Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia in Critically Ill Patients: A Cluster Analysis According to Baseline Characteristics, Biological Features, and Chest CT Scan on Admission.

BACKGROUND: Inconsistent results from COVID-19 studies raise the issue of patient heterogeneity. OBJECTIVE: The objective of this study was to identify homogeneous subgroups of patients (clusters) using baseline characteristics including inflammatory biomarkers and the extent of lung parenchymal lesions on CT, and to compare their outcomes. DESIGN: Retrospective single-center study. SETTING: Medical ICU of the University Hospital of Clermont-Ferrand, France. PATIENTS: All consecutive adult patients aged greater than or equal to 18 years, admitted between March 20, 2020, and August 31, 2021, for COVID-19 pneumonia. INTERVENTIONS: Characteristics at baseline, during ICU stay, and outcomes at day 60 were recorded. On the chest CT performed at admission the extent of lung parenchyma lesions was established by artificial intelligence software. MEASUREMENTS AND MAIN RESULTS: Clusters were determined by hierarchical clustering on principal components using principal component analysis of admission characteristics including plasma interleukin-6, human histocompatibility leukocyte antigen-DR expression rate on blood monocytes (HLA-DR) monocytic-expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day 60 mortality were investigated by univariate survival analysis. Two hundred seventy patients were included. Four clusters were identified and three were fully described. Cluster 1 (obese patients, with moderate hypoxemia, moderate extent of lung parenchymal lesions, no inflammation, and no down-regulation of mHLA-DR) had a better prognosis at day 60 (hazard ratio [HR] = 0.27 [0.15-0.46], p < 0.01), whereas cluster 2 (older patients with comorbidities, moderate extent of lung parenchyma lesions but significant hypoxemia, inflammation, and down-regulation of mHLA-DR) and cluster 3 (patients with severe parenchymal disease, hypoxemia, inflammatory reaction, and down-regulation of mHLA-DR) had an increased risk of mortality (HR = 2.07 [1.37-3.13], p < 0.01 and HR = 1.52 [1-2.32], p = 0.05, respectively). In multivariate analysis, only clusters 1 and 2 were independently associated with day 60 death. CONCLUSIONS: Three clusters with distinct characteristics and outcomes were identified. Such clusters could facilitate the identification of targeted populations for the next trials.

Early detection of pharyngocutaneous fistulae after total laryngectomy by cytokine in drainage: A pilot study (DEFILAC).

BACKGROUND: The determination of cytokines in the postoperative drainage (POD) fluid could be a method for early detection of the development of a pharyngocutaneous fistula (PCF). MATERIALS AND METHODS: We conducted a prospective two-center study involving 28 patients. PODs were collected on Day 1 (D1) and Day 2 (D2) postoperatively for determination of a cytokine panel and cytobacteriological examination. RESULTS: Eleven (39%) patients presented with PCF on average 13 ± 5.5 days after surgery. Patients with PCF had higher IL-10 (121 vs. 40.3, p = 0.04, effect size (ES) = 0.98 [0.16, 1.79]) and TNFα level (21.2 vs. 2.2, p = 0.02, ES = 0.83 [0.03, 1.63]) on D2. An IL-10 threshold of 72 pg/mL on D2 was diagnostic of the occurrence of PCF with a sensibility of 70%, specificity of 88%. CONCLUSION: The determination of cytokines in POD fluid on D2 is a reliable tool for predicting the development of a PCF after total laryngectomy.

Nitroglycerin trapping in melamine matrices.

Melamine (Mel) was used as host matrix for liquid nitroglycerin (NG), to prepare Mel/NG solid powdered compounds containing up to 45 wt% of this explosive. The two preparation processes used for this purpose consisted in evaporating a solution of both components, either in ambient conditions or under reduced pressure by the Spray Flash-Evaporation (SFE) process. In Mel/NG materials, amorphous nitroglycerin is distributed in the crystallized melamine matrix as inclusions, which were found to be smaller in size in the material prepared by the SFE process. Mel/NG materials are not stable over time: they gradually lose the nitroglycerin they contain by evaporation.

