Tissue engineering and regenerative medicine strategies for the repair of tympanic membrane perforations

Despite the high success rate of autologous grafts in tympanic membrane repair, clinical alternatives are required for the closure of unresponsive chronic perforations that can lead to recurring infection and hearing loss. Tissue engineering and regenerative medicine approaches have emerged as another strategy to repair the eardrum, in addition to negating the need for donor tissue harvest and related surgical iatrogenicities. This review highlights the main approaches using biomaterials, growth factors, and cell therapies towards the healing of complex TM perforations. In addition, we discuss the challenges and advances for the development of reliable animal models, which will allow the optimisation and development of novel techniques. Finally, we indicate technologies that are currently used clinically and others that are closer to the market. The advances here discussed on tissue engineering and regenerative medicine strategies applied to the field of TM perforations will allow otologists, surgeons, and researchers to better bring novel technologies to the bedside as well as to develop new ones

Sarcoplasmic reticulum calcium mishandling central tenet in heart failure?

Excitation-contraction coupling links excitation of the sarcolemmal surface membrane to mechanical contraction. In the heart this link is established via a Ca-induced Ca release process, which, following sarcolemmal depolarisation, prompts Ca release from the sarcoplasmic reticulum (SR)\ua0though the ryanodine receptor (RyR2). This substantially raises the cytoplasmic Ca concentration to trigger systole. In diastole, Ca is removed from the cytoplasm, primarily via the sarcoplasmic-endoplasmic reticulum Ca-dependent ATPase (SERCA) pump on the SR\ua0membrane, returning Ca to the SR store. Ca movement across the SR is thus fundamental to the systole/diastole cycle and plays an essential role in maintaining cardiac contractile function. Altered SR Ca homeostasis (due to disrupted Ca release, storage, and reuptake pathways) is a central tenet of heart failure and contributes to depressed contractility, impaired relaxation, and propensity to arrhythmia. This review will focus on the molecular mechanisms that underlie asynchronous Ca cycling around the SR in the failing heart. Further, this review will illustrate that the combined effects of expression changes and disruptions to RyR2 and SERCA2a regulatory pathways are critical to the pathogenesis of heart failure

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons