as non-ST-segment elevation acute coronary syndromes (NSTE-ACS) on a routine ECG may actually have TCO at angiography, typically involving left circumflex (LCx) or right coronary artery (RCA) as the IRA. These patients might be at higher risk of MACE due to a delayed diagnosis and, consequently, an inappropriately prolonged time window to revascularization. Herein, we aimed to describe clinical characteristics and outcomes of IRA location in patients presenting with ACS enrolled in a real-world prospective cohort. Methods Between 2009 and 2017, 4,787 ACS patients were prospectively recruited in the SPUM-ACS prospective study. The primary outcome measure was major adverse cardiovascular events (MACE), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at one year. Multivariable-adjusted Cox regression models were fit using backward selection. Coronary angiographies were reviewed by operators of each site to assess the IRA location and TCO was defined in the presence of TIMI 0 flow. Results 4,542 ACS patients (95% of the total cohort) had angiographic studies available. Patients with left main (n=75) and bypass graft (n=55) as culprit artery were excluded and a final sample size of 4,412 patients were included in the present analysis; 56% (n=2469) presented with ST-elevation myocardial infarction (STEMI) and 44% (n=1943) with NSTE-ACS. Overall, the IRA was the right coronary artery (RCA) in 33.9% (n=1494), the left-anterior descending coronary artery (LAD) in 45.6% (n=2013) and the left circumflex (LCx) in 20.5% (n=905). In those presenting with STEMI, patients with LAD as IRA had an increased risk of MACE (1.43, 95% CI 1.02-2.00, p = 0.04) as compared to those with RCA and LCx. In those presenting with NSTE-ACS, LCx and RCA as IRA had more frequently a TCO compared to the LAD (27% and 24%, respectively, vs. 9%, p&amp;lt;0.001). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher hs-CRP and hs-TnT, lower eGFR, and absent history of MI. Among patients with NSTE-ACS, LCx as IRA but not LAD and RCA was associated with an increased risk of MACE at one 1 year (fully adjusted HR 1.68, 95% CI 1.10-2.59, p=0.02; reference: RCA and LAD). Conclusion Among all ACS patients included in the SPUM-ACS, those with NSTE-ACS at initial ECG and RCA and LCx involvement had more often a TCO of the IRA, but only LCx as IRA was an independent predictor of MACE during follow-up. Hs-CRP levels, lymphocytes and neutrophils counts, hs-TnT, eGFR and history of MI at admission were found to be independent predictors of IRA occlusion at angiography. Thus, NSTE-ACS patients showing such features should further be evaluated for timely PCI.

A real-world 2-year prospective study of medication tapering in patients with well-controlled rheumatoid arthritis within the rheumatoid arthritis medication tapering (RHEUMTAP) cohort.

This study had two aims: (i) to investigate outcomes of medication tapering in stable RA patients on biologic or targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) and conventional synthetic DMARDs (csDMARDs) in a real-world prospective cohort; and (ii) to evaluate possible predictors of flare with medication taper. A prospective cohort of patients with RA in sustained remission or low disease activity while on stable bDMARD/tsDMARDs +/- csDMARDs for at least 6 months underwent medication tapering/stopping and was tracked for 2 years. Patients were evaluated for flares in four groups: no taper, only bDMARD/tsDMARD taper, only csDMARD taper and both csDMARD and bDMARD/tsDMARD taper. The RHEUMTAP cohort included 131 patients that met eligibility criteria, of which 52 patients underwent a medication taper. Flare was experienced by 15 patients in the taper and twoin the no-taper groups. Patients undergoing any taper/stop overall were 10 times more likely to experience a flare compared with those not tapered (HR 10.43, 95% CI 2.98-36.53, P = 0.0002). The group tapering bDMARD/tsDMARD had 31 times higher risk of flare (HR 31.43, 95% CI 6.35-155.55, P<0.0001) than the no-taper group. Patients tapering both csDMARDs and bDMARD/tsDMARDs had 18 times higher risk of flare than the no-taper group (HR 18.45, 95% CI 2.55-133.37, P = 0.0039). The only csDMARD taper group had a 91% lower risk of flare than the bDMARD/tsDMARD taper group (HR 0.09, 95% CI 0.01-0.69, P = 0.0213). In our real-world prospective RHEUMTAP cohort study on the outcomes of different medication tapering groups in well-controlled RA, patients who tapered or stopped bDMARDs/tsDMARDs with or without background therapy were more likely to experience a flare than patients that did not taper any medications and those that tapered only csDMARDs.

