BACKGROUND Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.)
Aims: Cardiopulmonary exercise test (CPET) is used to evaluate patients with chronic heart failure (HF) usually by means of a personalized ramp exercise protocol. Our aim was to evaluate if exercise duration or ramp rate influences the results. Methods and results: Ninety HF patients were studied (peak V O 2 : N20 ml/min/kg, n=28, 15-20 ml/min/kg, n=39 and b15 ml/min/kg, n=23). Each patient did four CPET studies. The initial study was used to separate the subjects into three groups, according to their exercise capacity. In the remaining studies, work-rate was increased at three different rates designed to have the subjects reach peak exercise in 5, 10 and 15 min from the start of the ramp increase in work-rate, respectively. The order was randomized. The work-rate applied for the total population averaged 22.7F8.0, 11.6F3.7, 7.5F2.9 W/min with effective loaded exercise duration of 5 min and 16 sF29 s, 9 min and 43 sF49 s and 14 min and 32 sF1 min and 12 s for the 5-, 10-and 15-min tests, respectively. Peak V O 2 averaged 16.9F4.3*, 18.0F4.4 and 18.0F5.4 ml/min/ kg for the 5-, 10-and 15-min tests, (*=pb0.001 vs. 10 min). The shortest test had the lowest peak heart rate and ventilation and highest peak work-rate. Peak V O 2 and heart rate were lowest in 5-min tests regardless of HF severity. The DV O 2 /Dwork-rate was lowest in 5-min tests and highest in 15-min tests. At all ramp rates, DV O 2 /Dwork-rate was lower for the subjects with the lower peak V O 2 . The V e /V CO 2 slope and V O 2 at anaerobic threshold were not affected by the protocol for any grade of HF. Conclusions: In chronic HF, exercise protocol has a small effect on peak V O 2 and DV O 2 /Dwork but does not affect V O 2 at anaerobic threshold and V e /V CO 2 slope. D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.Keywords: Exercise; Oxygen consumption; Heart failure In chronic heart failure (HF), a cardiopulmonary exercise test (CPET) is frequently done to evaluate the severity of the disease, and thereby the patient's prognosis, or to test the efficacy of therapy [1][2][3][4][5][6][7][8]. For these purposes, several CPET parameters have been studied including oxygen uptake (V O 2 ) at peak exercise and at anaerobic threshold, work-rate achieved at peak exercise, slope of ventilation (V e ) vs. carbon dioxide output (V CO 2 ), V e /V CO 2 ratio at anaerobic threshold, DV O 2 /Dwork-rate from unloaded cycling to peak, and the oxygen pulse (O 2 p) at peak V O 2 [9]. Some of these parameters are independent of each other and have specific prognostic relevance; as a consequence their combined use improves our capability to evaluate prognosis in HF patients [9,10]. While it is generally recommended to use a personalized exercise protocol in which work-rate is increased in ramp pattern aimed at achieving target time to peak exercise within 8-12 min [9,[11][12][13], the exercise protocol is rarely provided in clinical study reports. Because it is not known if and how the duration, or the rate of increase of e...
Dm decreases after exercise in HF patients but not in control subjects, which suggests a decrease in conductance across the alveolar-capillary barrier, as with pulmonary edema. The reductions were most marked in HF patients with periodic breathing and less reduced in less severe HF.
Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
There appears to be a consensus that the recent instability in global financial markets may be attributable in part to the failure of financial modeling. More specifically, current risk models have failed to properly assess the risks associated with large adverse stock price behavior. In this paper, we first discuss the limitations of classical time series models for forecasting financial market meltdowns. Then we set forth a framework capable of forecasting both extreme events and highly volatile markets. Based on the empirical evidence presented in this paper, our framework offers an improvement over prevailing models for evaluating stock market risk exposure during distressed market periods.
Managerial barriers consisted of silo budgeting, difficulties with preparing a business case, and fears about uncontrolled implementation. By collecting outcome data, we convinced senior managers to support and sustain investment. Clinical barriers consisted mainly of scepticism regarding clinical effectiveness and worries about training. Clinicians "championing" the technology took on responsibility for data collection, education, advocacy, and spanning boundaries. When barriers to adoption of oesophageal Doppler monitoring are overcome, outcome improvements suggested by research can be replicated in the real world. The project generated a web based guide (www.howtowhyto.nhs.uk) to provide tools and resources to support implementation.
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