Vast Majority Of Trials Research Articles

Clinical Trials on Cellular Therapy for Children and Adolescents With Cancer: A 15-Year Trend in the United States.

Cellular therapies are frequently studied in clinical trials for pediatric patients with malignant disease. Characteristics of ongoing and completed cellular therapy clinical trials in the U.S. involving children and adolescents have not previously been reported. We searched ClinicalTrials.gov for clinical trials involving cellular therapies enrolling patients under 18 years of age in the U.S. Trials were initially stratified into child-only (maximum age of eligibility <18 years), child/adolescent and young adult (AYA)(maximum age of eligibility ≤21 years), and child/adult (maximum age of eligibility >21 years). Descriptive characteristics and trends over time were analyzed. We included 202 trials posted 2007-2022. Of the 202 trials, only three trials were child-only; thus, our subsequent analysis focused on comparing child/AYA (≤21 years) and child/adult trials (>21 years). One hundred sixty-nine (84%)enrolled both child and adult populations. The vast majority of trials were early phase (phase 1, 1/2, and 2, 198/202, 98%). Chimeric antigen receptor T cell therapies were most commonly studied (88/202, 44%), while natural-killer cell therapies were most common in child/AYA trials (42% vs. 16%). Most trials were single institution-only (130/202, 64%) and did not receive industry funding (163/202, 81%). Studies with industry funding were more likely to be multicenter (64% vs. 29%) and international (31% vs. 0.6%). Notably, no central nervous system tumor-specific trials had industry funding. There was no difference in therapy type based on funding source. Yearly new trial activations increased over the time period studied (p=0.01). The frequency of cellular therapy trial activations enrolling child/AYA patients with cancer in the U.S. has increased over time. Most studies were phase 1 or 2, single institution-only, and not industry-supported. Future opportunities for cell therapy for pediatric cancer should include multi-institutional approaches.

Relationship of hyperglycaemic and glycaemic fluctuations to major adverse cardiovascular events in type 2 Diabetes Mellitus

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Dean's funds of the University of Malta Medical School. Background Type 2 diabetes mellitus (T2DM) is a known major risk factor for cardiovascular disease. Nonetheless, tight glycaemic control has not convincingly shown to lead to improved cardiovascular outcomes in clinical trials. This could be due to the fact that the vast majority of trials did not assess the effect of hypoglycaemia and glucose fluctuations in their study population. The aim of this study was thus to investigate the effects of hyperglycaemia, hypoglycaemia and glucose variability in subjects with T2DM at a median follow-up of 6.4 years. Methods Subjects with T2DM of less than 10 years duration, and on stable anti-glycaemic treatment were recruited. At baselines, all participants underwent 72-hour continuous glucose monitoring, as well as parameters assessment. Moreover, risk factor bloods, including an HbA1c level, were taken. Patients were consequently followed up at 6.4 years (median: 2338 days, IQR: 2116-2446 days) and MACE (major adverse cardiovascular events) was assessed. This comprised a composite of all-cause mortality, non-fatal myocardial infarction (both ST-elevation myocardial infarction and non-ST elevation myocardial infarction), revascularisation (both percutaneous and coronary artery bypass grafting), non-fatal stroke and hospitilisation for heart failure. The incidence of MACE was assessed from electronic database available at the local public hospital that caters for the entire Maltese population. Univariate analysis was performed using Mann-Whitney U test for non-parametric variables and independent samples t-test for parametric variables. Variables with a p value &amp;lt;0.1 were consequently put in the multivariate Cox regression model to assess for independent predictors of MACE. Statistical analysis was performed using SPSS version 24.0 for Windows. Findings: The study population comprised 122 subjects with T2DM (89 males: 32 females). The mean age was 62.6 years and the mean DM duration was 3.7 years at baseline. At follow-up, 19 participants exhibited MACE. Variables with a p value of &amp;lt;0.1 in univariate analysis comprised fructosamine, HbA1c, mean systolic blood pressure measurements as well as duration of BG (blood glucose) &amp;lt;3.9 mmol/L and standard deviation of BG (an indicator of intra-individual blood glucose variability; the latter two were derived from 72-hour continuous glucose monitoring). Following adjustment for both age and gender, HbA1c (OR: 1.9, 95% CI: 1.32-2.73, p= 0.001) levels at baseline as well as standard deviation of BG (OR: 1.93, 95% CI: 1.68-3.16, p= 0.009) were shown to be independent predictors of MACE. Interpretation: This study demonstrates that cardiovascular disease in subjects with T2DM of relatively short duration is not only influenced by poor glycaemic control but also by fluctuations in glucose levels, as evidenced by measurements obtained from continuous glucose monitoring obtained at baseline.

