Use of analgesics in France, following dextropropoxyphene withdrawal.

BACKGROUND: In 2009, the European Medicines Agency recommended withdrawal of dextropropoxyphene (DXP); in March 2011 it was withdrawn from the market in France. Up until that time the combination dextropropoxyphene-paracetamol (DXP/PC) was widely used for analgesia. At withdrawal, French regulators recommended that DXP/PC be replaced by other step 2 analgesics, i.e. tramadol, codeine, or opium-containing drugs, or by PC for a weak level of pain. To investigate prescribing behaviours after DXP/PC withdrawal, dispensations of analgesics before and after withdrawal were analysed. METHODS: Aggregated dispensation data of analgesics prescribed between January 2009 and December 2012 in the Rhône-Alpes region were obtained from the general health insurance claims data; changes in analgesic dispensation over time were analysed with the ATC/DDD methodology. Pre (Jan-June 2009) and post-withdrawal (Jan-June 2012) changes of DDDs where computed for each analgesic step. RESULTS: The dispensations of DXP/PC experienced a two-step decrease until 2011. Over the withdrawal period 2009-2012, there was a 14% decrease in the overall use of analgesic (from 109 to 94 DDDs), while the use of step 2 analgesics declined by 46% (- 22 DDDs, from 47 to 25 DDDs). This latter decline included a cessation of use of DXP/PC (29 DDDs in 2009) that were only in part (+ 7 DDDs, from 18 to 25 DDDs) compensated by increased use of codeine, tramadol and opium, in monotherapy or combined with PC. For step 1 analgesics, use increased with 9%, mostly PC (+ 8 DDDs, from 31 to 39 DDDs). Step 3 analgesics dispensations remained largely unchanged over this period (around 3 DDDs). CONCLUSIONS: In the Rhône-Alpes region, DXP/PC withdrawal was accompanied in part by an increased use of same level analgesics, and in part by an increased use of PC in monotherapy. The extent of DXP/PC use before withdrawal, and the increased use of PC after DXP withdrawal, underline the complexity of pain management.

Model of mucociliary clearance in cystic fibrosis lungs.

Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

Validation of a scanning technique with minimal compression for measuring muscle volume with freehand 3D ultrasound.

Freehand 3D ultrasound (3D-US) is a promising technique for measuring muscle volume but it requires gel pads or water tanks to limit probe compression on the skin which makes it hard to use in clinical applications. Our objectives were to measure the effect of different compressions on muscle volume in order to assess the clinical applicability of a minimal compression method for lower limb muscles. 4 muscles of the lower limb on 15 healthy volunteers were scanned with a new commercial freehand 3D-US setup accessible to clinical experimentators. Each muscle was scanned with 3 levels of compression: standard compression, minimal compression and gel pad (method validated against MRI). Volume was calculated using software segmentation tools. Acquisitions and segmentations were done by the same examiner. There was a significant impact of standard compression on volume measurements, but no difference between minimal compression and gel pad. Standard compression underestimated volume with a mean bias of 16 mL. For minimal compression, 75 % of measured differences were below the predefined clinically acceptable limits of 10 mL. Mean bias for this method was 1.1 mL. In conclusion, standard compression in freehand 3D-US induces a systematic bias in volume calculations. But, with a trained examiner and the necessary precautions to minimize compression, this bias could be abolished and become acceptable in clinical applications. When a high accuracy is required, gel pads could still be important to consider.

Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years.

BACKGROUND: Toxoplasma infection during pregnancy exposes the fetus to risks of congenital infection and sequelae that depend heavily on gestational age (GA) at time of infection. Accurate risk estimates by GA are necessary to counsel parents and improve clinical decisions. METHODS: We analyzed data from pregnant women diagnosed with acute Toxoplasma infection in Lyon (France) from 1987 to 2008 and assessed how the risks of congenital toxoplasmosis and of clinical signs at age 3 years vary depending on GA at the time of maternal infection. RESULTS: Among 2048 mother-infant pairs, 93.2% of mothers received prenatal treatment and 513 (24.7%) fetuses were infected. Because of a significant reduction in risk since 1992 when monthly screening was introduced (59.4% vs 46.6% at 26 GA weeks; P = .038), probabilities of infection were estimated on the basis of maternal infections diagnosed after mid-1992 (n = 1624). Probabilities of congenital infection were <10% for maternal infections before 12 weeks of gestation, rose to 20.0% at 19 weeks, and then continued increasing to 52.3% and almost 70% at 28 and 39 GA weeks, respectively. Because of a significant reduction in risk of clinical signs of congenital toxoplasmosis in infected children born from mothers diagnosed after 1995 when polymerase chain reaction testing on amniotic fluid was initiated (87/794 vs 46/1150; P = .012), probabilities of clinical signs at 3 years were estimated based on 1015 maternal infections diagnosed after 1995 including 207 infected children, with symptoms in 46 (22.2%). CONCLUSIONS: These analyses demonstrated that introduction of monthly prenatal screening and improvement in antenatal diagnosis were associated with a significant reduction in the rate of congenital infection and a better outcome at 3 years of age in infected children. Our updated estimates will improve individual management and counseling in areas where genotype II Toxoplasma is predominant.

Thigh muscle activities in elite rowers during on-water rowing.

This study analysed the muscle activity levels and patterns of the major thigh muscle activation during training sections at different intensities of on-water rowing. 9 experienced rowers performed 2 imposed-pace sections (B1 and B2) and 2 maximal-speed sections (start, 500 m) of on-water rowing. The knee angle, power output, mean torque and stroke rate were measured using specific instrumentation and were synchronised with surface electromyography signals of 5 superficial quadriceps and hamstring muscles. B1 and B2 sections were not significantly different regarding mechanical parameters and EMG activities, while the start phase induced large differences. The EMG patterns for B1, B2 were similar (cross-correlation coefficients (CC) ranged between 0.972-0.984) and the moderate CC found between both B1 and start (0.605-0.720) and B2 and start (0.629-0.720). Our results suggest that the hamstring muscles have a motor action and contribute to the power production during the leg drive. During an all-out 500 m section, a decrease in power and stroke rate was found (up to 20%). However, EMG patterns were not time shifted for all muscles. During the leg drive, the muscle activity levels of the quadriceps muscles were unchanged, while the activity of the hamstring muscles decreased.

In vivo assessment of both active and passive parts of the plantarflexors series elastic component stiffness using the alpha method: a reliability study.

The aim of this study was to investigate the reliability of an in vivo adaptation of the short range stiffness experiment associated with the application of a mathematical model to determine the stiffness of both torque dependent and independent components of the plantarflexors series elastic component. Fourteen subjects participated in this study. The experimental protocol consisted of quickly moving the ankle joint in dorsiflexion during constant voluntary isometric plantarflexion at 7 submaximal torque levels. Relationships between joint stiffness and torque were established and the stiffness of both torque dependent and independent components were determined using the alpha method. The day-to-day reliability was assessed for joint stiffness and stiffness of both torque dependent and independent components (ICC higher than 0.88 and CVs lower than 6.0%). This method could then be used to better understand adaptive subjacent mechanisms to assess the effects of training protocols, and the rehabilitation of neuromuscular pathologies or traumatisms.

Effects of plyometric training on passive stiffness of gastrocnemii and the musculo-articular complex of the ankle joint.

This study aimed to determine simultaneously the effects of plyometric training on the passive stiffness of the ankle joint musculo-articular complex, the gastrocnemii muscle-tendon complex (MTC) and the Achilles tendon in order to assess possible local adaptations of elastic properties. Seventeen subjects were divided into a trained (TG) group and a control (CG) group. They were tested before and after 8 weeks of a plyometric training period. The ankle joint range of motion (RoM), the global musculo-articular passive stiffness of the ankle joint, the maximal passive stiffness of gastrocnemii and the stiffness of the Achilles tendon during isometric plantar flexion were determined. A significant increase in the jump performances of TG relative to CG was found (squat jumps: +17.6%, P=0.008; reactive jumps: +19.8%, P=0.001). No significant effect of plyometric training was observed in the ankle joint RoM, musculo-articular passive stiffness of the ankle joint or Achilles tendon stiffness (P>0.05). In contrast, the maximal passive stiffness of gastrocnemii of TG increased after plyometric training relative to CG (+33.3%, P=0.001). Thus, a specific adaptation of the gastrocnemii MTC occurred after plyometric training, without affecting the global passive musculo-articular stiffness of the ankle joint.

