Single-centre Randomised Controlled Trial Research Articles

Neurological Outcome at 30 Months of Age after Mild Hypothermia via Selective Head Cooling in Term Neonates with Perinatal Asphyxia Using Low-Cost CoolCap: A Single-Center Randomized Control Pilot Trial in India

AbstractThe objective of this study was to determine the effectiveness and safety of mild systemic hypothermia by selective head cooling in hospital born neonates with hypoxic-ischemic encephalopathy using low-cost CoolCap. The primary outcome was to determine whether selective head cooling reduces neonatal mortality and neurodevelopmental delay (NDD) at > 30 months of age. The secondary outcome was to determine the serious adverse effects during selective head cooling such as thrombocytopenia requiring platelets transfusion, renal and hepatic dysfunction, bradycardia, hypoglycemia, and dyselectrolytemia (hyperkalemia, hyponatremia, and hypocalcemia). This is a single-center randomized control trial. The risk ratios, risk differences, and numbers needed to treat plus 95% confidence interval (CI) were measured. This study was done at the tertiary care perinatal center. Inborn neonates with ≥ 37 completed weeks of gestation with indicators of perinatal asphyxia and moderate to severe clinical encephalopathy were randomly allocated to hypothermia (n = 30) or standard care (n = 30) groups. The neonates were subjected to mild systemic hypothermia via selective head cooling using ice caps, the target rectal temperature being 34 to 35°C for 72 hours. Therapeutic hypothermia reduced the risk of death and NDD at ≥ 30 months of age: 6 of 30 infants (20%) in the hypothermia group and 18 of 30 infants (60%) in the control group died or had a NDD at ≥ 30 months (risk ratio: 0.33 [95% CI: 0.15–0.72]; p = 0 0.0015). The mortality rate decreased, and the survival rate free of any sensorineural disability increased. The benefits were statistically significant in moderately asphyxiated infants. Adverse effects of hypothermia were minimal. Selective head cooling with mild systemic hypothermia in term asphyxiated neonates is safe and inexpensive in low-resource setting. Hypothermia showed statistically significant reduction in mortality and NDD at ≥ 30 months of age when commenced within 6 hours of birth and was not associated with serious adverse effects. The Institutional Clinical Trial Registry number is CNMC/ETHI/317/P.

Antipyretic effect of clonidine in intensive care unit patients: a nested observational study

Fever in the intensive care unit (ICU) is usually an adaptive response to infection or inflammation. Pharmacological intervention is often required in addition to addressing the underlying causes of fever. Animal studies have examined the antipyretic effect of clonidine; however, to our knowledge there are no clinical data available in humans. The observation of an antipyretic effect of clonidine was made during a single-center randomized control trial that was designed to study the effect of clonidine addition to the commonly used sedative agents in mechanically ventilated ICU patients. Forty patients 18 years or older on mechanical ventilation for 3 days or longer were randomized into 2 groups receiving clonidine and placebo. In addition to the usual sedation/analgesia, patients in the clonidine arm received enteral clonidine in doses of 0.1 mg 3 times a day (TID), which was increased to 0.2 mg TID if the hemodynamics remained stable. Vital signs, laboratory data, all cultures, and daily ICU events were recorded. The odds ratio of temperature higher than 38.3°C was 3.96 times higher in the placebo group, after adjustment for the illness severity and the time of follow-up (P = .049). A lower temperature (0.52°C) was observed in the clonidine group after adjustment for the time of follow-up (P = .006). Our report is the first of its kind in humans that demonstrates possible antipyretic properties of enteral clonidine in the critically ill intensive care unit patient.

A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana.

BackgroundYaws is a treponemal infection that was almost eradicated fifty years ago; however, the disease has re-emerged in a number of countries including Ghana. A single-dose of intramuscular benzathine penicillin has been the mainstay of treatment for yaws. However, intramuscular injections are painful and pose safety and logistical constraints in the poor areas where yaws occurs. A single center randomized control trial (RCT) carried out in Papua New Guinea in 2012 demonstrated the efficacy of a single-dose of oral azithromycin for the treatment of yaws. In this study, we also compared the efficacy of a single oral dose of azithromycin as an alternative to intramuscular benzathine penicillin for the treatment of the disease in another geographic setting.MethodologyWe conducted an open-label, randomized non-inferiority trial in three neighboring yaws-endemic districts in Southern Ghana. Children aged 1–15 years with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or 50,000 units/kg of intramuscular benzathine penicillin. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a 4-fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin treatment was determined if the upper bound limit of a 2 sided 95% CI was less than 10%.FindingsThe mean age of participants was 9.5 years (S.D.3.1, range: 1–15 years), 247(70%) were males. The clinical cure rates were 98.2% (95% CI: 96.2–100) in the azithromycin group and 96.9% (95% CI: 94.1–99.6) in the benzathine penicillin group. The serological cure rates at 6 months were 57.4% (95% CI: 49.9–64.9) in the azithromycin group and 49.1% (95% CI: 41.2–56.9) in the benzathine penicillin group, thus achieving the specified criteria for non-inferiority.ConclusionsA single oral dose of azithromycin, at a dosage of 30mg/kg, was non-inferior to a single dose of intramuscular benzathine penicillin for the treatment of early yaws among Ghanaian patients, and provides additional support for the WHO policy for use of oral azithromycin for the eradication of yaws in resource-poor settings.Trial RegistrationPan African Clinical Trials Registry PACTR2013030005181 http://www.pactr.org/

Antipyretic Effect of Clonidine in Intensive Care Unit Patients: A Nested Observational Study.

Fever in the intensive care unit (ICU) is usually an adaptive response to infection or inflammation. Pharmacological intervention is often required in addition to addressing the underlying causes of fever. Animal studies have examined the antipyretic effect of clonidine; however, to our knowledge there are no clinical data available in humans. The observation of an antipyretic effect of clonidine was made during a single-center randomized control trial that was designed to study the effect of clonidine addition to the commonly used sedative agents in mechanically ventilated ICU patients. Forty patients 18 years or older on mechanical ventilation for 3 days or longer were randomized into 2 groups receiving clonidine and placebo. In addition to the usual sedation/analgesia, patients in the clonidine arm received enteral clonidine in doses of 0.1 mg 3 times a day (TID), which was increased to 0.2 mg TID if the hemodynamics remained stable. Vital signs, laboratory data, all cultures, and daily ICU events were recorded. The odds ratio of temperature higher than 38.3°C was 3.96 times higher in the placebo group, after adjustment for the illness severity and the time of follow-up (P = .049). A lower temperature (0.52°C) was observed in the clonidine group after adjustment for the time of follow-up (P = .006). Our report is the first of its kind in humans that demonstrates possible antipyretic properties of enteral clonidine in the critically ill intensive care unit patient.

A State-of-the-Science Overview of Randomized Controlled Trials Evaluating Acute Management of Moderate-to-Severe Traumatic Brain Injury.

Moderate-to-severe traumatic brain injury (TBI) remains a major global challenge, with rising incidence, unchanging mortality and lifelong impairments. State-of-the-science reviews are important for research planning and clinical decision support. This review aimed to identify randomized controlled trials (RCTs) evaluating interventions for acute management of moderate/severe TBI, synthesize key RCT characteristics and findings, and determine their implications on clinical practice and future research. RCTs were identified through comprehensive database and other searches. Key characteristics, outcomes, risk of bias, and analysis approach were extracted. Data were narratively synthesized, with a focus on robust (multi-center, low risk of bias, n > 100) RCTs, and three-dimensional graphical figures also were used to explore relationships between RCT characteristics and findings. A total of 207 RCTs were identified. The 191 completed RCTs enrolled 35,340 participants (median, 66). Most (72%) were single center and enrolled less than 100 participants (69%). There were 26 robust RCTs across 18 different interventions. For 74% of 392 comparisons across all included RCTs, there was no significant difference between groups. Positive findings were broadly distributed with respect to RCT characteristics. Less than one-third of RCTs demonstrated low risk of bias for random sequence generation or allocation concealment, less than one-quarter used covariate adjustment, and only 7% employed an ordinal analysis approach. Considerable investment of resources in producing 191 completed RCTs for acute TBI management has resulted in very little translatable evidence. This may result from broad distribution of research effort, small samples, preponderance of single-center RCTs, and methodological shortcomings. More sophisticated RCT design, large multi-center RCTs in priority areas, increased focus on pre-clinical research, and alternatives to RCTs, such as comparative effectiveness research and precision medicine, are needed to fully realize the potential of acute TBI research to benefit patients.

Caffeine Administration to Prevent Apnea in Very Premature Infants

Apnea intervals frequently occur in premature infants. Periods of apnea occur more often with decreases in gestational age. Periods of apnea can cause damage to the infant's developing brain and other organs. This study was designed to investigate the preventive effects of caffeine on apnea incidence in higher-risk neonates. In this single-center randomized control trial study, premature infants with a birth weight of ≤1200g were eligible for enrollment. Twenty-six infants were randomly assigned to receive 20mg/kg caffeine, as the loading dose, which was followed by 5mg/kg daily as the maintenance dose until the 10th day of life; these infants were compared with 26 infants in the control group. Primary outcomes were incidence of apnea, bradycardia, and cyanosis. Fifty-two infants were enrolled (26 in the caffeine group and 26 in the control group). The preventive effect of caffeine on apnea was significant in these infants. The relative risk for incidence of apnea in preterm neonates with a birth weight of <1200g was 0.250 (95% confidence interval, 0.097-0.647). Only four infants (15.4%) in the caffeine group developed apnea, compared with 16 (61.5%) in the control group (p=0.001). It seems that preventative effects of caffeine on apnea become apparent by using the drug in very premature infants.

Stapler versus scalpel resection followed by hand-sewn closure of the pancreatic remnant for distal pancreatectomy.

Resections of the pancreatic body and tail reaching to the left of the superior mesenteric vein are defined as distal pancreatectomy. Most distal pancreatectomies are elective treatments for chronic pancreatitis, benign or malignant diseases, and they have high morbidity rates of up to 40%. Pancreatic fistula formation is the main source of postoperative morbidity, associated with numerous further complications. Researchers have proposed several surgical resection and closure techniques of the pancreatic remnant in an attempt to reduce these complications. The two most common techniques are scalpel resection followed by hand-sewn closure of the pancreatic remnant and stapler resection and closure. To compare the rates of pancreatic fistula in people undergoing distal pancreatectomy using scalpel resection followed by hand-sewn closure of the pancreatic remnant versus stapler resection and closure. We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biosis and Science Citation Index from database inception to October 2015. We included randomised controlled trials (RCTs) comparing stapler versus scalpel resection followed by hand-sewn closure of the pancreatic remnant for distal pancreatectomy (irrespective of language or publication status). Two authors independently assessed trials for inclusion and extracted the data. Taking into consideration the clinical heterogeneity between the trials (e.g. different endpoint definitions), we analysed data using a random-effects model with Review Manager (RevMan), calculating risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). In two eligible trials, a total of 381 participants underwent distal pancreatic resection and were randomised to closure of the pancreatic remnant either with stapler (n = 191) or scalpel resection followed by hand-sewn closure (n = 190). One was a single centre pilot RCT and the other was a multicentre blinded RCT. The single centre pilot RCT evaluated 69 participants in five intervention arms (stapler, hand-sewn, fibrin glue, mesh and pancreaticojejunostomy), although we only assessed the stapler and hand-sewn closure groups (14 and 15 participants, respectively). The multicentre RCT had two interventional arms: stapler (n = 177) and hand-sewn closure (n = 175). The rate of postoperative pancreatic fistula was the main outcome, and it occurred in 79 of 190 participants in the hand-sewn group compared to 65 of 191 participants in the stapler group. Neither the individual trials nor the meta-analysis showed a significant difference between resection techniques (RR 0.90; 95% CI 0.55 to 1.45; P = 0.66). In the same way, postoperative mortality and operation time did not differ significantly. The single centre RCT had an unclear risk of bias in the randomisation, allocation and both blinding domains. However, the much larger multicentre RCT had a low risk of bias in all domains. Due to the small number of events and the wide confidence intervals that cannot exclude clinically important benefit or harm with stapler versus hand-sewn closure, there is a serious possibility of imprecision, making the overall quality of evidence moderate. The quality of evidence is moderate and mainly based on the high weight of the results of one multicentre RCT. Unfortunately, there are no other completed RCTs on this topic except for one relevant ongoing trial. Neither stapler nor scalpel resection followed by hand-sewn closure of the pancreatic remnant for distal pancreatectomy showed any benefit compared to the other method in terms of postoperative pancreatic fistula, overall postoperative mortality or operation time. Currently, the choice of closure is left up to the preference of the individual surgeon and the anatomical characteristics of the patient. Another (non-European) multicentre trial (e.g. with an equality or non-inferiority design) would help to corroborate the findings of this meta-analysis. Future trials assessing novel methods of stump closure should compare them either with stapler or hand-sewn closure as a control group to ensure comparability of results.

Obesity and lumbar fusion: increased risk of blood loss

Background: Several studies have demonstrated that obese patients are at increased risk of perioperative complication during lumbar spine surgery. Herein we quantify the association between blood loss and obesity during lumbar fusion. Methods: Outcomes were collected in the setting of a single center randomized control trial conducted among patients undergoing elective lumbar fusion. A univariate analysis of potential risk factors (gender, age, body mass index [BMI], number of levels fused, previous use of anticoagulants, and previous use of non-steroidal anti-inflammatories) for operative blood loss was performed. Logistic regression was conducted to estimate adjusted odds ratios (ORs) and 95% confidence intervals. Results: Among 85 patients, the mean estimated blood loss (EBL) was 563 ml, 47.1% were male, and the median number of levels fused was one. Obesity (BMI ≥30−kg/m2) was a significant risk (OR 2.46, P=0.025) for increased blood loss (EBL &gt; 500 ml). Number of levels fused was similarly associated with EBL (P&lt;0.01) while gender confounded the association between obesity and EBL. Conclusions: Surgeons should anticipate greater blood loss when performing lumbar fusion in obese patients. To reduce operative morbidity, consideration should be given to preoperative weight loss whenever possible.

Initiatives to reduce length of stay in acute hospital settings: a rapid synthesis of evidence relating to enhanced recovery programmes

BackgroundThere has been growing interest in the NHS over recent years in the use of enhanced recovery programmes for elective surgery to deliver productivity gains through reduced length of stay, fewer postoperative complications, reduced readmissions and improved patient outcomes.ObjectivesTo evaluate the clinical effectiveness and cost-effectiveness of enhanced recovery programmes for patients undergoing elective surgery in acute hospital settings. To identify and critically describe key factors associated with successful adoption, implementation and sustainability of enhanced recovery programmes in UK settings. To summarise existing knowledge about patient experience of enhanced recovery programmes in UK settings.Data sourcesEight databases, including Database of Abstracts of Reviews and Effects, International Prospective of Systematic Reviews, NHS Economic Evaluation Database and MEDLINE, were searched from 1990 to March 2013 without language restrictions. Relevant reports and guidelines and reference lists of retrieved articles were scanned to identify additional studies.Review methodsSystematic reviews, randomised controlled trials (RCTs), economic evaluations, and UK NHS cost analysis studies were included if they evaluated the impact of enhanced recovery programmes on any health- and cost-related outcomes. Eligible studies included patients undergoing elective surgery in an acute hospital setting. Implementation case studies and surveys of patient experience in a UK setting were also eligible for inclusion. Quality assessment of systematic reviews, RCTs and economic evaluations was based on existing Centre for Reviews and Dissemination processes. All stages of the review process were performed by one researcher and checked by a second with discrepancies resolved by consensus. The type and range of evidence precluded meta-analysis and we therefore performed a narrative synthesis, differentiating between clinical effectiveness and cost-effectiveness, implementation case studies and evidence on patient experience.ResultsSeventeen systematic reviews of varying quality were included in this report. Twelve additional RCTs were included; all were considered at high risk of bias. Most of the evidence focused on colorectal surgery. Fourteen innovation case studies and 15 implementation case studies undertaken in NHS settings were identified and provide descriptions of factors critical to the success of an enhanced recovery programme. Ten relevant economic evaluations were identified evaluating costs and outcomes over short time horizons. Despite the plethora of studies, robust evidence was sparse. Evidence for colorectal surgery suggests that enhanced recovery programmes may reduce hospital stays by 0.5–3.5 days compared with conventional care. There were no significant differences in reported readmission rates. Other surgical specialties showed greater variation in reported reductions in length of stay reflecting the limited evidence identified.LimitationsFindings relating to other clinical outcomes, cost-effectiveness, implementation and patient experience were hampered by a lack of robust evidence and poor reporting.ConclusionsThere is consistent, albeit limited, evidence that enhanced recovery programmes may reduce length of patient hospital stay without increasing readmission rates. The extent to which managers and clinicians considering implementing enhanced recovery programmes can realise reductions and cost savings will depend on length of stays achieved under their existing care pathway. RCTs comparing an enhanced recovery programme with conventional care continue to be conducted and published. Further single-centre RCTs of this kind are not a priority. Rather, what is needed is improved collection and reporting of how enhanced recovery programmes are implemented, resourced and experienced in NHS settings.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

G69(P) Hyperalimentation using current UK parenteral amino acid formulations does not prevent low plasma arginine levels in very preterm infants

BackgroundArginine deficiency is well recognised in very preterm infants (VPI) receiving parenteral nutrition (PN) and is associated with major morbidity. Current UK PN amino acid (AA) formulations are AA-P (arginine...

A randomized controlled trial of IV immunoglobulin in patients with postpolio syndrome

ObjectiveTo investigate in a single-center randomized control trial whether a single IVIg course improves short-term outcome in patients with postpolio syndrome (PPS). MethodsFifty-one patients with PPS were randomly allocated to receive 2g/kg IVIg body weight or placebo infused over 5 consecutive days. The primary endpoint was health-related quality of life (HRQoL) limited to the physical component score (PCS) in the Short-Form-36 (SF-36). Secondary endpoints included the SF-36 mental component score (MCS), 6-minute walk test, visual analog scale, 101-numeric rating, and fatigue severity scale. Muscle strength was graded according to the Medical Research Council scale and by dynamometer. Primary and secondary outcome variables were tested double-blind at baseline, 2months, and 4months. ResultsAt two months, although SF-36 PCS scores were similar in both arms, the role physical (RP) domain improved significantly in the treatment arm (p=0.05) and so did the composite MCS (p=0.015), and role emotional (RE) subscale (p=0.02). No differences were found in the remaining outcome measures. At 4months, none of the outcome variables differed significantly between groups. ConclusionsAlthough the study did not reach the primary endpoint, we showed that a single IVIg course improves HRQoL related to mental activity, as measured by the SF-36 composite MCS, and role limitations including RP and RE SF-36 subscales at 2months, in patients with PPS. A single IVIg course leaves, gait, muscle strength, fatigue and bodily pain unchanged in patients with PPS. Classification of evidenceClass I evidence indicates that IVIg did not change SF-36 PCS, and Class II evidence indicates that IVIg improved scores on the SF-36 MCS, RP, and RE.

An educational programme for patients with psoriasis and atopic dermatitis: a prospective randomized controlled trial

Patient education in addition to standard treatment, with the aim of affecting care through courses, is a relatively new concept in dermatology. Here we introduce a randomized controlled trial (RCT) regarding a previously described 12-week educational programme for chronic skin diseases. The primary objective of the RCT was to measure the effect of an educational programme on disease severity and quality of life in patients with psoriasis or atopic dermatitis. We recruited 50 patients from Ghent University Hospital. Patients with diagnosed psoriasis or atopic dermatitis were randomized (1 : 1) to the intervention or control group. The clinical outcome was measured by two blinded observers using the Psoriasis Area and Severity Index (PASI), Scoring Atopic Dermatitis or the Eczema Area and Severity Index. Quality of life was measured by dermatology-specific quality-of-life questionnaires. There was a follow-up period of 9 months. We found that disease severity and quality of life improved significantly for patients with psoriasis (n = 29) but not for patients with atopic dermatitis (n = 21) at 3 months. Patients in the intervention group showed a significant reduction in mean PASI (P = 0·036), mean Dermatology Life Quality Index (P = 0·019) and mean Psoriasis Disability Index (P = 0·015), compared with the control group at 3 months. This improvement continued for at least 6 months, i.e. 3 months after the intervention, but was lost at follow-up after 9 months. Evaluating this form of educational programme, by means of a single-centre RCT, indicates its added value in the longer term management of psoriasis.

Thyroid Dysfunction and Pregnancy: Where Are We Five Years Later?

This issue of the JCEM presents new guidelines for addressing thyroid dysfunction during pregnancy and the postpartum period (1). These guidelines follow on those published 5 yr ago, highlighting the importance of this topic and reflecting the knowledge gained in the last few years. The text discusses and gives recommendations related to maternal and fetal aspects of hypothyroidism, hyperthyroidism, autoimmunity, thyroid nodules and cancer, iodine nutrition, and postpartum thyroiditis. A final paragraph is dedicated to the issue of screening for thyroid dysfunction in pregnancy. As in the previous version, the new guidelines focus attention on either the pregnant woman or the fetus; there is no doubt that in this field, we need more randomized controlled trials (RCT) to assess the obstetrical impact of thyroid disease, but also studies that evaluate long-term outcomes such as child intelligence quotient (IQ), especially in cases of maternal subclinical hypothyroidism (2). Of about 140 references in the new guidelines, 20% date from 2007 (the year the previous guidelines were published). What have these new references added, and what are the gray areas that require further investigation? The present guidelines confirm the suggestion of treating subclinical autoimmune hypothyroidism with levothyroxine (LT4) because the potential benefits from treatment outweigh the risk of potential adverse events. Association studies have yielded conflicting results regarding outcomes such as miscarriage, hypertension, placental abruption, and preterm delivery, and to date, one singlecenter RCT has demonstrated a significant reduction in obstetrical and neonatal complications when subclinically hypothyroid women are treated from the first trimester (3, 4). The panel also recommends treating antibody-negative women who have subclinical hypothyroidism. Despite the absence of relevant RCT, this recommendation seems reasonable given that independent of thyroid autoimmunity, an increased TSH level is associated with a miscarriage risk, and an elevated TSH at the beginning of pregnancy may predispose the mother to further impairment of thyroid function in the following months. “Partial replacement therapy” with LT4 is also suggested in cases of isolated hypothyroxinemia, although at the discretion of the physician. This recommendation directly leads to another point examined in the guidelines: awareness about the possible inaccuracy of serum free T4 (FT4) measurement in pregnancy. The absence of a universally accepted trimester-specific reference range (and the common absence of each single laboratory-specific reference range) is an issue that makes defining cutoff values difficult and complicates clear identification of isolated hypothyroxinemia as a clinical entity. The issue of the potential inaccuracy of FT4 dosage, other than complicating the distinction between subclinical and overt hypothyroidism, is also reported in the hyperthyroidism section, where the guidelines recommend maintaining maternal thyroid FT4 levels at the upper limit of the nonpregnant reference range. An alternative suggestion is to use total T4, or the free T4 index (“adjusted T4”), at 1.5-fold the upper limit, given that many laboratories unfortunately have definitively dismissed total T4 measurement. Regarding hyperthyroidism, the new guidelines confirm the suggestion of using propylthiouracil in the first trimester and methimazole (MMI) in the second and the third trimesters because of the increased risk of malformations associated with the use of MMI [further confirmed by a very recent paper published in the JCEM (5)]. Like the American Thyroid Association (ATA)-American Association of Clinical Endocrinologists (AACE) guide-

Single-Center Trials Show Larger Treatment Effects Than Multicenter Trials: Evidence From a Meta-epidemiologic Study

A recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings. To perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs). MEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched. All individual RCTs included in the meta-analyses were selected. Data were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration. The primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I(2) = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]). Despite sensitivity analyses, meta-confounding cannot be fully excluded. Single-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted. Academic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).

Assessment of the Methodologic Quality of Medical and Surgical Clinical Trials in Patients with Arthroplasty

To assess the methodological quality of randomized controlled trials (RCT) of medical and surgical therapy in patients with arthroplasty. We conducted a Medline database search for all arthroplasty RCT from 1997 and 2006. The quality of the methods of all eligible RCT was assessed by a trained abstractor. We used a checklist of trial quality characteristics, and the overall trial quality was assessed by 3 scales: Jadad (range 0-5), Delphi list (range 0-9), and numeric rating scale (NRS; range 1-10), based on User's Guides to the Medical Literature. A total of 196 articles were included in the analysis; most included hip (n = 81) or knee (n = 80) or both hip/knee arthroplasty (n = 19); 66 (34%) assessed pharmacological treatments, 117 (60%) nonpharmacological treatments, and 13 (7%) both. Mean (SEM) overall quality scores of arthroplasty RCT were low: Jadad score 2.36 (1.4), Delphi list 5.33 (1.6), and NRS score 4.30 (2.6). Multivariable analyses revealed that nonpharmacological intervention RCT had lower odds (odds ratio 0.28-0.39; p = 0.008-0.033) and those with no funding had lower odds (OR 0.28-0.50; p = 0.014-0.119) of being in the highest quartiles of the 3 overall quality scores. In contrast, multicenter RCT had 1.8-4.7 times higher odds of being in highest tertiles of quality scores (p = 0.017-0.185). Methodological deficiencies in reporting of hip/knee arthroplasty RCT offer an opportunity for improvement. Type of intervention, number of trial centers, and presence of funding were independently associated with overall trial quality. In future, multicenter RCT (rather than single-center) and modeling protocols of single-center RCT similar in rigor to multicenter RCT may improve the quality of arthroplasty RCT.

Multicentre randomised controlled trials in obstetrics and gynaecology: an analysis of trends over three decades

To assess the trend in multicentre randomised controlled trials (RCTs), a database of 670 RCTs was assembled from four generic obstetric and gynaecological journals (Acta Obstetricia et Gynecologica Scandinavica, British Journal of Obstetrics & Gynaecology, Obstetrics & Gynecology and American Journal of Obstetrics & Gynecology) for 1975, 1980, 1985, 1990, 1995, 2000 and 2005. During this period, there was an inflationary trend with the proportion of published multicentre RCTs (from 12.9% in 1975 of all RCTs to 23.8% in 2005; P = 0.008). Multicentre RCTs had multiauthored publications (OR = 2.90; 95% CI 1.99-4.22) and more often received external funding (OR = 2.41; 95% CI 1.70-3.48) than single centre RCTs. The inflationary trend in multicentre RCTs requiring funding and collaboration represents the increasing complexity of medical research necessary to underpin evidence-based practice.

Is hepatic transplantation justified for primary liver cancer?

A concise, yet objective overview of Hepatocellular Carcinoma (HCC) treatment in 2006 with an intent to transplant is presented. The most significant variables impacting on the use of hepatic transplantation as therapy for primary liver cancer are developed under the headings of: Staging Criteria; Organ allocation; Transplant dropout minimization therapies; and Effects on the HCC general population. The pertinent medical literature and update of an ongoing intent-to-treat HCC with transplant single center randomized control trial are reviewed.

Screening for Abdominal Aortic Aneurysms: Single-Centre Randomized Control Trial

Conclusion: Screening for abdominal aortic aneurysm (AAA) in men aged 65 or more reduces aneurysm related mortality. Summary: The authors sought to determine whether screening of men 65 years of age or more for AAA reduces mortality. This was a single center randomized control trial conducted at five hospitals in Viborg County, Denmark. Participants included all 12,639 men born during 1921-33 and who are living in Viborg County. In 1994, men born between 1921 and 1929 (64-73 years) were also included. Included also were men who became 65 during the period 1995-1998. Participants were randomized to an intervention or control group. Intervention consisted of screening for AAA by ultrasonography. Those individuals discovered to have an AAA >5cm were evaluated for surgery and those with smaller aneurysms were offered annual follow-up ultrasound examinations. The endpoints included specific mortality due to AAA, overall mortality, and emergency operations for AAA. 6,333 men were offered screening, and 4,860 were actually screened (screening rate 76.5%). Four percent of the individuals screened (n = 191) had an AAA. Mean follow-up was 52 months. During follow-up the screened group had 75% fewer emergency operations than the control group (95% confidence interval, 34-31%). There were 27 deaths due to AAA in the control group and 9 in the screened group. Aneurysm related mortality was reduced by 67% (95% CI 29-84%). The number of individuals required to screen to save one life was 352. All cause mortality was insignificantly decreased in the screened group (hazard ratio 0.92, 0.84-1.00). Mortality from other causes was not significantly decreased (hazard ratio 0.92, 0.85-1.02). Comment: This is another one of the four major randomized trials evaluating the efficacy of screening for AAA. This trial, along with two of the other trials, only evaluated men. There is one of the pivotal trials utilized by the U.S. Preventative Task Force in generating recommendations for screening males for AAA who are, or had been, smokers and are aged 65-74 years.