Summary Background l -asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli ...asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l -asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods DFCI 05-001 enrolled patients aged 1–18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l -asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00400946. Findings Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l -asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 28% of 232 patients in the intravenous PEG-asparaginase group vs 59 26% of 231 patients in the intramuscular native E coli l -asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0–7·1). 5-year disease-free survival was 90% (95% CI 86–94) for patients assigned to intravenous PEG-asparaginase and 89% (85–93) for those assigned to intramuscular native E coli l -asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l -asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l -asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 20% of 232 in the intravenous PEG-asparaginase group vs 51 22% of 231 patients in the intramuscular E coli l -asparaginase group) and asparaginase-related allergic reactions (14 6% vs 6 3%). Interpretation Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l -asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding National Cancer Institute and Enzon Pharmaceuticals.
Study objective Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering ...progesterone to patients with acute traumatic brain injury. Methods This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale–Extended 30 days postinjury. Results Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale–Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. Conclusion In this small study, progesterone caused no discernible harm and showed possible signs of benefit.
Endomyocardial biopsy (EMB) is the current gold standard to screen for heart transplant rejection but has important risks and limitations. Cardiovascular magnetic resonance imaging (CMRI) is ...increasingly used to characterize cardiac function and myocardial tissue. We evaluated the diagnostic accuracy of CMRI compared with EMB and clinically diagnosed heart transplant rejection.
Comprehensive CMRI scans were performed on adult heart transplant recipients within 24 hours of EMB (routine or clinically indicated), before initiation of any anti-rejection therapy, and blinded to EMB results. Multivariable analysis was used to create CMRI diagnostic criteria for comparison with a positive EMB (Grade ≥ 2R or antibody-mediated rejection) and clinical rejection (change in medical therapy to treat rejection).
Sixty participants (75% male; mean age, 51 ± 14 years) were recruited, providing 73 comparisons between CMRI and EMB for the diagnosis of rejection. Multivariable logistic regression identified myocardial edema (T2 relaxation time) and right ventricular end-diastolic volume index as independent predictors of a positive EMB. Combining threshold right ventricular end-diastolic volume index and edema values predicted a positive EMB with very good accuracy: sensitivity, 93%; specificity, 78%; positive predictive value, 52%; and negative predictive valve, 98%. CMRI was more sensitive than EMB at predicting clinical rejection (sensitivity of 67% vs 58%).
CMRI has high sensitivity and high negative predictive value in predicting biopsy-positive heart transplant rejection and may be useful as a screening test before routine EMB. CMRI also has better sensitivity for clinically diagnosed heart transplant rejection and could be helpful in cases of negative rejection on the biopsy specimen.
Summary Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in children. We aimed to assess the safety and efficacy of an anti-RSV monoclonal ...antibody (motavizumab) in healthy term (≥36 weeks' gestational age) infants for the prevention of medically attended RSV acute lower respiratory tract infections. Methods This phase 3, double-blind, placebo-controlled, randomised trial enrolled healthy Native American infants aged 6 months or younger who were born at 36 weeks' gestational age in southwestern USA, on the Navajo Nation, the White Mountain Apache reservation, and the San Carlos Apache Indian reservation. Participants were randomly assigned (2:1) to receive either five monthly intramuscular doses of motavizumab (15 mg/kg) or placebo. They were followed up for 150 days after the first dose, and the primary endpoints were respiratory admission to hospital with a positive result for RSV by RT-PCR and death caused by RSV. Participants were followed up for medically attended wheezing until they reached age 3 years. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov , number NCT00121108. Findings During the autumn seasons (October to December) between 2004 and 2007, 2127 infants of the 2596 infants enrolled were randomly assigned to receive either motavizumab (1417) or placebo (710). After ITT analysis, motavizumab resulted in an 87% relative reduction (relative risk RR 0·13, 95% CI 0·08–0·21) in the proportion of infants admitted to hospital with RSV (21 2% of 1417 participants who received motavizumab; 80 11% of 710 participants who received placebo, p<0·0001). Serious adverse events were less common in particpants taking motavizumab (212 15%) than particpants on placebo (148 21%). Six deaths occurred in study participants (motavizumab, n=4 0·3%; placebo, n=2 0·3%); none were deemed to be related to the study product. Hypersensitivity events were more common in patients given motavizumab (208 14·7%) than in placebo recipients (87 12·3%; p=0·14). There was no effect on rates of medically attended wheezing in children aged 1–3 years (190 14·9% of participants randomly assigned to receive motavizumab vs 90 14·0% participants randomly assigned to receive placebo). Interpretation To our knowledge, this is the only trial of an anti-RSV antibody to prevent serious RSV disease in healthy term infants. Motavizumab significantly reduced the RSV-associated inpatient and outpatient burden and set a benchmark for the efficacy of RSV prevention strategies. The findings do not support a direct, generalisable, causal association between RSV lower respiratory tract infection and subsequent long-term wheezing in term infants. Funding MedImmune.
