Greater Treatment Effect Research Articles

Who Should Have Surgery for an Intervertebral Disc Herniation?

Combined prospective randomized controlled trial and observational cohort study of intervertebral disc herniation (IDH), an as-treated analysis.To determine modifiers of the treatment effect (TE) of surgery (the difference between surgical and nonoperative outcomes) for intervertebral disc herniation (IDH) using subgroup analysis.The Spine Patient Outcomes Research Trial demonstrated a positive surgical TE for IDH at the group level. However, individual characteristics may affect TE. No prior studies have evaluated TE modifiers in IDH.IDH patients underwent either discectomy (n = 788) or nonoperative care (n = 404) and were analyzed according to treatment received. Thirty-seven baseline variables were used to define subgroups for calculating the time-weighted average TE for the Oswestry Disability Index (ODI) across 4 years (TE = ΔODI(surgery) -ΔODI(nonoperative)). Variables with significant subgroup-by-treatment interactions (P < 0.1) were simultaneously entered into a multivariate model to select independent TE predictors.All analyzed subgroups improved significantly more with surgery than with nonoperative treatment (P < 0.05). In minimally adjusted univariate analyses, being married, absence of joint problems, worsening symptom trend at baseline, high school education or less, older age, no worker's compensation, longer duration of symptoms, and an SF-36 mental component score (MCS) less than 35 were associated with greater TEs. Multivariate analysis demonstrated that being married (TE, -15.8 vs. -7.7 single, P < 0.001), absence of joint problems (TE, -14.6 vs. -10.3 joint problems, P = 0.012), and worsening symptoms (TE, -15.9 vs. -11.8 stable symptoms, P = 0.032) were independent TE modifiers. TEs were greatest in married patients with worsening symptoms (-18.3) vs. single patients with stable symptoms (-7.8).IDH patients who met strict inclusion criteria improved more with surgery than with nonoperative treatment, regardless of specific characteristics. However, being married, without joint problems, and worsening symptom trend at baseline were associated with a greater TE.

Biofeedback therapy for stress urinary incontinence: is urodynamic assessment necessary?

Dear Editor In the recent issue of Nephro-Urology Monthly Journal, Bayrak et al. (1) presented a prospective, single institutional study to evaluate the effects of biofeedback therapy (BFT) on stress urinary incontinence (SUI) in women. The International Consultation on Incontinence Questionnaire – Short Form (ICIQ-SF) was utilized and ICIQ-SF scores were measured to evaluate the severity of their urinary incontinence symptoms. In addition, urodynamic investigation was performed and its parameters were examined. The results of this study demonstrated the remarkable improvement of ICIQ-SF scores following BFT while urodynamic parameters were not affected. The authors concluded that BFT is a good alternative to surgical treatment of SUI and urodynamic assessment is not recommended prior to BFT, as the values of urodynamic parameters did not change following BFT. The subject matter of this study is important and highly relevant as BFT has been intensively studied in women with urinary incontinence. Its potential efficacy has also been suggested in men, (2) and even in children (3) with urinary incontinence. A previous Cochrane systematic review and meta-analysis study (4) that critically evaluated 12 randomized control trials in the management of female urinary (stress, urge, and mixed) incontinence, demonstrated that pelvic floor muscle training (PFMT) alone gave better improvement of symptoms and continence specific quality of life, when compared to other treatments (no treatment, placebo, sham treatment, or other inactive control treatments), particularly in women with SUI alone, who seemed to have a greater treatment effect. In the management of SUI, BFT is a common adjunct used along with pelvic floor muscle training (PFMT) to improve training performance. Previous evidence also supported the possibility that BFT may provide benefits in addition to PFMT in women with urinary incontinence, the question remains as to what will be the impact of this study in supporting the benefits of using BFT for SUI. With respect to the important messages delivered, the methodology utilized requires critical appraisal in the absence of treatment control. Therefore, the improvement of ICIQ-SF may not only be affected by BFT, but may also be influenced by other behavioral treatments. Regardless of its limitations, the results support what has been demonstrated in other previous studies, as summarized by Herderschee et al. (5) in a more recent Cochrane systematic review and meta-analysis study. Among the 17 control trials and contributing data that was evaluated, they concluded that BFT in addition to PMFT may provide benefits in women with urinary incontinence. Nevertheless, further research is required as suggested by the authors, to differentiate whether the BFT, or some other differences between the trials, such as more contact with health professionals caused the beneficial effects. Unnecessary urodynamic evaluation prior to BFT as suggested in this study, is also questionable, if only based on this trial. As a matter of fact, urodynamic study is not routinely used prior to conservative or non-surgical treatment for SUI. Recently, urodynamic investigation has become controversial even for use prior to the surgical treatment of SUI. The inconclusive results regarding its ability to predict the outcome following surgery, due to the limited number of good clinical evidence, was considered to be one of the reasons. In contrast to the unchanged urodynamic parameters (bladder capacity, detrusor instability, sensation of the bladder, and residual urine volume) following BFT as reported in this trial, Capelini et al. (6) observed a significant increase in Valsalva leak point pressure, cystometric capacity and bladder volume at first desire to void following BFT. However, only a small number of patients (14) with SUI were included and accordingly, that may decrease the study’s reliability. Although both studies applied different types of validated questionnaire (ICIQ-SF versus King’s Health Questionnaire), the improvement in symptoms was consistent in both studies. As only a few studies have reported the effect of BFT on voiding performance, which focused on urodynamic assessment, this study represents a valuable and noteworthy addition to the field. Moreover, this trial also highlights an important point regarding the efficacy of BFT in patients who bordered on obese. The present trial and previous series provide us with valuable evidence that has rarely been found in other series.

Inflammatory Biomarkers and Clinical Remission in Patients with Active Crohnʼs Disease: Results from PRECiSE 2

Purpose: Low baseline (BL) C-reactive protein (CRP) concentrations (<10 mg/L) are associated with high placebo response rates (47%-60%) in patients (pts) with active Crohn's disease (CD)1,2 and greater treatment effects with anti-TNF agents vs placebo have been reported in pts with higher BL CRP concentrations.1 PRECiSE 2 (P2)3 has demonstrated efficacy for the anti-TNF certolizumab pegol (CZP) in pts with active CD. This post hoc analysis of P2 data aimed to determine the value of biomarkers in predicting longer term remission. Methods: In P2 (NCT00152425), pts who responded to CZP induction (n=428) were randomized to continuous therapy with CZP or placebo during Wks 6-26. BL CRP and fecal calprotectin (FC) concentrations were determined at Wk 0 and the Wk 26 remission rates were stratified according to CRP and FC cut-offs and analyzed for the difference between CZP and placebo remission rates (remission delta). Results: The highest remission deltas were achieved in pts on continuous CZP with high BL CRP or FC vs patients on placebo (Table). High levels of both CRP and FC at BL corresponded with lower absolute remission rates for both placebo and CZP group but still with preservation of a numerically high remission delta. In pts with no elevation in either CRP or FC, the Wk 26 remission rate was the highest observed among all of the placebo groups. CZP plasma concentrations were generally higher in patients with low levels of both CRP and FC and in patients with high FC but low CRP and conversely, were generally lower in patients with high levels of both CRP and FC and in patients with high CRP but low FC.TableConclusion: In CD pts receiving CZP, high levels of both CRP and FC coincide with lower remission rates; conversely, low levels of CRP and FC coincide with high levels of remission in both CZP- and placebo-treated patients. High CRP, with or without high FC, may be associated with lower CZP plasma concentrations. These data suggest that either high CRP or high FC levels at BL may be useful in predicting long-term remission and indicate that further work on understanding normalization of biomarkers in CD by adjusting anti-TNF therapy is warranted.

Patient Characteristics and Treatment Outcome in Functional Anorectal Pain

Functional anorectal pain occurs in the absence of any clinical abnormality. It is common and disabling; it has previously been reported in only a few studies involving small patient numbers. This study aimed to report the clinical characteristics and treatment outcomes for patients with functional anorectal pain. Patient demographics, clinical history, and tests results for all referrals for anorectal physiological testing between 1997 and 2009 were prospectively recorded. For patients with functional anorectal pain, further information was gained from clinical notes. Clinical history, anorectal physiology, and radiological imaging data were recorded for all patients; treatment outcome was noted for patients treated and followed up at the present unit. One hundred seventy patients, 99 female, with a median age of 48 years (range, 18-86), were studied. Patients were classified as having chronic proctalgia (pain duration ≥20 min, 158 patients) or proctalgia fugax (pain duration <20 min, 12 patients). The pain was most commonly located in the anal canal (90%) and aggravated by defecation or sitting (66%). A third of patients had a history of psychological disturbance. Internal anal sphincter thickness correlated with resting anal pressures. Patients with proctalgia fugax had a higher internal anal sphincter thickness and resting pressure than patients with chronic proctalgia, whereas patients with a family history of similar symptoms were more likely to have proctalgia fugax and higher resting pressures and internal anal sphincter thickness compared with those without a family history of these symptoms. Patients referred for treatment underwent a range of interventions including biofeedback (29 patients, 17 improved), tricyclic antidepressants (26 patients, 10 improved), Botox injection (9 patients, 5 improved), and sacral nerve stimulation (3 patients, 2 improved). Biofeedback had the greatest treatment effect, especially in patients with defecatory dysfunction. Biofeedback is beneficial in the subset of patients with functional anorectal pain and difficulty with defecation. Tricyclic antidepressants, Botox, and sacral nerve stimulation may also have a role.

Rivastigmine transdermal patch and capsule in Alzheimer's disease: influence of disease stage on response to therapy

The cholinesterase inhibitor rivastigmine is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). This exploratory, hypothesis-forming analysis assessed response to rivastigmine according to severity of dementia at baseline. This was a retrospective analysis of a large randomized, placebo-controlled trial (ENA713D2320). AD patients treated with 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, rivastigmine capsule (12 mg/day), or placebo were stratified according to baseline Mini-Mental State Examination (MMSE) scores: ≥7 to ≤12 (severe disease), ≥13 to ≤15 (moderately severe), ≥16 to ≤18 (moderate), or ≥19 to ≤25 (mild to moderate). Changes from baseline at Week 24 on Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) were assessed. Based on baseline MMSE scores, 141, 228, 333, and 348 patients had severe, moderately severe, moderate, and mild to moderate dementia. Worsening of ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients receiving placebo were greater in patients with more severe dementia. Significant improvements versus placebo were seen with rivastigmine patch and/or capsule on ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients with severe, moderately severe, and moderate AD (all p < 0.05). However, no significant improvements were seen in rivastigmine-treated patients with mild to moderate AD. Rivastigmine benefits AD patients across dementia stages. Similar to previous cholinesterase inhibitor studies, greatest treatment effects with rivastigmine patch and capsule were seen in patients with more advanced dementia, most likely driven by greater placebo decline in this population.

Determining the Optimum Outcome for Trials Evaluating Symptom Improvement in Functional Gastrointestinal Disorders

Purpose: Functional bowel diseases are common and therapy remains suboptimal. Trials often use how much the patients' symptoms have improved as an outcome but the optimum cut off that defines improvement is unclear. This has hampered the development of treatments for functional dyspepsia (FD) and irritable bowel syndrome (IBS) and an FDA report has highlighted the need for validated, well-defined outcome measures in these disorders. We have evaluated whether the stringency of definition of symptom improvement (e.g. improvement in symptoms versus absence of symptoms) impacts on the outcome of trials in a systematic review. Methods: We identified all placebo controlled randomized controlled trials (RCTs) that evaluated pharmacological therapy in FD or IBS from Cochrane systematic reviews. Eligible studies reported on pain or global symptom improvement as a dichotomous outcome and gave at least two cut-off points with different stringencies for symptom improvement. Interventions where there were four or more eligible RCTs were synthesized using a random effects model with relative risk (RR) of remaining symptomatic as the outcome. Heterogeneity was determined by the I squared statistic. Results: 132 RCTs were identified, 95 studies were excluded and 37 were eligible. There were 5 different intervention/functional disease combinations. In all cases the most stringent definition of symptom improvement resulted in a greater treatment effect and 2/5 comparisons the more stringent definition gave a statistically significant result in favor of active treatment whilst the less stringent definition did not (table). In 3/5 cases the more stringent definition gave less heterogeneity between studies, in one case the heterogeneity remained very similar and in one case the less stringent definition resulted in the least heterogeneity (Table).Table: [1334] Outcomes according to stringency of symptomatic improvementsConclusion: A systematic review of available data suggests that a stringent definition of symptoms, such complete absence of symptoms, is the best at differentiating active treatment from placebo in RCTs of functional gastrointestinal diseases and should be considered as the primary outcome in future trials of therapy. Disclosure: Dr Paul Moayyedi has been on the advisory boards for AstraZeneca, Nycomed and Johnson and Johnson. He has also accepted speaker fees from these companies as well as Wyeth and Takeda. His chair is funded in part by an unrestricted donation given to McMaster University by AstraZeneca. Dr Grigorios Leontiadis has acted as a consultant for AstraZeneca and Axcan Pharma and has received speaking honoraria from AstraZeneca, Sanofi-Aventis, Janssen-Cilag, and GlaxoSmithKline. Alexander Ford - None. Dixuan Zhang - None. Racquel Simpson - None. Karen Dearness - None.

Findings regarding reduced prevalence with hepatitis C treatment are still valid: A reply to Vickerman et al.

Vickerman et al. (this issue) replicate our hepatitis C (HCV) treatment model, with variation to two parameters: the underlying prevalence of HCV and the percentage that fail HCV treatment. Given these changes to the parameters it is unsurprising that they find a greater treatment effect. Pleasingly, however, it is in the same direction as our result, adding confidence to our findings. Dialogue about underlying assumptions, alternate parameters and model construction is encouraging because we believe that this can enhance model veracity and provide more reliable estimates upon which health policy can be formulated. Unfortunately Vickerman et al. do not model what we see as the central policy question of our two-group model: the impact on HCV prevalence of providing HCV treatment to injecting drug users in methadone maintenance versus those not in methadone maintenance treatment. Our original findings suggest that policy should preferentially direct treatment to current injectors.

Alterations in Speed of Squat Movement and the Use of Accommodated Resistance Among College Athletes Training for Power

The purpose of this study was to assess the effect of heavy/slow movements and variable resistance training on peak power and strength development. Forty-eight National Collegiate Athletic Association (NCAA) Division I athletes (age: 21.4 +/- 2.1 years, all men) were recruited for this 12-week training intervention study. Maximum strength and jumping power were assessed before and after the training program. Athletes were randomly assigned to 1 of 3 training groups: heavy resistance/slow movement (Slow), lighter resistance and fast movement (Fast), or fast movements with accommodated resistance (FACC). All training groups performed similar training programs comprising free weight resistance training with lower-body compound exercises. The only difference among the training interventions was the speed at which subjects performed the squat exercise and the use of bands (Slow group: 0.2-0.4 meters/second; Fast group: 0.6-0.8 meters/second; FACC group trained 0.6-0.8 meters/second with the addition of accommodated resistance in the form of large elastic bands). Post-test data revealed a significant difference between power improvements between the Slow and FACC groups (p = 0.02). Percent increases and effect sizes (ES) demonstrated a much greater treatment effect in the FACC group (17.8%, ES = 1.06) with the Fast group (11.0%, ES = 0.80) adapting more than the Slow group (4.8%, ES = 0.28). The FACC and Slow groups improved strength comparatively (FACC: 9.44%, ES = 1.10; Slow: 9.59%, ES = 1.08). The Fast group improved strength considerably less, 3.20% with an effect size of only 0.38. Variable resistance training with elastic bands appears to provide greater performance benefits with regard to peak force and peak power than heavy, slow resistance exercise. Sports conditioning professionals can utilize bands, and high-speed contractions, to increase power development.

Comorbidity and overall survival (OS) in cetuximab-treated patients with advanced colorectal cancer (ACRC)—Results from NCIC CTG CO.17: A phase III trial of cetuximab versus best supportive care (BSC)

4074 Background: The interplay between comorbidity, age and performance status (PS) as predictors of outcome in ACRC is not well described. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. Methods: Comorbidity was independently evaluated by 2 physicians using the Charlson Comorbidity Index (CCI), a previously validated measure of comorbidity based on the presence or absence of index medical conditions weighted according to their affect on mortality. CCI score was correlated with demographic data (age, gender), PS, site of primary, time from diagnosis to randomization, body mass index, hemoglobin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine clearance, K-ras status and OS. Results: 572 patients were included. 41% were ≥65 years and 25% had comorbidities at randomization. CCI score was 1 in 21% and ≥ 2 in 4%. In multivariate analysis (MVA) of all covariates, only older age (≥65 years) was associated with greater comorbidity (p=0.005). OS was different among 3 comorbidity groups (CCI score 0, 1, ≥ 2) in univariate analysis (median OS 4.9 vs 5.9 vs 4.8 months;, logrank p=0.04) but not in MVA. Conversely, lower PS remained associated with better OS in MVA (HR 1.96 for PS=2 vs. PS=0, p&lt;0.0001). Age was not associated with OS (p=0.11). Other factors significantly associated with OS in MVA included time from diagnosis to randomization, LDH, ALP, hemoglobin, Kras status and cetuximab treatment. In the BSC arm, comorbidity was not associated with OS in MVA (HR 0.83 CCI 1 vs. CCI0, p=0.26 and HR 0.90 for CCI2 vs. CCI0, p=0.78) suggesting comorbidity is not prognostic in this setting. Patients with higher CCI score had a nonsignificant trend toward greater treatment effects. Patients ≥65 years had less gr≥3 vomiting (1.8 vs 7.9%, p=0.034) but more dyspnea (24.5 vs 11.2%, p=0.005). Patients with higher CCI scores had less vomiting (p=0.008) but more non-neutropenic infection (p=0.012). Conclusions: In this clinical trial, comorbidity and age were not independent predictors of survival, highlighting the difference between comorbidity and PS. [Table: see text]

Acupuncture as an adjunct to standard treatment for pelvic girdle pain in pregnant women: randomised double‐blinded controlled trial comparing acupuncture with non‐penetrating sham acupuncture

To investigate whether acupuncture has a greater treatment effect than non-penetrating sham acupuncture in women with pelvic girdle pain (PGP) during pregnancy. Randomised double-blinded controlled trial. East Hospital, Gothenburg, and 25 antenatal primary care units in the region of Västra Götaland, Sweden. A total of 115 pregnant women with a clinical diagnosis of PGP who scored > or =50 on a 100-mm visual analogue scale (VAS). Women were randomly allocated to standard treatment plus acupuncture or to standard treatment plus non-penetrating sham acupuncture for 8 weeks. Main outcome measure was pain. Secondary outcomes were frequency of sick leave, functional status, discomfort of PGP, health-related quality of life and recovery of severity of PGP as assessed by the independent examiner. After treatment, median pain decreased from 66 to 36 in the acupuncture group and from 69 to 41 in the non-penetrating sham group (P = 0.493) as assessed on a VAS. Women in the acupuncture group were in regular work to a higher extent than women in the sham group (n = 28/57 versus 16/57, P = 0.041). The acupuncture group had superior ability to perform daily activities measured with the disability rating index (DRI) (44 versus 55, P = 0.001). There were no significant differences in quality of life, discomfort of PGP and recovery from severity of PGP between the groups. Acupuncture had no significant effect on pain or on the degree of sick leave compared with non-penetrating sham acupuncture. There was some improvement in performing daily activities according to DRI. The data imply that needle penetration contributes to a limited extent to the previously reported beneficial effects of acupuncture.

