Association of preoperative beta-blocker use and cardiac complications after major noncardiac surgery: a prospective cohort study.

INTRODUCTION: Cardiac complications after major noncardiac surgery are common and associated with high morbidity and mortality. How preoperative use of beta-blockers may impact perioperative cardiac complications remains unclear. METHODS: In a multicentre prospective cohort study, preoperative beta-blocker use was ascertained in consecutive patients at elevated cardiovascular risk undergoing major noncardiac surgery. Cardiac complications were prospectively monitored and centrally adjudicated by two independent experts. The primary endpoint was perioperative myocardial infarction or injury attributable to a cardiac cause (cardiac PMI) within the first three postoperative days. The secondary endpoints were major adverse cardiac events (MACE), defined as a composite of myocardial infarction, acute heart failure, life-threatening arrhythmia, and cardiovascular death and all-cause death after 365 days. We used inverse probability of treatment weighting to account for differences between patients receiving beta-blockers and those who did not. RESULTS: A total of 3839/10 272 (37.4%) patients (mean age 74 yr; 44.8% female) received beta-blockers before surgery. Patients on beta-blockers were older, and more likely to be male with established cardiorespiratory and chronic kidney disease. Cardiac PMI occurred in 1077 patients, with a weighted odds ratio of 1.03 (95% confidence interval [CI] 0.94-1.12, P=0.55) for patients on beta-blockers. Within 365 days of surgery, 971/10 272 (9.5%) MACE had occurred, with a weighted hazard ratio of 0.99 (95% CI 0.83-1.18, P=0.90) for patients on beta-blockers. CONCLUSION: Preoperative use of beta-blockers was not associated with decreased cardiac complications including cardiac perioperative myocardial infarction or injury and major adverse cardiac event. Additionally, preoperative use of beta-blockers was not associated with increased all-cause death within 30 and 365 days. CLINICAL TRIAL REGISTRATION: NCT02573532.

Diagnostic and prognostic value of mannan-binding lectin associated protein (MAp19) for functionally relevant coronary artery disease.

BACKGROUND: This study aimed to evaluate the diagnostic and prognostic potential of MAp19, a regulating component of the lectin pathway of the complement system, in patients with suspected functionally relevant coronary artery disease (fCAD) as well as the determinants of MAp19 levels. METHODS: The presence of fCAD was adjudicated using myocardial perfusion imaging with single-photon emission tomography and, where available, coronary angiography. MAp19 levels were measured in participants at rest, at peak stress tests, and two hours after the stress. The study also tracked major cardiovascular events, including non-fatal myocardial infarction and cardiovascular death, over a five-year follow-up period. RESULTS: Among the 1,571 patients analyzed (32.3 % women), fCAD was identified in 462 individuals (29.4 %). MAp19 demonstrated no diagnostic significance, yielding an area under the curve (AUC) of 0.51 (0.47-0.55). Throughout the five-year follow-up, 107 patients (6.8 %) experienced non-fatal myocardial infarctions, 99 (6.3 %) had cardiovascular death, 194 (12.3 %) experienced all cause death and 50 (3.1 %) suffered a stroke. Cox and Kaplan-Meier analysis confirmed prognostic value of MAp19 for myocardial infarction, but not for cardiovascular death. Significant increases in the concentration of MAp19 were observed during bicycle (p = 0.001) and combined stress tests (p = 0.001). CONCLUSION: MAp19 demonstrated an association with the risk of myocardial infarction. Increases in MAp19 concentration were observed during bicycle and combined stress-tests.

Combining anatomical and biochemical markers in the detection and risk stratification of coronary artery disease.

AIM: We aimed to test the hypothesis if combining coronary artery calcium score (Ca-score) as a quantitative anatomical marker of coronary atherosclerosis with high-sensitive cardiac troponin as a quantitative biochemical marker of myocardial injury provided incremental value in the detection of functional relevant CAD (fCAD) and risk stratification. METHODS AND RESULTS: Consecutive patients undergoing myocardial perfusion SPECT (MPS) without prior CAD were enrolled. The diagnosis of fCAD was based on the presence of ischemia on MPS and coronary angiography- fCAD was centrally adjudicated in the diagnostic and prognostic domain. Diagnostic accuracy was evaluated using the area under receiver-operating characteristic curve. The composite of cardiovascular death and non-fatal acute myocardial infarction (AMI) within 730 days were the primary prognostic endpoints.Among 1715 patients eligible for the diagnostic analysis, 399 patients had fCAD. The combination of Ca-Score and hs-cTnT had good diagnostic accuracy for the diagnosis of fCAD, AUC 0.79 (95 % CI 0.77-0.81), but no incremental value compared to the Ca-score alone (AUC 0.79 (95%CI 0.77-0.81, p=0.965). Similar results were observed using hs-cTnI (AUC 0.80, 95%CI 0.77-0.82) instead of hs-cTnT.Among 1709 patients (99.7%) with available follow-up, 59 patients (3.5%) suffered the composite primary prognostic endpoint (nonfatal AMI n=34, CV death n=28).Both, Ca-score and hs-cTnT had independent prognostic value. Increased risk was restricted to patients with elevation in both markers. CONCLUSION: The combination of the Ca-score with hs-cTnT increases the prognostic accuracy for future events defining fCAD, but does not provide incremental value versus the Ca-Score alone for the diagnosis of fCAD.

Biodistribution and safety of a single rAAV3B-AAT vector for silencing and replacement of alpha-1 antitrypsin in Cynomolgus macaques.

Alpha-1 antitrypsin deficiency (AATD) is characterized by both chronic lung disease due to loss of wild-type AAT (M-AAT) antiprotease function and liver disease due to toxicity from delayed secretion, polymerization, and aggregation of misfolded mutant AAT (Z-AAT). The ideal gene therapy for AATD should therefore comprise both endogenous Z-AAT suppression and M-AAT overexpression. We designed a dual-function rAAV3B (df-rAAV3B) construct, which was effective at transducing hepatocytes, resulting in a considerable decrease of Z-AAT levels and safe M-AAT augmentation in mice. We optimized df-rAAV3B and created two variants, AAV3B-E12 and AAV3B-G3, to simultaneously enhance the concentration of M-AAT in the bloodstream to therapeutic levels and silence endogenous AAT liver expression in cynomolgus monkeys. Our results demonstrate that AAV3b-WT, AAV3B-E12, and AAV3B-G3 were able to transduce the monkey livers and achieve high M-AAT serum levels efficiently and safely. In this nondeficient model, we did not find downregulation of endogenous AAT. However, the dual-function vector did serve as a potentially "liver-sparing" alternative for high-dose liver-mediated AAT gene replacement in the context of underlying liver disease.

Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Copeptin for the differentiation of type 1 versus type 2 myocardial infarction or myocardial injury.

BACKGROUND: The rapid and reliable differentiation of myocardial infarction (MI) due to atherothrombosis (T1MI) from MI due to supply-demand mismatch (T2MI) or acute myocardial injury is of major clinical relevance due to very different treatments, but still a major unmet clinical need. This study aimed to investigate whether copeptin, a stress hormone produced in the hypothalamus, helps to differentiate between T1MI versus T2MI or injury. METHODS: In a retrospective analysis, 1271 unselected consecutive patients presenting with symptoms suggestive of MI to the emergency department were evaluated. Patients diagnosed with ST-elevation MI were excluded. All patients with elevated cardiac troponin I (cTnI) concentration possibly indicating MI were classified into T1MI, T2MI, or acute myocardial injury using detailed clinical assessment and coronary imaging. Copeptin plasma concentration was measured in a blinded fashion. A multicenter diagnostic study with central adjudication of the final diagnosis served as external validation cohort (n = 1390). RESULTS: Among 1161 patients, 154 patients had increased cTnI concentration. Of these, 78 patients (51%) were classified as T1MI and 76 (49%) as T2MI or myocardial injury. Patients with T2MI or myocardial injury had significantly higher copeptin plasma concentration between patients versus T1MI (21,4 pmol/l versus 8,1 pmol/l, p = 0,001). A multivariable regression analysis revealed that higher concentrations of copeptin and C-reactive protein, higher heart rate at presentation and lower frequency of smoking remained significantly associated with T2MI and myocardial injury. Findings were largely confirmed in the external validation cohort. CONCLUSION: In patients without ST-segment elevation, copeptin concentration was higher in T2MI and myocardial Injury versus T1MI and may help in their differential diagnosis.

