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l-Carnitine Supplementation in Older Women. A Pilot Study on Aging Skeletal Muscle Mass and Function.

l-Carnitine Supplementation in Older Women. A Pilot Study on Aging Skeletal Muscle Mass and Function. Nutrients. 2018 Feb 23;10(2): Authors: Sawicka AK, Hartmane D, Lipinska P, Wojtowicz E, Lysiak-Szydlowska W, Olek RA Abstract Skeletal muscle wasting, associated with aging, may be regulated by the inflammatory cytokines as well as by insulin-like growth factor 1 (IGF-1). l-carnitine possesses anti-inflammatory properties and increases plasma IGF-1 concentration, leading to the regulation of the genes responsible for protein catabolism and anabolism. The purpose of the present study was to evaluate the effect of a 24-week l-carnitine supplementation on serum inflammatory markers, IGF-1, body composition and skeletal muscle strength in healthy human subjects over 65 years of age. Women between 65 and 70 years of age were supplemented for 24 weeks with either 1500 mg l-carnitine-l-tartrate or an isonitrogenous placebo per day in a double-blind fashion. Before and after the supplementation protocol, body mass and composition, as well as knee extensor and flexor muscle strength were determined. In the blood samples, free carnitine, interleukin-6, tumor necrosis factor-α, C-reactive protein and IGF-1 were determined. A marked increase in free plasma carnitine concentration was observed due to l-carnitine supplementation. No substantial changes in other parameters were noted. In the current study, supplementation for 24 weeks affected neither the skeletal muscle strength nor circulating markers in healthy women over 65 years of age. Positive and negative aspects of l-carnitine supplementation need to be clarified. PMID: 29473908 [PubMed - in process]

Interventions for paracetamol (acetaminophen) overdose.

Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018 Feb 23;2:CD003328 Authors: Chiew AL, Gluud C, Brok J, Buckley NA Abstract BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. SELECTION CRITERIA: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. MAIN RESULTS: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. AUTHORS' CONCLUSIONS: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed. PMID: 29473717 [PubMed - as supplied by publisher]

Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study.

Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study. Diabetes Obes Metab. 2018 Feb 23;: Authors: Guja C, Frías JP, Somogyi A, Jabbour S, Wang H, Hardy E, Rosenstock J Abstract AIMS: To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes inadequately controlled despite titrated insulin glargine (IG) ± metformin. METHODS: This multicentre, double-blind study randomized (1:1) patients with persistent hyperglycaemia after 8-week IG titration (glycated haemoglobin [HbA1c] 7.0-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose. RESULTS: Of 464 randomized patients (mean: age 58 years; HbA1c 8.5% [69 mmol/mol]; diabetes duration 11.3 years), 91% completed 28 weeks. Exenatide QW+IG versus placebo+IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P<.001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P<.001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P<.001). Significantly more exenatide QW+IG- versus placebo+IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P<.001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW+IG (15.1% and 7.8%, respectively) than with placebo+IG (10.8% and 3.0%); hypoglycaemia incidence was similar between exenatide QW+IG (29.7%) and placebo+IG (29.0%) groups, with no major hypoglycaemic events. CONCLUSIONS: Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings. (ClinicalTrials.gov identifier: NCT02229383). PMID: 29473704 [PubMed - as supplied by publisher]

Bayesian approach for assessing noninferiority in a three-arm trial with binary endpoint.

Bayesian approach for assessing noninferiority in a three-arm trial with binary endpoint. Pharm Stat. 2018 Feb 22;: Authors: Ghosh S, Tiwari RC, Ghosh S Abstract With the recent advancement in many therapeutic areas, quest for better and enhanced treatment options is ever increasing. While the "efficacy" metric plays the most important role in this development, emphasis on other important clinical factors such as less intensive side effects, lower toxicity, ease of delivery, and other less debilitating factors may result in the selection of treatment options, which may not beat current established treatment option in terms efficacy, yet prove to be desirable for subgroups of patients. The resultant clinical trial by means of which one establishes such slightly less efficacious treatment is known as noninferiority (NI) trial. Noninferiority trials often involve an active established comparator arm, along with a placebo and an experimental treatment arm, resulting into a 3-arm trial. Most of the past developments in a 3-arm NI trial consider defining a prespecified fraction of unknown effect size of reference drug, i.e., without directly specifying a fixed NI margin. However, in some recent developments, more direct approach is being considered with prespecified fixed margin, albeit in the frequentist setup. In this article, we consider Bayesian implementation of such trial when primary outcome of interest is binary. Bayesian paradigm is important, as it provides a path to integrate historical trials and current trial information via sequential learning. We use several approximation-based and 2 exact fully Bayesian methods to evaluate the feasibility of the proposed approach. Finally, a clinical trial example is reanalyzed to demonstrate the benefit of the proposed approach. PMID: 29473291 [PubMed - as supplied by publisher]

Effects of seawater ingestion on lactate response to exercise in runners.

Effects of seawater ingestion on lactate response to exercise in runners. Biol Sport. 2017 Dec;34(4):407-412 Authors: Pérez-Turpin JA, Trottini M, Chinchilla-Mira JJ, Cyganik W Abstract The aim of this study was to examine the effect of microfiltered and sterilized seawater ingestion on running performance in a hot environment. This cross-over, double-blind randomized trial included 12 experienced male runners. The subjects randomly consumed seawater (SW) or pure water (placebo) in an equivalent amount of 50 ml five minutes prior to running at 40% of their VO2 max for 95.0 ± 18.5 min, at 30°C, until they lost 3% of body weight. Every 20 minutes, a measurement of their body weight was taken and a blood lactate analysis was performed. The concentration of lactate was significantly lower after the running exercise in the SW condition compared to placebo. The results of this study provide evidence supporting the ergogenic effects of microfiltered and sterilized seawater ingestion on running performance and lactate production. PMID: 29472745 [PubMed]

Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania.

Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania. BMJ Open. 2018 Feb 22;8(2):e018962 Authors: Winje BA, Kvestad I, Krishnamachari S, Manji K, Taneja S, Bellinger DC, Bhandari N, Bisht S, Darling AM, Duggan CP, Fawzi W, Hysing M, Kumar T, Kurpad AV, Sudfeld CR, Svensen E, Thomas S, Strand TA Abstract INTRODUCTION: As many as 250 million children under the age of 5 may not be reaching their full developmental potential partly due to poor nutrition during pregnancy and the first 2 years of life. Micronutrients, including vitamin B12, are important for the development of brain structure and function; however, the timing, duration and severity of deficiencies may alter the impact on functional development outcomes. Consequently, to fully explore the effect of vitamin B12 on cognitive function, it is crucial to measure neurodevelopment at different ages, in different populations and with vitamin B12 supplementation at different times during the critical periods of neurodevelopment. METHODS AND ANALYSIS: In this project, we follow up children from four recently completed randomised placebo-controlled trials of oral vitamin B12 supplementation, two in India and two in Tanzania, to explore the long-term effects on neurodevelopmental outcomes and growth. All the included trials provided at least two recommended dietary allowances of oral vitamin B12 daily for at least 6 months. Vitamin B12 was supplemented either during pregnancy, early infancy or early childhood. Primary outcomes are neurodevelopmental status, cognitive function and growth later in childhood. We apply validated and culturally appropriate instruments to identify relevant developmental outcomes. All statistical analyses will be done according to intention-to-treat principles. The project provides an excellent opportunity to examine the effect of vitamin B12 supplementation in different periods during early life and measure the outcomes later in childhood. ETHICS AND DISSEMINATION: The study has received ethical approvals from all relevant authorities in Norway, USA, Tanzania and India and complies fully with ethical principles for medical research. Results will be presented at national and international research and policy meetings and published in peer-reviewed scientific journals, preferably open access. TRIAL REGISTRATION NUMBER: NCT00641862 (Bangalore); NCT00717730, updated CTRI/2016/11/007494 (Delhi); NCT00197548 and NCT00421668 (Dar es Salaam). PMID: 29472265 [PubMed - in process]

Adrenal activity and metabolic risk during randomized escitalopram or placebo treatment in PCOS.

Adrenal activity and metabolic risk during randomized escitalopram or placebo treatment in PCOS. Endocr Connect. 2018 Feb 22;: Authors: Glintborg D, Altinok ML, Ravn P, Stage KB, Højlund K, Andersen M Abstract BACKGROUND/AIMS: Polycystic ovary syndrome (PCOS) is associated with insulin resistance, adrenal hyperactivity and decreased mental health. We aimed to investigate changes in adrenal activity, metabolic status, and mental health in PCOS during treatment with escitalopram or placebo. METHODS: Forty-two overweight premenopausal women with PCOS and no clinical depression were randomized to 12-weeks SSRI (20 mg escitalopram/day, n=21) or placebo (n=21). Patients underwent clinical examination, fasting blood samples, adrenocorticotroph hormone (ACTH) test, 3 hours oral glucose tolerance test (OGTT) and filled in questionnaires regarding mental health and health related quality of life (HRQoL): WHO Well Being Index (WHO-5), Major Depression Inventory (MDI), Short Form 36 (SF-36), and PCOS questionnaire. RESULTS: Included women were aged 31 (6) years (mean (SD)) and had BMI 35.8 (6.5) kg/m2 and waist 102 (12) cm. Escitalopram was associated with increased waist (median(quartiles) change 1 (0; 3) cm), p= 0.005 vs. change during placebo and increased cortisol levels (cortisol 0, cortisol 60, peak cortisol, and area under the curve for cortisol during ACTH test), all p< 0.05 vs. changes during placebo. Escitalopram had no significant effect on measures of insulin sensitivity, insulin secretion, fasting lipids, mental health or HRQoL. CONCLUSION: Waist circumference and cortisol levels increased during treatment with escitalopram in women with PCOS and no clinical depression, whereas metabolic risk markers, mental health and HRQol were unchanged. PMID: 29472241 [PubMed - as supplied by publisher]

Efficacy of vedolizumab in fistulising Crohn's disease: Exploratory analyses of data from GEMINI 2.

Related Articles Efficacy of vedolizumab in fistulising Crohn's disease: Exploratory analyses of data from GEMINI 2. J Crohns Colitis. 2018 Feb 17;: Authors: Feagan BG, Schwartz D, Danese S, Rubin DT, Lissoos TW, Xu J, Lasch K Abstract Background and Aims: Medical management of fistulising Crohn's disease (CD) is constrained by the limited number of available therapies. We evaluated the efficacy of vedolizumab, a gut-selective α4β7 integrin antagonist approved for treating moderately to severely active CD, in a subpopulation of patients with fistulising CD who participated in the GEMINI 2 trial (NCT00783692). Methods: Exploratory analyses of data from the GEMINI 2 trial were conducted in 461 responders to 6-week vedolizumab induction therapy who received maintenance placebo (VDZ/PBO, N=153) or vedolizumab (VDZ/VDZ, N=308). Fistula closure rates were assessed at weeks 14 and 52, and the time to fistula closure was analysed by Cox proportional hazards model with adjustments for significant covariates. Results: At entry into maintenance period, 153 (33%) patients had a history of fistulising disease and 57 (12%) patients had ≥1 active draining fistula. By week 14, 28% of VDZ/VDZ-treated patients compared with 11% of VDZ/PBO-treated patients (95% confidence interval [CI], -11.4-43.9) achieved fistula closure. Corresponding rates at week 52 were 31% and 11% (absolute risk reduction [ARR]: 19.7%; 95% CI, -8.9-46.2). Similarly, VDZ/VDZ-treated patients had faster time to fistula closure and were more likely to have fistula closure at week 52 (33% vs 11%; HR: 2.54; 95% CI, 0.54-11.96). Prior failure of antibiotic therapy was a negative predictor of fistula closure (HR: 0.217; 95% CI, 0.059-0.795; p=0.021), whereas trough vedolizumab concentrations did not affect closure rates. Conclusions: Our findings are consistent with the beneficial effect of vedolizumab treatment for fistulising CD. PMID: 29471381 [PubMed - as supplied by publisher]

Effects of Varenicline, Depressive Symptoms, and Region of Enrollment on Smoking Cessation in Depressed Smokers.

Related Articles Effects of Varenicline, Depressive Symptoms, and Region of Enrollment on Smoking Cessation in Depressed Smokers. Nicotine Tob Res. 2018 Feb 17;: Authors: Doran N, Dubrava S, Anthenelli RM Abstract Introduction: Despite effective treatments, relapse to smoking remains a vexing global health problem. One predictor of relapse is depressive symptoms. Medications such as varenicline reduce withdrawal-related symptoms of depression, reducing relapse. This study examined whether varenicline moderated the effect of depressive symptoms on relapse, and whether this varied by region of enrollment. Methods: Adult smokers (n=525; 37% male) with past or current, stable major depressive disorder recruited from US (n=255), and European (n=270) sites participated in a randomized, double-blind cessation treatment trial including 12 weeks of varenicline or placebo, with 40-week non-treatment follow-up. Results: Longitudinal and binary logistic regression were used to model the probability of sustained abstinence by end of treatment and point-prevalence abstinence in follow-up. The association between depression symptoms and abstinence was moderated by intervention group at end of treatment, and by region during follow-up: more severe symptoms were associated with end-of-treatment relapse for placebo (OR = 0.91, p=.003), but not varenicline (OR = 0.99, p = .568). During follow-up, increased symptoms of depression predicted greater likelihood of smoking for European (p=.009) but not US participants. Europeans were more likely to be abstinent for both outcomes (p<.01). Conclusions: These results extend studies demonstrating varenicline is associated with less withdrawal-related depression, and suggest it aids cessation even in smokers with depressive symptoms. Findings also suggest regional differences in the relationship between depressive symptoms and cessation that may be related to differences in prevalence. Implications: This study indicates varenicline may aid cessation partially by reducing withdrawal-related symptoms of depression. It also suggests that the impact of depressive symptoms on cessation varies regionally, and that this variation may be related to differences in smoking prevalence. PMID: 29471329 [PubMed - as supplied by publisher]

Effects of sunitinib targeted chemotherapy on the osseointegration of titanium implants.

Related Articles Effects of sunitinib targeted chemotherapy on the osseointegration of titanium implants. Biomed Pharmacother. 2018 Feb 19;100:433-440 Authors: Al-Jandan B, Marei HF, Abuohashish H, Zakaria O, Al-Mahalawy H Abstract Targeted chemotherapies are novel therapeutic approaches for many malignancies. In contrast to conventional chemotherapies, which are given for a predetermined duration, treatment with targeted chemotherapies like sunitinib is routinely continuous over longer periods, sometimes years. During this prolonged treatment period, patients may need to restore their missing teeth with dental implants. The aim of this study was to examine the effect of the anti-angiogenic substance sunitinib targeted chemotherapy on the osseointegration of titanium implants in a rabbit model. Fourteen white New Zealand rabbits were randomly assigned to two groups of either oral sunitinib at 10 mg/kg twice per week dose for 4 weeks (n = 7) or placebo (n = 7). The first dose was given 2 days before the surgical intervention. Each rabbit received one titanium dental implant in the right distal femoral condyle. Four weeks following implant insertion, rabbits were sacrificed and bone specimens containing the implants were retrieved. Osseointegration of the implants was analyzed using micro-computed tomography and histomorphometric evaluation. Both micro-computed tomography and histomorphometric analysis showed that the osseointegration parameters, including the ratio of bone volume to total volume and bone-implant contact percent for the sunitinib group were significantly lower than those in the control group (P ≤ 0.05). Sunitinib targeted chemotherapy had a negative effect on the osseointegration of titanium implants inserted in a rabbit model. PMID: 29471246 [PubMed - as supplied by publisher]

Episodic Breathlessness in Patients with Advanced Cancer: Characteristics and Management.

Related Articles Episodic Breathlessness in Patients with Advanced Cancer: Characteristics and Management. Drugs. 2018 Feb 22;: Authors: Mercadante S Abstract The aim of this review is to present the way in which episodic breathlessness (EB) has been recognized over the years, with regard to definition, characteristics, and management of these acute episodes that have serious consequences for patients. EB is characterized by a sudden increase in intensity of dyspnea over a short duration of time, leading to high levels of anxiety. A significant aggravation of dyspnea may occur in patients with a background of dyspnea or intermittently even without basal breathlessness. Often, known precipitating factors may trigger EB. Flares of breathlessness are accompanied by degrees of psychological distress, although it is unclear whether psychological factors may precede or be induced by EB. In any case, there is a reinforcing circuit. The duration of EB ranges from 10-30 min. Given the specific temporal pattern, requiring rapid intervention, substances with a short onset of action are suitable to overlap this phenomenon. Short-onset opioids could provide a clinical effect overlapping the onset and duration of an episode, resembling what has been largely reported for breakthrough pain. Although data are still insufficient to suggest specific recommendations, strategies such as avoiding exertion, pacing or using devices, or keeping calm have been described. Few controlled studies have investigated the effects of different formulations of opioids. Some data were gathered from studies assessing the pre-emptive use of rapid onset opioids, such as transmucosal preparations of fentanyl, followed by a provocative test, while other studies attempted to reproduce real-life conditions, given as needed. All these trials were insufficiently powered to address the efficacy of fentanyl products over oral morphine or placebo, reflecting the difficulties in patient recruiting and finalizing the studies. Strategies to prevent the occurrence of EB should be taken into consideration, including optimization of the condition of persistent dyspnea or treating psychologic or environmental causes. PMID: 29470801 [PubMed - as supplied by publisher]

Angiotensin II receptor blockers for the treatment of portal hypertension in patients with liver cirrhosis: a systematic review and meta-analysis of randomized controlled trials.

Related Articles Angiotensin II receptor blockers for the treatment of portal hypertension in patients with liver cirrhosis: a systematic review and meta-analysis of randomized controlled trials. Ir J Med Sci. 2018 Feb 22;: Authors: Yao H, Zhang C Abstract BACKGROUND: Randomized controlled trials (RCTs) showed inconsistent results regarding the efficacy of angiotensin II receptor blockers (ARBs) on portal pressure as indicated by hepatic venous pressure gradient (HVPG). METHODS: A meta-analysis of RCTs was performed to evaluate the influence of ARBs treatment on HVPG. PubMed, Embase, and Cochrane's Library were searched for relevant RCTs. A fixed or a randomized effect model was used to pool the results according the heterogeneity. Subgroup analyses were performed to explore the source of heterogeneity. RESULTS: Eleven RCTs with 394 patients were included. ARBs treatment did not significantly change HVPG as compared with controls (weighted mean difference [WMD] = -0.63, 95% confidence interval [CI] -1.73 to 0.47 mmHg, p = 0.26; I2 = 60%). These results were consistent in studies comparing ARBs with propranolol (WMD = -0.40, 95% CI -2.22 to 1.41 mmHg, p = 0.67; I2 = 68%), and those comparing ARBs with non-active controls including placebo or no treatment (WMD = -1.05, 95% CI -2.33 to 0.24 mmHg, p = 0.13; I2 = 44%). These results were also not affected by the individual ARBs used. Moreover, treatment of ARBs significantly reduced mean arterial blood pressure (WMD = -6.12, 95% CI -9.69 to -2.55 mmHg, p = 0.008; I2 = 53%), and the risk of symptomatic hypotension was increased (RR = 4.13, 95% CI 0.94 to 18.18, p = 0.06; I2 = 0%). CONCLUSIONS: ARBs did not reduce portal pressure in patients with cirrhosis; moreover, the risk of symptomatic hypotension may increase. PMID: 29470765 [PubMed - as supplied by publisher]

Cost-Effectiveness of a Specialized Oral Nutritional Supplementation for Malnourished Older Adult Patients in Spain.

Related Articles Cost-Effectiveness of a Specialized Oral Nutritional Supplementation for Malnourished Older Adult Patients in Spain. Nutrients. 2018 Feb 22;10(2): Authors: Ballesteros-Pomar MD, Martínez Llinàs D, Goates S, Sanz Barriuso R, Sanz-Paris A Abstract Malnutrition has been related to prolonged hospital stays, and to increases in readmission and mortality rates. In the NOURISH (Nutrition effect On Unplanned Readmissions and Survival in Hospitalized patients) study, administering a high protein oral nutritional supplement (ONS) containing beta-hydroxy-beta-methylbutyrate (HP-HMB) to hospitalised older adult patients led to a significant improvement in survival compared with a placebo treatment. The aim of this study was to determine whether HP-HMB would be cost-effective in Spain. We performed a cost-effectiveness analysis from the perspective of the Spanish National Health System using time horizons of 90 days, 180 days, 1 year, 2 years, 5 years and lifetime. The difference in cost between patients treated with HP-HMB and placebo was €332.75. With the 90 days time horizon, the difference in life years gained (LYG) between both groups was 0.0096, resulting in an incremental cost-effectiveness ratio (ICER) of €34,700.62/LYG. With time horizons of 180 days, 1 year, 2 years, 5 years and lifetime, the respective ICERs were €13,711.68, €3377.96, €2253.32, €1127.34 and €563.84/LYG. This analysis suggests that administering HP-HMB to older adult patients admitted to Spanish hospitals during hospitalisation and after discharge could be a cost-effective intervention that would improve survival with a reduced marginal cost. PMID: 29470402 [PubMed - in process]

Caffeine increases both total work performed above critical power and peripheral fatigue during a 4-km cycling time trial.

Related Articles Caffeine increases both total work performed above critical power and peripheral fatigue during a 4-km cycling time trial. J Appl Physiol (1985). 2018 Feb 22;: Authors: Felippe LC, Ferreira GA, Learsi SK, Boari D, Bertuzzi R, Lima-Silva AE Abstract The link between total work performed above critical power (CP) and peripheral muscle fatigue during self-paced exercise is unknown. We investigated the influence of caffeine on the total work done above CP during a 4-km cycling time trial (TT), and the subsequent consequence on the development of central and peripheral fatigue. Nine cyclists performed three constant-load exercise trials to determine CP and two 4-km TT ~75 min after oral caffeine (5 mg·kg-1) or cellulose (placebo) ingestion. Neuromuscular functions were assessed before and 50 min after supplementation, and 1 min after TT. Oral supplementation alone had no effect on neuromuscular function (P>0.05). Compared to placebo, caffeine increased mean power output (~4%, P=0.01) and muscle recruitment (as inferred by EMG, ~17%, P=0.01), and reduced the time to complete the TT (~2%, P=0.01). Work performed above CP during the caffeine trial (16.7{plus minus}2.1 kJ) was significantly higher than during the placebo (14.7{plus minus}2.1 kJ, P=0.01). End-exercise decline in quadriceps twitch force (pre- to post-exercise decrease in twitch force at 1 and 10 Hz) was more pronounced after caffeine compared to placebo (121{plus minus}13 and 137{plus minus}14 N vs 146{plus minus}13 and 156{plus minus}11 N; P<0.05). There was no effect of caffeine on central fatigue. In conclusion, caffeine increases muscle recruitment which enables greater work performed above CP and higher end-exercise peripheral locomotor muscle fatigue. PMID: 29470151 [PubMed - as supplied by publisher]

The minimal clinically important difference of the Richmond Agitation-Sedation Scale in patients with cancer with agitated delirium.

Related Articles The minimal clinically important difference of the Richmond Agitation-Sedation Scale in patients with cancer with agitated delirium. Cancer. 2018 Feb 22;: Authors: Hui D, Hess K, Dibaj SS, Arthur J, Dev R, Dalal S, Reddy S, Bruera E Abstract BACKGROUND: The Richmond Agitation-Sedation Scale (RASS) is commonly used to assess psychomotor activity; however, to the authors' knowledge, its minimal clinically important difference (MCID) has not been determined to date. The objective of the current study was to identify the MCID for RASS using 2 anchor-based approaches. METHODS: The current study was a secondary analysis of a randomized controlled trial to compare the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium. The primary outcome was change in RASS (10-point numeric rating scale ranging from -5 [unarousable] to +4 [combative]) from baseline to 8 hours after treatment administration. The sensitivity-specificity and within-patient change methods were used to identify the MCID, with the anchor being patient comfort after the study intervention as perceived by caregivers and nurses. RESULTS: A total of 90 patients were randomized and 58 (64%) received the study medication for restlessness/agitation (mean baseline RASS, 1.6). A total of 23 caregivers (61%) and 23 nurses (55%) perceived that the patient was more comfortable after treatment. Using the sensitivity-specificity method, the optimal RASS reduction was ≥4 points according to both caregivers (sensitivity of 61% and specificity of 80%; area under the curve, 0.71) and nurses (sensitivity of 73% and specificity of 84%; area under the curve, 0.78). The RASS cutoff value based on the within-patient change method was similar (-4.2 for caregivers and -4.0 for nurses). CONCLUSIONS: For patients with persistent restlessness/agitation, a reduction of ≥4 points in RASS was considered to be the MCID for both nurses and caregivers. These preliminary findings may have implications for sample size calculation and the interpretation of treatment effect in future delirium trials. Cancer 2018. © 2018 American Cancer Society. PMID: 29469951 [PubMed - as supplied by publisher]

Vitamin D Supplementation in Adults with Vitamin D Deficiency and Its Effect on Metabolic Syndrome - A Randomized Controlled Study.

