High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening.

BACKGROUND: Our aim was to assess the cumulative risk of false-positive screening results, screen-detected cancer, and interval breast cancer in mammography screening among women with and without a previous benign breast disease and a family history of breast cancer. METHODS: The cohort included 42 928 women first screened at the age of 50-51 years at three areas of the Spanish Screening Programme (Girona, and two areas in Barcelona) between 1996 and 2011, and followed up until December 2012. We used discrete-time survival models to estimate the cumulative risk of each screening outcome over 10 biennial screening exams. RESULTS: The cumulative risk of false-positive results, screen-detected breast cancer, and interval cancer was 36.6, 5.3, and 1.4 for women with a previous benign breast disease, 24.1, 6.8, and 1.6% for women with a family history of breast cancer, 37.9, 9.0, and 3.2%; for women with both a previous benign breast disease and a family history, and 23.1, 3.2, and 0.9% for women without either of these antecedents, respectively. CONCLUSIONS: Women with a benign breast disease or a family history of breast cancer had an increased cumulative risk of favourable and unfavourable screening outcomes than women without these characteristics. A family history of breast cancer did not increase the cumulative risk of false-positive results. Identifying different risk profiles among screening participants provides useful information to stratify women according to their individualised risk when personalised screening strategies are discussed.

Cumulative risk of cancer detection in breast cancer screening by protocol strategy.

BACKGROUND: There is little information on the individual risk of screen-detected cancer in women over successive participations. This study aimed to estimate the 10-year cumulative breast cancer detection risk (ductal carcinoma in situ and invasive carcinoma) in a population-based breast cancer screening program according to distinct protocol strategies. A further aim was to determine which strategies maximized the cancer detection risk and how this risk was affected by the radiologic protocol variables. METHODS: Data were drawn from a retrospective cohort of women from nine population-based screening programs in Spain from 1990 to 2006. We used logistic regression with discrete intervals to estimate the cumulative detection risk at 10 years of follow-up according to radiologic variables and protocol strategies. RESULTS: In women starting screening at the age of 45-59 years, the cumulative risk of screen-detected cancer at 10 years ranged from 11.11 to 16.71 per 1,000 participants according to the protocol strategy. The cumulative detection risk for overall cancer and invasive cancer was the highest with strategies using digital mammography, double reading, and two projections (16.71 and 12.07 ‰, respectively). For ductal carcinoma in situ, cumulative detection risk was the highest with strategies using screen-film, double reading, and two projections (2.32 ‰). The risk was the lowest with strategies using screen-film mammography, single reading, and two projections. CONCLUSIONS: This study found that at least eleven cancers are detected per 1,000 women screened in the first 10 years of follow-up. Enhanced knowledge of the variability in cumulative risk of screen-detected cancer could improve protocol strategies.

Relationship between obsessive compulsive symptomatology and severity of psychotic symptoms in schizophrenia: Meta-analysis and meta-regression analysis.

BACKGROUND: Schizophrenia patients often show obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) and their presence has been associated with poorer prognosis. However, the impact of OCS/OCD on psychotic severity remains unclear. The aim of this study is twofold: 1) to investigate the effect of OCS/OCD on the severity of positive, negative, and global psychotic symptoms of schizophrenia patients and 2) to analyze the effect of patient and study-related covariates on moderating this relationship. METHODS: A systematic review and meta-analysis (SRMA) of studies comparing the severity of psychotic symptoms among schizophrenia patients with and without OCS/OCD was performed. Standardized mean difference (SMD) was calculated for positive, negative, and global psychotic symptoms. The difference of SMD (Diff SMD) was calculated to analyze the effect of covariates on study outcomes using meta-regression. RESULTS: Sixty-seven studies involving 7740 patients were included. Patients with schizophrenia and OCS/OCD showed a slightly higher severity of positive (SMD = 0.17, p value = 0.0089) and global psychotic symptoms (SMD = 0.24, p value = 0.0104) than patients without OCS/OCD but no differences in negative symptoms were found between groups (SMD = 0.11, p value = 0.0367). Only one covariate "proportion of patients without antipsychotics (AP)" was found to modify the effect on psychotic severity (Diff SMD = -0.008, p value = 0.002). CONCLUSIONS: Comorbid OCS/OCD in schizophrenia has, at most, a minor impact on psychotic severity. Variability in this effect was considerable and was poorly explained by the covariates analyzed.

Development of robust discriminant equations for assessing subtypes of glioblastoma biopsies.

BACKGROUND: In the preceding decade, various studies on glioblastoma (Gb) demonstrated that signatures obtained from gene expression microarrays correlate better with survival than with histopathological classification. However, there is not a universal consensus formula to predict patient survival. METHODS: We developed a gene signature using the expression profile of 47 Gbs through an unsupervised procedure and two groups were obtained. Subsequent to a training procedure through leave-one-out cross-validation, we fitted a discriminant (linear discriminant analysis (LDA)) equation using the four most discriminant probesets. This was repeated for two other published signatures and the performance of LDA equations was evaluated on an independent test set, which contained status of IDH1 mutation, EGFR amplification, MGMT methylation and gene VEGF expression, among other clinical and molecular information. RESULTS: The unsupervised local signature was composed of 69 probesets and clearly defined two Gb groups, which would agree with primary and secondary Gbs. This hypothesis was confirmed by predicting cases from the independent data set using the equations developed by us. The high survival group predicted by equations based on our local and one of the published signatures contained a significantly higher percentage of cases displaying IDH1 mutation and non-amplification of EGFR. In contrast, only the equation based on the published signature showed in the poor survival group a significant high percentage of cases displaying a hypothesised methylation of MGMT gene promoter and overexpression of gene VEGF. CONCLUSION: We have produced a robust equation to confidently discriminate Gb subtypes based in the normalised expression level of only four genes.

Effect of protocol-related variables and women's characteristics on the cumulative false-positive risk in breast cancer screening.

BACKGROUND: Reducing the false-positive risk in breast cancer screening is important. We examined how the screening-protocol and women's characteristics affect the cumulative false-positive risk. METHODS: This is a retrospective cohort study of 1,565,364 women aged 45-69 years who underwent 4,739,498 screening mammograms from 1990 to 2006. Multilevel discrete hazard models were used to estimate the cumulative false-positive risk over 10 sequential mammograms under different risk scenarios. RESULTS: The factors affecting the false-positive risk for any procedure and for invasive procedures were double mammogram reading [odds ratio (OR)=2.06 and 4.44, respectively], two mammographic views (OR=0.77 and 1.56, respectively), digital mammography (OR=0.83 for invasive procedures), premenopausal status (OR=1.31 and 1.22, respectively), use of hormone replacement therapy (OR=1.03 and 0.84, respectively), previous invasive procedures (OR=1.52 and 2.00, respectively), and a familial history of breast cancer (OR=1.18 and 1.21, respectively). The cumulative false-positive risk for women who started screening at age 50-51 was 20.39% [95% confidence interval (CI) 20.02-20.76], ranging from 51.43% to 7.47% in the highest and lowest risk profiles, respectively. The cumulative risk for invasive procedures was 1.76% (95% CI 1.66-1.87), ranging from 12.02% to 1.58%. CONCLUSIONS: The cumulative false-positive risk varied widely depending on the factors studied. These findings are relevant to provide women with accurate information and to improve the effectiveness of screening programs.

Perceptions from nurses, surgeons, and anesthetists about the use and benefits of the surgical checklist in a teaching hospital.

OBJECTIVE: To assess attitudes and perceptions from nursing staff, surgeons and anesthetists about compliance, utility, and impact on patient's safety of the surgical checklist in a teaching hospital. We also aimed to identify improvement opportunities for strengthening the usefulness of the checklist in the operating theater. METHODS: We carried out a questionnaire-based an observational cross-sectional study. A questionnaire was distributed to operating room staff, including nursing staff, surgeons, and anesthetists. In addition to the information about surgical checklist, We also collected information regarding years of experience in the operating theater. Fisher's exact was used to compare proportions in each statement. Group discussion meetings with key professionals were held to jointly assess the results, propose improvement actions, and evaluate their feasibility. RESULTS: The overall response rate was 36.2% (131/362). Nursing staff was perceived as the most supportive group in the use of surgical checklist. A 64.3% of surgeons considered that using the checklist prevented adverse events vs 84.2% and 85.7% among anesthetists and nurses, respectively; p=0.028. Junior staff showed a supportive attitude toward the use of surgical checklist, considering it as a tool that gives them confidence. We ended up with a list of improvement actions aiming at strengthening the surgical checklist reliability and compliance. CONCLUSIONS: The perception of the surgical checklist usefulness as a tool to prevent adverse events was moderate among surgeons, but well appreciated by junior staff. Nursing staff were especially critical regarding compliance and support by other professionals. To reinforce the usefulness perception of the surgical checklist it is needed to increase the involvement of all professionals, especially senior staff and surgical leaders.

