Statistical Methods for Dealing with Selective Crossover in Randomised Controlled Trials

Background Selective crossover (SCO) occurs when patients in a randomised controlled trial (RCT) are given the opportunity to switch from the arm in which they were initially allocated to the other arm. Problems in data analysis and interpretation may arise. Objectives Main objectives were to assess: (i) the prevalence of SCO in RCTs assessing the efficacy of therapies for breast cancer (BC); (ii) whether different statistical methods provide different results, in particular when the outcome of interest is a time-to-event outcome. Methods RCTs assessing the efficacy of therapies for BC were searched in the medical literature. Different methods for dealing with SCO exist. Among naïve methods, the Intention-To-Treat analysis (ITT), the censored analysis and the analysis considering the treatment as a time-varying covariate were contemplated; among more complex methods, the inverse probability of censoring weighting analysis, the Loeys and Goetghebeur estimator, and the rank preserving structural failure time models were considered. The methods were evaluated trough simulations, considering twelve scenarios which differed by the proportion of patients crossing over, their underlying prognosis, and the magnitude of true treatment effect. Results Crossover occurred in the 23.5% of RCTs identified. Simulations highlighted that ITT analysis, always presented, tend to underestimate the actual treatment effect across all scenarios. Other naïve methods are able to better estimate the treatment effect, but when the probability of crossover is assumed to depend on prognosis (i.e. patients with a poor prognosis cross over more frequently than patients with a good prognosis), they failed. More complex models work better, but each of them make assumptions not always verifiable or likely to occur in the considered context. Conclusions The present work aims to highlight the need for attention being paid on the phenomenon of SCO in RCTs, and underlines the concerns related to it

Gender matter in isotretinoin therapy for acne vulgaris? A retrospective study

Introduction: Gender differences have been recently highlighted for several aspects of acne vulgaris such as epidemiology, pathogenesis, clinical course, quality of life and treatment outcome. In particular a shorter but more severe clinical course has been reported in males than in females; nevertheless, usually men have their quality of life less affected. Aim: To determine if the response and the adverse events to 1 cycle of oral isotretinoin therapy can be influenced by gender. Methods: A retrospective study was conducted on consecutive patients affected by acne vulgaris and treated with oral isotretinoin. Global acne grading system (GAGS), acne-related quality of life (AQoL) and isotretinoin-related adverse events were considered as outcome measures and were evaluated before (T0), every month during administration and 4 weeks after the withdrawal (T1) of oral isotretinoin therapy. Mann-Whitney U test and Wilcoxon signed-rank test were used for quantitative parameters and Fisher exact test for qualitative ones. Results: Forty-nine acneic patients were retrospectively selected (33 males 67.3% and 16 females -32.7%; median age: 19 years). Patients had received a median dosage of isotretinoin of 0.4 mg/kg/die for a median period of 5 months; no differences in outcome measures among genders were reported. Limitations: The study is retrospective and the sample is small and not homogenously distributed among genders, as males are double in number than females. Conclusions: In our study population gender didn't influence neither the clinical and the quality of life outcome measures nor the occurrence of adverse events to oral isotretinoin therapy for acne

Factors influencing response to ingenol mebutate therapy for actinic keratosis of face and scalp

AIM To determine factors independently influencing response to ingenol mebutate therapy and assess efficacy on clinical setting of non-hypertrophic non-hyperkeratotic actinic keratosis (AK). METHODS Consecutive patients affected by non-hypertrophic non-hyperkeratotic AKs of the face or scalp were enrolled to receive ingenol mebutate 0.015% gel on a selected skin area of 25 cm2 for 3 consecutive days. Local skin reactions were calculated at each follow up visit using a validated composite score. Efficacy was evaluated by the comparison of clinical and dermoscopic pictures before the treatment and at day 57, and classified as complete, partial and poor response. RESULTS A number of 130 patients were enrolled, of which 101 (77.7%) were treated on the face, while 29 (22.3%) on the scalp. The great majority of our study population (n = 119, 91.5%) reached at least a 75% clearance of AKs and, in particular, 58 patients (44.6%) achieved a complete response while 61 (46.9%) a partial one. Logistic backward multivariate analysis showed that facial localization, level of local skin reaction (LSR) at day 2, the highest LSR values and level of crusts at day 8 were factors independently associated with the achievement of a complete response. CONCLUSION Ingenol mebutate 0.015% gel, when properly applied, is more effective on the face than on the scalp and efficacy is directly associated to LSR score

