Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta-analysis.

BACKGROUND: Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES: To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. AUTHORS' CONCLUSIONS: The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.

Dual bronchodilator versus inhaled corticosteroid/long-acting ß2-agonist in patients with chronic obstructive pulmonary disease: A meta-analysis of randomized controlled trials.

BACKGROUND: Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA, also known as dual bronchodilator) and inhaled corticosteroid/LABA (ICS/LABA) are the cornerstone of maintenance treatment for stable chronic obstructive pulmonary disease (COPD) patients. We aimed to comprehensively compare the efficacy and safety of the two maintenance treatment in COPD patients. METHODS: We searched the database Embase, Cochrane Library, PubMed, and Clinical Trials.gov systematically (from inception until September 2020). Randomized controlled trials (RCTs) comparing dual bronchodilator with ICS/LABA in the treatment of COPD were included. Efficacy and safety endpoints were pooled as mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). This meta-analysis was registered with PROSPERO prospectively # CRD42020203314). RESULTS: Fourteen RCTs including 21,496 patients were included. Dual bronchodilator showed a greater improvement in both trough FEV1 (MD = 0.06 L, 95% CI: 0.04-0.07, P < 0.001) and FVC (FVC: MD = 0.12 L, 95% CI: 0.07-0.16, P < 0.001), and a lower risk of pneumonia (RR = 0.62, 95% CI: 0.53-0.72, P < 0.001) in patients with COPD. There were no significant differences neither in the improvement of exacerbations, symptoms, and quality of life, nor in the incidence of cardiovascular events, serious adverse events, all-cause mortality, and withdrawals due to adverse events of treatment between these two maintenance treatments. CONCLUSIONS: Dual bronchodilator is superior to ICS/LABA in improving lung function and is associated with a lower risk of pneumonia in patients with COPD. There are no significant differences in other efficacy and safety profiles between these two maintenance treatments.

Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependant high-affinity choline transporter.

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and ß2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.

Aerobic performance among healthy (non-asthmatic) adults using beta2-agonists: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To examine the effect of beta2-agonists on aerobic performance in healthy, non-asthmatic study participants. DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: We searched four databases (PubMed, Embase, SPORTDiscus and Web of Science) for randomised controlled trials published until December 2019. Studies examining the effect of beta2-agonists on maximal physical performance lasting longer than 1 min were included in the meta-analysis. Data are presented as standardised difference in mean (SDM) with 95% CI. RESULTS: The present meta-analysis includes 47 studies. The studies comprise 607 participants in cross-over trials, including 99 participants in three-way cross-over trials and 27 participants in a four-way cross-over trial. Seventy-three participants were included in parallel trials. Beta2-agonists did not affect aerobic performance compared with placebo (SDM 0.051, 95% CI -0.020 to 0.122). The SDM for the included studies was not heterogeneous (I2=0%, p=0.893), and the effect was not related to type of beta2-agonist, dose, administration route, duration of treatment or performance level of participants. Beta2-agonists had no effect on time trial performance, time to exhaustion or maximal oxygen consumption (p<0.218). CONCLUSION/IMPLICATION: The present study shows that beta2-agonists do not affect aerobic performance in non-asthmatic subjects regardless of type, dose, administration route, duration of treatment or performance level of participants. The results of the present study should be of interest to WADA and to anyone who is interested in equal opportunities in competitive sports. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018109223.

Short-acting inhaled ß2-agonists: why, whom, what, how?

We showed the present data about the efficacy and safety of inhaled short-acting ß2-agonists (SABA), such as salbutamol and fenoterol, in the management of obstructive diseases in children and adults. Our work discusses major mechanisms of action, clinical effects, possible side effects and indications of inhaled SABA. We presented current recommendations for the position of SABA in the therapy of obstructive diseases in children and adults, particularly in asthma and chronic obstructive pulmonary disease.

Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?-Lessons Learned From Cancer.

SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I-viral response, stage II-pulmonary phase, and stage III-hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.

The Effect of ß2-Adrenoceptor Agonists on Leucocyte-Endothelial Adhesion in a Rodent Model of Laparotomy and Endotoxemia.

Background: The ß2-adrenoceptor agonist dopexamine may possess anti-inflammatory actions which could reduce organ injury during endotoxemia and laparotomy. Related effects on leucocyte-endothelial adhesion remain unclear. Methods: Thirty anesthetized Wistar rats underwent laparotomy followed by induction of endotoxemia with lipopolysaccharide and peptidoglycan (n = 24) or sham (n = 6). Animals received dopexamine at 0.5 or 1 µg kg-1 min-1 (D0.5 and D1), salbutamol at 0.1 µg kg-1 min-1, or saline vehicle (Sham and Control) for 5 h. Intravital microscopy was performed in the ileum of the small intestine to assess leucocyteendothelial adhesion, arteriolar diameter, and functional capillary density. Global hemodynamics and biochemical indices of renal and hepatic function were also measured. Results: Endotoxemia was associated with an increase in adherent leucocytes in post-capillary venules, intestinal arteriolar vasoconstriction as well-reduced arterial pressure and relative cardiac index, but functional capillary density in the muscularis was not significantly altered. Dopexamine and salbutamol administration were associated with reduced leucocyte-endothelial adhesion in post-capillary venules compared to control animals. Arteriolar diameter, arterial pressure and relative cardiac index all remained similar between treated animals and controls. Functional capillary density was similar for all groups. Control group creatinine was significantly increased compared to sham and higher dose dopexamine. Conclusions: In a rodent model of laparotomy and endotoxemia, ß2-agonists were associated with reduced leucocyte-endothelial adhesion in post-capillary venules. This effect may explain some of the anti-inflammatory actions of these agents.

The ADRB1 (Adrenoceptor Beta 1) and ADRB2 genes significantly co-express with commonly mutated genes in prostate cancer.

BACKGROUND: Beta blockers act on the beta-adrenergic receptors ADRB1 and ADRB2 to reduce heart rate and blood pressure. Observational studies have revealed strong risk reductions in metastasis and cancer-specific mortality with the use of beta-blockers in patients with some cancers. But observational studies of prostate cancer have reported conflicting results. OBJECTIVES: We examined the relationship of ADRB1 (Adrenoceptor beta 1) gene expression and ADRB2 (Adrenoceptor beta 2) gene expression with Forkhead box protein A1 (FOXA1) gene expression in prostate cancer. We also analyzed survival data of solid tumor patients with respect to beta 1 (ADRB1) and beta 2 (ADRB2) adrenergic receptor gene expression. METHODS: We examined the genomics of prostate cancer and other solid primary tumors in the GDC TCGA Prostate Cancer (PRAD) data set. The Cancer Genome Atlas (TCGA) contains the analysis of over 11,000 tumors from 33 of the most prevalent forms of cancer. RESULTS: The presence of somatic mutations [Single nucleotide polymorphisms (SNPs) and small insertion/deletion polymorphism (INDELS)] in FOXA1 alters ADRB1 and ADRB2 gene expression. The correlation of FOXA1 gene expression with ADRB1 and ADRB2 gene expression is highly significant. Alterations in FOXA1 genes, ADRB1 genes, and ADRB2 genes are significantly co-occurrent, indicating that they may work in tandem to drive tumor formation and development. Increased ADRB1 and ADRB2 expressions reduce the overall survival of solid tumor patients in the GDC Pan Cancer set. CONCLUSIONS: FOXA1 signaling may regulate ADRB1 and ADRB2 expression, as well as androgen receptor expression. Analysis of these tumor mutations might indicate whether an individual prostate cancer patient will respond to beta blockers.

Postnatal ß2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle.

KEY POINTS: Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole-body glucose clearance is normal, 1-month-old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose-stimulated insulin secretion in IUGR lambs is due to lower intra-islet insulin availability and not from glucose sensing. We investigated adrenergic receptor (ADR) ß2 desensitization by administering oral ADRß modifiers for the first month after birth to activate ADRß2 and antagonize ADRß1/3. In IUGR lambs ADRß2 activation increased whole-body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies. IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose-stimulated insulin secretion and insulin-stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. ABSTRACT: Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated ß adrenergic receptor (ADRß) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRß2 agonist and ADRß1/ß3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-body GUR were not different from controls. Of importance, ADRß2 stimulation with ß1/ß3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRß2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRß1 activation. We conclude that targeted ADRß2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

Influence of Anxiety/Depression on the Subjective Evaluation of Cough in Patients with Chronic Obstructive Pulmonary Disease and Obesity.

Background and objectives: Obesity and anxiety and/or depression are common comorbidities in patients with chronic obstructive pulmonary disease (COPD). For doctors treating COPD, cough has a certain importance as a symptom. The purpose of this study was to figure out how obesity and anxiety/depression may influence the subjective assessment of cough. Materials and Methods: 110 patients with COPD participated in the study. The patients were divided into two groups, one including obese patients, and the other including patients with normal body weight. All patients filled out the hospital anxiety and depression scale (HADS) questionnaire, evaluated the severity of their cough by using visual analogue scale (VAS) on the 1st and 10th day of treatment, and underwent a 12 hour cough monitoring with a special cough monitoring device both on the 1st and the 10th day of treatment. Results: The severity of anxiety according to the HADS in patients with COPD and normal body weight was significantly higher than in patients with COPD and obesity, corresponding to 9.25 ± 1.37 and 8.20 ± 1.18 points, respectively (p = 0.0063). The patients with normal body weight and obesity, but without anxiety and depression, subjectively noted an improvement in their well-being on the 10th day of treatment (p = 0.0022, p = 0.0021, respectively). In subgroups with normal body weight and obesity with anxiety and/or depression, the mean values for VAS on day 10 did not change significantly (p = 0.1917, p = 0.1921, respectively). Also, patients from the subgroup with normal body weight and anxiety/depression had a significantly higher assessment of their cough on day 10 than obese patients with anxiety/depression (p = 0.0411). The VAS values correlated positively with the actual amount of cough (r = 0.42, p = 0.0122 and r = 0.44, p = 0.0054, respectively) in patients without anxiety and/or depression, while in patients with anxiety and/or depression, there was an inverse correlation between VAS values and cough (r = -0.38, p = 0.0034 and r = -0.40, p = 0.0231). Conclusions: It is important to diagnose and treat anxiety and depression in patients with COPD for a better prognosis and higher efficacy of medical treatments. While treating such patients, it is preferable to use a cough monitoring device for objective assessments, since the patients may exaggerate or underestimate their symptoms.

Anti-doping Policy, Therapeutic Use Exemption and Medication Use in Athletes with Asthma: A Narrative Review and Critical Appraisal of Current Regulations.

Asthma is prevalent in athletes and when untreated can impact both respiratory health and sports performance. Pharmacological inhaler therapy currently forms the mainstay of treatment; however, for elite athletes competing under the constraints of the World Anti-Doping Code (Code), a number of established therapies are prohibited both in and/or out of competition and/or have a maximum permitted dose. The recent release of medical information detailing inhaler therapy in high-profile athletes has brought the legitimacy and utilisation of asthma medication in this setting into sharp focus. This narrative review critically appraises recent changes to anti-doping policy and the Code in the context of asthma management, evaluates the impact of asthma medication use on sports performance and employs a theory of behaviour to examine perceived determinants and barriers to athletes adhering to the anti-doping rules of sport when applied to asthma.

Adrenergic Regulation of Macrophage-Mediated Innate/Inflammatory Responses in Obesity and Exercise in this Condition: Role of ß2 Adrenergic Receptors.

