The current prevalence of chronic obstructive pulmonary disease (COPD) in France is estimated to be 2.6 million and is predicted to increase to 2.8 million by 2025. Presently, there is a lack of data ...on COPD management within the private healthcare setting. The aim of this study was to investigate the management of COPD exacerbations by pulmonologists within private practices in France.
A prospective, online, qualitative survey was distributed to private practice pulmonologists in France. The survey covered all aspects of COPD management from diagnosis and therapeutic management, to secondary prevention and organization of care. Survey responses were collected between 27 January 2018 and 18 June 2018 and all data were summarized descriptively.
The survey had a response rate of 20.6%, with 116 out of 563 pulmonologists providing responses. Overall, 87.4% of respondents stated that the management of COPD represented over 15% of their total clinical activity. Most respondents indicated that they work closely with general practitioners and a large multidisciplinary team to manage patients with numerous comorbidities. Following a COPD exacerbation, the majority of respondents (78.4%) were in favor of using respiratory-connected devices (class 2a-connected medical device according to the French HAS classification and available on medical prescription) to assist with patient follow-up at home.
COPD management forms part of the core clinical activity for pulmonologists within the private practice setting in France. Patients with COPD generally have multiple comorbidities and are managed by a multidisciplinary team in line with French guidelines. The use of respiratory-connected devices was highlighted as an important new strategy for improving patient care following a COPD exacerbation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diagnosis of pulmonary embolism (PE) is difficult in patients with chronic obstructive pulmonary disease (COPD) and exacerbation.
To evaluate PE in patients with COPD and exacerbation of unknown ...origin and explore factors associated with PE.
Prospective cohort study.
University-affiliated hospital in France.
211 consecutive patients, all current or former smokers with COPD, who were admitted to the hospital for severe exacerbation of unknown origin and did not require invasive mechanical ventilation.
Spiral computed tomography angiography (CTA) and ultrasonography within 48 hours of admission and assessment of the Geneva score. Patients were classified as PE positive (positive results on CTA or negative results on CTA and positive results on ultrasonography) or PE negative (negative results on CTA and negative results on ultrasonography or negative results on CTA and no recurrence of PE at follow-up 3 months later).
49 of 197 patients (25% 95% CI, 19% to 32%) met the diagnostic criteria for PE. Clinical factors associated with PE were previous thromboembolic disease (risk ratio, 2.43 CI, 1.49 to 3.94), malignant disease (risk ratio, 1.82 CI, 1.13 to 2.92), and decrease in PaCO2 of at least 5 mm Hg (risk ratio, 2.10 CI, 1.23 to 3.58). A total of 9.2% (CI, 4.7% to 15.9%) of patients with a low-probability Geneva score received a diagnosis of PE. An exploratory analysis suggested that substituting malignant disease for recent surgery in the Geneva score might improve its performance in excluding PE in this sample who were more likely to have malignant disease than to have had recent surgery. However, this improvement seems insufficient to exclude PE with enough certainty to withhold therapy for low-risk patients on the basis of the modified score.
This study was done in only 1 center. Patients with COPD requiring invasive mechanical ventilation in the intensive care unit were not included. The upper bound of the 95% CI for the low probability of PE according to the Geneva score is too high to rule out PE. The classification of COPD exacerbation of unknown origin was based on the clinician's assessment, not on a standard evaluation for all patients.
This study showed a 25% prevalence of PE in patients with COPD hospitalized for severe exacerbation of unknown origin. Three clinical factors are associated with the increased risk for PE. The Geneva score and the modified Geneva score should be prospectively evaluated in patients with COPD.
Cancer initiation and progression follow complex molecular and structural changes in the extracellular matrix and cellular architecture of living tissue. However, it remains poorly understood how the ...transformation from health to malignancy alters the mechanical properties of cells within the tumour microenvironment. Here, we show using an indentation-type atomic force microscope (IT-AFM) that unadulterated human breast biopsies display distinct stiffness profiles. Correlative stiffness maps obtained on normal and benign tissues show uniform stiffness profiles that are characterized by a single distinct peak. In contrast, malignant tissues have a broad distribution resulting from tissue heterogeneity, with a prominent low-stiffness peak representative of cancer cells. Similar findings are seen in specific stages of breast cancer in MMTV-PyMT transgenic mice. Further evidence obtained from the lungs of mice with late-stage tumours shows that migration and metastatic spreading is correlated to the low stiffness of hypoxia-associated cancer cells. Overall, nanomechanical profiling by IT-AFM provides quantitative indicators in the clinical diagnostics of breast cancer with translational significance.
Real World Justice Follesdal, Andreas; Pogge, Thomas
2005, 2005-06-08, Letnik:
1
eBook
The concept of global justice makes visible how we citizens of affluent countries are potentially implicated in the horrors so many must endure in the so-called less developed countries. Distinct ...conceptions of global justice differ in their specific criteria of global justice. However, they agree that the touchstone is how well our global institutional order is doing, compared to its feasible alternatives, in regard to the fundamental human interests that matter from a moral point of view. We are responsible for global regimes such as the global trading system and the rules governing military interventions. These institutional arrangements affect human beings worldwide, for instance by shaping the options and incentives of governments and corporations. Alternative paths of globalization would have differed in how much violence, oppression, and extreme poverty they engender. And global institutional reforms could greatly enhance human rights fullfillment in the future. The importance of this global justice approach reaches well beyond philosophy. It helps ordinary citizens evaluate their options and their responsibility for global institutional factors, and it challenges social scientists to address the causes of poverty and hunger that act across borders. The present volume addresses four main topics regarding global justice: The normative grounds for claims regarding the global institutional order, the substantive normative principles for a legitimate global order, the roles of legal human rights standards, and some institutional arrangements that may make the present world order less unjust. All royalties from this book have been assigned to Oxfam.
A gabbroic dyke swarm containing magmatic sapphirine occurs in the Finero phlogopite–peridotite (FPP), one of the major mantle massifs in the Ivrea–Verbano Zone (IVZ; western Southern Alps). ...Sapphirine is part of a particular mineral assemblage, including plagioclase, titanian pargasite, titanian phlogopite, and Cl-rich apatite; the latter mineral hosts calcite inclusions. The dykes cut the mantle foliation at a high angle, are bounded by orthopyroxenite layers, and show symmetric internal banding, represented by two outer hornblendite selvages and an inner leucogabbro band. The sapphirine occurs in up to 3 cm-thick irregular patches in both hornblendite salvages, along with Al-rich amphibole and green spinel.
We present major and trace elements of minerals and bulk rock, as well as mineral O, Sr, and Nd isotopic compositions of dykes and the host peridotite from two different outcrops in the FPP area.
Our data show that early melt migration developed through porous flow within cm-thick channels and was characterised by orthopyroxene dissolution. Following progressive percolation and reaction, the melt became silica saturated with segregation of orthopyroxenite in the centres of the channels. The banded internal structure of the dykes was caused by three different evolutionary stages, involving opening and enlargement of the conduits. The sapphirine and green spinel segregation took place at T > 1000 °C, in the presence of melt with transient composition, which interstitially migrated and reacted with the cumulus minerals to form the hornblendite layers. The mineral chemistry of the newly-formed amphiboles indicates that the sapphirine parental melt was Al-rich, depleted to strongly depleted in Hf, Zr, Nb, Ta, Ti, Sc, V, and middle and heavy rare earth elements, and characterised by a positive Eu anomaly and (Zr/Hf)N < 1. These data suggest a parental melt with a significant amount of normative plagioclase. However, the studied veins do not show evidence of plagioclase assimilation, and we argue that this process could have occurred in magmatic bodies that are not outcropping today to the surface or in the melt source.
The δ18O values of vein amphiboles and plagioclases vary from 6.9 to 8.6‰ SMOW, which is well above the mantle range, even when considering fractionation upon cooling. Given that orthopyroxene from the wall has “normal” mantle δ18O values (5.8‰), reaction with the host metasomatised peridotite cannot be responsible for the heavy δ18O signature, and the latter must have been imparted by crustal components deeper in the mantle.
Our petrographic and geochemical evidence demonstrates that the northern IVZ records an extremely prolonged release, from the Variscan orogenic cycle to the Mesozoic exhumation, of K-H2O-rich mantle-derived melts, mixed with subduction-related components. This finding provides valuable insights into the Triassic–Jurassic magmatism and the geodynamic environment at the Europe–Africa boundary.
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•Mesozoic Spr-bearing gabbroic dykes with continental crustal components•Reaction between dyke melts and the metasomatised host enhanced the crustal signature•The large Al content of the parent melt caused the segregation of magmatic sapphirine•Dykes record Triassic K-rich Calk-Alkaline to Shosonitic magmatism in Southern Alps
For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to ...investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma.
RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1–28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing.
Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4–89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6–83·2) with maintenance chemotherapy versus 69·8% (62·2–76·2) without maintenance chemotherapy (hazard ratio HR 0·68 95% CI 0·45–1·02; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2–90·9) with maintenance chemotherapy versus 73·7% (65·8–80·1) without (HR 0·52 95% CI 0·32–0·86; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3–4 leucopenia, 148 (82%) had grade 3–4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved.
Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials.
Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.
The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell ...RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
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•Loss of CD58 expression confers immune evasion through multiple mechanisms•CD58 and PD-L1 are co-regulated in cancer cells•Genome-scale screens identify CMTM6 as important regulator of CD58•CD58 and PD-L1 compete for CMTM6 for protein stability
Ho et al. identify a critical role for defects in the CD58-CD2 axis as drivers of immune evasion and impaired intratumoral T cell infiltration. CD58 and PD-L1 compete for CMTM6 for protein stabilization, thus representing an additional mechanism for balancing immune-stimulatory and -inhibitory signals.
Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established ...multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma.
We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m2 weekly during the first 7 weeks then only on day 1 of each cycle given as a single intravenous injection, and dactinomycin 1·5 mg/m2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up.
Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6–78·9). The 3-year event-free survival was 67·5% (95% CI 61·2–73·1) in the IVA plus doxorubicin group and 63·3% (56·8–69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65–1·16; p=0·33). Grade 3–4 leucopenia (232 93% of 249 patients in the IVA plus doxorubicin group vs 194 85% of 227 in the IVA group; p=0·0061), anaemia (195 78% vs 111 49%; p<0·0001), thrombocytopenia (168 67% vs 59 26%; p<0.0001), and gastrointestinal adverse events (78 31% vs 19 8%; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3–5 infections (198 79% vs 128 56%; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group.
The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe.
Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France.
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