New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients

Clinical Rheumatology - IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the...     

Cardiovascular disorders in patients with congenital portosystemic shunts: 23 years of experience in a tertiary referral centre

Central illustration. Time of occurrence and outcome of cardiovascular disorders in patients (pts) with congenital portosystemic shunt (CPSS). Patients with normal anatomy and those with congenital heart disease (CHD) were distinguished. Heart failure (HF) was the main symptom in both the prenatal and neonatal periods, whereas portopulmonary hypertension (PPH) and hepatopulmonary syndrome (HPS) represented the major concerns beyond the first months of life. CV: cardiovascular; NAS: no additional symptoms; PH: pulmonary hypertension; RD: respiratory distress. ^aFetal diagnosis of CPSS. ^bNeonatal diagnosis of CPSS. ^cDiagnosis of CPSS > 1 month of age

     

Impact of laughter on air trapping in severe chronic obstructive lung disease

Static and dynamic hyperinflation is an important factor of exertional dyspnea in patients with severe COPD. This proof-of-concept intervention trial sought to study whether laughter can reduce hyperinflation through repetitive expiratory efforts in patients with severe COPD. For small groups of patients with severe COPD (n = 19) and healthy controls (n = 10) Pello the clown performed a humor intervention triggering regular laughter. Plethysmography was done before and up to 24 hours after intervention. Laughing and smiling were quantified with video-analysis. Real-time breathing pattern was assessed with the LifeShirt™, and the psychological impact of the intervention was monitored with self-administered questionnaires. The intervention led to a reduction of TLC in COPD (p = 0.04), but not in controls (p = 0.9). TLC reduction was due to a decline of the residual volume. Four (22 [CI 95% 7 to 46] %) patients were ≥10% responders. The frequency of smiling and TLC at baseline were independent predictors of TLC response. The humor intervention improved cheerfulness, but not seriousness nor bad mood. In conclusion, smiling induced by a humor intervention was able to reduce hyperinflation in patients with severe COPD. A smiling-derived breathing technique might complement pursed-lips breathing in patients with symptomatic obstruction.     

(Finite) statistical size effects on compressive strength

The larger structures are, the lower their mechanical strength. Already discussed by Leonardo da Vinci and Edmé Mariotte several centuries ago, size effects on strength remain of crucial importance in modern engineering for the elaboration of safety regulations in structural design or the extrapolation of laboratory results to geophysical field scales. Under tensile loading, statistical size effects are traditionally modeled with a weakest-link approach. One of its prominent results is a prediction of vanishing strength at large scales that can be quantified in the framework of extreme value statistics. Despite a frequent use outside its range of validity, this approach remains the dominant tool in the field of statistical size effects. Here we focus on compressive failure, which concerns a wide range of geophysical and geotechnical situations. We show on historical and recent experimental data that weakest-link predictions are not obeyed. In particular, the mechanical strength saturates at a nonzero value toward large scales. Accounting explicitly for the elastic interactions between defects during the damage process, we build a formal analogy of compressive failure with the depinning transition of an elastic manifold. This critical transition interpretation naturally entails finite-size scaling laws for the mean strength and its associated variability. Theoretical predictions are in remarkable agreement with measurements reported for various materials such as rocks, ice, coal, or concrete. This formalism, which can also be extended to the flowing instability of granular media under multiaxial compression, has important practical consequences for future design rules.Owing to its importance for structural design (1), the elaboration of safety regulations (2), or the extrapolation of laboratory results to geophysical field scales (3), the size effects on strength of materials are one of the oldest problems in engineering, already discussed by Leonardo da Vinci and Edmé Mariotte (4) several centuries ago, but still an active field of research (5, 6). As early as 1686, Mariotte (4) qualitatively introduced the weakest-link concept to account for size effects on mechanical strength, a phenomenon evidenced by Leonardo da Vinci almost two centuries earlier. This idea, which states that the larger the system considered is, the larger the probability to find a particularly faulty place that will be at the origin of global failure, was formalized much later by Weibull (7). Considering a chain of elementary independent links, the failure of the chain is obtained as soon as one link happens to break. By virtue of the independence between the potential breaking events, the survival probability of a chain of N links is obtained by the simple multiplication of the N elementary probabilities. Depending on the properties of the latter, the global survival probability converges toward one of the three limit distributions identified by Weibull (7), Gumbel (8), and Fréchet (8), respectively. Together with Fisher and Tippett (9), these authors pioneered the field of extreme value statistics.This purely statistical argument, undoubtedly valid in 1D, was extended by Weibull (7, 10) to account for the risk of failure of 3D samples or structures. Besides the hypothesis of independence, it thus requires an additional hypothesis of brittleness: The nucleation of any elementary crack at the microscopic scale from a preexisting flaw is assumed to immediately induce the failure at the macroscale. More specifically, following linear elastic fracture mechanics (LEFM) stating that crack initiation from a flaw of size s occurs at a stress , one gets a probability of failure of a system of size L under an applied stress σ, , that depends on the distribution of preexisting defect sizes. Assuming a power law tail for this distribution, Weibull statistics are expected(7), , whereas Gumbel statistics are expected for any distribution of defect sizes whose the tail falls faster than that of a power law (8, 11, 12), , where m is the so-called Weibull’s modulus, d is the topological dimension, and L₀ and σ_u are normalizing constants. For Weibull statistics, the mean strength and the associated SD δ(σ_f) then scale with sample size L as . This approach has been successfully applied to the statistics of brittle failure strength under tension (7, 13), with m in the range 6–30 (14). It implies a vanishing strength for L → +∞, although this decrease can be rather shallow, owing to the large values of m often reported.Although relying on strong hypotheses, this weakest-link statistical approach was almost systematically invoked until the 1970s to account for size effects on strength whatever the material and/or the loading conditions. However, as shown by Bazant (1, 5), in many situations the hypothesis of brittleness is not obeyed. This is in particular the case when the size of the fracture process zone (FPZ) becomes nonnegligible with respect to the system size. In this so-called quasi-brittle case, an energetic, nonstatistical size effect applies (15), which has been shown to account for a large variety of situations (5). Toward large scales, i.e., L → +∞, the FPZ becomes negligible compared with L, and the hypothesis of brittleness should therefore be recovered and statistical size effects should dominate. Statistical numerical models of fracture of heterogeneous media also revealed deviations from the extreme value statistics predictions (16) but, as stated by Alava et al. (ref. 11, p. 9), “the role of damage accumulation for fracture size effects in unnotched samples still remains unclear.” As shown below, compressive failure results from such progressive damage accumulation.In what follows, we do not consider (deterministic) energetic size effects and explore a situation, compressive failure, where both the hypotheses of brittleness (in the sense given above) and independence are not fulfilled, up to very large scales. Relaxing these initial hypotheses of the weakest-link theory, our statistical physics approach remains statistical by nature and relies on the interplay between internal disorder and stress redistributions. It is based on a mapping of brittle compressive failure onto the critical depinning transition of an elastic manifold, a class of models widely used in nonequilibrium statistical physics characterized by a dynamic phase transition (17). This approach does not consider a sample’s shape effects (18), only statistical size effects. The critical scaling laws associated to this phase transition naturally predict a saturation of the compressive strength at a large scale and are in remarkable agreement with measurements reported for various materials such as rocks, ice, coal, or concrete.     

Comparison of 18FDG-PET/CT and conventional follow-up methods in colorectal cancer: A randomised prospective study

BackgroundA surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence.AimsTo assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up.MethodsA multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT.ResultsA total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038).ConclusionsPET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up.     

Digestive lesions related to N.S.A.I.D. (epidemiology and prevention)]

The frequency of gastrointestinal ulcers and ulcers complications induced by non steroidal anti inflammatory drugs (NSAID) increases continuously. This is a major health problem, since 1.5% of general population (mostly elderly people) take regularly NSAID'S. NSAID'S gastropathy is asymptomatic in nearly 50% of cases, even in case of big gastric ulcer. A severe hemorrhage or a gastric perforation can occurred in the absence of previous symptoms. When the patient had epigastric symptoms during a treatment with NSAID'S, upper GI endoscopy is normal in 50% of cases. NSAID'S are ulcerogenic by decreasing the capacity of the gastric mucosa to produce prostaglandin (PG) and by weakening gastric mucosal barrier. H2 blockers are not effective to prevent such lesions. Elderly women, are at high risk of gastric mucosal lesions and complications. In a prospective study, it was shown that misoprostol was effective to reduce the rate of NSAID'S induced gastric and duodenal ulcers. Up to date, epidemiologic studies don't show any population group at no risk of NSAID'S induced gastric lesions. The actual problem, now, is to determine which groups of patients are at high risk of complication in order to clarify the indications of preventive treatment. Today, in France, it's believed that old patients, with organic pathology (respiratory, cardiac, hepatic or urinary) and/or using two or more NSAID'S are at high risk.     

Multiplex PCR for Detection of Seven Virulence Factors and K1/K2 Capsular Serotypes of Klebsiella pneumoniae

A single multiplex PCR assay targeting seven virulence factors and the wzi gene specific for the K1 and K2 capsular serotypes of Klebsiella pneumoniae was developed and tested on 65 clinical isolates, which included 45 isolates responsible for community-acquired severe human infections. The assay is useful for the surveillance of emerging highly virulent strains.     

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m² were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m², and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Imeglimin is a first‐in‐class oral agent for the treatment of type 2 diabetes (T2DM) and is excreted unchanged into urine. A Japanese phase IIb study found that 1000 mg b.i.d. was optimal in Japanese population, and phase III studies confirmed significant glucose lowering effect. A Western phase IIb study found an optimal dose of 1500 mg b.i.d.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the key determinants of imeglimin pharmacokinetics (PKs), recommended doses for patients with renal impairment, and what drives the different optimal doses between Japanese and Western patients with T2DM.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Renal function significantly impacts imeglimin PKs. Recommended doses for patients with renal impairment have been proposed for exposure matching. Differences in estimated glomerular filtration rate (eGFR) comprised the key driver for different optimal doses at which estimated exposures were similar between Japanese and Western patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Doses of imeglimin could be reduced based on eGFR. Exposure responses seemed similar between Japanese and Western patients.