Factors affecting the adherence to an antenatal screening programme: an experience with toxoplasmosis screening in France.

Monthly serological testing is mandatory in France for pregnant women not immune to toxoplasmosis. We assessed for the first time the adherence to this national programme, using data from antenatal tests for Toxoplasma antibodies collected by the Union of Health Insurance Services in the French Rhone-Alpes region.

Shoulder rotators electro-mechanical properties change with intensive volleyball practice: a pilot study.

This pilot study was designed to assess the incidence of high-level volleyball practice on muscle strength production and muscle activation during internal and external shoulder rotations. Seven professional and seven French amateur league volleyball players performed maximal isometric at three forearm angles, concentric and eccentric isokinetic internal and external shoulder rotations. The torque production and muscle activation levels of PECTORALIS MAJOR and INFRASPINATUS were determined. Few significant differences were found for muscle activation and co-activation between amateur and professional volleyball players during both internal and external rotations. No significant difference in torque production was observed for shoulder internal rotation between professional and amateur volleyball players. Torque production was significantly higher during shoulder external rotation for amateur (46.58+/-2.62 N . m) compared to professional (35.35+/-1.17 N . m) volleyball players relative to isometric contractions, but it was not different during isokinetic efforts. The torque ratios for external/internal rotations were always significantly lower for professional (0.42+/-0.03 pooling isometric and concentric conditions) compared to amateur volleyball players (0.56+/-0.03 pooling isometric and concentric conditions). Those results emphasize that a high level of volleyball practice induces a strong external rotators deficit compared to sports such as swimming, baseball or tennis.

Characterization of muscle belly elastic properties during passive stretching using transient elastography.

Passive muscle stretching can be used in vivo to assess the viscoelastic properties of the entire musculo-articular complex, but does not allow the specific determination of the muscle or tendon viscoelasticity. In this respect, the local muscle hardness (LMH) of the gastrocnemius medialis (GM) belly was measured during a passive ankle stretching of 10 subjects using transient elastography. A Biodex isokinetic dynamometer was used to stretch ankle plantar flexors, to measure ankle angle, and the passive torque developed by the ankle joint in resistance to the stretch. Results show that the LMH increased during the stretching protocol, with an averaged ratio between maximal LMH and minimal LMH of 2.62+/-0.46. Furthermore, LMH-passive torque relationships were nicely fitted using a linear model with mean correlation coefficients (R(2)) of 0.828+/-0.099. A good reproducibility was found for the maximal passive torque (ICC=0.976, SEM=2.9Nm, CV=5.5%) and the y-intercept of the LMH-passive torque relationship (ICC=0.893, SEM=105Pa, CV=7.8%). However, the reproducibility was low for the slope of this relationship (ICC=0.631, SEM=10.35m(-2), CV=60.4%). The y-intercept of the LMH-passive torque relationship was not significantly changed after 10min of static stretching. This result confirms the finding of a previous study indicating that changes in passive torque following static stretching could be explained by an acute increase in muscle length without any changes in musculo-articular intrinsic mechanical properties.

Accuracy of Biodex system 3 pro computerized dynamometer in passive mode.

A specific experimental design has been developed to determine the accuracy of the Biodex system 3 pro dynamometer in passive mode. Five cyclic stretching repetitions were imposed to an elastic rubber band at different velocities using the dynamometer, and the torque produced was measured using both the dynamometer and external force and position sensors. Velocity patterns performed by the dynamometer were also characterized and our results show that these patterns were reliable (ICC=1.00). The torque measured with the dynamometer and the sensors were reliable (ICC=1.00), although significant differences were observed between both methods. However, the measured torque standard error was velocity independent and was lower than 0.33 Nm. Moreover, regressions between the two torque measurements were close to the axes-bisector (r=1.00, slope: 1.01+/-0.01, y-intercept: -0.36+/-0.22 Nm). Finally, our results showed decreases in torque during the five cycles, but these decreases were not due to the dynamometer. It can be concluded that the dynamometer performed valid torque measurements in passive mode, and was an accurate tool to determine passive mechanical properties of the musculo-articular system. However, some discrepancies between the programmed and the measured speed profiles have been observed when approaching the speed limit of the system.

Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients.

T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2-5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity.The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatment duration that could be tested in a future clinical trial.We developed a mathematical model of virtual patients with T-LBL in order to obtain a proportion of virtual relapses close to the one observed in the real population of patients from the EuroLB database. Our simulations reproduced a 2-year follow-up required to study the onset of the disease, the treatment of the acute phase and the maintenance treatment phase.

Sevoflurane preconditioning at 1 MAC only provides limited protection in patients undergoing coronary artery bypass surgery: a randomized bi-centre trial.

BACKGROUND: Volatile agents can mimic ischaemic preconditioning leading to a decrease in myocardial infarct size. The present study investigated if a 15 min sevoflurane administration before cardiopulmonary bypass (CPB) has a cardioprotective effect in patients undergoing coronary surgery. METHODS: Seventy-two patients were randomized in two centres. The intervention group (S) received 1 MAC sevoflurane administrated via the ventilator for 15 min followed by a 15 min washout before CPB, the control group did not. The primary outcome was the postoperative troponin Ic peak. A biopsy of the atrium was taken during canulation for enzyme dosages. Results are expressed as mean (SD). RESULTS: Neither troponin Ic nor tissular enzyme measurement exhibited any difference between the groups: peak of troponin Ic was 4.4 (5.6) in S group vs 5.2 (6.6) ng ml(-1) in control group (ns). Intratissular ecto-5'-nucleotidase activity was 7.1 (4.3) vs 8.5 (11.9), protein kinase C activity was 27.1 (15.7) vs 29.2 (28.7), tyrosine kinase activity was 101 (54.1) vs 98.5 (63.3), and P38 MAPKinase activity was 131.1 (76.1) vs 127.1 (86.8) nmol mg protein(-1) min(-1) in S group and control group, respectively (ns). However there were fewer patients with low postoperative cardiac index in S group (11% in S vs 35% in control group, P < 0.05) when considering the per protocol population. In S group, 25% of patients required an inotropic support during the postoperative period, vs 36% of patients in control group (ns). CONCLUSIONS: This study did not show a significant preconditioning signal after 15 min of sevoflurane administration. The 15 min duration might be too short or the concentration of sevoflurane too low to induce cardioprotection detected by troponin I levels.

[Antagonist muscle coactivation and muscle inhibition: effects on external torque regulation and resistance training-induced adaptations]. / Coactivation et inhibition musculaire: influences sur la régulation du couple de force développé et les adaptations induites par un entraînement en force.

This review aims at analysing the influence of antagonist muscle coactivation and muscle inhibition on the ability of the neuromuscular system to produce an external torque and to account for changes in these two mechanisms with resistance training. Indeed, antagonist muscle coactivation and muscle inhibition occur during muscle contraction in order to preserve joint integrity. The origin of these two mechanisms would be both spinal and supraspinal and would tend to decrease with resistance training, which allows, under certain conditions, increasing the external torque developed. However, antagonist muscle coactivation and muscle inhibition depend on the characteristics of movement. Moreover, the origin and the contribution of supraspinal mechanisms to the antagonist muscle coactivation and muscle inhibition processes have to be specified.

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. METHODS: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. RESULTS: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39). CONCLUSION: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

Factors associated with 12 week case-fatality in Staphylococcus aureus bacteraemia: a prospective cohort study.

Staphylococcus aureus bacteraemia (SAB) is a frequent and deadly disease. Given the lack of a randomized trial, optimal first-line antibiotic treatment is still debated. Our aim was to identify prognostic factors in SAB patients and to analyse the impact of first-line antibiotics. The VIRSTA prospective cohort study was conducted in eight tertiary care centres in France. Consecutive incident adults in whom a blood culture drawn in participating centres grew S. aureus between April 2009 and October 2011 were prospectively followed for 12 weeks. Factors associated with 12-week case-fatality were identified by multivariate logistic regression. We enrolled 2091 patients and analysed survival in 1972 (median age 67.8 years, interquartile range 55.5-78.9; females 692/1972, 35.1%). SAB was nosocomial or healthcare-related in 1372/1972 (69.6%) of cases and the primary focus was unknown in 414/1972 (21.0%) of cases. Week 12 case-fatality rate was 671/1972 (34.0%). The main independent prognostic factors on multivariate analysis were age (adjusted OR by 10-year increment 1.56; 95% CI 1.44-1.69), septic shock (OR 5.11; 95% CI 3.84-6.80), metastatic cancer (OR 4.28; 95% CI 2.88-6.38), and unknown primary focus (OR 2.62; 95% CI 2.02-3.41). In the 1538 patients with methicillin-sensitive S. aureus (MSSA) bacteraemia, first-line empiric antistaphylococcal penicillins (OR 0.40; 95% CI 0.17-0.95) and vancomycin (OR 0.37; 95% CI 0.17-0.83), alone or combined with an aminoglycoside, were associated with better outcome compared with other antibiotics. There are few modifiable prognostic factors for SAB. Initiating empiric antibiotics with antistaphylococcal penicillins or vancomycin may be associated with better outcome in MSSA bacteraemia.

[Readability of informed consent forms for subjects participating in biomedical research: updating is required]. / Lisibilité de l'information écrite destinée aux sujets se prêtant à une recherche biomédicale: une nécessaire remise en question.

OBJECTIVE: We compared informed consent forms of subjects participating in biomedical research with those of references texts in order to determine the factors that influence readability. METHODS: We assessed the readability of 73 informed consent forms of research protocols conducted in the clinical investigation centres in the Rhone-Alpes area, and then compared them with 33 reference texts corresponding to 5 French school grades (first year infant, primary school, GCS level, high school, and classics aggregation), using the Flesch test and Cordial" analyser. RESULTS: Median Flesch scores were 66 for the first year infant level, 62 for the primary school level, 58 for the GCS level, 42 for the high school level, and 43 for the aggregation level. It was 22 for the informed consent forms. Median Cordial scores were 86 for the first year infant level, 77 for the second, 74 for the third, 49 for the fourth, 43 for the fifth. It was 1 for the informed consent forms. No methodological factor correlated with Flesch and Cordial" results. CONCLUSION: The quantitative readability scores for informed consent forms for subjects participating in biomedical research are low, lower than those proposed to aggregation candidates, whatever the type of protocol. Some thought must be given to the impact of the reduced readability on patients' understanding, and steps should be taken to improve the readability of the forms.

Is HbA1c a valid surrogate for macrovascular and microvascular complications in type 2 diabetes?

Recent recommendations regarding type 2 diabetes (T2D) patients' treatments have focused on personalizing glycosylated haemoglobin (HbA1c) targets. Because the relationship between HbA1c and diabetes prognosis has been established from large prospective cohorts, it is valid to question the extrapolation from population-based risk reduction estimations to individual predictions. Our study aimed to investigate the relationship between HbA1c reductions and clinical outcomes in randomized controlled trials (RCTs), using a meta-regression approach. Included were RCTs comparing intensive vs. standard glucose-lowering regimens for cardiovascular events and microvascular complications in T2D patients. Eight studies (33,396 patients) providing data for HbA1c reductions were found. In our meta-regression, HbA1c decreases were not significantly associated with reductions in our main study outcomes: total and cardiovascular mortality. They were also not associated with any of the secondary endpoints, including myocardial infarction, stroke and severe hypoglycaemia. Sensitivity analysis showed a significant correlation only between HbA1c-lowering and severe hypoglycaemia (P = 0.014). Meta-regression analysis could find no significant association between HbA1c-lowering and a decrease in clinical outcomes, thereby questioning the use of HbA1c as a surrogate outcome for T2D-related complications. Thus, RCTs vs. placebo are urgently required to evaluate the risk-benefit ratios of therapeutic strategies beyond HbA1c control in T2D patients.

Gastrointestinal tolerance of erythritol-containing beverage in young children: a double-blind, randomised controlled trial.

BACKGROUND/OBJECTIVE: To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose. SUBJECTS/METHODS: A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h. RESULTS: Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25 g groups compared with placebo, but not in the 5 and 15 g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 -h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol. CONCLUSIONS: Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis.