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Skin care against aggravating factors is important to prevent skin lesions from flare‐up in the treatment of atopic dermatitis (AD). Tannic acid (TA), a natural polyphenolic and protein‐denaturing agent, has activity to denature antigens relevant to the AD flare. To assess the efficacy of a bath additive containing TA (TA‐bath additive) on pruritus of AD, we carried out a randomized double‐blind trial, in which 21 patients with AD completed the blinded sequential treatments with the TA‐bath additive and a bath additive without TA (placebo‐bath additive) in a cross‐over manner. A significant improvement of pruritus was observed in the afternoon and night by using the TA‐bath additive and in the afternoon by the placebo‐bath additive in patients with AD. No superiority of the TA‐bath additive to the placebo was revealed in the overall patient cohort. However, the added TA in the bath additive exerted its efficacy especially on itch at night in patients with mild‐to‐moderate disease. Bathing by using the series of the bath additive with TA and that without TA improved AD skin lesions throughout this study. No adverse effects related to the use of the TA‐ and placebo‐bath additives were observed. In conclusion, the bath additive containing TA may help skin care of patients with itch and skin lesions of the mild AD.

© 2020 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Aim: To assess the impact of purchasing wine in 50 cl bottles compared with 75 cl bottles on the amount of wine consumed at home. Design: Cross-over randomized controlled trial with a ‘usual behaviour’ period of a maximum of 3 weeks between conditions. Setting: Households in the United Kingdom. Participants: One hundred and eighty-six households that consumed between two and eight 75 cl bottles of wine each week. Intervention: Households were randomized to the order in which they purchased wine in two bottle sizes. During two 14-day intervention periods, households purchased a pre-set volume of wine—based on their baseline self-reported weekly consumption—in either 75 cl bottles or 50 cl bottles. On days 7 and 14 of each study period, participating households sent photographs of each purchased wine bottle. Measurements: The primary outcome was the volume of study wine in millilitres (ml) consumed during each study period estimated through returned photographs. The secondary outcome was the rate of consumption measured by the mean number of days taken to drink 1.5 litres from each bottle size. Findings: One hundred and sixty-six of 186 enrolled households satisfactorily completed the study. After accounting for pre-specified covariates, 191.1 ml [95% confidence interval (CI) = 42.03–339.2] or 4.5% (95% CI = 1.0–7.9%) more wine was consumed per 14-day period from 75-cl bottles than from 50-cl bottles. Consumption was 5.8% faster (95% CI = –10.9 to –0.4%) from 75 cl bottles than from 50 cl bottles. Conclusions: Consuming wine at home from 50 cl bottles, compared with 75 cl bottles, may reduce both amount consumed and rate of consumption.

A spectrum of anatomic variants of the conventional single patellar tendon have been described however a double patellar tendon is a highly rare finding, which has only been described once before where a cross-over tendon morphology was illustrated. We report the case of a 46-year-old man with a 3 month history of left knee pain who was found to have an incidental double patellar tendon without cross-over, with one deep bundle demonstrating a more conventional patellar tendon course, paralleled by a second anatomically-distinct superficial bundle of differing morphology coursing anterolateral to the deep conventional bundle, explicitly connecting patella to tibial tuberosity. A comprehensive understanding of the anatomic variations of the patellar tendon is essential for both radiologist and clinician to deliver safe clinical practice. We present a rare case of an uncrossed-doubled patellar tendon, which to our knowledge, has never been reported. Keywords: Anatomic variant, Cross-over, Doubled patellar tendon, Knee, MRI

Hypertensive patients who adopt a sodium-restricted diet have difficulty maintaining this change, and this could increase stress. On the other hand, soup rich in umami substances (dashi) was reported to reduce indexes of anxiety and stress. The objective of this study was to measure mood and physiological stress indexes during administration of a sodium-restricted diet with and without an umami substance (free L-glutamate) by a cross-over randomized, single-blind, placebo-controlled trial in Japanese female university students. The baseline was measured for 5 days followed by a sodium-restricted diet intervention phase that lasted for 10 days. The Profile of Mood States questionnaire was administered, a stress marker in saliva (chromogranin-A) was measured, and the amount of sodium intake was confirmed from 24 h urine collection samples. Results showed that the sodium reduction was verified by 24 h urine excretion. The percentage of change in the stress marker from the baseline showed that the stress level in group without the umami substance was significantly higher than that in the group with the umami substance (p = 0.013) after receiving a sodium-reduced diet for 6 or more days, indicating that stress was alleviated. This study suggested that umami substances might help to ameliorate stress during a sodium-reduced diet, especially in the initial phase.

Abstract Numerous studies addressed the topic of behavioral and symptomatic changes in eating disorders. Rates of transition vary widely across studies, ranging from 0 to 70.8%, depending on the diagnoses taken into account and the study design. Evidence shows that the specific transition from restrictive-type anorexia nervosa (AN-R) to disorders involving binging and purging behaviors (BPB) is related to a worsening of the clinical picture and worse long-term outcomes. The aim of this systematic review and meta-analysis is to focus on this specific transition, review existing literature, and summarize related risk factors. Medline and PsycINFO databases were searched, including prospective and retrospective studies on individuals with AN-R. The primary outcome considered was the rate of onset of BPB. Twelve studies (N = 725 patients) were included in the qualitative and quantitative analysis. A total of 41.84% (95% CI 33.58–50.11) of patients with AN-R manifested BPB at some point during follow-up. Risk factors for the onset of BPB included potentially treatable and untreatable factors such as the family environment, unipolar depression and higher premorbid BMI. These findings highlight that patients with AN-R frequently transition to BPB over time, with a worsening of the clinical picture. Existing studies in this field are still insufficient and heterogeneous, and further research is needed. Mental health professionals should be aware of the frequent onset of BPB in AN-R and its risk factors and take this information into account in the treatment of AN-R. Level of evidence Evidence obtained from a systematic review and meta-analysis, Level I.

Introduction Paclitaxel micellar is a novel formulation of paclitaxel in which retinoic acid derivates solubilize paclitaxel. The aim of the present study was to compare the unbound and total plasma pharmacokinetics of the new formulation with those of nanoparticle albumin-bound (nab)-paclitaxel and to further assess its safety. Methods In this open, randomized, cross-over study, 28 female patients with breast cancer were given paclitaxel micellar and nab-paclitaxel as a 1-h intravenous infusion at a dose of 260 mg/m2. Plasma samples were collected during 10 h, which were projected to cover at least 80% of the area to infinite time, AUCinf. Unbound paclitaxel was measured in ultrafiltrate of plasma. Total paclitaxel in plasma was measured after protein precipitation with acetonitrile. Both assays used ultra-performance liquid chromatography (UPLC) followed by MS/MS for drug quantification. The unbound fraction, fu, was calculated as the ratio between the unbound and the total concentration. Results No difference in fu of paclitaxel between the two formulations was observed. Statistical comparison of AUC0–10h and Cmax of unbound paclitaxel demonstrated that the two formulations met the criteria for bioequivalence. Regarding total paclitaxel levels, Cmax but not AUC0–10h met the criteria. This study supports a safe administration of paclitaxel micellar. Conclusion The two formulations, paclitaxel micellar and nab-paclitaxel, behaved similarly following infusion. Probably, both formulations dissociate immediately in the blood, whereupon released paclitaxel rapidly distributes into tissue. Judged from the bioequivalence demonstrated for unbound paclitaxel, the two formulations are considered clinically equivalent. Trial Registration EudraCT no.: 2010-019838-27. Funding Oasmia Pharmaceutical AB.

Background Treadmills are often used in research, clinical practice, and training. Biomechanical investigations comparing treadmill and overground running report inconsistent findings. Objective This study aimed at comparing biomechanical outcomes between motorized treadmill and overground running. Methods Four databases were searched until June 2019. Crossover design studies comparing lower limb biomechanics during non-inclined, non-cushioned, quasi-constant-velocity motorized treadmill running with overground running in healthy humans (18–65 years) and written in English were included. Meta-analyses and meta-regressions were performed where possible. Results 33 studies (n = 494 participants) were included. Most outcomes did not differ between running conditions. However, during treadmill running, sagittal foot–ground angle at footstrike (mean difference (MD) − 9.8° [95% confidence interval: − 13.1 to − 6.6]; low GRADE evidence), knee flexion range of motion from footstrike to peak during stance (MD 6.3° [4.5 to 8.2]; low), vertical displacement center of mass/pelvis (MD − 1.5 cm [− 2.7 to − 0.8]; low), and peak propulsive force (MD − 0.04 body weights [− 0.06 to − 0.02]; very low) were lower, while contact time (MD 5.0 ms [0.5 to 9.5]; low), knee flexion at footstrike (MD − 2.3° [− 3.6 to − 1.1]; low), and ankle sagittal plane internal joint moment (MD − 0.4 Nm/kg [− 0.7 to − 0.2]; low) were longer/higher, when pooled across overground surfaces. Conflicting findings were reported for amplitude of muscle activity. Conclusions Spatiotemporal, kinematic, kinetic, muscle activity, and muscle–tendon outcome measures are largely comparable between motorized treadmill and overground running. Considerations should, however, particularly be given to sagittal plane kinematic differences at footstrike when extrapolating treadmill running biomechanics to overground running. Protocol registration CRD42018083906 (PROSPERO International Prospective Register of Systematic Reviews).

Background Osteoarthritis (OA) affects nearly 20% of all dogs greater than one year of age. Clinical signs include pain, discomfort, lameness, and ultimately lead to disability. Although there is currently no known cure, there are many therapeutic options that can slow the progression and alleviate the associated signs. There is ample supportive evidence demonstrating the efficaciousness of carprofen, a non-steroidal anti-inflammatory drug, in managing signs of OA. Since the approval of the pioneer product (Rimadyl®, Zoetis; Kalamazoo, Michigan), the United States Food and Drug Administration (FDA) has assented to several other generic, bioequivalent products. The objective of this 2 × 2 complete cross-over design was to assess the acceptance of two bioequivalent carprofen liver-flavored chewable tablets (containing 25 mg carprofen), Rimadyl® and Carprieve® (Norbrook Laboratories Limited; Newry, Northern Ireland) in 37 healthy purpose-bred dogs. Results Overall, 73.0% (27/37) and 70.3% (26/37) of dogs voluntarily accepted Rimadyl® and Carprieve®, respectively. Considering acceptability tests paired by individual dog, 64.9% of dogs (n = 24) voluntarily accepted both Rimadyl® and Carprieve® chewable tablets whereas 21.6% (8) of dogs denied or partially accepted both products offered. Three dogs (8.1%) fully accepted Rimadyl® but did not accept Carprieve®. Conversely, two dogs (5.4%) fully accepted Carprieve® but did not accept Rimadyl®. Canine acceptability did not significantly differ between Carprieve® and Rimadyl® carprofen chewable tablets (P = 0.65). Conclusions Utilizing a 2 × 2 complete cross-over design, this study provides evidence that canine acceptability of a single-dose did not differ between Carprieve® and Rimadyl® chewable tablets.

IntroductionHereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.Methods and analysisWe designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2–4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.Ethics and disseminationThe protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.Trial registration numberNCT02941328.

Comparisons between the acid inhibitory effects of rabeprazole and esomeprazole after single oral administration with standard doses have not been previously presented. We examined intra-gastric pH after oral administrations of these two proton pump inhibitors using 24-h pH monitoring. Fifty-four normal volunteers not infected by Helicobacter pylori were investigated. Using a cross-over design, we administered 10 mg of rabeprazole or 20 mg of esomeprazole in 27 at 30 min after supper and in the remaining 27 subjects at 15 min before supper, and performed 24-h pH monitoring. Intra-gastric pH data were nearly identical when the proton pump inhibitors were taken after meals. Even if the data were compared in different CYP2C19 genotypes, rabeprazole and esomeprazole did not show the difference. In poor metabolizer, both of the drugs showed stronger acid inhibition. When taken before meals, intra-gastric pH after esomeprazole administration was slightly but not significantly higher than that observed after rabeprazole administration not only in daytime but also in nighttime period. In conclusion, rabeprazole and esomeprazole were similarly effective when administered after a meal.

Objective Contraversive pushing (CP) is a neurologic disorder characterized by a lateral postural imbalance. Pusher patients actively push toward their contralesional side due to a misperception of the body's orientation in relation to gravity. Although not every patient with CP suffers from spatial neglect (SN), both phenomena are highly correlated in right-hemispheric patients. The present study investigates whether peripersonal visuospatial functioning differs in neglect patients with versus without CP (NP+ vs. NP- patients). Method Eighteen right-hemispheric stroke patients with SN were included, of which 17 in a double-blind case-control study and 1 single case with posterior pushing to supplement the discourse. A computer-based visuospatial navigation task, in which lateralized deviation can freely emerge, was used to quantify visuospatial behavior. In addition, visuospatial orienting was monitored using line bisection. Results Significant intergroup differences were found. The NP+ patients demonstrated a smaller ipsilesional navigational deviation and more cross-over (contralesional instead of ipsilesional deviation) in long line bisection. As such, they demonstrated a contraversive (contralesionally directed) shift in comparison with the NP- patients. Conclusions These findings highlight the similarity between 2 systems of space representation. They are consistent with a coherence between the neural processing system that mainly provides for postural control, and the one responsible for nonpredominantly postural, visuospatial behavior.

To highlight methodological challenges in the design and conduct of randomized trials of surgical interventions and to propose strategies for addressing these challenges. This paper focuses on three broad areas: enrollment; intervention; and assessment including implications for analysis. For each challenge raised in the paper, we propose potential solutions. Enrollment poses challenges in maintaining investigator equipoise, managing conflict of interest and anticipating that patient preferences for specific treatments may reduce enrollment. Intervention design and implementation pose challenges relating to obsolescence, fidelity of intervention delivery, and adherence and crossover. Assessment and analysis raise questions regarding blinding and clustering of observations. This paper describes methodological problems in the design and conduct of surgical randomized trials and proposes strategies for addressing these challenges.

OBJECTIVES: We assessed whether a wheat bran extract (WBE) containing arabinoxylan oligosaccharides (AXOS) elicited a prebiotic effect and modulated gastrointestinal parameters in healthy preadolescent children upon consumption in a beverage. METHODS: This double-blind, randomized, placebo-controlled, crossover trial evaluated the effects of consuming WBE at 0 (control) or 5.0 g/day for 3 weeks in 29 healthy children (8-12 years). Faecal levels of microbiota, short-chain fatty acids, branched chain fatty acids, ammonia, moisture and faecal pH were assessed at the end of each treatment and at the end of a one-week run-in period. In addition, the subjects completed questionnaires scoring distress severity of 3 gastrointestinal symptoms. Finally, subjects recorded defecation frequency as well as stool consistency. RESULTS: Nominal faecal bifidobacteria levels tended to increase after 5 g/day WBE consumption (P = 0.069), whereas bifidobacteria expressed as percentage of total faecal microbiota was significantly higher upon 5 g/day WBE intake (P = 0.002). Additionally, 5 g/day WBE intake induced a significant decrease in faecal content of isobutyric acid and isovaleric acid (P 0.1). CONCLUSIONS: WBE is well tolerated at doses up 5 g/day in healthy children. In addition, intake of 5 g/day exerts beneficial effects on gut parameters, in particular increase of faecal bifidobacteria levels relative to total faecal microbiota, and reduction of colonic protein fermentation. ispartof: Journal of Pediatric Gastroenterology and Nutrition vol:58 issue:5 pages:647-653 ispartof: location:United States status: published

Background Everolimus and sunitinib have been approved for the treatment advanced pancreatic neuroendocrine tumors, but have not been compared to each other in a randomized trial and have not demonstrated prolonged overall survival compared to placebo. This study aimed to indirectly compare overall and progression-free among everolimus, sunitinib and placebo across separate randomized trials. Methods A matching adjusted indirect comparison was conducted in which individual patient data from the pivotal trial of everolimus (n = 410) were adjusted to match the inclusion criteria and average baseline characteristics reported for the pivotal trial of sunitinib (n = 171). Prior to matching, trial populations differed in baseline performance status and prior treatments. After matching, these and all other available baseline characteristics were balanced between trials. Results Compared to the placebo arm in the sunitinib trial, everolimus was associated with significantly prolonged overall survival (HR = 0.61, 95% CI = 0.38-0.98, p = 0.042). Compared to sunitinib, everolimus was associated with similar progression-free (hazard ratio for death (HR) = 0.84, 95% CI = 0.46–1.53, p = 0.578) and overall survival (HR = 0.81, 95% CI = 0.49–1.31, p = 0.383). Conclusion After adjusting for observed cross-trial differences, everolimus treatment was associated with longer overall survival than the placebo arm in the sunitinib trial for advanced pancreatic neuroendocrine tumors.

Asthma exacerbations are frequently triggered by rhinovirus infections. Both asthma and respiratory tract infection can activate haemostasis. Therefore we hypothesized that experimental rhinovirus-16 infection and asthmatic airway inflammation act in synergy on the haemostatic balance. 28 patients (14 patients with mild allergic asthma and 14 healthy non-allergic controls) were infected with low-dose rhinovirus type 16. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained before and 6 days after infection to evaluate markers of coagulation activation, thrombin-antithrombin complexes, von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator inhibitor type-1, endogenous thrombin potential and tissue factor-exposing microparticles by fibrin generation test, in plasma and/or BAL fluid. Data were analysed by nonparametric tests (Wilcoxon, Mann Whitney and Spearman correlation). 13 patients with mild asthma (6 females, 19-29 y) and 11 healthy controls (10 females, 19-31 y) had a documented Rhinovirus-16 infection. Rhinovirus-16 challenge resulted in a shortening of the fibrin generation test in BAL fluid of asthma patients (t = -1: 706 s vs. t = 6: 498 s; p = 0.02), but not of controls (t = -1: 693 s vs. t = 6: 636 s; p = 0.65). The fold change in tissue factor-exposing microparticles in BAL fluid inversely correlated with the fold changes in eosinophil cationic protein and myeloperoxidase in BAL fluid after virus infection (r = -0.517 and -0.528 resp., both p = 0.01). Rhinovirus-16 challenge led to increased plasminogen activator inhibitor type-1 levels in plasma in patients with asthma (26.0 ng/mL vs. 11.5 ng/mL in healthy controls, p = 0.04). Rhinovirus-16 load in BAL showed a linear correlation with the fold change in endogenous thrombin potential, plasmin-antiplasmin complexes and plasminogen activator inhibitor type-1. Experimental rhinovirus infection induces procoagulant changes in the airways of patients with asthma through increased activity of tissue factor-exposing microparticles. These microparticle-associated procoagulant changes are associated with both neutrophilic and eosinophilic inflammation. Systemic activation of haemostasis increases with Rhinoviral load. This trial was registered at the Dutch trial registry ( http://www.trialregister.nl ): NTR1677 .

Background: Salacia chinensis (S. chinensis) is widely distributed in India and Sri Lanka. Most of the species of genus Salacia are known to have effects on blood glucose levels; however, the effects of S. chinensis on glucose levels are seldom reported. Objective: To evaluate the oral hypoglycemic activity of NR- Salacia (1000 mg extract of S. chinensis) in healthy adults. Materials and Methods: Randomized, double-blind, placebo-controlled, cross-over study was conducted in healthy volunteers. Single dose of NR-Salacia (1000 mg extract of Salacia chinensis) and placebo were administered before carbohydrate-rich diet. A 6-point plasma glucose profile was performed at different time intervals up to 180 min. Results: NR-Salacia treatment significantly lowered plasma glucose level at 90 min, and the percentage reduction in glucose concentration was found to be 13.32 as compared to placebo group. A 33.85% decrease in the plasma glucose positive incremental area under curve (AUC) (0 to 180 min) was observed in comparison to placebo. No adverse events were recorded throughout the study period, except for some mild cases of abdominal discomforts like cramping and distention, vomiting, and headache in both placebo and NR-Salacia-treated groups. Conclusion: The study findings revealed that NR-Salacia lowered the post-prandial plasma glucose levels after a carbohydrate-rich meal and can be used as an oral hypoglycemic agent.

Made available in DSpace on 2019-09-12T16:57:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2013 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Objectives. The aim of this study was to evaluate the possible toxic effects of articaine and lidocaine on mental nerve, due to the increasing number of paresthesia cases after nerve blocks. Materials and methods. The drugs were injected in the anterior portion of mental nerve of 24 rats, divided into three groups: G1-4% articaine with 1: 100,000 epinephrine; G2-2% lidocaine with 1: 100,000 epinephrine and G3-plain 1: 100,000 epinephrine solution. These solutions were injected in the right side of the rat's mandible and the left side was used as control (0.9% saline solution). Previously to the injections, the animals were anesthetized with thiopental and, 24 h after the injections, their jaws were removed and submitted to routine histological techniques. A histopathological analysis was performed by optical microscopy. Results. An inflammatory infiltration was found around mental nerve, classified as intense for G3, moderate for G1 and light for both G2 and control groups. No injuries were found in nervous structure, despite the inflammatory reaction observed around it. Conclusion. The results suggest that articaine is not toxic to the nervous structure and further studies are necessary to explain the possible relation between articaine injection and paresthesia. [Baroni, Daniela Belisario; Franz-Montan, Michelle; Cogo, Karina; Berto, Luciana Aranha; Volpato, Maria Cristina; Groppo, Francisco Carlos] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Physiol Sci, UNICAMP, BR-13414903 Piracicaba, SP, Brazil [Franz-Montan, Michelle] Univ Estadual Campinas, Inst Biol, Dept Biochem, Campinas, SP, Brazil [Cogo, Karina] Universidade de Taubaté (Unitau), Sch Dent, Dept Oral Biol [Novaes, Pedro Duarte] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Morphol, Piracicaba, SP, Brazil

BackgroundPersistent symptoms after treatment of neuroborreliosis (NB) are well-documented, although the causative mechanisms are mainly unknown. The effect of repeated antibiotic treatment has not been studied in detail. The aim of this study was to determine whether: (1) persistent symptoms improve with doxycycline treatment; (2) doxycycline has an influence on systemic cytokine responses, and; (3) improvement of symptoms could be due to doxycycline-mediated immunomodulation.Methods/Design15 NB patients with persistent symptoms ≥6 months post-treatment were double-blindly randomized to receive 200 mg of doxycycline or a placebo for three weeks. After a six-week wash-out period, a cross-over with a three-week course of a placebo or doxycycline was conducted. The primary outcome measures were improvement of persistent symptoms assessed by neurological examinations, a symptom severity score and estimation of the quality of life. The secondary outcome measure was changes in systemic cytokine responses.ResultsAll 15 patients finished the study. No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events.DiscussionNo doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events. To conclude, in this pilot study, doxycycline-treatment did not lead to any improvement of either the persistent symptoms or quality of life in post-NB patients. Accordingly, doxycycline does not seem to be the optimal treatment of diverse persistent symptoms post-NB. However, the results need to be confirmed in larger studies.Trial registrationNCT01205464 (clinicaltrials.gov)

Validerat; 20120529 (anonymous)

Hintergrund Der HTA-Bericht (HTA = Health Technology Assessment) befasst sich mit Über-, Unter- oder Fehlversorgung in der Schmerztherapie. Chronische Schmerzen sind insbesondere in Deutschland ein häufiger Grund für Arbeitsausfälle und Frühberentung. Daher stellen sie neben einer Einschränkung der Lebensqualität für die Betroffenen eine beachtliche ökonomische Belastung für die Gesellschaft dar. Fragestellungen Welche Erkrankungen sind in Bezug auf die Schmerztherapie besonders relevant? Wie gestaltet sich die sozialmedizinische Versorgungslage hinsichtlich Schmerzinstitutionen in Deutschland? Wie ist die sozialmedizinische Versorgungssituation in der Schmerztherapie im internationalen Vergleich? Welche Effekte, Kosten bzw. Kosteneffekte lassen sich hinsichtlich der Schmerztherapie auf der Mikro-, der Meso- und der Makroebene darstellen? Bei welchen sozialmedizinischen Leistungen im Rahmen der Schmerztherapie besteht Unter-, Fehl-, Überversorgung bezüglich der Mikro-, der Meso- und der Makroebene? Welche sich auf die Kosten und/oder Kosteneffektivität auswirkenden medizinischen und organisatorischen Aspekte sind bei der Versorgung von Schmerz/chronischem Schmerz besonders zu beachten? Welchen Einfluss haben die individuellen Bedürfnisse des Patienten (Mikroebene) in unterschiedlichen Situationen der Schmerzbelastung (z. B. Palliativsituation) auf die Meso- und die Makroebene? Welche sozialmedizinischen und ethischen Aspekte sind bei der angemessenen Versorgung chronischer Schmerzen in den einzelnen Ebenen besonders zu berücksichtigen? Ist die Berücksichtigung dieser Aspekte geeignet, eine Über-, Unter- oder Fehlversorgung zu vermeiden? Sind juristische Fragestellungen im Versorgungsalltag chronischer Schmerzpatienten, vor allem in der Palliativversorgung, berücksichtigt? Auf welcher Ebene kann durch geeignete Maßnahmen einer Über-, Unter- oder Fehlversorgung vorgebeugt, diese verhindert und/oder behoben werden? Methodik Es erfolgt eine systematische Literaturrecherche in 35 Datenbanken. Eingeschlossen werden Übersichtsarbeiten, epidemiologische und klinische Studien sowie ökonomische Evaluationen, die über die Schmerztherapie und insbesondere die Palliativversorgung in den Jahren 2005 bis 2010 berichten. Ergebnisse Insgesamt werden 47 Publikationen berücksichtigt. Es wird Unterversorgung bei Akupunktur, Über- und Fehlversorgung hinsichtlich Opiatverschreibung und Überversorgung bei unspezifischen Brust- und bei chronischen Lendenwirbelsäulenschmerzen (LBP) beobachtet. Die Ergebnisse zeigen den Nutzen und die Kosteneffektivität interdisziplinären Vorgehens sowie multiprofessioneller Ansätze, multimodaler Schmerztherapie und sektorenübergreifender integrierter Versorgung. Über die Versorgungslage im Hinblick auf das Angebot an schmerztherapeutischen und palliativmedizinischen Einrichtungen können nur grobe Richtwerte ermittelt werden, da die Datenlage völlig unzureichend ist. Diskussion Aufgrund der weit gefassten Fragestellung enthält der Bericht zwangsläufig verschiedene Zielgrößen und Studiendesigns, die sich teilweise qualitativ stark unterscheiden. Im palliativen Bereich gewinnen stationäre Hospize und Palliativstationen sowie ambulante Hospizdienste zunehmend an Bedeutung. Palliativmedizinische Versorgung gilt als Grundrecht aller Sterbenskranker. Schlussfolgerung Der HTA-Bericht zeigt trotz der relativ hohen Anzahl an Untersuchungen aus Deutschland massive Defizite in der Versorgungsforschung. Basierend auf den Untersuchungen lässt sich ein weiterer Ausbau der ambulanten Schmerz- und Palliativversorgung empfehlen. Für alle beteiligten Berufsgruppen sind Verbesserungen der Aus-, Fort- und Weiterbildung anzustreben. Es bedarf einer eigenständigen empirischen Untersuchung zur Ermittlung der Über-, Unter- und Fehlversorgung in der Schmerzversorgung., Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland; 111; ISSN 1864-9645