Monocyte NLRP3 inflammasome and interleukin-1ß activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

A scoping review of Rasch analysis and item response theory in otolaryngology: Implications and future possibilities.

Objective: Item response theory (IRT) is a methodological approach to studying the psychometric performance of outcome measures. This study aims to determine and summarize the use of IRT in otolaryngological scientific literature. Methods: A systematic search of the Medline, Embase, and the Cochrane Library databases was performed for original English-language published studies indexed up to January 28, 2023, per the following search strategy: ("item response theory" OR "irt" OR "rasch" OR "latent trait theory" OR "modern mental test theory") AND ("ent" OR "otorhinolaryngology" OR "ear" OR "nose" OR "throat" OR "otology" OR "audiology" OR "rhinology" OR "laryngology" OR "neurotology" OR "facial plastic surgery"). Results: Fifty-five studies were included in this review. IRT was used across all subspecialties in otolaryngology, and most studies utilizing IRT methodology were published within the last decade. Most studies analyzed polytomous response data, and the most commonly used IRT models were the partial credit and the rating scale model. There was considerable heterogeneity in reporting the main assumptions and results of IRT. Conclusion: IRT is increasingly being used in the otolaryngological scientific literature. In the otolaryngology literature, IRT is most frequently used in the study of patient-reported outcome measures and many different IRT-based methods have been used. Future IRT-based outcome studies, using standardized reporting guidelines, might improve otolaryngology-outcome research sustainably by improving response rates and reducing patient response burden. Level of evidence: 2.

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

Machine Learning for Myocardial Infarction Compared With Guideline-Recommended Diagnostic Pathways.

BACKGROUND: Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) is a validated clinical decision support tool that uses machine learning with or without serial cardiac troponin measurements at a flexible time point to calculate the probability of myocardial infarction (MI). How CoDE-ACS performs at different time points for serial measurement and compares with guideline-recommended diagnostic pathways that rely on fixed thresholds and time points is uncertain. METHODS: Patients with possible MI without ST-segment-elevation were enrolled at 12 sites in 5 countries and underwent serial high-sensitivity cardiac troponin I concentration measurement at 0, 1, and 2 hours. Diagnostic performance of the CoDE-ACS model at each time point was determined for index type 1 MI and the effectiveness of previously validated low- and high-probability scores compared with guideline-recommended European Society of Cardiology (ESC) 0/1-hour, ESC 0/2-hour, and High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome) pathways. RESULTS: In total, 4105 patients (mean age, 61 years [interquartile range, 50-74]; 32% women) were included, among whom 575 (14%) had type 1 MI. At presentation, CoDE-ACS identified 56% of patients as low probability, with a negative predictive value and sensitivity of 99.7% (95% CI, 99.5%-99.9%) and 99.0% (98.6%-99.2%), ruling out more patients than the ESC 0-hour and High-STEACS (25% and 35%) pathways. Incorporating a second cardiac troponin measurement, CoDE-ACS identified 65% or 68% of patients as low probability at 1 or 2 hours, for an identical negative predictive value of 99.7% (99.5%-99.9%); 19% or 18% as high probability, with a positive predictive value of 64.9% (63.5%-66.4%) and 68.8% (67.3%-70.1%); and 16% or 14% as intermediate probability. In comparison, after serial measurements, the ESC 0/1-hour, ESC 0/2-hour, and High-STEACS pathways identified 49%, 53%, and 71% of patients as low risk, with a negative predictive value of 100% (99.9%-100%), 100% (99.9%-100%), and 99.7% (99.5%-99.8%); and 20%, 19%, or 29% as high risk, with a positive predictive value of 61.5% (60.0%-63.0%), 65.8% (64.3%-67.2%), and 48.3% (46.8%-49.8%), resulting in 31%, 28%, or 0%, who require further observation in the emergency department, respectively. CONCLUSIONS: CoDE-ACS performs consistently irrespective of the timing of serial cardiac troponin measurement, identifying more patients as low probability with comparable performance to guideline-recommended pathways for MI. Whether care guided by probabilities can improve the early diagnosis of MI requires prospective evaluation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00470587.