Particulate antigens administrated by intranasal and intravaginal routes in a prime-boost strategy improve HIV-specific TFH generation, high-quality antibodies and long-lasting mucosal immunity.

Mucosal surfaces serve as the primary entry points for pathogens such as SARS- CoV-2 coronavirus or HIV in the human body. Mucosal vaccination plays a crucial role to successfully induce long-lasting systemic and local immune responses to confer sterilizing immunity. However, antigen formulations and delivery methods must be properly selected since they are decisive for the quality and the magnitude of the elicited immune responses in mucosa. We investigated the significance of using particulate antigen forms for mucosal vaccination by comparing VLP- or protein- based vaccines in a mouse model. Based on a mucosal prime-boost immunization protocol combining (i) HIV- pseudotyped recombinant VLPs (HIV-VLPs) and (ii) plasmid DNA encoding HIV- VLPs (pVLPs), we demonstrated that combination of intranasal primes and intravaginal boosts is optimal to elicit both humoral and cellular memory responses in mucosa. Interestingly, our results show that in contrast to proteins, particulate antigens induce high-quality humoral responses characterized by a high breadth, long-term neutralizing activity and cross-clade reactivity, accompanying with high T follicular helper cell (TFH) response. These results underscore the potential of a VLP-based vaccine in effectively instigating long-lasting, HIV-specific immunity and point out the specific role of particulate antigen form in driving high-quality mucosal immune responses.

Epidemiology and Outcome of Early-Onset Acute Kidney Injury and Recovery in Critically Ill COVID-19 Patients: A Retrospective Analysis.

BACKGROUND: The clinical significance of early-onset acute kidney injury (EO-AKI) and recovery in severe COVID-19 intensive care unit (ICU) patients is poorly documented. OBJECTIVE: The aim of the study was to assess the epidemiology and outcome of EO-AKI and recovery in ICU patients admitted for SARS-CoV-2 pneumonia. DESIGN: This was a retrospective single-centre study. SETTING: The study was carried out at the medical ICU of the university hospital of Clermont-Ferrand, France. PATIENTS: All consecutive adult patients aged ≥18 years admitted between 20 March 2020 and 31 August 2021 for SARS-CoV-2 pneumonia were enrolled. Patients with chronic kidney disease, referred from another ICU, and with an ICU length of stay (LOS) ≤72 h were excluded. INTERVENTIONS: EO-AKI was defined on the basis of serum creatinine levels according to the Kidney Disease Improving Global Outcomes criteria, developing ≤7 days. Depending on renal recovery, defined by the normalization of serum creatinine levels, EO-AKI was transient (recovery within 48 h), persistent (recovery between 3 and 7 days) or AKD (no recovery within 7 days after EO-AKI onset). MEASUREMENTS: Uni- and multivariate analyses were performed to determine factors associated with EO-AKI and EO-AKI recovery. MAIN RESULTS: EO-AKI occurred in 84/266 (31.5%) study patients, of whom 42 (50%), 17 (20.2%) and 25 (29.7%) had EO-AKI stages 1, 2 and 3, respectively. EO-AKI was classified as transient, persistent and AKD in 40 (47.6%), 15 (17.8%) and 29 (34.6%) patients, respectively. The 90-day mortality was 87/244 (35.6%) and increased with EO-AKI occurrence and severity: no EO-AKI, 38/168 (22.6%); EO-AKI stage 1, 22/39 (56.4%); stage 2, 9/15 (60%); and stage 3, 18/22 (81.8%) (p < 0.01). The 90-day mortality in patients with transient or persistent AKI and AKD was 20/36 (55.6%), 8/14 (57.1%) and 21/26 (80.8%), respectively (p < 0.01). MAKE-90 occurred in 42.6% of all patients. CONCLUSIONS: In ICU patients admitted for SARS-CoV-2 pneumonia, the development of EO-AKI and time to recovery beyond day 7 of onset were associated with poor outcome.

