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Background and aims: The anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis. Methods: Twenty-two rabbits were fed a 0.5% cholesterol-enriched diet for 10 weeks and then randomized to receive either oral saline (n=11) or colchicine (350 μg/kg/day; n=11) for 6 weeks, with 0.2% cholesterol-diet during the treatment period. We performed intravascular ultrasound imaging (at start and end of treatment) and histology analyses of the descending thoracic aorta. Leucocyte activation was assessed in vitro on blood samples obtained during treatment. Results: Colchicine prevented positive aortic vascular remodelling (p=0.029 vs placebo). This effect was even more marked at high plasma cholesterol level (third quartile of plasma cholesterol, p=0.020). At high cholesterol level, both atherosclerotic plaque and media areas on histomorphology were reduced by colchicine compared to placebo (p=0.031 and p=0.039, respectively). Plaque fibrosis and macrophage area were reduced by colchicine (Masson's trichrome stain: p=0.038; RAM-11: p=0.026). The plaque vulnerability index, assessed by histology, was reduced by colchicine (p=0.040). Elastin/type I collagen ratio in media was significantly higher with colchicine compared to placebo (p=0.013). At a high level of plasma cholesterol, in vitro LPS challenge revealed a decrease in monocyte activation following treatment with colchicine (p

To overcome the physical limitations of mechanical bone cutting in minimally invasive surgery, we are developing a miniature parallel robot that enables positioning of a pulsed laser with an accuracy below 0.25 mm and minimizes the required manipulation space above the target tissue. This paper presents the design, control, device characteristics, functional testing, and performance evaluation of the robot. The performance of the robot was evaluated within the scope of a path-following experiment. The required accuracy for continuous cuts was achieved and reached 0.176 mm on the test bench.

Massive rotator cuff tears have always been a worrisome situation to every orthopaedic surgeon. Patients’ functional demands are increasing with time, and this is why we aim to offer them the best options to preserve their quality of life. We found that using the Banana SutureLasso (Arthrex) has made this type of surgery much easier. We think that with the Banana SutureLasso (Arthrex) we have more access to the medial part of the rotator cuff, and that we can grab both the deep and superficial layers of the tendons while diminishing the risk of laceration. We combined an X-suture with a double-row fixation using a Corkscrew (Arthrex) on the humeral tuberosity and a SwiveLock (Arthrex) screw on lateral side of the humerus. We used only 3 portals with an extra parking portal. Another advantage is that we can adjust the sutures so they would be perpendicular to both ends of the tear. Our technique is simple, safe, and reproducible., Technique Video Video 1 The patient is at a beach chair position. The scope and the shaver are introduced laterally just over the tear. The first step is to have an interrupted X-suture. This why we introduce the Banana SutureLasso anteriorly through the tear. We use the tracking wire in order to pass the fibertape from the deep into the superficial layer of the rotator cuff tissue. Then we leave the fibertape in the parking portal just over the tear. We do the same posteriorly; you can see how the Banana Lasso passes through both the superficial and the deep layers of the rotator cuff tear, something you can't do while using the scorpion forceps. Note how easily the fibertape is passed while using the tracking wire. The first part of the X-suture is now complete. Contrary to it, we proceed to the second part by inverting the loop of the tracking in order to pass the fibertape from the superficial into the deep layer of the rotator cuff tissue. In that way enough tissue is taken and no tension will be applied while tying the knots. We do the same on the posterior part, also by inverting the loop of the tracking wire so we can have a complete X-suture. The tracking wire is then passed through the canula and the fibertape is inserted through the tear and again put on hold in the parking portal. With this X-suture technique, using the Banana Lasso, we have enough tissue taken medially to ensure a better fixation with no tissue laceration. After preparing the footprint, a corkscrew is then inserted in the humeral tuberosity, to begin the double row fixation. The corkscrew and the fibertape wires are taken together with a grasping forceps through the canula and this what makes the originality of this technique. Then again, the Banana Lasso is inserted anteriorly, this time the tracking wire holding both the fibertape and the corkscrew wires are again passed anteriorly from the deep into the superficial layer of the anterior of the rotator cuff tear. We do the same posteriorly by passing the 2 wires from the deep into the superficial layer of the posterior part of the rotator cuff tear. After passing both ends of the tear, the fibertape wire is put on hold in the parking portal while the corkscrew wire is passed through the canula and is tightened with half surgical hitches so we can slide them and then lock them with an inverted half hitch. Now we have a rotator cuff that is sutured and pinned down to the greater tuberosity. An external rotation and abduction is performed in order to have a better exposure of the lateral side of the humerus. All 4 sutures are passed through the canula and through the eyelet of the swivelock screw, then pinned down to the lateral side of the humerus. You can see the parachute effect of the wires on the rotator cuff, grabbing it and covering all the head of the humerus without any tension.

It is well known that mechanically stimulating the perineal region potently facilitates hindlimb locomotion and weight support in mammals with a spinal transection (spinal mammals). However, how perineal stimulation mediates this excitatory effect is poorly understood. We evaluated the effect of mechanically stimulating (vibration or pinch) the perineal region on ipsilateral (9-14 ms onset) and contralateral (14-18 ms onset) short-latency cutaneous reflex responses evoked by electrically stimulating the superficial peroneal or distal tibial nerve in seven adult spinal cats where hindlimb movement was restrained. Cutaneous reflexes were evoked before, during, and after mechanical stimulation of the perineal region. We found that vibration or pinch of the perineal region effectively triggered rhythmic activity, ipsilateral and contralateral to nerve stimulation. When electrically stimulating nerves, adding perineal stimulation modulated rhythmic activity by decreasing cycle and burst durations and by increasing the amplitude of flexors and extensors. Perineal stimulation also disrupted the timing of the ipsilateral rhythm, which had been entrained by nerve stimulation. Mechanically stimulating the perineal region decreased ipsilateral and contralateral short-latency reflex responses evoked by cutaneous inputs, a phenomenon we observed in muscles crossing different joints and located in different limbs. The results suggest that the excitatory effect of perineal stimulation on locomotion and weight support is mediated by increasing the excitability of central pattern-generating circuitry and not by increasing excitatory inputs from cutaneous afferents of the foot. Our results are consistent with a state-dependent modulation of reflexes by spinal interneuronal circuits.

People living with HIV (PLWH) are at risk of noninfectious comorbidities. It is important to individualize those at higher risk. In a single-center cohort of PLWH, we performed a cross-sectional analysis of comorbidities, diagnosed according to standard procedures. The primary endpoint was the prevalence of subclinical carotid/coronary atherosclerosis. Secondary endpoints were its association with selected inflammatory/immune activation biomarkers and with other comorbidities. Associations were examined by using Chi-square or Fisher's exact test for categorical variables and Student or Wilcoxon tests for quantitative variables, and a stepwise multivariate logistical model was performed for further exploration. Among 790 participants [median age: 49.8 years (interquartile range, IQR: 44.5-55.6), 77.1% males, median CD4: 536/mm

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

Ultrafine particles represent a growing concern in the public health community but their precise role in many illnesses is still unknown. This lack of knowledge is related to the experimental difficulty in linking their biological effects to their multiple properties, which are important determinants of toxicity. Our aim is to propose an interdisciplinary approach to study fine (FP) and ultrafine (UFP) particles, generated in a controlled manner using a miniCAST (Combustion Aerosol Standard) soot generator used with two different operating conditions (CAST1 and CAST3). The chemical characterization was performed by an untargeted analysis using ultra-high resolution mass spectrometry. In conjunction with this approach, subsequent analysis by gas chromatography–mass spectrometry (GC–MS) was performed to identify polycyclic aromatic hydrocarbons (PAH). CAST1 enabled the generation of FP with a predominance of small PAH molecules, and CAST3 enabled the generation of UFP, which presented higher numbers of carbon atoms corresponding to larger PAH molecules. Healthy normal human bronchial epithelial (NHBE) cells differentiated at the air-liquid interface (ALI) were directly exposed to these freshly emitted FP and UFP. Expression of MUC5AC, FOXJ1, OCLN and ZOI as well as microscopic observation confirmed the ciliated pseudostratified epithelial phenotype. Study of the mass deposition efficiency revealed a difference between the two operating conditions, probably due to the morphological differences between the two categories of particles. We demonstrated that only NHBE cells exposed to CAST3 particles induced upregulation in the gene expression of IL-8 and NQO1. This approach offers new perspectives to study FP and UFP with stable and controlled properties.

Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P

The aim of this work was the study of the energy efficiency of the dehydration process of cranberry juice using osmotic distillation (OD) in combination with freeze-drying. To achieve this process, OD was performed on a hollow fiber membrane contactor with an initial sugar content of 8°Brix in the cranberry juice. This solution was concentrated to four different final concentrations (25, 35, 45 and 57°Brix) with the purpose of reducing the lyophilization time obtaining a 100% dried product, using as a response variable the processing time. From these obtained results, and when comparing the 8°Brix juice lyophilization to the process achieved by the combination of OD and freeze-drying, a decrease in the total process time could not be achieved for any experimental assay. However, the 57°Brix cranberry juice previously concentrated by OD presented an 86% decrease in the energy requirements to obtain the same dehydrated product. Finally, a reduction of the energy consumption for all the experimental runs was observed in the samples concentrated by OD, as the step previous to lyophilization, achieving an intensification in the efficient energy use during this process, maintaining the same characteristics of the final product.

Resume Objectifs L’objectif de cette etude etait de quantifier les risques de morbidite maternelle et perinatale en fecondation in vitro (FIV) par rapport aux grossesses non issues de FIV sur une cohorte nationale francaise recente. Methode Les donnees etaient issues du systeme d’information des donnees d’hospitalisation incluant toutes les grossesses ayant conduit a un accouchement et les naissances de 2013 a 2016. Les risques d’accouchement premature, de morbidite maternelle (thrombose veineuse et arterielle, diabete gestationnel, troubles vasculaires, placenta praevia, hematome retroplacentaire), d’hypotrophie et de malformation congenitale ont ete compares entre les deux groupes en analyse univariee et multivariee apres ajustement sur les caracteristiques des femmes (l’âge, la primiparite, l’obesite, la dependance au tabac, les antecedents de diabete ou d’hypertension arterielle), les accouchements multiples et le sexe des enfants. Resultats Au total, 2 875 662 grossesses ayant conduit a un accouchement et 2 922 712 naissances ont ete analysees, dont 49 224 (1,7 %) issues de FIV avec transfert d’embryons frais. En analyse multivariee, tous les risques de morbidite etaient significativement plus eleves en FIV : les accouchements prematures (ORajuste = 1,28 ; IC95 % = 1,24–1,32), la morbidite maternelle (ORajuste = 1,24 ; IC95 % = 1,21–2,28) (principalement pour les thromboses veineuses dans les accouchements multiples, le placenta praevia et les hematomes retroplacentaires). Les risques d’hypotrophie (ORajuste = 1,13 ; IC95 % = 1,10–1,16) et de malformations congenitales (ORajuste = 1,11 ; IC95 % = 1,05–1,17) etaient faiblement augmentes. Conclusion Les resultats de cette premiere etude portant sur un large effectif de naissances recentes en France confirment qu’il existait une augmentation des risques de morbidite maternelle et perinatale en FIV. Ces risques etaient comparables a ceux publies dans la litterature internationale. Cette etude constitue le point de depart d’une surveillance de la morbidite maternelle et perinatale en FIV.

The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

Background Hemotropic mycoplasmas, previously classified in the genus Eperythrozoon, have been reported as causing human infections in Brazil, China, Japan, and Spain. Methods In 2017, we detected DNA from Candidatus Mycoplasma haemohominis in the blood of a Melanesian patient from New Caledonia presenting with febrile splenomegaly, weight loss, life-threatening autoimmune hemolytic anemia, and hemophagocytosis. The full genome of the bacterium was sequenced from a blood isolate. Subsequently, we retrospectively (2011–2017) and prospectively (2018–2019) tested patients who had been hospitalized with a similar clinico-biological picture. In addition, as these patients had been in contact with frugivorous bats (authorized under conditions for hunting and eating in New Caledonia), we investigated the role of these animals and their biting flies by testing them for hemotropic mycoplasmas. Results There were 15 patients found to be infected by this hemotropic mycoplasma. Among them, 4 (27%) died following splenectomy performed either for spontaneous spleen rupture or to cure refractory autoimmune hemolytic anemia. The bacterium was cultivated from the patient’s blood. The full genome of the Neocaledonian Candidatus M. haemohominis strain differed from that of a recently identified Japanese strain. Of 40 tested Pteropus bats, 40% were positive; 100% of collected bat flies Cyclopodia horsfieldi (Nycteribiidae, Diptera) were positive. Human, bat, and dipteran strains were highly similar. Conclusions The bacterium being widely distributed in bats, Candidatus M. haemohominis, should be regarded as a potential cause of severe infections in humans.

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model, here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differentiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis, relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.

International audience; Background: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI.Methods: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290.Findings: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070).Interpretation: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI.Funding: ACTION Study Group and AstraZeneca.

Somatosensory feedback from peripheral receptors dynamically interacts with networks located in the spinal cord and brain to control mammalian locomotion. Although somatosensory feedback from the limbs plays a major role in regulating locomotor output, those from other regions, such as lumbar and perineal areas also shape locomotor activity. In mammals with a complete spinal cord injury, inputs from the lumbar region powerfully inhibit hindlimb locomotion, while those from the perineal region facilitate it. Our recent work in cats with a complete spinal cord injury shows that they also have opposite effects on cutaneous reflexes from the foot. Lumbar inputs increase the gain of reflexes while those from the perineal region decrease it. The purpose of this review is to discuss how somatosensory feedback from the lumbar and perineal regions modulate the spinal locomotor central pattern generator and reflex circuits after spinal cord injury and the possible mechanisms involved. We also discuss how spinal cord injury can lead to a loss of functional specificity through the abnormal activation of functions by somatosensory feedback, such as the concurrent activation of locomotion and micturition. Lastly, we discuss the potential functions of somatosensory feedback from the lumbar and perineal regions and their potential for promoting motor recovery after spinal cord injury.

The appropriate management of early treatment failures in patients with elbow injuries requires the identification of the cause of failure. In this work, six types of elbow injury are considered: (i) identification of early failed reduction of a dislocation or fracture-dislocation of the elbow should lead to a repeat reduction procedure, testing for elbow instability, and ligament repair, followed by the use of a hinged external fixator to allow early mobilisation. Differentiating an isolated dislocation from a dislocation combined with a fracture of the coracoid process is crucial. Re-implantation of the coronoid process allows repair of the ligaments and restoration of stability in the sagittal plane; (ii) early secondary displacement of a distal humeral fracture after internal fixation is usually due to insufficient fixation confined to a single humeral pillar. If both humeral pillars are fractured, then both must be repaired; (iii) early treatment failure of an intra-articular distal humeral fracture in an elderly patient with bone loss warrants distal humeral hemiarthroplasty or total elbow arthroplasty; (iv) in fractures of the olecranon, treatment failures are due to insufficient fixation or to a mistaken diagnosis of trans-olecranon fracture-dislocation; (v) in fractures of the radial head, causes of early revision include excessive tilting of the head in radial neck fractures, with secondary displacement due to insufficient internal fixation, and adverse effects on the wrist of radial head resection performed without assessing the ulnar variance. In patients with radial head fractures, no treatment decisions can be made before performing an anteroposterior radiograph of the wrist; (vii) in fracture-dislocations of both the radius and ulna, accurate reduction of the ulnar fracture is a pre-requisite to proper reduction of the radio-humeral and proximal radio-ulnar joints. An early postoperative assessment, within 10 days after surgery, is of paramount importance to re-evaluate the initial treatment and, if needed, to introduce modifications. Early failure of the initial treatment of an elbow injury should lead to the prompt implementation of corrective measures: follow-up anteroposterior and lateral radiographs must be obtained on day 8 to ensure the diagnosis of initial treatment failure and to allow the institution of an appropriate management strategy; the dogma stating that the elbow should never be immobilised remains valid, and every effort should be made to ensure that mobilisation starts as early as possible.

Background Patients missing the distal humeral condyles are prone to premature bushing wear after total elbow arthroplasty. A midterm study has demonstrated that a custom triflange outrigger ulnar component was successful in preventing this. The aim of this study was to determine whether these results remained stable over time. Materials and methods The outcomes of 6 patients who underwent revision of a loose ulnar component using a custom triflange outrigger component were reviewed in this retrospective case study. The average patient age at the time of revision was 51. The average number of prior operations was 2 (range, 1-3). The mean follow-up was 15 years (range, 10-18 years). Results At final follow-up, the mean range of extension-flexion was 35° to 135°, and pronation-supination was 65° to 63°. The average Mayo Elbow Performance Score improved to 75 of 100. Four implants were still in place with no radiolucencies or osteolysis. Three patients required revision surgery for broken humeral stems. Two required conversion to another total elbow arthroplasty system after 18 and 14 years for humeral component loosening. Conclusions These components lasted an average of 4 times longer than the original ulnar components. In our experience, periarticular osteolysis caused by polyethylene wear creates a region of unsupported stem and a stress riser at the junction with the remaining well-supported stem and causes component stem fractures. The concept of an outrigger type of hinge might be useful for active patients requiring an elbow prosthesis in the setting of deficient condyles.

Background:Rotator cuff tears are common shoulder injuries that often cause pain and loss of function. Nonanatomic side-to-side techniques facilitate repair by minimizing tensions within tendons to improve healing and optimize the thickness of sutured tissues.Purpose/Hypothesis:The purpose was to evaluate long-term clinical and radiographic outcomes of arthroscopic side-to-side repair of massive rotator cuff tears (mRCTs). The hypothesis was that, at a minimum follow-up of 12 years, arthroscopic side-to-side repair maintains clinically important improvements.Study Design:Case series; Level of evidence, 4.Methods:The authors reviewed records of all patients who underwent arthroscopic repair of mRCTs over 2 consecutive years. A total of 30 adult patients met the eligibility criteria and underwent side-to-side repair. Patients were evaluated clinically using the Constant score (CS) and ultrasound to assess retears at 3 timepoints after surgery: 2 to 4 years, 5 to 7 years, and 12 to 14 years.Results:At first follow-up (3.2 ± 0.5 years), all 30 patients had clinical and ultrasound assessment, which revealed 13 retears (43%). At second follow-up (6.2 ± 0.5 years), all 30 patients had clinical and ultrasound assessment, which revealed 2 new retears (total 50%). At final follow-up (13.0 ± 0.7 years), only 21 patients had clinical assessment (1 died and 8 could not be reached), and only 19 patients had ultrasound assessment, which revealed 6 new retears (total 79%). Both absolute CS and age-/sex-adjusted CS improved significantly from baseline values at first follow-up (73.5 and 96.6, respectively), and remained stable at second follow-up (69.0 and 91.9, respectively), and final follow-up (64.4 and 87.0, respectively). Compared to shoulders with intact repairs, those with retears tended to have lower absolute CS at all follow-up visits, although differences were not statistically significant.Conclusion:Patients with mRCTs maintain satisfactory clinical scores at 12 to 14 years after arthroscopic side-to-side repair despite a high incidence of retears. Repair is a safe and effective treatment for mRCTs, providing a less invasive and less complex alternative to reverse shoulder arthroplasty and tendon transfer procedures.

Summary Loss of membrane potential of sperm mitochondria has been regarded as the first step preceding mitophagy degradation after their entry into the C. elegans oocyte at fertilization. This is in line with the classical view of mitophagy of defective or abnormal mitochondria and could serve as a recognition signal for their specific and quick autophagy degradation. Here, using TMRE (tetramethylrhodamine ethyl ester) and live imaging we show that this is not the case. Instead, sperm inherited mitochondria show a stable labeling with TMRE before and at the time of autophagosomes formation. Interestingly, this labeling remains in late-stage-embryos of autophagy-defective-mutants suggesting that the loss of membrane potential occurs upon the entry of the mitochondria into the autophagy pathway. These stabilized and still polarized sperm mitochondria remain distinct but associated with the maternal-derived mitochondrial network suggesting a mechanism that prevents their fusion and represents an efficient additional protective system against fertilization-induced heteroplasmy., Graphical abstract, Highlights • Oocyte-derived mitochondria become tubular only during the first zygotic division • Sperm mitochondria can not fuse but associate with the oocyte-derived mitochondria • Sperm mitochondria are still polarized when engulfed for autophagy degradation, Reproductive Medicine; Cell Biology

International audience; Renewed consumer demand motivates the nutritional and sensory quality improvement of fruits and vegetables. Specialized metabolites being largely involved in nutritional and sensory quality of carrot, a better knowledge of their phenotypic variability is required. A metabolomic approach was used to evaluate phenotypic plasticity level of carrot commercial varieties, over three years and a wide range of cropping environments spread over several geographical areas in France. Seven groups of metabolites have been quantified by HPLC or GC methods: sugars, carotenoids, terpenes, phenolic compounds, phenylpropanoids and polyacetylenes. A large variation in root metabolic profiles was observed, in relation with environment, variety and variety by environment interaction effects in decreasing order of importance. Our results show a clear diversity structuration based on metabolite content. Polyacetylenes, beta-pinene and alpha-carotene were identified mostly as relatively stable varietal markers, exhibiting static stability. Nevertheless, environment effect was substantial for a large part of carrot metabolic profile and various levels of phenotypic plasticity were observed depending on metabolites and varieties. A strong difference of environmental sensitivity between varieties was observed for several compounds, particularly myristicin, 6MM and D-germacrene, known to be involved in responses to biotic and abiotic stress. This work provides useful information about plasticity in the perspective of carrot breeding and production. A balance between constitutive content and environmental sensitivity for key metabolites should be reached for quality improvement in carrot and other vegetables.

International audience

Background In 2017, New Caledonia experienced an outbreak of severe dengue causing high hospital burden (4379 cases, 416 hospital admissions, 15 deaths). We decided to build a local operational model predictive of dengue severity, which was needed to ease the healthcare circuit. Methods We retrospectively analyzed clinical and biological parameters associated with severe dengue in the cohort of patients hospitalized at the Territorial Hospital between January and July 2017 with confirmed dengue, in order to elaborate a comprehensive patient’s score. Patients were compared in univariate and multivariate analyses. Predictive models for severity were built using a descending step-wise method. Results Out of 383 included patients, 130 (34%) developed severe dengue and 13 (3.4%) died. Major risk factors identified in univariate analysis were: age, comorbidities, presence of at least one alert sign, platelets count 9/L, prothrombin time 10 N, and previous dengue infection. Severity was not influenced by the infecting dengue serotype nor by previous Zika infection. Two models to predict dengue severity were built according to sex. Best models for females and males had respectively a median Area Under the Curve = 0.80 and 0.88, a sensitivity = 84.5 and 84.5%, a specificity = 78.6 and 95.5%, a positive predictive value = 63.3 and 92.9%, a negative predictive value = 92.8 and 91.3%. Models were secondarily validated on 130 patients hospitalized for dengue in 2018. Conclusion We built robust and efficient models to calculate a bedside score able to predict dengue severity in our setting. We propose the spreadsheet for dengue severity score calculations to health practitioners facing dengue outbreaks of enhanced severity in order to improve patients’ medical management and hospitalization flow.

Constitutional thinness (CT) is a nonpathological state of underweight. The current study aimed to explore skeletal muscle energy storage in individuals with CT and to further characterize muscle phenotype at baseline and in response to overfeeding. Thirty subjects with CT (15 females, 15 males) and 31 normal-weight control subjects (16 females, 15 males) participated in the study. Histological and enzymological analyses were performed on muscle biopsy specimens before and after overfeeding. In the skeletal muscle of CT participants compared with controls, we observed a lower content of intramuscular triglycerides for type I (−17%, p < 0.01) and type IIA (−14%, p < 0.05) muscle fibers, a lower glycogen content for type I (−6%, p < 0.01) and type IIA (−5%, p < 0.05) muscle fibers, a specific fiber-type distribution, a marked muscle hypotrophy (−20%, p < 0.001), a low capillary-to-fiber ratio (−19%, p < 0.001), and low citrate synthase activity (−18%, p < 0.05). In response to overfeeding, CT participants increased their intramuscular triglycerides content in type I (+10%, p < 0.01) and type IIA (+9%, p < 0.01) muscle fibers. CT individuals seem to present an unusual muscle phenotype and different adaptations to overfeeding compared with normal-weight individuals, suggesting a specific energy metabolism and muscle adaptations. ClinicalTrials.gov registration no. NCT02004821. Novelty Low intramuscular triglycerides and glycogen content in skeletal muscle of constitutionally thin individuals. Low oxidative capacity, low capillary supply, and fiber hypotrophy in skeletal muscle of constitutionally thin individuals. Increase in intramuscular triglycerides in constitutional thinness in response to overfeeding.

Background We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS. Methods Rabbits were exposed to three different protocols to develop LVDD. First, rabbits were exposed to 0.5% cholesterol-rich diet for an average of 17 weeks. Second, rabbits were subjected to surgical ascending aortic constriction (AAC), to mimic the effect of fixed reduced aortic valve area, and studied after 10 weeks. The third model combined both cholesterol-enriched diet (for 12 weeks) and surgical AAC. The control group consisted of age-matched rabbits under normal diet. After development of LVDD, rabbits were randomized to receive infusions of saline or apoA-I mimetic (25 mg/kg) 3 times per week for 4 weeks. Detailed cardiac structure and function measurements were assessed at baseline and weekly during treatment period. Histological and molecular analyses were performed on LV samples. Results In the three models, echocardiographic results showed development of LVDD over time, with preserved LV systolic and aortic valve functions versus controls. ApoA-I mimetic infusions did not significantly improve echocardiographic parameters nor molecular markers of cardiac inflammation, oxidative stress and fibrosis. Conclusion ApoA-I mimetic therapy did not directly improve LVDD. These results indicate that previously observed changes of LVDD were caused by AVS improvement induced by this treatment.

It is well known that mechanically stimulating the perineal region potently facilitates hindlimb locomotion and weight support in mammals with a spinal transection (spinal mammals). However, how perineal stimulation mediates this excitatory effect is poorly understood. We evaluated the effect of mechanically stimulating (vibration or pinch) the perineal region on ipsilateral (9-14 ms onset) and contralateral (14-18 ms onset) short-latency cutaneous reflex responses evoked by electrically stimulating the superficial peroneal or distal tibial nerve in seven adult spinal cats where hindlimb movement was restrained. Cutaneous reflexes were evoked before, during, and after mechanical stimulation of the perineal region. We found that vibration or pinch of the perineal region effectively triggered rhythmic activity, unilateral and bilateral to nerve stimulation. When electrically stimulating nerves, adding perineal stimulation modulated rhythmic activity by decreasing cycle and burst durations and by increasing the amplitude of flexors and extensors. Perineal stimulation also disrupted the timing of the ipsilateral rhythm, which had been entrained by nerve stimulation. Mechanically stimulating the perineal region decreased ipsilateral and contralateral short-latency reflex responses evoked by cutaneous inputs, a phenomenon we observed in muscles crossing different joints and located in different limbs. The results suggest that the excitatory effect of perineal stimulation on locomotion and weight support is not mediated by increasing cutaneous reflex gain and instead points to an excitation of central pattern-generating circuitry. Our results are consistent with a state-dependent modulation of reflexes by spinal interneuronal circuits.Significance StatementMechanically stimulating the skin of the perineal region strongly facilitates hindlimb locomotion in mammals following a complete spinal cord injury (SCI). Despite its remarkable effectiveness in promoting hindlimb locomotion in spinal cord-injured mammals, we do not know how this is mediated. The present study provides data on how inputs from the perineal region interact with neuronal circuits that generate locomotor-like activity and reflexes from the foot. A better understanding of how inputs from the perineal region interact with neuronal circuits of the spinal cord could lead to non-invasive approaches to restore walking in people with SCI.

International audience; Introduction: Camel-hump condylo-mandibular dysplasia is a specific form of condyle dysostosis, first described by Delaire. The aim of this study was to describe the clinical and radiographic phenotype of the disease, and to discuss therapeutic options.Case series: Twenty-one patients were analyzed retrospectively. They exhibited the same unilateral facial asymmetry, which was of mandibular origin, with an elevated commissural line and occlusal cant, and a deviated chin on the side of the deformity. The soft tissues and the ears were always normal in terms of their physical appearance. Radiographic analysis generally revealed a short, curved, and anteriorly displaced condyle, with a high and sharp coronoid process. CT scans revealed that the glenoid fossa was empty. Twelve patients exhibited dental abnormalities, consisting mainly of dental inclusions affecting the lower first and/or second molars (10 patients). A good response to functional orthodontic treatment was achieved in eight patients, while 13 patients required a surgical mandibular lengthening procedure.Conclusion: Condylo-mandibular dysplasia is a congenital condyle deformity that needs to be recognized and differentiated from craniofacial microsomia in order to be able to provide patient-specific treatments.

We describe the first case report of a patient with COVID19 infection and metastatic breast cancer, while on systemic therapy with a CDK4/6 inhibitor. The patient had unique disease course, characterized with delayed symptomatology. The case highlights novel findings and stress careful and extended follow-up during COVID19 infection in patients taking biologic therapies affecting the immune system.

International audience; Transcranial Direct brain stimulation (tDCS) is commonly used in order to modulate cortical networks activity during physiological processes through the application of weak electrical fields with scalp electrodes. Cathodal stimulation has been shown to decrease brain excitability in the context of epilepsy, with variable success. However, the cellular mechanisms responsible for the acute and the long-lasting effect of tDCS remain elusive. Using a novel approach of computational modeling that combines detailed but functionally integrated neurons we built a physiologically-based thalamocortical column. This model comprises 10,000 individual neurons made of pyramidal cells, and 3 types of gamma-aminobutyric acid (GABA) -ergic cells (VIP, PV, and SST) respecting the anatomy, layers, projection, connectivity and neurites orientation. Simulating realistic electric fields in term of intensity, main results showed that 1) tDCS effects are best explained by modulation of the presynaptic probability of release 2) tDCS affects the dynamic of cortical network only if a sufficient number of neurons are modulated 3)VIP GABAergic interneurons of the superficial layer of the cortex are especially affected by tDCS 4) Long lasting effect depends on glutamatergic synaptic plasticity.

The phonological deficit in dyslexia is associated with altered low-gamma oscillatory function in left auditory cortex, but a causal relationship between oscillatory function and phonemic processing has never been established. After confirming a deficit at 30 Hz with electroencephalography (EEG), we applied 20 minutes of transcranial alternating current stimulation (tACS) to transiently restore this activity in adults with dyslexia. The intervention significantly improved phonological processing and reading accuracy as measured immediately after tACS. The effect occurred selectively for a 30-Hz stimulation in the dyslexia group. Importantly, we observed that the focal intervention over the left auditory cortex also decreased 30-Hz activity in the right superior temporal cortex, resulting in reinstating a left dominance for the oscillatory response. These findings establish a causal role of neural oscillations in phonological processing and offer solid neurophysiological grounds for a potential correction of low-gamma anomalies and for alleviating the phonological deficit in dyslexia., The phonological deficit in dyslexia is associated with altered low-gamma oscillatory function in left auditory cortex; this study shows that enhancing low-gamma neural oscillations by applying 30-Hz transcranial electrical stimulation to the left auditory cortex improves phonemic processing and reading accuracy in dyslexia.

International audience; Pellet stoves arouse a real interest from consumers because they are perceived as a renewable and carbon neutral energy. However, wood combustion can contribute significantly to air pollution, in particular through the emission of particulate matter (PM). In this article, five brands of wood pellets were burnt under optimal combustion conditions and trace element and inorganic salt emission factors (EFs) in PM were determined. Results show that a significant proportion of metals such as lead, zinc, cadmium, and copper initially present in pellets were emitted into the air during combustion with 20 ± 6%, 31 ± 12%, and 19 ± 6% of the initial content respectively for Zn, Pb, and Cd. The median emission factors for Pb, Cu, Cd, As, Zn, and Ni were respectively 188, 86, 9.3, 8.7, 2177, and 3.5 μg kg−1. The inorganic fraction of the PM emissions was dominated by K+, SO42−, and Cl− with respective EFs of 33, 28.7, and 11.2 mg kg−1. Even taking into account a consumption of 40.1 million tons by 2030 in the EU, the resulting pollution in terms of heavy metal emissions remains minimal in comparison with global emissions in the EU.

Mechanically stimulating the dorsal lumbar region inhibits locomotion and reduces weight support during standing in rabbits and cats. However, how this inhibitory effect from the lumbar skin is mediated is poorly understood. Here we evaluated the effect of mechanically stimulating (vibration or pinch) the dorsal lumbar region on short-latency (8- to 13-ms onset) cutaneous reflex responses, evoked by electrically stimulating the superficial peroneal or distal tibial nerves, in seven adult cats with a low thoracic spinal transection (spinal cats). Cutaneous reflexes were evoked before, during, and after mechanical stimulation of the dorsal lumbar region. We found that mechanically stimulating the lumbar region by vibration or manual pinch abolished alternating bursts of activity between flexors and extensors initiated by nerve stimulation. The activity of extensor muscles was abolished bilaterally, whereas the activity of some ipsilateral flexor muscles was sustained during vibration/pinch. Mechanically stimulating the lumbar region increased ipsilateral and contralateral short-latency excitatory responses evoked by cutaneous inputs, a phenomenon that was generalized to muscles crossing different joints and located in different limbs. Our results indicate that the inhibitory effect on locomotion and weight support is not mediated by reducing cutaneous reflex gain and instead points to an inhibition of central pattern-generating circuitry, particularly the extensor component. The results provide greater insight into interactions between different types of somatosensory inputs within spinal motor circuits. NEW & NOTEWORTHY Vibration or pinch of the lumbar region in spinal-transected cats abolished alternating bursts of activity between flexors and extensors initiated by nerve stimulation. Mechanically stimulating the lumbar region increased ipsilateral and contralateral short-latency excitatory responses evoked by cutaneous inputs in hindlimb muscles. Sensory inputs from mechanoreceptors of the lumbar region do not mediate their inhibitory effect on locomotion and weight support by reducing the gain of short-latency excitatory cutaneous reflexes from the foot.

Background: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Methods: Adcy9 -inactivated ( Adcy9 Gt/Gt ) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9 Gt/Gt and CETPtg Adcy9 WT ), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. Results: Adcy9 Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P Adcy9 Gt/Gt mice compared to WT animals ( P Adcy9 Gt/Gt mice (versus WT, P Adcy9 Gt/Gt ( P Adcy9 Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P Adcy9 Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P Adcy9 Gt/Gt compared to WT mice ( P P P =0.0572). Adcy9 inactivation–induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9 Gt/Gt mice ( P >0.05 versus CETPtg Adcy9 WT ). Conclusions: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.

Aims Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac β-adrenergic (β-AR) remodeling at the early phase of endotoxemic shock. Main methods Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, β-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE. Key findings Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a β1-AR stimulation, whereas β2-AR and β3-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify β1-AR-induced contractility in controls, whereas it abolished the increased β1-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased β1-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased β1-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat. Significance Our results suggest that the EE is involved in the increased cardiac β1-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.

Background: The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients. Methods: We used metabolic PET parameters, at diagnosis and after two cycles of chemotherapy and proliferation gene expression profile on biopsy at diagnosis, in particular, the genomic grade index (GGI) analyzed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The pathological response was the surrogate endpoint. Results: The change of FDG uptake between baseline PET and interim PET after 2 cycles of neoadjuvant chemotherapy (ΔSUVmax) was highly associated with pCR (p=0.008). We also observed an ability of P53 mutated status (p=0.042), in addition to histological grade (p=0. 0004), and PR expression (p=0.01) to predict pCR in ERpositive BCs, whereas no proliferation marker predicted pCR (P=0.39 for GGI). Finally, only ΔSUVmax was significantly associated with event free survival (p=0.047). Conclusions: Our results confirm the predictive and prognostic value of tumor ΔSUVmax in ER-positive /HER2-negative advanced BCs patients. These findings can be helpful to select high-risk patients within trials investigating novel treatment strategies., SCOPUS: ar.j, info:eu-repo/semantics/published

No methodical assessment of the lung, cardiac, and sleep function of patients surviving an acute hypercapnic respiratory failure episode requiring admission to the intensive care unit (ICU) has been reported in the literature.To prospectively investigate the prevalence and impact of comorbidities in patients treated by mechanical ventilator support (invasive or noninvasive) for acute hypercapnic respiratory failure in the ICU.Seventy-eight consecutive patients admitted for an episode of acute hypercapnic respiratory failure underwent an assessment of lung, cardiac, and sleep function by pulmonary function tests, transthoracic echocardiography, and polysomnography 3 months after ICU discharge.Sixty-seven percent (52 of 78) of patients exhibited chronic obstructive pulmonary disease (COPD), although only 19 had been previously diagnosed. Patients without COPD were primarily obese. Prevalence of severe obstructive sleep apnea was 51% (95% confidence interval, 34-69) in patients with COPD and 81% (95% confidence interval, 54-96) in patients without COPD. Previously undiagnosed cardiac dysfunction with preserved ejection fraction was highly prevalent (44%), as was hypertension (67%). More than half of the population demonstrated at least three major comorbidities known to precipitate acute hypercapnic respiratory failure. Multimorbidity was associated with longer time to hospital discharge. Hospital readmission or death occurred in 46% of patients over an average of 3.5 months after discharge.Severe hypercapnic respiratory failure requiring ICU admission resulted primarily from COPD or obesity. Major comorbidities are highly prevalent in both cases and most often ignored. Surviving acute hypercapnic respiratory failure should be an opportunity to systematically evaluate lung, heart, and sleep functions to improve poor outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02111876).

An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, 18F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for 18F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. 18F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. 18F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, 18F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion:18F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, 18F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, 18F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, 18F-FLT PET may be foreseen as an alternative to BMS.

PDMS-grafted alumina membranes have already demonstrated high organic solvent permeabilities; described and modeled in this paper are their retention capabilities. In contrast to pure PDMS polymeric membranes, higher retentions were found in nonpolar solvents than in polar solvents. This is attributed to a solvent-induced pore-constriction behavior: confined swelling of PDMS, grafted into the membrane pores, was found to increase retention. To test this hypothesis, pore sizes were obtained by integrating the Ferry, Verniory and steric hindrance pore (SHP) equations into the Spiegler Kedem Katchalsky (SKK) model in order to predict the retention of dyes. Ultimately, a diffusion pore size was introduced into the SKK model to reflect the ability of the solute to diffuse through the swollen PDMS graft. A better understanding of the transport mechanisms that impact performance was achieved by incorporating the unique pore structure of these ceramic-based hybrid membranes into the SKK model.

Background Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies can reduce low-density lipoprotein cholesterol (LDL-C) to very low levels when added to background lipid-lowering therapy. Objectives The safety of alirocumab was evaluated in patients with at least 2 consecutive LDL-C values Methods Pooled data from 14 trials were analyzed (double-blind treatment 8 to 104 weeks; n = 3,340 alirocumab, n = 1,894 control [placebo or ezetimibe]; representing 4,029 [alirocumab] and 2,114 [control] double-blind patient-years’ exposure). Results In alirocumab-treated patients, 839 (25.1%) achieved 2 consecutive LDL-C values Conclusions LDL-C levels NCT01288443 , NCT01288469 , NCT01266876 , NCT01812707 , NCT01507831 , NCT01617655 , NCT01623115 , NCT01709500 , NCT01644175 , NCT01644188 , NCT01730040 , NCT01730053 , NCT01644474 , and NCT01709513 )

Ten new mercury (II) complexes ( 1 – 10 ) were synthesized from the reaction of mercury (II) chloride with O - F -alkylated thiocarbamates. These compounds were fully characterized by multinuclear ( 1 H, 19 F, 13 C and 199 Hg) NMR and IR spectroscopic techniques, HRMS and in one case (complex 3 ) by X-ray crystallography. The absence of NH proton ( 1 H) and C S ( 13 C) NMR signals as well as the presence of C N ( 13 C) and S-Hg ( 199 Hg) NMR signals for complexes 1 – 10 suggest that the thiocarbamate ligand is coordinated to the mercury center through its sulfur atom. This was further confirmed by X-ray crystallographic data obtained for complex 3 .