Job description and perception of clinical research personnel working in a network of French intensive care units.

BACKGROUND: There is a lack of information about the organisation and management of clinical research personnel in Europe and of their professional activity in intensive care. We therefore conducted a cross-sectional survey among personnel currently working in a French intensive care research network that involves 41 centres nationwide. The aim of the survey was to describe the personnel's personal and institutional organisation and management, their job perception in terms of satisfaction and stress, and suggestions for improvement. METHODS: Over 3 months in 2023, the research personnel received an electronic questionnaire on their personal and professional profile, past and present training, workplace and functions currently performed, personal knowledge about job skills required, job satisfaction and stress by as measured on a rating scale, and suggested ways of improvement. RESULTS: Ninety seven people replied to the questionnaire (a response rate of 71.3%), of whom 78 (57.3%) were sufficiently involved in intensive care to provide complete answers. This core sample had profiles in line with French recruitment policies and comprised mainly Bachelor/Master graduates, with nurses accounting for only 21.8%. The female to male ratio was 77:23%. Many responders declared to have a shared activity of technician (for investigation) and assistant (for quality control). More than 70% of the responders considered that most of the tasks required of each worker were major. Figures were much lower for project managers, who were few to take part in the survey. On a scale of 10, the median of job satisfaction was 7 for personal work organisation, 6 for training and for institutional organisation, and only 5 for personal career management. The median of job stress was 5 and was inversely correlated with satisfaction with career management. Respect of autonomy, work-sharing activity between investigation and quality control, a better career progression, financial reward for demanding tasks, and participation in unit staff meetings were the main suggestions to improve employee satisfaction. CONCLUSION: This nationwide survey provides a new insight into the activity of French clinical research personnel and points to ways to improve the quality and efficiency of this workforce.

Enhanced pain sensitivity in obese patients with obstructive sleep apnoea syndrome is partially reverted by treatment: An exploratory study.

BACKGROUND: Obesity is frequently associated with obstructive sleep apnoea syndrome (OSA) and chronic pain. OSA as well as continuous positive airway pressure (CPAP) treatment may modulate the pain perception threshold (PT) in patients with obesity. METHODS: In this prospective, longitudinal study, all patients admitted for obesity assessment were screened for OSA by nocturnal polygraphy (SOMNOcheck® , IAH ≥10) and performed mechanical (Von Frey electronic device) and electrical (PainMatcher® ) pain tests. Those with severe OSA were retested for PT 1 month after initiation of CPAP therapy. Newly diagnosed patients with severe OSA (hypopnea apnoea index >30) have been offered to start CPAP treatment. RESULTS: Among 85 patients, there were 27 OSA patients, aged between 40 ± 13.2 years with a BMI of 42 ± 7.2 kg/m2 . Severe OSA patients (N = 11) showed a lower PT than non-OSA patients (N = 58) during mechanical (177 ± 120 vs. 328 ± 136 g, p < 0.01) and electrical methods (7.4 ± 6.4 vs. 12.9 ± 6.7 stimulation duration steps; p = 0.03). In the severe OSA group (N = 7), an increased PT was observed 1 month after CPAP treatment during mechanical pain testing (298 ± 69 vs. 259 ± 68 g, p < 0.05), but not during electrical pain testing (11.5 ± 3.0 vs. 12.4 ± 3.8 stimulation duration steps, p = 0.50). CONCLUSION: In patients with obesity, this exploratory study showed that the presence of an OSA is associated with a decreased PT, whereas implantation of a CPAP device tends to normalize pain perception.

Using Magnetic Resonance Imaging During Childbirth to Demonstrate Fetal Head Moldability and Brain Compression: Prospective Cohort Study.