Related Articles Vitamin D Supplementation in Adults with Vitamin D Deficiency and Its Effect on Metabolic Syndrome - A Randomized Controlled Study. Int J Vitam Nutr Res. 2018 Feb 22;:1-6 Authors: Mahmood SF, Idiculla J, Joshi R, Joshi S, Kulkarni S Abstract BACKGROUND: Inverse relationship between metabolic syndrome (MetS) and 25-hydroxyvitamin D (25(OH) D) levels is controversial. Hypovitaminosis-D has long been suspected as a risk factor for glucose intolerance. AIM: A randomized double blind placebo controlled study to evaluate effects of vitamin D supplementation on insulin resistance in subjects with hypovitaminosis-D and MetS. MATERIALS AND METHODS: Subjects were randomized to receive either oral 25(OH) D3 supplement (60000 (IU) per week for 8 weeks followed by 60,000 IU monthly for 4 months) or a placebo for six months. The parameters measured were blood pressure, vitamin D, fasting blood sugar (FBS), insulin, homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), body mass index (BMI), and waist circumference (WC). RESULTS: There were no significant changes in parameters of vitamin-D group compared to placebo group except serum vitamin-D was significantly increased in vitamin-D group (p < 0.0001). In vitamin-D group, mean WC at baseline was 95.9 ± 6.66, which significantly changed to 94.6 ± 7.47 (p = 0.001). Mean BMI at baseline was 29.1 ± 4.06 which significantly changed to 28.5 ± 4.16 (p = 0.001). The mean vitamin-D concentration at baseline was 15.4 ± 9.03 which significantly (p < .0001) increased to 26.1 ± 11.8. In placebo group mean insulin levels was 10.7 ± 4.81IU / L which increased significantly (p = 0.03) to 15.4 ± 14.0. Mean QUICKI at baseline was 0.34 ± 0.03 which decreased significantly (p = 0.02) to 0.32 ± 0.03. CONCLUSION: In this study the relationship between vitamin D supplementation and MetS or IR was not established. Whether achieving vitamin D sufficiency in large population-based trials with a longer duration would produce more favorable results needs to be assessed. PMID: 29469682 [PubMed - as supplied by publisher]

The Effects of Netarsudil Ophthalmic Solution on Aqueous Humor Dynamics in a Randomized Study in Humans.

Related Articles The Effects of Netarsudil Ophthalmic Solution on Aqueous Humor Dynamics in a Randomized Study in Humans. J Ocul Pharmacol Ther. 2018 Feb 22;: Authors: Kazemi A, McLaren JW, Kopczynski CC, Heah TG, Novack GD, Sit AJ Abstract PURPOSE: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown. METHODS: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. RESULTS: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 (-10%; P = 0.01). Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P = 0.08). No treatment changes were seen in uveoscleral outflow rate. CONCLUSIONS AND RELEVANCE: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways. PMID: 29469601 [PubMed - as supplied by publisher]

l-Carnosine as Adjunctive Therapy in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Related Articles l-Carnosine as Adjunctive Therapy in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Child Adolesc Psychopharmacol. 2018 Feb 22;: Authors: Ghajar A, Aghajan-Nashtaei F, Afarideh M, Mohammadi MR, Akhondzadeh S Abstract OBJECTIVES: This study aimed to investigate the efficacy and tolerability of l-carnosine as an add-on to methylphenidate in management of children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was an 8-week, randomized, double-blind placebo-controlled study. Fifty-six drug-free children and adolescents aged 6-17 years old with a diagnosis of ADHD entered the study. The patients were randomly assigned to l-carnosine (800 mg/d in two divided doses) or placebo plus methylphenidate (0.5-1.5 mg/kg/d) for 8 weeks. Children were assessed using the Teacher and Parent ADHD Rating Scale-IV (ADHD-RS-IV) at baseline and at weeks 4 and 8 postbaseline. RESULTS: Fifty patients completed the study, and all had two postbaseline measurements. Using the general linear model repeated measures, significant effect was observed for time × treatment interaction on total and inattention subscales of the Parent ADHD-RS (Greenhouse-Geisser corrected: F = 3.783, df = 1.444, p = 0.041 and F = 4.032, df = 1.600, p = 0.030). Improvements in the Teacher ADHD-RS were not significantly different between the two groups in total (Greenhouse-Geisser corrected: F = 0.200, df = 1.218, p = 0.705), as well as inattention and hyperactivity subscale scores (p = 0.956 and 0.281, respectively). The frequency of side effects was not significantly different between the two treatment arms. CONCLUSIONS: l-carnosine, as a supplementary medication, might be beneficial in treatment of children with ADHD. However, further investigations and different doses of l-carnosine are required to replicate these findings in children with ADHD. PMID: 29469593 [PubMed - as supplied by publisher]

Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials.

Related Articles Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials. Indian J Cancer. 2017 Apr-Jun;54(2):470-477 Authors: Kim MK, Myung SK, Tran BT, Park B Abstract PURPOSE: Several meta-analyses of randomized controlled trials (RCTs) reported no association between the use of statins and the risk of cancer. However, they included open-label RCTs, which did not use placebo as a control group. This study aimed to evaluate the effect of statins on cancer risk using a meta-analysis of randomized, double-blind, placebo-controlled trials (RDBPCTs). METHODS: We searched PubMed, EMBASE, and the Cochrane Library in March 2016. Two individual authors reviewed and selected RDBPCTs based on selection criteria. RESULTS: Out of 676 retrieved articles, a total of 21 RDBPCTs with 65,196 participants (32,618 in the statin group and 32,578 in the placebo group) were included in the meta-analysis. Overall, we found that there was no significant association between the use of statins and the risk of cancer (relative risk 0.97, 95% confidence interval 0.92-1.02, I2 = 0.0%) in a fixed-effect meta-analysis. In addition, in the subgroup meta-analyses, no beneficial effect of statins was observed when analyzed by statin type, country, follow-up period, methodological quality, underlying diseases/population, and type of cancer. CONCLUSIONS: The current meta-analysis of RDBPCTs found that there was no association between the use of statins and the risk of cancer. PMID: 29469081 [PubMed - in process]

Lenvatinib in the Therapy of Aggressive Thyroid Cancer: State of the Art and New Perspectives with Patents Recently Applied.

Related Articles Lenvatinib in the Therapy of Aggressive Thyroid Cancer: State of the Art and New Perspectives with Patents Recently Applied. Recent Pat Anticancer Drug Discov. 2018 Feb 19;: Authors: Ferrari SM, Ruffilli I, Centanni M, Virili C, Materazzi G, Alexopoulou M, Miccoli M, Antonelli A, Fallahi P Abstract BACKGROUND AND OBJECTIVE: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR1-VEGFR3), fibroblast growth factor receptors (FGFR1-FGFR4), platelet-derived growth factor receptor (PDGFR)α, rearranged during transfection (RET), and v-kit (KIT) signaling networks implicated in tumor angiogenesis. METHOD: Here we review the scientific literature about lenvatinib in the treatment of thyroid cancer. RESULTS: In vitro studies have shown antineoplastic activity of lenvatinib in differentiated thyroid cancer (DTC), mainly because of its antiangiogenetic effects, but a slight effect on thyroid cancer cell proliferation has been shown. In vivo phase II, and phase III studies in patients with aggressive DTC not responsive to radioiodine, have shown that lenvatinib administration was associated with an amelioration in progression-free survival (PFS) with respect to placebo (median PFS 18.2 vs. 3.6 months). However overall survival was not significantly changed. Lenvatinib is also effective in patients resistant to sorafenib as salvage therapy. Adverse effects of any grade occur in more than 40% of lenvatinib-treated patients, mainly hypertension, diarrhea, asthenia or fatigue, nausea, decreased appetite, and decreased weight. Discontinuations of the therapy because of adverse effects occur in about 14% of patients. Moreover, deaths considered to be drug-related can occur. CONCLUSION: On the base of the above mentioned considerations, it is necessary to prove the effectiveness of lenvatinib in the context of associated moderate to severe toxicities requiring frequent dose reduction and delays, and for this reason many interesting patents have been recently applied. PMID: 29468981 [PubMed - as supplied by publisher]
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