Characteristics of endodontic clinical trials registered in clinicalTrials.gov between 2000 and 2022

ABSTRACT Aim: This study aims to examine the characteristics of endodontic clinical trials registered in the ClinicalTrials.gov database. Methods: The ClinicalTrials.gov website was searched for endodontic clinical trials that were registered between 2000 and 2022. The search term used was “endodontics.” As a result of the search strategy, 613 trials were identified. Out of which, 500 clinical trials met our inclusion criteria. For each clinical trial, information was extracted including the year of registration, location of the trial, type of trial, study design (allocation, intervention model, and masking) estimated enrollment, participants’ age, health condition/problems studied, intervention/treatment, the status of the trial, study results, phase of the trial, and source of funding. Fisher’s exact test was applied to identify the characteristics of clinical trials associated with funding. Results: The number of registered clinical trials gradually increased from 2000 to 2022. Out of 500 clinical trials, 456 were interventional, and 44 were observational. Only 18 clinical trials had secured funding. The majority of interventional trials (90.8%) are randomized, and the most common interventional model was parallel assignment (88.4%). It was observed that irreversible pulpitis was the most common condition studied (32.2%). Nonsurgical endodontic therapy was the most common intervention used in the trials (42.2%). Conclusion: The study provided an overview of endodontic clinical trials that were registered in the ClinicalTrials.gov. The findings showed that registered endodontic clinical trials have increased rapidly since 2000. The vast majority of trials took place in Africa. The majority of endodontic clinical trials followed rigorous methods in terms of allocation, intervention model, and masking. However, only a small portion of trials had secured funding. The findings also indicate the need for trial results to be made publicly available to enhance evidence-based practice in endodontics.

A Narrative Review of New Treatment Options for Diabetic Nephropathy.

Diabetic nephropathy (DN) is a type of nephropathy that is caused by a diabetic condition. Diabetic nephropathyis seen in type 1 and type2 diabetes. End-stage renal disorders are brought on by DN. Diabetic nephropathy is thought to be linked to metabolic changes in the body. Proteinuria and glomerular filtration rate are the two most crucial diagnostic and prognosis measures for diabetic kidney disease (DKD), yet both have significant disadvantages. Novel biomarkers are thus increasingly required to improve risk factors and detect disease at an early stage. Controlling blood glucose and vital sign like body temperature and blood pressure, reducing cholesterol levels, and blocking the renin-angiotensin system are the standard treatments for diabetic patients. On the other hand, if used too late within the course of the disease, these therapeutic techniques can only provide partial relief from nephropathy. The complicated pathophysiology of the diabetic kidney, which experiences a variety of severe structural, metabolic, and functional alterations, represents one of the most important obstacles to the event of effective therapeutics for DN. Despite these issues, new diabetes models have identified promising treatment targets by identifying the mechanisms that control important functions of podocytes and glomerular endothelial cells. It has been shown in the vast majority of trials that renin-angiotensin system inhibitors combined with integrative therapies work well for DN. Combining sodium-glucose cotransporter-2 inhibitors and renin-angiotensin-aldosterone system blockers is a novel way to slow down the course of DKD by lowering inflammatory and fibrotic indicators brought on by hyperglycemia, which is more effective than using either medicine alone. Aldosterone receptor inhibitors and advanced glycation end-product inhibitors are two recently produced medications that may be used successfully to treat DN.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the “what,” “for whom,” and “how” of exercise to promote cognitive function

BackgroundTargeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms.MethodsTwo hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up).DiscussionEstablishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as “medicine” to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health.Trial registrationClinicalTrials.gov NCT02737878. Registered on April 14, 2016.

Immunotherapy in pancreatic cancer—an emerging role: a narrative review

Immunotherapy is the fastest growing branch in oncology that have already revolutionized the treatment of few solid cancers. The number of immunotherapy trials for pancreatic cancer (PC) is growing but the vast number of different agents used make it difficult to comprehend a possible success trait of a certain type of immunotherapy. The aim of this review is to summarize and critically evaluate the outcome of immunotherapy trials for PC intended to aid the comprehensiveness for the treating physicians. A PubMed search was performed to identify clinical trials in patients with PC, published in English from year 2000 to June 2021 and using combination of the terms immunotherapy, PC, and cross-checked the bibliography of the revised literature as the dublettes have been removed. Studies were divided into three groups depending on what immune components have been applied: passive products (peptides, antibodies, etc.), antigen-presenting cells, and adoptive cell transfer trials. The vast majority of trials, including those from most recent years, used passive products of the immune system-peptide vaccines and antibodies. The administration was often parallel to chemotherapy that was prevalently gemcitabine-based. Although immunological responses have been detected, the clinical efficacy was very limited. Trials with check point inhibitors did not show survival advantage. Dendritic cell (DC) vaccines have been associated with some clinical objective response and prolonged survival in few patients with delayed type hypersensitivity reactions. Trials with adoptive transfer therapy are lacking. The very few trials with lymphokine-activated killer (LAK)/cytokine-induced killer (CIK) cells tested only in Asian population have resulted in some clinical effects with prolonged survival. In none of the trials have the patients been preconditioned before receiving immunotherapy. Although the clinical effectiveness in the majority of the reported trials has been limited, the immunological effects observed in almost all trials show a proof of concept-that immunotherapy can work. Careful re-evaluation of the clinical premises and focus on combination and cell therapy may be the way to achieve improved survival by immunotherapy in PC.

Surface color under environmental illumination

Objects in real three-dimensional environments receive illumination from all directions, characterized in computer graphics by an environmental illumination map. The spectral content of this illumination can vary widely with direction [1], which means that the computational task of recovering surface color under environmental illumination cannot be reduced to correction for a single illuminant. We report the performance of human observers in selecting a target surface color from three distractors, one rendered under the same environmental illumination as the target, and two rendered under a different environmental illumination. Surface colors were selected such that, in the vast majority of trials, observers could identify the environment that contained non-identical surface colors, and color constancy performance was analyzed as the percentage of correct choices between the remaining two surfaces. The target and distractor objects were either matte or glossy and presented either with surrounding context or in a dark void. Mean performance ranged from 70% to 80%. There was a significant improvement in the presence of context, but no difference for matte and glossy stimuli, and no interaction between gloss and context. Analysis of trial-by-trial responses showed a dependence on the statistical properties of previously viewed images. Such analyses provide a means of investigating mechanisms that depend on environmental features, and not only on the properties of the instantaneous proximal image.

Methodology, results, and publication of oncology clinical trials: Insights from all the world’s randomized controlled trials (RCTs) 2014-2017.

2019 Background: Clinical cancer research is now a global effort. Most published overviews of oncology trials are restricted to a specific disease site or cohort of high-profile journals. Here we describe authorship, trial characteristics, design, and results of all oncology RCTs published globally during 2014-2017. Methods: A structured literature search was designed using PUBMED to identify all RCTs evaluating anti-cancer therapies published during 2014-2017. Data were captured regarding authorship, participants, study characteristics, design, and results. Among superiority RCTs that met the primary endpoint (i.e. statistically “positive”), we calculated the ESMO-MCBS to identify trials with substantial clinical benefit (MCBS scores 4/5 or A/B). Outcomes were compared with Chi Square or Fisher’s Exact tests. Results: The study cohort included 694 RCTs. The most common cancers evaluated were breast (17%, 121/694), lung (15%, 104/694) and colorectal (8%, 58/694). Treatment intent was curative, adjuvant/neoadjuvant, and palliative in 10% (68/694), 25% (176/694), and 65% (448/694) of trials respectively. Median sample size was 443 (IQR 246-718). Seventy percent (488/694) of RCTs were supported by industry; 87% (601/694) of experimental arms tested systemic therapy. Ninety-two percent (636/694) of RCTs were led by investigators in 28 high-income countries; the most common countries leading these trials were US (27%, 174/636), France (10%, 64/636), Germany (10%, 62/636), Japan (9%, 59/636), and UK (9%, 57/636). The most common primary endpoints were PFS (32%, 220/694), OS (31%, 215/694), and DFS (11%, 79/694); Forty-six percent of all trials (318/694) met their primary endpoint. Among superiority trials with “positive” results, 33% met ESMO-MCBS threshold for substantial clinical benefit. The median impact factor (IF) of journals which published the overall study cohort of trials was 21 (IQR 7-27); trials meeting their primary endpoint were published in higher profile journals (median IF 25 vs 18, p &lt; 0.001). Conclusions: At the global level, oncology clinical trials are dominated by high-income countries and study diseases which do not necessarily reflect the global burden of cancer. The vast majority of trials are funded by industry and only one third of “positive” trials meet ESMO-MCBS threshold for substantial clinical benefit.

Effects of sodium glucose cotransporter 2 inhibitors on mineral metabolism in type 2 diabetes mellitus.

Purpose of reviewSodium glucose cotransporter 2 (SGLT2) inhibitors are relatively novel antidiabetic drugs that improve glycemic control and reduce cardiovascular outcomes as well as renal function decline. SGLT2 inhibitors act by inhibiting glucose reabsorption in the proximal tubule of the kidney. Emerging data suggest that these drugs may also influence bone and mineral metabolism. This review summarizes clinical trial data on bone and mineral outcomes, and discusses potential underlying mechanisms.Recent findingsThree large randomized controlled trials documented cardiovascular and renal protective effects of SGLT2 inhibitors. Recent studies indicate that SGLT2 inhibitors influence renal phosphate reabsorption and calciuria. Although the CANVAS trial suggested an increased fracture risk associated with canagliflozin compared with placebo, the vast majority of trials and meta-analyses did not demonstrate an increased fracture risk associated with SGLT2 inhibitor use.SummarySGLT2 inhibitors have shown clinically relevant cardiovascular and renal protective effects. The long-term implications for bone health, in particular in the context of chronic kidney disease, are still incompletely understood and warrant further investigation.

Platelet GP IIb-IIIa Receptor Antagonists in Primary Angioplasty: Back to the Future.

