Norfloxacin prophylaxis effect on multidrug resistance in patients with cirrhosis and bacterial infections.

It is unclear whether norfloxacin predisposes to infections by multidrug-resistant organisms (MDROs). We aimed to evaluate if patients with cirrhosis receiving norfloxacin prophylaxis at the time of the diagnosis of bacterial infections were more likely to present a multidrug-resistant isolate than those without prophylaxis. This is a cross-sectional study of hospitalized patients with cirrhosis and bacterial infections from Argentina and Uruguay (NCT03919032) from September 2018 to December 2020. The outcome variable was a multidrug-resistant bacterial infection. We used inverse probability of treatment weighting to estimate the odds ratio (OR) of norfloxacin on infection caused by MDROs considering potential confounders. Among the 472 patients from 28 centers, 53 (11%) were receiving norfloxacin at the time of the bacterial infection. Patients receiving norfloxacin had higher MELD-sodium, were more likely to have ascites or encephalopathy, to receive rifaximin, beta-blockers, and proton-pump inhibitors, to have a nosocomial or health-care-associated infection, prior bacterial infections, admissions to critical care units or invasive procedures, and to be admitted in a liver transplant center. In addition, we found that 13 (24.5%) patients with norfloxacin and 90 (21.5%) of those not receiving it presented infections caused by MDROs (adjusted OR 1.55; 95% CI: 0.60-4.03; p = 0.360). The use of norfloxacin prophylaxis at the time of the diagnosis of bacterial infections was not associated with multidrug resistance. These results help empiric antibiotic selection and reassure the current indication of norfloxacin prophylaxis in well-selected patients.Study registration number: NCT03919032.

Environmental conditions experienced upon first breeding modulate costs of early breeding but not age-specific reproductive output in peregrine falcons.

Although once considered uncommon, there is growing evidence of widespread senescence in wildlife populations. However, few studies have examined the traits involved, inter-sexual differences, and environmental correlates of age-specific performance in raptors. We studied age-specific reproductive performance and actuarial senescence (decrease in survival probability with age) in a peregrine falcon population monitored for 21 years. We analysed changes with age in the number of offspring produced and incubation start date. We also inspected variation in lifespan and breeding lifespan (number of breeding occasions in a lifetime). In every case, we assessed associations between variations in traits and age, sex, recruitment age, and environmental conditions (cumulative rainfall during breeding season) experienced upon the first breeding attempt. We found scarce evidence for reproductive senescence. Only the incubation start date in females, which was delayed after approximately 8 cy (calendar years), suggested reproductive senescence in our study population. Regarding actuarial senescence, our data did not support it as we only found evidence of higher juvenile mortality. Furthermore, expected lifespan in peregrines recruited at 2 cy was associated with conditions experienced upon the first breeding attempt. The lifespan and breeding career of individuals recruited as yearlings and experiencing low rainfall upon first breeding did not significantly differ from those recruited as adults. However, those recruited as yearlings and experiencing poor environmental conditions upon the first breeding attempt showed reduced lifespan and breeding lifespan.

Effect of nest composition, experience and nest quality on nest-building behaviour in the Bonelli's Eagle.

In bi-parentally built nests, there is evidence to suggest that nests are extended phenotypic signals that accurately indicate the quality of the building parent/s. Raptors often use a variety of materials to build their nests (natural, such as branches, but also non-natural objects), presumably due to their insulating properties, their suitability to advertise occupancy of the nest, and to decrease pathogen and parasite loads. However, in raptors where both sexes collaborate in nest construction, it is unclear whether nest building (taking the amount of material carried to the nest as the potential predictor) is an indicator of parental quality, and whether the effort expended by both sexes could constitute an honest signal of parental quality to their partners. Between 2011 and 2016, we monitored 16 nests of Bonelli's Eagles (Aquila fasciata), and we examined data on sex, type of material brought to the nest, breeding experience, nest quality, timing, and nest-building investment prior to egg-laying from 32 identifiable Bonelli's Eagles during the pre-laying period to investigate the relative contribution of the sexes to the amount of nest material gathered. Our results indicate that sex is not a determining factor in nest-building effort, and that females did not increase their parental effort in response to the male's contribution, and supply of materials did not increase during the pre-laying period. In contrast, our models showed that: (1) the type of material supplied to the nest by both sexes varied significantly throughout the pre-laying period and (2) nest-building effort was determined by individual experience and nest quality. Therefore, our study suggests that male nest-building behaviour and investment by Bonelli's Eagles cannot be considered as an extended phenotypic signal. The differential use of hard and green material by both sexes in the early and late stages of nest-building period, and the fact that the more experienced individuals contributed a larger amount of material on low quality nests, are discussed in the contexts of signaling nest occupancy to conspecifics and competitors and the decrease of ectoparasite loads during the pre-laying period.

