Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study.

BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %)  + 1.3  × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. PATIENTS AND METHODS: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. RESULTS: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. CONCLUSIONS: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.

Emerging Hyalomma lusitanicum: From identification to vectorial role and integrated control.

In the Mediterranean basin, the tick species Hyalomma lusitanicum Koch stands out among other species of the Hyalomma genus due to its wide distribution, and there is great concern about its potential role as a vector and/or reservoir and its continuous expansion to new areas because of climate warming and human and other animal movements. This review aims to consolidate all the information on H. lusitanicum, including taxonomy and evolution, morphological and molecular identification, life cycle, sampling methods, rearing under laboratory conditions, ecology, hosts, geographical distribution, seasonality, vector role and control methods. The availability of adequate data is extremely relevant to the development of appropriate control strategies in areas where this tick is currently distributed as well as in new areas where it could become established in the near future.

Internet, video game and mobile phone addiction in children and adolescents diagnosed with ADHD: A case-control study. / Adicción a Internet, videojuegos y teléfonos móviles en niños y adolescentes: Un estudio de casos y controles.

The use of new technologies has become widespread worldwide. There is increasing concern about "Internet addiction disorder" (IAD), "Internet gaming disorder" (IGD), and "Mobile phone addiction" (MPA). Attention Deficit Hyperactivity Disorder (ADHD) has been associated with IAD and IGD. However, evidence is lacking about the relationship between ADHD and MPA. Naturalistic case-control study. 112 patients (51 children with and 61 children without ADHD) between 7 and 17 years old were compared regarding IAD, IGD, and MPA. We used the TEA questionnaire for the assessment of executive function and ADHD (ATENTO), and the ADITEC questionnaire to get gender-differentiated information for IAD, IGD, and MPA. Female children scored higher on MPA (Mean ± Standard Deviation, M ± SD) (25.93 ±  17.64 vs. 14.77 ±  19.43, p=0.03), while male children scored higher on IGD (30.09 ± 21.65 vs. 12.51 ± 16.61, p < 10^-3). Severity of hyperactivity/impulsivity and IGD were moderately correlated (r=0.349, p=0.013), but the correlation disappeared after controlling for the impact on the social domain as measured by the ATENTO questionnaire (r=171, p=0.250). Most parents are concerned that their children may be addicted to IAD/IGD/MPA. Female gender is associated with MPA, while male gender is associated with IGD. ADHD is a risk factor for developing IAD and IGD. Combined type and predominantly hyperactive/impulsive ADHD are each associated with IGD. Good social adjustment protects against developing IGD. There are gender vulnerabilities for IAD/IGD/MPA. ADHD is a risk factor for IGD, but good social adjustment buffers this association.

El uso de las nuevas tecnologías se ha generalizado a nivel mundial. Hay una creciente preocupación respecto del «trastorno de adicción a Internet¼ (TAI), el «trastorno de juego en Internet¼ (TJI) y la «adicción al teléfono móvil¼ (ATM). El trastorno por el déficit de atención con hiperactividad (TDAH) se ha asociado con el TAI y el TJI. Sin embargo, falta evidencia sobre la relación entre el TDAH y la ATM. Estudio naturalista de casos y controles. Comparación de 112 pacientes (51 niños con el TDAH y 61 niños sin el TDAH) con edades entre 7-17 años respecto del TAI, el TJI y la ATM. Utilizamos el cuestionario de TEA para evaluar la función ejecutiva y el TDAH (ATENTO) y el cuestionario ADITEC para obtener información diferenciada por género para el TAI, el TJI y la ATM. Las niñas obtuvieron puntuaciones más altas en la ATM (desviación típica ± media, DT ± M) (25,93 ± 17,64 vs. 14,77 ± 19,43, p = ,03), mientras que los niños obtuvieron puntuaciones más altas en el TJI (30,09 ± 21,65 vs. 12,51 ± 16,61, p < 10

Analysis of outcomes of emergency general and gastrointestinal surgery during the COVID-19 pandemic.

BACKGROUND: Few surgical studies have provided adjusted comparative postoperative outcome data among contemporary patients with and without COVID-19 infection and patients treated before the pandemic. The aim of this study was to determine the impact of performing emergency surgery in patients with concomitant COVID-19 infection. METHODS: Patients who underwent emergency general and gastrointestinal surgery from March to June 2020, and from March to June 2019 in 25 Spanish hospitals were included in a retrospective study (COVID-CIR). The main outcome was 30-day mortality. Secondary outcomes included postoperative complications and failure to rescue (mortality among patients who developed complications). Propensity score-matched comparisons were performed between patients who were positive and those who were negative for COVID-19; and between COVID-19-negative cohorts before and during the pandemic. RESULTS: Some 5307 patients were included in the study (183 COVID-19-positive and 2132 COVID-19-negative during pandemic; 2992 treated before pandemic). During the pandemic, patients with COVID-19 infection had greater 30-day mortality than those without (12.6 versus 4.6 per cent), but this difference was not statistically significant after propensity score matching (odds ratio (OR) 1.58, 95 per cent c.i. 0.88 to 2.74). Those positive for COVID-19 had more complications (41.5 versus 23.9 per cent; OR 1.61, 1.11 to 2.33) and a higher likelihood of failure to rescue (30.3 versus 19.3 per cent; OR 1.10, 0.57 to 2.12). Patients who were negative for COVID-19 during the pandemic had similar rates of 30-day mortality (4.6 versus 3.2 per cent; OR 1.35, 0.98 to 1.86) and complications (23.9 versus 25.2 per cent; OR 0.89, 0.77 to 1.02), but a greater likelihood of failure to rescue (19.3 versus 12.9 per cent; OR 1.56, 95 per cent 1.10 to 2.19) than prepandemic controls. CONCLUSION: Patients with COVID-19 infection undergoing emergency general and gastrointestinal surgery had worse postoperative outcomes than contemporary patients without COVID-19. COVID-19-negative patients operated on during the COVID-19 pandemic had a likelihood of greater failure-to-rescue than prepandemic controls.

Combined effects of land-use intensification and plant invasion on native communities.

Land-use intensification (LUI) and biological invasions are two of the most important global change pressures driving biodiversity loss. However, their combined impacts on biological communities have been seldom explored, which may result in misleading ecological assessments or mitigation actions. Based on an extensive field survey of 445 paired invaded and control plots of coastal vegetation in SW Spain, we explored the joint effects of LUI (agricultural and urban intensification) and invasion on the taxonomic and functional richness, mean plant height and leaf area of native plants. Our survey covered five invasive species with contrasting functional similarity and competitive ability in relation to the native community. We modeled the response of native communities for the overall and invader-specific datasets, and determined if invader-native functional differences could influence the combined impacts of LUI and invasion. Overall, we found that urban intensification reduced taxonomic richness more strongly at invaded plots (synergistic interactive effects). In contrast, functional richness loss caused by urban intensification was less pronounced at invaded plots (antagonistic interactive effects). Overall models showed also that urban intensification led to reduced mean leaf area, while agriculture was linked to higher mean plant height. When exploring invader-specific models, we observed that the combined effects of agricultural and urban intensification with invasion were heterogeneous. At invaded plots, invader-native functional differences accounted for part of this variability. Our findings demonstrate the importance of considering the interactive effects of global change pressures for a better assessment and management of ecosystems.

Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection.

For precision medicine to be implemented through the lens of in silico technology, it is imperative that biophysical research workflows offer insight into treatments that are specific to a particular illness and to a particular subject. The boundaries of precision medicine can be extended using multiscale, biophysics-centred workflows that consider the fundamental underpinnings of the constituents of cells and tissues and their dynamic environments. Utilising numerical techniques that can capture the broad spectrum of biological flows within complex, deformable and permeable organs and tissues is of paramount importance when considering the core prerequisites of any state-of-the-art precision medicine pipeline. In this work, a succinct breakdown of two precision medicine pipelines developed within two Virtual Physiological Human (VPH) projects are given. The first workflow is targeted on the trajectory of Alzheimer's Disease, and caters for novel hypothesis testing through a multicompartmental poroelastic model which is integrated with a high throughput imaging workflow and subject-specific blood flow variability model. The second workflow gives rise to the patient specific exploration of Aortic Dissections via a multi-scale and compliant model, harnessing imaging, computational fluid-dynamics (CFD) and dynamic boundary conditions. Results relating to the first workflow include some core outputs of the multiporoelastic modelling framework, and the representation of peri-arterial swelling and peri-venous drainage solution fields. The latter solution fields were statistically analysed for a cohort of thirty-five subjects (stratified with respect to disease status, gender and activity level). The second workflow allowed for a better understanding of complex aortic dissection cases utilising both a rigid-wall model informed by minimal and clinically common datasets as well as a moving-wall model informed by rich datasets.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

BACKGROUND: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. RESULTS: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. CONCLUSIONS: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

Pretreatment HIV-1 drug resistance in Argentina: results from a surveillance study performed according to WHO-proposed new methodology in 2014-15.

BACKGROUND: In Argentina, current national guidelines recommend starting with NNRTI-based regimens. Recently, there have been some local reports regarding concerning levels of NNRTI-transmitted resistance, but surveillance has never been carried out at a national level. OBJECTIVES: To determine the prevalence of HIV drug resistance in people starting ART in Argentina using a WHO-proposed methodology. METHODS: This was a cross-sectional, nationally representative study. Twenty-five antiretroviral-dispensing sites throughout the country were randomly chosen to enrol at least 330 persons starting ART, to generate a point prevalence estimate of resistance-associated mutations (RAMs) with a 5% CI (for the total population and for those without antiretroviral exposure). All consecutive patients older than 18 years starting or restarting ART in the chosen clinics were eligible. Samples were processed with Trugene and analysed using the Stanford algorithm. RESULTS: Between August 2014 and March 2015, we obtained 330 samples from people starting ART. The mean ±â€ŠSD age was 35 ±â€Š11 years, 63.4% were male, 16.6% had prior antiretroviral exposure and the median (IQR) CD4 count was 275 cells/mm3 (106-461). The prevalence of RAMs found was 14% (±4%) for the whole population (3% NRTI-RAMs; 11% NNRTI-RAMs and 2% PI-RAMs) and 13% (±4%) for those without prior antiretroviral exposure (3%, 10% and 2%, respectively). The most common mutation was K103N. CONCLUSIONS: This surveillance study showed concerning levels of HIV drug resistance in Argentina, especially to NNRTIs. Due to this finding, Argentina's Ministry of Health guidelines will change, recommending performing a resistance test for everyone before starting ART. If this is taken up properly, it also might function as a continuing surveillance tool.

Incidence of moisture-associated skin damage in an intensive care unit. / Incidencia de lesiones cutáneas asociadas a la humedad en una unidad de cuidados intensivos.

OBJECTIVES: To determine the incidence of moisture-associated skin damage (MASD) in the nappy area, identify predisposing factors and know the preventive measures and nursing records. METHOD: Descriptive longitudinal study (June 2014-April 2015) in a general ICU. Patients whose stay >48hours and without skin lesions were included. The skin was assessed daily until the appearance of MASD, discharge or a maximum of 14 days. Demographics, stay, MASD type, incontinence, number and consistency of stools, obesity, Braden scale and prevention were recorded. RESULTS: 145 patients (66.2% male) were studied, median age was 69 (P25=56.5, P75=76) and median length of stay was five days (P25=3, P75=11.25), 29.9% were obese. Incontinence-associated dermatitis (IAD) was detected in 26.2% and intertriginous dermatitis (ITD) in 15.9%. MASD was recorded in 23.8%. The variables causing IAD to develop were faecal incontinence, number of stools, liquid stools, and stay. Those for ITD were obesity and score on the Braden scale. Multivariate analysis selected faecal incontinence (OR=5.4, CI95%: 1.1-26) and the number of stools (OR=1.1, CI95%:1.0-1.2) as independent variables for developing IAD and obesity (OR=2.8, CI95%:1.0-8.2) and Braden (OR=0.8, CI95%:0.7-1.0) for developing ITD. Prevention to 23.8% of obese and 42.9% of incontinent was performed. CONCLUSIONS: There is a high incidence in MASD. Faecal incontinence and higher number of stools are the risk factors for developing IAD. Obesity and a lower score on the Braden scale may affect susceptibility to ITD. Recording of MASD and its prevention in patients at risk is insufficient.

Unmet need in the hyperlipidaemia population with high risk of cardiovascular disease: a targeted literature review of observational studies.

BACKGROUND: The aim of this study was to examine recommended target levels of low-density lipoprotein cholesterol (LDL-C) for hyperlipidaemia patients at high risk (i.e., with two or more risk factors or coronary heart disease or its risk equivalents) for cardiovascular disease (CVD); to determine LDL-C targets recommended by guidelines, and to examine the proportions of patients who do not achieve targeted LDL-C levels in real-world studies. METHODS: Electronic databases were searched: Medline, Medline In-Process, Embase, BIOSIS, and the Cochrane Library (1 January 2005 to 31 December 2013). Guideline searches were limited to publications in the last 5 years. There were no geographical or language restrictions. RESULTS: Seventeen guidelines and 42 observational studies that reported on high-risk hyperlipidaemia patients were identified. The National Cholesterol Education Program-Adult Treatment Panel III's LDL-C target levels were the most common guidelines used for patients with very high hyperlipidaemia. However, between 68 and 96 % of patients in the studies did not achieve an LDL-C goal <70 mg/dL, except in one study conducted in China (16.9 %). In high-risk patients, 61.8 to 93.8 % did not achieve a target of <100 mg/dL. Regarding common comorbidities, patients with concomitant CVD or diabetes were least likely to reach their target LDL-C goals. CONCLUSION: In patients with high risk for CVD, the majority of patients do not attain recommended LDL-C goals, highlighting worldwide suboptimal hyperlipidaemia management and missed opportunities for reduction of the patients CVD risk. Lipid-modifying management strategies need to be intensified.

