Microfragmented Fat and Biphasic Calcium Phosphates for Alveolar Cleft Repair: Protocol for a Prospective, Nonblinded, First-in-Human Clinical Study.

BACKGROUND: Biphasic calcium phosphates (BCP) may serve as off-the-shelf alternatives for iliac crest-derived autologous bone in alveolar cleft reconstructions. To add osteoinductivity to the osteoconductive BCPs to achieve similar regenerative capacity as autologous bone, a locally harvested buccal fat pad will be mechanically fractionated to generate microfragmented fat (MFAT), which has been shown to have high regenerative capacity due to high pericyte and mesenchymal stem cell content and a preserved perivascular niche. OBJECTIVE: Our primary objectives will be to assess the feasibility and safety of the BCP-MFAT combination. The secondary objective will be efficacy, which will be evaluated using radiographic imaging and histological and histomorphometric evaluation of biopsies taken 6 months postoperatively, concomitant with dental implant placement. METHODS: Eight patients with alveolar cleft (≥15 years) will be included in this prospective, nonblinded, first-in-human clinical study. MFAT will be prepared intraoperatively from the patient's own buccal fat pad. Regular blood tests and physical examinations will be conducted, and any adverse events (AEs) or serious EAs (SAEs) will be meticulously recorded. Radiographic imaging will be performed prior to surgery and at regular intervals after reconstruction of the alveolar cleft with the BCP-MFAT combination. Biopsies obtained after 6 months with a trephine drill used to prepare the implantation site will be assessed with histological and histomorphometric analyses after methylmethacrylate embedding and sectioning. RESULTS: The primary outcome parameter will be safety after 6 months' follow-up, as monitored closely using possible occurrences of SAEs based on radiographic imaging, blood tests, and physical examinations. For efficacy, radiographic imaging will be used for clinical grading of the bone construct using the Bergland scale. In addition, bone parameters such as bone volume, osteoid volume, graft volume, and number of osteoclasts will be histomorphometrically quantified. Recruitment started in November 2019, and the trial is currently in the follow-up stage. This protocol's current version is 1.0, dated September 15, 2019. CONCLUSIONS: In this first-in-human study, not only safety but also the histologically and radiographically assessed regenerative potential of the BCP-MFAT combination will be evaluated in an alveolar cleft model. When an SAE occurs, it will be concluded that the BCP-MFAT combination is not yet safe in the current setting. Regarding AEs, if they do not occur at a higher frequency than that in patients treated with standard care (autologous bone) or can be resolved by noninvasive conventional methods (eg, with analgesics or antibiotics), the BCP-MFAT combination will be considered safe. In all other cases, the BCP-MFAT combination will not yet be considered safe. TRIAL REGISTRATION: Indonesia Clinical Trial Registry INA-EW74C1N; https://tinyurl.com/28tnrr64. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42371.

Stem Cell-Based Tissue Engineering for Cleft Defects: Systematic Review and Meta-Analysis.

This study aimed to analyze the efficacy of stem cell-based tissue engineering for the treatment of alveolar cleft (AC) and cleft palate (CP) defects in animal models.Systematic review and meta-analysis.Preclinical studies on alveolar cleft repair in maxillofacial practice.Electronic search was performed using PubMed, Embase, and Cochrane databases. Pre-clinical studies, where stem cell-based tissue engineering was used in the reconstruction of AC and CP in animal models were included. Quality of the selected articles was evaluated using SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation).Review of alveolar cleft bone augmentation interventions in preclinical models.Outcome parameters registered were new bone formation (NBF) and/or bone mineral density (BMD).Thirteen large and twelve small animal studies on AC (21) and CP (4) reconstructions were included. Studies had an unclear-to-high risk of bias. Bone marrow mesenchymal stem cells were the most widely used cell source. Meta-analyses for AC indicated non-significant benefits in favor of: (1) scaffold + cells over scaffold-only (NBF P = .13); and (2) scaffold + cells over empty control (NBF P = .66; BMD P = .31). Interestingly, dog studies using regenerative grafts showed similar to superior bone formation compared to autografts. Meta analysis for the CP group was not possible.AC and CP reconstructions are enhanced by addition of osteogenic cells to biomaterials. Directions and estimates of treatment effect are useful to predict therapeutic efficacy and guide future clinical trials of bone tissue engineering.

Changes in QTc interval after hydroxychloroquine therapy in patients with COVID-19 infection: a large, retrospective, multicentre cohort study.

OBJECTIVE: To evaluate the extent of hydroxychloroquine-induced corrected QT (QTc) prolongation and its relation to COVID-19 infection severity and incidence of polymorphic ventricular arrhythmias and sudden arrhythmic deaths. DESIGN: A large-scale cohort study with retrospective analysis of baseline and on-therapy QT interval corrected using Bazett and Fridericia formulas. SETTING: A multicentre study involving eight secondary and tertiary care hospitals of the Abu Dhabi Health Services Company (SEHA), United Arab Emirates. PARTICIPANTS: 2014 patients consecutively admitted with PCR-confirmed SARS-CoV-2 infection between 1 March 2020 and 1 June 2020. INTERVENTIONS: Treatment with hydroxychloroquine alone or in combination with azithromycin for at least 24 hours and with a baseline ECG and at least one ECG after 24 hours of therapy. MAIN OUTCOME MEASURES: Maximal QTc interval prolongation and its relationship to clinical severity, polymorphic ventricular tachycardia and sudden arrhythmic death while on treatment. RESULTS: The baseline QTc(Bazett) was 427.6±25.4 ms and the maximum QTc(Bazett) during treatment was 439.2±30.4 ms (p<0.001). Severe QTc prolongation (QTc ≥500 ms) was observed in 1.7%-3.3% of patients (Fridericia and Bazett, respectively). There were no cases of polymorphic ventricular arrhythmia or hydroxychloroquine-related arrhythmic death. QTc prolongation was more pronounced in combination therapy compared with hydroxychloroquine alone (22.2 ms vs 11.0 ms, p<0.001) and in patients with higher COVID-19 clinical severity (asymptomatic: 428.4±25.4 ms, severe COVID-19 infection: 452.7±35.7 ms, p<0.001). The overall in-hospital mortality was 3.97% and deceased patients had longer on-therapy QTc(Bazett) than survivors (459.8±21.4 ms vs 438.4±29.9 ms, p<0.001). CONCLUSIONS: The incidence of severe QTc prolongation with hydroxychloroquine was low and not associated with ventricular arrhythmia. The safety concerns surrounding the use of hydroxychloroquine may have been overestimated; however, caution should be exercised when using hydroxychloroquine in patients with risk factors for QT prolongation.

Safety and feasibility study of using polyphosphate (PolyP) in alveolar cleft repair: a pilot study.

BACKGROUND: Bone grafting is an important surgical procedure to reconstruct alveolar bone defects in patients with cleft lip and palate. Polyphosphate (PolyP) is a physiological polymer present in the blood, primarily in platelets. PolyP plays a role as a phosphate source in bone calcium phosphate deposition. Moreover, the cleavage of high-energy bonds to release phosphates provides local energy necessary for regenerative processes. In this study, polyP is complexed with calcium to form Calcium polyP microparticles (Ca-polyP MPs), which were shown to have osteoinductive properties in preclinical studies. The aim of this study was to evaluate the feasibility, safety, and osteoinductivity of Ca-polyP MPs, alone or in combination with BCP, in a first-in-human clinical trial. METHODS: This single-blinded, parallel, prospective clinical pilot study enrolled eight adolescent patients (mean age 18.1: range 13-34 years) with residual alveolar bone cleft. Randomization in two groups (four receiving Ca-polyP MPs only, four a combination of Ca-polyP MPs and biphasic calcium phosphate (BCP)) was performed. Patient follow-up was 6 months. Outcome parameters included safety parameters and close monitoring of possible adverse effects using radiographic imaging, regular blood tests, and physical examinations. Osteoinductivity evaluation using histomorphometric analysis of biopsies was not possible due to COVID restrictions. RESULTS: Due to surgical and feasibility reasons, eventually, only 2 patients received Ca-polyP MPs, and the others the combination graft. All patients were assessed up to day 90. Four out of eight were able to continue with the final assessment day (day 180). Three out of eight were unable to reach the hospital due to COVID-19 restrictions. One patient decided not to continue with the study. None of the patients showed any allergic reactions or any remarkable local or systematic side effects. Radiographically, patients receiving Ca-polyP MPs only were scored grade IV Bergland scale, while patients who got the BCP/Ca-polyP MPs combination had scores ranging from I to III. CONCLUSIONS: Our results indicate that Ca-polyP MPs and the BCP/Ca-polyP MPs combination appear to be safe graft materials; however, in the current setting, Ca-polyP MPs alone may not be a sufficiently stable defect-filling scaffold to be used in alveolar cleft repair. TRIAL REGISTRATION: Indonesian Trial Registry under number INA-EW74C1N by the ethical committee of Faculty of Medicine, Hasanuddin University, Makassar, Indonesia with code number 1063/UN4.6.4.5.31/PP36/2019 .

A clinical risk score to predict in-hospital mortality in critically ill patients with COVID-19: a retrospective cohort study.

OBJECTIVES: To identify factors influencing the mortality risk in critically ill patients with COVID-19, and to develop a risk prediction score to be used at admission to intensive care unit (ICU). DESIGN: A multicentre cohort study. SETTING AND PARTICIPANTS: 1542 patients with COVID-19 admitted to ICUs in public hospitals of Abu Dhabi, United Arab Emirates between 1 March 2020 and 22 July 2020. MAIN OUTCOMES AND MEASURES: The primary outcome was time from ICU admission until death. We used competing risk regression models and Least Absolute Shrinkage and Selection Operator to identify the factors, and to construct a risk score. Predictive ability of the score was assessed by the area under the receiver operating characteristic curve (AUC), and the Brier score using 500 bootstraps replications. RESULTS: Among patients admitted to ICU, 196 (12.7%) died, 1215 (78.8%) were discharged and 131 (8.5%) were right-censored. The cumulative mortality incidence was 14% (95% CI 12.17% to 15.82%). From 36 potential predictors, we identified seven factors associated with mortality, and included in the risk score: age (adjusted HR (AHR) 1.98; 95% CI 1.71 to 2.31), neutrophil percentage (AHR 1.71; 95% CI 1.27 to 2.31), lactate dehydrogenase (AHR 1.31; 95% CI 1.15 to 1.49), respiratory rate (AHR 1.31; 95% CI 1.15 to 1.49), creatinine (AHR 1.19; 95% CI 1.11 to 1.28), Glasgow Coma Scale (AHR 0.70; 95% CI 0.63 to 0.78) and oxygen saturation (SpO2) (AHR 0.82; 95% CI 0.74 to 0.91). The mean AUC was 88.1 (95% CI 85.6 to 91.6), and the Brier score was 8.11 (95% CI 6.74 to 9.60). We developed a freely available web-based risk calculator (https://icumortalityrisk.shinyapps.io/ICUrisk/). CONCLUSION: In critically ill patients with COVID-19, we identified factors associated with mortality, and developed a risk prediction tool that showed high predictive ability. This tool may have utility in clinical settings to guide decision-making, and may facilitate the identification of supportive therapies to improve outcomes.

The Gulf Implantable Cardioverter-defibrillator Registry: Rationale, Methodology, and Implementation.

BACKGROUND: The implantable cardioverter-defibrillator (ICD) is effective in the prevention of sudden cardiac death in high-risk patients. Little is known about ICD use in the Arabian Gulf. We designed a study to describe the characteristics and outcomes of patients receiving ICDs in the Arab Gulf region. METHODS: Gulf ICD is a prospective, multi-center, multinational, and observational study. All adult patients 18 years or older, receiving a de novo ICD implant and willing to sign a consent form will be eligible. Data on baseline characteristics, ICD indication, procedure and programing, in-hospital, and 1-year outcomes will be collected. Target enrollment is 1500 patients, which will provide adequate precision across a wide range of expected event rates. RESULTS: Fifteen centers in six countries are enrolling patients (Saudi Arabia, United Arab Emirates, Kuwait, Oman, Bahrain, and Qatar). Two-thirds of the centers have dedicated electrophysiology laboratories, and in almost all centers ICDs are implanted exclusively by electrophysiologists. Nearly three-quarters of the centers reported annual ICD implant volumes of ≤150 devices, and pulse generator replacements constitute <30% of implants in the majority of centers. Enrollment started in December 2013, and accrual rate increased as more centers entered the study reaching an average of 98 patients per month. CONCLUSIONS: Gulf ICD is the first prospective, observational, multi-center, and multinational study of the characteristics and, the outcomes of patients receiving ICDs in the Arab Gulf region. The study will provide valuable insights into the utilization of and outcomes related to ICD therapy in the Gulf region.

QRS prolongation in patients with acute coronary syndromes.

BACKGROUND: QRS prolongation with or without bundle branch block (BBB) has been associated with adverse outcome in myocardial infarction; we examined the relationship between QRS duration and outcome in a broad spectrum of patients with acute coronary syndrome (ACS). METHOD AND RESULTS: Core laboratory evaluation of the presenting electrocardiogram in Canadian ACS Registry patients (n = 5,003) showed 4,289 (85.7%) had QRS <120 milliseconds, 202 (4.0%) patients had QRS > or =120 milliseconds without BBB, 262 (5.2%) had left BBB (LBBB), and 250 (5.0%) had right BBB. Compared to patients with QRS <120 milliseconds, patients with QRS > or =120 milliseconds without BBB had higher in-hospital (3.5% vs 1.9%, odds ratio [OR] 1.87, 95% CI 0.85-4.09, P = .12) and 1-year mortality (14.9% vs 7.7%, OR 2.10, 95% CI 1.38-3.18, P = .001). In-hospital and 1-year mortality was significantly higher in patients with BBB (eg, LBBB compared with QRS <120 milliseconds) (5.0% vs 1.9%, OR 2.71, 95% CI 1.49-4.94, P = .001, and 23.8% vs 7.7%, OR 3.74, 95% CI 2.72-5.13, P < .001). Analyzed as a continuous variable and after adjustment for validated prognosticators, QRS duration was an independent predictor of 1-year death (OR 1.11, 95% CI 1.06-1.16, P < .001) and death/myocardial infarction (OR 1.06, 95% CI 1.02-1.11, P = .003). However, when using clinically applicable QRS duration evaluation, only LBBB was an independent predictor of 1-year mortality (OR 1.93, 95% CI 1.28-2.90, P = .002). CONCLUSIONS: In patients presenting with a broad spectrum of suspected ACS, QRS prolongation-particularly in the setting of LBBB-is an independent predictor of in-hospital and 1-year mortality.

Effect of saline water and sludge addition on biodegradation of municipal solid waste in bioreactor landfills.

Bioreactor landfills require sufficient moisture to optimize the biodegradation processes and methane generation. In arid regions, this is problematic given the lack of fresh water supplies. Saline water can be used but may inhibit the biodegradation of the municipal solid waste (MSW) in landfills. Sludge may be used to enhance the biodegradation of MSW under saline conditions. For this study, two groups of laboratory-scale bioreactor cells were used to study the impact of saline water and sludge addition on the biodegradation of MSW in bioreactor landfills. The first group (four bioreactors) operated without sludge addition. The second group (four bioreactors) operated with the addition of sludge. The salt concentrations in the two groups were 0, 0.5, 1 and 3% (w/v), respectively. All bioreactors were operated at neutral pH levels with leachate recycling. The methane yield was 70.6, 61.7 and 47.5 L kg(-1) dry waste for bioreactors R1, R2 and R4, respectively; and 84.7, 78.7, 72.6 and 59 L kg(-1) dry waste for bioreactors R5, R6, R7 and R8, respectively. The high salt content (3%) inhibited the MSW biodegradation as evidenced by the methane yield, the percentage reduction in leachate concentration and the settlement that occurred during the study. Sludge addition was able to improve the methane yield at all salt concentrations.

Clinical implications of a next-day follow-up electrocardiogram in patients with non-ST elevation acute coronary syndromes.

BACKGROUND: The prognostic value of admission ST-segment changes in patients with non-ST elevation acute coronary syndromes (NSTE ACS) is well established; however, the value of a next-day follow-up electrocardiogram (ECG) is unclear. METHOD: We evaluated ST-depression (ST(downward arrow)) and Q-wave status on the admission and 24 to 36-hour follow-up ECG in 2,743 patients in a prospective Canadian ACS registry. RESULTS: Of patients with ST(downward arrow) > or =1 mm on admission (n = 533 [19.4%]), 366 (68.7%) normalized their ST segment on follow-up ECG. Among patients without ST(downward arrow) on admission (n = 2,110), 97 (4.4%) developed new ST(downward arrow) at follow-up. Patients with normalized ST(downward arrow) at follow-up had higher 1-year myocardial infarction (MI) (10.1% vs 5.7%, odds ratio [OR] 1.77, 95% CI 1.12-2.81, P = .015) and death/MI rates (19.5% vs 10.2%, OR 1.69, 95% CI 1.18-2.41, P = .004), respectively, as compared to those who never had ST(downward arrow). Patients with persistent ST(downward arrow) had higher 1-year MI (10.8% vs 5.7%, OR 1.95, 95% CI 1.09-3.51, P = .025) and death/MI rates (25.6% vs 10.2%, OR 1.78, 95% CI 1.13-2.79, P = .013), respectively. In multivariable analysis, ST(downward arrow) on baseline ECG was an independent predictor of 1-year mortality; however, ST(downward arrow) on the follow-up ECG did not provide additional prognostic value. There were no differences in outcomes between the 4 different Q-wave status groups. CONCLUSIONS: Although dynamic and persistent ST(downward arrow) are associated with worse unadjusted outcome in patients with NSTE ACS, there was no incremental prognostic value of a follow-up ECG evaluating ST depression and/or Q-wave status beyond that already provided by the initial ECG together with established prognostic factors.