Sound Trials Research Articles

Separating wheat from chaff: examining the obesity paradox in the critically ill

Obesity is an increasing burden globally. In the general population, the obese have an increased mortality risk. Regarding the critically ill, a growing body of literature supports the obesity paradox, the notion that obesity confers a protective effect in certain disease states. However, the paucity of methodologically sound trials prevents definitive interpretation and may obscure risks.

Are there metabolic costs of vocal responses to noise in marine mammals?

Many species respond to increases in environmental noise by increasing the amplitude, duration, and/or repetition rate of their vocalizations. Potential costs of noise-induced vocal modifications include increased energetic costs but no empirical data in marine mammals exist. This study’s objective was to compare the metabolic costs of communicative sounds produced by captive bottlenose dolphins (N = 2) under two conditions (low- and high-amplitude vocalization trials) to assess energetic costs of vocal responses to noise. An experimental trial consisted of a 10-min rest period to determine resting metabolic rate, followed by a two-minute vocalization period, and concluded with another 10-min rest period to measure recovery. Open-flow respiratory was used to measure oxygen consumption during each trial component. Vocalizations were recorded using a calibrated hydrophone for analysis. Both dolphins tended to produce longer vocalizations during high-amplitude trials. Thus, metabolic rates were related to total sound energy of all vocalizations produced during the vocal period for each trial. Metabolic costs tended to be higher during high sound energy trials, but only verged on statistical significance when vocal-performance differences were at least 10 dB (in cumulative sound exposure level). This study provides key data to assess biological consequences of anthropogenic noise exposure in marine mammals.

Erythropoetin in der Plastischen Chirurgie

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated.

Multidimensional rehabilitation programmes for adult cancer survivors.

Multidimensional rehabilitation programmes (MDRPs) have developed in response to the growing number of people living with and surviving cancer. MDRPs comprise a physical component and a psychosocial component. Studies of the effectiveness of these programmes have not been reviewed and synthesised. To conduct a systematic review of studies examining the effectiveness of MDRPs in terms of maintaining or improving the physical and psychosocial well-being of adult cancer survivors. We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsychINFO up to February 2012. Selection criteria focused on randomised controlled trials (RCTs) of multidimensional interventions for adult cancer survivors. Interventions had to include a physical component and a psychosocial component and to have been carried out on two or more occasions following completion of primary cancer treatment. Outcomes had to be assessed using validated measures of physical health and psychosocial well-being. Non-English language papers were included. Pairs of review authors independently selected trials, rated their methodological quality and extracted relevant data. Although meta-analyses of primary and secondary endpoints were planned there was a high level of study heterogeneity and only one common outcome measure (SF-36) could be statistically synthesised. In addition, we conducted a narrative analysis of interventions, particularly in terms of inspecting and identifying intervention components, grouping or categorising interventions and examining potential common links and outcomes. Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional. There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.

Use of Prothrombin Complex Concentrates and Fibrinogen Concentrates in the Perioperative Setting: A Systematic Review

The use of prothrombin complex concentrates (PCCs) and fibrinogen concentrates (FIBCs) to achieve hemostasis in the perioperative setting as alternatives to allogeneic blood products remains controversial. To examine the efficacy and safety of PCCs and FIBCs, we conducted a systematic review-in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement-to compare the use of these transfusion alternatives in bleeding surgical patients. We performed a literature search of English articles published between July 1997 and July 2012 in MEDLINE via PubMed, The Cochrane Library, and CINAHL. Five randomized trials and 15 nonrandomized studies with a comparator group were included in the final review. Studies were sorted into 1 of the following 3 clinical settings: cardiac surgery, non-cardiac surgery, and reversal of warfarin anticoagulation. Risk of bias was assessed using the Cochrane risk of bias tool. With the exception of 2 randomized controlled trials, the existing body of literature on the use of PCCs and FIBCs in the perioperative setting was assessed to have a high degree of methodological bias. Overall, prospective studies in the cardiac surgery grouping suggested that patients receiving FIBC and/or PCCs required less allogeneic blood transfusion and had less chest tube drainage. In studies of warfarin reversal, PCCs more rapidly corrected the International Normalized Ratio compared to plasma; however, in the setting of intracranial hemorrhage, functional outcomes were poor regardless of the reversal strategy. With regards to safety outcomes, reporting was not uniform and raises concerns of underreporting. Adequately powered, methodologically sound trials would be required for more definitive conclusions to be drawn about the efficacy of PCCs and FIBC over conventional blood components for the treatment of perioperative coagulopathy in bleeding patients.

Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma

“Success . . . comes not from having the right cards, but from playing bad ones properly.” —Joshua Dool. At least two thirds of children and adolescents with intermediateand higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy. Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity. The best established therapy is a three-drug chemotherapy combination using vincristine, dactinomycin, and an alkylator (either cyclophosphamide or ifosfamide) and local control measures that cause substantial morbidity, particularly in our youngest patients. The therapy approach and anticipated outcome have not substantially changed in the last two decades. Oberlin et al report in Journal of Clinical Oncology the results of the MMT95 trial, a well-designed prospective, randomized study comparing intensified six-drug therapy versus standard three-drug chemotherapy in nonmetastatic rhabdomyosarcoma and other chemosensitive childhood soft tissue sarcomas. Intensification of chemotherapy provided no survival advantage, no reduction in the intensity of local therapy, and added toxicity—certainly not the answer for which these investigators had hoped. Why have we been unable to make any recent progress in treating rhabdomyosarcoma? Successful clinical trials must be well designed. Most advances in pediatric oncology have used prospective, randomized comparative study designs. However, good trial design certainly does not guarantee success. The two most recently completed intermediate-risk rhabdomyosarcoma studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRS-IV comparing vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide; and vincristine, ifosfamide, and etoposide) and the Children’s Oncology Group (COG; D9803 comparing VAC v VAC plus topotecan and cyclophosphamide) were well designed and appropriately powered and evaluated agents with substantial clinical activity, yet they failed to show any improvement in the experimental arms. The MMT95 (Malignant Mesenchymal Tumor 1995) study prospectively randomly assigned patients to receive threeor six-drug therapy, with a switch to the six-drug combination in patients who had disease progression, less than 50% imaging response, or poor histologic response. This design decreased the number of patients who received either only threeor only six-drug therapy. In addition, a relatively high number of eligible patients were not randomly assigned (149 of 606; 25%). However, these flaws, while decreasing the statistical power of this study, are relatively minor and do not seem to have affected the final negative results. Selection of the right patient population is a key component of sound clinical trial design. The MMT95 study enrolled higher-risk patients with rhabdomyosarcoma with both embryonal and alveolar histologies. These two histologies are biologically distinct, yet all cooperative group trials in higher-risk rhabdomyosarcoma have included both histologies, with few data to suggest substantial differences in treatment response for the different histologic entities. In addition, the MMT95 study enrolled 72 patients with chemotherapy-sensitive nonrhabdomyosarcoma soft tissue sarcomas. Soft tissue primitive neuroectodermal tumors (27 patients enrolled onto MMT95) share morphologic, immunohistochemical, and genetic features with Ewing tumors arising in bone, are classified by WHO inclusively as Ewing sarcoma/primitive neuroectodermal tumor, and are currently treated in studies of the Ewing family of tumors. COG trials previously enrolled patients with undifferentiated sarcomas together with rhabdomyosarcomas, but these patients were recently treated on a study for other nonrhabdomyosarcoma soft tissue sarcomas (COG ARST0332: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas in patients under30yearsofage).Ratesofmetastasis inMMT95werehigher inthese patient subsets (P .03); the number of patients enrolled with these histologies was insufficient to provide insights into the impact of more intensive therapy. Cure rates have improved in some childhood cancers with the optimization of chemotherapy schedules and doses. Decades of empiric adjustments using a modest number of active chemotherapy

Carnitine supplementation for inborn errors of metabolism.

Inborn errors of metabolism are genetic conditions which can lead to abnormalities in the synthesis and metabolism of proteins, carbohydrates, or fats. It has been proposed that in some instances carnitine supplementation should be provided to infants with a suspected metabolic disease as an interim measure, particularly whilst awaiting test results. Carnitine supplementation is used in the treatment of primary carnitine deficiency, and also where the deficiency is a secondary complication of several inborn errors of metabolism, such as organic acidaemias and fatty acid oxidation defects in children and adults. To assess the effectiveness and safety of carnitine supplementation in the treatment of inborn errors of metabolism. We searched the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 4) and MEDLINE via Ovid (1950 to July week 4 2007), LILACS (15/05/2008) and Iranmedex (15/05/2008) and also the reference lists of retrieved articles.Date of most recent search of the Group's Inborn Errors of Metabolism Register: 27 October 2011. Randomised controlled trials and quasi-randomised controlled trials comparing carnitine supplementation (in different dose, frequency, or duration) versus placebo in children and adults diagnosed with an inborn error of metabolism. Two authors independently screened and assessed the eligibility of the identified trials. No trials were included in the review. There are no published or ongoing randomised controlled clinical trials relevant to this review question. Therefore, in the absence of any high level evidence, clinicians should base their decisions on clinical experience and in conjunction with preferences of the individual where appropriate. This does not mean that carnitine is ineffective or should not be used in any inborn error of metabolism. However, given the lack of evidence both on the effectiveness and safety of carnitine and on the necessary dose and frequency to be prescribed, the current prescribing practice should continue to be observed and monitored with care until further evidence is available. Methodologically sound trials, reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement, are required. It should be considered whether placebo-controlled trials in potentially lethal diseases, e.g. carnitine transporter disorder or glutaric aciduria type I, are ethical.

Interventions for smoking cessation in Indigenous populations.

Tobacco use in Indigenous populations (people who have inhabited a country for thousands of years) is often double that of the non-Indigenous population. A disproportionate burden of substance-related morbidity and mortality exists as a result. To evaluate the effectiveness of smoking cessation interventions in Indigenous populations and to summarise these approaches for future cessation programmes and research. The Cochrane Tobacco Addiction Group Specialised Register of Trials was searched (April 2011), with additional searches of MEDLINE (May 2011). Online clinical trial databases and publication references were also searched for potential studies. We included randomized and non-randomized controlled trials for smoking cessation interventions in Indigenous populations. Interventions could include pharmacotherapies, cognitive and behavioural therapies, alternative therapies, public policy and combination therapies. No attempts were made to re-define Indigenous status for the purpose of including a study in this review. Data pertaining to methodology, participants, interventions and outcomes were extracted by one reviewer and checked by a second, whilst methodological quality was extracted independently by two reviewers. Studies were assessed by qualitative narrative synthesis and where possible meta-analysis. The review process was examined by an Indigenous (Aboriginal) Australian for applicability, acceptability and content. Four studies met all of the eligibility criteria for inclusion within the review. Two used combination therapies consisting of a pharmacotherapy combined with cognitive and behavioural therapies, whilst the remaining two used cognitive and behavioural therapy through counselling, one via text message support and the other delivered via clinic doctors trained in smoking cessation techniques. Smoking cessation data were pooled across all studies producing a statistically and clinically significant effect in favour of the intervention (risk ratio 1.43, 95%CI 1.03 to 1.98, p=0.032), however following sensitivity analysis a statistically non-significant but clinically significant effect was observed in favour of the intervention (risk ratio 1.33, 95%CI 0.95 to 1.85, p=NS) . A significant health disparity exists, whereby Indigenous populations, a minority, are over-represented in the burden of smoking-related morbidity and mortality. This review highlights the paucity of evidence available to evaluate the effectiveness of smoking cessation interventions, despite the known success of these interventions in non-Indigenous populations. Due to this lack of published investigations, the external validity of this review is limited, as is the ability to draw reliable conclusions from the results. The limited but available evidence reported does indicate that smoking cessation interventions specifically targeted at Indigenous populations can produce smoking abstinence. However this evidence base is not strong with a small number of methodologically sound trials investigating these interventions. More rigorous trials are now required to assist in bridging the gap between tobacco related health disparities in Indigenous and non-Indigenous populations.