Effect of intrauterine treatment with cephapirin on the reproductive performance of seasonally calving dairy cows at risk of endometritis following periparturient disease

To determine the effect of intrauterine cephapirin (0.5 g) treatment on the reproductive performance of cows diagnosed as at risk of developing endometritis. Cows (n = 1325) from 17 seasonal calving dairy herds were enrolled if they had been calved for more than 6 days and had a condition that placed them at risk of endometritis. Half were treated with intrauterine cephapirin at an examination performed 28-37 days prior to mating start date (MSD). Cows were scored for body condition, their vaginal discharge was scored using vaginoscopy (VV), and the uterus and ovaries were assessed by rectal palpation. Overall, there was no significant treatment effect on reproductive performance. In 945 modified at risk (MAR) cows the effect of treatment varied with the calving to treatment interval (CTI) and VV status. For the subset of 229 MAR cows with CTI < or = 28 days, treatment improved the proportions of first-service conception (OR 3.1; P < 0.01) and 6-week in-calf (OR 2.1; P < 0.05), and reduced the mean MSD to conception interval by 20 days (P < 0.05). The difference was greater in cows with a positive VV score (1-3). Treated VV-negative cows with CTI > 48 days had a reduced proportion of cows in-calf by 6 weeks (OR 0.58; P = 0.056) compared with untreated cows. Intrauterine cephapirin infusion of MAR cows improved reproductive performance, depending on CTI. The greater treatment effect in VV-positive cows suggests that VV scoring is a useful tool for the diagnosis of endometritis.

Nuclear factor-κB activation in response to active site-inhibited factor VIIa pretreatment during acute pancreatitis in the rat

Objective. Active site-inhibited factor VII (fVIIai) has previously been reported to reduce remote organ inflammation during acute pancreatitis. The aim of this study was to investigate whether the anti-inflammatory properties of fVIIai in remote organs are mediated through nuclear factor (NF)-κB. Material and methods. Acute pancreatitis in the rat was induced using retrograde intraductal infusion of sodium taurodeoxycholate. Upregulation of NF-κB activity was evaluated using an enzyme-linked immunosorbent assay. Results. An increase in NF-κB activity could be seen in the lungs, which was reduced to normal levels at both 1 and 6 h following pretreatment with fVIIai. In the liver, the greatest treatment effects were seen at 1 h, but were still notable at 6 h. In the ileum, treatment effects were seen only at 6 h. Simultaneous fVIIai and N-acetylcysteine treatment ameliorated many of the treatment effects of fVIIai. In the pancreas, no differences could be seen. Conclusion. fVII inhibition reduces NF-κB act...

Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: A systematic review and meta-analysis*

To systematically review the literature to assess whether adjunctive therapy with polyclonal intravenous immunoglobulin (ivIg) reduces mortality among critically ill adults with severe sepsis and septic shock. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases; the meta-register of controlled trials; and the Medical Editors Trial Amnesty register. Prospective randomized clinical trials (RCTs) evaluating ivIg treatment in critically ill adults with severe sepsis or septic shock were included. Two reviewers conducted assessment of suitability for inclusion. Two authors independently determined the validity of included studies and extracted data. The effect of ivIg on all-cause mortality was quantified using a fixed-effect meta-analysis. Fourteen RCTs published between 1988 and 2006 were included. Most were small, used relatively low doses of ivIg, and included predominantly surgical patients with Gram-negative infections. There was a significant reduction in mortality associated with use of ivIg treatment with a pooled odds ratio of 0.66 (95% confidence interval 0.53-0.83; p < .0005). In general, a greater treatment effect was seen among studies of lower methodological quality, studies using higher doses of ivIg, and studies that did not use albumin as a control. There was evidence of between-study heterogeneity (chi-square p = .009), and this was at least moderate as measured by the I2 value (I2 = 53.8%). When only high-quality studies were pooled, the odds ratio for mortality was 0.96 (95% confidence interval 0.71-1.3; p = .78). This meta-analysis demonstrates an overall reduction in mortality with the use of ivIg for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high-quality studies were analyzed. These data warrant a well-designed, adequately powered, and transparently reported clinical trial.

Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: A systematic review and meta-analysis *

Objectives: To systematically review the literature to assess whether adjunctive therapy with polyclonal intravenous immunoglobulin (ivIg) reduces mortality among critically ill adults with severe sepsis and septic shock. Data Source: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases; the meta-register of controlled trials; and the Medical Editors Trial Amnesty register. Study Selection: Prospective randomized clinical trials (RCTs) evaluating ivIg treatment in critically ill adults with severe sepsis or septic shock were included. Two reviewers conducted assessment of suitability for inclusion. Data Extraction: Two authors independently determined the validity of included studies and extracted data. Data Synthesis: The effect of ivIg on all-cause mortality was quantified using a fixed-effect meta-analysis. Results: Fourteen RCTs published between 1988 and 2006 were included. Most were small, used relatively low doses of ivIg, and included predominantly surgical patients with Gram-negative infections. There was a significant reduction in mortality associated with use of ivIg treatment with a pooled odds ratio of 0.66 (95% confidence interval 0.53–0.83;p< .0005). In general, a greater treatment effect was seen among studies of lower methodological quality, studies using higher doses of ivIg, and studies that did not use albumin as a control. There was evidence of between-study heterogeneity (chi-squarep= .009), and this was at least moderate as measured by theI2 value (I2 = 53.8%). When only high-quality studies were pooled, the odds ratio for mortality was 0.96 (95% confidence interval 0.71–1.3;p= .78). Conclusions: This meta-analysis demonstrates an overall reduction in mortality with the use of ivIg for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high-quality studies were analyzed. These data warrant a well-designed, adequately powered, and transparently reported clinical trial.

Subgroups of the BENEFIT study: Risk of developing MS and treatment effect of interferon beta-1b

The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and > or = 2 clinically silent brain MRI lesions. Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression. The risk of CDMS was increased in placebo-treated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with > or = 9 T2-lesions (48%) or > or = 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (> or = 1 Gd-lesion) and dissemination (> or = 9 T2-lesions). Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had > or = 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %). This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS.

Grey literature in meta-analyses of randomized trials of health care interventions

The inclusion of grey literature (i.e. literature that has not been formally published) in systematic reviews may help to overcome some of the problems of publication bias, which can arise due to the selective availability of data. To review systematically research studies, which have investigated the impact of grey literature in meta-analyses of randomized trials of health care interventions. We searched the Cochrane Methodology Register (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to 20 May 2005), the Science Citation Index (June 2005) and contacted researchers who may have carried out relevant studies. A study was considered eligible for this review if it compared the effect of the inclusion and exclusion of grey literature on the results of a cohort of meta-analyses of randomized trials. Data were extracted from each report independently by two reviewers. The main outcome measure was an estimate of the impact of trials from the grey literature on the pooled effect estimates of the meta-analyses. Information was also collected on the area of health care, the number of meta-analyses, the number of trials, the number of trial participants, the year of publication of the trials, the language and country of publication of the trials, the number and type of grey and published literature, and methodological quality. Five studies met the inclusion criteria. All five studies showed that published trials showed an overall greater treatment effect than grey trials. This difference was statistically significant in one of the five studies. Data could be combined for three of the five studies. This showed that, on average, published trials showed a 9% greater treatment effect than grey trials (ratio of odds ratios for grey versus published trials 1.09; 95% CI 1.03-1.16). Overall there were more published trials included in the meta-analyses than grey trials (median 224 (IQR 108-365) versus 45(IQR 40-102)). Published trials had more participants on average. The most common types of grey literature were abstracts (55%) and unpublished data (30%). There is limited evidence to show whether grey trials are of poorer methodological quality than published trials. This review shows that published trials tend to be larger and show an overall greater treatment effect than grey trials. This has important implications for reviewers who need to ensure they identify grey trials, in order to minimise the risk of introducing bias into their review.

P Less Than .05: What Does It Really Mean?

Although there is a growing body of literature criticizing the use of mere statistical significance as a measure of clinical impact, we submit that this concept has not been widely incorporated in the pediatric literature. This is especially problematic because an understanding of the limitations of using only statistical significance to evaluate treatments is necessary for readers of Pediatrics to draw accurate conclusions from data presented in this journal. Here we highlight some of the issues related to the complex problem of evaluating treatment effects and the importance of using clinical significance in addition to the traditional P value. Currently, the magical boundary of P < .05 holds great importance in whether a manuscript is accepted for publication, a research application is funded, or a new drug is approved by the Food and Drug Administration. We submit that if a treatment is to be useful to our children, it is not enough for treatment effects to be statistically significant; they also need to be large enough to be clinically meaningful. Evaluating treatment outcomes on the basis of P value alone is problematic for several reasons. First, with a large sample, it is quite possible to have a statistically significant result between groups despite a minimal effect of treatment (ie, small effect size). Second, study outcomes with lower P values are typically misinterpreted by pediatricians as having stronger effects than those with higher P values. That is, most clinicians believe that a result with P = .002 has a much greater treatment effect than a result of P = .045. Although this is true if the sample size is the same in both studies, it is not true if the sample size is larger in the study with the smaller P value. This confusion becomes particularly concerning when … Address correspondence to Jill MacLaren, PhD, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510. E-mail: zeev.kain{at}yale.edu

Randomized controlled trial of exercise for chronic whiplash-associated disorders

Whiplash-associated disorders are common and incur considerable expense in social and economic terms. There are no known effective treatments for those people whose pain and disability persist beyond 3 months. We conducted a randomized, assessor-blinded, controlled trial at two centres in Australia. All participants received 3 advice sessions. In addition the experimental group participated in 12 exercise sessions over 6 weeks. Primary outcomes were pain intensity, pain bothersomeness and function measured at 6 weeks and 12 months. Exercise and advice was more effective than advice alone at 6 weeks for all primary outcomes but not at 12 months. The effect of exercise on the 0–10 pain intensity scale was −1.1 (95%CI −1.8 to −0.3, p = 0.005) at 6 weeks and −0.2 (0.6 to −1.0, p = 0.59) at 12 months; on the bothersomeness scale the effect was −1.0 (−1.9 to −0.2, p = 0.003) at 6 weeks and 0.3 (−0.6 to 1.3, p = 0.48) at 12 months. The effect on function was 0.9 (0.3 to 1.6, p = 0.006) at 6 weeks and 0.6 (−0.1 to 1.4, p = 0.10) at 12 months. High levels of baseline pain intensity were associated with greater treatment effects at 6 weeks and high levels of baseline disability were associated with greater treatment effects at 12 months. In the short-term exercise and advice is slightly more effective than advice alone for people with persisting pain and disability following whiplash. Exercise is more effective for subjects with higher baseline pain and disability.

Randomized trials are also essential for device therapy: reply

Randomized trials are also essential for device therapy: reply

Randomized, Controlled Trial of Metformin for Obesity and Insulin Resistance in Children and Adolescents: Improvement in Body Composition and Fasting Insulin

Metformin therapy for adults and children with type 2 diabetes is well established. However, its role in the treatment of insulin resistance and obesity in children and adolescents is less clearly defined. We assessed the effect of metformin on body composition and insulin sensitivity in pediatric subjects with exogenous obesity. Patients referred to a pediatric endocrine clinic were enrolled in a randomized, double-blind, crossover trial. Twenty-eight patients (13 males) aged 9-18 yr participated in the study. Patients received metformin (1 g twice daily) and placebo for 6 months, each with a 2-wk washout period. Body composition (anthropometry, dual-energy x-ray absorptiometry, and abdominal magnetic resonance imaging), and insulin sensitivity (Si; minimal model, fasting insulin and glucose) were measured at baseline and 6 and 12 months. Mean age of subjects at baseline was 12.5 +/- 2.2 yr, median body mass index z-score 2.54 (range, 1.93-2.85). Metformin had a greater treatment effect over placebo for weight (-4.35 kg, P = 0.02), body mass index (-1.26 kg/m(2), P = 0.002), waist circumference (-2.8 cm, P = 0.003), sc abdominal adipose tissue (-52.5 cm(2), P = 0.002), and fasting insulin (-2.2 mU/liter, P = 0.011). Si improved in 45% of subjects while on metformin and 27% of subjects while on placebo (P = 0.21). Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.