Non-Invasive Imaging for Native Aortic Valve Regurgitation.

Aortic regurgitation (AR) is associated with left ventricular volume and pressure overload, resulting in eccentric left ventricular (LV) remodeling and enlargement. This condition may be well tolerated for years before the onset of myocardial dysfunction and symptoms. Echocardiography plays a crucial role in the diagnosis of AR, assessing its mechanism and severity, and detecting LV remodeling. The assessment of AR severity is challenging and frequently requires the integration of information from multiple different measurements to assess the severity. Recent data suggests that echocardiographically derived LV volumes (end-systolic volume index > 45 ml/m2), an ejection fraction threshold of <60%, and abnormal global longitudinal strain may help identify early dysfunction and may be used to improve clinical outcomes. Consequently, these parameters can identify candidates for surgery. Cardiac magnetic resonance imaging is emerging as a valuable tool for assessing severity when it remains unclear after an echocardiographic evaluation. This review emphasizes the importance of imaging, particularly echocardiography, in the evaluation of AR. It focuses on various echocardiographic parameters, including technical details, and how to integrate them for assessing the mechanism and severity of AR, as well as LV remodeling.

Infective endarteritis of coronaries following percutaneous coronary intervention (stentocarditis) leading to pseudoaneurysm - a retrospective study of eleven cases.

Background: Coronary endarteritis and stent abscess following percutaneous coronary intervention (PCI) are rare and challenging conditions with no clear treatment guidelines available. Aims: This retrospective study aims to present the clinical features, patient and procedural factors, management strategies, and outcomes in 11 consecutive cases referred between 2018 and 2022. Methods: We retrospectively analysed 11 cases of coronary endarteritis and stent abscess post-PCI that were referred from various centres. We recorded clinical features, patient demographics, procedural factors, and management approaches, and evaluated treatment outcomes. Results: Among the 11 patients, 7 (63.6%) were male. PCIs had been performed in the right coronary artery (6, 54.5%), left anterior descending artery (3, 27.3%), and circumflex artery (2, 18.2%). The presenting symptoms included fever, pericarditis with effusion, tamponade, and postinterventional angina due to stent occlusion. Fever occurred in 10 (90.9%) patients, and the majority (70%) of patients experienced fever within one week of PCI. Staphylococcus aureus was the predominant organism (54.5%), followed by Pseudomonas aeruginosa. Transthoracic echocardiography revealed abscess cavities in 10 patients. All patients received vancomycin and piperacillin-tazobactam. Surgery was considered in 7 cases with abscesses >2 cm; one patient refused and responded to antibiotics for 4 weeks. Possible risk factors included repeated use of local sites, reuse of hardware, multiple guidewire manipulations, prolonged catheterisation, inadequate sterility, and diabetes. Conclusions: This study provides insights into coronary endarteritis and stent abscess following PCI. The lack of clear treatment guidelines highlights the challenges in managing this condition. Identifying risk factors may aid in preventive strategies. Further research is needed to develop standardised approaches for effective management.

Cardiac Masses Discovered by Echocardiogram; What to Do Next?

Cardiac tumors are rare conditions, typically diagnosed on autopsy, but with the advancement of imaging techniques they are now encountered more frequently in clinical practice. Echocardiography is often the initial method of investigation for cardiac masses and provides a quick and valuable springboard for their characterization. While some cardiac masses can be readily identified by echocardiography alone, several require incorporation of multiple data points to reach diagnostic certainty. Herein, we will provide an overview of the main clinical, diagnostic, and therapeutic characteristics of cardiac masses within the framework of their location.

Clinical Impact of Cardiac Fibromas.