A Real-World Prospective Cohort Study of Patients With Newly Diagnosed Crohn's Disease Treated by a Multidisciplinary Team: 1-Year Outcomes.

Real-world data on outcomes of patients with newly diagnosed Crohn's disease (ndCD) is limited. We aimed to assess the achievement of corticosteroid-free clinical remission (CS-free CR) and other therapeutic targets 1 year after diagnosis in a cohort of patients with ndCD treated by a multidisciplinary team (MDT). A prospective observational cohort study was conducted on consecutive treatment-naïve adults with ndCD. Patients received management at the treating physician's discretion, along with a tailored nutritional plan provided by an inflammatory bowel disease (IBD)-oriented dietitian. Patients were guided and educated by an IBD nurse, with flexible communication access to the IBD team. Therapeutic targets were assessed at 1 year. Multivariable logistic regression was used to evaluate predictors of CS-free CR. Seventy-six patients (50% female) with a median age of 27 (22-39) years were eligible. Over 75% of patients were assessed by IBD-oriented dietitians and the IBD nurse. Within a median of 4.3 (2.5-6.7) months from diagnosis 60.5% initiated biologics (96% anti- tumor necrosis factor). Dietary intervention was applied to 77.6% of the cohort, either monotherapy (33.9%) or add-on (66.1%). At 1 year, 64.5% of patients achieved sustained CS-free CR, 56.6% biochemical remission, 55.8% endoscopic response, 44.2% endoscopic remission, 30.8% deep remission, and in 39.5% there was an improvement in health-related quality of life (HRQoL). Predictors for CS-free CR were uncomplicated phenotype (B1/P0), lower body mass index, and lower patient-reported outcome 2 scores at diagnosis. In a real-world setting at a tertiary medical center, a cohort of ndCD patients treated by an MDT resulted in favorable 1-year outcomes. Over 60% achieved CS-free CR, along with significant improvements in biomarkers and HRQoL.

Effectiveness and safety of REBACIN as a non-invasive intervention for persistent high-risk human papillomavirus infection: A real-world prospective multicenter cohort study

BackgroundWe previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. MethodsAccording to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. ResultsThe clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. ConclusionThis study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. Clinical trial registrationChinese Clinical Trial RegistryRegistration Number: ChiCTR1800015617http://www.chictr.org.cn/showproj.aspx?proj=26529Date of Registration: 2018-04-11

D-dimer to fibrinogen ratio predicts early neurological deterioration in ischemic stroke with atrial fibrillation

IntroductionThe D-dimer to fibrinogen ratio (DFR) is a good indicator of clot-producing activity in thrombotic disease, but its clinical usefulness in stroke patients with nonvalvular atrial fibrillation (NVAF) has not been studied. We evaluated the association between the DFR and early neurological deterioration (END) in acute ischemic stroke (AIS) patients with NVAF. MethodsWe included consecutive AIS patients with NVAF between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. END was defined as an increase ≥2 in the total NIHSS score or ≥ 1 in the motor NIHSS score within the first 72 h of admission. The DFR was calculated as follows: DFR = D-dimer (mg/L)/fibrinogen (mg/dL) x 100. ResultsA total of 1018 AIS patients with NVAF were evaluated. In multivariable logistic regression analysis, the highest DFR tertile was closely associated with END (adjusted odds ratio [aOR] = 2.14, 95 % confidence interval [CI]: 1.24–3.69). Hypertension (aOR = 1.71, 95 % CI: 1.09–2.70), initial NIHSS score (aOR = 1.05, 95 % CI: 1.02–1.07) and use of anticoagulants (aOR = 0.41, 95 % CI: 0.28–0.60) were also correlated with END. In addition to END, the DFR was correlated with discharge NIHSS and modified Rankin Scale (mRS) scores and the 3-month mRS score. ConclusionsHigh DFR values were associated with END in AIS patients with NVAF. As the DFR is an indicator directly related to the main pathological mechanism of NVAF patients (fibrinolysis and coagulation), it may be useful in predicting their prognosis.

