Technologies for global health Howitt, Peter, MA; Darzi, Ara, Prof; Yang, Guang-Zhong, Prof ...
The Lancet (British edition),
08/2012, Volume:
380, Issue:
9840
Journal Article
Peer reviewed
Mechanical ventilation and intravenous sedation were initiated. Because of continuing spasms, intrathecal baclofen (1200 µg per day) was started on day 3 with a good clinical response. No ...recommendations about tetanus prophylaxis procedures for wound man agement in patients with blood diseases are available, except for bone-marrow transplantation.
Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood ...eosinophil count and prospective annual asthma outcomes for a large UK cohort.
This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541.
Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio RR 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less.
Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment.
Teva Pharmaceuticals.
Summary Background Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, ...and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. Methods In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18–65 years and had severe (Murray score >3·0 or pH <7·20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H2 O of peak inspiratory pressure) or high FiO2 (>0·8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. Findings 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0·69; 95% CI 0·05–0·97, p=0·03). Referral to consideration for treatment by ECMO treatment led to a gain of 0·03 quality-adjusted life-years (QALYs) at 6-month follow-up. A lifetime model predicted the cost per QALY of ECMO to be £19 252 (95% CI 7622–59 200) at a discount rate of 3·5%. Interpretation We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3·0 or who have a pH of less than 7·20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. Funding UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.
Summary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve ...both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio HR 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 28% of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 15% vs 60 12%), whereas nausea and vomiting were more common on intermittent treatment (11 2% vs 43 8%). Grade 3 or worse peripheral neuropathy (126 27% vs 25 5%) and hand–foot syndrome (21 4% vs 15 3%) were more frequent on continuous than on intermittent treatment. Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding Cancer Research UK.
Background Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1) . To date, only 3 families ...have been reported. Objective We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. Methods Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. Results No mutations were identified in DSG1 ; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. Conclusions SAM syndrome can be caused by mutations in both DSG1 and DSP . Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.
Background Women undergoing office-based surgical management of a failed or undesired pregnancy often report fear of pain and anxiety pertaining to the procedure. Doulas are trained to specifically ...address women’s physical and emotional needs in obstetric care, and recently have extended their practice to support women through all pregnancy outcomes. Objective We sought to evaluate the impact of doulas on patients’ physical and emotional responses to surgical management of a first-trimester failed or undesired pregnancy under local anesthesia. Study Design In this nonblinded, randomized trial, women received doula support or routine care during office uterine aspiration for failed or unwanted pregnancies in the first trimester. The primary outcome was pain measured on a 100-mm visual analog scale. Secondary outcomes included satisfaction, emotional state, sense of personal empowerment, and ability to cope immediately and 1 month after the procedure, as well as medical assistants’ assessment of the doula’s utility. A sample size of 35 per group (N = 70) was planned to detect a 20% difference in pain score. Results From April 2014 through January 2015, 129 women were screened and 70 were randomized. The 2 study groups were similar on all baseline characteristics. The primary outcome was not different between the doula and control groups (pain score 70.7 ± 24.5 mm vs 59.7 ± 32.5 mm, P = .11, respectively), even after controlling for procedure indication ( P = .20). While 97% of women who received doula support reported this helped with their experience, there was no statistically significant difference in satisfaction, emotional response, sense of empowerment, or perceived ability to cope between the 2 groups of women immediately following or 1 month after the procedure. Of all study participants, 72% reported that it was important to have someone with them during the procedure, but that the support person did not have to be a doula. Conclusion Doula support during office uterine aspiration for failed or undesired pregnancies is well received and desired by women undergoing this procedure despite no significant effect on physical comfort or emotional responses related to the procedure. This may suggest an unmet psychosocial need for procedure-related support among such women.
Summary Background The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. ...We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. Methods We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. Findings Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine 9% vs 16 16%; odds ratio 0·51 95% CI 0·19–1·32; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 54% and grade 2 in four 4% of 92 patients vs grade 1 in three 60% and grade 2 in two 40% of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 39% in the immediate radiotherapy group vs two 40% in the deferred radiotherapy group) within 3 months of receiving radiotherapy. Interpretation Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Funding Research for Patient Benefit Programme from the UK National Institute for Health Research.
To describe the outcomes of peer review across all 14 cancer centers in Ontario.
We identified all peer-reviewed, curative treatment plans delivered in Ontario within a 3-month study period from 2013 ...to 2014 using a provincial cancer treatment database and collected additional data on the peer-review outcomes.
Considerable variation was found in the proportion of peer-reviewed plans across the centers (average 70.2%, range 40.8%-99.2%). During the study period, 5561 curative plans underwent peer review. Of those, 184 plans (3.3%) had changes recommended. Of the 184 plans, the changes were major (defined as requiring repeat planning or having a major effect on planning or clinical outcomes, or both) in 40.2% and minor in 47.8%. For the remaining 12.0%, data were missing. The proportions of recommended changes varied among disease sites (0.0%-7.0%). The disease sites with the most recommended changes to treatment plans after peer review and with the greatest potential for benefit were the esophagus (7.0%), uterus (6.7%), upper limb (6.3%), cervix and lower limb (both 6.0%), head and neck and bilateral lung (both 5.9%), right supraclavicular lymph nodes (5.7%), rectum (5.3%), and spine (5.0%). Although the heart is an organ at risk in left-sided breast treatment plans, the proportions of recommended changes did not significantly differ between the left breast treatment plans (3.0%, 95% confidence interval 2.0%-4.5%) and right breast treatment plans (2.4%, 95% confidence interval 1.5%-3.8%). The recommended changes were more frequently made when peer review occurred before radiation therapy (3.8%) than during treatment (1.4%-2.8%; P=.0048). The proportion of plans with recommended changes was not significantly associated with patient volume (P=.23), peer-review performance (P=.36), or center academic status (P=.75).
Peer review of treatment plans directly affects the quality of care by identifying important clinical and planning changes. Provincial strategies are underway to optimize its conduct in radiation oncology.
Background Mastocytosis associated with germline KIT activating mutations is exceedingly rare. We report the unique clinicopathologic features of a patient with systemic mastocytosis caused by a de ...novo germline KIT K509I mutation. Objectives We sought to investigate the effect of the germline KIT K509I mutation on human mast cell development and function. Methods Primary human mast cells derived from CD34+ peripheral blood progenitors were examined for growth, development, survival, and IgE-mediated activation. In addition, a mast cell transduction system that stably expressed the KIT K509I mutation was established. Results KIT K509I biopsied mast cells were round, CD25− , and well differentiated. KIT K509I progenitors cultured in stem cell factor (SCF) demonstrated a 10-fold expansion compared with progenitors from healthy subjects and developed into mature hypergranular mast cells with enhanced antigen-mediated degranulation. KIT K509I progenitors cultured in the absence of SCF survived but lacked expansion and developed into hypogranular mast cells. A KIT K509I mast cell transduction system revealed SCF-independent survival to be reliant on the preferential splicing of KIT at the adjacent exonic junction. Conclusion Germline KIT mutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somatic KIT D816V disease, the oncogenic potential of which might be influenced by SCF and selective KIT splicing.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and ...collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe .
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