Cardiac fibromas are rare primary tumors that can cause significant morbidity and mortality. There has not been a large clinical case review since 1994. This study provides an updated analysis of clinical impact, thereby enhancing understanding, increasing awareness, and revealing important factors in the diagnosis and management of cardiac fibromas. A retrospective case series was conducted at a tertiary care institution by reviewing radiology, surgical and pathology archives (1964 to 2020). Cases were included if cardiac fibroma was diagnosed through imaging or pathology. Demographics, symptomatology, electrophysiologic data, radiographic findings, pathology, interventions, and outcomes were examined. A total of 26 patients with cardiac fibromas were identified, including 12 women. The median age was 20.5 years (0 days to 72 years). Symptoms included palpitations (commonly due to ventricular tachycardia, 31%), syncope (15%), angina (15%), heart failure (12%), emboli (4%), and murmur (27%). One patient had Gorlin syndrome. A total of 22 patients were diagnosed through imaging, 15 of whom were biopsy-confirmed. A total of 9 patients were initially observed. A total of 2 eventually had surgery, 1 was lost to follow-up, 3 were asymptomatic, 1 had heart failure and atrial fibrillation, and 1 had atrial fibrillation and tachy-brady syndrome, requiring ablation and pacemaker placement. A total of 19 underwent resection. A total of 4 required complex operations, 1 required a second resection, and 1 operative death occurred. In conclusion, cardiac fibromas primarily affect the pediatric population; however, this study demonstrates a significant prevalence in adults. Ventricular tachycardia is common, and multimodality imaging is diagnostically sensitive. Resection is largely successful in symptomatic patients. Surveillance may be appropriate for asymptomatic patients.

Association of Left Ventricular Volume in Predicting Clinical Outcomes in Patients with Aortic Regurgitation.

BACKGROUND: Aortic regurgitation (AR) is a common valvular lesion associated with increased mortality once the left ventricle enlarges significantly or develops systolic dysfunction (ejection fraction < 50%). Valve guidelines recommend aortic valve repair or replacement (AVR) for left ventricular (LV) linear end-systolic dimension ≥ 50 mm or end-diastolic dimension ≥ 65 mm. However, chamber quantification guidelines recommend using LV volume for LV size determination because linear measurements may not accurately reflect LV remodeling. The aim of this study was to evaluate the correlation of LV volumes with linear dimensions, interobserver variability in the estimation of volumes, and the association of volumes with outcomes in patients with AR. METHODS: A total of 1,100 consecutive patients with chronic moderate to severe and severe AR on echocardiography between 2004 and 2019 were retrospectively analyzed. The modified Simpson disk summation method was used for LV volume estimation. The primary outcome was all-cause mortality; the secondary outcome was mortality censored at AVR. RESULTS: Patients' age was 60 ± 17 years, and 198 were women (18%). Volumes were measured using the biplane method in 939 patients (85%) and the monoplane method in 161 (15%); end-systolic volume was normal in 169 (11%). Correlations between volumes and linear dimensions were 0.5 for end-diastolic volume and 0.6 for end-systolic volume. At median follow-up of 5.4 years (interquartile range, 2.4-10.0 years), 216 patients had died and 539 had undergone AVR. Indexed LV end-systolic volume (iLVESV) and indexed left ventricular end-systolic dimension were both associated with mortality and symptoms, but the association of iLVESV was stronger. iLVESV, age, male gender, Charlson comorbidity index, New York Heart Association functional class III or IV, and time-dependent AVR were independently associated with all-cause mortality. Interobserver variability in the estimation of LV volumes in 200 patients included intraclass coefficients of 0.94 (95% CI, 0.92-0.95) for end-diastolic volume and 0.88 (95% CI, 0.78-0.93) for end-systolic volume. Patients with iLVESV ≥ 45 mL/m2 had lower survival and a higher prevalence of symptoms than those with volumes < 45 mL/m2. CONCLUSIONS: Echocardiographic LV volume assessment had good reproducibility in patients with moderate to severe and severe AR. The correlation between linear dimensions and volumes was limited. Both iLVESV and indexed left ventricular end-systolic dimension were associated with worse outcomes, but the association of iLVESV was stronger. iLVESV ≥ 45 mL/m2 was associated with worse outcomes.