Coronary artery disease and acute myocardial infarction still represent the leading cause of mortality in developed countries. Therefore, great efforts have been made in the last decades to improve reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite optimal epicardial recanalisation, a large proportion of patients still experience impaired reperfusion and in-stent thrombosis. The adjunctive use of glycoprotein (GP) IIb-IIIa inhibitors may certainly contribute in the reduction of such complications, especially when administered in the early phase of infarction. In fact, in this phase a larger platelet composition of the thrombus and the presence of a larger amount of viable myocardium, as compared to a delayed phase, may increase the benefits from this therapy and counterbalance the potential higher risk of bleeding. A large body of evidence has been accumulated on the benefits from GP IIb-IIIa inhibitors in terms of prevention of stent thrombosis, and benefits in mortality, especially among high-risk patients and as upstream strategy. Therefore, based on current available data, GP IIb-IIIa inhibitors can be recommended as early as possible (upstream strategy) among high-risk patients, such as those with advanced Killip class or anterior myocardial infarction (MI), and those presenting within the first three hours. Even though it is not universally accepted, in our opinion this strategy should be implemented in a pre-hospital setting (in ambulance) or at first hospital admission (Emergency Room or Coronary Care Unit, irrespective of whether they are in the spoke or hub hospitals). Peri-procedural intracoronary administration of GP IIb-IIIa inhibitors has not provided additional benefits as compared to intravenous administration and therefore cannot be recommended. Even though the vast majority of trials have been conducted with abciximab, several meta-analyses comparing small molecules (mainly high-dose tirofiban rather than eptifibatide) versus abciximab showed similar angiographic and clinical results between the molecules. Several recent investigations and meta-analyses have documented the higher risk of stent thrombosis associated with bivalirudin as compared to unfractionated heparin (UFH). Being that these results are independent from the use of GP IIb-IIIa inhibitors, UFH should still remain the anticoagulation therapy of choice in ST-segment elevation myocardial infarction (STEMI) patients. Minimisation of bleeding complications by extensive use of the radial approach, in the setting of STEMI, may further contribute to the adoption of a more aggressive antithrombotic and antiplatelet therapy incorporating the use of GP IIb-IIIa inhibitors. The establishment of dedicated networks for STEMI, and the large STEMI campaign, will certainly contribute to increase the proportion of patients presenting at first medical contact within the early phase (3h) of infarction and therefore highly suitable for a more aggressive pharmacoinvasive approach with upstream administration of GP IIb-IIIa inhibitors. In fact, although the current therapeutic targets of increased rates of timely reperfusion, mainly by primary percutaneous coronary intervention (PCI), has been achieved, a deep look into the future in the fight against MI will certainly put aborting infarction as the major desirable target to be achieved.

Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art.

Renal cell carcinoma (RCC) is among the most prevalent malignancies in the USA. Most RCCs are sporadic, but hereditary syndromes associated with RCC account for 2-3 % of cases and include von Hippel-Lindau, hereditary leiomyomatosis, Birt-Hogg-Dube, tuberous sclerosis, hereditary papillary RCC, and familial renal carcinoma. In the past decade, our understanding of the genetic mutations associated with sporadic forms of RCC has increased considerably, with the most common mutations in clear cell RCC seen in the VHL, PBRM1, BAP1, and SETD2 genes. Among these, BAP1 mutations are associated with aggressive disease and decreased survival. Several targeted therapies for advanced RCC have been approved and include sunitinib, sorafenib, pazopanib, axitinib (tyrosine kinase inhibitors (TKIs) with anti-vascular endothelial growth factor (VEGFR) activity), everolimus, and temsirolimus (TKIs that inhibit mTORC1, the downstream part of the PI3K/AKT/mTOR pathway). High-dose interleukin 2 (IL-2) immunotherapy and the combination of bevacizumab plus interferon-α are also approved treatments. At present, there are no predictive genetic markers to direct therapy for RCC, perhaps because the vast majority of trials have been evaluated in unselected patient populations, with advanced metastatic disease. This review will focus on our current understanding of the molecular genetics of RCC, and how this may inform therapeutics.

Reporting outcome measures in trials of infant colic.

Infant colic (IC), with an estimated prevalence of 5% to 25%, has a high impact on health care costs. Furthermore, reported negative sequelae are disturbed parent-infant interaction, increased susceptibility to abdominal pain, and even child abuse. Its etiology remains unknown, leading to a wide variety in interventions. We hypothesize that definitions and outcome measures in studies on IC will be heterogeneous as well. Our objective is to systematically assess how definitions and outcome measures are reported in randomized controlled trials (RCTs) of IC. CENTRAL, Embase, and MEDLINE/PubMed were searched from inception to December 2012. English-language systematic reviews (SRs) and RCTs concerning IC in children ages 0 to 9 months were included. Bibliographies of included SRs were searched for additional articles. Quality was assessed using the Delphi list. A total of 1702 studies were found; 55 articles were included (16 SRs, 39 RCTs). In 39 trials, we found 20 different definitions for IC, 11 different definitions for improvement, 28 different interventions, and 19 different outcomes. Fifty-one percent of the trials were of good methodological quality. All of the trials used parental diaries; only 31% stated that their instrument was validated. Too many different definitions and outcome measures for IC are used in RCTs. Only a minority of the trials reported parental perception as primary outcome. Uniform definitions, outcomes, and validated instruments are needed to make a comparison between intervention studies possible.

Combining Anti-Epidermal Growth Factor Receptor (EGFR) and Anti-Angiogenic Strategies in Advanced NSCLC: We Should have Known Better…

Drugs directed against Epidermal Growth Factor Receptor (EGFR), namely tyrosine kinase inhibitors erlotinib and gefitinib, and anti-angiogenic agents, namely the anti-Vascular Endothelial Growth Factor (VEGF) antibody bevacizumab, have independently demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC), and are currently approved for use in clinical practice. Pre-clinical studies have shown promising results with the combination of anti-EGFR and anti-angiogenesis drugs in different tumor models, including NSCLC. Several clinical trials have been conducted to verify if the combination of the two therapeutic strategies could improve the outcome in the setting of advanced NSCLC. The largest body of evidence has been produced testing the combination of erlotinib plus bevacizumab, or erlotinib plus a multi-targeted receptor tyrosine kinase inhibitor, namely sunitinib or sorafenib. Furthermore, several dual inhibitors, targeting both EGFR and VEGFR, have been tested in advanced NSCLC, with the greatest body of evidence produced with vandetanib. However, despite an intriguing pre-clinical background, the combination strategy has not yet produced clinically relevant results. Several phase III trials showed an improvement in progression-free survival, underlining some activity of targeting both pathways concurrently, but no trial has demonstrated an impact on overall survival to date. Unfortunately, the vast majority of trials conducted in this setting have been performed without any selection criteria based on molecular characteristics, compromising the chance of detecting a potentially relevant benefit in selected subgroup of patients. In recent years, the important interaction between the efficacy of EGFR inhibitors and the presence of EGFR activating mutations in tumor cells has been repeatedly demonstrated. On the other hand, we still have no clear idea about predictive factors of efficacy for bevacizumab and other anti-angiogenic drugs. This is probably the real challenge to optimize the use of these drugs and to fully evaluate the real clinical potential of a combination strategy.

Domperidone

Domperidone

Should the measurement of blood pressure in the office be redefined?

or almost a century the measurement of blood pres-sure(BP)intheofficeorclinicbythedoctorornurseusing a standard mercury sphygmomanometer com-bined with the auscultatory method has been the standardapproach to hypertension diagnosis and management [1].The vast majority of trials that demonstrated the risksassociated with elevated BP and the benefits of treat-ment-induced BP reduction have used conventional officeBPmeasurements.Althoughmultipleoutcometrialsinclud-ingthousandsofindividualshaveconsistentlyshownofficeBP to be a strong predictor of risk, in the individual patient,office BPhas less prognostic value [1].Themaindrawbacksof office BP are due to operator (doctor or nurse)-relatedproblems, such as observer’s prejudice and bias (expec-tations), readingerrors(terminaldigitpreference,roundingand random error) and the so-called ‘white-coat’ and‘masked hypertension’ phenomena [1,2]. Moreover, it isacknowledged that in clinical practice, office BP measure-ments are less standardized than in clinical trials andmightbemisleadinginaconsiderableproportionofpatients[1,3–6]. Recently, the conventional office BP measurementshave entered a period of fundamental change, which is notonly dictated by the need for more reliable measures, but isalso due to the demise of the mercury sphygmomanometerand to the recent development of accurate electronic BPmonitors for professional use [3–13].

Prevention of diabetes and cardiovascular disease among prediabetic individuals: lifestyle versus drug interventions

Prediabetes refers to impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), the stage preceding the development of clinical diabetes. IGT is defined as 2-h post-load glucose 140mg/dl (7.8mmol/l) and <200mg/dl (11.1mmol/l); IFG as fasting plasma glucose 110mg/dl (6.1mmol/l) and <126mg/dl (7.0mmol/l). More recently, HbA1c of 5.7–6.4% was added as another criterion for defining prediabetes. According to the Third National Health and Nutrition Examination Survey, 1988–1994, the prevalence of IFG in the US population 20 years of age was 6.9% and that of IGT in those 40–74 years of age was 15.8%. No matter how it is defined, prediabetes is associated with a substantially elevated risk of cardiovascular disease (CVD). This finding provides support for the ‘ticking clock’ hypothesis, which postulates that ‘the clock for coronary heart disease starts ticking before the onset of clinical diabetes.’ The evidence is also compatible with the ‘common soil’ hypothesis, which posits that diabetes and cardiovascular disease share common pathophysiological and environmental antecedents, i.e., ‘they spring from a common soil.’ In the Nurses’ Health Study cohort, participants who converted from prediabetes to type 2 diabetes during follow-up had a more atherogenic risk profile (e.g., higher BMI values and greater prevalence of hypertension and hypercholesterolemia) and increased incidence of CVD than those who did not convert. However, individuals with preexisting diabetes at baseline had the most adverse CVD risk profiles and the highest incidence of CVD during follow-up. Therefore, prediabetes, diabetes, and cardiovascular disease constitute a continuum of cardiometabolic risk. As a consequence, early management of prediabetes through lifestyle interventions or pharmacological means is not only critical to reduce the progression from prediabetes to diabetes, but also to decrease the long-term risk of CVD. In this issue of European Journal of Cardiovascular Prevention and Rehabilitation, Hopper et al. reported a meta-analysis of prospective, randomized controlled trials (RCTs) that evaluated the effects of lifestyle intervention or pharmacological treatment on diabetes prevention among individuals with IGT and/or IFG. Ten RCTs with 23,152 patients were included in the metaanalysis. The average duration of the trials was 3.75 years. Overall, the interventions reduced the risk of diabetes by 17% (95%CI 14–20%), with lifestyle interventions more effective than drug-based ones (RR1⁄4 0.52, 0.46–0.58 vs 0.70, 0.58–0.85, p< 0.05). No significant benefit in either total or cardiovascular mortality was observed for either intervention. This meta-analysis confirms earlier data showing the superiority of lifestyle interventions over drug-based treatment for diabetes prevention among prediabetic individuals. In the Diabetes Prevention Program (DPP), the lifestyle intervention group experienced a 58% decrease in the risk of diabetes over a 3-year period compared to controls. This effect was considerably greater than that in the metformin group (31%). Findings were similar for incidence of the metabolic syndrome, with the lifestyle group experiencing 41% risk reduction, and the metformin group 17% risk reduction, compared with placebo. The strong relationship between diabetes and CVD outcomes suggests that interventions that are effective in preventing diabetes would also reduce risk of CVD. However, this meta-analysis found no benefits of lifestyle or pharmacological interventions on total or CVD death. Lack of power is a major limitation of this metaanalysis as the vast majority of trials were not designed to examine CVD outcomes. Of the 10 RCTs combined, there were only 274 CVD deaths in the intervention groups and 85 in the control groups. Some trials had no CVD deaths in either group. Besides relatively small

