Step by step guide to do a systematic review and meta-analysis for medical professionals.

INTRODUCTION: Systematic review and meta-analysis are statistical tools used to review researches performed on a same topic. They extract the collective effect of the studies performed on the topic of interest after statistically analysing the data of all the studies included. AIMS AND OBJECTIVES: Systematic reviews and meta-analysis are getting more and more popular in the medical field. Statistics is never the strong aspect of medical professionals, and facing a large number of statistical tests and values could be quite confusing for them. The aim of this article is to simplify these two very important research modalities for medical professionals. CONCLUSION: This article will provide a step-to-step guide for the medical colleagues to perform a meta-analysis if they are interested.

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

Intravenous amiodarone for the pharmacological termination of haemodynamically-tolerated sustained ventricular tachycardia: is bolus dose amiodarone an appropriate first-line treatment?

OBJECTIVE: To examine the efficacy of bolus dose intravenous amiodarone for the pharmacological termination of haemodynamically-tolerated sustained monomorphic ventricular tachycardia (VT). DESIGN, SETTING AND PARTICIPANTS: Retrospective case series of consecutive emergency admissions with haemodynamically-tolerated sustained monomorphic VT administered bolus dose intravenous amiodarone 300 mg, according to current UK advanced life support practice guidelines. MAIN OUTCOME MEASURES: Pharmacological termination rates within 20 min and 1 h and incidence of hypotension requiring emergency direct current cardioversion (DCCV) during this period. RESULTS: 41 patients (35 men) of mean (SD) age 68 (10) years, the majority (85%) with ischaemic heart disease and impaired left ventricular function (mean (SD) ejection fraction 0.31 (0.11)), were enrolled in the study. The median VT duration was 70 min (range 15-6000), mean heart rate was 174 (34) bpm and systolic and diastolic blood pressures were 112 (22) and 73 (19) mm Hg, respectively. Pharmacological VT termination occurred within 20 min in 6/41 patients (15%; 95% CI 7% to 29%) and within 1 h in 12/41 patients (29%; 95% CI 18% to 45%). Haemodynamic deterioration requiring emergency DCCV occurred in 7/41 patients (17%; 95% CI 8% to 32%). CONCLUSIONS: Although advocated by advanced life support guidelines, bolus dose intravenous amiodarone was relatively ineffective for acutely terminating haemodynamically-tolerated sustained monomorphic VT with a significant incidence of haemodynamic destabilisation requiring emergency DCCV. Previous studies in the identical clinical setting suggest that alternative antiarrhythmic agents, particularly intravenous procainamide and sotalol, may be superior. A prospective randomised trial is required to determine the optimal drug treatment for stable sustained monomorphic VT in the emergency setting.

A simplified approach to temporary DDD pacing using a single lead, balloon-tipped catheter with overlapping biphasic impulse stimulation.

Temporary DDD pacing offers significant hemodynamic benefits in emergency management of bradyarrhythmias but is underused because of its complexity (two leads) and unreliability. Single lead VDD pacing with atrial sensing via a floating dipole is feasible, but atrial pacing is limited by high thresholds and phrenic nerve stimulation (PNS). Overlapping biphasic impulse (OLBI) stimulation may avoid these problems. The authors designed a single lead balloon-tipped catheter for temporary transvenous DDD pacing, incorporating noncontact atrial dipoles for OLBI stimulation. This catheter was deployed using fluoroscopic guidance in 74 patients (43 men, 31 women) with mean age 56.9 +/- 17.0 years. Pacing parameters were assessed at implantation and follow-up. The median procedural time was 6.6 (range 1.2-25.0) minutes and fluoroscopy time 1.9 (range 0.2-7.8) minutes. Stable VDD pacing was achieved in all cases. Atrial capture was achieved in 73 of 74 cases with both modes at maximum output but was restricted by PNS at outputs below atrial capture threshold in 3 of 74 cases with OLBI and 10 of 74 cases with standard bipolar mode (P = 0.04). At outputs > or = 1.0 V above atrial threshold, reliable DDD pacing without PNS was achieved and maintained in 67 (91%) of 74 patients in OLBI compared to 53 (72%) of 74 patients in bipolar mode (P = 0.003). Pacing parameters were stable during follow-up (median 53 hours, range 6-168 hours). In conclusion, the single lead catheter with OLBI stimulation allows temporary VDD and DDD pacing without PNS to be achieved in > 90% of patients. This rapid and convenient approach should facilitate DDD pacing in emergency settings.

