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Background: The aim of this study is to compare the effects of %4 articaine and %2 lidocaine on inferior alveolar nerve block (IANB) for implant surgery in the posterior mandible.Material and Methods: The patients who have inserted implants in the posterior mandible were divided into 2 groups for IANB: lidocaine and articaine. VAS = visual analog scale, pain during surgery and injection, lip numb-ness time, mandibular canal-implant apex distance, age, gender, bone density, implant number, release incision, adjacent teeth, and duration of surgery were analyzed using t-test, Mann-Whitney U test, Spearman's coefficient, and, Pearson's chi-squared test. This trial followed the recommendations of the Consort Statement for reporting randomized controlled trials. Results: 577 patients were included and 1185 dental implants were analyzed. There was no significant difference between the two groups in terms of injection and surgery VAS values (p>0.05). The lip numbness time of lido-caine was 3.06 +/- 3.22min while articaine was found to be 2.96 +/- 3.09min (p>0.05). Mandibular canal-implant apex distance was found to be 2.28 +/- 0.75mm in the articaine and 2.45 +/- 0.86mm in the lidocaine group (p

Introduction: Non-traumatic back pain constitutes roughly 5% of the admissions to emergency departments. This study seeks to compare the efficacy of intravenously administered paracetamol, dexketoprofen, and ibuprofen in patients with non-traumatic acute low back pain. Methods: This study was designed as a randomized, double-blinded investigation and carried out at a tertiary hospital. 210 eligible patients without trauma who presented with low back pain were recruited for the study and randomized into paracetamol (n = 71), dexketoprofen (n = 70), and ibuprofen (n = 69) groups. The measurements at 0, 15, 30 and 60 min were noted down by using a 100 mm VAS, and the relevant comparisons were made. Results: The VAS scores at 0 and 60 min in the paracetamol, dexketoprofen, and ibuprofen groups decreased on average by 40 mm, 42 mm, and 43 mm, respectively. The baseline and final pain scores of each drug group differed significantly (p < 0.05), though the between-group analysis revealed no significant difference (p > 0.05). Conclusion: Given the obtained data, we did not note a significant difference between intravenous paracetamol, dexketoprofen and ibuprofen with respect to pain efficacy in non-traumatic acute low back pain. Based on the patients' clinical conditions and histories, we concluded that the choice of medication might not change the efficacy of the treatment and patient comfort. © 2022 Elsevier Inc.

This study was conducted to evaluate the effect of ShotBlocker on the intramuscular injection pain and satisfaction in emergency adult patients. This research was designed as a randomized controlled, double-blind, experimental study. The study was conducted with 74 patients who applied to the adult emergency department. Patients were randomized to ShotBlocker and control groups. Patient Assessment Form, Visual Analog Scale, and Visual Analog Patient Satisfaction Scale were used. The mean scores of postinjection pain and satisfaction level were analyzed between the groups; it was determined that while postinjection pain mean score of the experimental group was statistically significantly lower than that of the control group (p = 0.0001), satisfaction scores were statistically significantly higher in the experimental group than in the control group (p = 0.004). When the correlation between the intragroup Pain Scores (VAS) and the Satisfaction Scores (VAS) of the groups after injection was examined, a statistically significant and inverse correlation was found (p < 0.05). It was determined that ShotBlocker was effective in reducing intramuscular injection pain and increasing satisfaction levels. © 2021 Lippincott Williams and Wilkins. All rights reserved.

OBJECTIVE: The aim of this study was to investigate the effects of neuromuscular electric stimulation applied to the erector spinae on balance, motor function and functional capacity in patients with stroke in a randomized controlled trial. METHODS: Sixty patients with stroke were recruited and randomly distributed into two groups: control group and neuromuscular electric stimulation group. All participants underwent conventional physical therapy five times a week for six weeks. The neuromuscular electric stimulation group received additional electrical stimulation. Outcome measures were evaluated with Brunnel Balance Assessment, Stroke Rehabilitation Movement Assessment, Functional Ambulation Classification, Adapted Patient Evaluation and Conference System, Postural Assesment Scale for Stroke patients, Short Form-36, and Minimental State Examination scales. RESULTS: Significant differences were observed in all scores at the end of the study in both groups. Postural Assesment Scale for Stroke patients and Stroke Rehabilitation Movement Assessment scores were higher in the neuromuscular electric stimulation group compared to the control group (p

Background/Aims: This study is designed to determine which drug forms provide ideal pharyngeal anesthesia when used during upper gastrointestinal system endoscopy. Materials and Methods: A total of 180 patients were included in the study. Using the random number table, these patients were divided into three groups. Group 1, lidocaine gel+isotonic spray; Group 2, base lubricant gel+lidocaine spray; and Group 3: lidocaine gel+lidocaine spray. Data were collected from the patient identification form, compliance to operation form, and State Anxiety Inventory. Results: Anesthetization and compliance to procedure scores were higher and anxiety scores were lower in Group 3 than in other groups (p

[No abstract available]

BACKGROUND: The aim of the current study is to investigate the efficacy and safety of Transcranial magnetic stimulation (TMS) treatment, a non-invasive brain stimulation technique, on depressive symptoms in treatment-resistant bipolar depression (TRBD). SUBJECTS AND METHODS: The study included 29 patients between the ages of 18-65, with bipolar disorder depressive episode according to DSM-5 and with the decision of non-response to treatment according to the Canadian Mood and Anxiety Treatment Network (CANMAT). Patients were divided into two groups double-blind-randomly, 20 sessions of TMS and 20 sessions of sham TMS were applied crossover. Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), Young Mania Rating Scale (YMRS) and TMS Side Effect Questionnaire were applied to the patients before the treatment, at the 2nd week which is the crossover phase, and at the end of the treatment at 4th week. RESULTS: In both groups, the severity of depression was decreased significantly according to HAM-D and BDI scores after the procedure. As well as active stimulation, some positive placebo effects were observed with sham stimulation. But the decreases seen in HAM-D and BDI scores and response to the treatment were higher during the weeks when the groups received active stimulation (respectively p=0.000, p=0.001, p=0.005). At the end of the study, according to HAM-D, 55.7% of the patients showed response to the treatment, 24.13% partial response. According to BDI, 41.37% of the patients showed response to the treatment, and 31.03% partial response. No associations were found between TMS response and sociodemographic - clinical features, or type of the disease (p>0.05). During the study, no serious adverse effects such as seizures or manic / hypomanic switches were observed. CONCLUSIONS: The results of our study showed that TMS treatment is an effective and safe treatment for patients with treatment-resistant bipolar depression.

Objective The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. Methods In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. Results Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (− 2.7 and − 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. Conclusion CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. ClinicalTrials.gov identifier NCT02149121. Electronic supplementary material The online version of this article (10.1007/s40259-018-00331-4) contains supplementary material, which is available to authorized users.

Background Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed “radical cure”). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. Methods This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to Results In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P Conclusions Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167. opens in new tab.)

BACKGROUND NSAIDs are the most common agents used in dysmenorrhea treatment. They reduce menstrual pain by reducing uterine pressure and PGF2alpha levels in the menstrual fluid. The aim of this study was to compare the effects of piroxicam and diclofenac sodium as treatments for primary dysmenorrhea. MATERIAL AND METHODS The study was conducted using a randomized and double-blind method. Patients with Visual Analogue Scale (VAS) scores greater than 5 were accepted into the study. The patients who were suitable for inclusion were randomized into 2 groups and received either intramuscular piroxicam or diclofenac sodium. The patients' pain levels were measured at baseline and at 15, 30, 45, and 60 min. A VAS of 10 cm, a numeric scale, a verbal scale, and additional symptoms, as well as pain relapse after 24 hours and required analgesics, were recorded. RESULTS The study included 400 patients. Overall, 200 patients (50%) were in the proxicam group, and 200 patients were in the diclofenac sodium group. The average decrease on the VAS after piroxicam or diclofenac administration was measured as 7.9±1.8 cm and 7.9±1.7 cm (median ± standard deviation), respectively. The pain-reducing efficiency of all the treatments was compared using the Mann-Whitney U test (p=0.929). Rescue medication was needed for 25 patients in the proxicam group (p=0.014). Overall, 30 patients in the proxicam group and 41 patients in the proxicam group needed analgesics again in the 24-hour period after treatment (p=0.150). CONCLUSIONS At the end of our study, it was observed that there was no difference in the results of primary dysmenorrhea treatment with 20 mg piroxicam or 75 mg diclofenac sodium.

Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine–carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ?1 or, Breast Cancer Research Foundation, BCRF; Pfizer; AstraZeneca; Merck; Roche; Samsung; Merck Sharp and Dohme, MSD; Eisai, JC reports personal fees and research funding paid to his institution from Roche, AstraZeneca, Merck Sharp & Dohme, and Eisai; personal fees from Celgene, Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, Novartis, Pfizer, Samsung Bioepis; research funding paid to his institution from Ariad Pharmaceuticals, Bayer Healthcare, F Hoffman-La Roche, Guardanth Health, Piqur Therapeutics, Puma C, and Queen Mary University of London, outside the submitted work. In addition, JC has a MedSIR patent pending. DWC reports research support from Merck during the conduct of the study; research support paid to his institution from Merck, Pfizer, and GlaxoSmithKline; personal fees from Merck, Roche–Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Puma, Agenda, Exact Sciences, and Dynamo Therapeutics, outside the submitted work. In addition, DWC has a Biomarkers of TTK inhibitors patent pending. HSR reports funding for sponsored studies paid to the University of California San Francisco from Pfizer, Novartis, Lilly, Roche–Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; travel support for educational meetings from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics; and consulting fees from Samsung and Puma, outside the submitted work. S-AI reports grants from AstraZeneca, Eisai, Pfizer, Roche, and Daewoong; an advisory role for AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Lily, MedPacto, Pfizer, and Roche; and travel expenses for presentation from Novartis, outside the submitted work. CG reports Advisory Board fees from Merck Sharp & Dohme and Roche; and speaker's bureau fees from Bristol Myers Squibb and AstraZeneca, outside the submitted work. CHB reports grants and fees from Merck Sharp & Dohme for clinical research consulting during the conduct of the study; consulting–advisory role fees from Boehringer Ingelheim, GlaxoSmithKline, and Bayer; consulting–advisory role fees and grants for clinical research from Novartis, Pfizer, Roche–Genentech, Eisai, Merck Sharp & Dohme, and AstraZeneca; grants for clinical research from Abbvie, Amgen, Astellas Pharma, Bristol Myers Squibb, Celgene, Covance, Lilly, Medication, Merck Serono, and PharmaMar; grants for academic research projects from CPO, Pontificia Universidade Católica do Rio Grande do Sul, Latin American Cooperative Oncology Group, Grupo Brasileiro Estudos Câncer Mama, and Instituto Nacional de Câncer-Brazil, outside the submitted work. HI reports a grant from Merck Sharp & Dohme during the conduct of the study; honoraria and consulting fees from Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Eisai, and Chugai; and a grant from Chugai, outside the submitted work. NM reports honoraria and research funding paid to his institution from Chugai, AstraZeneca, Pfizer, Eli-Lilly, Eisai, Takeda, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, and Daiichi Sankyo, outside the submitted work. EG reports non-financial support from Merck Sharp & Dohme during the conduct of the study; honoraria, consulting–advisory fees and meeting support from Novartis, Roche, Bristol Myers Squibb, and Pfizer; and honoraria from AstraZeneca and Astellas, outside the submitted work. SL reports research funding or consulting fees paid to her institution from Bristol Myers Squibb, Roche–Genentech, Puma Biotechnology, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, Eli Lilly, Aduro Biotech, GI Therapeutics, AstraZeneca, and GlaxoSmithKline; and non-remunerated consultancy for Bristol Myers Squibb, Roche–Genentech, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, and AstraZeneca, outside the submitted work. In addition, SL is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. ZG, JZ, GA, and VK are employees of Merck Sharp & Dohme and own stock or stock options in Merck. PS reports consultancy fees from Pfizer, AstraZeneca, Novartis, Roche, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; consultancy fees to his spouse from Genentech and Roche; and grants or funding to his institution from Roche, Genentech, Oncogenex, Novartis, Astellas, and AstraZeneca, outside the submitted work. All other authors declare no competing interests., The authors thank the patients, their families and caregivers for participating in this trial, all of the investigators and site personnel, and the following employees of Merck Sharp & Dohme: Wilbur Pan, Deborah Card, Eleanor Readinger, Shana Hamm, Roger Maxwell, and Krystal Bourdon, for collection of data, supervision of research, provision of study materials or patients or administrative or logistical support; Aline Galvao, for collection of data, supervision of research, administrative or logistical support, and review of imaging data related to the primary end point; Donna Letizia, for collection of data and imaging expertise; Jennifer Kimmel, for study management; Mercedes Bustamante, for data collection and management; Xuan Zhou and Madhusudhan Reddy Papasani, for statistical expertise; Christine McCrary Sisk, for medical writing and editorial assistance; and Joseph C Naggar and Michele McColgan, for administrative or logistical support.

INTRODUCTION: Effective treatment for cocaine use disorder should dampen hypersensitive cue-induced motivational processes and/or strengthen executive control. Using a randomized, double-blind, placebo-controlled intervention, the primary aim of this study was to investigate the effect of N-Acetylcysteine (NAC) and working memory (WM)-training to reduce cocaine use and craving and to improve inhibition assessed in the laboratory and during Ecological Momentary Assessment (EMA). The second aim was to examine correspondence between laboratory and EMA data.METHODS: Twenty-four of 38 cocaine-using men completed a 25-day intervention with 2400mg/day NAC or placebo and WM-training as well as two lab-visits assessing cocaine use, craving and inhibition (Stop Signal task). Additionally, cocaine use, craving and cognition (Stroop task) were assessed using EMA during treatment, with 26 participants completing 819 assessments.RESULTS: Cocaine problems according to the Drug Use Disorder Identification Test (DUDIT) decreased more after NAC than after placebo, and the proportion of cocaine-positive urines at lab-visit 2 was lower in the NAC group. No NAC effects were found on craving. For cocaine use and craving, results from the lab data were generally similar to EMA results. NAC also showed some effects on cognitive control: improved inhibition assessed with the Stop Signal task in the lab, and decreased classic Stroop performance during EMA. There were no significant effects of number of completed WM-training sessions.CONCLUSIONS: Overall this study revealed mixed findings regarding the treatment of cocaine use disorders with NAC and WM-training. The effect of NAC on inhibition should be further investigated.

Background: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. Methods: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16–26 years, and an immunogenicity and safety study in girls and boys aged 9–15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. Results: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden. Keywords: Human papillomavirus, Vaccine, Cervical cancer, Persistent infection, 9vHPV

Bu çalışma, 22-24 Kasım 2012 tarihleri arasında İstanbul[Türkiye]’da düzenlenen 16. Annual Meeting of the European-Society-of-Surgery (ESS)’da bildiri olarak sunulmuştur. Background: Laparoscopic cholecystectomy (LC) is the gold standard for the treatment of symptomatic gallbladder stones. As infections are rare in uncomplicated LC, it is widely accepted that prophylactic antibiotics need not be administered, and guidelines do not support routine antibiotic prophylaxis during elective LC. However, routine antibiotic prophylaxis for elective LC is still popular in many clinical settings. We investigated this situation in our department. Method: This randomized double-blind controlled study included 570 patients who underwent LC between March 2007 and February 2010. The exclusion criteria were antibiotic intake before surgery, steroid treatment, and the presence of pancreatitis, cholangitis, obstructive jaundice, cephalosporin allergy, or pregnancy. The patients were randomized into three groups. Group 1 (n = 193) received physiologic saline as placebo, Group 2 (n = 191) received a first-generation cephalosporin (cefazolin; 1 g), and Group 3 (n = 186) received a second-generation cephalosporin (cefuroksim aksetil; 750mg). Bile and epigastric and umbilical port tissue samples were harvested for culture. All patients were observed until the end of the fourth week after surgery. Patient age, sex, weight, American Society of Anesthesiologists (ASA) score, diabetes mellitus, smoking history, history of biliary colic in the past month, length of the hospital stay before the operation, operational findings (acute or chronic cholecystitis), operation duration, use of drainage, type of prophylaxis administered if any, culture results, surgical site infection (SSI) development, and time to SSI development along with associated treatments were evaluated. Results: There was no statistically significant difference between the groups with respect to any of the demographic and clinical features analyzed in this study. The SSI rate was 1.2% in total, and in Groups 1, 2, and 3, it was 1.5%, 1.04%, and 1.07%, respectively. There was no statistical difference regarding SSI among the groups (p = 1.00). Superficial SSI was observed in all groups, and in all patients, the site of infection was the entrance to the epigastric port through which the gallbladder had been removed. Conclusions: Surgical site infection is rare after LC, and antibiotic prophylaxis does not appear to affect the outcome significantly. Moreover, factors such as positive bile cultures, history of biliary attack, ASA score, diabetes, obesity, and smoking do not have any effect on SSI development. Thus, we conclude that antibiotic prophylaxis is not needed for elective LC. European Soc Surgery

Objective This study was performed to determine the effects of scalp blocks with bupivacaine versus levobupivacaine on the haemodynamic response during craniotomy and the efficacies and analgesic requirements of these drugs postoperatively. Methods This randomized, prospective, placebo-controlled, double-blind study included 90 patients (age, 18–85 years; American Society of Anesthesiologists physical status, I or II). The patients were randomly divided into three groups: those who received 20 mL of 0.5% bupivacaine (Group B, n = 30), 20 mL of 0.5% levobupivacaine (Group L, n = 30), or saline as a placebo (Group C, n = 30). Scalp blocks were performed 5 min before head pinning. The primary outcome was the mean arterial pressure (MAP), and the secondary outcomes were the heart rate (HR), visual analogue scale (VAS) scores, and additional intraoperative and postoperative drug use. Postoperative pain was evaluated using a 10-cm VAS. Results During head pinning and incision, the MAP and HR were significantly higher in Group C. The additional drug requirement for intraoperative hypertension and tachycardia was significantly higher in Group C. There were no significant differences in MAP, HR, or VAS scores between Groups B and L. Conclusion Both bupivacaine and levobupivacaine can be effectively and safely used for scalp blocks to control haemodynamic responses and postoperative pain.

Background There is a lack of specificity of the analgesic agents used to treat headache and underlying acute carbon monoxide poisoning. Objective To compare effectiveness of “oxygen alone” vs “metoclopramide plus oxygen” vs “metamizole plus oxygen” therapy in treating carbon monoxide–induced headache. Design A prospective, multicenter, double-blind, controlled trial. Setting Three emergency departments in Turkey. Population Adult carbon monoxide poisoning patients with headache. Methods A total of 117 carbon monoxide-intoxicated patients with headache were randomized into 3 groups and assessed at baseline, 30 minutes, 90 minutes, and 4 hours. Main Outcome Measure The primary outcome was patient-reported improvement rates for headache. Secondary end points included nausea, need for rescue medication during treatment, and reduction in carboxyhemoglobin levels. Results During observation, there was no statistical difference between drug type and visual analog scale score change at 30 minutes, 90 minutes, or 4 hours, for either headache or nausea. No rescue medication was needed during the study period. The reduction in carboxyhemoglobin levels did not differ among the 3 groups. Conclusion The use of “oxygen alone” is as efficacious as “oxygen plus metoclopramide” or “oxygen plus metamizole sodium” in the treatment of carbon monoxide–induced headache.

Introduction Musculoskeletal system traumas are among the most common presentations in the emergency departments. In the treatment of traumatic musculoskeletal pain, paracetamol and non-steroidal anti-inflammatory analgesics (NSAID) are frequently used. Our aim in this study is to compare the efficacy of intravenous dexketoprofen and paracetamol in the treatment of traumatic musculoskeletal pain. Methods This prospective, randomised, double blind, controlled study was conducted in a tertiary care emergency unit. The participating patients were randomised into two groups to receive either 50 mg of dexketoprofen or 1000 mg of paracetamol intravenously by rapid infusion in 150 mL of normal saline. Visual analogue scale (VAS), Numeric Rating Scala (NRS) and Verbal Rating Scale (VRS) was employed for pain measurement at baseline, after 15, after 30 and after 60 mins. Results 200 patients were included in the final analysis. The median age of the paracetamol group was 34 (24–48), while that of the dexketoprofen group was 35 (23–50), and 63% (n = 126) of them consisted of men. Paracetamol and dexketoprofen administration reduced VAS pain scores over time (p = 0.0001). Median reduction in VAS score at 60 min was 55 (IQR 30–65) for the paracetamol group and 50(IQR 30.25–60) for the dexketoprofen group. There was no statistically significant difference between the paracetamol and dexketoprofen groups in terms of VAS reductions (p = 0.613). Conclusion Intravenous paracetamol and dexketoprofen seem to produce equivalent pain relief for acute musculoskeletal trauma in the emergency department. CLINICALTRIALS.GOV NO: NCT03428503

Summary Background Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. Methods We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659 . Findings Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Interpretation Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. Funding The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

The present study evaluates the effects of leukocyte-platelet-rich fibrin (L-PRF) combined with open flap debridement (OFD) on clinical parameters and growth factors levels (GFL) in chronic periodontitis (CP) patients. This trial was registered at clinicaltrials.gov as NCT02594605. 16 patients (32 sites) with chronic periodontitis who had at least two areas of horizontal bone loss, were treated with OFD alone or L-PRF with OFD (OFD + L-PRF). GFL in gingival crevicular fluid (GCF) were analyzed at baseline, 1 week, 2 weeks and 4 weeks after operation. Probing depth (PD) and clinical attachment level (CAL) were measured at baseline and 6 months postoperatively. PD reduction and CAL gain were significantly higher in the OFD + L-PRF sites than in OFD sites. OFD + L-PRF group showed significantly increased bone morphogenetic protein-2 and insulin-like growth factor-1 at 2 weeks compared with baseline. L-PRF combined with OFD significantly increases GFL and thus, it enhances the periodontal healing on CP patients. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Consortia for the ALBINO Study Group: Axel R. Franz, Mario Rüdiger, Christian F. Poets, Manon Benders, Frank van Bel, Karel Allegaert, Gunnar Naulaers, Dirk Bassler, Katrin Klebermaß-Schrehof, Maximo Vento, Hercilia Guimarães, Tom Stiris, Luigi Cattarossi, Marjo Metsäranta, Sampsa Vanhatalo, Jan Mazela, Tuuli Metsvaht, Cees van Veldhuizen, Corinna Engel, Christian A. Maiwald, Gabriele von Oldershausen, Iris Bergmann, Monika Weiss, Caroline J. B. R. Wichera, Andreas Eichhorn, Michael Raubuch, Birgit Schuler, Cees K. W. van Veldhuizen, Bas Laméris, Yannique Jacobs, Roselinda van der Vlught-Meijer, Elke Griesmaier, Johannes Brandner, Marie Tackoen, Ruth Reibel, Chantal Lecart, Luc Cornette, Genevieve Malfilatre, Renaud Viellevoye, Tuuli Metsvaht, Mari-Liis Ilmoja, Pille Saik, Ruth Käär, Pille Andresson, Marjo Metsaranta, Axel R. Franz, Rolf Schloesser, Torsten Ott, Stefan Winkler, Thomas Hoehn, Norbert Teig, Michael Schroth, Ulrich H. Thome, Harald Ehrhardt, Luigi Cattarossi, Isabella Mauro, Eugenio Baraldi, Virgilio Carnielli, Giuseppe Paterlini, Marcello Napolitano, Paola Francesca Faldini, Gianluca Lista, Gianluca Visintin, Mario Barbarini, Laura Pagani, Emmanuele Mastretta, Giovanni Vento, Monica Fumagalli, Marco Binotti, Mirjam M. van Weissenbruch, Henrica L. M. van Straaten, Manon J. N. L. Benders, Kim V. Annink, Frank van Bel, Jeroen Dudink, Jan B. Derks, Inge P. de Boer, Clemens B. Meijssen, Timo R. de Haan, Linda G. van Rooij, Jacqueline L. van Hillegersberg, Minouche van Dongen, Jos Bruinenberg, Koen P. Dijkman, Marlies A. van Houten, Sophie R. D. van der Schoor, Tom Stiris, Bodil Salvesen, Moritz Schneider, Eirik Nestaas, Britt Nakstad, Jan Mazela, Lukas Karpinski, Ewa Gulczynska, Barbara Królak-Olejnik, Renata Bokiniec, Ana I. Vilan, Liliana Flores de Pinho, Claudia Ferraz, Almerinda Pereira, Rosalina Barroso, André Mendes da Graça, Teresa Tomé, Filomena Pinto, Maximo Vento, Juan Martínez Rodilla, Simón Lubián, Marta Campubri Camprubí, José Antonio Hurtado Suazo, Eva Valverde, José Ramón Fernández Lorenzo, José Martinez Orgado, Héctor Boix, Francisco Jimenez Parrilla, Maria Teresa Moral-Pumarega, Julia Maletzki, Claudia Knoepfli, Cornelia Hagmann, Sven Schulzke, Martin Stocker, André Birkenmaier, Thomas Riedel, Hans-Jörg Ehni, Annie Janvier & Georg Marckmann., [Background]: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia., [Methods]: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion., [Discussion]: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia., [Trial registration]: NCT03162653, www.ClinicalTrials.gov, May 22, 2017., This study is funded under the Horizon 2020 Framework Program of the European Union, call H2020-PHC-2015-two-stage, grant 667224. Publication of this manuscript was supported by Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of the University of Tuebingen.

Introduction: Although acute musculoskeletal pain has a wide range of causes from tendinitis, muscle spasm, to bone and joint injuries, it is a frequent occurrence in emergency services. Paracetamol and non-steroidal anti-inflammatory analgesics (NSAID) are common used in the treatment of musculoskeletal pain. This study sets out to compare the effectiveness of intravenous dexketoprofen and paracetamol in musculoskeletal pain relief. Methods: This prospective, randomized, double blind, controlled study was carried out in a university emergency room. The participating patients were randomized into two groups to receive either 50 mg of dexketoprofen or 1000 mg of paracetamol intravenously by rapid infusion in 150 ml of normal saline. Visual analogue scale (VAS), Numeric Rating Scala (NRS) was employed for pain measurement at baseline, after 15, after 30 and after 60 mins. Results: 200 patients were included in the study, excluding 7342 of them. The mean age of the patients was calculated as 32,6. Paracetamol and dexketoprofen intervention decreases NRS pain scores over time. When compared to all pain locations, the NRS pain score of the patients was found to be statistically more effective in dexketoprofen than in paracetamol (p = 0.001). Paracetamol and dexketoprofen intervention reduces pain VAS scores over time. When the VAS pain score of the patients was compared to all pain locations, dexketoprofen was found to be statistically more effective than paracetamol (p = 0.001). Conclusion: Intravenous dexketoprofen seemed to achieve superior analgesia to intravenous paracetamol when compared with all pain locations in patients with non-traumatic musculoskeletal pain. © 2019 Elsevier Inc.

BACKGROUND Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.” METHODS We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of

OBJECTIVE: To evaluate the combined prognostic value of neurological examination, head circumference and cranial ultrasound for neurodevelopmental delay (NDD) in very low birth weight (VLBW

Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety, and tolerability of oxfendazole were evaluated in healthy volunteers in this phase 1 first-in-human (FIH) study. Seventy subjects were randomly assigned to receive a single oral dose of oxfendazole (0.5, 1, 3, 7.5, 15, 30, or 60 mg oxfendazole/kg body weight) or placebo and were followed for 14 days. Blood and urine samples were collected, and the concentrations of oxfendazole were measured using a validated ultraperformance liquid chromatography mass spectrometry method. The pharmacokinetic parameters of oxfendazole were estimated using noncompartmental analysis. Oxfendazole was rapidly absorbed with a mean plasma half-life ranging from 8.5 to 11 h. The renal excretion of oxfendazole was minimal. Oxfendazole exhibited significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses of 0.5 mg/kg to 60 mg/kg. This nonlinearity of oxfendazole is likely due to the dose-dependent decrease in bioavailability that is caused by its low solubility. Oxfendazole was found to be well tolerated in this study at different escalating doses without any serious adverse events (AEs) or deaths. There were no significant differences in the distributions of hematology, biochemistry, or urine parameters between oxfendazole and placebo recipients. (This study has been registered at ClinicalTrials.gov under identifier NCT02234570.).

Background: Screening for specific IgE against 2S albumin proteins Ara h 2 and 6 has good positive predictive value in diagnosing peanut allergy. From the third 2S member Ara h 7, 3 isoforms have been identified. Their allergenicity has not been elucidated. Objective: This study investigated the allergenicity of Ara h 7 isoforms compared to Ara h 2 and 6. Methods: Sensitization of 15 DBPCFC-confirmed peanut-allergic patients to recombinant Ara h 2.0201, Ara h 6.01 and isoforms of recombinant Ara h 7 was determined by IgE immunoblotting strips. A basophil activation test (BAT) was performed in 9 patients to determine IgE-cross-linking capacities of the allergens. Sensitivity to the allergens was tested in 5 patients who were sensitized to at least 1 Ara h 7 isoform, by a concentration range in the BAT. 3D prediction models and sequence alignments were used to visualize differences between isoforms and to predict allergenic epitope regions. Results: Sensitization to Ara h 7.0201 was most frequent (80%) and showed to be equally potent as Ara h 2.0201 and 6.01 in inducing basophil degranulation. Sensitization to Ara h 7.0201 together with Ara h 2.0201 and/or 6.01 was observed, indicating the presence of unique epitopes compared to the other 2 isoforms. Differences between the 3 Ara h 7 isoforms were observed in C-terminal cysteine residues, pepsin and trypsin cleavage sites and 3 single amino acid substitutions. Conclusion & clinical relevance: The majority of peanut-allergic patients are sensitized to isoform Ara h 7.0201, which is functionally as active as Ara h 2.0201 and 6.01. Unique epitopes are most likely located in the C-terminus or an allergenic loop region which is a known allergenic epitope region for Ara h 2.0201 and 6.01. Due to its unique epitopes and allergenicity, it is an interesting candidate to improve the diagnostic accuracy for peanut allergy.

Background: Dysmenorrhea is one of the most common acute pain disorders among women of reproductive age. Aims: To compare the effects of IV paracetamol with dexketoprofen in patients presenting with primary dysmenorrhea to the emergency department. Study Design: Randomized controlled trial. Methods: Patients over 18 years old presenting with pelvic pain related to menstruation were eligible for the study. Study patients received 1 g paracetamol or 50 mg dexketoprofen in 100 mL normal saline with a 4-5 minute infusion via the intravenous route. Pain intensity was measured by a visual analog scale at 15 and 30 minutes. Patients were randomized and assigned to either of two study arms via sealed envelopes. Study drugs were identical in color, and thus both personnel and patients were blinded to the study drug. The dexketoprofen group comprised 49 patients, and the paracetamol group had 50 patients in the final analysis. Results: The mean age of the study subjects was 20.9±2.5 and the mean duration of the pain was 1.9±1.7 (median: 1, interquartile range: 1 to 2) hours. Both dexketoprofen (median change: 33, 95% CI: 24 to 38) and paracetamol (median change: 21, 95% CI: 12 to 32) effectively reduced the pain at 15 minutes, which was repeated at 30 minutes (median change: 63, 95% CI: 57 to 65 vs 55.5, 95% CI: 50 to 59, respectively). Pain improvement in the dexketoprofen group was better than in the paracetamol group at 15 (median difference: 8, 95% CI: 0 to 16, p=0.048) and 30 (median difference: 6, 95% CI: 1 to 12, p=0.028) minutes, which was statistically significant but not clinically significant. Conclusion: Dexketotoprofen has a better visual analogue scale score that is not clinically relevant compared to paracetamol. © 2018, Galenos Publishing House. All rights reserved.

Background: The use of aspirin in the primary prevention of cardiovascular events remains controversial. We aimed to assess the efficacy and safety of aspirin versus placebo in patients with a moderate estimated risk of a first cardiovascular event. Methods: ARRIVE is a randomised, double-blind, placebo-controlled, multicentre study done in seven countries. Eligible patients were aged 55 years (men) or 60 years (women) and older and had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors. We excluded patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes. Patients were randomly assigned (1:1) with a computer-generated randomisation code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once daily. Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation. The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack. Safety endpoints were haemorrhagic events and incidence of other adverse events, and were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00501059. Findings: Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4·29%) patients in the aspirin group versus 281 (4·48%) patients in the placebo group (hazard ratio [HR] 0·96; 95% CI 0·81–1·13; p=0·6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36–3·28; p=0·0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20·19%] in the aspirin group vs n=1311 [20·89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82·01%] vs n=5129 [81·72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n=1050 [16·75%] vs n=850 [13·54%] in the placebo group; p

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of ‘one size fits all’, and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects’ genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

PubMedID: 29481636 Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23(FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m 2 ], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m 2 ). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and - 1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70mL/min/1.73m 2 . Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD. © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. American Society of Pediatric Nephrology: ESPN 2014.3 This work was supported by the European Society for Pediatric Nephrology (reference number ESPN 2014.3), KfH Foundation for Preventive Medicine and ERA-EDTA (to D.H.).

Scope: The main findings of the “Virgin Olive Oil and HDL Functionality” (VOHF) study and other related studies on the effect of phenol-enriched virgin olive oil (VOO) supplementation on cardiovascular disease are integrated in the present work. Methods and results: VOHF assessed whether VOOs, enriched with their own phenolic compounds (FVOO) or with those from thyme (FVOOT), improve quantity and functionality of HDL. In this randomized, double-blind, crossover, and controlled trial, 33 hypercholesterolemic subjects received a control VOO (80 mg kg-1), FVOO (500 mg kg-1), and FVOOT (500 mg kg-1; 1:1) for 3 weeks. Both functional VOOs promoted cardioprotective changes, modulating HDL proteome, increasing fat-soluble antioxidants, improving HDL subclasses distribution, reducing the lipoprotein insulin resistance index, increasing endogenous antioxidant enzymes, protecting DNA from oxidation, ameliorating endothelial function, and increasing fecal microbial metabolic activity. Additional cardioprotective benefits were observed according to phenol source and content in the phenol-enriched VOOs. These insights support the beneficial effects of OO and PC from different sources. Conclusion: Novel therapeutic strategies should increase HDL-cholesterol levels and enhance HDL functionality. The tailoring of phenol-enriched VOOs is an interesting and useful strategy for enhancing the functional quality of HDL, and thus, it can be used as a complementary tool for the management of hypercholesterolemic individuals. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Pain management is one of the essentials of emergency care. Renal colic secondary to urinary stone disease forms one of the most intense pain types. The present study aimed to compare the effect of intravenous ibuprofen to paracetamol in ceasing renal colic. This randomised double-blind study was composed of two intervention arms, intravenous paracetamol and intravenous ibuprofen. Study subjects were randomised to receive a single dose of either paracetamol, 1 g in 100 ml normal saline, or ibuprofen (800 mg in 100 ml normal saline) in a blinded fashion. Subjects reported pain intensity on a visual analogue scale with lines intersection multiples of ten just before the drug administration, 15 and 30 min after the study drug administration. Two hundred patients were randomised to either of two study arms: however, 97 patients in ibuprofen group and 99 patients in paracetamol groups were included into 30 minute analysis. Differences of pain improvements between two groups was 9.5 (5.4–13.7) at 15 min (p = 0.000) and 17.1 (11.9–22.5) at 30 min, those both favouring ibuprofen over paracetamol (p = 0.000). Although ten (10.1%) patients in paracetamol group needed rescue drug, there were only two (2%) patients in ibuprofen group (difference: 8%; 95% CI 0.7–16%, p = 0.02). Intravenous 800 mg ibuprofen is more effective than IV paracetamol in ceasing renal colic at 30 min. © 2017, Springer-Verlag GmbH Germany.

WOS: 000460932900018, PubMed ID: 30040706, BACKGROUND: In treatment of adhesive capsulitis, deep heating agents have been shown to have positive effects on pain and function. OBJECTIVE: To evaluate if addition of ultrasound used in treatment of adhesive capsulitis will provide additional benefits. METHODS: Thirty patients with adhesive capsulitis were included in a prospective, double-blind, randomized controlled trial. Hotpack, TENS (Transcutaneus Electrical Nerve Stimulation), exercise and active ultrasound therapies were applied to the first group (n = 15), whereas sham ultrasound was applied to the second group (n = 15) in addition to hotpack, TENS and exercise. The patients were evaluated using joint range of motion, UCLA shoulder scale and Shoulder Disability Questionnaire scales at baseline and at 6th and 24th weeks post-treatment. RESULTS: When pain and the clinical and functional parameters were compared in both groups, significant improvement was found compared to baseline (p < 0.001). At week 24, no difference was found in terms of pain at rest, but all other parameters were improved compared to week 6. When the groups were compared, no difference was found in any comparison between 6th and 24th week (p > 0.05). CONCLUSION: Adding ultrasound treatment to a combination of physical therapy modalities did not provide any additional benefits for the treatment of adhesive capsulitis.

Background In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. Aim To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. Methods 497 women (21–70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). Outcomes The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. Results In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57–2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44–3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58–2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17–1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57–2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17–1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). Clinical Implications T + S and T + B are promising treatments for women with FSIAD. Strengths and Limitations The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. Conclusions T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups.

Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes-related complications. We conducted a pooled analysis of patient-level data from three 24-week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add-on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC-F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC-F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI). © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley and Sons Ltd.

Background: Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses.Methods: In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18–60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 μg FLU-v in saline (arm 1), one dose of emulsified 500 μg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity.Discussion: Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated.Trial registration: EudraCT number 2015–001932-38; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).

Background: Acute respiratory distress syndrome (ARDS) results in vascular leakage, inflammation and respiratory failure. There are currently no approved pharmacological treatments for ARDS and standard of care involves treatment of the underlying cause, and supportive care. The vascular leakage may be related to reduced concentrations of local adenosine, which is involved in maintaining endothelial barrier function. Interferon (IFN) beta-1a up-regulates the cell surface ecto-5'-nucleotidase cluster of differentiation 73 (CD73), which increases adenosine levels, and IFN beta-1 may, therefore, be a potential treatment for ARDS. In a phase I/II, open-label study in 37 patients with acute lung injury (ALI)/ARDS, recombinant human IFN beta-1a was well tolerated and mortality rates were significantly lower in treated than in control patients. Methods/design: In this phase III, double-blind, randomized, parallel-group trial, the efficacy and safety of recombinant human IFN beta-1a (FP-1201-lyo) will be compared with placebo in adult patients with ARDS. Patients will be randomly assigned to receive 10 μg FP-1201-lyo or placebo administered intravenously once daily for 6 days and will be monitored for 28 days or until discharged from the intensive care unit. Follow-up visits will then take place at days 90, 180 and 360. The primary endpoint is a composite endpoint including any cause of death at 28 days and days free of mechanical ventilation within 28 days among survivors. Secondary endpoints include: all-cause mortality at 28, 90, 180 and 360 days; organ failure-free days; length of hospital stay; pharmacodynamic assessment including measurement of myxovirus resistance protein A concentrations; and measures of quality of life, respiratory and neurological function at 180 and 360 days. The estimated sample size to demonstrate a reduction in the primary outcome between groups from 30% to 15% is 300 patients, and the study will be conducted in 70-80 centers in nine countries across Europe. Discussion: There are no effective specific treatments for patients with ARDS and mortality rates remain high. The results from this study will provide evidence regarding the efficacy of a potential new therapeutic agent, FP-1201-lyo, in improving the clinical course and outcome for patients with moderate/severe ARDS. Trial registration: European Union Clinical Trials Register, no: 2014-005260-15. Registered on 15 July 2017., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. Methods We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. Findings Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. Interpretation The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. Funding Merck and Co, Inc. © 2017 Elsevier Ltd

Background: A 12-week, double-blind, parallel, multi-center randomized controlled trial in 316 adult patients with major depressive disorder (MDD) was conducted to evaluate the effectiveness of pharmacogenetic (PGx) testing for drug therapy guidance. Methods: Patients with a CGI-S = 4 and requiring antidepressant medication de novo or changes in their medication regime were recruited at 18 Spanish public hospitals, genotyped with a commercial PGx panel (Neuropharmagen®), and randomized to PGx-guided treatment (n = 155) or treatment as usual (TAU, control group, n = 161), using a computer-generated random list that locked or unlocked psychiatrist access to the results of the PGx panel depending on group allocation. The primary endpoint was the proportion of patients achieving a sustained response (Patient Global Impression of Improvement, PGI-I = 2) within the 12-week follow-up. Patients and interviewers collecting the PGI-I ratings were blinded to group allocation. Between-group differences were evaluated using ?2-test or t-test, as per data type. Results: Two hundred eighty patients were available for analysis at the end of the 12-week follow-up (PGx n = 136, TAU n = 144). A difference in sustained response within the study period (primary outcome) was not observed (38.5% vs 34.4%, p = 0.4735; OR = 1.19 [95%CI 0.74-1.92]), but the PGx-guided treatment group had a higher responder rate compared to TAU at 12 weeks (47.8% vs 36.1%, p = 0.0476; OR = 1.62 [95%CI 1.00-2.61]), and this difference increased after removing subjects in the PGx-guided group when clinicians explicitly reported not to follow the test recommendations (51.3% vs 36.1%, p = 0.0135; OR = 1.86 [95%CI 1.13-3.05]). Effects were more consistent in patients with 1-3 failed drug trials. In subjects reporting side effects burden at baseline, odds of achieving a better tolerability (Frequency, Intensity and Burden of Side Effects Rating Burden subscore =2) were higher in the PGx-guided group than in controls at 6 weeks and maintained at 12 weeks (68.5% vs 51.4%, p = 0.0260; OR = 2.06 [95%CI 1.09-3.89]). Conclusions: PGx-guided treatment resulted in significant improvement of MDD patient's response at 12 weeks, dependent on the number of previously failed medication trials, but not on sustained response during the study period. Burden of side effects was also significantly reduced. © 2017 The Author(s).

Background: We estimated the prevalence and incidence of 14 human papillomavirus (HPV) types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS), using predefined algorithms that adjusted for multiple-type infected lesions. Methods: A total of 10,656 women ages 15 to 26 years and 1,858 women ages 24 to 45 years were enrolled in the placebo arms of one of three clinical trials of a quadrivalent HPV vaccine. We estimated the cumulative incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by a prophylactic 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine. Results: The cumulative incidence of persistent infection with ≥1 of the seven high-risk types included in the 9-valent vaccine was 29%, 12%, and 6% for women ages 15 to 26, 24 to 34, and 35 to 45 years, respectively. A total of 2,507 lesions were diagnosed as CIN or AIS by an expert pathology panel. After adjusting for multiple-type infected lesions, among women ages 15 to 45 years, these seven high-risk types were attributed to 43% to 55% of CIN1, 70% to 78% of CIN2, 85% to 91% of CIN3, and 95% to 100% of AIS lesions, respectively. The other tested types (HPV35/39/51/56/59) were attributed to 23% to 30% of CIN1, 7% to 14% of CIN2, 3% to 4% of CIN3, and 0% of AIS lesions, respectively. Conclusions: Approximately 85% or more of CIN3/AIS, >70% CIN2, and approximately 50% of CIN1 lesions worldwide are attributed to HPV6/11/16/18/31/33/45/52/58. Impact: If 9-valent HPV vaccination programs are effectively implemented, the majority of CIN2 and CIN3 lesions worldwide could be prevented, in addition to approximately one-half of CIN1. Cancer Epidemiol Biomarkers Prev; 23(10); 1997–2008. ©2014 AACR.

ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H-1 antihistamine treatment at licensed doses. Patients aged 12-75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H-1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N=319: placebo n=80, omalizumab 75 mg n=78, 150 mg n=80, 300 mg n=81), 262 (82.1%) completed the study. Compared with placebo (n=80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (Cl): -4.71 to -1.21; P=0.0010), 2.95 points (95% CI: -4.72 to -1.18; P=0.0012), and 5.80 points (95% Cl: -7.49 to -4.10; P= 5-point decrease) in weekly ISS (P