Perioperative copeptin: predictive value and risk stratification in patients undergoing major noncardiac surgery-a prospective observational cohort study.

PURPOSE: Biomarkers can aid in perioperative risk stratification. While preoperative copeptin has been associated with adverse events, intraoperative information is lacking and this association may rather reflect a baseline risk. Knowledge about correlations between postoperative copeptin measurements and clinically relevant outcomes is scarce. We examined the association of perioperative copeptin concentrations with postoperative all-cause mortality and/or major adverse cardiac and cerebrovascular events (MACCE) at 12 months and 30 days as well as with perioperative myocardial injury (PMI). METHODS: We conducted a prospective observational cohort study of adults undergoing noncardiac surgery with intermediate to high surgical risk in Basel, Switzerland, and Düsseldorf, Germany from February 2016 to December 2020. We measured copeptin and cardiac troponin before surgery, immediately after surgery (0 hr) and once between the second and fourth postoperative day (POD 2-4). RESULTS: A primary outcome event of a composite of all-cause mortality and/or MACCE at 12 months occurred in 48/502 patients (9.6%). Elevated preoperative copeptin (> 14 pmol·L-1), immediate postoperative copeptin (> 90 pmol·L-1), and copeptin on POD 2-4 (> 14 pmol·L-1) were associated with lower one-year MACCE-free and/or mortality-free survival (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.62 to 5.2; HR, 2.07; 95% CI, 1.17 to 3.66; and HR, 2.47; 95% CI, 1.36 to 4.46, respectively). Multivariable analysis continued to show an association for preoperative and postoperative copeptin on POD 2-4. Furthermore, elevated copeptin on POD 2-4 showed an association with 30-day MACCE-free survival (HR, 2.15; 95% CI, 1.18 to 3.91). A total of 64 of 489 patients showed PMI (13.1%). Elevated preoperative copeptin was not associated with PMI, while immediate postoperative copeptin was modestly associated with PMI. CONCLUSION: The results of the present prospective observational cohort study suggest that perioperative copeptin concentrations can help identify patients at risk for all-cause mortality and/or MACCE. Other identified risk factors were revised cardiac risk index, body mass index, surgical risk, and preoperative hemoglobin. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02687776); first submitted 9 February 2016.