Effect of false-positives and women's characteristics on long-term adherence to breast cancer screening.

False-positive results may influence adherence to mammography screening. The effectiveness of breast cancer screening is closely related to adequate adherence among the target population. The objective of this study was to evaluate how false-positives and women's characteristics affect the likelihood of reattendance at routine breast cancer screening in a sequence of routine screening invitations. We performed a retrospective cohort study of 1,371,218 women aged 45-69 years, eligible for the next routine screening, who underwent 4,545,346 screening mammograms from 1990 to 2006. We estimated the likelihood of attendance at seven sequential screening mammograms. Multilevel discrete time hazard models were used to estimate the effect of false-positive results on reattendance, and the odds ratios (OR) of non-attendance for the women's personal characteristics studied. The overall reattendance rate at the second screening was 81.7% while at the seventh screening was 95.6%. At the second screening invitation reattendance among women with and without a false-positive mammogram was 79.3 vs. 85.3%, respectively. At the fourth and seventh screenings, these percentages were 86.3 vs. 89.9% and 94.6 vs. 96.0%, respectively. The study variables associated with a higher risk of failing to participate in subsequent screenings were oldest age (OR = 8.48; 95% CI: 8.31-8.65), not attending their first screening invitation (OR = 1.12; 95% CI: 1.11-1.14), and previous invasive procedures (OR = 1.09; 95% CI: 1.07-1.10). The risk of non-attendance was lower in women with a familial history of breast cancer (OR = 0.97; 95% CI: 0.96-0.99), and those using hormone replacement therapy (OR = 0.96; 95% CI: 0.94-0.97). In conclusion, reattendance was lower in women with false-positive mammograms than in those with negative results, although this difference decreased with the number of completed screening participations, suggesting that abnormal results in earlier screenings more strongly influence behavior. These findings may be useful in providing women with accurate information and in improving the effectiveness of screening programs.

Clinical guideline for the treatment of dual pathology in the adult population.

Editorial del vol 28-1.

[Factors that influence compliance with hand hygiene in healthcare professionals: A concept mapping study]. / Factores que influyen en el cumplimiento de la higiene de manos en profesionales sanitarios: un estudio de mapeo de conceptos.

OBJECTIVE: To identify factors that may influence hand hygiene compliance by professional category and clinical department. MATERIALS AND METHODS: Use was made of concept mapping methodology, a tool that combines a qualitative analysis with a quantitative statistical analysis, in order to identify the most influential and important factors for the fulfilment of hand hygiene in 2 clinical departments (Infectious and General Surgery) of the Hospital del Mar. RESULTS: The study included a total of 42 volunteer professionals from General Surgery (6 doctors and 10 nurses) and from Infectious Diseases (11 doctors and 10 nurses) clinical departments, as well as 5 hospital porters. High correlations of influential and important factors for hand hygiene compliance were observed between nurses and doctors in the Infectious Diseases Department (r=0.93 vs. r=0.69, respectively). In contrast, the correlation was lower among surgical professionals (r=-0.17 for influence and r=0.51 for importance). Professionals identified the most influential factors in compliance as training and adequate resources, taking into account professional category and clinical department. CONCLUSION: The design of interventions to improve compliance with hand hygiene should take into account the perceptions of different professionals in order to adapt actions to each professional group.

Detection of incident breast and colorectal cancer cases from an administrative healthcare database in Catalonia, Spain.