Relationship between Respiratory Load Perception and Perception of Nonrespiratory Sensory Modalities in Subjects with Life-Threatening Asthma.

Subjects with life-threatening asthma (LTA) have reported decreased sensitivity to inspiratory resistive (R) loads. It is unknown if decreased sensitivity is specific for inspiratory R loads, other types of respiratory loads, or a general deficit affecting sensory modalities. This study hypothesized that impairment is specific to respiratory stimuli. This study tested perceptual sensitivity of LTA, asthmatic (A), and nonasthmatic (NA) subjects to 4 sensory modalities: respiratory, somatosensory, auditory, visual. Perceptual sensitivity was measured with magnitude estimation (ME): respiratory loads ME, determined using inspiratory R and pressure threshold (PT) loads; somatosensory ME, determined using weight ranges of 2–20 kg; auditory ME, determined using graded magnitudes of 1 kHz tones delivered for 3 seconds bilaterally; visual ME, determined using gray-to-white disk intensity gradations on black background. ME for inspiratory R loads lessened for LTA over A and NA subjects. There was no significant difference between the 3 groups in ME for PT inspiratory loads, weight, sound, and visual trials. These results demonstrate that LTA subjects are poor perceivers of inspiratory R loads. This deficit in respiratory perception is specific to inspiratory R loads and is not due to perceptual deficits in other types of inspiratory loads, somatosensory, auditory, or visual sensory modalities.

The Aftereffects of Ventriloquism: The Time Course of the Visual Recalibration of Auditory Localization

Exposure to synchronous but spatially discordant auditory and visual inputs produces adaptive recalibration of the respective localization processes, which manifest themselves in measurable aftereffects. Here we report two experiments that examined the time course of visual recalibration of apparent sound location in order to establish the build-up and dissipation of recalibration. In Experiment 1 participants performed a sound localization task before and during exposure to an auditory-visual discrepancy. In Experiment 2, participants performed a sound localization task before and after 60, 180 or 300 exposures to the discrepancy and aftereffects were measured across a series of post-adaptation sound localization trials. The results show that recalibration is very fast. Substantial aftereffects are obtained after only 18-24 exposures and asymptote appears to be reached between 60 and 180 exposures. The rate of adaptation was independent of the size of the discrepancy. The retention of the aftereffect was strong, as we found no dissipation, not even after as few as 60 exposure trials.

EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors

BackgroundDue to the aging of the population, the number of older patients diagnosed with a malignant disease is increasing. A multidisciplinary approach to the senior adult cancer patient is mandatory, to assure optimal diagnosis and therapeutic management. DesignEuropean Organisation for Research and Treatment of Cancer (EORTC) has currently defined senior adult oncology as one of its priorities and has established an active Elderly Task Force (ETF). Under the auspices of the EORTC, the ETF organized a workshop on clinical trial methodology in older cancer patients and in this article, we present the conclusions of this workshop. ResultsBesides the ‘classical’ efficacy end points, quality of life, functional status and independence of the patient should be assessed in clinical trials in older patients. The participants of the workshop agreed on the use of a minimum dataset for the assessment of global health and functional status in older cancer patients. The panel also recommended that optimization of collaboration with pharmaceutical industry requires reporting of age-related data (subgroup analyses of clinical trials, age-related pooled analyses and obligatory post-marketing studies in vulnerable and frail older patients). ConclusionThe identification of proper clinical outcomes and the validation of geriatric screening tools are needed for conducting sound and comparable clinical trials.

