Abstract Objective To derive EuroQol five-dimensional (EQ-5D) health states values from the Thai general population. Methods Forty-eight trained individuals successfully conducted interviews with a ...representative sample of 1409 respondents in 2007. A total of 12 sets of health states were used with one set allocated to each respondent. A respondent was requested to assign values for 11 states using the ranking and visual analogue scale methods and 10 states using the time trade-off method. The variables from the three existing models were used in model specifications and the best model was chosen on the basis of the extent of logical inconsistency in the estimated scores, predictive performance, parsimony, and sensitivity to changes in health. Results Eighty-six health states were valued. The mean age of respondents was 44.6 years old. The highly consistent respondents tend to give higher scores for mild states and lower scores for severe states, compared with those given by the highly inconsistent respondents. The best model used variables from the Dolan 1997 study and estimated from the scores given by the respondents with fewer than 11 inconsistencies. The estimated scores are completely consistent, R2 is 0.448. The second highest score was 0.766 given to state 11112 and the lowest score was –0.454 for state 33333. Conclusion Values for EQ-5D health states were estimated from the Thai general population. This is the first Thai generic health state value results to be used in evaluating health interventions in Thailand.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of ...severe influenza.
In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480.
Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 95% CI 0·02-1·65, p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days IQR 4-16 vs 11 days 5-25, p=0·13) and days on mechanical ventilation (median 0 days IQR 0-6 vs 3 days 0-14, p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine 20% of 46 vs 20 38% of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one 2% vs two 4% patients) and stroke (one 2% vs two 4% patients).
Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention.
National Institute of Allergy and Infectious Diseases, US National Institutes of Health.
The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation ...(ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial.
BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up.
Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 35%) versus oral weekly cyclophosphamide (n=44 52%). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months 95% CI 16-26 vs 11 months 9-12; hazard ratio HR 0·45 95% CI 0·31-0·64 log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months 95% CI 55-not estimable vs 52 months 42-60; log-rank p=0·022; HR 0·56 0·35-0·90, p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months 52-not estimable vs 35 months 31-43; HR 0·37 0·24-0·57, log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT n=7 vs oral weekly cyclophosphamide n=5). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2).
Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse.
Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.
Abstract Background Limited heart rate (HR) rise (HRR) during exercise, known as chronotropic incompetence (CI), is commonly observed in chronic heart failure (CHF). HRR is closely related to ...workload, the limitation of which is characteristic of CHF. Whether CI is a causal factor for exercise intolerance, or simply an associated feature remains unknown. Objectives This study sought to clarify the role of the HR on exercise capacity in CHF. Methods This series of investigations consisted of a retrospective cohort study and 2 interventional randomized crossover studies to assess: 1) the relationship between HRR and exercise capacity in CHF; and 2) the effect of increasing and lowering HR on exercise capacity in CHF as assessed by symptom-limited treadmill exercise testing and measurement of peak oxygen consumption in patients with CHF due to left ventricular systolic dysfunction. Results The 3 key findings were: 1) the association of exercise capacity and HRR is much weaker in severe CHF compared to normal left ventricular function; 2) increasing HRR using rate-adaptive pacing (versus fixed-rate pacing) in unselected patients with CHF does not improve peak exercise capacity; and 3) acutely lowering baseline and peak HR by adjusting pacemaker variables in conjunction with a single dose of ivabradine does not adversely affect exercise capacity in unselected CHF patients. Conclusions The data refute the contention that CI contributes to impaired exercise capacity in CHF. This finding has widespread implications for pacemaker programming and the use of heart-rate lowering agents. (The Influence of Heart Rate Limitation on Exercise Tolerance in Pacemaker Patients TREPPE; NCT02247245 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Global Point Prevalence Survey (Global-PPS) established an international network of hospitals to measure antimicrobial prescribing and resistance worldwide. We aimed to assess antimicrobial ...prescribing and resistance in hospital inpatients.
We used a standardised surveillance method to collect detailed data about antimicrobial prescribing and resistance from hospitals worldwide, which were grouped by UN region. The internet-based survey included all inpatients (adults, children, and neonates) receiving an antimicrobial who were on the ward at 0800 h on one specific day between January and September, 2015. Hospitals were classified as primary, secondary, tertiary (including infectious diseases hospitals), and paediatric hospitals. Five main ward types were defined: medical wards, surgical wards, intensive-care units, haematology oncology wards, and medical transplantation (bone marrow or solid transplants) wards. Data recorded included patient characteristics, antimicrobials received, diagnosis, therapeutic indication according to predefined lists, and markers of prescribing quality (eg, whether a stop or review date were recorded, and whether local prescribing guidelines existed and were adhered to). We report findings for adult inpatients.
The Global-PPS for 2015 included adult data from 303 hospitals in 53 countries, including eight lower-middle-income and 17 upper-middle-income countries. 86 776 inpatients were admitted to 3315 adult wards, of whom 29 891 (34·4%) received at least one antimicrobial. 41 213 antimicrobial prescriptions were issued, of which 36 792 (89·3%) were antibacterial agents for systemic use. The top three antibiotics prescribed worldwide were penicillins with β-lactamase inhibitors, third-generation cephalosporins, and fluoroquinolones. Carbapenems were most frequently prescribed in Latin America and west and central Asia. Of patients who received at least one antimicrobial, 5926 (19·8%) received a targeted antibacterial treatment for systemic use, and 1769 (5·9%) received a treatment targeting at least one multidrug-resistant organism. The frequency of health-care-associated infections was highest in Latin America (1518 11·9%) and east and south Asia (5363 10·1%). Overall, the reason for treatment was recorded in 31 694 (76·9%) of antimicrobial prescriptions, and a stop or review date in 15 778 (38·3%). Local antibiotic guidelines were missing for 7050 (19·2%) of the 36 792 antibiotic prescriptions, and guideline compliance was 77·4%.
The Global-PPS showed that worldwide surveillance can be accomplished with voluntary participation. It provided quantifiable measures to assess and compare the quantity and quality of antibiotic prescribing and resistance in hospital patients worldwide. These data will help to improve the quality of antibiotic prescribing through education and practice changes, particularly in low-income and middle-income countries that have no tools to monitor antibiotic prescribing in hospitals.
bioMérieux.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Objectives There are no commonly accepted standards for monitoring patients treated for head and neck cancer. The aim of this study was to assess patients’ preferences for different aspects ...of follow-up. Methods A best-worst survey was conducted in a sample of head and neck cancer patients in clinical follow-up at the National Cancer Institute (Milan, Italy). Conditional logit regression with choice as the dependent variable was run to analyse the data. A covariate-adjusted analysis was performed in order to identify socio-demographic and clinical factors related to the selection of best-worst items. The participants were asked to report any difficulties encountered during the survey. Results A total of 143 patients, predominantly male (74%) and with a mean age of 58 years were enrolled in the survey. The strongest positive preference was expressed for a hospital-based program of physical examinations with frequency decreasing over time. Conversely, the lowest valued item was not performing any positron emission tomography (PET) scan during follow-up. Patients with high educational levels were more likely to value attending a primary care-based program and undergoing intensive radiological investigations. Other patient-specific variables significantly associated with the choice of items were employment and living status, time already spent in follow-up and number of treatments received. Conclusions Overall, patients were more likely to choose an intensive follow-up scheme broadly consistent with the program currently administered by the hospital. There is little evidence of preference heterogeneity that might justify customized programs based on demographics. The best-worst scaling task appeared feasible for most participants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare ...data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. Methods We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. Findings The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia 5·6%, 3·9–7·2, aphasia 23·0%, 20·0–26·0, and behavioural changes 31·7%, 28·4–35·1). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. Interpretation The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. Funding National Institutes of Health and German Center for Neurodegenerative Diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The prism adaptation test (PAT) is a preoperative tool that may fine-tune surgical dosage and reduce under- and overcorrection in pediatric partially accommodative esotropia; however, it is resource ...intensive and the benefits are uncertain. PAT involves correction of esodeviation with prisms, with subsequent assessment for and quantification of change in angle of esodeviation, thereby augmenting the surgical target angle in a subset of patients. We evaluated PAT response and postoperative outcomes in a cohort of children who underwent bilateral medial rectus recession and found that 36% of patients showed a requirement for increase of prism dosage to retain orthotropia during PAT; these patients did better than those whose deviation was stable, with postoperative rate of motor success (defined as ≤10Δ esotropia) of 100% versus 56%. PAT may be a useful positive prognostic test, and it also identifies a substantial patient population who may avoid undercorrection, the prism builders. However, this cohort may do better postoperatively regardless of the target angle for surgery. Additional randomized studies are required to demonstrate definitive benefit of PAT. Identification of the builder phenotype prior to commencing adaptation may reduce the workload involved in the PAT technique.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV1 %pred) variability as potential predictors of future FEV1 %pred decline in patients ...with cystic fibrosis. Study design We included 13 827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV1 %pred to best follow-up FEV1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV1 %pred. Results All 5 measures of FEV1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV1 %pred in the baseline period. The contribution to explanatory power (R2 ) was substantial and exceeded the total contribution of all other factors excluding the FEV1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Conclusions Median deviation from the best FEV1 %pred is a simple metric that markedly improves prediction of FEV1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Extracorporeal membrane oxygenation (ECMO) and cardiac transplantation are recognized to be expensive.
We performed a cost utility evaluation with a decision model approach, including 75 children ...with dilated cardiomyopathy. A cohort of patients with end stage heart failure who were offered ECMO bridging was compared with a similar cohort offered only conventional intensive care. Outcome was measured in cost per quality adjusted life year (QALY).
Median follow-up was 4.39 years (interquartile range, 1.83-5.74 years), during which 50 children underwent transplantation, 16 had a period of recovery, and 25 died. ECMO bridging was highly effective (hazard ratio, 0.181; 95% confidence interval, 0.067-0.489; p = 0.001) but exceeded conventional criteria for cost-effectiveness. The reference incremental cost-effectiveness ratio (ICER) was pound65,645 per QALY and pound54,284 per life-year gained. Average life expectancy rose from 6.78 to 9.79 years and costs from pound146,398 to pound309,599 per patient with ECMO bridging. The ICER was sensitive to ECMO cost, the long-term transplant survival rate, and quality of life in transplant recipients.
ECMO bridging is effective but expensive. The eligible target population is small, nationally, positively influencing affordability. We strongly support our national policy of mechanical bridge to transplant for suitable children in end stage heart failure. Cost effectiveness could be optimized by: 1) increased availability of organ donors, 2) reduction in mechanical support costs possibly by alternate devices and 3) inclusion of patients most likely to benefit.
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