Do effects of methylphenidate on cognitive performance last beyond treatment? A randomized placebo-controlled trial in boys and men with ADHD.

Methylphenidate (MPH) is the first-choice pharmacological treatment for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. However, it is unclear whether MPH affects cognitive development, while recent (pre-) clinical studies suggest effects on the developing brain. The present randomized, placebo-controlled trial aims to determine whether MPH has short-term, age-dependent effects on cognitive performance in ADHD after a 1-week washout. Effects of 16 weeks MPH treatment were assessed after a one-week washout on cognitive functioning. Boys (age=10-12) and men (age=23-40) with ADHD were assigned to MPH treatment (boys n=25, men n=24) or placebo (boys n=25, men n=24). Outcome measures were working memory, response inhibition, response speed, episodic memory, and delay aversion. Differences in task performances over time (pre-, mid-, and post-treatment, following a 1-week wash-out) were compared between age and treatment conditions with mixed ANOVAs. MPH improved working memory and response speed, but only during treatment. No lasting age*treatment effects were observed post intervention. Overall, the results from the present randomized, placebo-controlled trial show that the effects of MPH on cognition do not extend past treatment in children or adults. While treatment with MPH improves cognition during treatment, these effects appear transient after 16-weeks of treatment. (Title trial: "Effects of methylphenidate on the developing brain"; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3103).

Anterior versus posterior instrumentation for treatment of thoracolumbar tuberculosis : A meta-analysis.

BACKGROUND: To compare clinical and functional outcomes of anterior versus posterior debridement and spinal fixation for surgical treatment of thoracolumbar tuberculosis. METHODS: A computer-based online search of the Cochrane Library, PubMed, EMBase, Wanfang, VIP, and the CNKI database was performed. The methodological quality of included studies was evaluated, and data analyses were performed using RevMan 5.0 software (The Nordic Cochrane Centre, The Cochrane Collaboration Copenhagen, Denmark). RESULTS: Eleven trials were studied, with eight performed in China, two in Egypt, and one in India. The results showed significant differences between the two operative approaches in terms of correction of kyphotic angle and intraoperative blood loss, but not in terms of operation time, hospital stay, fusion time, and loss of correction at the final follow-up. CONCLUSION: The anterior and posterior approaches are equally good methods for treatment of thoracolumbar tuberculosis. The anterior approach results in less blood loss, whereas posterior instrumentation is better suited for correction of kyphotic angle.

Sertraline Versus Placebo in Patients with Major Depressive Disorder Undergoing Hemodialysis: A Randomized, Controlled Feasibility Trial.

BACKGROUND AND OBJECTIVES: Depression is common in patients on hemodialysis, but data on the benefits and risks of antidepressants in this setting are limited. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis at five United Kingdom renal centers completed the Beck Depression Inventory II. Those scoring ≥16 and not already on treatment for depression were invited to undergo diagnostic interview to confirm major depressive disorder. Eligible patients with major depressive disorder were randomized to receive the study medication-either sertraline or placebo. Outcomes included recruitment and dropout rates, change in the Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory II, and qualitative information to guide design of a large-scale trial. RESULTS: In total, 709 patients were screened and enrolled between April of 2013 and October of 2014; 231 (32.6%) had Beck Depression Inventory II scores ≥16, and 68 (29%) of these were already receiving treatment for depression. Sixty-three underwent diagnostic interview, 37 were diagnosed with major depressive disorder, and 30 were randomized; 21 completed the trial: eight of 15 on sertraline and 13 of 15 on placebo (P=0.05). Dropouts due to adverse and serious adverse events were greater in the sertraline group. All occurred in the first 3 months. Over 6 months, depression scores improved in both groups. Beck Depression Inventory II score fell from 29.1±8.4 to 17.3±12.4 (P<0.001), and Montgomery-Asberg Depression Rating Scale score fell from 24.5±4.1 to 10.3±5.8 (P<0.001). There were no differences between sertraline and placebo groups. CONCLUSIONS: Although small, this is the largest randomized trial to date of antidepressant medication in patients on hemodialysis. Our results highlight recruitment issues. No benefit was observed, but trial size and the substantial dropout render consideration of benefit inconclusive. A definitive trial could use shorter follow-up and include depressed patients already taking antidepressants.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III.

BACKGROUND AND PURPOSE: The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP). METHODS: In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. RESULTS: In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. CONCLUSIONS: ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Additive beneficial effects of valsartan combined with rosuvastatin in the treatment of hypercholesterolemic hypertensive patients.

BACKGROUND AND OBJECTIVES: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients. SUBJECTS AND METHODS: Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed. RESULTS: A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study. CONCLUSION: Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.

Additive Beneficial Effects of Valsartan Combined with Rosuvastatin in the Treatment of Hypercholesterolemic Hypertensive Patients

BACKGROUND AND OBJECTIVES: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients. SUBJECTS AND METHODS: Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed. RESULTS: A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study. CONCLUSION: Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.

Botulinum toxin type B in the spastic arm: a randomized, double-blind, placebo-controlled, preliminary study.