OBJECTIVE: To validate the Catalan minimum basic data set (MBDS) of hospital discharges as an information source for detecting incident breast (BC) and colorectal cancer (CRC), against the Hospital del Mar Cancer Registry (RTHMar) in Barcelona (Spain) as the gold standard. METHODS: Using ASEDAT software (Analysis, Selection and Extraction of Tumour Data), we identified Catalan public hospital discharge abstracts in patients with a first-time diagnosis of BC and CRC in the years 2005, 2008, and 2011, aggregated by unique patient identifiers and sorted by date. Once merged with the RTHMar database and anonymized, tumour-specific algorithms were validated to extract data on incident cases, tumour stage, surgical treatment, and date of incidence. RESULTS: MBDS had a respective sensitivity and positive predictive value (PPV) of 78.0% (564/723) and 90.5% (564/623) for BC case detection; and 83.9% (387/461) and 94.9% (387/408) for CRC case detection. The staging algorithms overestimated the proportion of local-stage cases and underestimated the regional-stage cases in both cancers. When loco-regional stage and surgery were combined, sensitivity and PPV reached 98.3% and 99.8%, respectively, for BC and 96.4% and 98.4% for CRC. The differences between dates of incidence between RTHMar and MBDS were greater for BC cases without initial surgery, whereas they were generally smaller and homogeneous for CRC cases. CONCLUSIONS: The MBDS is a valid and efficient instrument to improve the completeness of a hospital-based cancer registry (HBCR), particularly in BC and CRC, which require hospitalization and are predominantly surgical.

Dissemination of health technologies: Trends in the use of diagnostic test in breast cancer screening.

OBJECTIVE: To analyse trends in the use of diagnostic test in breast cancer screening programs in Spain. MATERIALS AND METHODS: Retrospective study of 542,695 women who had undergone at least one screening mammogram in any of the screening centres of three administrative regions in Spain, between 1996 and 2011. Process measures were: overall recall rate, overall invasive test rate, and rates of each type of invasive test (fine-needle aspiration biopsy, core-needle biopsy and surgical biopsy). As results measures were included detection of benign lesions rate, ductal in situ cancer rate and invasive cancer rate. Adjusted by age rates were estimated year by year for each measure and, also, the annual percent of change and its corresponding joint points. RESULTS: Core-needle biopsy rates decreased between 1996 and 1999 and changed trends in 1999-2011 with an increase of 4.9% per year. Overall recall rate declined by 4.6% from 1999 to 2004, invasive test rate declined between 1996 and 2004 by 24.3%. Fine-needle aspiration biopsy rate changes were: a 22.4% declined per year (1996-1998), and 13.5% declined per year (1998-2005). Benign lesions rate decreased from 1996 to 2011, 21.4% per year (1996-2001) and 6.0% (2001-2011). Ductal carcinoma in situ and invasive cancer had no-statistically significant changes. CONCLUSION: The introduction of core-needle biopsy was slow and not concurrent with the reduction in the use of other diagnostic tests, but also represented a reduction in the rate of overall diagnostic tests and in the detection rate of benigns lesions without affecting the cancer detection rates.

Wide social participation in prioritizing patients on waiting lists for joint replacement: a conjoint analysis.

OBJECTIVE: The aim was to develop a priority scoring system for patients on waiting lists for joint replacement based on a wide social participation, and to analyze the differences among participants. METHODS: Conjoint analysis. Focus groups in combination with a nominal technique were employed to identify the priority criteria (N=36). A rank-ordered logit model was then applied for scoring estimations. Participants (N=860) represented: consultants, allied-health professionals, patients and their relatives, and the general population of Catalonia. RESULTS: Clinical and social criteria were selected, and their relative importance (over 100 points) was: pain (33), difficulty in doing activities of daily living (21), disease severity (18), limitations on ability to work (10), having someone to look after the patient (9), being a caregiver (6), and recovery probability (4). Estimated criteria coefficients had the expected positive sign and all were statistically significant (P < 0.001). There were differences between groups; pain was rated higher by patients/relatives, and difficulty in doing activities was rated lower by patients/relatives and the general public. Most interaction terms for these criteria and groups were significant (P < 0.001). Consultants and allied-health professionals had the most similar prioritization pattern (r=0.97). CONCLUSION: Both clinical and social criteria are considered for prioritization of joint replacement surgery from a wide social perspective. The preference among professional and social groups varies and this might impact the result of patient prioritization. A wide social participation for obtaining adequate prioritizing systems for patients on waiting lists is desirable.

Discontinuation of pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder: meta-analysis of 63 studies enrolling 11,788 patients.

BACKGROUND: The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear. METHODS: A systematic review and meta-analysis of randomised, placebo-controlled clinical trials (RPCCTs) investigating the efficacy of pharmacological treatment in children or adolescents with ADHD was carried out. Meta-analysis of treatment discontinuation, clinician-, parent- and teacher-rated efficacy and adverse events was performed. The effect of covariates was studied. RESULTS: Sixty-three studies were included. Ten drugs were investigated, with atomoxetine and methylphenidate the most frequently studied. RPCCTs had mostly a short duration (7.9 weeks). All-cause treatment discontinuation was lower with pharmacological treatment than placebo (OR = 0.68). Pharmacological treatment was more efficacious than placebo independently of the rater (clinician, standardised mean difference (SMD) 0.74; parent, SMD = 0.63; or teacher, SMD = 0.75). Evidence of publication bias was found for clinician-rated efficacy, especially in industry-sponsored RPCCT. Psychostimulants showed a higher efficacy and were associated with a better outcome on treatment discontinuation than non-stimulant drugs. Efficacy was smaller in RPCCTs for which a psychiatric comorbid disorder was an inclusion criterion, was larger in studies with a commercial sponsorship and showed a negative association with treatment length. CONCLUSIONS: In the short term, pharmacological treatment provides moderate-high symptom relief, is safe and shows lower treatment discontinuation than placebo, suggesting a suitable risk-benefit balance, particularly with psychostimulants. The efficacy is lower in patients with a comorbid psychiatric disorder and should be assessed periodically, as it appears to reduce over time. Publication bias of clinician-rated efficacy in studies with a commercial sponsor is suggested.

[Agreement in the determination of electrolytes in samples of serum and plasma. Stability of these samples kept for 2 hours at room temperature with uncovered tubes]. / Détermination des électrolytes dans des échantillons de sérum et de plasma, et stabilité dans des tubes ouverts pendant 2 heures à température ambiante.

UNLABELLED: The determination of electrolytes in the clinical laboratories is carried out in samples of serum or plasma in situations that tubes remain open during a lingering time. OBJECTIVE: To estimate the agreement and the interchangeability in the determination of electrolytes for three types of tubes (serum with separator, plasma with and without separator) in samples that remain at room temperature and open up to two hours. MATERIAL AND METHODS: Samples of 36 voluntary patients were selected determining the levels of sodium, potassium, chlorine, calcium, magnesium and phosphate in the three tubes on time 0 (basal), 60 and 120 minutes. The agreement was estimated by means of the intraclass correlation coefficient (ICC) and the interchangeability of results by means of lineal regression. RESULTS: Agreement among the samples was very high with ICC higher than 0.9 in all basal determinations except for the potassium for which the presence of a constant systematic error was detected between serum and two tubes of plasma. The stability of the parameters is good in all the samples. CONCLUSIONS: It is possible the use of different types of tubes in the determination of electrolytes under the working conditions of the clinical laboratories. The determination of potassium needs to be corrected before the exchange of results obtained with serum and plasma. The stability in the two first hours is good in all the cases.

[Systematic review of population-based studies of the prevalence of cataracts]. / Revisión sistemática de estudios poblacionales de prevalencia de catarata.

OBJECTIVE: The prevalence of cataracts has increased due to the progressive ageing of the population and the fact that cataracts affect a wide and increasing proportion of the population. The goal of the present study was to describe the prevalence of cataracts through a systematic and exhaustive review of population-based studies. METHODS: A systematic review of population-based studies of the prevalence and incidence of cataracts was performed. Inclusion criteria were: a healthy non- institutionalised population, older than 40 years of age, of white race, with a sample size of greater than 1,000 and published between 1980 and 2002. RESULTS: Ten studies met the inclusion criteria (3 European, 5 from the United States and 2 from Australia), and were performed between 1984 and 2001. The cataract prevalence, according to lens opacity criteria, ranged between 15% and 19%. When the cataract was defined as a lens opacity combined with a decreased visual acuity, the prevalence ranged from 15% to 30%. The overall prevalence increased with age, reaching 40% and more than 60% in populations older than 70 and 75 years respectively. The prevalence among women was higher than that among men, with a more marked increase being evident at older ages than for men. CONCLUSIONS: There were variations among the criteria used to measure the prevalence of cataract, which made it difficult to compare all the studies. Overall the prevalence was higher in the older population, especially among women. The increasing prevalence associated with age predicts an increasing burden of cataract to health services, this being particularly related to the ageing of the population.

Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients.

RATIONALE: The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. METHODS: A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. RESULTS: Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95 % confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95 % CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95 % CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). CONCLUSION: Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.