Giant coronary artery aneurysm presenting as a mediastinal mass.

An asymptomatic mediastinal mass in a 72-year-old man was imaged by computer tomography, magnetic resonance imaging, and coronary arteriography, revealing a giant atheromatous aneurysm of the right coronary artery.

Coronary artery aneurysm rupture mimicking dissection of the thoracic aorta.

Acute dissection of the ascending aorta may present with chest pain and haemopericardium. The following case illustrates an unusual differential diagnosis: rupture of a very large coronary artery aneurysm, diagnosed by transoesophageal echocardiography.

Cardiac catheterisation performed by a clinical nurse specialist.

OBJECTIVE: To establish the feasibility and safety of an appropriately trained clinical nurse specialist performing diagnostic cardiac catheterisation. DESIGN: Non-randomised retrospective comparison between the first 100 and second 100 consecutive investigations by a clinical nurse specialist and 200 consecutive patients investigated by two cardiology registrars over a similar period. SETTING: Regional cardiac centre performing 3200 catheterisation procedures per annum. PATIENTS: 200 patients undergoing routine (non-emergency) cardiac catheterisation for investigation of ischaemic heart disease. MAIN OUTCOME MEASURES: Procedural complications, image quality, fluoroscopy times. RESULTS: Satisfactory diagnostic images in all nurse specialist cases with no deaths and two complications (coronary artery dissection and femoral pseudoaneurysm). Procedure duration and fluoroscopy times slightly shorter for clinical nurse specialist by 3 and 1.6 minutes, respectively (P < 0.05). CONCLUSIONS: Non-medical practitioners can be trained to perform straightforward cardiac angiography in low risk patients with consultant supervision, as for cardiology registrars. With important restrictions such posts may have a limited role in supporting future consultant based services.

Effect of magnesium sulphate in patients with unstable angina. A double blind, randomized, placebo-controlled study.

AIMS: Administration of intravenous magnesium sulphate has been shown to be protective during acute myocardial ischaemia and it may therefore have beneficial effects in unstable angina. The purpose of this study was to assess the effects of a 24-h infusion of magnesium in patients with unstable angina. METHODS AND RESULTS: Patients who presented with unstable angina with electrocardiographic changes were randomized to receive a 24-h intravenous infusion of magnesium or placebo within 12 h of admission. The primary endpoint was myocardial ischaemia, as assessed by 48 h Holter monitoring. Resting 12-lead ECGs, creatine kinase-MB release and urinary catecholamines were also assessed. Patients were followed for 1 month. Thirty-one patients received magnesium sulphate and 31 placebo. Baseline characteristics and extent of coronary disease were similar in both groups. On 48 h Holter monitoring, 14 patients (50%) had transient ST segment shifts in the magnesium group vs 12 patients (46%) in the placebo group. However, there were fewer ischaemic episodes in the magnesium group (51 vs 101, P < 0.001) and there was a trend towards an increase in the total duration of ischaemia in the placebo group compared to the magnesium group in the second 24 h (2176 min vs 719 min respectively, P = 0.08). Regression of T wave changes on the 24 h ECG occurred more frequently in patients who received magnesium compared to those treated with placebo (11 patients vs 0 patients respectively, P < 0.005). Creatine kinase-MB release was significantly less at 6 and 24 h in patients who received magnesium compared to those treated with placebo. Catecholamine excretion was lower in patients treated with magnesium than in those treated with placebo (adrenaline: 1.05 +/- 0.16 vs 1.61 +/- 0.32 ng.mmol-1 creatinine; noradrenaline: 9.99 +/- 1.82 vs 18.48 +/- 2.41 ng.mmol-1 creatinine respectively in the first 12 h sample, P < 0.05). CONCLUSIONS: Intravenous magnesium reduces ischaemic ECG changes, creatine kinase-MB release and urinary catecholamine excretion in the acute phase of unstable angina. Thus, magnesium may be a beneficial additional therapy for these patients. Further studies are required to confirm these finding.

