Dual-mobility socket in challenging total hip arthroplasty : 2-6 years follow-up.

The success of dual-mobility sockets in achieving implant stability in primary hip replacement is already well established. However, stability cannot always be achieved, especially when dealing with more difficult indications. At our department, 104 dual-mobility sockets (92 uncemented and 12 cemented) were implanted for primary total hip arthroplasty in 97 patients between 2009 and 2013. Indications for hip arthroplasty included primary and secondary coxarthrosis, acetabular and subcapital fractures, avascular necrosis, tumor surgery and metastatic fractures. Although no loosenings were observed, 2 dislocations and 1 infection occurred shortly after surgery. In this challenging group of patients no fixation problems or intraprosthetic dislocations have been observed. The design therefore seems to be a valid alternative to constrained implants, especially in high-risk cases, although dislocation cannot be prevented at all times. Although the findings are very promising, long-term survival studies are mandatory to evaluate intraprosthetic stability and fixation longevity of dual-mobility sockets

Managing uncertainty:financial, actuarial and statistical modelling.

present value; Value; Actuarial;

First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing

Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration.</p> <p>Conclusions</p> <p>Influenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians.</p

ORGANIC FARMERS IN EUROPE: MOTIVATIONS AND PROBLEMS FOR USING CONSERVATION AGRICULTURE PRACTICES. "TILMAN-ORG Session"

As conservation agriculture and organic farming are currently considered as environmentally friendly options for producing food, this study explores the motivations and problems of organic European farmers that apply at least two of the following techniques: (i) no-tillage, (ii) reduced tillage and/or (iii) green manures conservation practices. We carried out a survey about motivations and problems of 159 farmers located in 10 European countries with a questionnaire with closed-ended questions. Data were analysis with a principal component analysis followed by clustering to identify groups of farmers that share the same type of motivations and problems. The most important motivations are related to soil preservation concerns and problems are mainly linked to agronomic conditions and crop management. There are three groups of farmers that share the same type of attitude: “atypical farmers”, “soil conservationists” and “agro-technically challenged farmers”. According to this study, research may address in priority agronomic problems, such as weed infestation, caused by adoption of conservation agriculture in organic agriculture

Shallow non-inversion tillage in organic farming maintains crop yields and increases soil C stocks: a meta-analysis

Reduced tillage is increasingly promoted to improve sustainability and productivity of agricultural systems. Nonetheless, adoption of reduced tillage by organic farmers has been slow due to concerns about nutrient supply, soil structure, and weeds that may limit yields. Here, we compiled the results from both published and unpublished research comparing deep or shallow inversion tillage, with various categories of reduced tillage under organic management. Shallow refers to less than 25 cm. We found that (1) division of reduced tillage practices into different classes with varying degrees of intensity allowed us to assess the trade-offs between reductions in tillage intensity, crop yields, weed incidence, and soil C stocks. (2) Reducing tillage intensity in organic systems reduced crop yields by an average of 7.6 % relative to deep inversion tillage with no significant reduction in yield relative to shallow inversion tillage. (3) Among the different classes of reduced tillage practice, shallow non-inversion tillage resulted in non-significant reductions in yield relative to deep inversion; whereas deep non-inversion tillage resulted in the largest yield reduction, of 11.6 %. (4) Using inversion tillage to only a shallow depth resulted in minimal reductions in yield, of 5.5 %, but significantly higher soil C stocks and better weed control. This finding suggests that this is a good option for organic farmers wanting to improve soil quality while minimizing impacts on yields. (5) Weeds were consistently higher, by about 50 %, when tillage intensity was reduced, although this did not always result in reduced yields

Cancer cell–derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo

Recent publications have demonstrated the presence of tissue factor (TF)–bearing microparticles (MPs) in the blood of patients suffering from cancer. However, whether these MPs are involved in thrombosis remains unknown. We show that pancreatic and lung cancer cells produce MPs that express active TF and P-selectin glycoprotein ligand 1 (PSGL-1). Cancer cell–derived MPs aggregate platelets via a TF-dependent pathway. In vivo, cancer cell–derived MPs, but not their parent cells, infused into a living mouse accumulate at the site of injury and reduce tail bleeding time and the time to occlusion of venules and arterioles. This thrombotic state is also observed in mice developing tumors. In such mice, the amount of circulating platelet-, endothelial cell–, and cancer cell–derived MPs is increased. Endogenous cancer cell–derived MPs shed from the growing tumor are able to accumulate at the site of injury. Infusion of a blocking P-selectin antibody abolishes the thrombotic state observed after injection of MPs or in mice developing a tumor. Collectively, our results indicate that cancer cell–derived MPs bearing PSGL-1 and TF play a key role in thrombus formation in vivo. Targeting these MPs could be of clinical interest in the prevention of thrombosis and to limit formation of metastasis in cancer patients

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Cooperation Between Jak2 V617F and Srsf2 P95H Mutations in Hematopoïetic System

La mutation JAK2 V617F est fréquemment observée en cas de néoplasme myéloprolifératif (NMP). D’autres mutations somatiques peuvent être associées et sont corrélées au stade myélofibrotique ou à une évolution en leucémie aigüe. L’une de ces mutations touche le gène SRSF2, codant pour une protéine du complexe d’épissage. Pour étudier l’interaction entre les mutations Jak2 V617F et Srsf2 P95H dans le tissu hématopoïétique, nous avons généré un modèle murin knock-in conditionnel des deux mutations s’exprimant sous le contrôle du gène Scl. Notre étude montre que Srsf2 P95H limite peu le développement de la polyglobulie et de la thrombocytose induites par Jak2 V617F mais freine l’évolution vers une fibrose médullaire et protège les cellules souches hématopoïétiques de l’épuisement en transplantations sériées. L’étude des mégacaryocytes (MK), impliqués dans le processus fibrotique, montre que Srsf2 P95H induit une quasi-normalisation des anomalies induites par Jak2 V617F (taille, ploïdisation, expression de c-Mpl). L’analyse de la signalisation c-Mpl/Jak2 par cytométrie de masse révèle une discrète diminution de la proportion de MK exprimant de haut niveau de P-Stat5 en cas de mutation Srsf2 P95H associée à Jak2 V617F tandis que l’injection d’un agoniste de la thrombopoïetine à fortes doses confirme l’impact négatif de Srsf2 P95H sur le développement de la fibrose. L’étude de l’expression génique de MK triés confirme l’altération de la voie Jak/Stat induite par Srsf2 P95H et révèle que Srsf2 P95H induit plus fréquemment une perte de l’exon 14 (incluant la mutation V617F) de l’ARNm de Jak2. Ce résultat est confirmé sur des échantillons de granulocytes de patients atteints de NMP JAK2 V617F avec mutation SRSF2 P95H associée.JAK2 V617F mutation is frequently identified in myeloproliferative neoplasms (MPN). Additional somatic variants are supposed to contribute to bone marrow fibrosis or acute myeloid leukemia evolution. One of these mutations affects SRSF2, a gene encoding a component of the splicing machinery. To investigate how Jak2 V617F and Srsf2 P95H mutations interact in the hematopoietic tissue, we generated conditional knock-in mice in which the two mutations were expressed upon the control of Scl gene. Our study shows that Srsf2 P95H mutation initially exhibits limited effect on Jak2 V617F polycythemia and thrombocytosis but induces a delay in myelofibrosis development and protect hematopoietic stem cell from exhaustion observed after serial transplantation in Jak2 V617F single mutant cells. We focused on megakaryocyte (MK), implied in fibrosis development and found that Srsf2P95H partially reversed MK abnormalities induced by Jak2 V617F (cell size, normalized ploidy and expression of c-Mpl). Analysis of c-Mpl/Jak2 signaling with mass cytometry revealed a slight reduced proportion of MK expressing high levels of P-Stat5 in case of Srsf2 P95H co-occurrence with Jak2 V617F while treatment with high dose of the thrombopoietin-mimetic romiplostim in mice transplanted with wild-type or Srsf2 P95H bone marrow cells confirms the negative impact of Srsf2 P95H on fibrosis development. Gene expression analysis on sorted MK confirms down-regulation of Jak/Stat signaling pathway induced by Srsf2 P95H and reveals that Srsf2 P95H mutation more frequently induces exon 14 skipping of Jak2 mRNA. These result was confirmed in granulocytes samples from patients with JAK2 V617F MPN with associated SRSF2 P95H mutation

Coopération entre les mutations Jak2 V617F et Srsf2 P95Hdans le système hématopoïétique

JAK2 V617F mutation is frequently identified in myeloproliferative neoplasms (MPN). Additional somatic variants are supposed to contribute to bone marrow fibrosis or acute myeloid leukemia evolution. One of these mutations affects SRSF2, a gene encoding a component of the splicing machinery. To investigate how Jak2 V617F and Srsf2 P95H mutations interact in the hematopoietic tissue, we generated conditional knock-in mice in which the two mutations were expressed upon the control of Scl gene. Our study shows that Srsf2 P95H mutation initially exhibits limited effect on Jak2 V617F polycythemia and thrombocytosis but induces a delay in myelofibrosis development and protect hematopoietic stem cell from exhaustion observed after serial transplantation in Jak2 V617F single mutant cells. We focused on megakaryocyte (MK), implied in fibrosis development and found that Srsf2P95H partially reversed MKabnormalities induced by Jak2 V617F (cell size, normalized ploidy and expression of c-Mpl). Analysis of c-Mpl/Jak2 signaling with mass cytometry revealed a slight reduced proportion of MK expressing high levels of P-Stat5 in case of Srsf2 P95H co-occurrence with Jak2 V617F while treatment with high dose of the thrombopoietin-mimetic romiplostim in mice transplanted with wild-type or Srsf2 P95H bone marrow cells confirms the negative impact of Srsf2 P95H on fibrosis development. Gene expression analysis on sorted MK confirms down-regulation of Jak/Stat signaling pathway induced by Srsf2 P95H and reveals that Srsf2 P95H mutation more frequently induces exon 14 skipping of Jak2 mRNA. These result was confirmed in granulocytes samples from patients with JAK2 V617F MPN with associated SRSF2 P95H mutation.La mutation JAK2 V617F est fréquemment observée en cas de néoplasme myéloprolifératif (NMP). D’autres mutations somatiques peuvent être associées et sont corrélées au stade myélofibrotique ou à une évolution en leucémie aigüe. L’une de ces mutations touche le gène SRSF2, codant pour une protéine du complexe d’épissage. Pour étudier l’interaction entre les mutations Jak2 V617F et Srsf2 P95H dans le tissu hématopoïétique, nous avons généré un modèle murin knock-in conditionnel des deux mutations s’exprimant sous le contrôle du gène Scl. Notre étude montre que Srsf2 P95H limite peu le développement de la polyglobulie et de la thrombocytose induites par Jak2 V617F mais freine l’évolution vers une fibrose médullaire et protège les cellules souches hématopoïétiques de l’épuisement en transplantations sériées. L’étude des mégacaryocytes (MK), impliqués dans le processus fibrotique, montre que Srsf2 P95H induit une quasi-normalisation des anomalies induites par Jak2 V617F (taille, ploïdisation, expression de c-Mpl). L’analyse de la signalisation c-Mpl/Jak2 par cytométrie de masse révèle une discrète diminution de la proportion de MK exprimant de haut niveau de P-Stat5 en cas de mutation Srsf2 P95H associée à Jak2 V617F tandis que l’injection d’un agoniste de la thrombopoïetine à fortes doses confirme l’impact négatif de Srsf2 P95H sur le développement de la fibrose. L’étude de l’expression génique de MK triés confirme l’altération de la voie Jak/Stat induite par Srsf2 P95H et révèle que Srsf2 P95H induit plus fréquemment une perte de l’exon 14 (incluant la mutation V617F) de l’ARNm de Jak2. Ce résultat est confirmé sur des échantillons de granulocytes de patients atteints de NMP JAK2 V617F avec mutation SRSF2 P95H associée