Current prognostication in primary myelofibrosis (PMF) is based on the dynamic international prognostic scoring system (DIPSS)-plus, which employs clinical and cytogenetic variables. We recently ...reported DIPSS-plus independent prognostic significance for calreticulin (CALR) (favorable) and ASXL1 (unfavorable) mutations. In the current study, 570 PMF patients were recruited for derivation (n=277) and validation (n=293) of a molecular prognostic model based on these two mutations. Survival was the longest in CALR(+)ASXL1(-) (median 10.4 years) and shortest in CALR(-)ASXL1(+) patients (median, 2.3 years; hazard ratio (HR), 5.9; 95% confidence interval (CI), 3.5-10.0). CALR(+)ASXL1(+) and CALR(-)ASXL1(-) patients had similar survival and were grouped together in an intermediate-risk category (median survival, 5.8 years; HR, 2.5; 95% CI, 1.5-4.0). The CALR/ASXL1 mutations-based prognostic model was DIPSS-plus independent (P<0.0001) and effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median 20 years) survival and high-/intermediate-2-risk patients with shorter (median, 2.3 years) survival. Multivariable analysis distinguished CALR(-)ASXL1(+) mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype. These observations signify immediate clinical relevance and warrant i) CALR and ASXL1 mutation determination in all patients with PMF and ii) molecular revision of DIPSS-plus.
An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that ...selectively depletes CD20-expressing B cells, in the primary progressive form of the disease.
In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis.
The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval CI, 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T
-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections.
Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).
B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.
In two identical phase 3 trials, we randomly assigned ...821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.
The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval CI, 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T
-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.
Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential ...thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio HR, 1.8; 95% confidence interval CI, 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative.
•Survival in ET is superior to that of PV, regardless of mutational status, but remains inferior to the sex- and age-matched US population.•JAK2/CALR/MPL mutational status is prognostically informative in PMF, regarding overall and leukemia-free survival.
As adolescence is a transition period from childhood to adulthood malnutrition occurring at this age resonates through generations. Although there were many individual studies in Ethiopia about ...different form of malnutrition among adolescent, their results are inconclusive indicating the need for generating a pooled estimate of adolescent nutritional status and associated factors. This review and meta-analyses aimed at estimating the pooled prevalence of different forms of malnutrition and associated factors among adolescents in Ethiopia.
We searched data bases from Pub Med, Cochrane Library, Health Inter Network Access to Research Initiative (HINARI), Science Direct and search engines; Google and Google Scholar and other sources; Reference of References and expert contact which were used to select the studies. Joanna Briggs Institute (JBI) quality appraisal tool was applied to identify eligible studies. STATA/SE V.14 was used to analyze the data. Effect size with 95% Confidence Interval (CI) and heterogeneity were estimated. Heterogeneity of studies was quantified with I2 statistic >50% used as an indicator of heterogeneity. Potential publication bias was assessed using Funnel plots and Egger's regression test. Trim and fill analysis was also performed. The presences of a statistical association between independent and dependent variables were declared at P <0.05. The PROSPERO registration number for the review is CRD42020159734.
The pooled prevalence of overweight/obesity, stunting and thinness were 10.63% (95% CI: 8.86, 12.40), 20.06% (95% CI: 15.61, 24.51) and 21.68% (95% CI: 9.56, 33.81), respectively. Being female (OR: 2.02, CI: 1.22-3.34), low dietary diversity score (OR: 2.26 CI: 1.28-3.99) and high physical activity (OR: 0.36, 95%CI: 0.14-0.88) were significantly associated with adolescent overweight/obesity. Urban residence (OR: 0.82, 95%CI: 0.68-0.99), protected drinking water source (OR: 0.50, CI: 0.27-0.90) and having family size<5 people (OR: 0.54, CI: 0.44-0.66) were independent predictors of adolescent stunting. Early adolescent age (10-14 years) (OR: 2.38, CI: 1.70-3.34), protected water source for drinking (OR: 0.36, CI: 0.21-0.61), low wealth index (OR: 1.80, CI: 1.01-3.19) and family size <5 people (OR: 0.50, CI: 0.28-0.89) were significantly (P < 0.05) associated with adolescent thinness.
The prevalence of overweight/obesity, stunting and thinness are high in Ethiopian adolescents indicating the upcoming challenge of double burden of malnutrition. The results imply the presence of double burden of malnutrition among adolescents which heralds the need for programmatic and policy response in terms of addressing modifiable risk factors including: dietary practices, physical activity, water source and economic status of these adolescents.
Summary 60 years ago, the Universal Declaration of Human Rights laid the foundations for the right to the highest attainable standard of health. This right is central to the creation of equitable ...health systems. We identify some of the right-to-health features of health systems, such as a comprehensive national health plan, and propose 72 indicators that reflect some of these features. We collect globally processed data on these indicators for 194 countries and national data for Ecuador, Mozambique, Peru, Romania, and Sweden. Globally processed data were not available for 18 indicators for any country, suggesting that organisations that obtain such data give insufficient attention to the right-to-health features of health systems. Where they are available, the indicators show where health systems need to be improved to better realise the right to health. We provide recommendations for governments, international bodies, civil-society organisations, and other institutions and suggest that these indicators and data, although not perfect, provide a basis for the monitoring of health systems and the progressive realisation of the right to health. Right-to-health features are not just good management, justice, or humanitarianism, they are obligations under human-rights law.
The impact of calreticulin (CALR) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for ...Janus kinase 2 (JAK2), 32% for CALR and 3% for MPL; the remaining 12% were 'triple-negative'. We confirmed the association of mutant CALR (vs JAK2V617F) with younger age (P=0.002), male sex (P=0.01), higher platelet count (0.0004), lower hemoglobin (P<0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2-mutated counterparts (P=0.003) and displayed lower hemoglobin (P=0.003), lower leukocyte count (<0.0001) and lower thrombotic events (P=0.02). Median follow-up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases (P=0.32); the corresponding figures for patients of age ⩽65 years were 26 and 32 years (P=0.56). The two mutational categories were also similar for leukemic (P=0.28) and fibrotic (P=0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis.
Results regarding the association of thrombus length, stent retriever length, and recanalization success in patients with acute ischemic stroke are inconsistent. We hypothesized that the ratio of ...thrombus length to stent retriever length may be of particular relevance.
Patients with acute ischemic stroke undergoing stent retriever thrombectomy at our institution between January 2010 and December 2018 were reviewed retrospectively. Thrombus length was assessed by measuring the susceptibility vessel sign on SWI using a 1.5T or 3T MR imaging scanner. Multivariable logistic regression models were used to determine the association between thrombus length, stent retriever length, and thrombus length/stent retriever length ratio with first-pass recanalization, overall recanalization, and embolization in new territories. Results are shown as adjusted ORs with 95% CIs. Additional mediation analyses were performed to test for indirect effects on first-pass recanalization and overall recanalization success.
The main analysis included 418 patients (mean age, 74.9 years). Increasing stent retriever length was associated with first-pass recanalization. Decreasing thrombus length and lower thrombus length/stent retriever length ratios were associated with first-pass recanalization and overall recanalization. Thrombus length and stent retriever length showed no association with first-pass recanalization or overall recanalization once thrombus length/stent retriever length ratio was factored in, while thrombus length/stent retriever length ratio remained a significant factor in both models (adjusted OR, 0.316 95% CI, 0.112-0.892;
= .030 and adjusted OR, = 0.366 95% CI, 0.194-0.689;
= .002). Mediation analyses showed that decreasing thrombus length and increasing stent retriever length had a significant indirect effect on first-pass recanalization mediated through thrombus length/stent retriever length ratio. The only parameter associated with embolization in new territories was an increasing thrombus length/stent retriever length ratio (adjusted OR, 5.079 95% CI, 1.332-19.362;
= .017).
Information about thrombus and stent length is more valuable when combined. High thrombus length/stent retriever length ratios, which may raise the risk of unsuccessful recanalization and embolization in new territories, should be avoided by adapting stent retriever selection to thrombus length whenever possible.
The world has faced an unprecedented challenge when coronavirus (COVID-19) emerged as a pandemic. Millions of people have contracted the virus and a significant number of them lost their lives, ...resulting in a tremendous social and economic shock across the globe. Amid the growing burden of the pandemic, there are parallel emergencies that need to be simultaneously tackled: the proliferation of fake medicines, fake news and medication misinformation surrounding COVID-19. Pharmacists are key health professionals with the required skills and training to contribute to the fight against these emergencies. Primarily, they can be a relevant source of accurate and reliable information to the public or other fellow health professionals thereby reducing the spread of COVID-19 medication misinformation. This can be achieved by providing accurate and reliable information based on recommendations given by relevant health authorities and professional associations to make sure the community understand the importance of the message and thus minimise the detrimental consequences of the pandemic. This commentary aims to summarise the existing literature in relation to the promising treatments currently under trial, the perils of falsified medications and medicine-related information and the role of pharmacists in taking a leading role in combating these parallel global emergencies.
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