9 research outputs found
Osteochondral transplantation using autografts from the upper tibio-fibular joint for the treatment of knee cartilage lesions
Purpose Treatment of large cartilage lesions of the knee
in weight-bearing areas is still a controversy and challenging topic. Autologous osteochondral mosaicplasty has
proven to be a valid option for treatment but donor site
morbidity with most frequently used autografts remains a
source of concern. This study aims to assess clinical results
and safety proïŹle of autologous osteochondral graft from
the upper tibio-ïŹbular joint applied to reconstruct symptomatic osteochondral lesions of the knee.
Methods Thirty-one patients (22 men and 9 women) with
grade 4 cartilage lesions in the knee were operated by
mosaicplasty technique using autologous osteochondral
graft from the upper tibio-ïŹbular joint, between 1998 and
2006. Clinical assessment included visual analog scale
(VAS) for pain and Lysholm score. All patients were
evaluated by MRI pre- and post-operatively regarding joint
congruency as good, fair (inferior to 1 mm incongruence),
and poor (incongruence higher than 1 mm registered in any
frame). Donor zone status was evaluated according to
speciïŹc protocol considering upper tibio-ïŹbular joint
instability, pain, neurological complications, lateral collateral ligament insufïŹciency, or ankle complaints.
Results Mean age at surgery was 30.1 years (SD 12.2). In
respect to lesion sites, 22 were located in weight-bearing
area of medial femoral condyle, 7 in lateral femoral condyle, 1 in trochlea, and 1 in patella. Mean follow-up was
110.1 months (SD 23.2). Mean area of lesion was 3.3 cm
2
(SD 1.7), and a variable number of cylinders were used,
mean 2.5 (SD 1.3). Mean VAS score improved from 47.1
(SD 10.1) to 20.0 (SD 11.5); p = 0.00. Similarly, mean
Lysholm score increased from 45.7 (SD 4.5) to 85.3
(SD 7.0); p = 0.00. The level of patient satisfaction was
evaluated, and 28 patients declared to be satisïŹed/very
satisïŹed and would do surgery again, while 3 declared as
unsatisïŹed with the procedure and would not submit to
surgery again. These three patients had lower clinical scores
and kept complaints related to the original problem but
unrelated to donor zone. MRI score signiïŹcantly improved
at 18â24 months comparing with pre-operative (p = 0.004).
No radiographic or clinical complications related to donor
zone with implication in activity were registered.
Conclusions This work corroborates that mosaicplasty
technique using autologous osteochondral graft from the
upper tibio-ïŹbular joint is effective to treat osteochondral
defects in the knee joint. No relevant complications related
to donor zone were registered
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Geno-Clinical Model for the Diagnosis of Bone Marrow Myeloid Neoplasms
Background
Myelodysplastic syndromes (MDS) and other myeloid neoplasms are mainly diagnosed based on morphological changes in the bone marrow. Diagnosis can be challenging in patients (pts) with pancytopenia with minimal dysplasia, and is subject to inter-observer variability, with up to 40% disagreement in diagnosis (Zhang, ASH 2018). Somatic mutations can be identified in all myeloid neoplasms, but no gene or set of genes are diagnostic for each disease phenotype.
We developed a geno-clinical model that uses mutational data, peripheral blood values, and clinical variables to distinguish among several bone marrow disorders that include: MDS, idiopathic cytopenia of undetermined significance (ICUS), clonal cytopenia of undetermined significance (CCUS), MDS/myeloproliferative neoplasm (MPN) overlaps including chronic myelomonocytic leukemia (CMML), and MPNs such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (PMF).
Methods
We combined genomic and clinical data from 2471 pts treated at our institution (684) and the Munich Leukemia Laboratory (1787). Pts were diagnosed with MDS, ICUS, CCUS, CMML, MDS/MPN, PV, ET, and PMF according to 2016 WHO criteria. Diagnoses were confirmed by independent hematopathologists not associated with the study. A panel of 60 genes commonly mutated in myeloid malignancies was included. The cohort was randomly divided into learner (80%) and validation (20%) cohorts. Machine learning algorithms were applied to predict the phenotype. Feature extraction algorithms were used to extract genomic/clinical variables that impacted the algorithm decision and to visualize the impact of each variable on phenotype. Prediction performance was evaluated according to the area under the curve of the receiver operator characteristic (ROC-AUC).
Results
Of 2471 pts, 1306 had MDS, 223 had ICUS, 107 had CCUS, 478 had CMML, 89 had MDS/MPN, 79 had PV, 90 had ET, and 99 had PMF. The median age for the entire cohort was 71 years (range, 9-102); 38% were female. The median white blood cell count (WBC) was 3.2x10^9/L (range, 0.00-179), absolute monocyte count (AMC) 0.21x10^9/L (range, 0-96), absolute lymphocyte count (ALC) 0.88x10^9/L (range, 0-357), absolute neutrophil count (ANC) 0.60x10^9/L (range, 0-170), and hemoglobin (Hgb) 10.50 g/dL (range, 3.9-24.0).
The most commonly mutated genes in all pts were: TET2 (28%), ASXL1 (23%), SF3B1 (15%). In MDS, they were: TET2 (26%), SF3B1 (24%), ASXL1 (21%). In CCUS: TET2 (46%), SRSF2 (24%), ASXL1 (23%). In CMML, TET2 (51%), ASXL1 (43 %), SRSF2 (25%). In MDS/MPN: SF3B1 (39%), JAK2 (37%), TET2 (20%). In PV, JAK2 (94%), TET2 (22%), DNMT3A (8%). In ET: JAK2 (44%), TET2 (13%), DNMT3A (8%). In PMF: JAK2 (67%), ASXL1 (43%), SRSF2 (17%).
71 genomic/clinical variables were evaluated. Feature extraction algorithms were used to identify the variables with the most significant impacts on prediction. The top variables are shown in the Figure 1. Overall, the most important variables were: age, AMC, ANC, Hgb, Plt, ALC, total number of mutations, JAK2, ASXL1, TET2, U2AF1, SRSF2, SF3B1, BCOR, EZH2, and DNMT3A. The top variables for each disease were different, see Figure.
When applying the model to the validation cohort, AUC performance was as follows (a perfect predictor has an AUC of 1, and AUC â„ 0.90 are generally considered excellent): MDS: 0.95 +/- 0.04, ICUS: 0.96 +/- 0.05, CCUS: 0.95 +/- 0.05, CMML: 0.95 +/- 0.05, MDS/MPN: 0.95 +/- 0.05, PV: 0.95 +/- 0.05, ET: 0.96 +/- 0.05, PMF: 0.95 +/- 0.05. When the analysis was restricted to MDS, ICUS, and CCUS, the AUC remained high, 0.95 +/- 0.4. The model can also provide personalized explanations of the variables supporting the prediction and the impact of each variable on the outcome (Figure).
Conclusions
We propose a new approach using interpretable, individualized modeling to predict myeloid neoplasm phenotypes based on genomic and clinical data without bone marrow biopsy data. This approach can aid clinicians and hematopathologists when encountering pts with cytopenias and suspicion for these disorders. The model also provides feature attributions that allow for quantitative understanding of the complex interplay among genotypes, clinical variables, and phenotypes. A web application to facilitate the translation of this model into the clinic is under development and will be presented at the meeting.
Figure 1
Disclosures
Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Walter:MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Savona:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Gerds:Incyte: Consultancy, Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy
GlobalizaciĂłn, cambios en la estructura de poder y nuevas elites empresariales: una mirada comparada de Uruguay
El artĂculo tiene como objetivo principal abordar la problemĂĄtica de los cambios en la composiciĂłn de las elites empresariales en el Ășltimo ciclo de globalizaciĂłn econĂłmica neoliberal desde la literatura teĂłrica comparada reciente y luego un anĂĄlisis especĂfico a partir de los estudios existentes en la temĂĄtica sobre Uruguay. El trabajo desarrolla un anĂĄlisis comparativo de enfoques y estudios sobre elites econĂłmicas que señalan cinco tipos de procesos de cambios en las Ășltimas dĂ©cadas de hegemonĂa del ciclo de desarrollo neoliberal. En primer tĂ©rmino, procesos de convergencia y divergencia entre las trayectorias de las elites polĂticas y econĂłmicas. En segundo lugar, procesos de especializaciĂłn funcional y diversificaciĂłn de grupos dirigentes en las distintas fuentes de poder econĂłmico. Tercero, la existencia de mecanismos de reclutamiento y reproducciĂłn de las elites econĂłmicas que se relacionan con las formas de dominaciĂłn en la sociedad. Cuarto, la producciĂłn nuevos y viejos mecanismos de legitimaciĂłn del poder econĂłmico, que combinan formas de capital econĂłmico y simbĂłlico. Por Ășltimo, la creciente centralidad de las redes globales y modos de transnacionalizaciĂłn del capital en la conformaciĂłn de los grupos de elites empresariales. El anĂĄlisis de la literatura y estudios sobre elites empresariales en el Uruguay en las Ășltimas dĂ©cadas muestra tendencias similares (a escala de una economĂa y paĂs pequeño) donde se estĂĄ asistiendo a cambios en las composiciĂłn de las elites empresariales con una creciente importancia del capital transnacional, y de nuevos elencos ejecutivos que se apoyan mĂĄs en una forma de control y gestiĂłn profesionalizada de las empresas, en redes globales y nuevas formas de capital social. Estas transformaciones contrastan con los perfiles clĂĄsicos de empresarios reclutados por medio del capital familiar y prestigio heredado y la pertenencia a gremiales tradicionales y cĂrculos empresariales exclusivos, asĂ como de una canalizaciĂłn colectiva mĂĄs orgĂĄnica de las relaciones con el Estado y la polĂtica. El estudio de las elites econĂłmicas es una temĂĄtica clĂĄsica que en las Ășltimas dos dĂ©cadas es una temĂĄtica que ha regresado al debate acadĂ©mico y pĂșblico debido a los impactos de los procesos de la globalizaciĂłn econĂłmica. En Uruguay la temĂĄtica adquiere fuerte relevancia debido a que se trata de una economĂa de escala pequeña, alto desarrollo humano y que en los Ășltimos años ha atravesado mĂșltiples transformaciones en el modelo de desarrollo econĂłmico, la creciente presencia de capital y empresas trasnacionales, con la emergencia de nuevos actores empresariales en la escena nacional y en un contexto polĂtico de giro a la izquierda
Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial
Meeting abstract FRAB0101LB from 21st International AIDS Conference 18â22 July 2016, Durban, South Africa.
Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIVâinfected adults and children with advanced disease in subâSaharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown.
Methods:
The REALITY 2Ă2Ă2 factorial openâlabel trial (ISRCTN43622374) randomized ARTânaĂŻve HIVâinfected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (antiâtuberculosis) and fluconazole (antiâcryptococcal/candida), 5 days azithromycin (antiâbacterial/protozoal) and singleâdose albendazole (antiâhelminth)), versus standardâofâcare cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixedâdose combination. Two other randomizations investigated 12âweek adjunctive raltegravir or supplementary food. The primary endpoint was 24âweek mortality.
Results:
1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% lossâtoâfollowâup). Median baseline CD4 was 36 cells/mm3 (IQR: 16â62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54â0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58â0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2).
Conclusions:
Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIVâinfected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this lowâcost broad infection prevention package which could save 3.3 lives for every 100 individuals treated