RéSUMé: OBJECTIF: Les biomarqueurs peuvent aider à la stratification du risque périopératoire. Bien que la copeptine préopératoire ait été associée à des événements indésirables, les informations peropératoires font défaut; plutôt, cette association pourrait refléter un risque de base. Les connaissances sur les corrélations entre les mesures postopératoires de la copeptine et les résultats cliniquement pertinents sont rares. Nous avons examiné l'association entre les concentrations de copeptine périopératoires et la mortalité postopératoire toutes causes confondues et/ou les événements indésirables cardiaques et cérébrovasculaires majeurs (EICCM/MACCE) à 12 mois et 30 jours ainsi qu'en cas de lésion myocardique périopératoire (LMP/PMI). MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective d'adultes bénéficiant d'une chirurgie non cardiaque à risque chirurgical intermédiaire à élevé à Bâle, en Suisse, et à Düsseldorf, en Allemagne, de février 2016 à décembre 2020. Nous avons mesuré la copeptine et la troponine cardiaque avant la chirurgie, immédiatement après la chirurgie (0 h) et une fois entre le deuxième et le quatrième jour postopératoire (JPO 2-4). RéSULTATS: Un événement constituant un critère d'évaluation principal d'un composite de mortalité toutes causes confondues et/ou de MACCE à 12 mois est survenu chez 48/502 patient·es (9,6 %). Une élévation de la copeptine préopératoire (> 14 pmol·L−1), de la copeptine postopératoire immédiate (> 90 pmol·L−1) et de la copeptine aux JPO 2 à 4 (> 14 pmol·L−1) était associée à une survie sans MACCE et/ou sans mortalité à un an plus faible (rapport de risque [RR], 2,89; intervalle de confiance [IC] à 95 %, 1,62 à 5,2; RR, 2,07; IC 95 %, 1,17 à 3,66; et RR, 2,47; IC 95 %, 1,36 à 4,46, respectivement). L'analyse multivariée a aussi montré une association entre la copeptine préopératoire et postopératoire aux JPO 2 à 4. De plus, un taux élevé de copeptine aux JPO 2 à 4 a montré une association avec la survie sans MACCE à 30 jours (RR, 2,15; IC 95 %, 1,18 à 3,91). Au total, 64 des 489 patient·es présentaient une LMP (13,1 %). Un taux élevé de copeptine préopératoire n'a pas été associé à la LMP, tandis que la copeptine postopératoire immédiate était modestement associée à la LMP. CONCLUSION: Les résultats de la présente étude de cohorte observationnelle prospective suggèrent que les concentrations périopératoires de copeptine peuvent aider à identifier les personnes à risque de mortalité toutes causes confondues et/ou de MACCE. Les autres facteurs de risque identifiés étaient l'indice de risque cardiaque révisé, l'indice de masse corporelle, le risque chirurgical et l'hémoglobine préopératoire. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02687776); première soumission le 9 février 2016.

External validation of the 0/1h-algorithm and derivation of a 0/2h-algorithm using a new point-of-care Hs-cTnI assay.

BACKGROUND: The high-sensitivity cardiac troponin (hs-cTn) I point-of-care (POC) hs-cTnI-PATHFAST assay has recently become clinically available. METHODS: We aimed to externally validate the hs-cTnI-PATHFAST 0/1h-algorithm recently developed for the early diagnosis of non-ST-segment-elevation myocardial infarction (NSTEMI) and derive and validate a 0/2-algorithm in patients presenting to the emergency department with acute chest discomfort included in a multicenter diagnostic study. Two independent cardiologists centrally adjudicated the final diagnoses using all the clinical and study-specific information available including serial measurements of hs-cTnI-Architect. RESULTS: Among 1,532 patients (median age 60 years, 33% [n = 501] women), NSTEMI was the final diagnosis in 13%. External validation of the hs-cTnI-PATHFAST 0/1h-algorithm showed very high negative predictive value (NPV; 100% [95%CI, 99.5%-100%]) and sensitivity 100% (95%CI, 98.2%-100%) for rule-out of NSTEMI. Positive predictive value (PPV) and specificity for rule-in of NSTEMI were high (74.9% [95%CI, 68.3%-80.5%] and 96.4% [95%CI, 95.2%-97.3%], respectively). Among 1,207 patients (median age 61 years, 32% [n = 391] women) available for the derivation (n = 848) and validation (n = 359) of the hs-cTnI-PATHFAST 0/2h-algorithm, a 0h-concentration <3 ng/L or a 0h-concentration <4 ng/L with a 2h-delta <4ng/L ruled-out NSTEMI in 52% of patients with a NPV of 100% (95%CI, 98-100) and sensitivity of 100% (95%CI, 92.9%-100%) in the validation cohort. A 0h-concentration ≥90ng/L or a 2h-delta ≥ 55ng/L ruled-in 38 patients (11%): PPV 81.6% (95%CI, 66.6-90.8), specificity 97.7% (95%CI, 95.4-98.9%). CONCLUSIONS: The POC hs-cTnI-PATHFAST assay allows rapid and effective rule-out and rule-in of NSTEMI using both a 0/1h- and a 0/2h-algorithm with high NPV/sensitivity for rule-out and high PPV/specificity for rule-in. CLINICAL TRIAL REGISTRATION: NCT00470587.

Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial.

PURPOSE: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC). PATIENTS AND METHODS: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers. RESULTS: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels. CONCLUSIONS: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

Artificial intelligence to improve ischemia prediction in Rubidium Positron Emission Tomography-a validation study.

Background: Patients are referred to functional coronary artery disease (CAD) testing based on their pre-test probability (PTP) to search for myocardial ischemia. The recommended prediction tools incorporate three variables (symptoms, age, sex) and are easy to use, but have a limited diagnostic accuracy. Hence, a substantial proportion of non-invasive functional tests reveal no myocardial ischemia, leading to unnecessary radiation exposure and costs. Therefore, preselection of patients before ischemia testing needs to be improved using a more predictive and personalised approach. Aims: Using multiple variables (symptoms, vitals, ECG, biomarkers), artificial intelligence-based tools can provide a detailed and individualised profile of each patient. This could improve PTP assessment and provide a more personalised diagnostic approach in the framework of predictive, preventive and personalised medicine (PPPM). Methods: Consecutive patients (n = 2417) referred for Rubidium-82 positron emission tomography were evaluated. PTP was calculated using the ESC 2013/2019 and ACC 2012/2021 guidelines, and a memetic pattern-based algorithm (MPA) was applied incorporating symptoms, vitals, ECG and biomarkers. Five PTP categories from very low to very high PTP were defined (i.e., < 5%, 5-15%, 15-50%, 50-85%, > 85%). Ischemia was defined as summed difference score (SDS) ≥ 2. Results: Ischemia was present in 37.1%. The MPA model was most accurate to predict ischemia (AUC: 0.758, p < 0.001 compared to ESC 2013, 0.661; ESC 2019, 0.673; ACC 2012, 0.585; ACC 2021, 0.667). Using the < 5% threshold, the MPA's sensitivity and negative predictive value to rule out ischemia were 99.1% and 96.4%, respectively. The model allocated patients more evenly across PTP categories, reduced the proportion of patients in the intermediate (15-85%) range by 29% (ACC 2012)-51% (ESC 2019), and was the only tool to correctly predict ischemia prevalence in the very low PTP category. Conclusion: The MPA model enhanced ischemia testing according to the PPPM framework:The MPA model improved individual prediction of ischemia significantly and could safely exclude ischemia based on readily available variables without advanced testing ("predictive").It reduced the proportion of patients in the intermediate PTP range. Therefore, it could be used as a gatekeeper to prevent patients from further unnecessary downstream testing, radiation exposure and costs ("preventive").Consequently, the MPA model could transform ischemia testing towards a more personalised diagnostic algorithm ("personalised"). Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00341-5.

Growth mindset: An umbrella for protecting socially stressed adolescents' life satisfaction.

Research suggests that growth mindset shows positive effects on adolescents' academic achievement, especially in overcoming academic-related setbacks. It remains unclear, however, how growth mindset functions in the presence of social stress, a risk factor for adolescent mental health. In the present study, we explored how growth mindset of thoughts-emotions-behaviors predicted dual indicators of adolescents' mental health (life satisfaction and emotional problems), and if and how growth mindset interacted with peer and family stress to predict mental health. A total of 791 adolescents (Mage = 16.32 years, SD = 1.1, range 14-18; 60.8% female; 9th-12th grades; African American 34.5%, White 31.4%, Asian 13.2%, Hispanic 11.6%, biracial or multiracial 8.2%, others 1%, and missing 1%) participated via self-report surveys. A structural equation modeling approach was adopted to simultaneously model both the main and interaction effects. Results showed one significant interaction effect-between growth mindset and peer stress-on predicting life satisfaction (ß = 0.13) and a significant main effect of growth mindset on predicting emotional problems (ß = -0.35). The main effects of family stress on both outcomes (ß = -0.22, life satisfaction; ß = 0.18, emotional problems) were significant in the expected directions. Thus, growth mindset is a contributing factor to better mental health (higher life satisfaction, fewer emotional problems) and a buffering factor that mitigates the negative impact of peer stress on life satisfaction. These findings enhance the understanding of growth mindset, which can be integrated into school psychologists' work to assess or promote adolescent mental health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).