Effect of magnesium on the monophasic action potential during early ischemia in the in vivo human heart.

OBJECTIVES: This study sought to examine the effects of magnesium on epicardial action potential duration in patients during early myocardial ischemia. BACKGROUND: Magnesium has been shown to reduce arrhythmias in experimental models of myocardial ischemia. Experimental and clinical observations suggest an effect on repolarization. METHODS: Patients undergoing elective coronary artery bypass surgery were randomized (double blind) to receive intravenous magnesium (n = 10) or placebo (n = 10). Patients were placed on cardiopulmonary bypass and paced at 600 ms, and stable monophasic action potentials were obtained. Ischemia was achieved by aortic cross-clamping for 2 min while normothermia was maintained. RESULTS: Serum magnesium levels increased from 0.60 +/- 0.03 to 1.69 +/- 0.07 mmol/liter (mean +/- SEM) in the magnesium group, with no change in the placebo group. Epicardial temperature was identical in the two groups and did not alter during ischemia. At 90% repolarization, initial action potential prolongation was observed in the placebo group over the first minute of ischemia (282.0 +/- 6.0 to 294.0 +/- 4.8 ms) but not in the magnesium group (278.3 +/- 5.9 to 274.5 +/- 7.4 ms). At 2 min of ischemia, action potential duration was shorter in the magnesium group than in the placebo group (258.1 +/- 5.5 vs. 281.3 +/- 5.9 ms, respectively, p < 0.05). CONCLUSIONS: Intravenous magnesium infusion altered the epicardial action potential response to ischemia in patients. These findings may have important implications in the pathogenesis of arrhythmias in ischemic myocardium.

Electrophysiologic profile and efficacy of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with sustained monomorphic ventricular tachycardia. Dofetilide Arrhythmia Study Group.

There is increasing evidence that class III antiarrhythmic agents may be superior to class I agents for the long-term treatment of life-threatening ventricular tachyarrhythmias. This open study evaluated the acute electrophysiologic effects, antiarrhythmic efficacy, and safety of different doses of intravenous dofetilide, a new class III drug, in 50 patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation who had previously been unsuccessfully treated with 0 to 7 (median 3) other drugs. Intravenous dofetilide was administered over 60 minutes at the following dose levels: 1.5, 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Significant class III activity was apparent at doses of 3.0 to 15.0 micrograms/kg, as evidenced by dose-related prolongation of the QTc interval by 13.4% to 14.2%, ventricular effective refractory period by 7.9% to 20.6%, and ventricular functional refractory period by 7.3% to 25.0%. The corresponding mean +/- SD plasma dofetilide concentrations ranged from 1.45 +/- 0.52 to 6.48 +/- 1.31 ng/ml. There was no evidence of reverse use-dependence. At these electrophysiologically active dose levels, intravenous dofetilide suppressed (complete response) or slowed (partial response) inducible ventricular tachycardia in 17 of 41 patients (41%) compared with 0 of 9 patients receiving only 1.5 micrograms/kg. The response rate was fairly uniform among the groups receiving 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Intravenous dofetilide was hemodynamically well tolerated. Torsades de pointes (which was self-limiting) developed in only 1 patient, who was allocated to receive 15.0 micrograms/kg. There were no other proarrhythmic episodes or serious adverse effects. Further evaluation of the therapeutic potential of dofetilide in the management of life-threatening ventricular arrhythmias is justified.