Inpatient Palliative Care Use in Patients With Pulmonary Arterial Hypertension: Temporal Trends, Predictors, and Outcomes.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Despite the negative impact of PAH on quality of life and survival, data on use of specialty palliative care services (PCS) is scarce. RESEARCH QUESTION: We sought to evaluate the inpatient use of PCS in patients with PAH. STUDY DESIGN AND METHODS: Using the National (Nationwide) Inpatient Sample, 30,495 admissions with a primary diagnosis of PAH were identified from 2001 through 2017. The primary outcome of interest was temporal trends and predictors of inpatient PCS use in patients with PAH. RESULTS: The inpatient use of PCS was low (2.2%), but increased during the study period from 0.5% in 2001 to 7.6% in 2017, with a significant increase starting in 2009. White race, private insurance, higher socioeconomic status, hospital-specific factors, higher comorbidity burden (Charlson Comorbidity Index), cardiac and noncardiac organ failure, and use of extracorporeal membrane oxygenation and noninvasive mechanical ventilation were independent predictors of increased PCS use. PCS use was associated with a higher prevalence of do-not-resuscitate status, a longer length of stay, higher hospitalization costs, and increased in-hospital mortality with less frequent discharges to home, likely because these patients were also sicker (higher comorbidity index and illness acuity). INTERPRETATION: The inpatient use of PCS in patients with PAH is low, but has been increasing over recent years. Despite increased PCS use over time, patient- and hospital-specific disparities in PCS use continue. Further studies evaluating these disparities and the role of PCS in the comprehensive care of PAH patients are warranted.

What Is New in Low Gradient Aortic Stenosis: Surgery, TAVR, or Medical Therapy?

BACKGROUND: A significant proportion of patients with aortic stenosis (AS) have discordance in severity by mean gradient/peak velocity and aortic valve area. Low gradient aortic stenosis (LG-AS) is defined when the aortic valve area is < 1 cm2 consistent with severe AS and mean aortic gradient is < 40 mmHg consistent with non-severe AS. LG-AS represents a diagnostic and therapeutic challenge. PURPOSE OF REVIEW: To summarize the different categories, diagnosis, management, and prognosis of LG-AS. LG-AS is classified as classical (ejection fraction (EF) < 50%, indexed stroke volume (SVi) < 35 ml/m2), paradoxical (EF > 50%, SVi < 35 ml/m2), pseudo-severe (moderate AS with reduced EF), or normal flow low gradient AS. RECENT FINDINGS: Recent findings emphasize the importance of low-dose dobutamine stress echocardiography and CT calcium score in the assessment of aortic valve. In addition, flow reserve (increase in SV > 50%) can be evaluated during dobutamine stress echocardiography and helps predict perioperative prognosis. Patients with LG-AS have better survival with aortic valve replacement (AVR) compared to medical therapy, irrespective of presence or absence of flow reserve. Some recent studies suggest that transcatheter aortic valve replacement (TAVR) may be superior to surgical AVR for patients with a lack of contractile flow reserve or those with paradoxical LG-AS, but further investigation is needed to clarify optimal treatment. The role of TAVR in patients with moderate AS and reduced EF is also under investigation.

Incidence, Mechanisms, and Predictors of Mean Systolic Gradients ≥20 mm Hg after Transcatheter Aortic Valve Implantation.

There is a significant increase in transvalvular gradients after transcatheter aortic valve implantation (TAVI) in some patients; however, mechanisms underlying the greater than expected gradients are unknown. We sought to determine the incidence and mechanisms of greater than expected gradients post-TAVI. A total of 424 patients who underwent TAVI at our institution between November 2008 and August 2015 and had at least 1 follow-up echocardiogram were included in the study. Greater than expected gradients were defined as mean systolic Doppler gradients ≥20 mm Hg. The primary end-point was incidence and mechanisms of mean systolic Doppler gradients ≥20 mm Hg. A total of 36 (8%) patients had mean systolic Doppler gradients ≥20 mm Hg. The mechanisms of mean systolic Doppler gradients ≥20 mm Hg were: patient prosthesis mismatch in 15 (42%) patients, high cardiac output in 13 (36%), prosthetic and periprosthetic regurgitation in 11 (31%), stenosis in 5 (14%), and multiple mechanisms in 8 (22%). Patients with mean systolic Doppler gradients ≥20 mm Hg had higher cardiac re-hospitalization rate, but no difference in mortality or major cardiovascular events when compared with the normal gradient group. Smaller prosthetic valve size (p <0.0001) and larger body mass index (p = 0.02) were associated with mean systolic Doppler gradients ≥20 mm Hg; warfarin therapy at discharge had no effect on gradients. In conclusion, about 8% patients had mean systolic Doppler gradients ≥20 mm Hg following TAVI, and patient-prosthesis mismatch was the most common mechanism. The mean systolic Doppler gradients ≥20 mm Hg after TAVI are not benign and warrant careful surveillance.

Intravenous versus inhalational techniques for rapid emergence from anaesthesia in patients undergoing brain tumour surgery.

BACKGROUND: Brain tumour surgery usually is carried out with the patient under general anaesthesia. Over past years, both intravenous and inhalational anaesthetic agents have been used, but the superiority of one agent over the other is a topic of ongoing debate. Early and rapid emergence from anaesthesia is desirable for most neurosurgical patients. With the availability of newer intravenous and inhalational anaesthetic agents, all of which have inherent advantages and disadvantages, we remain uncertain as to which technique may result in more rapid early recovery from anaesthesia. OBJECTIVES: To assess the effects of intravenous versus inhalational techniques for rapid emergence from anaesthesia in patients undergoing brain tumour surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 6) in The Cochrane Library, MEDLINE via Ovid SP (1966 to June 2014) and Embase via Ovid SP (1980 to June 2014). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov (October 2014). We reran the searches for all databases in March 2016, and when we update the review, we will deal with the two studies of interest found through this search that are awaiting classification. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the use of intravenous anaesthetic agents such as propofol and thiopentone with inhalational anaesthetic agents such as isoflurane and sevoflurane for maintenance of general anaesthesia during brain tumour surgery. Primary outcomes were emergence from anaesthesia (assessed by time to follow verbal commands, in minutes) and adverse events during emergence, such as haemodynamic changes, agitation, desaturation, muscle weakness, nausea and vomiting, shivering and pain. Secondary outcomes were time to eye opening, recovery from anaesthesia using the Aldrete or Modified Aldrete score (i.e. time to attain score ≥ 9, in minutes), opioid consumption, brain relaxation (as assessed by the surgeon on a 4- or 5-point scale) and complications of anaesthetic techniques, such as intraoperative haemodynamic instability in terms of hypotension or hypertension (mmHg), increased or decreased heart rate (beats/min) and brain swelling. DATA COLLECTION AND ANALYSIS: We used standardized methods in conducting the systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methods and outcome data from reports of all trials considered eligible for inclusion. We performed all analyses on an intention-to-treat basis. We used a fixed-effect model when we found no evidence of significant heterogeneity between studies, and a random-effects model when heterogeneity was likely. For assessments of the overall quality of evidence for each outcome that included pooled data from RCTs only, we downgraded the evidence from 'high quality' by one level for serious (or by two levels for very serious) study limitations (risk of bias), indirectness of evidence, serious inconsistency, imprecision of effect or potential publication bias. MAIN RESULTS: We included 15 RCTs with 1833 participants. We determined that none of the RCTs were of high methodological quality. For our primary outcomes, pooled results from two trials suggest that time to emergence from anaesthesia, that is, time needed to follow verbal commands, was longer with isoflurane than with propofol (mean difference (MD) -3.29 minutes, 95% confidence interval (CI) -5.41 to -1.18, low-quality evidence), and time to emergence from anaesthesia was not different with sevoflurane compared with propofol (MD 0.28 minutes slower with sevoflurane, 95% CI -0.56 to 1.12, four studies, low-quality evidence). Pooled analyses for adverse events suggest lower risk of nausea and vomiting with propofol than with sevoflurane (risk ratio (RR) 0.68, 95% CI 0.51 to 0.91, low-quality evidence) or isoflurane (RR 0.45, 95% CI 0.26 to 0.78) and greater risk of haemodynamic changes with propofol than with sevoflurane (RR 1.85, 95% CI 1.07 to 3.17), but no differences in the risk of shivering or pain. Pooled analyses for brain relaxation suggest lower risk of tense brain with propofol than with isoflurane (RR 0.88, 95% CI 0.67 to 1.17, low-quality evidence), but no difference when propofol is compared with sevoflurane. AUTHORS' CONCLUSIONS: The finding of our review is that the intravenous technique is comparable with the inhalational technique of using sevoflurane to provide early emergence from anaesthesia. Adverse events with both techniques are also comparable. However, we derived evidence of low quality from a limited number of studies. Use of isoflurane delays emergence from anaesthesia. These results should be interpreted with caution. Randomized controlled trials based on uniform and standard methods are needed. Researchers should follow proper methods of randomization and blinding, and trials should be adequately powered.

Methadone maintenance dose/weight ratio, long QTc, and EKG screening.

BACKGROUND AND OBJECTIVES: Electrocardiogram (EKG) monitoring during methadone maintenance treatment (MMT) has been recommended to prevent potentially fatal prolonged computed QT intervals (QTc). However, risk indicators for obtaining EKGs do not exist. This study assessed 23 variables that might help identify prolonged QTc during MMT. METHODS: EKGs concurrent with methadone serum levels were obtained from 69 veterans during a 5-year study, encompassing 302.8 person-years. Two cardiologists hand-measured QT intervals, selecting each patient's longest QTc. QTc categories included: normal duration <440 ms; borderline duration of 440-469 ms; and abnormal duration ≥470 ms. QTc's were compared with seven methadone parameters and 16 bio-psycho-social variables using two QTc cut-offs (440 and 470 ms). RESULTS: Among the 69 patients, 19 had normal QTc's, 28 had borderline QTc's, and 22 had abnormal QTc's. Methadone dose/weight was moderately correlated with QTc, and independently associated with longer QTc at both 440 and 470 cut-offs. DISCUSSION AND CONCLUSION: Dose/weight ≥.49 is useful for screening EKGs for QTc's ≥440 cut-off. Dose/weight ≥.65 produces high-yield abnormal QTc's ≥470 cut-off. SCIENTIFIC SIGNIFICANCE: Methadone dose/weight provides moderately reliable thresholds for making routine screening decisions and urgent clinical decisions to obtain an EKG for prolonged QTc. (Am J Addict 2016;25:499-507).

Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis.

Opioid drug abusers have a greater susceptibility to gram positive (Gram (+)) bacterial infections. However, the mechanism underlying opioid modulation of Gram (+) versus Gram (-) bacterial clearance has not been investigated. In this study, we show that opioid treatment resulted in reduced phagocytosis of Gram (+), when compared to Gram (-) bacteria. We further established that LPS priming of chronic morphine treated macrophages leads to potentiated phagocytosis and killing of both Gram (+) and Gram (-) bacteria in a P-38 MAP kinase dependent signaling pathway. In contrast, LTA priming lead to inhibition of both phagocytosis and bacterial killing. This study demonstrates for the first time the differential effects of TLR4 and TLR2 agonists on morphine induced inhibition of phagocytosis. Our results suggest that the incidence and severity of secondary infections with Gram (+) bacteria would be higher in opioid abusers.

Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia.

BACKGROUND: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin in the bloodstream. It may occur in patients with acute and chronic leukemia and is particularly associated with acute promyelocytic leukemia (a subtype of acute myeloid leukemia). OBJECTIVES: To assess the clinical benefits and harms of any pharmacological intervention for treating DIC in patients with acute or chronic leukemia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 05), MEDLINE (1946 to 7 May 2015), LILACS (1982 to 7 May 2015) and African Index Medicus (7 May 2015). There was no language restrictions. We sought additional randomized controlled trials (RCTs) from the World Health Organization International Clinical Trials Registry Platform and the reference lists of primary studies identified. SELECTION CRITERIA: RCTs assessing the clinical benefits and harms of interventions for treating DIC in patients with acute and chronic leukemia. DATA COLLECTION AND ANALYSIS: Two review authors independently performed trial selection, 'Risk of bias' assessment and data extraction. Primary outcomes were overall mortality, in-hospital mortality from any cause (15-day and 30-day) and adverse events. MAIN RESULTS: In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution.According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size.One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment.In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence).No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive.The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock. AUTHORS' CONCLUSIONS: Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion.

Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis.

BACKGROUND: Myelofibrosis is a bone marrow disorder characterized by excessive production of reticulin and collagen fiber deposition caused by hematological and non-hematological disorders. The prognosis of myelofibrosis is poor and treatment is mainly palliative. Janus kinase inhibitors are a novel strategy to treat people with myelofibrosis. OBJECTIVES: To determine the clinical benefits and harms of Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis secondary to hematological or non-hematological conditions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2014, Issue 11), Ovid MEDLINE (from 1946 to 13 November 2014), EMBASE (from 1980 to 12 January 2013), and LILACS (from 1982 to 20 November 2014). We searched WHO International Clinical Trials Registry Platform and The metaRegister of Controlled Trials. We also searched for conference proceedings of the American Society of Hematology (from 2009 to October 2013), European Hematology Association (from 2009 to October 2013), American Society of Clinical Oncology (from 2009 to October 2013), and European Society of Medical Oncology (from 2009 to October 2013). We included searches in FDA, European Medicines Agency, and Epistemonikos. We handsearched the references of all identified included trials, and relevant review articles. We did not apply any language restrictions. Two review authors independently screened search results. SELECTION CRITERIA: We included randomized clinical trials comparing Janus kinase-1 and Janus kinase-2 inhibitors with placebo or other treatments. Both previously treated and treatment naive patients were included. DATA COLLECTION AND ANALYSIS: We used the hazard ratio (HR) and 95% confidence interval (95% CI) for overall survival, progression-free survival and leukemia-free survival, risk ratio (RR) and 95% CI for reduction in spleen size and adverse events binary data, and standardized mean differences (SMD) and 95% CI for continuous data (health-related quality of life). Two review authors independently extracted data and assessed the risk of bias of included trials. Primary outcomes were overall survival, progression-free survival and adverse events. MAIN RESULTS: We included two trials involving 528 participants, comparing ruxolitinib with placebo or best available therapy (BAT). As the two included trials had different comparators we did not pool the data. The confidence in the results estimates of these trials was low due to the bias in their design, and their limited sample sizes that resulted in imprecise results.There is low quality evidence for the effect of ruxolitinib on survival when compared with placebo at 51 weeks of follow-up (HR 0.51, 95% CI 0.27 to 0.98) and compared with BAT at 48 weeks of follow-up (HR 0.70, 95% CI 0.20 to 2.47). Similarly there was very low quality evidence for the effect of ruxolitinib on progression free survival compared with BAT (HR 0.81, 95% CI 0.47 to 1.39).There is low quality evidence for the effect of ruxolitinib in terms of quality of life. Compared with placebo, the drug achieved a greater proportion of patients with a significant reduction of symptom scores (RR 8.82, 95% CI 4.40 to 17.69), and treated patients with ruxolitinib obtained greater MFSAF scores at the end of follow-up (MD -87.90, 95% CI -139.58 to -36.22). An additional trial showed significant differences in EORTC QLQ-C30 scores when compared ruxolitinib with best available therapy (MD 7.60, 95% CI 0.35 to 14.85).The effect of ruxolitinib on reduction in the spleen size of participants compared with placebo or BAT was uncertain (versus placebo: RR 64.58, 95% CI 9.08 to 459.56, low quality evidence; versus BAT: RR 41.78, 95% CI 2.61 to 669.75, low quality evidence).There is low quality evidence for the effect of the drug compared with placebo on anemia (RR 2.35, 95% CI 1.62 to 3.41), neutropenia (RR 3.57, 95% CI 1.02 to 12.55) and thrombocytopenia (RR 9.74, 95% CI 2.32 to 40.96). Ruxolitinib did not result in differences versus BAT in the risk of anemia (RR 1.35, 95% CI 0.91 to 1.99, low quality evidence) or thrombocytopenia (RR 1.20; 95% CI 0.44 to 3.28, low quality evidence). The risk of non-hematologic grade 3 or 4 adverse events (including fatigue, arthralgia, nausea, diarrhea, extremity pain and pyrexia) was similar when ruxolitinib was compared with placebo or BAT. The rate of neutropenia comparing ruxolitinib with standard medical treatment was not reported by the trial. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to allow any conclusions regarding the efficacy and safety of ruxolitinib for treating myelofibrosis. The findings of this Cochrane review should be interpreted with caution as they are based on trials sponsored by industry, and include a small number of patients. Unless powered randomized clinical trials provide strong evidence of a treatment effect, and the trade-off between potential benefits and harms is established, clinicians should be cautious when administering ruxolitinib for treating patients with myelofibrosis.

Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy

BACKGROUND: Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain tumour difficult. To ease surgical tumour removal, measures are taken to reduce brain swelling, often referred to as brain relaxation. Brain relaxation can be achieved with intravenous fluids such as mannitol or hypertonic saline. This review was conducted to find out which of the two fluids may have a greater impact on brain relaxation. OBJECTIVES: To compare the effects of mannitol versus those of hypertonic saline on intraoperative brain relaxation in patients undergoing craniotomy. METHODS: Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), Medline via Ovid SP (1966 to October 2013) and Embase via Ovid SP (1980 to October 2013). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov. Selection criteria: We included randomized controlled trials (RCTs) that compared the use of hypertonic saline versus mannitol for brain relaxation. We also included studies in which any other method used for intraoperative brain relaxation was compared with mannitol or hypertonic saline. Primary outcomes were longest follow-up mortality, Glasgow Outcome Scale score at three months and any adverse events related to mannitol or hypertonic saline. Secondary outcomes were intraoperative brain relaxation, intensive care unit (ICU) stay, hospital stay and quality of life. Data collection and analysis: We used standardized methods for conducting a systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a fixed-effect ...

An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut.

Opioids are known to exacerbate HIV pathogenesis, however current studies have been limited by models of HIV infection. Given that HIV causes many systemic effects via direct infection of host cells as well as indirect bystander effects, it is important to establish a systemic infection model in a small animal so that genetic tools can be utilized to elucidate the mechanisms of action. In this study, the systemic effects of EcoHIV infection, a modified HIV which can infect mouse cells, are examined in conjunction with morphine. EcoHIV infection with opioid treatment induced bacterial translocation from the lumen of the gut into systemic compartments such as liver, which is similar to observations in human patients with LPS. Bacterial translocation corresponds with alterations in gut morphology, disorganization of the tight junction protein occludin, and a concurrent increase in systemic inflammation in both IL-6 and TNFα. Long term infection also had increased expression of inflammatory cytokines in the CNS when co-treated with morphine. Overall, this study shows that EcoHIV is an appropriate model to study the effects of opioids on HIV pathogenesis, including the HIV-induced pathology at early stages of pathogenesis in the gut.

Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, not malignant, disease of the hematopoietic stem cells, associated with significant morbidity and mortality. It is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year. The treatment of PNH has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron. Eculizumab, a biological agent that inhibits complement cascade, was developed for preventing hemolytic anemia and severe thrombotic episodes. OBJECTIVES: To assess the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH). SEARCH METHODS: We conducted a comprehensive search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 5), Ovid MEDLINE (from 1946 to 15 May 2014), EMBASE (from 1980 to 25 June 2014), and LILACS (from 1982 to 25 June 2014). We did not apply any language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of their publication status or language. No limits were applied with respect to period of follow-up. We excluded quasi-RCTs. We included trials comparing eculizumab with placebo or best available therapy. We included any patient with a confirmed diagnosis of PNH. Primary outcome was overall survival. DATA COLLECTION AND ANALYSIS: We independently performed a duplicate selection of eligible trials, risk of bias assessment, and data extraction. We estimated risk ratios (RRs) and 95% confidence interval (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used a random-effects model for analysis. MAIN RESULTS: We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. AUTHORS' CONCLUSIONS: This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias.Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.

Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy.