OBJECTIVE: To determine the efficacy and safety of 2 doses of botulinum toxin type B (rimabotulinumtoxinB, BoNT/B) in spastic upper limb muscles. DESIGN: Randomized, double-blind, placebo-controlled trial with a 3-month follow-up. SETTING: Tertiary care center. PARTICIPANTS: Referred sample of adult hemiparetic patients (N=24) with disabling elbow flexor overactivity after stroke or traumatic brain injury. INTERVENTIONS: Injection of 10,000U of rimabotulinumtoxinB (fixed 2500U dose into elbow flexors; n=8), 15,000U (5000U into elbow flexors; n=8), or placebo (n=8) into overactive upper limb muscles selected as per investigator's discretion. MAIN OUTCOME MEASURES: At 1 month postinjection, active range of elbow extension (goniometry; primary outcome); active upper limb function (Modified Frenchay Scale [MFS]); subjective global self-assessment (GSA) of arm pain, stiffness, and function; rapid alternating elbow flexion-extension movement frequency over the maximal range; elbow flexor spasticity grade and angle (Tardieu), and tone (Ashworth). RESULTS: No adverse effects were associated with either BoNT/B dose. Both doses improved active elbow extension versus placebo (+8.3°; 95% confidence interval, 1.1°-15.5°; analysis of covariance, P=.028). The high dose of BoNT/B also improved subject-perceived stiffness (P=.005) and the composite pain, stiffness, and function GSA (P=.017), effects that persisted 3 months from injection. No MFS change was demonstrated, although subjects with a baseline MFS <70/100 seemed more likely to benefit from BoNT/B. CONCLUSIONS: In this short-term study, BoNT/B up to 15,000U into spastic upper limb muscles, including the elbow flexors, was well tolerated and improved active elbow extension and subject-perceived stiffness.

Rethinking the continuum of stroke rehabilitation.

Suffering a stroke can be a devastating and life-changing event. Although there is a large evidence base for stroke rehabilitation in the acute and subacute stages, it has been long accepted that patients with stroke reach a plateau in their rehabilitation recovery relatively early. We have recently published the results of a systematic review designed to identify all randomized controlled trials (RCTs) where a rehabilitation intervention was initiated more than 6 months after the onset of the stroke. Of the trials identified, 339 RCTs met inclusion criteria, demonstrating an evidence base for stroke rehabilitation in the chronic phase as well. This seems at odds with the assumption that further recovery is unlikely and the subsequent lack of resources devoted to chronic stroke rehabilitation and management.

The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers.

INTRODUCTION: Ulcers as a result of diabetes mellitus are a serious problem with an enormous impact on the overall global disease burden due to the increasing prevalence of diabetes. Because of long hospital stays, rehabilitation, often required home care and the use of social services diabetic foot complications are costly. Therapy with growth factors could be an effective and innovative add-on to standard wound care. RESEARCH QUESTIONS: What is the benefit of therapies with growth factors alone or in combination with other technologies in the treatment of diabetic foot ulcer assessed regarding medical, economical, social, ethical and juridical aspects? METHODS: We systematically searched relevant databases limited to English and German language and publications since 1990. Cost values were adjusted to the price level of 2008 and converted into Euro. A review and an assessment of the quality of publications were conducted following approved methodical standards conforming to evidence-based medicine and health economics. RESULTS: We identified 25 studies (14 randomized controlled trials (RCT), nine cost-effectiveness analyses, two meta-analyses). The RCT compared an add-on therapy to standard wound care with standard wound care/placebo alone or extracellular wound matrix: in six studies becaplermin, in two rhEGF, in one bFGF, and in five studies the metabolically active skin grafts Dermagraft and Apligraf. The study duration ranged from twelve to 20 weeks and the study population included between 17 to 382 patients, average 130 patients. The treatment with becaplermin, rhEGF and skin implants Dermagraft and Apligraf showed in eight out of 13 studies an advantage concerning complete wound closure and the time to complete wound healing. Evidence for a benefit of treatment with bFGF could not be found. In four out of 14 studies the proportion of adverse events was 30% per study group with no difference between the treatment groups. The methodological quality of the studies was affected by significant deficiencies. The results showed becaplermin being cost-effective whereas no obvious statement can be made regarding Dermagraft and Apligraf because of diverging cost bases and incremental cost-effectiveness ratios. DISCUSSION: Differences in standard wound care are complicating the comparison of study results. Taking into consideration the small to very small sample sizes and other methodological flaws with high potential of bias, the validity of the results with regard to effectiveness and cost-effectiveness has to be considered limited. The duration of treatment and follow-up examinations is not long enough to assess the sustainability of the intervention and the surveillance of ulcer recurrences or treatment related adverse events like the development of malignancy. CONCLUSIONS: There are indications of an advantage for the add-on therapy with growth factors in diabetic foot ulcers concerning complete wound closure and the time to complete wound healing. Further more studies of high methodological quality with adequate sample sizes and sufficient follow-up periods are necessary also investigating patient-relevant parameters like the health-related quality of life, the acceptance and tolerance of the intervention in addition to clinical outcomes.