Engineering Airway Epithelium

Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990). In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium

A method for translational rat ex vivo lung perfusion experimentation

The application of ex vivo lung perfusion (EVLP) has significantly increased the successful clinical use of marginal donor lungs. While large animal EVLP models exist to test new strategies to improve organ repair, there is currently no rat EVLP model capable of maintaining long-term lung viability. Here, we describe a new rat EVLP model that addresses this need, while enabling the study of lung injury due to cold ischemic time (CIT). The technique involves perfusing and ventilating male Lewis rat donor lungs for 4 h before transplanting the left lung into a recipient rat and then evaluating lung function 2 h after reperfusion. To test injury within this model, lungs were divided into groups and exposed to different CITs (i.e., 20 min, 6 h, 12 h, 18 h and 24 h). Experiments involving the 24-h-CIT group were prematurely terminated due to the development of severe edema. For the other groups, no differences in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO₂/FIO₂) were observed during EVLP; however, lung compliance decreased over time in the 18-h group (P = 0.012) and the PaO₂/FIO₂ of the blood from the left pulmonary vein 2 h after transplantation was lower compared with 20-min-CIT group (P = 0.0062). This new model maintained stable lung function during 4-h EVLP and after transplantation when exposed to up to 12 h of CIT

De-Epithelialization Protocol with Tapered Sodium Dodecyl Sulfate Concentrations Enhances Short-Term Chondrocyte Survival in Porcine Chimeric Tracheal Allografts

Background: Tracheal transplantation is indicated in cases where injury exceeds 50% of the organ in adults and 30% in children. However, transplantation is not yet considered a viable treatment option partly due to high morbidity and mortality associated with graft rejection. Recently, decellularization (decell) has been explored as a technique for creating bioengineered tracheal grafts. However, risk of post-operative stenosis increases due to the death of chondrocytes, which are critical to maintain the biochemical and mechanical integrity of tracheal cartilage. In this project, we propose a new de-epithelialization protocol that adequately removes epithelial, mucosal, and submucosal cells while maintaining a greater proportion of viable chondrocytes. Methods: The trachea of adult male outbred Yorkshire pigs were extracted, decontaminated, and decellularized according to the original and new protocols before incubation at 37 °C in DMEM for 10 days. Chondrocyte viability was quantified immediately following post-decellularization and on days 1, 4, 7, and 10. Histology was performed pre-decellularization, post-decellularization, and post-incubation. Results: The new protocol showed a significant (p < 0.05) increase in chondrocyte viability up to four days after de-ep when compared to the original protocol. We also found that the new protocol preserves ECM composition to a similar degree as the original protocol. When scaffolds created using the new protocol were re-epithelialized, cell growth curves were near identical to published data from the original protocol. Conclusion: While not without limitations, our new protocol may be used to engineer chimeric tracheal allografts without the need for cartilage regeneration

Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non–small cell lung cancer

ObjectiveOptimal management of stage IIIA-N2 non–small cell lung cancer remains controversial. The surgical arm of the North American Intergroup 0139 trial was adopted as the standard treatment for patients with resectable N2 disease at the University Health Network. Results after 7 years of experience are reported.MethodsThis is a retrospective study of consecutive patients with biopsy-proved T1-3 N2 M0 lung cancer who underwent induction chemoradiation before surgical intervention from January 1997 through August 2004. Induction chemotherapy consisted of cisplatin, 50 mg/m2, on days 1 and 8; etoposide, 50 mg/m2, on days 1 to 5, weeks 1 and 5; and concurrent daily external beam radiotherapy to 45 Gy. Lung resection was performed within 6 weeks of completion of chemoradiation, followed by 2 further cycles of consolidation chemotherapy.ResultsBetween January 1997 and August 2004, 40 patients were treated according to this protocol (25% T1, 62.5% T2, 7.5% T3, and 5% T4). Overall and disease-free median survivals were 40 and 37.1 months, respectively, whereas overall and disease-free 3-year survivals were 51.7% and 52.3%, respectively. R0 resection was achieved in 92.5%. The overall operative mortality rate was 7.5% (0% for lobectomy and 27% for pneumonectomy). Notably, all mortalities occurred within the first 2 years of our experience with this regimen.ConclusionChemoradiation before pulmonary resection in carefully selected patients with surgically resectable stage IIIA (N2) non–small cell lung cancer can lead to improved overall and disease-free survival

Design considerations in a clinical trial of a cognitive behavioural intervention for the management of low back pain in primary care : Back Skills Training Trial

Background Low back pain (LBP) is a major public health problem. Risk factors for the development and persistence of LBP include physical and psychological factors. However, most research activity has focused on physical solutions including manipulation, exercise training and activity promotion. Methods/Design This randomised controlled trial will establish the clinical and cost-effectiveness of a group programme, based on cognitive behavioural principles, for the management of sub-acute and chronic LBP in primary care. Our primary outcomes are disease specific measures of pain and function. Secondary outcomes include back beliefs, generic health related quality of life and resource use. All outcomes are measured over 12 months. Participants randomised to the intervention arm are invited to attend up to six weekly sessions each of 90 minutes; each group has 6–8 participants. A parallel qualitative study will aid the evaluation of the intervention. Discussion In this paper we describe the rationale and design of a randomised evaluation of a group based cognitive behavioural intervention for low back pain

Determinants for receiving acupuncture for LBP and associated treatments: a prospective cohort study

BACKGROUND: Acupuncture is a frequently used but controversial adjunct to the treatment of chronic low back pain (LBP). Acupuncture is now considered to be effective for chronic LBP and health care systems are pressured to make a decision whether or not acupuncture should be covered. It has been suggested that providing such services might reduce the use of other health care services. Therefore, we explored factors associated with acupuncture treatment for LBP and the relation of acupuncture with other health care services. METHODS: This is a post hoc analysis of a longitudinal prospective cohort study. General practitioners (GPs) recruited consecutive adult patients with LBP. Data on physical function, subjective mood and utilization of health care services was collected at the first consultation and at follow-up telephone interviews for a period of twelve months. RESULTS: A total of 179 (13 %) out of 1,345 patients received acupuncture treatment. The majority of those (59 %) had chronic LBP. Women and elderly patients were more likely to be given acupuncture. Additional determinants of acupuncture therapy were low functional capacity and chronicity of pain. Chronic (vs. acute) back pain OR 1.6 (CL 1.4–2.9) was the only significant disease-related factor associated with the treatment. The strongest predictors for receiving acupuncture were consultation with a GP who offers acupuncture OR 3.5 (CL 2.9–4.1) and consultation with a specialist OR 2.1 (CL 1.9–2.3). After adjustment for patient characteristics, acupuncture remained associated with higher consultation rates and an increased use of other health care services like physiotherapy. CONCLUSION: Receiving acupuncture for LBP depends mostly on the availability of the treatment. It is associated with increased use of other health services even after adjustment for patient characteristics. In our study, we found that receiving acupuncture does not offset the use of other health care resources. A significant proportion of patients who received did not meet the so far only known selection criterion (chonicity). Acupuncture therapy might be a reflection of helplessness in both patients and health care providers

Proportional lumbar spine inter-vertebral motion patterns: a comparison of patients with chronic, non-specific low back pain and healthy controls

Introduction: Identifying biomechanical subgroups in chronic, non-specific low back pain (CNSLBP) populations from inter-vertebral displacements has proven elusive. Quantitative fluoroscopy (QF) has excellent repeatability and provides continuous standardised inter-vertebral kinematic data from fluoroscopic sequences allowing assessment of mid-range motion. The aim of this study was to determine whether proportional continuous IV rotational patterns were different in patients and controls. A secondary aim was to update the repeatability of QF measurement of range of motion (RoM) for inter-vertebral (IV) rotation

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

IMPORTANCE Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. OBJECTIVE To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. DESIGN, SETTING, AND PARTICIPANTS This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. INTERVENTIONS Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. MAIN OUTCOME AND MEASURES The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. RESULTS Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. CONCLUSIONS AND RELEVANCE This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04863924

Function after spinal treatment, exercise and rehabilitation (FASTER): improving the functional outcome of spinal surgery

Background: The life-time incidence of low back pain is high and diagnoses of spinal stenosis and disc prolapse are increasing. Consequently, there is a steady rise in surgical interventions for these conditions. Current evidence suggests that while the success of surgery is incomplete, it is superior to conservative interventions. A recent survey indicates that there are large differences in the type and intensity of rehabilitation, if any, provided after spinal surgery as well as in the restrictions and advice given to patients in the post-operative period. This trial will test the hypothesis that functional outcome following two common spinal operations can be improved by a programme of post-operative rehabilitation that combines professional support and advice with graded active exercise and/or an educational booklet based on evidence-based messages and advice.Methods/Design: The study design is a multi-centre, factorial, randomised controlled trial with patients stratified by surgeon and operative procedure. The trial will compare the effectiveness and cost-effectiveness of a rehabilitation programme and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression, each compared with "usual care" using a 2 x 2 factorial design. The trial will create 4 sub-groups; rehabilitation-only, booklet-only, rehabilitation-plus-booklet, and usual care only. The trial aims to recruit 344 patients, which equates to 86 patients in each of the four sub-groups. All patients will be assessed for functional ability (through the Oswestry Disability Index - a disease specific functional questionnaire), pain (using visual analogue scales), and satisfaction pre-operatively and then at 6 weeks, 3, 6 and 9 months and 1 year post-operatively. This will be complemented by a formal analysis of cost-effectiveness.Discussion: This trial will determine whether the outcome of spinal surgery can be enhanced by either a postoperative rehabilitation programme or an evidence-based advice booklet or a combination of the two and as such will contribute to our knowledge on how to manage spinal surgery patients in the post-operative period