BACKGROUND: Childbirth is a physiological process with significant medical risk, given that neurological impairment due to the birthing process can occur at any time. Improvements in risk assessment and anticipatory interventions are constantly needed; however, the birthing process is difficult to assess using simple imaging technology because the maternal bony pelvis and fetal skeleton interfere with visualizing the soft tissues. Magnetic resonance imaging (MRI) is a noninvasive technique with no ionizing radiation that can monitor the biomechanics of the birthing process. However, the effective use of this modality requires teamwork and the implementation of the appropriate safeguards to achieve appropriate safety levels. OBJECTIVE: This study describes a clinically effective and safe method to perform real-time MRI during the birthing process. We reported the experience of our team as part of the IMAGINAITRE study protocol (France), which aimed to better understand the biomechanics of childbirth. METHODS: A total of 27 pregnant women were examined with 3D MRI sequences before going into labor using a 1-Tesla open-field MRI. Of these 27 patients, 7 (26%) subsequently had another set of 3D MRI sequences during the second stage of labor. Volumes of 2D images were transformed into finite element 3D reconstructions. Polygonal meshes for each part of the fetal body were used to study fetal head moldability and brain compression. RESULTS: All 7 observed babies showed a sugarloaf skull deformity and brain compression at the middle strait. The fetus showing the greatest degree of molding and brain shape deformation weighed 4525 g and was born spontaneously but also presented with a low Apgar score. In this case, observable brain shape deformation demonstrated that brain compression had occurred, and it was not necessarily well tolerated by the fetus. Depending on fetal head moldability, these observations suggest that cephalopelvic disproportion can result in either obstructed labor or major fetal head molding with brain compression. CONCLUSIONS: This study suggests the presence of skull moldability as a confounding factor explaining why MRI, even with the best precision to measure radiological landmarks, fails to accurately predict the modality of childbirth. This introduces the fetal head compliance criterion as a way to better understand cephalopelvic disproportion mechanisms in obstetrics. MRI might be the best imaging technology by which to explore all combined aspects of cephalopelvic disproportion and achieve a better understanding of the underlying mechanisms of fetal head molding and moldability.

Grapefruit Juice Flavanones Modulate the Expression of Genes Regulating Inflammation, Cell Interactions and Vascular Function in Peripheral Blood Mononuclear Cells of Postmenopausal Women.

Grapefruit is a rich source of flavanones, phytochemicals suggested excreting vasculoprotective effects. We previously showed that flavanones in grapefruit juice (GFJ) reduced postmenopausal women's pulse-wave velocity (PWV), a measure of arterial stiffness. However, mechanisms of flavanone action in humans are largely unknown. This study aimed to decipher molecular mechanisms of flavanones by multi-omics analysis in PBMCs of volunteers consuming GFJ and flavanone-free control drink for 6 months. Modulated genes and microRNAs (miRNAs) were identified using microarrays. Bioinformatics analyses assessed their functions, interactions and correlations with previously observed changes in PWV. GFJ modified gene and miRNA expressions. Integrated analysis of modulated genes and miRNA-target genes suggests regulation of inflammation, immune response, cell interaction and mobility. Bioinformatics identified putative mediators of the observed nutrigenomic effect (STAT3, NF-κB) and molecular docking demonstrated potential binding of flavanone metabolites to transcription factors and cell-signaling proteins. We also observed 34 significant correlations between changes in gene expression and PWV. Moreover, global gene expression was negatively correlated with gene expression profiles in arterial stiffness and hypertension. This study revealed molecular mechanisms underlying vasculoprotective effects of flavanones, including interactions with transcription factors and gene and miRNA expression changes that inversely correlate with gene expression profiles associated with cardiovascular risk factors. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01272167].

The Added Value of Sensitivity to Nonnoxious Stimuli to Predict an Individual's Sensitivity to Pain.

BACKGROUND: Simple tools are needed to predict postoperative pain. Questionnaire-based tools such as the Pain Sensitivity Questionnaire (PSQ) are validated for this purpose, but prediction could be improved by incorporating other parameters. OBJECTIVES: To explore the potency of sensitivity to nonpainful stimuli and biometric data to improve prediction of pain. STUDY DESIGN: Transversal exploratory study. SETTING: Single clinical investigation center. METHODS: Eighty-five healthy volunteers of both genders underwent a multimodal exploration including biometry, questionnaire-based assessment of anxiety, depression, pain catastrophizing, sensitivity to smell, and the PSQ, followed by a psychophysical assessment of unpleasantness thresholds for light and sound, and sensitivity to mechanical, heat, and cold pain. These last 3 parameters were used to calculate a composite pain score. After a multi-step selection, multivariable analyses identified the explanative factors of experimental pain sensitivity, by including biometric, questionnaire-based, and psychophysical nonnociceptive sensitivity parameters, with the aim of having each domain represented. RESULTS: Female gender predicted mechanical pain, a younger age and dark eyes predicted cold pain, and the PSQ predicted heat pain. Sensitivity to unpleasantness of sound predicted mechanical and heat pain, and sensitivity to unpleasantness of light predicted cold pain. Sensitivity to smell was unrelated. The predictors of the composite pain score were the PSQ, the light unpleasantness threshold, and an interaction between gender and eye color, the score being lower in light-eyed men and higher in all women. The final multivariable multi-domain model was more predictive of pain than the PSQ alone (R2 = 0.301 vs 0.122, respectively). LIMITATIONS: Sensitivity to smell was only assessed by a short questionnaire and could lack relevance. Healthy volunteers were unlikely to elicit psychological risk factors such as anxiety, depression, or catastrophizing. These results have not been validated in a clinical setting (e.g., perioperative). CONCLUSION: The predictive potential of the PSQ can be improved by including information about gender, eye color, and light sensitivity. However, there is still a need for a technique suitable for routine clinical use to assess light sensitivity.

Effects of Totum-63 on glucose homeostasis and postprandial glycemia: a translational study.

Global prevalence of type 2 diabetes (T2D) is rising and may affect 700 million people by 2045. Totum-63 is a polyphenol-rich natural composition developed to reduce the risk of T2D. We first investigated the effects of Totum-63 supplementation in high-fat diet (HFD)-fed mice for up to 16 wk and thereafter assessed its safety and efficacy (2.5 g or 5 g per day) in 14 overweight men [mean age 51.5 yr, body mass index (BMI) 27.6 kg·m-2] for 4 wk. In HFD-fed mice, Totum-63 reduced body weight and fat mass gain, whereas lean mass was unchanged. Moreover, fecal energy excretion was higher in Totum-63-supplemented mice, suggesting a reduction of calorie absorption in the digestive tract. In the gut, metagenomic analyses of fecal microbiota revealed a partial restoration of HFD-induced microbial imbalance, as shown by principal coordinate analysis of microbiota composition. HFD-induced increase in HOMA-IR score was delayed in supplemented mice, and insulin response to an oral glucose tolerance test was significantly reduced, suggesting that Totum-63 may prevent HFD-related impairments in glucose homeostasis. Interestingly, these improvements could be linked to restored insulin signaling in subcutaneous adipose tissue and soleus muscle. In the liver, HFD-induced steatosis was reduced by 40% (as shown by triglyceride content). In the subsequent study in men, Totum-63 (5 g·day-1) improved glucose and insulin responses to a high-carbohydrate breakfast test (84% kcal carbohydrates). It was well tolerated, with no clinically significant adverse events reported. Collectively, these data suggest that Totum-63 could improve glucose homeostasis in both HFD-fed mice and overweight individuals, presumably through a multitargeted action on different metabolic organs.NEW & NOTEWORTHY Totum-63 is a novel polyphenol-rich natural composition developed to reduce the risk of T2D. Totum-63 showed beneficial effects on glucose homeostasis in HFD-fed mice, presumably through a multitargeted action on different metabolic organs. Totum-63 was well tolerated in humans and improved postprandial glucose and insulin responses to a high-carbohydrate breakfast test.

From the pharmaceutical to the clinical: the case for effervescent paracetamol in pain management. A narrative review.

OBJECTIVE: Paracetamol has an established place in the management of mild-to-moderate pain, but has certain limitations, including varying bioavailability, and potential hepatotoxicity if taken in overdose. Effervescent formulations may help to overcome these limitations. METHODS: Pubmed searches, with no limits on date or language, were conducted in February 2020. Further references were identified from the reference lists of retrieved articles, and from the authors' knowledge of the field. RESULTS: Effervescent formulations contain an organic acid (usually citric acid) and carbonate or bicarbonate salts (usually sodium bicarbonate). Upon contact with water, these react to form carbon dioxide, which facilitates the disintegration of the tablet and dissolution of the active drug. Moreover, sodium bicarbonate dose-dependently increases gastric emptying, which together with rapid dissolution facilitates drug absorption. In pharmacokinetic studies, effervescent formulations result in faster absorption of paracetamol than conventional oral formulations, and this translates into a faster onset of analgesia in clinical trials. Effervescent paracetamol has a favorable safety profile, with good tolerability. Importantly, the sodium content of some preparations does not appear to increase cardiovascular risk under real world conditions. Effervescent formulations may also offer advantages in terms of ease of administration and palatability. CONCLUSIONS: Effervescent formulations of paracetamol result in faster drug absorption, and hence more rapid analgesia, than oral tablets, and offer a favorable tolerability and safety profile. The use of such formulations may therefore help to promote appropriate use of paracetamol.

Impact of magnesium supplementation, in combination with vitamin B6, on stress and magnesium status: secondary data from a randomized controlled trial.

Primary findings from a recent study reported that magnesium supplementation significantly reduced stress in severely stressed subjects with low magnesemia, and additional vitamin B6 enhanced this effect. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress in these subjects remains to be elucidated. This secondary analysis investigated the impact of magnesium and vitamin B6 supplementation and perceived stress on erythrocyte magnesium levels, as a marker of body magnesium status. This was a secondary analysis from an 8-week randomized controlled trial comparing oral magnesium (300 mg) and magnesium-vitamin B6 (300 mg + 30 mg) supplementation. Stress level and erythrocyte magnesium level at baseline, and change in erythrocyte magnesium and serum vitamin B6 levels at weeks 4 and 8, were analyzed. Overall, 264 subjects were randomized to treatment and had evaluable Depression Anxiety Stress Scale scores (132 in each treatment arm). At baseline, stress scores, and mean serum magnesium, erythrocyte magnesium, and serum vitamin B6 concentrations were similar between arms. Although not significant between groups, a significant increase over time in erythrocyte magnesium levels was observed in the subgroup of subjects with low baseline erythrocyte magnesium levels (<1.6 mmol/L) following treatment with magnesium and magnesium-vitamin B6 (week 4:0.21 mmol/L [95% confidence interval (CI), 0.10 to 0.31], p = 0.0003; and 0.13 mmol/L [95% CI, 0.02 to 0.23], p = 0.0233, respectively). Change from baseline in circulating vitamin B6 levels at weeks 4 and 8 in the magnesium-vitamin B6 supplemented group (314.96 nmol/L [95%CI, 294.61 to 335.31]) was significantly different (p < 0.0001) compared with the magnesium supplemented group (-0.39 nmol/L [95% CI, -20.73 to 19.94]). Magnesium alone and magnesium-vitamin B6 provided statistically significant increases in erythrocyte magnesium in subjects with low magnesium status (<1.6mmol/L). Vitamin B6 supplementation did not further increase magnesium levels.

Three-dimensional magnetic resonance imaging of fetal head molding and brain shape changes during the second stage of labor.

To demonstrate and describe fetal head molding and brain shape changes during delivery, we used three-dimensional (3D) magnetic resonance imaging (MRI) and 3D finite element mesh reconstructions to compare the fetal head between prelabor and the second stage of labor. A total of 27 pregnant women were examined with 3D MRI sequences before going into labor using a 1 Tesla open field MRI. Seven of these patients subsequently had another set of 3D MRI sequences during the second stage of labor. Volumes of 2D images were transformed into finite element 3D reconstructions. Polygonal meshes for each part of the fetal body were used to study fetal head molding and brain shape changes. Varying degrees of fetal head molding were present in the infants of all seven patients studied during the second phase of labor compared with the images acquired before birth. The cranial deformation, however, was no longer observed after birth in five out of the seven newborns, whose post-natal cranial parameters were identical to those measured before delivery. The changing shape of the fetal brain following the molding process and constraints on the brain tissue were observed in all the fetuses. Of the three fetuses presenting the greatest molding of the skull bones and brain shape deformation, two were delivered by cesarean-section (one after a forceps failure and one for engagement default), while the fetus presenting with the greatest skull molding and brain shape deformation was born physiologically. This study demonstrates the value of 3D MRI study with 3D finite element mesh reconstruction during the second stage of labor to reveal how the fetal brain is impacted by the molding of the cranial bones. Fetal head molding was systematically observed when the fetal head was engaged between the superior pelvic strait and the middle brim.

Transcultural adaptation and French validation of the Pain Sensitivity Questionnaire.