Abstract Background Context Numerous studies have demonstrated poorer outcomes in patients with Workers' compensation (WC) when compared with those without WC following treatment of various of health ...conditions, including spine disorders. It is thus important to consider compensation status when assessing treatment outcomes in spine surgery. However, reported strengths of association have varied significantly (1.31–7.22). Purpose The objective of this study was to evaluate the association of unsatisfactory outcomes on compensation status in spine surgery patients. Study Design/Setting A meta-analysis was performed. Patient Sample Patient sample is not applicable in this study. Outcome Measure Demographics, type of surgery, country, follow-up time, patient satisfaction, return to work and non-union events were the outcome measures. Methods Both prospective and retrospective studies that compared outcomes between compensated and non-compensated patients in spine surgery were included. Two independent investigators extracted outcome data. The meta-analysis was performed using Revman software. Random effects model was used to calculate risk ratio (RR, 95% confidence interval CI) for dichotomous variables. Results Thirty-one studies (13 prospective; 18 retrospective) with a total of 3,567 patients were included in the analysis. Follow-up time varied from 4 months to 10 years. Twelve studies involved only decompression; the rest were fusion. Overall RR of an unsatisfactory outcome was 2.12 1.74, 2.58; p<.001 in patients with WC when compared with those without WC after surgery. The RR ofan unsatisfactory outcome in patients with WC, compared with those without, was 2.09 1.38, 3.17; p<.01 among studies from Europe and Australia, and 2.14 1.48, 2.60; p<.01 among US studies. The RR of decompression-only procedures was 2.53 1.85, 3.47; p<.01,and 1.79 1.45, 2.21; p<.01 for fusion. Forty-three percent (209 of 491) of patients with WC did not return to work versus 17% (214 of 1250) of those without WC (RR 2.07 1.43, 2.98; p<.001). Twenty-five percent (74 of 292) and 13.5% (39 of 287) of patients had non-union in the compensated and non-compensated groups, respectively. This was not statistically significant (RR 1.33 0.92, 1.91; p=.07). Conclusions Workers' compensation patients have a two-fold increased risk of an unsatisfactory outcome compared with non-compensated patients after surgery. This association was consistent when studies were grouped by country or procedure. Compensation status must be considered in all surgical intervention studies.
Right ventricular (RV) failure is a significant complication after implantation of a left ventricular assist device (LVAD). It is therefore important to identify patients at risk a priori. However, ...prognostic models derived from multivariate analyses have had limited predictive power.
This study retrospectively analyzed the records of 183 LVAD recipients between May 1996 and October 2009; of these, 27 later required a RVAD (RVAD(+)) and 156 remained on LVAD only (RVAD(-)) until transplant or death. A decision tree model was constructed to represent combinatorial non-linear relationships of the pre-operative data that are predictive of the need for RVAD support.
An optimal set of 8 pre-operative variables were identified: transpulmonary gradient, age, right atrial pressure, international normalized ratio, heart rate, white blood cell count, alanine aminotransferase, and the number of inotropic agents. The resultant decision tree, which consisted of 28 branches and 15 leaves, identified RVAD(+) patients with 85% sensitivity, RVAD(-) patients with 83% specificity, and exhibited an area under the receiver operating characteristic curve of 0.87.
The decision tree model developed in this study exhibited several advantages compared with existing risk scores. Quantitatively, it provided improved prognosis of RV support by encoding the non-linear, synergic interactions among pre-operative variables. Because of its intuitive structure, it more closely mimics clinical reasoning and therefore can be more readily interpreted. Further development with additional multicenter, longitudinal data may provide a valuable prognostic tool for triage of LVAD therapy and, potentially, improve outcomes.
Summary Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of ...results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.
The Millennium Villages Project (MVP) was a 10 year, multisector, rural development project, initiated in 2005, operating across ten sites in ten sub-Saharan African countries to achieve the ...Millennium Development Goals (MDGs). In this study, we aimed to estimate the project's impact, target attainment, and on-site spending.
In this endline evaluation of the MVP, we retrospectively selected comparison villages that best matched the project villages on possible confounding variables. Cross-sectional survey data on 40 outcomes of interest were collected from both the project and the comparison villages in 2015. Using these data, as well as on-site spending data collected during the project, we estimated project impacts as differences in outcomes between the project and comparison villages; target attainment as differences between project outcomes and prespecified targets; and on-site spending as expenditures reported by communities, donors, governments, and the project. Spending data were not collected in the comparison villages.
Averaged across the ten project sites, we found that impact estimates for 30 of 40 outcomes were significant (95% uncertainty intervals UIs for these outcomes excluded zero) and favoured the project villages. In particular, substantial effects were seen in agriculture and health, in which some outcomes were roughly one SD better in the project villages than in the comparison villages. The project was estimated to have no significant impact on the consumption-based measures of poverty, but a significant favourable impact on an index of asset ownership. Impacts on nutrition and education outcomes were often inconclusive (95% UIs included zero). Averaging across outcomes within categories, the project had significant favourable impacts on agriculture, nutrition, education, child health, maternal health, HIV and malaria, and water and sanitation. A third of the targets were met in the project sites. Total on-site spending decreased from US$132 per person in the first half of the project (of which $66 was from the MVP) to $109 per person in the second half of the project (of which $25 was from the MVP).
The MVP had favourable impacts on outcomes in all MDG areas, consistent with an integrated rural development approach. The greatest effects were in agriculture and health, suggesting support for the project's emphasis on agriculture and health systems strengthening. The project conclusively met one third of its targets.
The Open Society Foundations, the Islamic Development Bank, and the governments of Japan, South Korea, Mali, Senegal, and Uganda.
Summary Background In 2005, Uruguay initiated a series of comprehensive anti-smoking measures. We aimed to assess the effect of Uruguay's anti-tobacco campaign. Methods We did a population-based ...trend analysis, using neighbouring Argentina, which has not instituted such extensive anti-tobacco measures, as a control. We assessed three key endpoints in both countries: per-person consumption of cigarettes, as measured by tax records; the prevalence of tobacco use in adolescents, as measured by school-based surveys; and the prevalence of tobacco use in adults, as measured by nationwide household-based surveys. Findings During 2005–11, per-person consumption of cigarettes in Uruguay decreased by 4·3% per year (95% CI 2·4 to 6·2), whereas per-person consumption in Argentina increased by 0·6% per year (–1·2 to 2·5; p=0·002 for difference in trends). During 2003–09, the 30-day prevalence of tobacco use in Uruguayan students aged 13 years, 15 years, and 17 years decreased by an estimated 8·0% per year (4·5 to 11·6), compared with a decrease of 2·5% annually (0·5 to 4·5) in Argentinian students during 2001–09 (p=0·02 for difference in trends). From 2005 to 2011, the prevalence of current tobacco use in Uruguay decreased annually by an estimated 3·3% (2·4 to 4·1), compared with an annual decrease in Argentina of 1·7% (0·8 to 2·6; p=0·02 for difference in trends). Interpretation Uruguay's comprehensive tobacco-control campaign has been associated with a substantial, unprecedented decrease in tobacco use. Decreases in tobacco use in other low-income and middle-income countries of the magnitude seen in Uruguay would have a substantial effect on the future global burden of tobacco-related diseases. Funding J William Fulbright Foreign Scholarship Board and the US Department of State.
Chronic diseases such as heart disease, cancer, and diabetes are the leading causes of death and disability in the U. S. Because the central mission of state and local health departments (HDs) is to ...protect, promote, and improve population health, these agencies are well-positioned to address risk behaviors for chronic disease. HD-employer partnerships could enhance worksite wellness programming, but few studies have explored this topic. Building upon previously published findings, the purpose of this qualitative study was to describe the context and environment for HDs’ delivery of worksite wellness programs, including interest, barriers, facilitators, and decision-making processes. We conducted 12 interviews with directors of state chronic disease programs, 21 interviews with local directors, and three focus groups with local staff. We performed a thematic analysis of the data. Key themes include the following: (1) worksite wellness programs delivered by HDs were diverse in topic and scope and delivered both internally (at the HD for their agency) and externally (for other employers); (2) decisions made about chronic disease prevention were largely driven by funding priorities, with federal, state, and local entities playing roles in the decision-making process; and (3) HDs expressed potential interest in worksite wellness program delivery, dependent upon staff capacity, available funding, and employer buy-in. Our results suggest that funding should be increased for and reallocated towards chronic disease prevention, including worksite wellness. To overcome HD barriers to program delivery, key funders and stakeholders should prioritize and communicate the importance of worksite wellness.
PDF