Bioequivalence study between two formulations of ciclosporin A (Cyclavance® oral solution and Atopica® soft capsules) following a single oral administration to dogs.

BACKGROUND: Ciclosporin is a selective immunomodulator used for the treatment of atopic dermatitis in dogs. A new 100 mg/ml oral solution formulation (Cyclavance®, Virbac) was developed as a pharmaceutical equivalent to the marketed capsule formulations (Atopica®, Novartis Animal Health) containing 25, 50 mg, or 100 mg of ciclosporin A. The aim of this study was to assess and compare the pharmacokinetic profiles and bioequivalence of the two formulations following a single oral administration to dogs. This randomised, two-period, two-sequence, crossover bioequivalence study was conducted in 40 healthy dogs under fasting conditions. Each dog received either one 50 mg capsule of Atopica® or 0.5 ml of Cyclavance®. After dosing, blood samples were collected during a 48-h time period at 0, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h. Blood ciclosporin A concentrations were measured by using an HPLC-MS/MS method. Cmax, Tmax, t1/2, AUC0-t, AUC0-∞ and Kel were determined for the two ciclosporin formulations. Bioequivalence was to be concluded if the 90% confidence intervals were within the range of 80% to 125% for Cmax and AUC0-t. Dogs were monitored once daily throughout the study period for adverse effects. RESULTS: The 90% confidence intervals for Cyclavance®/Atopica® mean ratios of the log-transformed pharmacokinetic variables Cmax and AUC0-t were within the conventional bioequivalence range of 80% to 125% (Point estimate: 101.2% and 101.4% respectively). Except for salivation reported after administration of both products, or vomiting and diarrhoea reported after Atopica® administration, both formulations were well tolerated in the 40 healthy dogs over the 48-h study period. CONCLUSIONS: The two ciclosporin oral formulations demonstrated similar pharmacokinetic profiles and were found to be bioequivalent, and therefore, interchangeable.

Recommendations in dispatcher-assisted bystander resuscitation from emergency call center.

Dispatch-assisted bystander cardiopulmonary resuscitation in out-of-hospital cardiac arrest has been shown as an effective measure to improve the survival of this process. The development of a unified protocol for all dispatch centers of the different emergency medical services can be a first step towards this goal in our environment. The process of developing a recommendations document and the realization of posters of dispatch-assisted cardiopulmonary resuscitation, agreed by different actors and promoted by the Spanish Resuscitation Council, is presented.

Triggering cell death by nanographene oxide mediated hyperthermia.

Graphene oxide (GO) has been proposed as an hyperthermia agent for anticancer therapies due to its near-infrared (NIR) optical absorption ability which, with its small two-dimensional size, could have a unique performance when compared to that of any other nanoparticle. Nevertheless, attention should be given to the hyperthermia route and the kind of GO-cell interactions induced in the process. The hyperthermia laser irradiation parameters, such as exposure time and laser power, were investigated to control the temperature rise and consequent damage in the GOs containing cell culture medium. The type of cell damage produced was evaluated as a function of these parameters. The results showed that cell culture temperature (after irradiating cells with internalized GO) increases preferentially with laser power rather than with exposure time. Moreover, when laser power is increased, necrosis is the preferential cell death leading to an increase of cytokine release to the medium.

[Synthetic indicator of compliance with standards for Quality Units of health centers and multicenter prospective pilot study]. / Indicador sintético de cumplimiento de estándares para Unidades de Calidad de centros sanitarios y estudio de pilotaje prospectivo multicéntrico.

BACKGROUND AND OBJECTIVE: In Spain, Quality Units play a key and unique role in advising healthcare centers on the methodology of healthcare quality. The objectives of the study were to develop computer algorithms to obtain a synthetic indicator of standard compliance for Quality Units and to pilot its functioning in these units. MATERIALS AND METHODS: The Excel program was used to establish evaluation algorithms, and quantitatively interrelate and weight various categories of standards, as a computer evaluation tool, to build a continuous improvement cycle system, and offer a global synthetic indicator of compliance. The tool was tested in a prospective multicenter pilot study, in which coordinators of Quality Units from different health centers and care settings participated, to evaluate the usefulness of the tool and compliance with the standards, in addition to analyzing the content validity of each standard. RESULTS: The formulas for the structured computer algorithms were developed, consecutively, in a «PLAN-DO-CHECK-ACT¼ improvement cycle for the 9 categories of standards, resulting in a single synthetic indicator of compliance. Twenty-one Quality Units participated in the piloting. The overall average compliance rate for the synthetic indicator was 55.63% with differences between centers (P=.002) and between categories (P<.0001), but not by autonomous communities (P=.86) or by areas (P=.97). Content validity was ensured through the variable of «understanding¼ of the standards (P<.001), and through their «justification¼ with documentary evidence (P<.001). CONCLUSIONS: The computer tool with the synthetic indicator have allowed for the evaluation of standard compliance in Quality Units of healthcare centers.

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

Cost-effectiveness of inguinal hernia surgery in northwestern Ecuador.

BACKGROUND: Cost-effectiveness of tension-free inguinal hernia repair at a private 20-bed rural hospital in Esmeraldas Province, Ecuador, was calculated relative to no treatment. METHODS: Lichtenstein repair using mosquito net or polypropylene commercial mesh was provided to patients with inguinal hernia by surgeons from Europe and North America. Prospective data were collected from provider, patient, and societal perspectives, with component costs collected on site and from local supply companies or published literature. Patient outcomes were forecasted using disability adjusted life years (DALYs) averted. Uncertainty in patient-level data was evaluated with Monte-Carlo simulation. RESULTS: Surgery was provided to 102 patients with inguinal hernias of various sizes. Local anesthesia was used for 80 % of operations during the first mission, and spinal anesthesia was used for 89 % in the second mission. Few complications were observed. An average 6.39 DALYs (3,0) were averted per patient (95 % confidence interval: 6.22-6.84). The average cost per patient was US$499.33 (95 % CI: US$490.19-$526.03) from a provider perspective, US$118.79 (95 % CI: US$110.28-$143.72) from a patient perspective, and US$615.46 (95 % CI: US$603.39-$650.40) from a societal perspective. Mean cost-effectiveness from a provider perspective was US$78.18/DALY averted (95 % CI: US$75.86-$85.78) according to DALYs (3,0) averted using the West Life Table level 26, well below the Ecuadorian per-capita Gross National Income (US$3,850). Results were robust to all sensitivity analyses. CONCLUSIONS: Inguinal hernia repair was cost-effective in western Ecuador through international collaboration.

Prevalence of verotoxigenic Escherichia coli O157 (VTEC O157) and compliance with microbiological safety standards in bovine carcasses from an industrial beef slaughter plant.

UNLABELLED: The presence of Salmonella spp. and levels of Enterobacteriaceae and aerobic plate count were determined in 300 bovine carcasses randomly collected in an industrial cattle slaughterhouse in Catalonia (Spain) as part of a control programme to validate good slaughter practices according to Commission Regulation No 2073/2005. The verotoxigenic Escherichia coli O157 (VTEC O157), although not currently legislated, was also investigated in the same carcasses due to the importance of bovines as a reservoir for this micro-organism. Virulence genes (vtx1, vtx2 and eae), the presence of fliCH 7 and antimicrobial susceptibility were studied in E. coli O157 isolates. Levels of Enterobacteriaceae and aerobic colonies and the presence of Salmonella were within the admissible range stipulated by current legislation. However, VTEC O157 was detected in 14·7% of carcasses. Among the VTEC O157 strains tested for antimicrobial susceptibility, 65% were multiresistant. Overall, the results of this study indicate that even with good manufacturing practices, contamination with VTEC O157 can occur and cattle meat can pose a risk to human health. These results confirm the need for a review of the appropriateness of introducing antimicrobial treatments in the processing of cattle carcasses in Europe. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes the prevalence of verotoxigenic and multidrug-resistant E. coli O157 strains in bovine carcasses. These results suggest that despite the good manufacturing practices used in the slaughterhouse studied (the largest in Catalonia slaughtering over 81 000 cattle per year), the absence of verotoxigenic E. coli O157 in bovine carcasses cannot be guaranteed.

Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D.

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.