Increase over time of antibody levels 3 months after a booster dose as an indication of better protection against Omicron infection.

The third, "booster", vaccination increases the overall immune response against SARS-CoV-2 variants. However, after the initial peak at around 3 weeks post-vaccination, anti-spike antibody levels decline. Post-booster kinetics of cellular response has been less investigated and there is no documented evidence of a true boosting effect. Furthermore, multiple studies underline the less effective immune responses against Omicron, the latest variant of concern, at both humoral and cellular levels. In this letter, we analyse humoral (anti-RBD IgG levels) and cellular (IFN-γ release assay) immune response in 205 health care workers 3 weeks and 3 months after administration of an mRNA-based booster dose, either mRNA-1273 or BNT162b2. Since all subjects were SARS-CoV-2 infection-naïve, we also looked at the incidence of Omicron infection between 3 and 6 months post-booster.At both timepoints, 3x mRNA-1273 vaccination had the highest overall antibody and IFN-γ levels, followed by 3x BNT162b2 vaccination and heterologous mRNA-based regimens. Heterologous ChAdOx1-mRNA-based regimen had the lowest antibody levels while cellular response equal to that of 3x BNT162b2 vaccination and heterologous mRNA-based regimens. Our results show that both humoral and cellular responses waned at 3 months for all vaccination regimens. However, we identified three trajectories of dosage variation. Interestingly, the subgroup of subjects with increasing anti-RBD IgG levels over time had a lower incidence of Omicron infection. Whether increasing humoral response at 3 months post-booster is more indicative of protection than a high initial peak remains to be confirmed in a larger cohort.

Hypercoagulability in critically ill patients with COVID 19, an observational prospective study.

OBJECTIVE: COVID 19 is often associated with hypercoagulability and thromboembolic (TE) events. The aim of this study was to assess the characteristics of hypercoagulability and its relationship with new-onset TE events and the composite outcome of need for intubation and/or death in intensive care unit (ICU) patients admitted for COVID. DESIGN: Prospective observational study. SETTING: Monocentric, intensive care, University Hospital of Clermont Ferrand, France. PATIENTS: Patients admitted to intensive care from January 2020 to May 2021 for COVID-19 pneumonia. INTERVENTIONS: Standard hemostatic tests and rotational thromboelastometry (ROTEM) were performed on admission and on day 4. Hypercoagulability was defined by at least one of the following criteria: D-dimers > 3000 µg/dL, fibrinogen > 8 g/L, EXTEM CFT below the normal range, EXTEM A5, MCF, Li 60 above the normal range, and EXTEM G-score ((5000 x MCF) / (100-MCF)) ≥ 11 dyne/cm2. MEASUREMENTS AND MAIN RESULTS: Of the 133 patients included, 17 (12.7%) developed new-onset TE events, and 59 (44.3%) required intubation and/or died in the ICU. ROTEM was performed in 133 patients on day 1 and in 67 on day 4. Hypercoagulability was present on day 1 in 115 (86.4%) patients. None of the hypercoagulability indices were associated with subsequent new-onset TE events on days 1 and 4 nor with the need for intubation and/or ICU death. Hyperfibrinogenemia > 8g/dL, higher D-dimers and higher EXTEM Li 60 on day 4 were predictive of need for intubation and/or of ICU death. CONCLUSIONS: Our study confirmed that most COVID-19 ICU patients have hypercoagulability on admission and almost all on day 4. Hyperfibrinogenemia or fibrinolysis shutdown on day 4 were associated with unfavorable outcome.

Association of nitrogen balance trajectories with clinical outcomes in critically ill COVID-19 patients: A retrospective cohort study.