Local injection of micro-dose anti-interleukin-17A antibody for palmoplantar pustulosis: A real-world study

Palmoplantar pustulosis (PPP), a chronic and stubborn skin disease, is mainly confined to the palms or/and soles, making it possible for localized use of therapeutic antibodies. In this real-world prospective cohort study, 8 patients with PPP received palms/soles injections of ixekizumab (0.8 mg in 0.1 ml) every 2 to 8 weeks due to the COVID-19 pandemic. The treatment endpoint was a 75% improvement from baseline in Palmoplantar Pustulosis/Psoriasis Area and Severity Index (PPPASI 75). At week 8, 75%, 50% and 12.5% of 8 patients reached PPPASI 50, PPPASI 75 and PPPASI 90. At week 12, 100%, 75% and 25% of 8 patients reached PPPASI 50, PPPASI 75 and PPPASI 90. This is the first study to evaluate the efficacy and safety of local injection of micro-dose ixekizumab for PPP in real clinical practice. A high proportion of patients rapidly achieved PPPASI 75, and maintained long-term efficacy with satisfactory safety.

Comprehensive analysis of the mutational status of early colon cancer: Real world data from the AIO ColoPredict registry study.

e15535 Background: The comprehensive analysis of the mutational status of colon cancer (CC) may identify targetable alterations also in early stages. This may open up potential beneficial treatment choices, e.g. immunotherapy in microsatellite instable (MSI) tumors. So far, there is few data regarding the distribution of molecular alterations in CC in a real world setting in Germany. Methods: We analyzed clinical and molecular data from our Colopredict Plus (CPP) registry trial including CC patients (pts.) stage I-III. Samples were tested for MS status by immunohistochemistry and for gene mutations (MT) using a 71 gene panel comprised for CC. Molecular data was correlated with clinicopathologic parameters. Disease free Survival (DFS) was estimated by the Kaplan-Meier method. Results: Data from 2746 pts. was included. Female: 1476/2746 (53,8 %), median age: 72 yrs (range: 22-100 yrs), right sided tumor: 1607/2746 (58,5 %), stage distribution I/II/III/NA: 414 (15,1 %)/1198 (43,6 %)/1076 (39,2 %)/58 (2,1 %). MSI/MSS: 544(19,8%)/2202/ (80,2%). A KRAS mutation was observed in 846/2746 (30,8 %). The most frequent hotspot MT were codon 12 KRAS MT with p.G12D (27%), p.G12V (19%), p.G12A (6%), and p.G12C (6%) followed by codon 13 MT with p.G13D (18%). The subtypes p.G12D, p.G12V, and p.Q61K were significantly more frequent in the right colon. BRAF MT was seen in 560/2746 (20,4%). Observed rare MT were: POLE (76/2746 (2,8 %), PTEN 188/2746 (6,8 %), and EGFR (21/2746; 0,8%). MSI CC were more frequent in the right colon and associated with BRAF MT (346/560; 61,8 %), and also MT in BRCA1 (35/53; 66 %), BRCA2 (119/171; 69,6 %), POLE (45/76 (59,2 %), PTEN 107/188 (56,9 %), and EGFR (18/21, 85,7%). In contrast, TP53 MT (1223/2746 (44,5 %)) were associated with MSS (1090/2746 (49,5 %)). 3 yrs DFS in MSI BRAF WT vs. MSS BRAF MT pts. was 0,75 (0,67 – 0,81 vs 0,52 (0,36 – 0,65) (p =0,11). DFS did not differ in specific KRAS MT variants. Conclusions: We here show a comprehensive analysis of genetic alterations in early CC in a prospective real world cohort. As expected, MSI was correlated with female sex, right sided primary tumor and BRAF MT. Interestingly, we also found a strong correlation of BRCA1 MT, BRCA2 MT, EGFR MT, POLE MT, and PTEN MT with presence of MSI while MSS was associated with TP53 MT. Broad molecular characterization of early CC may help individualize treatment strategies in the future.

Clinical and hemodynamic outcomes of the Perceval sutureless aortic valve from a real-world registry.

Perceval sutureless valve has been in clinical use for >15 years. The aim of this study is to report the real-word clinical and haemodynamic performance from the SURE-aortic valve replacement international prospective registry in patients who underwent aortic valve replacement with Perceval valve. From 2011 to 2021, patients from 55 institutions received a Perceval valve. Postoperative, follow-up, and echocardiographic outcomes were analysed. A total of 1652 patients were included; mean age was 75.3 ± 7.0 years (53.9% female); mean EuroSCORE II was 4.1 ± 6.3. Minimally invasive approach was performed in 45.3% of patients; concomitant procedures were done in 35.9% of cases. Within 30 days, 0.3 and 0.7% valve-related reinterventions were reported. Transient ischaemic attack, disabling and non-disabling strokes were limited (0.4%, 0.4% and 0.7%, respectively). Pacemaker implant was required in 5.7% of patients. Intra-prosthetic regurgitation ≥2 was present in 0.2% of cases, while paravalvular leak ≥2 in only 0.1%. At a maximum follow-up of 8 years, 1.9% of cardiovascular deaths and 0.8% of valve-related reintervention occurred. Among the 10 cases of structural valve deterioration (mean 5.6 ± 1.4 years after implant; range: 2.6-7.3 years), 9 were treated with a transcatheter vale-in-valve implantation and 1 with explant. Mean pressure gradient decreased from 45.8 ± 16.5 mmHg preoperatively to 13.3 ± 5.2 mmHg at discharge and remained stable during follow-up. This experience represents the largest prospective real-world cohort of patients treated with Perceval showing that Perceval is a safe and effective alternative to conventional surgical aortic valve replacement, providing favourable clinical and haemodynamic results also at mid-term follow-up.

Occlusion of the infarct-related coronary artery presenting as acute coronary syndrome with and without ST-elevation: impact of inflammation and outcomes in a real-world prospective cohort.

Patients with ST-segment elevation typically feature total coronary occlusion (TCO) of the infarct-related artery (IRA) on angiography, which may result in worse outcomes. Yet, relying solely on electrocardiogram (ECG) findings may be misleading and those presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) may have TCO as well. Herein, we aimed to delineate clinical characteristics and outcomes of patients with ACS stratified by IRA location. A total of 4787 ACS patients were prospectively recruited between 2009 and 2017 in SPUM-ACS (ClinicalTrials.gov Identifier: NCT01000701). The primary endpoint was major adverse cardiovascular events (MACEs), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at 1 year. Multivariable-adjusted survival models were fitted using backward selection. A total of 4412 ACS patients were included in this analysis, 56.0% (n=2469) ST-elevation myocardial infarction (STEMI) and 44.0% (n=1943) NSTE-ACS. The IRA was the right coronary artery (RCA) in 33.9% (n=1494), the left-anterior descending coronary artery (LAD) in 45.6% (n=2013), and the left circumflex (LCx) in 20.5% (n=905) patients. In STEMI patients, TCO (defined as TIMI 0 flow at angiography) was observed in 55% of cases with LAD, in 63% with RCA, and in 55% with LCx. In those presenting with NSTE-ACS, TCO was more frequent in those with LCx and RCA as compared to the LAD (27 and 24%, respectively, vs. 9%, P<0.001). Among patients with NSTE-ACS, occlusion of the LCx was associated with an increased risk of MACE during 1 year after the index ACS (fully adjusted hazard ratio 1.68, 95% confidence interval 1.10-2.59, P=0.02; reference: RCA and LAD). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher levels of high-sensitivity C reactive protein (hs-CRP) and high-sensitivity cardiac troponin T, lower eGFR, and notably a negative history of MI. In NSTE-ACS, both LCx and RCA involvement was associated with TCO at angiography despite the absence of ST-segment elevation. Involvement of the LCx, but not the LAD or RCA, as the IRA represented an independent predictor of MACE during 1-year follow-up. Hs-CRP, lymphocyte, and neutrophil counts were independent predictors of total IRA occlusion, suggesting a possible role of systemic inflammation in the detection of TCO irrespective of ECG presentation.

The unreversible reduced but persistent activated NK and CD8+ T cells in severe/critical COVID-19 during omicron pandemic in China

ABSTRACT As a hallmark of COVID-19 progression, lymphopenia alongside its subtle immune disturbance has been widely reported, but yet to be thoroughly elucidated. Aiming at exploring clinical immune biomarkers with accessibility in the current and acute omicron epidemic abrupted in China post-control era, we design a real-world prospective observation cohort in Peking Union Medical College Hospital to describe immunological, haematological profiles inducing lymphocyte subsets related to SARS-CoV-2 infection. In this COVID-19 cohort, we enrolled 17 mild/moderate (M/M), 24 severe (S) and 25 critical (C) patients. The dynamics of lymphocytes of COVID-19 demonstrated that the sharp decline of NK, CD8+, and CD4+ T cell counts was the main contributor to lymphopenia in the S/C group, compared to the M/M group. Expressions of activation marker CD38 and proliferation marker Ki-67 both in CD8+ T and NK cells were significantly higher in all COVID-19 patients than that in healthy donors, independent of disease severity. The subsequent analysis showed in contrast to the M/M group, NK and CD8+ T cell counts remained low-level after therapy in the S/C group. CD38 and Ki-67 expressions in NK and CD8+ T cells still stay at a high level, despite active treatment. Targeting relatively elderly patients with SARS-CoV-2 infection, severe COVID-19 features the unreversible reduction of NK and CD8+ T cells with persistent activation and proliferation, which assist clinicians in early recognizing and saving severe or critical COVID-19 patients. Given that immunophenotype, the new immunotherapy improving NK and CD8+ T lymphocyte antiviral efficiency should be considered.

Analysing patient-generated data to understand behaviours and characteristics of women with epilepsy of childbearing years: A prospective cohort study

BackgroundWomen with epilepsy (WWE) are vulnerable in pregnancy, with increased risks to mother and baby including teratogenic risks, especially from valproate. The free EpSMon mobile-phone app allows self-monitoring to afford patient-centred feedback on seizure related risks, such as sudden death in epilepsy (SUDEP) to its users. We sought to generate insights into various seizure related risks and its treatments in WWE of childbearing age (16 to 60 years ) using EpSMon. MethodsThe study utilizes a prospective real-world cohort of 5.5 years. Patient reported data on demographics, medication taken, diagnoses, seizure types and recognised biological, psychological, and social factors of seizure related harm were extracted. Data was stratified according to frequent and infrequent users and those scoring lower and higher risk scores. Multivariate logistic regression and different statistical tests were conducted. FindingsData from 2158 WWE of childbearing age encompassing 4016 self-assessments were analysed. Overall risk awareness was 25.3% for pregnancy and 54.1% for SUDEP. Frequent users were more aware of pregnancy risks but not of SUDEP. Repeated EpSMon use increased SUDEP awareness but not pregnancy risks. Valproate was used by 11% of WWE, ranging from 6.5% of younger to 31.5% of older women. ConclusionsThe awareness to risks to pregnancy, SUDEP and valproate is low. Valproate is being used by a significant minority. It is imperative risk communication continues for WWE based on their individual situation and need. This is unlikely to be delivered by current clinical models. Digital solutions hold promise but require work done to raise implementation and acceptability.

Factor Analysis in Distinguishing Coronavirus Disease 2019 From Other Influenza-like Illness Using a Validated Patient-Reported Outcome Instrument FLU-PRO Plus: A Prospective Real-world Cohort Study.

InFLUenza Patient-reported Outcome (FLU-PRO Plus) is a 34-item patient-reported outcome instrument designed to capture the intensity and frequency of viral respiratory symptoms. This study evaluates whether FLU-PRO Plus responses could discriminate between symptoms of coronavirus disease 2019 (COVID-19) and influenza-like illness (ILI) with no COVID diagnosis, as well as forecast disease progression. FLU-PRO Plus was administered daily for 14 days. Exploratory factor analysis was used to reduce the FLU-PRO Plus responses on the first day to 3 factors interpreted as "symptom clusters." The 3 clusters were used to predict COVID-19 versus ILI diagnosis in logistic regression. Correlation between the clusters and quality of life (QoL) measures was used to assess concurrent validity. The timing of self-reported return to usual health in the 14-day period was estimated as a function of the clusters within COVID-19 and ILI groups. Three hundred fourteen patients completed day 1 FLU-PRO Plus, of which 65% had a COVID-19 diagnosis. Exploratory factor analysis identified 3 symptom clusters: (1)general Body, (2) tracheal/bronchial, and (3) nasopharyngeal. Higher nasopharyngeal scores were associated with higher odds of COVID-19 compared with ILI diagnosis [adjusted odds ratio = 1.61 (1.21, 2.12)]. Higher tracheal/bronchial scores were associated with lower odds of COVID-19 [0.58 (0.44, 0.77)]. The 3 symptom clusters were correlated with multiple QoL measures ( r = 0.14-0.56). Higher scores on the general body and tracheal/bronchial symptom clusters were associated with prolonged time to return to usual health [adjusted hazard ratios: 0.76 (0.64, 0.91), 0.80 (0.67, 0.96)]. Three symptom clusters identified from FLU-PRO Plus responses successfully discriminated patients with COVID-19 from non-COVID ILI and were associated with QoL and predicted symptom duration.

Predictors for insufficient SARS-CoV-2 vaccination response upon treatment in multiple sclerosis.

Disease-modifying therapies (DMT) for multiple sclerosis (MS) influence SARS-CoV-2 vaccination response, which might have implications for vaccination regimens in individual patients. Expanding the knowledge of predictors for an insufficient vaccination response as a surrogate for protection against severe disease courses of infection in people with MS (pwMS) under DMT is of great importance in identifying high-risk populations. Cross-sectional analysis of vaccination titre and its modifiers, in a prospective real-world cohort of 386 individuals (285 pwMS and 101 healthy controls) by two independent immunoassays between October 2021 and June2022. In our cohort, no difference in vaccination antibody level was evident between healthy controls (HC) and untreated pwMS. In pwMS lymphocyte levels, times vaccinated and DMT influence SARS-CoV-2 titre following vaccination. Those treated with selective sphingosine-1-phosphate receptor modulators (S1P) showed comparable vaccination titres to untreated; higher CD8 T cell levels prior to vaccination in B cell-depleted patients resulted in increased anti-spike SARS-CoV2 antibody levels. PwMS under DMT with anti-CD20 treatment, in particular those with decreased CD8 levels before vaccination, as well as non-selective S1P but not selective S1P are at increased risk for insufficient SARS-CoV-2 vaccination response. This argues for a close monitoring of anti-spike antibodies in order to customize individual vaccination regimens within these patients. This work was supported by the German Research Foundation (DFG, CRC-TR-128 to TU, SB, and FZ).