A two-choice sound localization procedure for detecting lateralized tinnitus in animals

Rats were trained in a two-choice procedure to respond in the direction of left and right sounds. Silent trials, on which no sound was presented and for which the animals received no feedback, were interspersed among the sound trials to determine each animal's natural side preference. Following training, the rats were exposed to a loud tone in the ear opposite their side preference. A shift in responding on the silent trials to the side of the exposed ear indicated that the animals were hearing a sound in that ear (i.e., tinnitus). Simulating lateralized tinnitus by presenting a low-level, continuous sound on one side also caused the rats to shift their responding on the silent trials to that side. Sham exposures indicated that halothane/nitrous oxide anesthesia could reinstate tinnitus in animals that had previously tested positive for it. Exposing rats to loud tones of various frequencies indicated that frequencies near the limits of the rat's hearing range were less likely to cause tinnitus than tones in the midrange.

An overview of randomization and minimization programs for randomized clinical trials

Randomization is an essential component of sound clinical trials, which prevents selection biases and helps in blinding the allocations. Randomization is a process by which subsequent subjects are enrolled into trial groups only by chance, which essentially eliminates selection biases. A serious consequence of randomization is severe imbalance among the treatment groups with respect to some prognostic factors, which invalidate the trial results or necessitate complex and usually unreliable secondary analysis to eradicate the source of imbalances. Minimization on the other hand tends to allocate in such a way as to minimize the differences among groups, with respect to prognostic factors. Pure minimization is therefore completely deterministic, that is, one can predict the allocation of the next subject by knowing the factor levels of a previously enrolled subject and having the properties of the next subject. To eliminate the predictability of randomization, it is necessary to include some elements of randomness in the minimization algorithms. In this article brief descriptions of randomization and minimization are presented followed by introducing selected randomization and minimization programs.

Hand assisted laparoscopic surgery versus conventional laparoscopy for colorectal surgery

Laparoscopic surgery for colon disease has been shown to have advantages over the open approach in the perioperative period in terms of shorter hospital stay, decreased analgesic use and a more rapid return of bowel function but provides these benefits at the expense of increased technical difficulty and operative time. Hand assisted surgery which a is a hybrid of open surgery and laparoscopic surgery may offer patients the perioperative advantages of minimally invasive surgery without the technical difficulty and increased operative time associated with the conventional laparoscopic approach. This review compares the benefits and harms of laparoscopic and hand assisted laparoscopic surgery for colon disease. To estimate the perioperative outcomes of hand assisted laparoscopic surgery compared to conventional laparoscopic surgery in adult patients requiring colorectal resections. We searched EMBASE (1980- Feb 2010), Medline (1966- Feb 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, 2010 issue 1), references of included studies, relevant review articles and conference abstracts. Randomised controlled trials (RCTs) in which adult patients were allocated to either receive hand-assisted laparoscopic surgery or conventional laparoscopic colorectal resection for benign or malignant colorectal disease. Studies were not restricted by language of publication. Reports of potentially relevant articles were retrieved in full text, and two reviewers independently assessed the eligibility of these studies. Data abstraction was performed independently by two reviewers. Meta-analysis of perioperative outcome measures was carried out using a random effects model. Three randomised controlled studies met the inclusion criteria (n=189).One study focused exclusively on malignant pathology, the second study focused mostly on benign pathology and the third trial had a mixed variety of pathology with approximately a third representing malignant pathology. Conversion rates were significantly decreased in patients undergoing hand assisted surgerybut there was no statistically significant difference in operative time or complication rates when comparing hand assisted surgery to conventional laparoscopy. All studies were associated with methodological limitations. Despite the limited number of trials performed, meta-analysis demonstrated a statistically significant decrease in conversion rates among the hand assisted group.There was no difference in operating time or perioperative complication rates. Additional adequately powered and methodologically sound trials are needed to determine if there is a clinically important difference in perioperative outcomes. Due to significant costs associated with the use of hand-assist devices, economic analyses are also warranted.