BACKGROUND & AIMS: The intensity and duration of the catabolic phase in COVID-19 patients can differ between survivors and non-survivors. The purpose of the study was to assess the determinants of, and association between, nitrogen balance trajectories and outcome in critically ill COVID-19 patients. METHODS: This retrospective monocentric observational study involved patients admitted to the intensive care unit (ICU) of the University Hospital of Clermont Ferrand, France, from January 2020 to May 2021 for COVID-19 pneumonia. Patients were excluded if referred from another ICU, if their ICU length of stay was <72 h, or if they were treated with renal replacement therapy during the first seven days after ICU admission. Data were collected prospectively at admission and during ICU stay. Death was recorded at the end of ICU stay. Comparisons of the time course of nitrogen balance according to outcome were analyzed using two-way ANOVA. At days 3, 5, 7, 10 and 14, uni- and multivariate logistic regression analyses were performed to assess the impact of a non-negative nitrogen-balance on ICU death. To investigate the relationships between nitrogen balance, inflammatory markers and protein intake, linear and non-nonlinear models were run at days 3, 5 and 7, and the amount of protein intake necessary to reach a neutral nitrogen balance was calculated. Subgroup analyses were carried out according to BMI, age, and sex. RESULTS: 99 patients were included. At day 3, a similar negative nitrogen balance was observed in survivors and non-survivors: -16.4 g/d [-26.5, -3.3] and -17.3 g/d [-22.2, -3.8] (p = 0.54). The trajectories of nitrogen balance over time thus differed between survivors and non-survivors (p = 0.01). In survivors, nitrogen balance increased over time, but decreased from day 2 to day 6 in non-survivors, and thereafter increased slowly up to day 14. At days 5 and 7, a non-negative nitrogen-balance was protective from death. Administering higher protein amounts was associated with higher nitrogen balance. CONCLUSION: We report a prolonged catabolic state in COVID patients that seemed more pronounced in non-survivors than in survivors. Our study underlines the need for monitoring urinary nitrogen excretion to guide the amount of protein intake required by COVID-19 patients.

Utility of the Basophil Activation Test Using Gly m 4, Gly m 5 and Gly m 6 Molecular Allergens for Characterizing Anaphylactic Reactions to Soy.

There are two major clinically described forms of IgE-dependent soy allergy: (i) a primary dietary form, linked to sensitization against soy storage proteins Gly m 5 and Glym 6, and (ii) a form included in birch-soy syndromes linked to Gly m 4, a PR-10-like allergen. This second form sometimes causes severe systemic reactions, even anaphylaxis, especially on consuming certain forms of soy such as soymilks or smoothies. Skin prick tests and specific IgE assays against soy whole extracts lack sensitivity. Assays of anti-Gly m 4, Gly m 5 and Gly m 6 specific IgEs have been developed to overcome this obstacle, but they unfortunately lack specificity, especially for anti-Gly m 4. We hypothesized that the basophil activation test (BAT) using molecular soy allergens Gly m 4, Gly m 5 and Gly m 6 would both remedy the lack of sensitivity of other tests and offer, through its mechanistic contribution, greater specificity than the assay of anti-Gly m 4 specific IgEs. This would enable the two types of soy allergy to be separately identified. In a characteristic clinical example of PR-10-induced anaphylactic reaction after consuming soymilk, we report preliminary results of Gly m 4-exclusive positivity of BAT supporting our hypothesis. It will be necessary to confirm these results on more patients in subsequent studies, and to specify the place of the BAT in an overall diagnostic strategy. Meanwhile, soy BAT using molecular allergens is a promising diagnostic tool for soy allergy and probably also for follow-up in specific immunotherapies.

Decline of Humoral and Cellular Immune Responses Against SARS-CoV-2 6 Months After Full BNT162b2 Vaccination in Hospital Healthcare Workers.

