Background: Predicting fluid responsiveness remains a difficult question in hemodynamically unstable patients. The author's objective was to test whether noninvasive assessment by transthoracic echocardiography of subaortic velocity time index (VTI) variation after a low volume of fluid infusion (100 ml hydroxyethyl starch) can predict fluid responsiveness. Methods: Thirty-nine critically ill ventilated and sedated patients with acute circulatory failure were prospectively studied. Subaortic VTI was measured by transthoracic echocardiography before fluid infusion (baseline), after 100 ml hydroxyethyl starch infusion over 1 min, and after an additional infusion of 400 ml hydroxyethyl starch over 14 min. The authors measured the variation of VTI after 100 ml fluid (ΔVTI 100) for each patient. Receiver operating characteristic curves were generated for (ΔVTI 100). When available, receiver operating characteristic curves also were generated for pulse pressure variation and central venous pressure. Results: After 500 ml volume expansion, VTI increased ≥ 15% in 21 patients (54%) defined as responders. ΔVTI 100 ≥ 10% predicted fluid responsiveness with a sensitivity and specificity of 95% and 78%, respectively. The area under the receiver operating characteristic curves of ΔVTI 100 was 0.92 (95% CI: 0.78-0.98). In 29 patients, pulse pressure variation and central venous pressure also were available. In this subgroup of patients, the area under the receiver operating characteristic curves for ΔVTI 100, pulse pressure variation, and central venous pressure were 0.90 (95% CI: 0.74-0.98, P < 0.05), 0.55 (95% CI: 0.35-0.73, NS), and 0.61 (95% CI: 0.41-0.79, NS), respectively. Conclusion: In patients with low volume mechanical ventilation and acute circulatory failure, ΔVTI 100 accurately predicts fluid responsiveness.

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)—versus surgical lung biopsy (SLB) as the current gold standard—in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5–8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01–0.44), percentage agreement = 38% (95% CI, 18–62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06–0.56), percentage agreement = 48% (95% CI, 26–70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27–0.75), percentage agreement = 62% (95% CI, 38–82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Rationale: There is a need to minimize oral corticosteroid (OCS) use in patients with asthma to prevent their costly and burdensome adverse effects. Current guidelines do not provide recommendations for OCS tapering in patients with asthma. Objectives: To develop expert consensus on OCS tapering among international experts. Methods: A modified Delphi method was used to develop expert consensus statements relating to OCS use, tapering, adverse effects, adrenal insufficiency, and patient–physician shared decision-making. Initial statements proposed by experts were categorized, filtered for repetition, and presented back to experts over three ranking rounds to obtain consensus (≥70% agreement). Measurements and Main Results: One hundred thirty-one international experts participated in the study, and 296 statements were ranked. Numerous recommendations and guidance regarding appropriate OCS use were established. Experts agreed that OCS tapering should be attempted in all patients with asthma receiving maintenance OCS therapy, with personalization of tapering rhythm and speed. The importance of recognizing individual adverse effects was also established; however, a unified approach to the assessment of adrenal insufficiency was not reached. Shared decision-making was considered an important goal during the tapering process. Conclusions: In this Delphi study, expert consensus statements were generated on OCS use, tapering, adverse-effect screening, and shared decision-making, which may be used to inform clinical practice. Areas of nonconsensus were identified, highlighting uncertainty among the experts around some aspects of OCS use in asthma, such as adrenal insufficiency, which underscores the need for further research in these domains.

Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).

This study, based on morphological and isozyme analysis, clearly discriminates two invasive Carpobrotus taxa, C. edulis and C. acinaciformis, in the Hyères archipelago off the southeastern coast of France. However, three different allelic combinations demonstrate the presence of intermediate individuals resulting from an introgression of part of the C. edulis genome into that of C. acinaciformis. Both taxa have higher than average genetic (C. edulis: P(0.95)=62.5%, A=2.25±0.70, H_o=0.329±0.324; C. acinaciformis: P(0.95)=75%, A=2.38±0.42, H_o=0.645±0.109) and clonal diversities (C. edulis: IP=0.37; C. acinaciformis: IP=0.48). Furthermore, C. acinaciformis has an excess of heterozygotes (F=−0.585±0.217), probably due to introgression. The relationship between the probability of clonal identity for two individuals and distance indicates that C. acinaciformis relies more on clonal reproduction than on sexual recruitment (seed recruitment/vegetative propagation=u/v=0.027), in contrast to C. edulis, whose probability of clonal identity did not vary with distance. The overwhelming clonal growth and high genetic diversities of C. acinaciformis and the previously recorded invasion potential for C. edulis raises concern for intensified invasion via hybridisation.