Facial soft tissue response to anterior segmental osteotomies: A systematic review

Bimaxillary protrusion is prevalent among Asians and anterior segmental osteotomies are commonly used for its surgical correction. The objective of this study was to evaluate the soft tissue changes resulting from anterior segmental osteotomies. The electronic databases PubMed, Scopus and ISI Web of knowledge were searched for potentially eligible studies using a set of predetermined keywords. Full texts meeting the inclusion criteria were retrieved and their references were manually searched for additional relevant articles. The study details and outcome data of these reports were extracted using spreadsheets for comparison. The methodological quality of each study was assessed. Eleven studies met the inclusion criteria. Lateral cephalometry was used in all studies. A reduction of the labial prominence with an increase in the nasolabial angle was noted subsequent to anterior segmental osteotomies. The magnitude of the reported soft tissue changes and their ratios corresponding to the osseous movements varied among studies. Long-term, prospective, methodologically sound clinical trials with larger samples and three-dimensional quantification are required to provide sufficient information for predicting the soft tissue response to anterior segmental osteotomies.

Criteria for the ethical conduct of psychiatric neurosurgery clinical trials

There is an urgent need for an effective therapy for treatment-refractory mental illness. Trials ongoing globally that explore surgical treatment, such as deep brain stimulation, for refractory psychiatric disease have produced some promising early results. However, diverse inclusion criteria and variable methodological and ethical standards, combined with the sordid past of neuromodulation, confound trial interpretation and threaten the integrity of a new and emerging science. What is required is a standard of ethical practice, globally applied, for neurosurgical trials in psychiatry that protects patients and maintains a high ethical benchmark for clinicians and researchers to meet. With mental illness, as well as treatment resistance, reaching epidemic proportions, ethically and scientifically sound clinical trials will lead to effective and safe surgical treatments that will become vital components of the clinicians' armamentarium. Ethical criteria, such as the ones proposed here, need to be established now and applied in earnest if the field is to move forward and if patients with no other therapeutic options are to receive much-needed treatment.

Measurement Issues in Trials of Pediatric Acute Diarrheal Diseases: A Systematic Review

Worldwide, diarrheal diseases rank second among conditions that afflict children. Despite the disease burden, there is limited consensus on how to define and measure pediatric acute diarrhea in trials. In RCTs of children involving acute diarrhea as the primary outcome, we documented (1) how acute diarrhea and its resolution were defined, (2) all primary outcomes, (3) the psychometric properties of instruments used to measure acute diarrhea and (4) the methodologic quality of included trials, as reported. We searched CENTRAL, Embase, Global Health, and Medline from inception to February 2009. English-language RCTs of children younger than 19 years that measured acute diarrhea as a primary outcome were chosen. We identified 138 RCTs reporting on 1 or more primary outcomes related to pediatric acute diarrhea/diseases. Included trials used 64 unique definitions of diarrhea, 69 unique definitions of diarrhea resolution, and 46 unique primary outcomes. The majority of included trials evaluated short-term clinical disease activity (incidence and duration of diarrhea), laboratory outcomes, or a composite of these end points. Thirty-two trials used instruments (eg, single and multidomain scoring systems) to support assessment of disease activity. Of these, 3 trials stated that their instrument was valid; however, none of the trials (or their citations) reported evidence of this validity. The overall methodologic quality of included trials was good. Even in what would be considered methodologically sound clinical trials, definitions of diarrhea, primary outcomes, and instruments employed in RCTs of pediatric acute diarrhea are heterogeneous, lack evidence of validity, and focus on indices that may not be important to participants.

Early enteral nutrition in the ICU

In a recent article published in Intensive Care Medicine, Doig et al. [1] describe a systematic review assessing the value of early enteral nutrition in the intensive care unit. The last paragraph of the paper begins “Meta-analysis conducted on the methodologically sound clinical trials identified by our systematic review of the literature revealed a statistically significant reduction in mortality and pneumonia attributable to the provision of standard EN within 24 h of injury.” “Methodologic soundness” was defined as trials that were free of major methodological flaws, namely pseudo-randomization (because of the loss of concealment of allocation) and >10% loss to follow-up. (Although the investigators also assessed the trials for any element of blinding, blinding itself did not appear to be a criterion for inclusion.) Six such trials (Chiarelli 1990, Chuntrasakul 1996, Kompan 1999, Pupelis 2001, Kompan 2004, Nguyen 2008) were identified and employed in the meta-analyses. Even for these reports, Doig et al. in the Validity appraisal of the Results section, acknowledged that it was unclear if allocation concealment was accomplished (in addition to noting that there was no instance where blinding was done). Hence, the methodologic soundness only depended on the single criterion of <10% loss to followup. The situation is more problematic. In the Methods section of Chiarelli 1990 [2], it is stated that the 20 patients were “randomly assigned to one of two groups by the case-control method.” That method is not explained. The term “case-control” usually refers to an observational (and retrospective) study, not a prospective randomized one. If this study was prospective, one possible meaning of “case-control” is that the patients were assigned alternately; if so, there would be no concealment of allocation. Given the description by Chiarelli et al. how can we be sure that this was a properly randomized trial? The Pupelis 2001 trial is also problematic [3]. As Doig et al. noted, there was an earlier report of this trial [4]; in that report, 11 patients were in the enteral nutrition group and 18 in the control group. In the final report, there were 30 patients in each arm, meaning that, in the period following the preliminary report, 19 and 12 patients were enrolled into treatment and control groups. If this trial was randomized, a patient had a 50% chance of being assigned to either arm. The likelihood that at least 18 of 29 patients would be assigned to the same arm is about 26%. Similarly, the likelihood that no more than 11 of the next 31 would be assigned to the same arm is 14%. Thus, the probability of having these events occur back to back is 14 × 26%, or < 4% (equivalent to a p value <0.04). There is concern that, at least for the second half of the trial, the randomization was somehow distorted. It may even be that this trial was not randomized at all. There is a separate confounding factor in three of the other trials (Chuntrasakul 1996, Kompan 1999, Kompan 2004), namely a disproportionate use of parenteral nutrition. There is evidence that parenteral nutrition increases the risk of infections [5]. Both protocols by Kompan et al. [6, 7] called for parenteral nutrition to be given to the entire control group beginning on the first day. In the Chuntrasakul trial, parenteral nutrition supplementation was given to enteral nutrition recipients when the enteral intake was “insufficient”; the control patients received nutritional support by “conventional method” (not defined) [8]. Thus, in all three trials, the use of parenteral nutrition became a confounding issue. The problem with the randomized trials in the entire enteral nutrition literature is the absence of methodologic soundness, resulting in high risks of bias. Trials with high risks of bias typically overestimate purported treatment benefits [9]. Claims to the contrary notwithstanding, the evidence cited by Doig et al. is not methodologically sound. As such, it is not capable of supporting the claim that enteral nutrition reduces mortality and pneumonia in the critically ill.

Applying Themes from Research Ethics to International Education Partnerships

The ethics of international research have been much discussed over the past decade in academic literature. These papers have primarily focused on the challenge of conducting ethically sound clinical trials. The related domain of medical education has also been affected by trends of globalization, but the literature addressing ethical issues in international medical education is insufficient.

Use of Active Video Games to Increase Physical Activity in Children: A (Virtual) Reality?

There has been increased research interest in the use of active video games (in which players physically interact with images onscreen) as a means to promote physical activity in children. The aim of this review was to assess active video games as a means of increasing energy expenditure and physical activity behavior in children. Studies were obtained from computerized searches of multiple electronic bibliographic databases. The last search was conducted in December 2008. Eleven studies focused on the quantification of the energy cost associated with playing active video games, and eight studies focused on the utility of active video games as an intervention to increase physical activity in children. Compared with traditional nonactive video games, active video games elicited greater energy expenditure, which was similar in intensity to mild to moderate intensity physical activity. The intervention studies indicate that active video games may have the potential to increase free-living physical activity and improve body composition in children; however, methodological limitations prevent definitive conclusions. Future research should focus on larger, methodologically sound intervention trials to provide definitive answers as to whether this technology is effective in promoting long-term physical activity in children.