BACKGROUND: The effects of exercise on the innate/inflammatory immune responses are crucially mediated by catecholamines and adrenoreceptors; and mediations in both stimulatory and anti-inflammatory responses have been attributed to them. Obesity and metabolic syndrome are included among low-grade chronic inflammatory pathologies; particularly because patients have a dysregulation of the inflammatory and stress responses, which can lead to high levels of inflammatory cytokines that induce insulin resistance, contributing to the onset or exacerbation of type 2 diabetes. Macrophages play a crucial role in this obesity-induced inflammation. Although most of the antiinflammatory effects of catecholamines are mediated by ß adrenergic receptors (particularly ß2), it is not known whether in altered homeostatic conditions, such as obesity and during exercise, innate/ inflammatory responses of macrophages to ß2 adrenergic stimulation are similar to those in cells of healthy organisms at baseline. OBJECTIVE: This review aims to emphasize that there could be possible different responses to ß2 adrenergic stimulation in obesity, and exercise in this condition. METHODS: A revision of the literature based on the hypothesis that obesity affects ß2 adrenergic regulation of macrophage-mediated innate/inflammatory responses, as well as the effect of exercise in this context. CONCLUSION: The inflammatory responses mediated by ß2 adrenoreceptors are different in obese individuals with altered inflammatory states at baseline compared to healthy individuals, and exercise can also interfere with these responses. Nevertheless, it is clearly necessary to develop more studies that contribute to widening the knowledge of the neuroimmune regulation process in obesity, particularly in this context.

Methods of accelerating orthodontic tooth movement: A review of contemporary literature.

Technological progress and the introduction of modern therapeutic methods are constantly changing contemporary orthodontics. More and more orthodontic patients are working adults, who expect satisfactory therapeutic effects as soon as possible, increasing the importance of methods accelerating tooth movement. The aim of this study was to review the current literature regarding methods of accelerating tooth movement and reducing the duration of the active phase of therapy. The literature was collected from the PubMed and EBSCO databases using "accelerated orthodontic tooth movement" as the search key words. The methods described were categorized as conservative and surgical. The pharmacological agents used in conservative treatment, such as growth hormone, parathyroid hormone, thyroxine, and vitamin D, are especially worth mentioning. They stimulate osteoclasts to increase resorption through a variety of mechanisms. Effective methods also include physical stimuli, e.g., vibrations or photobiomodulation. Most studies describing the effects of pharmacological agents were based on animal subjects and they may therefore lack clinical relevancy. Corticotomy and its modifications based on the regional acceleratory phenomenon (RAP) might prove to be a useful augmentation of orthodontic treatment, especially in adults, including patients with periodontal disease.

[The Overrated Impact of Inhaled Substances (LABA, LAMA, ICS) on Exacerbation Rates in COPD]. / Die überschätzte Beeinflussung der Exazerbationsrate bei COPD durch Inhalativa (LABA, LAMA, ICS).

Numerous studies have shown that exacerbation rates in COPD can be significantly reduced by long acting beta-2-agonists (LABA), long acting anticholinergic agents (LAMA) and inhaled steroids (ICS). Elaborate and extensive investigations however failed to prove that the reduction in exacerbation rates leads to life prolongation. As opposed to this, numerous studies have shown a reduction in life expectancy with increasing number and severity of exacerbations.This review aimed at comparing these studies and to elaborate the relevance and reduction of exacerbations rates by LABA, LAMA and ICS application through effect size calculation by means of Cohens' d. These studies display a common pattern. The reduction of exacerbation rates is only being achieved for less severe exacerbations (Cohens' d max. 0.21). For more severe exacerbations and for the comparison of different substances Cohens' d remains below 0.1, indicating that the effect of the medications is practically irrelevant. The impact of LABA's, LAMA's and ICS on exacerbation rates in COPD patients is obviously overrated.

Inhibition of ß2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative ß-blockade.

In response to recent studies, we investigated an association between perioperative ß-blockade and breast cancer metastases. First, a retrospective study examining perioperative ß-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to ß2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative ß-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased ß2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to ß2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased ß2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding ß2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative ß-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases.

Asthma in adults (acute): magnesium sulfate treatment.

INTRODUCTION: About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This overview does not endorse or follow any particular protocol, but presents the evidence about a specific intervention, magnesium sulfate. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of magnesium sulfate for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 50 studies. After deduplication and removal of conference abstracts, 24 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 10 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review was updated and one systematic review was added at this update. We performed a GRADE evaluation for five PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two comparisons based on information about the effectiveness and safety of magnesium sulfate (iv) versus placebo and magnesium sulfate (nebulised) plus short-acting beta2 agonists (inhaled) versus short-acting beta2 agonists (inhaled) alone.