The impact of shift work on the psychological and physical health of nurses in a general hospital: a comparison between rotating night shifts and day shifts

Background: Shift work is considered necessary to ensure continuity of care in hospitals and residential facilities. In particular, the night shift is one of the most frequent reasons for the disruption of circadian rhythms, causing significant alterations of sleep and biological functions that can affect physical and psychological well-being and negatively impact work performance. Objectives: The aim of this study was to highlight if shift work with nights, as compared with day work only, is associated with risk factors predisposing nurses to poorer health conditions and lower job satisfaction. Methods: This cross-sectional study was conducted from June 1, 2015 to July 31, 2015 in 17 wards of a general hospital and a residential facility of a northern Italian city. This study involved 213 nurses working in rotating night shifts and 65 in day shifts. The instrument used for data collection was the “Standard Shift Work Index,” validated in Italian. Data were statistically analyzed. Results: The response rate was 86%. The nurses engaged in rotating night shifts were statistically significantly younger, more frequently single, and had Bachelors and Masters degrees in nursing. They reported the lowest mean score in the items of job satisfaction, quality and quantity of sleep, with more frequent chronic fatigue, psychological, and cardiovascular symptoms in comparison with the day shift workers, in a statistically significant way. Conclusion: Our results suggest that nurses with rotating night schedule need special attention due to the higher risk for both job dissatisfaction and undesirable health effects

netmeta: An R Package for Network Meta-Analysis Using Frequentist Methods

Network meta-analysis compares different interventions for the same condition, by combining direct and indirect evidence derived from all eligible studies. Network metaanalysis has been increasingly used by applied scientists and it is a major research topic for methodologists. This article describes the R package netmeta, which adopts frequentist methods to fit network meta-analysis models. We provide a roadmap to perform network meta-analysis, along with an overview of the main functions of the package. We present three worked examples considering different types of outcomes and different data formats to facilitate researchers aiming to conduct network meta-analysis with netmeta

Impact of anaemia on tumor response to neoadjuvant chemotherapy in breast cancer patients .

BACKGROUND - Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) in patients with breast cancer (BC) predicts long-term outcomes. Anaemia is one of the most common side effects of cytotoxic drugs. Biologically, anaemia induces adaptive responses due to the low intra-tumoral oxygen levels that may be responsible for increase chemotherapy resistance. In literature, data regarding this issue are lacking. AIM - To evaluate the influence of anaemia throughout treatment course on tumour shrinkage induced by NST. METHODS - Patients - 317 patients diagnosed with stage I-III BC treated with NST and with available blood tests were included. Patients and tumor characteristics and treatments information were collected. We focused on Haemoglobin (Hb) level (at baseline, at the end of NST, drop in Hb throughout treatment and duration of anaemia) and its correlation with pCR rate. Anaemia was defined as a drop of Hb under the local limit of normal in women (12 mg/dl). Statistical analysis - Categorical variables were analyzed using chi-square test or Fisher's exact test, continuous variables using t test. Univariate and multivariate analyses were fit to determinate the association between anaemia and pCR rate. A p-value < 0.05 was considered statistically significant; hazard ratio was estimated with 95% of confidence limits. RESULTS- No difference in Hb levels was observed stratifying patients according to nuclear grade, tumor stage, cancer subtypes and chemotherapy regimens. Median baseline Hb was 13.3 g/dl while median Hb level at the end of NST was 10 g/dl. 31 patients had pre-treatment anaemia. 60% of patients developed anaemia during NST period. In the subgroup of anaemic patients, who had a decrease in Hb ≥ 2 g/dl from baseline or anaemia longer than two months, a lower rate of pCR was observed (16% vs 29%, p=0.03 and 16% vs 25%, p=0.01, respectively). Patients with both these characteristics had the lowest rate of pCR (10%, p=0.01). CONCLUSIONS - Anaemia is a negative predictive factor for tumor response in women treated with NST for BC. This evidence suggests that anaemia should be improved in order to improve response to NST

Retrospective Cohort Study on Acute Care in Obstetrics and Gynecology. Analogies and Differences When Compared to Emergency Medicine

Introduction: the demand for urgent obstetric and gynecology care has progressively increased: in the United States approximately 1.4 million gynecologic visits are made to the emergency department (ED) annually, while almost 75% of women make at least 1 unscheduled visit during pregnancy. Moreover, research has recently focused on setting standards in unscheduled care, and developing quality indicators to improve patients’ health. Therefore, we investigated the characteristics of women with acute gynecological or pregnancy complaints using quality indicators developed for emergency medicine, to better define the needs of this population and improve care. Methods: Retrospective cohort study on ED, and Obstetrics and Gynecology (ObGyn) triage visits, at a tertiary care hospital in Italy, during 2012. Data were analyzed with population-averaged logistic regression and Poisson regression. Results: When compared to the 33,557 ED visits, the 9245 ObGyntriage referrals were more frequently associated with pregnancy (≤12 weeks’ gestation, OR: 30.7, 95%CI; 24.5 - 38.4; &gt;12 weeks’ gestation, OR 81.2, 95%CI; 64.8 - 101.4), vaginal bleeding (OR 156.6, 95%CI; 82.7 - 294.4), diurnal (night access OR 0.87, 95% CI; 0.78 - 0.96) and weekday access (holiday access OR 0.87, 95%CI; 0.78 - 0.95), frequent users (recurrent ED visits IRR 0.87, 95%CI; 0.83 - 0.9) and lower hospital admissions (ED admission OR 1.6, 95%CI; 1.4 - 1.8). Conclusion: ObGyn triage patients differed from ED users, and were at higher risk of “crowding”. Such diversities should be considered to improve female healthcare services and allocate resources more efficiently

Therapeutic Options for the Treatment of Actinic Keratosis with Scalp and Face Localization

Actinic keratosis (AK) is a common skin disease related to ultraviolet chronic exposure, that is now considered a squamous cell carcinoma in situ. Primary skin cancer prevention strategies should be recommended for high risk patients. There is a wide spectrum of treatment options available for AKs, and several variables should be taken into account regarding the best therapeutic choice for each patient. The purpose of this article is to review the current treatment strategies for AKs localized on the face and scalp, with a focus on the practical point of view that could be useful for choosing the best therapeutic option. The two main therapeutic approaches will be distinguished first: lesiondirected and field-directed. Afterwards, the treatment based on clinical type and patient comorbidity will be discussed

Therapeutic Options for the Treatment of Actinic Keratosis with Scalp and Face Localization

Actinic keratosis (AK) is a common skin disease related to ultraviolet chronic exposure, that is now considered a squamous cell carcinoma in situ. Primary skin cancer prevention strategies should be recommended for high risk patients. There is a wide spectrum of treatment options available for AKs, and several variables should be taken into account regarding the best therapeutic choice for each patient. The purpose of this article is to review the current treatment strategies for AKs localized on the face and scalp, with a focus on the practical point of view that could be useful for choosing the best therapeutic option. The two main therapeutic approaches will be distinguished first: lesiondirected and field-directed. Afterwards, the treatment based on clinical type and patient comorbidity will be discussed

Validation of the American Joint Committee on Cancer new prognostic stage groups for HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the prospective ShortHER trial

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