Contemporary trends in the level of evidence in general thoracic surgery clinical research.

OBJECTIVES: The large volume of scientific publications and the increasing emphasis on high-quality evidence for clinical decision-making present daily challenges to all clinicians, including thoracic surgeons. The objective of this study was to evaluate the contemporary trend in the level of evidence (LOE) for thoracic surgery clinical research. METHODS: All clinical research articles published between January 2010 and December 2017 in 3 major general thoracic surgery journals were reviewed. Five authors independently reviewed the abstracts of each publication and assigned a LOE to each of them using the 2011 Oxford Centre for Evidence-Based Medicine classification scheme. Data extracted from eligible abstracts included study type, study size, country of primary author and type of study designs. Three auditing processes were conducted to establish working definitions and the process was validated with a research methodologist and 2 senior thoracic surgeons. Intra-class correlation coefficient was calculated to assess inter-rater agreement. Chi-square test and Spearman correlation analysis were then used to compare the LOE between journals and by year of publication. RESULTS: Of 2028 publications reviewed and scored, 29 (1.4%) were graded level I, 75 (3.7%) were graded level II, 471 (23.2%) were graded level III, 1420 (70.2%) were graded level IV and 33 (1.6%) were graded level V (lowest level). Most publications (94.9%) were of lower-level evidence (III-V). There was an overall increasing trend in the lower LOE (P < 0.001). Inter-rater reliability was substantial with 95.5% (95%, confidence interval: 0.95-0.96) level of agreement between reviewers. CONCLUSIONS: General thoracic surgery literature consists mostly of lower LOE studies. The number of lower levels of evidence is dominating the recent publications, potentially indicating a need to increase the commitment to produce and disseminate higher-level evidence in general thoracic surgery.

Heteroallene Capture and Exchange at Functionalised Heptaphosphane Clusters.

Despite being known for decades the chemical reactivity of homoatomic seven-atom phosphorus clusters towards small molecules remains largely unexplored. Here, we report that neutral tris(silyl) functionalised heptaphosphane (P7 (SiR3 )3 ) cages are capable of heteroallene capture between the P-Si bonds of the cluster. A range of isocyanates and an isothiocyanate were investigated. In the case of isocyanates, silyl bonding at oxygen or nitrogen is regioselectively directed by the functional group on the isocyanate and substituents on the silyl moiety. Above all, we find that captured isothiocyanate molecules can be exchanged for isocyanate molecules, indicative of small molecule catch and release. Small molecule catch and release at these Zintl-derived clusters reveals their potential application as chemical storage materials or as reusable probes.

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

Near-infrared mapping with indocyanine green is associated with an increase in oncological margin length in minimally invasive segmentectomy.

BACKGROUND: Near-infrared fluorescence mapping with indocyanine green dye is a recent advancement in minimally invasive segmental resection. This technique has not yet been reproduced, validated, or objectively evaluated in a large prospective case series. We hypothesized that near-infrared fluorescence mapping is associated with an increased oncological margin distance from the tumor, over and above the best judgment of the surgeon. METHODS: This was a phase 2 prospective cohort trial in patients who are undergoing robotic segmentectomy for lung tumors <3 cm. The predicted intersegmental plane was first identified by consensus between 2 thoracic surgeons. The true plane was then mapped by indocyanine green injection. A 7-item binary rating scale was used for the evaluation of feasibility, reproducibility, and added oncological margin distance from the tumor. The margin distance between the tumor and the true plane was compared with the margin distance between the tumor and the predicted plane. RESULTS: Fifty-three patients were enrolled between September 2016 and May 2018 and 31 patients (58.4%) received the planned operation with indocyanine green mapping. In 74.2% of cases (23 out of 31), a score of 7 out of 7 was achieved, indicating the true intersegmental plane identified by indocyanine green mapping was different than the predicted plane identified by the surgeon. In 61.2% (19 out of 31) of those cases, the mean additional margin distance from the tumor to the staple line attributable to the indocyanine green mapping was 2.41 ± 1.6 cm. The overall complication rate was 18.5% (10 out of 53) and there were no deaths. CONCLUSIONS: Near-infrared fluorescence mapping in robotic segmentectomy is associated with increased oncological margin length, over and above the best judgment of the surgeon, in the majority cases where it is used.

Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome.

BACKGROUND: Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients. METHODS: Plasma from 39 TB-IRIS and 42 non-IRIS patients was collected during a prospective study of HIV-associated tuberculosis patients starting ART. In total, 26% of patients received corticosteroid (CTC) therapy pre-ART for severe tuberculosis. Concentrations of total 25-hydroxyvitamin D (25(OH)D) and 14 cytokines/chemokines were determined at ART initiation and 2 weeks later. RESULTS: Patients prescribed concurrent CTC had lower interferon γ (IFN-γ), IP-10, tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, IL-10, IL-12p40, and IL-18 pre-ART (P ≤ .02). TB-IRIS presented at 12 days (median) of ART, irrespective of CTC use. In patients who developed TB-IRIS (not on CTC) IL-6, IL-8, IL-12p40, IL-18, IP-10, and TNF increased during 2 weeks (P ≤ .04) of ART. Vitamin D deficiency (total 25(OH)D <75 nmol/L) was highly prevalent (89%) at baseline. Although vitamin D deficiency at either baseline or 2 weeks was not associated with TB-IRIS, in those not on CTC the median 25(OH)D decreased during 2 weeks (P = .004) of ART. Severe vitamin D deficiency (total 25(OH)D <25 nmol/L) was associated with higher baseline TNF, IL-6, and IL-8 irrespective of IRIS status. CONCLUSIONS: CTC modifies the inflammatory profile of those who develop TB-IRIS. The association between severe vitamin D deficiency and elevated proinflammatory cytokines support a study of vitamin D supplementation in HIV-TB co-infected patients starting ART.

Post-bronchoscopy sputum: improving the diagnostic yield in smear negative pulmonary TB.

INTRODUCTION: Patients with suspected active Pulmonary Tuberculosis (PTB) who are Acid-Fast Bacilli (AFB) smear negative or non-productive of sputum may undergo bronchoalveolar lavage. However, post-bronchoscopy sputum (PBS) sampling is not routine. The aim of this study was to establish the potential diagnostic value of PBS sampling. METHODS: A retrospective study of patients attending a London University hospital with microbiologically confirmed PTB between January 2004 and December 2010. Patients who were AFB smear negative or non-productive of sputum were eligible if sputum sampling was performed within 7 days of bronchoscopy. RESULTS: Over the study period, 236 patients had microbiologically confirmed smear negative PTB of which 57 patients were eligible for the study. 15 patients (26.3%) were infected with HIV. 19 patients (33.3%) converted to AFB sputum smear positivity post-bronchoscopy and 5 patients (8.8%) were exclusively AFB sputum smear positive on PBS microscopy. Mycobacterium tuberculosis was cultured from the PBS of 43 patients (75.4%) and of these, 4 (7.0%) were exclusively PBS culture positive. CONCLUSION: PBS analysis can provide a simple method of rapidly diagnosing pulmonary tuberculosis. In this cohort, M. tuberculosis culture yield was increased by 7% through PBS sampling. This study has important infection control implications with nearly one third of patients becoming more infectious after bronchoscopy.