BACKGROUND: Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain tumour difficult. To ease surgical tumour removal, measures are taken to reduce brain swelling, often referred to as brain relaxation. Brain relaxation can be achieved with intravenous fluids such as mannitol or hypertonic saline. This review was conducted to find out which of the two fluids may have a greater impact on brain relaxation. OBJECTIVES: The objective of this review was to compare the effects of mannitol versus those of hypertonic saline on intraoperative brain relaxation in patients undergoing craniotomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), MEDLINE via Ovid SP (1966 to October 2013) and EMBASE via Ovid SP (1980 to October 2013). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the use of hypertonic saline versus mannitol for brain relaxation. We also included studies in which any other method used for intraoperative brain relaxation was compared with mannitol or hypertonic saline. Primary outcomes were longest follow-up mortality, Glasgow Outcome Scale score at three months and any adverse events related to mannitol or hypertonic saline. Secondary outcomes were intraoperative brain relaxation, intensive care unit (ICU) stay, hospital stay and quality of life. DATA COLLECTION AND ANALYSIS: We used standardized methods for conducting a systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a fixed-effect model when no evidence was found of significant heterogeneity between studies, and a random-effects model when heterogeneity was likely. MAIN RESULTS: We included six RCTs with 527 participants. Only one RCT was judged to be at low risk of bias. The remaining five RCTs were at unclear or high risk of bias. No trial mentioned the primary outcomes of longest follow-up mortality, Glasgow Outcome Scale score at three months or any adverse events related to mannitol or hypertonic saline. Three trials mentioned the secondary outcomes of intraoperative brain relaxation, hospital stay and ICU stay; quality of life was not reported in any of the trials. Brain relaxation was inadequate in 42 of 197 participants in the hypertonic saline group and in 68 of 190 participants in the mannitol group. The risk ratio for brain bulge or tense brain in the hypertonic saline group was 0.60 (95% confidence interval (CI) 0.44 to 0.83, low-quality evidence). One trial reported ICU and hospital stay. The mean (standard deviation (SD)) duration of ICU stay in the mannitol and hypertonic saline groups was 1.28 (0.5) and 1.25 (0.5) days (P value 0.64), respectively; the mean (SD) duration of hospital stay in the mannitol and hypertonic saline groups was 5.7 (0.7) and 5.7 (0.8) days (P value 1.00), respectively AUTHORS' CONCLUSIONS: From the limited data available on the use of mannitol and hypertonic saline for brain relaxation during craniotomy, it is suggested that hypertonic saline significantly reduces the risk of tense brain during craniotomy. A single trial suggests that ICU stay and hospital stay are comparable with the use of mannitol or hypertonic saline. However, focus on other related important issues such as long-term mortality, long-term outcome, adverse events and quality of life is needed.

Challenges of managing elderly men with prostate cancer.

The incidence of prostate cancer increases with age. Current evidence suggests that prostate cancer is under treated in patients aged ≥70 years, despite evidence of efficacy and acceptable toxicity. Radical cystectomy and definitive radiotherapy are often denied owing to fears of post-operative complications and radiotherapy-associated gastrointestinal and genitourinary toxicity. However, modern radical prostatectomy techniques provide excellent clinical outcomes with low perioperative morbidity. Moreover, volume-restricted intensity-modulated radiation therapy is a significant improvement over previous 2D conformal radiotherapy with similar efficacy and lower toxicity. Androgen-deprivation therapy is also under-prescribed among the elderly, owing to concerns of increases in cardiac deaths and osteoporosis acceleration. However, prospective trials have not identified any increase in cardiovascular mortality among elderly men receiving androgen-deprivation therapy compared to age-matched controls. Most patients on androgen deprivation eventually progress to a castration-resistant state. At this stage, the disease still responds to newer agents that target the androgen pathway and to chemotherapy. Among the elderly, chemotherapy is under-prescribed even though it has been demonstrated to be palliative and improve survival. We describe the trends in prostate cancer management in the elderly and the importance of assessing comorbidity status, tumour characteristics, and health status, including a complete geriatric evaluation, before making treatment recommendations.

Vascular endothelial growth factor signaling in hypoxia and inflammation.

Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by re-programming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions.