Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients: Results of the Prospective Randomized Study EVERHEART.

Background: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization. Methods: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion (PCEs), pleural effusion (PLEs) needing drainage, and renal insufficiency events (estimated glomerular filtration rate [eGFR] = 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint. Results: Overall, 181 patients were randomized to the EVR-I (n=89) or EVR-D (n=92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P=0.104), mainly driven by a higher rate of PCEs (33.7% vs 19.6%; P=0.04); wound healing delays, acute renal insufficiency events, and PLEs occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm vs EVR-D arm (37.1% vs 28.3%; P=0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm vs EVR-D arm (P=0.02). Conclusions: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Navigating T Cell Immunometabolism in Transplantation.

Recently, a new discipline termed "immunometabolism" has transformed the field of immunology. It encompasses the study of the intrinsic metabolic pathways of different immune subsets and their impact on cellular fate and function. For instance, broadly speaking, pro-inflammatory cells depend upon glycolysis and glutamine oxidation while cells involved in anti-inflammatory response such as Foxp3+ regulatory T cells (Tregs) utilize predominantly fatty acid oxidation. However, while a useful paradigm, this actually is a reductionist view and the engagement of these metabolic pathways is not mutually exclusive between these subsets. Over the past several years, new insights and new methods to better dissect, define, and harness the metabolic properties of immune cells for immunotherapeutic purposes have come to the forefront. In this review, we will discuss the metabolic heterogeneity of different T cells subsets as well as basic principles of integrative technologies, such as metabolomics, that can be used to better understand the metabolic signatures of immune responses. Given the interest of exploiting this information in the context of transplantation, we will highlight the scope of immunometabolism in unraveling novel mechanisms of immune regulation that can be manipulated to promote Treg stability and function while inhibiting T effectors to establish long-term transplantation tolerance. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control

Abstract

Background

Classic spirometry is effort-dependent and of limited value in assessing small airways. Peripheral airway involvement, and relation to poor control, in asthma, has been highlighted recently. Forced oscillation technique (FOT) offers an effort-independent assessment of overall and peripheral lung mechanics. We studied the association between lung function variables, obtained either by spirometry or multi-frequency (5, 11 and 19 Hz) FOT, and asthma diagnosis and control.

Methods

Spirometry measures, resistance at 5 (R5) and 19 Hz (R19), reactance at 5 Hz (X5), resonant frequency (f_res), resistance difference between 5-19 Hz (R5-R19) and Asthma Control Test scores were determined in 234 asthmatic and 60 healthy subjects (aged 13-39 years). We used standardised lung function variables in logistic regression analyses, unadjusted and adjusted for age, height, gender, weight.

Results

Lower FEV₁/FVC (OR (95% CI) 0.47 (0.32, 0.69)) and FEF₅₀ (0.62 (0.46, 0.85)) per standard deviation increase, and higher R5 (3.31 (1.95, 5.62)) and R19 (2.54 (1.65, 3.91)) were associated with asthma diagnosis. Independent predictive effects of FEV₁/FVC and R5 or R19, respectively, were found for asthma diagnosis. Lower FEV₁/FVC and altered peripheral FOT measures (X5, f_res and R5-R19) were associated with uncontrolled asthma (p-values < 0.05).

Conclusions

Resistance FOT measures were equally informative as spirometry, related to asthma diagnosis, and furthermore, offered additive information to FEV₁/FVC, supporting a complementary role for FOT. Asthma control was related to FOT measures of peripheral airways, suggesting a potential use in identifying such involvement. Further studies are needed to determine a clinical value, and relevant reference values in children, for the multi-frequency FOT measurements.

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Small airway involvement in the late allergic response in asthma

Abstract

Background

Allergy and asthma are closely linked. Inhalation of allergen induces an early allergic response (EAR) within the airways of allergic asthmatic subjects, which is followed by a late allergic response (LAR) in approximately 50% of the subjects. The LAR is defined as a drop in forced expiratory volume in 1 s (FEV₁) from baseline usually occurring 4–8 h after exposure, and is believed to affect small airways. However, FEV₁ is insensitive to changes in small airway physiology.

Objective

Our aim was to investigate and compare the pathophysiological processes in large and small airways during the EAR and the LAR, and to characterize subjects with both an EAR and a LAR (dual responders) versus those with an EAR only (single responders).

Methods

Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Lung physiology was assessed by spirometry, impulse oscillometry (IOS), body plethysmography, inert gas washout, single breath methane dilution carbon monoxide diffusion and exhaled breath temperature, at baseline and repeatedly for 23 h post-allergen challenge.

Results

Peripheral airway resistance, air trapping and ventilation heterogeneity were significantly increased in dual responders (n=15) compared to single responders (n=19) 6–8 h post-challenge. Parameters of peripheral airway resistance and ventilation heterogeneity, measured with IOS and inert gas washout, respectively, correlated at baseline and during the allergic airway response in all subjects.

Conclusion

The LAR involves increased resistance and ventilation defects within the peripheral airways. Alternative definitions of the LAR including small airways pathophysiology could be considered.

Clinical relevance

Small airway dysfunction during the LAR suggests that dual responders may have more extensive airway pathology and underscores the relevance of small airways assessment in asthma.

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Fractures of the Nasal Bones: Is External Splinting Really Warranted?.

Background: It has been advocated that reduction of nasal bone fractures should be followed by internal packing and/or external splinting. Despite the ample literature concerning the advantages and limitations of various splint types, the necessity and effectiveness of external splinting has not been well documented. Objective: To present the authors' experience and review the literature on treatment of nasal bone fractures, focusing on the indications and effectiveness of external splinting following closed reduction. Study Design: Retrospective analysis and literature review. Patients and Methods: Medical records of all patients, treated at the Department of Oral and Maxillofacial Surgery of the "KAT" General Hospital of Attica between January 2010 and December 2016 for facial trauma including nasal bone fractures, were retrospectively reviewed. Patient demographic data, fracture type, applied treatment, complications, and final outcome were registered. Results: A total of 77 patients (58 males; 19 females) were included in the study. The age range was 18 to 65 years (mean, 37.8). Closed reduction without external splinting was performed in 63 patients and open reduction with internal fixation in 6; 8 severely comminuted fractures were treated with closed reduction and external splinting. The mean follow-up was 4.8 months. All severely comminuted fractures presented complications. Conclusions: External splinting following closed reduction of nasal bone fractures should not be used routinely but only in selected patients with severe comminution. Since the pertinent literature is inconclusive on the indications and effectiveness of external splinting, randomized controlled studies are warranted to fully elucidate the issue. (C) 2017 by Mutaz B. Habal, MD.

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Oral Behaviors and Parafunctions: Comparison of Temporomandibular Dysfunction Patients and Controls.

The aim of this study is to evaluate the frequency of oral behaviors in patients with temporomandibular disorders (TMD) and a control group without TMD. In this baseline case-control study, 260 controls and 260 subjects with TMD completed the oral behaviors checklist defined as a "self-report scale for identifying and quantifying the frequency of jaw overuse behavior" and underwent clinical examinations using the DC/TMJ international examination form (version May 12, 2013). Relationships of oral parafunctions' frequencies between groups were examined. The statistical analysis was performed with IBM SPSS Statistics 23 software. Age and gender distribution in the study groups did not reveal statistical differences (P > 0.05). Multivariate logistic regression analysis was conducted to establish system of independent oral behaviors for prognosis TMD. The stepwise regression analysis demonstrated that very frequent expression of holding, tightening, or tense muscles is associated with 10.83 times (P

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Forehead Sparganosis.

No abstract available

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