PURPOSE: To validate a French translation of the Pain Sensitivity Questionnaire (PSQ), which is a valuable tool to predict an individual's natural disposition to feel pain that could be used after surgery. METHODS: We studied content validity, internal consistency, convergent validity (anxiety, depression and catastrophism) and test-retest reliability of the French version of the PSQ (PSQ-F) in 146 patients either before scheduled surgery or during pregnancy; then, convergent and concurrent validity in 85 healthy volunteers submitted to nociceptive tests. RESULTS: Internal consistency of the PSQ-F was found to be excellent, with Cronbach's α at 0.866, 0.886, and 0.927, respectively for its "minor", "moderate" and "total" scores. Test-retest reliability was significant, with intraclass correlation coefficients at 0.629, 0.629, and 0.635, respectively for the above- mentioned scores. These three scores correlated with anxiety, depression and catastrophizing scores in patients, but not in healthy volunteers, possibly because of low and few variant psychometric scores in this group. They were inversely correlated to the temperature needed to evoke heat pain rated 6 out of 10, but not to the mechanical pain threshold (electronic von Frey), nor to the heat pain threshold. Finally, they directly correlated to the pain induced by the cold pressor test (minor and total scores only). DISCUSSION: This validated version can now be used by French-speaking researchers and physicians. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT03113903); 14 April, 2017.

RéSUMé: OBJECTIF: Valider une version en langue française du Pain Sensitivity Questionnaire (PSQ), qui permet d'identifier la sensibilité naturelle d'un individu à la douleur, ce qui pourrait être applicable après une chirurgie. MéTHODE: Nous avons étudié la validité de structure interne, la validité convergente (anxiété, dépression et catastrophisme) et la reproductibilité par test-retest de la version française du PSQ (PSQ-F) chez 146 patients en situation préopératoire ou en cours de grossesse, puis la validité convergente et de structure contre critère externe chez 85 sujets volontaires sains soumis à des tests nociceptifs. RéSULTATS: La consistance interne du PSQ-F était excellente avec des α de Cronbach égaux à 0,866, 0,886 et 0,927, respectivement pour ses scores « mineur ¼, « modéré ¼ et « total ¼. La reproductibilité était satisfaisante, avec des coefficients de corrélation intra-classe, respectivement à 0,629, 0,629 et 0,635. Ces trois scores étaient corrélés à l'anxiété, la dépression et le catastrophisme, mais pas chez les volontaires sains qui avaient des scores psychométriques bas et peu variables. Ils étaient anti-corrélés au seuil de nociception thermique chaud en épreuve supra-liminale, mais pas au seuil de nociception mécanique ponctuelle, ni au seuil de nociception thermique chaud en épreuve liminale. Enfin, les scores « mineur ¼ et « total ¼ étaient corrélés à la douleur moyenne ressentie à l'immersion du pied en eau froide. CONCLUSION: Cette version validée peut être utilisée par les chercheurs et cliniciens francophones. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT03113903); le 14 avril 2017.

Genetics and postsurgical neuropathic pain: An ancillary study of a multicentre survey.

BACKGROUND: Neuropathic pain following surgery could be a useful model for the study of the genetic mechanisms of peripheral neuropathic pain. OBJECTIVE: The aim of this study was to identify genetic predictors of persistent postsurgical neuropathic pain. DESIGN: An ancillary study from a prospective cohort. SETTING: Eighteen French university hospitals. PATIENTS: Five hundred and sixty-one patients at risk of persistent postoperative pain who underwent scheduled surgery were classified as 159 cases and 402 controls. INTERVENTION: Pre-operative blood sampling for DNA analysis and questionnaires sent at the third and sixth month after surgery. MAIN OUTCOME MEASURES: The phenotype was the report of pain at the site of surgery with a positive response in the DN4 questionnaire within 6 months after surgery. Out of a list of 126 candidate genes involved in the initial processes of peripheral neuropathic pain, a set of 4599 single nucleotide polymorphisms was tested on an Illumina chip. We carried out the association tests, based on an additive model, on 4422 single nucleotide polymorphisms. RESULTS: After correcting for type-I error inflation, only one suggestive association was reached for one single nucleotide polymorphism, the rs2286614, which we had selected to tag KCNK4. This gene encodes for TRAAK, a two-pore domain background K channel involved in the modulation of the primary thermoreceptors of the transient receptor potential channels family. CONCLUSION: This is the first genetic association study specifically investigating the occurrence of persistent postsurgical neuropathic pain. Its results help target future research to better understand the mechanisms of peripheral neuropathic pain. TRIAL REGISTRATION: ClinicalTrials.gov (ref. NCT00812734).

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial.

INTRODUCTION: Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress. METHODS: In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs). RESULTS: In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related. CONCLUSIONS: These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.

How are patients with heart failure treated in primary care?
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OBJECTIVE: The aim of this study was to assess the adherence of general practitioners (GPs) to guidelines in patients with heart failure with reduced ejection fraction (HFrEF) and to describe GPs' prescribing behavior regarding patients with heart failure with preserved ejection fraction (HFpEF). MATERIALS AND METHODS: Cross-sectional study as part of the ETIC trial. Five classes of drugs were described: angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs); ß-blockers (BBs); mineralocorticoid receptor antagonists (MRAs); diuretics (thiazide or loop diuretics); and digoxin. RESULTS: 178 patients were studied: their mean age was 73.5 years (± 10.6). Of the 128 patients with HFpEF, 81.3% received ACEIs or ARBs, 63.3% received BBs, 13.3% received MRAs, 75.8% received diuretics, and 12.5% received digoxin. Of the 50 patients with HFrEF, 84% received ACEIs or ARBs, 74% received BBs, 20% received MRAs, 76% received diuretics, and 2% received digoxin. 25% of the patients were given a drug in accordance with the recommendations for drug class but not a drug authorized for the HFrEF indication. Among the patients with HFrEF who were treated in accordance with the recommendations, target doses were achieved in 1/3 given ACEIs/ARBs, 1/4 given BBs, and 1/2 given MRAs. Only 6% of the patients had a perfect Global Adherence Indicator-3 (GAI-3) with all target doses achieved. CONCLUSION: Several drugs were prescribed even though they were not recommended, and few patients were treated optimally. It seems to be necessary to develop a pragmatic tool to help GPs and cardiologists in optimizing treatment.
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An Advanced Formulation of a Magnesium Dietary Supplement Adapted for a Long-Term Use Supplementation Improves Magnesium Bioavailability: In Vitro and Clinical Comparative Studies.

While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag® versus reference tablet (3 × 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use.

Using connected objects in clinical research.

Connected objects (CO), whether medical devices or not, are used in clinical research for data collection, a specific activity (communication, diagnosis, effector, etc.), or several functions combined. Their validation should be based on three approaches: technical and clinical reliability, data protection and cybersecurity. Consequently, the round table recommends that the typology of COs, their uses and limitations, be known and shared by all, particularly for implementing precise specifications. COs are used in clinical research during observational studies (assessment of the device itself or data collection), randomized studies, where only one group has a CO (assessment of its impact on patient follow-up or management), or randomized studies where both groups have a CO, which is then used as a tool to help with assessment. The benefits of using COs in clinical research includes: improved collection and quality of data, compliance of patients and pharmacovigilance, easier implementation of e-cohorts and a better representative balance of patients. The societal limits and risks identified relate to the sometimes intrusive nature of certain collected parameters and the possible misuse of data. The round table recommends the following on this last point: anticipation, by securing transmission methods, the qualification of data hosts, and assessment of the object's vulnerability. For this, a risk analysis appears necessary for each project. It is also necessary to accurately document the data flow, in order to inform both patients and healthcare professionals and to ensure adequate security. Anticipating regulatory changes and involving users starting from the study design stage are also recommended.

Activation state of circulating eosinophils in nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease with an uncertain pathophysiology. It is characterized by polyps rich in eosinophils, with an activation status already investigated at the tissue level. In a group of CRSwNP patients, we assessed the activation status of circulating eosinophils in the blood before migration into tissues. METHODS: Thirteen patients with CRSwNP and 16 healthy volunteers were enrolled. Several biologic parameters were studied: blood count of eosinophils; plasma eosinophil cationic protein; oxidative metabolism by chemiluminescence at baseline or when activated by phorbol 12-myristate 13-acetate or platelet-activating factor, with or without interleukin-5 (IL-5); percent of granulosar cells; and mean fluorescence intensity (MFI) by flow cytometry. RESULTS: The mean number of eosinophils was significantly higher in patients with CRSwNP, whose eosinophils showed increased oxidative metabolism in the basal or activated state significantly decreasing in the presence of IL-5. There was also a higher percentage of CD49d+ , CD25+ , and CCR3+ cells in patients, and a nonsignificant decrease in descending order in MFI between the control group, patients with normal eosinophil levels, patients with hypereosinophilia, and patients with aspirin-exacerbated respiratory disease. CONCLUSION: This study demonstrates a priming state of circulating eosinophils in CRSwNP patients when compared with healthy controls, as evidenced by the extent of oxidative metabolism, with increased sensitivity to IL-5 and by the observed variations of percent and MFI of CD49d, CCR3, and CD25. This priming is thus found at the peripheral level and occurs before the migration of eosinophils to polyps, reflecting the systemic and not just local nature of abnormalities in CRSwNP.

