Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study ...was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy.
HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline–taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety.
A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89–1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74–1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22–0.50, P < 0.0001).
This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.
EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
During locomotion over land, vertebrates’ limb bones are exposed to loads. Like most biological structures, limb bones have a capacity to withstand greater loads than they usually experience, termed ...a safety factor (SF). How diverse are limb-bone SFs, and what factors correlate with such variation? We have examined these questions from two perspectives. First, we evaluated locomotor SF for the femur in diverse lineages, including salamanders, frogs, turtles, lizards, crocodilians, and marsupials (opossums). Comparisons with values for hind-limb elements in running birds and eutherian mammals indicate phylogenetic diversity in limb-bone SF. A high SF (∼7) is primitive for tetrapods, but low magnitudes of load and elevated strength of bones contribute to different degrees across lineages; moreover, birds and eutherians appear to have evolved lower SFs independently. Second, we tested the hypothesis that SFs would be similar across limb bones within a taxon by comparing data from the humerus and femur of alligators. Both in bending and in torsion, we found a higher SF for the humerus than for the femur. Such a “mixed chain” of different SFs across elements has been predicted if bones have differing variabilities in load, different costs to maintain, or high SF values in general. Although variability in load is similar for the humerus and femur, a high SF may be less costly for the humerus because it is smaller than the femur. The high SFs of alligators also might facilitate differences in SF among their limb bones. Beyond these specific findings, however, a more general implication of our results is that evaluations of the diversity of limb-bone SFs can provide important perspective to direct future research. In particular, more complete understanding of variation in SF could provide insight into factors that promoted the evolutionary radiation of terrestrial locomotor function in vertebrates.
Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but ...its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study.
To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR.
Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively.
VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.
To consider methods and related evidence for evaluating bias in non-randomised intervention studies.
Systematic reviews and methodological papers were identified from a search of electronic ...databases; handsearches of key medical journals and contact with experts working in the field. New empirical studies were conducted using data from two large randomised clinical trials.
Three systematic reviews and new empirical investigations were conducted. The reviews considered, in regard to non-randomised studies, (1) the existing evidence of bias, (2) the content of quality assessment tools, (3) the ways that study quality has been assessed and addressed. (4) The empirical investigations were conducted generating non-randomised studies from two large, multicentre randomised controlled trials (RCTs) and selectively resampling trial participants according to allocated treatment, centre and period.
In the systematic reviews, eight studies compared results of randomised and non-randomised studies across multiple interventions using meta-epidemiological techniques. A total of 194 tools were identified that could be or had been used to assess non-randomised studies. Sixty tools covered at least five of six pre-specified internal validity domains. Fourteen tools covered three of four core items of particular importance for non-randomised studies. Six tools were thought suitable for use in systematic reviews. Of 511 systematic reviews that included non-randomised studies, only 169 (33%) assessed study quality. Sixty-nine reviews investigated the impact of quality on study results in a quantitative manner. The new empirical studies estimated the bias associated with non-random allocation and found that the bias could lead to consistent over- or underestimations of treatment effects, also the bias increased variation in results for both historical and concurrent controls, owing to haphazard differences in case-mix between groups. The biases were large enough to lead studies falsely to conclude significant findings of benefit or harm. Four strategies for case-mix adjustment were evaluated: none adequately adjusted for bias in historically and concurrently controlled studies. Logistic regression on average increased bias. Propensity score methods performed better, but were not satisfactory in most situations. Detailed investigation revealed that adequate adjustment can only be achieved in the unrealistic situation when selection depends on a single factor.
Results of non-randomised studies sometimes, but not always, differ from results of randomised studies of the same intervention. Non-randomised studies may still give seriously misleading results when treated and control groups appear similar in key prognostic factors. Standard methods of case-mix adjustment do not guarantee removal of bias. Residual confounding may be high even when good prognostic data are available, and in some situations adjusted results may appear more biased than unadjusted results. Although many quality assessment tools exist and have been used for appraising non-randomised studies, most omit key quality domains. Healthcare policies based upon non-randomised studies or systematic reviews of non-randomised studies may need re-evaluation if the uncertainty in the true evidence base was not fully appreciated when policies were made. The inability of case-mix adjustment methods to compensate for selection bias and our inability to identify non-randomised studies that are free of selection bias indicate that non-randomised studies should only be undertaken when RCTs are infeasible or unethical. Recommendations for further research include: applying the resampling methodology in other clinical areas to ascertain whether the biases described are typical; developing or refining existing quality assessment tools for non-randomised studies; investigating how quality assessments of non-randomised studies can be incorporated into reviews and the implications of individual quality features for interpretation of a review's results; examination of the reasons for the apparent failure of case-mix adjustment methods; and further evaluation of the role of the propensity score.
To survey the frequency of use of indirect comparisons in systematic reviews and evaluate the methods used in their analysis and interpretation. Also to identify alternative statistical approaches ...for the analysis of indirect comparisons, to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within reviews.
Electronic databases.
The Database of Abstracts of Reviews of Effects (DARE) was searched for systematic reviews involving meta-analysis of randomised controlled trials (RCTs) that reported both direct and indirect comparisons, or indirect comparisons alone. A systematic review of MEDLINE and other databases was carried out to identify published methods for analysing indirect comparisons. Study designs were created using data from the International Stroke Trial. Random samples of patients receiving aspirin, heparin or placebo in 16 centres were used to create meta-analyses, with half of the trials comparing aspirin and placebo and half heparin and placebo. Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin. The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results. Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken.
Of the reviews identified through DARE, 31/327 (9.5%) included indirect comparisons. A further five reviews including indirect comparisons were identified through electronic searching. Few reviews carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest. Few methodological papers were identified. Some valid approaches for aggregate data that could be applied using standard software were found: the adjusted indirect comparison, meta-regression and, for binary data only, multiple logistic regression (fixed effect models only). Simulation studies showed that the naive method is liable to bias and also produces over-precise answers. Several methods provide correct answers if strong but unverifiable assumptions are fulfilled. Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly randomised comparisons. Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies, but the direction of such discrepancy is unpredictable.
Direct evidence from good-quality RCTs should be used wherever possible. Without this evidence, it may be necessary to look for indirect comparisons from RCTs. However, the results may be susceptible to bias. When making indirect comparisons within a systematic review, an adjusted indirect comparison method should ideally be used employing the random effects model. If both direct and indirect comparisons are possible within a review, it is recommended that these be done separately before considering whether to pool data. There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect. Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons. Research into how evidence from indirect comparisons compares to that from non-randomised studies may also be warranted. Investigations using individual patient data from a meta-analysis of several RCTs using different protocols and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful.
Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In ...2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula ‘D×M/N2’, was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. Objectives This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. Methods CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. Results 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514. Conclusions The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.
Sarcopenia was reported to be associated with poor clinical outcome, higher incidence of community-acquired pneumonia, increased risk of infections and reduced survival in different clinical ...settings. The aim of our work is to evaluate the prognostic role of sarcopenia in patients with the 2019 novel coronavirus disease (COVID-19).
272 COVID-19 patients admitted to the University Hospital of Modena (Italy) from February 2020 to January 2021 were retrospectively studied. All included patients underwent a chest computed tomography (CT) scan to assess pneumonia during their hospitalization and showed a positive SARS-CoV-2 molecular test. Sarcopenia was defined by skeletal muscle area (SMA) evaluation at the 12th thoracic vertebra (T12). Clinical, laboratory data and adverse clinical outcome (admission to Intensive Care Unit and death) were collected for all patients.
Prevalence of sarcopenia was high (41.5%) but significantly different in each pandemic wave (57.9% vs 21.6% p < 0.0000). At the multivariate analysis, sarcopenia during the first wave (Hazard Ratio 2.29, 95% confidence intervals 1.17 to 4.49 p = 0.0162) was the only independent prognostic factor for adverse clinical outcome. There were no significant differences in comorbidities and COVID19 severity in terms of pulmonary involvement at lung CT comparing during the first and second wave. Mixed pattern with peripheral and central involvement was found to be dominant in both groups.
We highlight the prognostic impact of sarcopenia in COVID-19 patients hospitalized during the first wave. T12 SMA could represent a potential tool to identify sarcopenic patients in particular settings. Further studies are needed to better understand the association between sarcopenia and COVID-19.
Abstract
Objective
To compare neurocognitive scores between the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) Quick Test (QT) and Online Versions in non-concussed high school ...athletes.
Methods
A sample of 47 high school athletes completed the ImPACT Online Version pre-season and the ImPACT QT approximately 3 months later. Paired sample t-tests and Pearson’s correlations examined differences and relationships between the ImPACT batteries.
Results
The ImPACT QT scores were significantly higher for performance on the Three Letters: Average Counted (p < .001, d = .88), Three Letters: Average Counted Correctly (p < .001, d = .80), and Symbol Match: Correct RT Visible (p < .001, d = .72), and Symbol Match: Correct RT Hidden (p = .002, d = .50) subtests. There were significant relationships for Three Letters: Average Counted (r = .85, p < .001), Three Letters: Average Counted Correctly (r = .82, p < .001), and Symbol Match: Total Correct Hidden (r = .40, p = .006) subtests.
Conclusions
Post-injury evaluation data using ImPACT QT should be compared to normative referenced data, and not to pre-season data from the ImPACT Online Version.
Tests of the T, CP and CPT symmetries in the neutral kaon system are performed by the direct comparison of the probabilities of a kaon transition process to its symmetry-conjugate. The exchange of in ...and out states required for a genuine test involving an antiunitary transformation implied by time-reversal is implemented exploiting the entanglement of K0K‾0 pairs produced at a ϕ-factory.
A data sample collected by the KLOE experiment at DAΦNE corresponding to an integrated luminosity of about 1.7 fb−1 is analysed to study the Δt distributions of the ϕ→KSKL→π+π−π±e∓ν and ϕ→KSKL→π±e∓ν3π0 processes, with Δt the difference of the kaon decay times. A comparison of the measured Δt distributions in the asymptotic region Δt≫τS allows to test for the first time T and CPT symmetries in kaon transitions with a precision of few percent, and to observe CP violation with this novel method.
PDF