Hintergrund Trotz verschiedenster Maßnahmen zur Prävention des riskanten Alkoholkonsums von Jugendlichen und jungen Erwachsenen ist ein Anstieg der Alkoholvergiftungen von Zehn- bis unter 20-Jährigen zu beobachten. Fragestellungen Es wird eine Übersicht der aktuellen Literatur sowie des deutschen föderalen Präventionssystems zu verhältnis- und verhaltenspräventiven Maßnahmen hinsichtlich riskanter Alkoholkonsummuster bei Kindern, Jugendlichen und jungen Erwachsenen, Identifikation effektiver Komponenten sowie die Beurteilung aktueller Präventionsprogramme hinsichtlich ihrer Wirksamkeit und Wirtschaftlichkeit erstellt. Methodik Es erfolgt eine systematische Literaturrecherche in 34 Datenbanken mit vier Schlagwortblöcken (Alkohol; Prävention; Behandlung; Kinder, Jugendliche, junge Erwachsene). Ergebnisse Es werden 401 Studien gefunden und 59 für den HTA-Bericht (HTA = Health Technology Assessment) ausgewählt. Die Mehrzahl der Studien stammt aus den USA, neun Studien sind aus Deutschland. Wirksam sind ein Familieninterventionsprogramm, personalisierte computergestützte Interventionen an Schulen, Colleges und Universitäten, kurze motivierende Interventionen und Elemente der Verhältnisprävention, z. B. die Erhöhung von Alkoholpreisen und Steuern. Diskussion Unter den 59 Studien sind drei Metaanalysen, 15 Reviews und 17 randomisierte kontrollierte Studien (RCT) und 18 Kohortenstudien. Trotz dieser insgesamt hohen Qualität der Studienanlage, leiden zahlreiche Studien unter methodischen Mängeln (fehlende Randomisierungen, fehlende oder kurze Nachkontrollen, unklar definierte Messparameter). Die Übertragbarkeit US-amerikanischer Ergebnisse auf Deutschland ist problematisch. Nur wenige Maßnahmen erzielen dauerhafte Reduktionen der Alkoholkonsumhäufigkeit oder -menge. Schlussfolgerung Der HTA-Bericht zeigt die Notwendigkeit der Entwicklung von spezifischen und zielgruppenorientierten Präventionsmaßnahmen für den deutschen Kontext. Dazu gehören die verbindliche Definition von Zielgrößen (Reduktion des Konsums, Änderung des Verhaltens) sowie eine verbindliche Definition und empirische Bestimmung riskanten Alkoholkonsums. Vor der Einführung von Präventionsmaßnahmen sollte deren Wirksamkeit eindeutig belegt sein. Gegenwärtig sind Präventionsmaßnahmen zur Reduktion oder Verhinderung von riskantem Alkoholkonsum in Deutschland nicht ausreichend auf ihre nachhaltige Wirksamkeit hin evaluiert., Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland; 112; ISSN 1864-9645

Background Despite many activities to prevent risky alcohol consumption among adolescents and young adults there is an increase of alcohol intoxications in the group of ten to twenty year old juveniles. Objectives This report gives an overview about the recent literature as well as the German federal prevention system regarding activities concerning behavioral and policy prevention of risky alcohol consumption among children, adolescents and young adults. Furthermore, effective components of prevention activities are identified and the efficiency and efficacy of ongoing prevention programs is evaluated. Methods A systematic literature review is done in 34 databases using Bool’sche combinations of the key words alcohol, prevention, treatment, children, adolescents and young adults. Results 401 studies were found and 59 studies were selected for the health technology assessment (HTA). Most of the studies are done in USA, nine in Germany. A family strengthening program, personalized computer based intervention at schools, colleges and universities, brief motivational interventions and policy elements like increase of prices and taxes proved effective. Discussion Among the 59 studies there are three meta-analyses, 15 reviews, 17 randomized controlled trials (RCT) and 18 cohort studies. Despite the overall high quality of the study design, many of them have methodological weaknesses (missing randomization, missing or too short follow-ups, not clearly defined measurement parameters). The transferability of US-results to the German context is problematic. Only a few prevention activities reach a sustainable reduction of frequency and/or amount of alcohol consumption. Conclusion The HTA-report shows the need to develop specific and target group focused prevention activities for the German situation. Essential for that is the definition of target goals (reduction of consumption, change of behaviour) as well as the definition and empirical validation of risky alcohol consumption. The efficacy of prevention activities should be proven before they are launched. At present activities for the reduction or prevention of risky alcohol consumption are not sufficiently evaluated in Germany concerning their sustainable efficacy., GMS Health Technology Assessment; 7:Doc04; ISSN 1861-8863

Background The HTA-report (HTA = Health Technology Assessment) deals with the primary prevention of cardiovascular diseases and diabetes mellitus type 2. In 2009 approximately 356,000 people died in Germany due to cardiovascular diseases. According to estimations about 6.3 million people are suffering from diabetes mellitus type 2. The interventions that are subsidized by the public health insurance are mainly focused on sufficient physical activities, healthy nutrition, stress management and the reduction of the consumption of addictive drugs and luxury food. Objectives Which lifestyle-related measures and/or programmes for primary prevention of cardiovascular diseases and of the metabolic syndrome are effective? To what extent will the health status be improved by these offers? To what extent will existing health resources and skills be strengthened by these offers? Are there any differences regarding the effectiveness among the interventions with respect to different settings or subgroups? Which lifestyle-related interventions and/or programmes for primary prevention of cardiovascular diseases and of the metabolic syndrome are sustainable and cost-effective? Which outcome parameters are in the view of the contributors decisive for the evaluation of the effectiveness? In the view of the contributor are there different values between the outcome parameters? In the view of the payers and other actors are there different values between the outcome parameters? Which ethical and juridical factors have to be considered? Which social and/or socio-economic parameters influence the use of the services and effectiveness? Methods A systematic literature research is done in 35 databases. For the period 2005 to 2010, reviews, epidemiological and clinical studies as well as economical evaluations which deal with primary prevention programmes regarding cardiovascular diseases or the metabolic syndrome are included. Results 44 publications meet the inclusion criteria. These studies confirm the effectiveness of the primary prevention programmes. Physical activity programs seem to have a stronger effect than nutrition programmes. Psychological programmes prove as well effectiveness, if they include cognitive behaviour therapy. The identified economical studies indicate that programmes for cardiovascular prevention can be conducted cost-effectively. Interventions that focus on the general population turn out to be particularly cost-effective and sustainable. Discussion There is a wide range of primary preventive effective lifestyle-related interventions with high evidence. The outcomes and results are consistent with the recommendations of the two identified evidence-based guidelines regarding the recommendations on lifestyle and healthy nutrition. Furthermore, the cost-effectiveness of primary prevention services is proven. With regard to the economical studies it is however worth noting that this result is based on very few publications. The transferability has to be critically assessed as the studies mainly originate from the American health system. Conclusion On the whole a comprehensive setting approach with educative, somatic, psychosocial and activity therapeutic components is recommended. The sustainability of a prevention intervention must be ensured from programme to programme. Long-term studies are necessary to make valid statements regarding the sustainable effectiveness: There is an essential deficit in the current practiced evaluation of the use of primary prevention services provided by the health insurance – mainly regarding the comprehensive setting approach – regarding the evidence-based evaluation of the prescribed preventive interventions. With regard to the ethical, social and economical evaluation the research situation is deficient. The situation has to be particularly analyzed for the socially deprived and one has to respond to their specific needs for prevention., GMS Health Technology Assessment; 7:Doc02; ISSN 1861-8863

Background “Patient-Reported Outcome” (PRO) is used as an umbrella term for different concepts for measuring subjectively perceived health status e. g. as treatment effects. Their common characteristic is, that the appraisal of the health status is reported by the patient himself. In order to describe the informative value of PRO in Health Technology Assessment (HTA) first an overview of concepts, classifications and methods of measurement is given. The overview is complemented by an empirical analysis of clinical trials and HTA-reports on rheumatoid arthritis and breast cancer in order to report on type, frequency and consequences of PRO used in these documents. Methods For both issues systematic reviews of the literature have been performed. The search for methodological literature covers the publication period from 1990 to 2009, the search for clinical trials of rheumatoid arthritis and breast cancer covers the period 2005 to 2009. Both searches were performed in the medical databases of the German Institute of Medical Documentation and Information (DIMDI). The search for HTA-reports and methodological papers of HTA-agencies was performed in the CRD-Databases (CRD = Centre for Reviews and Dissemination) and by handsearching the websites of INAHTA member agencies (INAHTA = International Network of Agencies for Health Technology Assessment). For all issues specific inclusion and exclusion criteria were defined. The methodological quality of randomized controlled trials (RCT) was assessed by a modified version of the Cochrane Risk of Bias Tool. For the methodological part information extraction from the literature is structured by the report’s chapters, for the empirical part data extraction sheets were constructed. All information is summarized in a qualitative manner. Results Concerning the methodological issues the literature search retrieved 158 documents (87 documents related to definition or classification, 125 documents related to operationalisation of PRO). For the empirical analyses 225 RCT (rheumatoid arthritis: 77; breast cancer: 148) and 40 HTA-reports and method papers were found. The analysis of the methodological literature confirms the role of PRO as an umbrella term for a variety of different concepts. The newest classification system facilitates the description of PRO measures by construct, target population and the method of measurement. Steps of operationalisation involve defining a conceptual framework, instrument development, exploration of measurement properties or, possibly, the modification of existing instruments. Seven out of 59 RCT analysing the effects of antibody therapy for rheumatoid arthritis define PRO as the primary endpoint, 38 trials utilize composite measures (ACR, DAS) and ten trials report clinical or radiological parameters as the primary endpoint. Six out of 123 chemotherapy trials for breast cancer define PRO as the primary endpoint, while 98 trials report clinical endpoints (survival, tumour response, progression) in their primary analyses. Discrepancies in the number of trials result from inaccurate specifications of endpoints in the publications. This distribution is reflected in the HTA-reports: while almost all reports on rheumatoid arthritis refer to PRO, this is only the case in about half of the reports on breast cancer. Conclusions As definition and classification of PRO are concerned, coherent concepts are found in the literature. Their operationalisation and implementation must be guided by scientific principles. The type and frequency of PRO used in clinical trials largely depend on the disease analysed. The HTA-community seems to pursue the utilization of PRO proactively – in case of missing data the need for further research is stated., GMS Health Technology Assessment; 7:Doc01; ISSN 1861-8863

Background The HTA-report (Health Technology Assessment) deals with over- and undertreatment of pain therapy. Especially in Germany chronic pain is a common reason for the loss of working hours and early retirement. In addition to a reduction in quality of life for the affected persons, chronic pain is therefore also an enormous economic burden for society. Objectives Which diseases are in particular relevant regarding pain therapy? What is the social-medical care situation regarding pain facilities in Germany? What is the social-medical care situation in pain therapy when comparing on international level? Which effects, costs or cost-effects can be seen on the micro-, meso- and macro level with regard to pain therapy? Among which social-medical services in pain therapy is there is an over- or undertreatment with regard to the micro-, meso- and macro level? Which medical and organisational aspects that have an effect on the costs and/or cost-effectiveness have to be particularly taken into account with regard to pain treatment/chronic pain? What is the influence of the individual patient's needs (micro level) in different situations of pain (e. g. palliative situation) on the meso- and macro level? Which social-medical and ethical aspects for an adequate treatment of chronic pain on each level have to be specially taken into account? Is the consideration of these aspects appropriate to avoid over- or undertreatment? Are juridical questions included in every day care of chronic pain patients, mainly in palliative care? On which level can appropriate interventions prevent over- or undertreatment? Methods A systematic literature research is done in 35 databases. In the HTA, reviews, epidemiological and clinical studies and economic evaluations are included which report about pain therapy and in particular palliative care in the years 2005 till 2010. Results 47 studies meet the inclusion criteria. An undertreatment of acupuncture, over- and misuse with regard to opiate prescription and an overuse regarding unspecific chest pain and chronic low back pain (LBP) can be observed. The results show the benefit and the cost-effectiveness of interdisciplinary as well as multi-professional approaches, multimodal pain therapy and cross-sectoral integrated medical care. Only rough values can be determined about the care situation regarding the supply of pain therapeutic and palliative medical facilities as the data are completely insufficient. Discussion Due to the broad research question the HTA-report contains inevitably different outcomes and study designs which partially differ qualitatively very strong from each other. In the field of palliative care hospices for in-patients and palliative wards as well as hospices for out-patients are becoming more and more important. Palliative care is a basic right of all terminally ill persons. Conclusion Despite the relatively high number of studies in Germany the HTA-report shows a massive lack in health care research. Based on the studies a further expansion of out-patient pain and palliative care is recommended. Further training for all involved professional groups must be improved. An independent empirical analysis is necessary to determine over or undertreatment in pain care., GMS Health Technology Assessment; 7:Doc03; ISSN 1861-8863

It is increasingly acknowledged that clinical interventions for young persons with mental disorders need to optimize social, vocational and physical functioning, and take into account developmental needs, rather than focusing only on the traditional target of psychiatric symptom change. However, few interventions for youth presenting to mental health services offer a coherent rationale for multi-faceted approaches that efficiently address all these targets. This trial uses two facilitated group therapy modules (social and physical activity) as a vehicle for promoting clinical, cognitive, social and vocational change. The modules are an adjunct to usual treatments offered to youth attending mental health services in Sydney, Australia. The design is a 2-arm, parallel group cross-over, randomized clinical trial (RCT) that examines the efficacy of this adjunctive youth early intervention program (called “YES”) for improving social, vocational, mental and physical health functioning in a trans-diagnostic sample of 120 young persons aged 14–25 years who are currently receiving a range of “usual treatments” for clinically diagnosed anxiety, affective and/or psychotic disorders. Individuals who provide written informed consent are offered 2 group therapy modules (each comprising 4 hours per week for 8 weeks) with a 3-week “pause” between modules. Randomization determines whether individuals commence with module A or module B. The sample will be assessed pre-randomization, and at week 1 and week 8 (after completion of the first module), and at week 11 (commencement of second module) and week 19 (completion of second module). Final follow–up is 1-year post trial entry. If the findings of this exploratory trial demonstrate benefits in the target domains, then it will be important to extend the research by undertaking: (a) a comparison of the YES program to a control intervention in a randomized controlled trial, (b) an explanatory study of putative mediators of change, and (c) a multi-center trial with a number of trained therapists offering the group modules combined with a longer follow-up period. Australian New Zealand Controlled Trial Registration: ACTRN1262400175673 , Date: 16 July 2015

N-of-1 trial is a type of clinical trial which has been applied in chronic recurrent conditions that require long-term non-curative treatment. In this type of trials, each patient will be randomly assigned to one of the treatment sequences and repeatedly crossed over two or more treatments of interests. Through this cross-comparing method (cross-over phase), investigator can identify an optimal treatment (medicine or therapy) for the patient and treat the patient with the optimal treatment in an extension phase. This design could efficiently reduce the placebo effect, which is often seen in clinical trials, and maximize the true treatment effect. This type of design has been used in some traditional Chinese medicine (TCM) clinical trials lately. However, it brings some challenges for collecting and analyzing the data. Research on statistical methodology of this type of design is rarely found in the literature. The goal of this research is to discuss the application of the N-of-1 design to personalized treatment studies. We will demonstrate a real study conducted in TCM and present some theoretical and simulation results. Electronic supplementary material The online version of this article (doi:10.1007/s12561-016-9165-9) contains supplementary material, which is available to authorized users.

Background The risk of venous thromboembolism (VTE) in women taking combined oral contraceptives (COCs) is attributed to changes in coagulation and fibrinolysis. Their impact may be greater in women with preexistent thrombophilic defects. Methods We assessed the effects of COCs on absolute VTE risk in women with single or multiple thrombophilic defects in a retrospective family cohort study. Female relatives of probands with VTE and hereditary deficiencies of protein S, protein C, or antithrombin were tested for known thrombophilic defects, including the index deficiency. Absolute incidences of VTE were compared in deficient vs nondeficient women, in deficient and nondeficient women who ever or never used COCs, and in deficient and nondeficient women with 0, 1, or more than 1 other thrombophilic defect during exposure to COCs. Results Of 222 women, 135 (61%) ever used COCs. Overall, annual incidences of VTE were 1.64% and 0.18% in deficient and nondeficient women, respectively; the adjusted relative risk was 11.9 (95% confidence interval, 3.9-36.2). The risk was comparable in deficient ever and never users (1.73% vs 1.54%). Annual incidences during actual COC use were 4.62% in deficient women and 0.48% in nondeficient women; the relative risk was 9.7 (95% confidence interval, 3.0-42.4). The incidence increased by concomitant thrombophilic defects, from 3.49% to 12.00% in deficient women and from 0% to 3.13% in nondeficient women. Conclusions Women with hereditary deficiencies of protein S, protein C, or antithrombin are at high risk of VTE during use of COCs, particularly when other thrombophilic defects are present. They have VTE at a younger age, but the overall risk is not increased by COCs.