Clinical trials and real-world evidence on COVID-19 vaccines have shown their effectiveness against severe disease and death but the durability of protection remains unknown. We analysed the humoral and T-cell immune responses in 110 healthcare workers (HCWs) vaccinated according to the manufacturer's recommended schedule of dose 2 three weeks after dose 1 from a prospective on-going cohort in early 2021, 3 and 6 months after full vaccination with the BNT162b2 mRNA vaccine. Anti-RBD IgG titres were lower in HCWs over 60 years old 3 months after the second dose (p=0.03) and declined in all the subjects between 3 and 6 months with a median percentage change of -58.5%, irrespective of age and baseline comorbidities. Specific T-cell response measured by IGRA declined over time by at least 42% (median) in 91 HCWs and increased by 33% (median) in 17 others. Six HCWs had a negative T-cell response at 6 months. Ongoing follow-up should provide correlates of long-term protection according to the different immune response profiles observed. COVIDIM study was registered under the number NCT04896788 on clinicaltrials.gov.

Severe COVID-19 is characterized by the co-occurrence of moderate cytokine inflammation and severe monocyte dysregulation.

BACKGROUND: SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination. METHODS: In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections. FINDINGS: Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections. INTERPRETATION: The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease. FUNDING: None.

Renal dysfunction improves risk stratification and may call for a change in the management of intermediate- and high-risk acute pulmonary embolism: results from a multicenter cohort study with external validation.

BACKGROUND: Renal dysfunction influences outcomes after pulmonary embolism (PE). We aimed to determine the incremental value of adding renal dysfunction, defined by estimated glomerular filtration rate (eGFR), on top of the European Society of Cardiology (ESC) prognostic model, for the prediction of 30-day mortality in acute PE patients, which in turn could lead to the optimization of acute PE management. METHODS: We performed a multicenter, non-interventional retrospective post hoc analysis based on a prospectively collected cohort including consecutive confirmed acute PE stratified per ESC guidelines. We first identified which of three eGFR formulae most accurately predicted death. Changes in global model fit, discrimination, calibration and reclassification parameters were evaluated with the addition of eGFR to the prognostic model. RESULTS: Among 1943 patients (mean age 67.3 (17.1), 50.4% women), 107 (5.5%) had died at 30 days. The 4-variable Modification of Diet in Renal Disease (eGFRMDRD4) formula predicted death most accurately. In total, 477 patients (24.5%) had eGFRMDRD4 < 60 ml/min. Observed mortality was higher for intermediate-low-risk and high-risk PE in patients with versus without renal dysfunction. The addition of eGFRMDRD4 information improved model fit, discriminatory capacity, and calibration of the ESC model. Reclassification parameters were significantly increased, yielding 18% reclassification of predicted mortality (p < 0.001). Predicted mortality reclassifications across risk categories were as follows: 63.1% from intermediate-low risk to eGFR-defined intermediate-high risk, 15.8% from intermediate-high risk to eGFR-defined intermediate-low risk, and 21.0% from intermediate-high risk to eGFR-defined high risk. External validation in a cohort of 14,234 eligible patients from the RIETE registry confirmed our findings with a significant improvement of Harrell's C index and reclassification parameters. CONCLUSION: The addition of eGFRMDRD4-derived renal dysfunction on top of the prognostic algorithm led to risk reclassification within the intermediate- and high-risk PE categories. The impact of risk stratification integrating renal dysfunction on therapeutic management for acute PE requires further studies.

Clinical patterns and significance of non-compliance with guideline-recommended treatment of acute pulmonary embolism.

BACKGROUND: Evidence-based clinical practice guidelines define initial management of acute pulmonary embolism (PE) according to risk stratification for early death. AIMS: The aims of the present study were to investigate patterns of non-compliance with guidelines for the acute PE treatment, and the associated risk of adverse events. METHODS: We performed an observational, multicentre, cohort study of acute PE. Inclusion criteria were all patients with pulmonary embolism admitted to the participating centres between January 2011 and April 2017. The measure of 100% compliance was used to allocate patients in the compliant or non-compliant groups. The primary outcome was all-cause death at 6 months. Secondary outcomes included recurrent venous thromboembolism and major bleeding. RESULTS: In total, 1285 patients were included. Treatment was not in compliance with the guidelines in 172 patients (13.4%). Four factors were identified to be related to non-compliance with the guidelines: shock or hypotension (relative risk [RR] 5.23, 95% confidence interval [CI] 2.64-10.30; P<0.001), renal insufficiency (RR 1.80, 95% CI 1.41-2.28; P<0.001), active cancer (RR 1.35, 95% CI 1.24-1.48; P<0.001) and right ventricular dysfunction at admission (RR 1.06, 95% CI 1.01-1.11; P=0.01). The primary endpoint of all-cause death at 6 months occurred in 62 of 172 patients (36.0%) in the non-compliant group and in 131 of 1113 patients (11.8%) in the compliant group (hazard ratio 2.02, 95% CI 1.45-2.81; P<0.001). The rates of recurrent venous thromboembolism (8.7% vs 1.1%; P<0.001) and major bleeding (13.4% vs 4.9%, P=0.04) from admission to 6-month follow-up were higher in the non-compliant group. CONCLUSION: Non-compliance with guidelines was independently associated with worse outcomes, including death, recurrent venous thromboembolism and bleeding.

Short Communication: Extremely Severe CD4 Lymphopenia During HIV-1 Primary Infection.

We report the case of a patient with a very profound CD4 T cell lymphopenia <20 cells/mm3 in the context of a primary HIV-1 infection, associated with both delayed HIV-specific antibody and CD8 T cell responses. A long-term immune reconstitution was observed after immediate initiation of antiretroviral therapy.

Prescription patterns of direct oral anticoagulants in pulmonary embolism: A prospective multicenter French registry.

BACKGROUND: Data regarding the use of direct oral anticoagulants (DOACs) for the treatment of acute pulmonary embolism (PE) are sparse. We conducted a prospective multicentre registry study to describe patterns of DOAC prescription for the treatment of acute PE, and the associated risk of 6-month adverse events in daily practice. METHODS: We included all PE patients discharged since the availability of DOACs for the dedicated indication of acute PE treatment. Clinical data and 6-month outcomes, including death, recurrent venous thromboembolism (VTE), bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH) were recorded prospectively. Temporal trends in DOAC prescription were tested. RESULTS: Between 09/2012 and 04/2017, 1082 patients were included: 60.6% (n = 656) were treated with DOACs and 39.4% (n = 426) with another anticoagulant. The prescription rate of DOACs increased sharply just after their release on the market to reach a plateau over time, between 56% and 72% of the total prescription per year in PE patients (p for trend = 0.33). Active malignancy and renal function impairment were factors independently associated with non-prescription of DOACs. Overall, prescription of DOACs was appropriate in 95.3% of patients. The rate of use of non-recommended DOAC doses was 4.2% (n = 28). The rate of death, recurrent VTE, bleeding and CTEPH were 2.4%, 1.2%, 7.2%, and 1.9%, respectively in the DOAC group. CONCLUSION: The choice to prescribe DOACs or not is related to patient characteristics. The overall appropriateness of prescription is high, while the rate of adverse events observed in patients treated with DOAC is low in our registry.

High-resolution repertoire analysis reveals a major bystander activation of Tfh and Tfr cells.

T follicular helper (Tfh) and regulatory (Tfr) cells are terminally differentiated cells found in germinal centers (GCs), specialized secondary lymphoid organ structures dedicated to antibody production. As such, follicular T (Tfol) cells are supposed to be specific for immunizing antigens, which has been reported for Tfh cells but is debated for Tfr cells. Here, we used high-throughput T cell receptor (TCR) sequencing to analyze the repertoires of Tfh and Tfr cells, at homeostasis and after immunization with self- or foreign antigens. We observed that, whatever the conditions, Tfh and Tfr cell repertoires are less diverse than those of effector T cells and Treg cells of the same tissues; surprisingly, these repertoires still represent thousands of different sequences, even after immunization with a single antigen that induces a 10-fold increase in Tfol cell numbers. Thorough analysis of the sharing and network of TCR sequences revealed that a specific response to the immunizing antigen can only, but hardly, be detected in Tfh cells immunized with a foreign antigen and Tfr cells immunized with a self-antigen. These antigen-specific responses are obscured by a global stimulation of Tfh and Tfr cells that appears to be antigen-independent. Altogether, our results suggest a major bystander Tfol cell activation during the immune response in the GCs.

Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events.

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute PE treatment according to the manufacturer's labelling, beyond the contraindication in severe renal insufficiency. We designed a prospective, multicenter cohort study to investigate the impact of prescription of non-recommended DOAC doses on 6-month adverse events. The primary endpoint was a composite of all-cause death, recurrent VTE, major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). In total, among 656 patients discharged with DOACs between 09/2012 and 10/2016, 28 (4.3%) were not treated with a recommended DOAC dose. All the non-recommended DOAC dose prescriptions were under-dosed according to the drug labelling. After multivariate adjustment, age > 70 years, a history of coronary artery disease, creatinine clearance < 50 mL/min and concomitant aspirin therapy were independently associated with non-recommended DOAC dose prescription (C-statistic: 0.82; Hosmer Lemeshow test: 0.50). The primary composite endpoint occurred in 7/28 patients (25.0%) in the non-recommended dose group and in 38/628 patients (6.1%) in the recommended dose group, yielding a relative risk of 3.19 in the non-recommended dose group (95% CI 1.16-8.70; p < 0.001). The higher primary endpoint rate observed in the non-recommended dose group was driven by a significantly higher rate of major bleeding (7.1 vs. 1.4%; p = 0.008), with a non-significant trend toward a higher rate of death (7.1 vs. 2.2%; p = 0.23), recurrent VTE (3.6 vs. 1.4%; p = 0.31), and CTEPH (7.1 vs. 1.6%; p = 0.32). In conclusion, empiric dose reduction of DOACs was associated with 6-month adverse events in our real-life registry.

Incidence, Predictors, and Impact on Six-Month Mortality of Three Different Definitions of Contrast-Induced Acute Kidney Injury After Coronary Angiography.

We assessed incidence, predictors, and impact on 6-month mortality of contrast-induced acute kidney injury (CI-AKI) after coronary angiography with or without percutaneous coronary intervention in patients with acute coronary syndrome (ACS), according to 3 different CI-AKI definitions. Serum creatinine (sCr) was assessed at baseline and 48 to 72 hours after procedure to classify patients into 3 CI-AKI groups: Group 1: increase in sCR ≥25% over baseline but absolute increase <0.5 mg/dl; Group 2: absolute increase ≥0.5 mg/dl; Group 3: absolute increase ≥0.3 mg/dl or ≥50% over baseline. The association between CI-AKI and all-cause 6-month mortality was assessed using multivariate Cox regression. Among 1,002 patients included, median age was 68 [57 to 79] years. The sample had the following characteristics: 70% men, 25% diabetics, 22% had a history of myocardial infarction, 21% had baseline estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease) <60 ml/min/1.72 m2, 34% had ST-segment elevation myocardial infarction, 61% underwent percutaneous coronary intervention, and 43% had multivessel disease. Based on changes in sCr, 89 patients (8.9%) were classified in Group 1; 69 (6.9%) in Group 2; and 157 (15.7%) in Group 3, whereas sCr did not increase >25% in the remaining 844 (84.2%). CI-AKI was significantly associated with 6-month all-cause mortality using the definitions for Group 2 (hazard ratio 3.1, 95% confidence interval [CI] 1.5 to 6.6, p = 0.002) and Group 3 (hazard ratio 2.03, 95% CI 1.03 to 4.0, p = 0.04), but not Group 1. In conclusion, based on the definition used for CI-AKI, CI-AKI is observed in 6% to 15.7% of patients. An increase of 25% over baseline sCr does not identify high-risk patients. CI-AKI defined as an increase in sCr >0.3 mg/dl identifies 15.7% of the population at 2-fold higher risk of mortality.