Human Microbiota Network: Unveiling Potential Crosstalk between the Different Microbiota Ecosystems and Their Role in Health and Disease.

The human body is host to a large number of microorganisms which conform the human microbiota, that is known to play an important role in health and disease. Although most of the microorganisms that coexist with us are located in the gut, microbial cells present in other locations (like skin, respiratory tract, genitourinary tract, and the vaginal zone in women) also play a significant role regulating host health. The fact that there are different kinds of microbiota in different body areas does not mean they are independent. It is plausible that connection exist, and different studies have shown that the microbiota present in different zones of the human body has the capability of communicating through secondary metabolites. In this sense, dysbiosis in one body compartment may negatively affect distal areas and contribute to the development of diseases. Accordingly, it could be hypothesized that the whole set of microbial cells that inhabit the human body form a system, and the dialogue between the different host microbiotas may be a contributing factor for the susceptibility to developing diseased states. For this reason, the present review aims to integrate the available literature on the relationship between the different human microbiotas and understand how changes in the microbiota in one body region can influence other microbiota communities in a bidirectional process. The findings suggest that the different microbiotas may act in a coordinated way to decisively influence human well-being. This new integrative paradigm opens new insights in the microbiota field of research and its relationship with human health that should be taken into account in future studies.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

Long-term population monitoring of a territorial forest raptor species.

We provide field monitoring data of a territorial raptor (the booted eagle, Hieraaetus pennatus), that was intensively monitored over a period of 18 years (1998-2015) in a Mediterranean forested area of south-eastern Spain designated as a Special Protection Area (Natura 2000 Network) for this species. The data set compiles all the relevant information about the occupation of territories and nests, reproductive ecology, long-term monitoring of marked individuals and influence of parent's colour morph on brood size. Several questions concerning the population ecology of forest-dwelling raptors and factors conditioning territorial occupancy, such as location cues or site fidelity, are addressed. This type of long-term population monitoring has high potential for replication, reuse and comparison purposes, providing insights for monitoring other long-lived, territorial species.

Copulatory behaviour in the Bonelli´s Eagle: Assessing the paternity assurance hypothesis.

We examined copulatory behaviour in the Bonelli´s Eagle (Aquila fasciata) at nesting sites in the eastern zone of the Baetic Cordillera, southern Spain, between 2010 and 2012. We observed the copulatory behaviour of 15 pairs during the pre-laying period. Bonelli´s Eagles commenced sexual activity ca. 69 days before egg-laying. Ninety-six percent of mounting attempts were successful. Bonelli´s Eagle pairs averaged 99.8 copulation attempts per clutch, with an average copulation frequency of 0.86 copulation attempts per day. Pairs displayed a daily bimodal pattern of copulation activity, with copulations occurring most frequently in the evening. We used our data to test three predictions with regard to the paternity assurance hypothesis. Prediction 1, that within-pair copulations increase with local breeding density, was rejected because our models showed no evidence for it. Prediction 2, that within-pair copulations increase during the female fertile period, was marginally supported. Finally, Prediction 3, that mate attendance increases during the female fertile period, was also rejected because mate-guarding did not increase as the fertile period approached. However, mate-guarding was positively correlated with within-pair copulation frequency. Moderate copulation rates compared to other raptors and the absence of mate-guarding suggest that, in the study area, Bonelli´s Eagles exhibit only partially adaptive behaviour to assure their paternity. A possible explanation could be related to the low number of extra-pair encounters observed (opportunities for which appear to be rare), although the gradual increase in within-pair copulations during the female fertile period is consistent with the sperm competition hypothesis. The results are discussed based on the signalling hypothesis, which proposes that raptors signal territory ownership to conspecifics, and possibly to other raptor species, by copulating frequently and conspicuously in the defended nesting area.

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Nest sites as a key resource for population persistence: A case study modelling nest occupancy under forestry practices.

Natural nest sites are important breeding resource in terms of population dynamics, especially in forest systems where nest trees limit populations or timber harvesting destroys nests. Nest structures usually have a long life and can be reused by breeding pairs across multiple breeding seasons, so studying their dynamics is of relevance for biodiversity conservation. In this study, we develop a dynamic model to evaluate nest site availability and its influence on the breeding settlement of a forest raptor community composed of booted eagle (Hieraaetus pennatus), common buzzard (Buteo buteo) and northern goshawk (Accipiter gentilis) in a Mediterranean forest ecosystem in southeast Spain. This model approach is also applied to analyse the influence of forestry practices on the dynamics of occupied nests for a simulated period (2010-2050). The simulated scenarios include unmanaged forest and timber harvesting practices of clearcuttings every ten years considering two factors: the age class of trees for clearcutting (40, 50, 60 and 70 years old) and the type of forest management (with or without nest protection). Our simulated results show that the number of breeding pairs is constant during the period without timber harvest, whereas breeding pairs gradually decrease in the scenario of clearcutting trees aged from 70 to 50-years without nest protection, and populations become extinct with the clearcutting of 40-year old trees. Considering the practice of clearcutting and nest protection, nest occupancy can reach the maximum number of occupied nests for the scenarios of cutting 70 and 60-year old trees, and maintain populations without extinction for the scenarios of cutting 40-year old trees. We conclude that nest sites (whether occupied or not) are key resources for increasing the occupancy of the forest raptor community and that nest protection measures buffer the effects of clearcuttings, thus preventing population extinction.

CLARITY-BPA: Effects of chronic Bisphenol A exposure on the immune system: Part 1 - Quantification of the relative number and proportion of leukocyte populations in the spleen and thymus.

Bisphenol A (BPA) is extensively used in manufacturing of a broad range of consumer products worldwide. Due to its widespread use, human exposure to BPA is virtually ubiquitous. Broad human exposure coupled with a large scientific literature describing estrogenic activity of BPA in animals has raised public health concerns. To comprehensively evaluate the health effects of BPA exposure, a chronic toxicity study using a wide-range of BPA doses (2.5-25000 µg/kg bw/day) was conducted jointly by the NTP, thirteen NIEHS-supported grantees, and the FDA, which is called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, the objective of the current study was to evaluate the effects of chronic BPA exposure in Sprague-Dawley rats on the relative number and proportion of defined leukocyte populations in the spleen and the thymus. Toward this end, lymphoid tissues from a total of 641 rats were assayed after being continuously dosed with BPA or controls for up to one year. To comprehensively evaluate the effects of BPA on leukocyte compositions, extensive endpoints that cover major populations of leukocytes were assessed, including B cells, T cells, NK cells, granulocytes, monocytes, macrophages and dendritic cells. In total, of the 530 measurements in BPA-treated rats, 10 measurements were statistically different from vehicle controls and were mainly associated with either the macrophage or dendritic cell populations. Most, if not all, of these alterations were found to be transient with no persistent trend over the one-year time period. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and not dose-dependent. Due to the aforementioned, it is unlikely that the observed BPA-mediated changes alone would adversely affect immune competence.

CLARITY-BPA: Effects of chronic bisphenol A exposure on the immune system: Part 2 - Characterization of lymphoproliferative and immune effector responses by splenic leukocytes.

Bisphenol A (BPA) is commonly used in the manufacturing of a wide range of consumer products, including polycarbonate plastics, epoxy resin that lines beverage and food cans, and some dental sealants. Consumption of food and beverages containing BPA represents the primary route of human BPA exposure, which is virtually ubiquitous. An increasing number of studies have evaluated the effects of BPA on immune responses in laboratory animals that have reported a variety of effects some of which have been contradictory. To address the divergent findings surrounding BPA exposure, a comprehensive chronic treatment study of BPA was conducted in Sprague-Dawley rats, termed the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, our studies evaluated the effects of BPA on a broad range of immune function endpoints using spleen cells isolated from BPA or vehicle treated rats. This comprehensive assessment included measurements of lymphoproliferation in response to mitogenic stimuli, immunoglobulin production by B cells, and cellular activation of T cells, NK cells, monocytes, granulocytes, macrophages and dendritic cells. In total, 630 different measurements in BPA treated rats were performed of which 35 measurements were statistically different from vehicle controls. The most substantive alteration associated with BPA treatment was the augmentation of lymphoproliferation in response to pokeweed mitogen stimulations in 1 year old male rats, which was also observed in the reference estrogen ethinyl estradiol treated groups. With the exception of the aforementioned, the statistically significant changes associated with BPA treatment were mostly sporadic and not dose-dependent with only one out of five BPA dose groups showing a statistical difference. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and showed no persistent trend over the one-year time period. Based on these findings, we conclude that the observed BPA-mediated changes observed in this study are unlikely to alter immune competence in adult rats.

Abordaje laparoscópico colorrectal con anastomosis totalmente intracorpórea / Laparoscopic colorectal approach with intracorporeal anastomosis

Antecedentes: el abordaje laparoscópico en el tratamiento de las afecciones colorrectales ha demostrado numerosas ventajas en relación con la cirugía convencional; sin embargo, la necesidad frecuente de tener que emplear una incisión complementaria para la extracción de la pieza operatoria u otros gestos quirúrgicos genera efectos adversos vinculados con el dolor posoperatorio, íleo y las complicaciones propias de la herida. Objetivo: análisis de una serie de pacientes intervenidos por afecciones colorrectales mediante abordaje laparoscópico en quienes se realizó anastomosis intracorpórea comparada con otra de anastomosis extracorpórea. Material y métodos: entre abril de 2010 y mayo de 2013 fueron operados 85 pacientes con afecciones colorrectales, abordados por vía laparoscópica, los que se agruparon en dos lotes: Grupo 1, con anastomosis extracorpórea, 50 (58,8%) y Grupo 2, con variante intracorpórea, 35 (41,2 %). Resultados: no hubo diferencias entre ambos grupos (extracorpórea/intracorpórea), en cuanto a sexo (F/M:23/27, 22/13, respectivamente; p=0,052), edad promedio en años (63/60; p=0,222), índice de masa corporal (24,38 kg/m2/27,37 kg/m2; p=0,315), ASA (p=0,817), tpo de afección tratada (p= 0,312), sector resecado (p=0,282), longitud de la pieza operatoria (p=0,384) y cantidad de ganglios extrpados (p=0,537). Tampoco se hallaron diferencias en relación con la conversión, 7 (14%) versus 4 (11,4%), p= 0,379; tempo operatorio en minutos, (178,3 min/188,6 min), p= 0,257; complicaciones, 12 (24%/) versus 8 (22,8%), p= 0,493 y reoperaciones, 5 (10%) versus 4 (11,4%), p= 1. En ambos grupos no hubo mortalidad. Hubo diferencias en relación con el tamaño promedio en centmetros de la incisión empleada (7,7 cm/4,4 cm; p= 0,042) y el dolor posoperatorio inmediato (4,7/3,1; p=0,022). Conclusiones: la confección de anastomosis intracorpórea ofrece un menor dolor posoperatorio, con una menor herida quirúrgica y mejor estética, e iguales resultados posoperatorios inmediatos y alejados.

Background: the laparoscopic approach for the treatment of colorectal diseases has shown many ad-vantages over conventonal surgery. However, the frequent need of an additonal incision to extract the specimen or to perform further surgical techniques may cause adverse efectis related to postope-rative pain, ileus and complicatons of the wound. Objective: to compare a series of patentis undergoing laparoscopic surgery for colorectal disease with intracorporeal versus extracorporeal anastomosis. Material and methods: between April 2010 and May 2013, 85 patentis who were operated on lapa-roscopically for colorectal disease, were divided in two groups. Group I, extracorporeal, 50 (58.8%) and Group II, intracoroporeal anastomosis, 35 (41.2%). Results: there was no diference between groups in terms of gender (F/M-23/27, 22/13, p=0.052), mean age (63/60 years, p=0.222), body mass index (24.38 vs. 27.37 kg/m2), p = 0.315, ASA (p = 0.817), type of disease (p=0.312), resected segment (p=0.282), specimen length (p=0,384) and number of removed lymph nodes (p=0,537). No diferences were found in relaton to conversion, 7 (14%) vs. 4 (11.4%) p=0.379, operative tme (178.3 vs. 188,6 min), p=0.257, complicatons 12 (24% /) vs. 8 (22.8%) p=0.493 and reoperatons, 5 (10%) vs. 4 (11.4%;), p=1. No mortality occurred in both groups. There were diferences in the average size of the incision (7.7 cm vs. 4.4 cm, p = 0.042) and immediate postoperative pain (4.7 vs. 3.1, p = 0.022). Conclusions: laparoscopic approach with intracorporeal anastomosis for colorectal disease ofers less postoperative pain, a smaller wound and beter cosmetic result, with equal postoperative outicome.

Factors influencing territorial occupancy and reproductive success in a Eurasian Eagle-owl (Bubo bubo) population.

Modelling territorial occupancy and reproductive success is a key issue for better understanding the population dynamics of territorial species. This study aimed to investigate these ecological processes in a Eurasian Eagle-owl (Bubo bubo) population in south-eastern Spain during a seven-year period. A multi-season, multi-state modelling approach was followed to estimate the probabilities of occupancy and reproductive success in relation to previous state, time and habitat covariates, and accounting for imperfect detection. The best estimated models showed past breeding success in the territories to be the most important factor determining a high probability of reoccupation and reproductive success in the following year. In addition, alternative occupancy models suggested the positive influence of crops on the probability of territory occupation. By contrast, the best reproductive model revealed strong interannual variations in the rates of breeding success, which may be related to changes in the abundance of the European Rabbit, the main prey of the Eurasian Eagle-owl. Our models also estimated the probabilities of detecting the presence of owls in a given territory and the probability of detecting evidence of successful reproduction. Estimated detection probabilities were high throughout the breeding season, decreasing in time for unsuccessful breeders but increasing for successful breeders. The probability of detecting reproductive success increased with time, being close to one in the last survey. These results suggest that reproduction failure in the early stages of the breeding season is a determinant factor in the probability of detecting occupancy and reproductive success.

Immunological characterization of the aryl hydrocarbon receptor (AHR) knockout rat in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The aryl hydrocarbon receptor (AHR) has been extensively characterized for the essential role it plays in mediating the toxic responses elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Despite similarities across animal species, species-specific differences exist in the profile of toxicity and sensitivity to TCDD owing, in part, to differences in the AHR. Newer reports have implicated the importance of AHR in the development and regulation of the immune system. Our present studies seek to further explore the essential role of AHR in lymphoid tissue composition, B cell function and the immunological responses after TCDD administration using the recently established AHR KO rats. Comprehensive immune cell phenotyping showed a decrease in the CD8+ T cell, CD11c+ populations and an increase in NKT cells in 3-week-old AHR KO rats compared to the WT controls. The lipopolysaccharide-induced IgM response and proliferation was markedly suppressed in the WT but not in the AHR KO B cells in the presence of TCDD. However, the percentage of LPS-activated IgM+ B cells was significantly higher in the AHR KO B cells as compared to that of WT suggesting the role of AHR in regulating the IgM response. The use of an AHR antagonist further alluded to the endogenous role of AHR in regulating B cell responses in the rat. Overall, the studies report for the first time, comprehensive immune cell phenotyping of the AHR KO rat and the endogenous role of AHR in the regulation of B cell function in the rat.

Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer.

PURPOSE: Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. PATIENTS AND METHODS: Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. RESULTS: Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. CONCLUSION: Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

Lifespan analyses of forest raptor nests: patterns of creation, persistence and reuse.

Structural elements for breeding such as nests are key resources for the conservation of bird populations. This is especially true when structural elements require a specific and restricted habitat, or if the construction of nests is costly in time and energy. The availability of nesting-platforms is influenced by nest creation and persistence. In a Mediterranean forest in southeastern Spain, nesting-platforms are the only structural element for three forest-dwelling raptor species: booted eagle Aquila pennata, common buzzard Buteo buteo and northern goshawk Accipiter gentilis. From 1998 to 2013, we tracked the fate of 157 nesting-platforms built and reused by these species with the aim of determining the rates of creation and destruction of nesting-platforms, estimating nest persistence by applying two survival analyses, describing the pattern of nest reuse and testing the effects of nest use on breeding success. Nest creation and destruction rates were low (0.14 and 0.05, respectively). Using Kaplan Meier survival estimates and Cox proportional-hazards regression models we found that median nest longevity was 12 years and that this was not significantly affected by nest characteristics, nest-tree dimensions, nest-builder species, or frequency of use of the platform. We also estimated a transition matrix, considering the different stages of nest occupation (vacant or occupied by one of the focal species), to obtain the fundamental matrix and the average life expectancies of nests, which varied from 17.9 to 19.7 years. Eighty six percent of nests were used in at least one breeding attempt, 67.5% were reused and 17.8% were successively occupied by at least two of the study species. The frequency of nest use had no significant effects on the breeding success of any species. We conclude that nesting-platforms constitute an important resource for forest raptors and that their longevity is sufficiently high to allow their reuse in multiple breeding attempts.

Recalibration of the Gail model for predicting invasive breast cancer risk in Spanish women: a population-based cohort study.

The Gail model for predicting the absolute risk of invasive breast cancer has been validated extensively in US populations, but its performance in the international setting remains uncertain. We evaluated the predictive accuracy of the Gail model in 54,649 Spanish women aged 45-68 years who were free of breast cancer at the 1996-1998 baseline mammographic examination in the population-based Navarre Breast Cancer Screening Program. Incident cases of invasive breast cancer and competing deaths were ascertained until the end of 2005 (average follow-up of 7.7 years) through linkage with population-based cancer and mortality registries. The Gail model was tested for calibration and discrimination in its original form and after recalibration to the lower breast cancer incidence and risk factor prevalence in the study cohort, and compared through cross-validation with a Navarre model fully developed from this cohort. The original Gail model overpredicted significantly the 835 cases of invasive breast cancer observed in the cohort (ratio of expected to observed cases 1.46, 95 % CI 1.36-1.56). The recalibrated Gail model was well calibrated overall (expected-to-observed ratio 1.00, 95 % CI 0.94-1.07), but it tended to underestimate risk for women in low-risk quintiles and to overestimate risk in high-risk quintiles (P = 0.01). The Navarre model showed good cross-validated calibration overall (expected-to-observed ratio 0.98, 95 % CI 0.92-1.05) and in different cohort subsets. The Navarre and Gail models had modest cross-validated discrimination indexes of 0.542 (95 % CI 0.521-0.564) and 0.544 (95 % CI 0.523-0.565), respectively. Although the original Gail model cannot be applied directly to populations with different underlying rates of invasive breast cancer, it can readily be recalibrated to provide unbiased estimates of absolute risk in such populations. Nevertheless, its limited discrimination ability at the individual level highlights the need to develop extended models with additional strong risk factors.

Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region.

Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with hormone receptor-positive, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001-03 phase 2 randomized trial.

BACKGROUND: Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer. METHODS: Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored. RESULTS: In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥ 2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported. CONCLUSIONS: In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting.