Alfaxalone provides reliable sedation for intradermal allergen testing in dogs and does not significantly affect results when compared to dexmedetomidine.

BACKGROUND: Dexmedetomidine (Dexmedetomidine hydrochloride-Dexdomitor; Zoetis) is the preferred sedative used for canine intradermal allergen testing (IDT) in the United States. Alfaxalone (Alfaxan Multidose; Jurox Animal Health) is a neuroactive steroid, and its effect on sedation and allergen reactivity scores is unknown. HYPOTHESIS/OBJECTIVES: We hypothesised that alfaxalone would produce an adequate level of sedation with fewer cardiovascular adverse effects and would not affect allergen reactivity scores or histamine wheal size compared to dexmedetomidine. MATERIALS AND METHODS: Twenty client-owned dogs were included in two groups: 10 atopic and 10 nonatopic. In a randomised, controlled, blinded, cross-over design all dogs underwent two modified IDT, 1-4 weeks apart, using intravenous dexmedetomidine (2.87-5.22 µg/kg) or alfaxalone (1.8-2.4 mg/kg). Anaesthetic parameters and sedation level were recorded over 25 min using a validated canine sedation scale described by Grint et al. (Small Anim Pract, 2009, 50, 62). Simultaneously, both objective and subjective reactivity scores were measured in technical triplicates at 10, 15 and 20 min. The modified IDT included eight allergens, histamine-positive and saline-negative controls. RESULTS: Alfaxalone produced a significantly higher sedation score across all time points (p < 0.05). All objective scores were significantly correlated to the corresponding subjective scores (Spearman R = 0.859, p < 0.0001). Sedative used did not significantly affect subjective allergen scores for nine atopic dogs (p > 0.05, 15 min). Sedative used did not affect the diameter of objective scores for individual allergens and histamine wheals (p > 0.05, 15 min). CONCLUSIONS AND CLINICAL RELEVANCE: Intravascular alfaxalone is an alternative sedative for IDT in dogs. Alfaxalone may be preferred to dexmedetomidine in some clinical scenarios as a result of having fewer cardiovascular adverse effects.

Novel Supreme Drug-Eluting Stents With Early Synchronized Antiproliferative Drug Delivery to Inhibit Smooth Muscle Cell Proliferation After Drug-Eluting Stents Implantation in Coronary Artery Disease: Results of the PIONEER III Randomized Clinical Trial.

BACKGROUND: Accelerated endothelial healing after targeted antiproliferative drug delivery may limit the long-term inflammatory response of drug-eluting stents (DESs). The novel Supreme DES is designed to synchronize early drug delivery within 4 to 6 weeks of implantation, leaving behind a prohealing permanent base layer. Whether the Supreme DES is safe and effective in the short term and can improve long-term clinical outcomes is not known. METHODS: In an international, 2:1 randomized, single-blind trial, we compared treatment with Supreme DES to durable polymer everolimus-eluting stents (DP-EES) in patients with acute and chronic coronary syndromes. The primary end point was target lesion failure-a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. The trial was designed to demonstrate noninferiority (margin of 3.58%) of the Supreme DES at 12 months compared with DP-EES (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776). RESULTS: From October 2017 to July 2019, a total of 1629 patients were randomly assigned (2:1) to the Supreme DES (N=1086) or DP-EES (N=543). At 12 months, target lesion failure occurred in 57 of 1057 patients (5.4%) in the Supreme DES group and in 27 of 532 patients (5.1%) in the DP-EES group (absolute risk difference, 0.32% [95% CI, -1.87 to 2.5]; Pnoninferiority=0.002]. There were no significant differences in rates of device success, clinically driven target lesion revascularization, or stent thrombosis at 12 months, and the safety composite of cardiovascular death and target vessel myocardial infarction was 3.5% versus 4.6% (hazard ratio, 0.76 [95% CI, 0.46-1.25]) with Supreme DES compared with DP-EES, although rates of combined clinically and non-clinically driven target lesion revascularization at 12 months were higher with Supreme DES. CONCLUSIONS: Among patients with acute and chronic coronary syndromes undergoing percutaneous coronary intervention, the Supreme DES proved to be noninferior to the standard DP-EES. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776.

Non-surgical treatment of mild to moderate peri-implantitis using an oscillating chitosan brush or a titanium curette-A randomized multicentre controlled clinical trial.

OBJECTIVES: This prospective, parallel-group, examiner-blinded, multicentre, randomized, controlled clinical trial aimed to assess the efficacy of an oscillating chitosan brush (OCB) versus titanium curettes (TC) on clinical parameters in the non-surgical treatment of peri-implantitis. MATERIAL AND METHODS: In five dental specialist clinics, 39 patients with one implant with mild to moderate peri-implantitis, defined as 2-4 mm radiographic reduced bone level, bleeding index (BI) ≥ 2, and probing pocket depth (PPD) ≥ 4 mm were randomly allocated to test and control groups, receiving OCB or TC debridement, respectively. Treatment was performed at baseline and three months. PPD, BI, and Plaque index (PI) were measured at six sites per implant and recorded by five blinded examiners at baseline, one, three, and six month(s). Pus was recorded as present/not present. Changes in PPD and BI were compared between groups and analysed using multilevel partial ordinal and linear regression. RESULTS: Thirty-eight patients completed the study. Both groups showed significant reductions in PPD and BI at six months compared with baseline (p < .05). There was no statistically significant difference in PPD and BI changes between the groups. Eradication of peri-implant disease as defined was observed in 9.5% of cases in the OCB group and 5.9% in the TC group. CONCLUSIONS: Within the limitations of this six-month multicentre clinical trial, non-surgical treatment of peri-implantitis with OCB and TC showed no difference between the interventions. Eradication of disease was not predictable for any of the groups.

Pelvic floor muscle training with and without supplementary KAATSU for women with stress urinary incontinence - a randomized controlled pilot study.

AIMS: To explore if adding occlusion training of a thigh (KAATSU) to low-intensity pelvic floor muscle training (PFMT) could increase effect of PFMT in women with stress urinary incontinence (SUI). METHODS: Single-blinded randomized controlled pilot study. Women with SUI and an ICIQ-UI-SF (International Consultation on Incontinence Questionnaire-Short form) score of ≥12 were randomized to a low-intensity PFMT program followed by KAATSU (KAATSU + PFMT) or to a low-intensity PFMT program without KAATSU (PFMT group), both performed four times a week for 12 weeks. PRIMARY OUTCOME: Change in the ICIQ-UI-SF score at a 12-week follow-up. SECONDARY OUTCOMES: a 3-day leakage diary, the PGI-I (Patient Global Index of Improvement scale), bother with KAATSU in a numeric rank scale and change in urethral opening pressure (UOP) measured with urethral pressure reflectometry (UPR) at rest, contraction and straining at the 12-week follow-up. RESULTS: Forty-one women with SUI and an ICIQ-UI-SF of 13 (range 12-16) were included. Fourteen in the KAATSU + PFMT and 17 in the PFMT group completed the study. Both groups had a significant and clinically relevant improvement of the ICIQ-UI-SF score and decrease in number of incontinence episodes with no significant between group differences. UOP did not increase significantly in either group. Bother with KAATSU was low but seven of 14 women expressed dislike with KAATSU. CONCLUSIONS: The added KAATSU protocol did not increase the effect of low-intensity PFMT and it was not well tolerated. While subjective effect was significant in both intervention groups this was not reflected in the UPR measures.

A brief treatment for fear of heights.

Objective To assess the effectiveness of a novel imaginal intervention for people with acrophobia. Methods The design was a randomized controlled trial with concealed randomization and blinded to other participants' intervention. The intervention was a single novel imaginal intervention session or a 15-min meditation. The setting was in Auckland, New Zealand. The participants were a convenience sample of the public with a score >29 on the Heights Interpretation Questionnaire (HIQ), a questionnaire validated against actual height exposure. The primary outcomes were the proportion of participants with a score <26 on the HIQ at eight weeks and difference between the HIQ scores between the two arms of the study. Results Ninety-eight participants (92%) returned their questionnaire and were included in the intention to treat analysis. The HIQ score <26 was 34.6% (18/52) in the intervention group and 15.2% (7/46) in the control group RR = 2.26, 95% CI (1.05, 4.95) and p = 0.028. The numbers needed to treat is six 95% CI (3 to 36). Participants with scores <26 report their fear of heights is very much improved. There was a 4.5-point difference in the HIQ score at eight weeks (p = 0.055) on the multiple regression analysis. Conclusions This is the first randomized trial of this novel imaginal intervention which is probably effective, brief, easily learnt, and safe. It may be worth considering doing this prior to some of the longer or more expensive exposure therapies. This study will be of interest to family doctors, psychiatrists, and psychologists.

Randomized controlled trial on the efficacy of new alcohol-free chlorhexidine mouthrinses after 8 weeks.

OBJECTIVES: To evaluate the efficacy of two alcohol-free antimicrobial mouthrinses in reducing plaque and gingivitis compared to an alcohol-containing rinse and toothbrushing alone. METHODS: One hundred and sixty healthy volunteers were enrolled in the randomized controlled trial. Participants were randomly and equally assigned to four groups: (i) toothbrushing + rinsing (0.06% CHX + 0.025% NaF, alcohol-containing rinse, positive control); (ii) toothbrushing + rinsing (0.06% CHX + 0.025% NaF, alcohol-free experimental rinse); (iii) toothbrushing + rinsing (0.06% CHX + 0.03% CPC + 0.025% NaF, alcohol-free experimental rinse); (iv) toothbrushing alone (negative control). At baseline, Quigley-Hein plaque index (QHI), modified proximal plaque index (MPPI), and papillary bleeding index (PBI) were recorded. All subjects brushed their teeth as usual during the study. Additionally, groups 1-3 rinsed twice daily. Eight weeks after baseline, indices were recorded again. anova with Bonferroni adjustment served for statistical analysis. RESULTS: One hundred and fifty-five participants were included into final analysis (i: n = 39, 2: n = 39, 3: n = 37, 4: n = 40). Experimental rinses (ii, iii) reduced QHI and MPPI to a higher extent than the negative control (iv), whereas no significant difference to the positive control was found. QHI: (i) 36.6%, (ii) 32.3%, (iii) 36.8%, (iv) 21.6%; MPPI: (i) 11.9%, (ii) 12.2%, (iii) 13.6%, (iv) 3.5%. For PBI, no statistically significant difference was found between groups: (i) 80.2%, (ii) 77.8%, (iii) 76.5% and (iv) 78.8%. CONCLUSIONS: With respect to QHI and MPPI, toothbrushing in combination with any rinse was more effective than toothbrushing alone. No statistically significant differences were found between the alcohol-free and the alcohol-containing control rinses.

Effectiveness of neurobic exercise program on memory performance in community-dwelling older adults with mild cognitive impairment: A randomized controlled crossover trial.

Background: Mild cognitive impairment (MCI) is an early stage of cognitive decline in individuals who are still able to perform their activities of daily living. They are at increased risk of developing dementia. Improving and maintaining cognitive functions are essential goals for older people with MCI to delay or prevent the transition to dementia. Objective: This study investigated the effect of the neurobic exercise program on memory performance among community-dwelling older adults with MCI. Methods: A single-blind, randomized, controlled, two-period crossover design was used. Thirty-two older adults who met the study criteria were randomly assigned to one of two sequence groups, A (n =16) and B (n = 16). Group A received three weeks of neurobic exercise, followed by a three-week washout period, and then three weeks of the traditional brain exercise program. Group B received the treatments in the reverse order but otherwise in a similar manner. Two aspects of memory performance were evaluated: subjective memory and objective memory. Blinded evaluators measured the outcomes four times at baseline, post-intervention (week 3), follow-up stage (week 7), and the end of the study (week 9). Descriptive statistics, independent t-tests, and repeated measures ANOVA were employed for data analyses. Results: For subjective memory, rmANOVA revealed a significant difference of within-subject (F1.437, 43.113 = 9.324, p <0.05) and interaction effect (time*group) (F1.437, 43.113 = 12.313, p <0.05) and also showed significant differences of within-subject (F1.794,53.811 = 28.931, p < .05) and interaction effect (time*group) (F1.794, 53.811 = 31.190, p <0.05) for objective memory. The study results revealed that the participants in both groups had significantly lower mean scores on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), indicating better or improved subjective memory. They also had significantly higher mean scores on the Common Objects Memory Test (COMT) after receiving the neurobic exercise program, indicating improvement in cognitive performance. Conclusion: The neurobic exercise intervention could improve subjective and objective memory among community-dwelling older adults with MCI more than those who received the traditional brain exercise program. Therefore, the neurobic exercise program can be used by nurses and multidisciplinary teams to enhance memory performance among older adults with MCI. Trial registration: Thai Clinical Trials Registry (TCTR) 20210326003.

Midline catheter tip position and catheter-related complications in antimicrobial therapy: A multi-center randomized controlled trial.

BACKGROUND: The use of midline catheters (MCs) in intravenous therapy has increased over the last few years; however, scientific evidence is scarce. The recommendations for its specific tip position and safe use in antimicrobial therapy are not well established, which increases the risk of catheter-related complications. OBJECTIVE: This study aimed to provide evidence for selecting MC tip positions for safe use in antimicrobial therapy. DESIGN: This prospective, randomized controlled trial compared catheter-related complications with different tip positions. Participants were assigned to three different catheter tip groups, and the relationship between the tip position and catheter-related complications was observed during antimicrobial therapy. SETTING: Multicenter trial based in intravenous therapy centers at six Chinese hospitals. PARTICIPANTS: A fixed-point continuous convenience sampling method was used to enroll 330 participants. Three different study groups with equal numbers of participants (n = 110) were established using a randomization technique. METHODS: The incidence of catheter-related complications and catheter retention time was compared among the three groups. The catheter measurement data between the three groups were compared using one-way ANOVA or the Kruskal-Wallis tests. Counting data were compared using chi-square tests, Fisher's exact tests, and Kruskal-Wallis tests. Post-hoc tests were conducted to compare the incidence of complications among the three groups. We followed a time-to-event analysis approach and used Kaplan-Meier curves and log-rank tests to analyze the relationship between catheter-related complications and different tip positions. RESULTS: The total incidence of catheter-related complications in Experimental Groups 1 and 2 as well as the control group were 10.09%, 17.98%, and 33.73%, respectively. Statistically significant differences existed between the groups (p < 0.0001). In pairwise comparisons of the three groups, significant differences were evident in the incidence of complications between Experimental Group 1 and the control group (RD 19.40%, confidence interval 7.71-31.09). No statistical significance in the incidence of complications between Experimental Group 1 and Experiment Group 2 (RD -4.93%, confidence interval -14.80-4.95) and in the incidence of complications between Experimental Group 2 and the control group (RD 14.47%, confidence interval 1.82-27.12) were noted. CONCLUSION: Catheter-related complications were reduced when the tip of the Midline Catheter was located in the subclavian or axillary vein of the chest wall. TRIAL REGISTRATION: NCT04601597(https://clinicaltrials.gov/ct2/show/NCT04601597). Registration date: September 1, 2020.

Association Between the Cool Temperature-dependent Suppression of Colonic Peristalsis and Transient Receptor Potential Melastatin 8 Activation in Both a Randomized Clinical Trial and an Animal Model.