Substantial Variability Across Individuals in the Vascular and Nutrigenomic Response to an Acute Intake of Curcumin: A Randomized Controlled Trial.

SCOPE: Curcumin exerts biological activities of interest in cardiovascular prevention. However, its vascular protective effect is still poorly investigated in humans. The present study aims to assess vascular effect of an acute intake of curcumin and its nutrigenomic impact in circulating immune cells. METHODS AND RESULTS: In a randomized, double-blind, crossover design, 18 healthy smokers consume a placebo or a 5-g curcumin. Before and 2 h after the intake, vascular function measurements are performed by using flow-mediated dilation (FMD). In addition, endothelial function in the microcirculation and blood pressure are evaluated. Plasma curcumin concentrations and changes in gene expression in peripheral blood mononuclear cells (PBMC) are analyzed. No significant effect of curcumin on FMD is observed when considering the entire study population, mainly due to a high interindividual variability. A subgroup analysis according to the gender or the cardiovascular-risk score reveals a significant effect of curcumin on FMD in women and in subjects presenting lower cardiovascular risk. No change in gene expression is observed when data are analyzed for all volunteers but changes in expression are observed when analyzed according to gender. CONCLUSIONS: This clinical trial highlights that a substantial variability in efficacy of curcumin exists across individuals.

Impact of sympathetic activation on pain threshold in human subjects.

This study examined the effect of the sympathetic activation with the head-up tilt test (HUT) on electrocutaneous pain in 56 young normotensive volunteers. Systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), heart rate (HR), sensory and pain thresholds to electrocutaneous stimulation were measured 30s before (in supine position), during (at 10s, 90s, 3min and 5min) and 10min after HUT (in supine position). No relationship was found between resting BP and pain perception. HUT significantly increased DAP and HR, but did not change SAP. During HUT, both sensory and pain electrocutaneous thresholds were significantly increased, indicating reduced nociception. While changes in HR and changes in sensory threshold were correlated, no other correlation could be found between hemodynamic changes (DAP or HR) and changes in sensory and pain threshold. These results suggest that the mechanisms underlying the sympathetic adaptation to HUT and HUT-induced analgesia are different.

Assessment of the effectiveness and safety of Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain: EDONOT-protocol of a randomised, parallel, controlled, double-blinded and multicentre clinical trial.

INTRODUCTION: Currently available analgesics are ineffective in 30-50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use. Despite numerous preclinical data demonstrating an antinociceptive effect of ethosuximide in various animal models of neuropathic pain, no clinical studies have been published to date on the analgesic efficacy of ethosuximide in patients with neuropathic pain. METHODS AND ANALYSIS: The Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain (EDONOT) trial is a randomised, parallel, controlled, double-blinded, multicentre clinical study. It is the first clinical trial to evaluate the efficacy and safety of ethosuximide in the treatment of non-diabetic peripheral neuropathic pain. Adult patients exhibiting peripheral neuropathic pain (Numeric Rating Scale (NRS) ≥4 and Douleur Neuropathique 4 (DN4)≥4) for at least 3 months and under stable analgesic treatment for at least 1 month will be included. Patients (n=220) will be randomly assigned to receive either ethosuximide or control treatment for 6 weeks following a 1 week run-in period. The primary end point is the intensity of neuropathic pain, assessed by NRS (0-10) before and after 6 weeks of treatment. The secondary end points are safety (adverse events are collected during the study: daily by the patient on the logbook and during planned phone calls by investigators), the intensity and features of neuropathic pain (assessed by Brief Pain Inventory (BPI) and Neuropathic Pain Symptom Inventory (NPSI) questionnaires) and health-related quality of life (assessed by Medical Outcome Study Short Form 12 (MOS SF-12) and Leeds questionnaires). ETHICS AND COMMUNICATION: The study was approved by an independent ethics committee (CPP Sud-Est VI, France, IRB00008526) and registered by the French competent authority (Agence nationale de sécurité du médicament (ANSM)). TRIAL REGISTRATION NUMBER: NCT02100046, Recruiting.