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Background
Right ventricular–pulmonary artery coupling (RVPAC) predicts outcomes after transcatheter tricuspid valve edge-to-edge repair (T-TEER), but its role in patient selection remains unclear.
Objectives
The aim of this study was to evaluate the prognostic implications of RVPAC in a European registry of patients with tricuspid regurgitation undergoing either T-TEER or medical management.
Methods
Among 1,885 patients with tricuspid regurgitation (n = 585 medical, n = 1,300 T-TEER), 946 were propensity matched (1:1). RVPAC, assessed as the ratio of tricuspid annular plane systolic excursion to systolic pulmonary artery pressure was analyzed for its association with 1-year mortality.
Results
RVPAC was significantly associated with mortality (HR: 0.11; 95% CI: 0.04-0.29; P < 0.01), with an optimized cutoff of 0.41 mm/mm Hg. Mortality differed significantly by RVPAC in both treatment groups (log-rank P < 0.01). Across RVPAC tertiles (<0.32, 0.32-0.46, and >0.46 mm/mm Hg), tricuspid annular plane systolic excursion increased (14 mm [Q1-Q3: 12-17 mm] vs 18 mm [Q1-Q3: 15-20 mm] vs 21 mm [Q1-Q3: 18-24 mm]; P < 0.01), while systolic pulmonary artery pressure (60 mm Hg [Q1-Q3: 50-70 mm Hg] vs 45 mm Hg [Q1-Q3: 40-52 mm Hg] vs 34 mm Hg [Q1-Q3: 29-41 mm Hg]; P = 0.30) and kidney function (43 mL/min/m2 [Q1-Q3: 30-57 mL/min/m2] vs 49 mL/min/m2 [Q1-Q3: 38-67 mL/min/m2] vs 53 mL/min/m2 [Q1-Q3: 40-69 mL/min/m2]; P = 0.03) declined. Mortality was highest in the low RVPAC tertile, with no difference between treatment modalities (HR: 1.04; 95% CI: 0.68-1.61; P = 0.85). T-TEER was associated with better survival than medical management in the intermediate RVPAC tertile (HR: 0.54; 95% CI: 0.31-0.94; P = 0.03). This difference persisted but weakened in the high RVPAC tertile, with the overall most favorable outcomes (HR: 0.69; 95% CI: 0.35-1.36; P = 0.27).
Conclusions
Poorer RVPAC reflects higher baseline risk and mortality, regardless of treatment. T-TEER is associated with better survival across a range of RVPAC values, including those less than previously suggested thresholds.
Background
In the early COVID-19 pandemic concerns about the correct choice of analgesics in patients with COVID-19 were raised. Little data was available on potential usefulness or harmfulness of prescription free analgesics, such as paracetamol. This international multicentre study addresses that lack of evidence regarding the usefulness or potential harm of paracetamol intake prior to ICU admission in a setting of COVID-19 disease within a large, prospectively enrolled cohort of critically ill and frail intensive care unit (ICU) patients.
Methods
This prospective international observation study (The COVIP study) recruited ICU patients ≥ 70 years admitted with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, prior paracetamol intake within 10 days before admission, ICU therapy, limitations of care and survival during the ICU stay, at 30 days, and 3 months. Paracetamol intake was analysed for associations with ICU-, 30-day- and 3-month-mortality using Kaplan Meier analysis. Furthermore, sensitivity analyses were used to stratify 30-day-mortality in subgroups for patient-specific characteristics using logistic regression.
Results
44% of the 2,646 patients with data recorded regarding paracetamol intake within 10 days prior to ICU admission took paracetamol. There was no difference in age between patients with and without paracetamol intake. Patients taking paracetamol suffered from more co-morbidities, namely diabetes mellitus (43% versus 34%, p < 0.001), arterial hypertension (70% versus 65%, p = 0.006) and had a higher score on Clinical Frailty Scale (CFS; IQR 2–5 versus IQR 2–4, p < 0.001). Patients under prior paracetamol treatment were less often subjected to intubation and vasopressor use, compared to patients without paracetamol intake (65 versus 71%, p < 0.001; 63 versus 69%, p = 0.007). Paracetamol intake was not associated with ICU-, 30-day- and 3-month-mortality, remaining true after multivariate adjusted analysis.
Conclusion
Paracetamol intake prior to ICU admission was not associated with short-term and 3-month mortality in old, critically ill intensive care patients suffering from COVID-19.
Trial registration.
This prospective international multicentre study was registered on ClinicalTrials.gov with the identifier “NCT04321265” on March 25, 2020.
Introduction
Whereas CDK4/6 inhibitors (CDK4/6i) are the standard first-line therapy for patients with hormone receptor-positive (HRpos), HER2-negative (HER2neg) metastatic breast cancer, guidelines on treatment options after progression on CDK4/6i are more diverse. Chemotherapy is recommended if a patient develops endocrine resistance or experiences a visceral crisis. However, the impact of the choice of chemotherapy remains unknown.
Methods
HRpos/HER2neg patients who received first-line CDK4/6i, followed by second-line chemotherapy (N = 215) were selected from the prospective PRAEGNANT registry (NCT02338167). Cox regression analyses were used to evaluate the correlation between the choice of chemotherapy (capecitabine monotherapy, capecitabine + bevacizumab, taxane monotherapy, taxane + bevacizumab, anthracycline, other chemotherapeutics) and progression-free survival (PFS) and overall survival (OS).
Results
Patients who received second-line chemotherapy mostly had high-grade tumors (G2: 62.3 %, G3: 33.3 %), visceral metastases (62.3 %) and developed metastatic disease following a primary breast cancer diagnosis (73.8 %). Capecitabine was the most common regimen (25.1 %), followed by taxane + bevacizumab (17.2 %). When adjusting for other prognostic factors (age, BMI, grading, ECOG, metastasis group and time to metastases), the choice of chemotherapy did not influence PFS (p = 0.16) nor OS (p = 0.47). Adjusted hazard ratios for PFS were lowest in regimens with bevacizumab (capecitabine as reference; capecitabine + bevacizumab: 0.53 (95 %CI: 0.29, 0.97); taxane + bevacizumab: 0.64 (95 %CI 0.35, 1.15)).
Conclusion
Although the choice of chemotherapy post-CDK4/6i did not significantly affect PFS or OS, combinations with bevacizumab may have some benefit. Nevertheless, considering side effects may be most important when choosing the type of second-line chemotherapy.
Background
Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder.
Methods
Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response—defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)—was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction.
Results
The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R2) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile).
Conclusions
PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.