Background/Aims: Several studies have assessed the effect of cool temperature on colonic peristalsis. Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensitive ion channel activated by mild cooling expressed in the colon. We examined the antispasmodic effect of cool temperature on colonic peristalsis in a prospective, randomized, single-blind trial and based on the video imaging and intraluminal pressure of the proximal colon in rats and TRPM8-deficient mice. Methods: In the clinical trial, we randomly assigned a total of 94 patients scheduled to undergo colonoscopy to 2 groups: the mildly cool water (n = 47) and control (n = 47) groups. We used 20 mL of 15°C water for the mildly cool water. The primary outcome was the proportion of subjects with improved peristalsis after treatment. In the rodent proximal colon, we evaluated the intraluminal pressure and performed video imaging of the rodent proximal colon with cool water administration into the colonic lumen. Clinical trial registry website (Trial No. UMIN-CTR; UMIN000030725). Results: In the randomized controlled trial, after treatment, the proportion of subjects with no peristalsis with cool water was significantly higher than that in the placebo group (44.7% vs 23.4%; P < 0.05). In the rodent colon model, cool temperature water was associated with a significant decrease in colonic peristalsis through its suppression of the ratio of peak frequency (P < 0.05). Cool temperature-treated TRPM8-deficient mice did not show a reduction in colonic peristalsis compared with wild-type mice. Conclusion: For the first time, this study demonstrates that cool temperature-dependent suppression of colonic peristalsis may be associated with TRPM8 activation.

Effect of Music in Reducing Pain during Hemodialysis Access Cannulation: A Crossover Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Pain during cannulation for vascular access is a considerable problem for patients with kidney disease who are undergoing hemodialysis. We examined whether listening to music can reduce cannulation pain in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a multicenter, single-blind, crossover, randomized trial of 121 patients who reported pain during cannulation for hemodialysis. We compared participants listening to "Sonata for Two Pianos in D Major, K.448" or white noise as control while undergoing the cannulation procedure. The cannulation operator was blinded to the intervention, and the hypothesized superiority of music over white noise was concealed during explanations to the participants. The primary end point was the visual analog scale score for cannulation pain independently evaluated by participants. RESULTS: The primary analysis was on the basis of the modified intention-to-treat principle. The median baseline visual analog scale pain score was 24.7 mm (interquartile range, 16.5-42.3). Median change of the visual analog scale pain score from the "no sound" to the music period was -2.7 mm (interquartile range, -9.2 to 3.6), whereas it was -0.3 mm (interquartile range, -5.8 to 4.5) from "no sound" to white noise. The visual analog scale pain score decreased when listening to music compared with white noise. (Adjusted difference of visual analog scale pain score: -12%; 95% confidence interval, -21 to -2; P=0.02.) There were no significant differences in the secondary outcomes of anxiety, BP, or stress assessed by salivary amylase (adjusted difference of visual analog scale anxiety score -8%, 95% confidence interval, -18 to 4; P=0.17). No intervention-related adverse events were reported. CONCLUSIONS: Listening to music reduced cannulation pain in patients on hemodialysis, although there was no significant effect on anxiety, BP, or stress markers.

Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.

Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.

Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial.

BACKGROUND: Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function. METHODS: This single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was -8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well. CONCLUSION: Patients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects.

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing.

Randomized Crossover Trial of Blood Volume Monitoring-Guided Ultrafiltration Biofeedback to Reduce Intradialytic Hypotensive Episodes with Hemodialysis.

BACKGROUND AND OBJECTIVES: Intradialytic hypotension (IDH) is associated with morbidity. The effect of blood volume-guided ultrafiltration biofeedback, which automatically adjusts fluid removal rate on the basis of blood volume parameters, on the reduction of IDH was tested in a randomized crossover trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a 22-week, single blind, randomized crossover trial in patients receiving maintenance hemodialysis who had >30% of sessions complicated by symptomatic IDH in five centers in Calgary, Alberta, Canada. Participants underwent a 4-week run-in period to standardize dialysis prescription and dry weight on the basis of clinical examination. Those meeting inclusion criteria were randomized to best clinical practice hemodialysis (control) or best clinical practice plus blood volume-guided ultrafiltration biofeedback (intervention) for 8 weeks, followed by a 2-week washout and subsequent crossover for a second 8-week phase. The primary outcome was rate of symptomatic IDH. RESULTS: Thirty-five participants entered, 32 were randomized, and 26 completed the study. The rate of symptomatic IDH with biofeedback was 0.10/h (95% confidence interval, 0.06 to 0.14) and 0.07/h (95% confidence interval, 0.05 to 0.10) during control (P=0.29). There were no differences in the rate or proportion of sessions with asymptomatic IDH or symptoms alone. Results remained consistent when adjusted for randomization order and study week. There were no differences between intervention and control in the last study week in interdialytic weight gain (difference [SD], -0.02 [0.8] kg), brain natriuretic peptide (1460 [19,052] ng/L), cardiac troponins (3 [86] ng/L), extracellular water-to-intracellular water ratio (0.05 [0.33]), ultrafiltration rate (1.1 [7.0] ml/kg per hour), and dialysis recovery time (0.43 [19.25] hours). CONCLUSION: The use of blood volume monitoring-guided ultrafiltration biofeedback in patients prone to IDH did not reduce the rate of symptomatic IDH events.

Randomized, Controlled Trial of the Effect of Dietary Potassium Restriction on Nerve Function in CKD.

BACKGROUND AND OBJECTIVES: Neuromuscular complications are almost universal in CKD by the time that a patient commences dialysis. Recent studies have indicated that chronic hyperkalemia may contribute to the development of neuropathy in CKD. This study was undertaken to determine whether dietary restriction of potassium intake may be a neuroprotective factor in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 24-month prospective, single-blind, randomized, controlled trial was undertaken in 47 consecutively recruited patients with stages 3 and 4 CKD. The intervention arm (n=23) was prescribed a diet focusing on potassium restriction to meet a monthly serum potassium level of ≤4.5 mEq/L, with oral sodium polystyrene sulfonate provided if dietary advice failed to achieve the target. The control arm (n=24) received dietary advice regarding general nutrition. The primary outcome was the change in the total neuropathy score evaluated by a blinded observer. Secondary outcomes included electrolyte levels, gait speed, neurophysiologic parameters, and health-related quality of life scores. Five patients withdrew before initiation of treatment, and final analysis consisted of n=21 in each group. RESULTS: There was a greater increase in total neuropathy score from baseline to final assessment in the control arm compared with the intervention arm (6.1±6.2-8.6±7.9 controls; 7.8±7.4-8.2±7.5 intervention; change 2.8±3.3-0.4±2.2, respectively; P<0.01). The intervention significantly reduced mean serum potassium compared with controls (4.6±0.1-4.8±0.1 mEq/L mean recorded every 6 months over the trial duration; P=0.03). There were no adverse changes in other nutritional parameters. Improved gait speed was also noted in the intervention arm compared with the control arm, with a mean increase of 0.15±0.17 m/s in the intervention group versus 0.02±0.16 m/s in the control group (P=0.01). CONCLUSIONS: Our results provide important preliminary evidence that dietary potassium restriction confers neuroprotection in CKD and should be confirmed in a larger multicenter trial.

A randomized trial of specialized versus standard neck physiotherapy in cervical dystonia.

BACKGROUND: Anecdotal reports suggested that a specialized physiotherapy technique developed in France (the Bleton technique) improved primary cervical dystonia. We evaluated the technique in a randomized trial. METHODS: A parallel-group, single-blind, two-centre randomized trial compared the specialized outpatient physiotherapy programme given by trained physiotherapists up to once a week for 24 weeks with standard physiotherapy advice for neck problems. Randomization was by a central telephone service. The primary outcome was the change in the total Toronto Western Spasmodic Torticollis Rating (TWSTR) scale, measured before any botulinum injections that were due, between baseline and 24 weeks evaluated by a clinician masked to treatment. Analysis was by intention-to-treat. RESULTS: 110 patients were randomized (55 in each group) with 24 week outcomes available for 84. Most (92%) were receiving botulinum toxin injections. Physiotherapy adherence was good. There was no difference between the groups in the change in TWSTR score over 24 weeks (mean adjusted difference 1.44 [95% CI -3.63, 6.51]) or 52 weeks (mean adjusted difference 2.47 [-2.72, 7.65]) nor in any of the secondary outcome measures (Cervical Dystonia Impact Profile-58, clinician and patient-rated global impression of change, mean botulinum toxin dose). Both groups showed large sustained improvements compared to baseline in the TWSTR, most of which occurred in the first four weeks. There were no major adverse events. Subgroup analysis suggested a centre effect. CONCLUSION: There was no statistically or clinically significant benefit from the specialized physiotherapy compared to standard neck physiotherapy advice but further trials are warranted.

Informative value of Patient Reported Outcomes (PRO) in Health Technology Assessment (HTA).

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.

Over-, under- and misuse of pain treatment in Germany.

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.

Estimulação magnética transcraniana de repetição: comparação da eficácia com a eletroconvulsoterapia / Repetitive transcranial magnetic stimulation: comparison of efficacy with electroconvulsive therapy

Os estudos publicados nos últimos anos sobre a utilização da estimulação magnética transcraniana de repetição (EMTr) têm sugerido significativas ações antidepressivas. Neste trabalho foi realizado um estudo comparativo da EMTr com a eletroconvulsoterapia (ECT) que é um método consagrado para o tratamento de transtornos depressivos. Foi feita, em primeiro lugar, uma extensa revisão a respeito destes dois métodos de tratamento não medicamentoso, expondo a sua história, a sua eficácia, as principais indicações, contra-indicações e efeitos colaterais, além dos possíveis mecanismos de ação, que ainda não estão completamente esclarecidos. A seguir foi realizado um ensaio clínico controlado, randomizado, simples-cego, comparando a eficácia de ambos para o tratamento da Depressão Maior unipolar refratária, sem sintomas psicóticos, com indicação de ECT. Também foi realizada uma avaliação dos efeitos cognitivos, especialmente da memória. Trinta e cinco pacientes foram incluídos. A eletroconvulsoterapia foi realizada com indução anestésica geral e relaxamento muscular. Foram feitas aplicações na posição unilateral direita com carga 4,5 vezes o limiar convulsígeno. A EMTr foi aplicada no córtex pré-frontal dorso-lateral esquerdo com intensidade de 100% do limiar motor. Os pacientes receberam 20 sessões (cinco dias por semana por quatro semanas), com 25 séries de estimulação por dia (com freqüência de 10 Hz por 10 segundos, com intervalos de 20 segundos). As escalas de avaliação foram aplicadas nos tempos basal, após duas semanas de tratamento e após quatro semanas de tratamento. Ambos os tratamentos tiveram eficácia equivalente, com uma taxa de redução média dos escores na escala de Hamilton para depressão de 42 %, uma resposta clínica de 46 % e uma taxa de remissão de 14%. A EMTr apresentou um perfil mais benigno de efeitos colaterais (cefaléia em 1 %). A ECT resultou em cefaléia (em 20 %) e náuseas (em 10%).Não houve diferença nos efeitos cognitivos...

Studies published over the past few years suggest that repetitive transcranial magnetic stimulation (rTMS) may have significant antidepressant actions. This work performs a comparison between rTMS and electroconvulsive therapy (ECT), an established method to treat depression disorders. First there was an extensive review on the knowledge of both non pharmacological treatments including their history, efficacy, main indications, contraindications and side effects, in addition to the possible mechanisms of action, not yet fully understood. After that, a controlled randomized, single-blind clinical trial was conducted, comparing the efficacy to treat unipolar resistant nonpsychotic major depression that were referred to receive ECT. An evaluation of cognitive effects was also performed, specially memory effects. Thirty five patients were included. Electroconvulsive therapy was performed with general anesthesia and muscular relaxation. Right unilateral electrodes positioning was used, with a charge 4.5 times the convulsive threshold. rTMS was performed over the left dorsolateral prefrontal cortex at 100% motor threshold. Patients were treated with 20 sessions (five times per week for four weeks) with 25 trains a day (frequency of 10 Hz, duration of 10 seconds with 20 seconds intertrain interval). Patients were evaluated at baseline, after two weeks and after four weeks of either treatment. Both groups were equivalent in efficacy, showing a means of reduction on Hamilton depression rating scale of 42%, an overall clinical response of 46% and a remission rate of 14%. rTMS showed a more benign profile regarding side effects (headache on 1%). ECT induced headache (20%) and nausea (10%). No cognitive effects were observed on either treatments. This study adds to the growing literature supporting an antidepressant effect for rTMS, similar to ECT on patients with unipolar nonpsychotic major depression.