Motor planning and control in autism. A kinematic analysis of preschool children

Kinematic recordings in a reach and drop task were compared between 12 preschool children with autism without mental retardation and 12 gender and age-matched normally developing children. Our aim was to investigate whether motor anomalies in autism may depend more on a planning ability dysfunction or on a motor control deficit. Planning and control processes were separately investigated by examining kinematic recordings divided into primary movement- (planning-based) and corrective submovement- (control-based) phases. Despite longer movement durations, participants with autism were as accurate in their movements as normally developing children were and showed a preserved movement structure. No differences were observed for the initial movement phases for hand velocity, accuracy and inter-trial variability. Our main finding was that of a group difference in proximity of the target, at transition from planning-based to control-based movement guidance. At primary movement conclusion, the normally developing children had already reduced velocity and begun orienting their hands for ball drop. Also, they tended to terminate movements within the same movement unit that had transported the hand into the target box. Compared to this group, participants with autism reached this stage with less preparation: their speed was significantly higher, wrist inclination reduced and they showed further movement units after entering the box over the vast majority of trials. These additional movement units were presumed to represent late control-based spatial adjustments. Hence, our data support the hypothesis that children with autism have a greater need for corrective submovements. We provide evidence that motor anomalies in autism might be determined either by a disruption in planning-control integration, or by a limited planning process capacity, as participants with autism might have been able to plan only the very beginning of the movement, leaving its final phases to further planning on the fly, with important consequences on movement time optimization.

Beurteilungs- und Prognosekriterien bei COPD

A standard outcome parameter for pharmacological trials in COPD has not yet been defined. Therefore, it is the aim of this review to evaluate frequently used parameters for their eligibility as assessment and outcome parameters in COPD. A review of the actual scientific literature was performed. It is recommended to continue to rely primarily on the FEV (1), which has been used as a primary variable in the vast majority of trials. In addition, further parameters, such as FVC and IC/TLC should be determined. If available, additional information is provided by RV/TLC, K (co), PaO (2) and PaCO (2). FEV (1) is not a surrogate parameter for dyspnoea, quality of life, and exercise tolerance, which should therefore be assessed separately. Frequency and severity of exacerbations and mortality are important outcome parameters in long-term trials. Complex indices, such as the BODE index, may be superior to single variables. No single additional parameter has been evaluated sufficiently in order to substitute FEV (1) as the standard parameter for the assessment and outcome in COPD.

Methodological arguments for the necessity of randomized trials in high-dose chemotherapy for breast cancer.

In the past ten years high-dose chemotherapy with autologous haematopoietic stem-cell support (HD-CT) has increasingly been used for breast cancer. But the vast majority of trials are small phase I/II studies showing until now not enough evidence that HD-CT is superior to conventional-dose chemotherapy (CD-CT). In contrast to this, the public perception of this treatment is different. Patients as well as physicians often uncritically believe in reports contrasting the positive results obtained in case series treated by HD-CT with those of historical control groups. This leads to the problem that many patients and also clinicians are not willing to participate in randomized trials on this topic. A critical assessment of current knowledge on the effectiveness of HD-CT in breast cancer is given. The problems related to the use of historical controls, in general, and especially in the setting of HD-CT are demonstrated. Using data of patients treated with CD-CT within trials of the German Breast Cancer Study Group (GBSG) it will be shown that results similarly favorable to those reported from patients treated with a high-dose regimen may be produced using quite simple selection mechanisms. Comparisons of patients treated with HD-CT with historical control groups of patients treated with CD-CT may be misleading. A valid treatment comparison is only possible by means of large randomized trials. Clinicians should participate in the ongoing trials and enter all eligible patients.

Addressing the Adversarial Deficit in Non-Jury Criminal Trials

It is a curious quirk of legal scholarship that so much attention has been devoted to the rules and procedures that operate injury trials and so little to the way in which these rules and procedures operate in the vast majority of trials which are conducted without a jury. This “jury-centredness” as it has been called was noted almost thirty years ago by the American scholar Kenneth Culp Davis when he urged scholars and the legal profession to escape from the deep-seated habit of allowing all thinking about evidence law to be dominated by the needs of the 3% of trials that involve juries and to think instead about the needs of the remaining 97% of trials that are tried without a jury. It is certainly true that the withdrawal of the jury from many categories of cases throughout this century in many jurisdictions has not been accompanied by any instant changes in the law of evidence. Certain commentators have noted that in spite of Thayer's claim that the rules are the “child of the jury”, the rules of evidence have proved remarkably resilient in outlasting the demise of the jury. The parent may have ceased to exist in many legal proceedings but the child has lived on.