Microplastic accumulation in endorheic river basins - The example of the Okavango Panhandle (Botswana).

The Okavango Panhandle is the main influent watercourse of the Okavango Delta, an inland sink of the entire sediment load of the Cubango-Okavango River Basin (CORB). The sources of pollution in the CORB, and other endorheic basins, are largely understudied when compared to exorheic systems and the world's oceans. We present the first study of the distribution of microplastic (MP) pollution in surface sediments of the Okavango Panhandle in Northern Botswana. MP concentrations (64 µm-5 mm size range) in sediment samples from the Panhandle range between 56.7 and 399.5 particles kg-1 (dry weight) when analysed with fluorescence microscopy. The concentrations of MP in the 20 µm to 5 mm grain size range (analysed with Raman spectroscopy) range between 1075.7 and 1756.3 particles kg-1. One shallow core (15 cm long) from an oxbow lake suggests that MP size decreases with depth while MP concentration increases downcore. Raman Spectroscopy revealed that the compositions of the MP are dominated by polyethene terephthalate (PET), polypropylene (PP), polyethene (PE), polystyrene (PS), and polyvinyl chloride (PVC). From this novel data set it was possible to estimate that 10.9-336.2 billion particles could be transported into the Okavango Delta annually, indicating that the region represents a significant sink for MP, raising concerns for the unique wetland ecosystem.

Remote consultations: experiences of UK patients with prostate cancer during the COVID-19 pandemic.

Aim: Explore UK prostate cancer patients' experiences and preferences for in-person and remote consultations. Materials & methods: In January-March 2021, patients completed a survey of consultation format preferences. Results: Of 971 patients, most preferred in-person consultations when receiving diagnosis and results (92.3 and 66.5%, respectively) and discussing first and further treatment options (92.0 and 84.0%, respectively). Fewer patients considered follow-up (40.9%) or side effect consultations (47.7%) should be in person. Patients with longer travel preferred telephone consultations for receiving test results post-treatment. Patients over 55 preferred in-person consultations for discussing first treatment. Conclusion: To optimize prostate cancer care in the wake of COVID-19, we recommend patients have the option of consultation format, although key decisions should be made in person.

During the COVID-19 pandemic, there was a move away from in-person to remote consultations for patients with prostate cancer. However, it is not clear if remote consultations work well for every interaction. We surveyed UK-based men with prostate cancer about their preferences for consultation format. Patients wanted in-person consultations when receiving their diagnosis, discussing treatment options or getting test results after treatment. They were more accepting of remote consultations for regular follow-up or support with treatment side effects. Patients should ideally be offered a choice between in-person and remote consultations, although consultations should be in person when key decisions have to be made. These findings will be of value in planning care for patients with prostate cancer post pandemic.

The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

BACKGROUND: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. METHODS: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. RESULTS: In pooled analyses, later age at menarche was associated with higher per cent density (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. CONCLUSIONS: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Patient and clinician satisfaction and clinical outcomes of Magseed compared with wire-guided localisation for impalpable breast lesions.

BACKGROUND: Guide-wire localisation remains the most commonly used technique for localisation of impalpable breast lesions in the UK. One alternative is magnetic seed localisation. We aimed to investigate patient and clinician satisfaction in two consecutive cohorts, describe re-excision and positive margin rates, and explore reasons for positive margins and the implications for localisation techniques. METHODS: A single-institution prospective service evaluation of two cohorts of consecutive cases of wire and then Magseed localisation was carried out. Data were collected on patient and clinician satisfaction, clinico-pathological findings, and causes of involved margins. T tests were used to compare continuous variables and Chi-squared test for satisfaction outcomes. RESULTS: 168 consecutive cases used wire-guided localisation (WGL) and 128 subsequent cases used Magseeds. Patients reported less anxiety between localisation and surgery in the Magseed group, and clinicians reported greater ease of use of Magseeds. There were no differences in lesion size, surgical complexity, or re-excision rate between the groups. In a subset of patients receiving standard wide local excision (i.e., excluding mammoplasties), the impact on margin involvement was investigated. There was no significant difference in radiological under-sizing or accuracy of localisation. However, specimen weight and eccentricity of the lesion were statistically significantly lower in the Magseed group. Despite this, re-excision rates were not significantly different (p = 0.4). CONCLUSIONS: This is the first large study of satisfaction with localisation and showed clinician preference for Magseed and a reduction in patient anxiety. It also demonstrated similar positive margin rates despite smaller specimen weights in the Magseed group. Magnetic seed localisation offers an acceptable clinical alternative to guide wire localisation. The impact on local service provision should also be considered.

Adjusting for BMI in analyses of volumetric mammographic density and breast cancer risk.

BACKGROUND: Fully automated assessment of mammographic density (MD), a biomarker of breast cancer risk, is being increasingly performed in screening settings. However, data on body mass index (BMI), a confounder of the MD-risk association, are not routinely collected at screening. We investigated whether the amount of fat in the breast, as captured by the amount of mammographic non-dense tissue seen on the mammographic image, can be used as a proxy for BMI when data on the latter are unavailable. METHODS: Data from a UK case control study (numbers of cases/controls: 414/685) and a Norwegian cohort study (numbers of cases/non-cases: 657/61059), both with volumetric MD measurements (dense volume (DV), non-dense volume (NDV) and percent density (%MD)) from screening-age women, were analysed. BMI (self-reported) and NDV were taken as measures of adiposity. Correlations between BMI and NDV, %MD and DV were examined after log-transformation and adjustment for age, menopausal status and parity. Logistic regression models were fitted to the UK study, and Cox regression models to the Norwegian study, to assess associations between MD and breast cancer risk, expressed as odds/hazard ratios per adjusted standard deviation (OPERA). Adjustments were first made for standard risk factors except BMI (minimally adjusted models) and then also for BMI or NDV. OPERA pooled relative risks (RRs) were estimated by fixed-effect models, and between-study heterogeneity was assessed by the I2 statistics. RESULTS: BMI was positively correlated with NDV (adjusted r = 0.74 in the UK study and r = 0.72 in the Norwegian study) and with DV (r = 0.33 and r = 0.25, respectively). Both %MD and DV were positively associated with breast cancer risk in minimally adjusted models (pooled OPERA RR (95% confidence interval): 1.34 (1.25, 1.43) and 1.46 (1.36, 1.56), respectively; I2 = 0%, P >0.48 for both). Further adjustment for BMI or NDV strengthened the %MD-risk association (1.51 (1.41, 1.61); I2 = 0%, P = 0.33 and 1.51 (1.41, 1.61); I2 = 0%, P = 0.32, respectively). Adjusting for BMI or NDV marginally affected the magnitude of the DV-risk association (1.44 (1.34, 1.54); I2 = 0%, P = 0.87 and 1.49 (1.40, 1.60); I2 = 0%, P = 0.36, respectively). CONCLUSIONS: When volumetric MD-breast cancer risk associations are investigated, NDV can be used as a measure of adiposity when BMI data are unavailable.

Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events.

This study demonstrates highly dynamic spatial and temporal pattern of SULF1/SULF2 expression in a number of neuronal cell types growing in normal culture medium that included their transient nuclear mobilisation. Their nuclear translocation became particularly apparent during cell proliferation as both SULF1/SULF2 demonstrated not only cell membrane associated expression, their known site of function but also transient nuclear mobilisation during nuclear cell division. Nuclear localisation was apparent not only by immunocytochemical staining but also confirmed by immunoblotting staining of isolated nuclear fractions of C6, U87 and N2A cells. Immunocytochemical analysis demonstrated rapid nuclear exit of both SULF1/SULF2 following cell division that was slightly delayed but not blocked in a fraction of the polyploid cells observed in C6 cells. The overexpression of both Sulf1 and Sulf2 genes in C6 and U87 cells markedly promoted in vitro growth of these cells accompanied by nuclear mobilisation while inhibition of both these genes inhibited cell proliferation with little or no nuclear SULF1/SULF2 mobilisation. SULF1/SULF2 activity in these cells thus demonstrated a clear co-ordination of extracellular cell signalling with nuclear events related to cell proliferation.

Resource Usage Implementing the Surgical Resident Prep Curriculum at a Single Institution.

OBJECTIVE: The Resident Prep Curriculum (RPC), published in 2014 and developed as a collaboration of the American College of Surgeons, Association of Program Directors in Surgery, and the Association for Surgical Education, was designed to improve the quality and consistency of medical student preparation for surgical residency. We aim to assess the feasibility of and resource usage for implementation of this curriculum at our institution. DESIGN: Our institution expanded upon a pre-existing 2-week surgical preparatory course, adding modules designed to meet the goals and objectives of the RPC. We performed an evaluation of the resources required for these additions, namely time, logistics and incremental cost. SETTING: The course took place at the Perelman School of Medicine, which is a large, academic medical center affiliated with the Hospital of the University of Pennsylvania. RESULTS: Our course satisfied each of the six domains outlined in the RPC. In 2015, 22 students were enrolled in the course. It was run over a consecutive 4-week period in the spring of 2015, with 9 full and 9 half days. To meet the needs of the Curriculum, approximately 33 hours (38%) were spent in the classroom, 34 hours (39%) in a simulation center, and 20 hours (23%) in the anatomical laboratory. Seventy faculty-hours (from 5 disciplines) and 73 resident-hours (double-counting for cotaught modules) were required to support the course. Besides room availability, funding was required for certain aspects of the course such as cadavers, dedicated anatomy teaching, and the costs of supplies in the simulation center. There is also a cost associated with the use of the Penn Medicine Simulation Center. Taking these into account, the total cost of implementing the curriculum amounted to $30,627.10. CONCLUSION: The implementation of the RPC was feasible but relied heavily upon faculty/resident time. As a result of the success of this initiative, our medical school seeks to expand the idea across multiple specialties.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide.

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines. CONCLUSIONS: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non-constant and reader-specific difference.

Using community outreach to explore health-related beliefs and improve surgeon-patient engagement.

BACKGROUND: Fostering surgeon engagement in community outreach was recently identified as a major priority toward reducing health care disparities in surgery. We aimed to increase surgeon engagement in the local community, understand prevalent beliefs, and identify educational opportunities in the local community regarding cancer screening and treatment using community outreach. MATERIALS AND METHODS: In collaboration with the university's cancer center, the medical student surgical interest group, surgical faculty, and residents developed a community outreach program. The program consisted of networking time, a formal presentation, panel discussion, and question and answer time. A survey was distributed to all participants before the educational session, and a program assessment was distributed at the program's conclusion. RESULTS: A total of 256 community members and 22 surgical volunteers attended at least one of the two events. Attendees were insured (175; 92.7%), female (151; 80%), and African-American (176; 93.1%), with a mean age of 61 y (standard deviation 14.0). About 56 participants (29.6%) were unwilling to undergo screening colonoscopy. Forty-eight respondents (25.4%) endorsed mistrust in doctors and 25% believed surgery causes cancer to spread; a significantly higher proportion of them aged <60 y old. About 113 (59.8%) and 87 (46.1%) misunderstood the definitions of malignant and metastatic, respectively. Males were more unsure than females (61% versus 55%, P = 0.5 and 70% versus 55%; P = 0.01). CONCLUSIONS: Risk perceptions related to fatalism, mistrust, or lack of knowledge were prevalent. The ability of surgeons to reach at-risk populations in the prehospital setting is an important opportunity waiting to be capitalized upon.

Impact of type of full-field digital image on mammographic density assessment and breast cancer risk estimation: a case-control study.

BACKGROUND: Full-field digital mammography, which is gradually being introduced in most clinical and screening settings, produces two types of images: raw and processed. However, the extent to which mammographic density measurements, and their ability to predict breast cancer risk, vary according to type of image is not fully known. METHODS: We compared the performance of the semi-automated Cumulus method on digital raw, "analogue-like" raw and processed images, and the performance of a recently developed method - Laboratory for Breast Radiodensity Assessment (LIBRA) - on digital raw and processed images, in a case-control study (414 patients (cases) and 684 controls) by evaluating the extent to which their measurements were associated with breast cancer risk factors, and by comparing their ability to predict breast cancer risk. RESULTS: Valid Cumulus and LIBRA measurements were obtained from all available images, but the resulting distributions differed according to the method and type of image used. Both Cumulus and LIBRA percent density were inversely associated with age, body mass index (BMI), parity and postmenopausal status, regardless of type of image used. Cumulus percent density was strongly associated with breast cancer risk, but with the magnitude of the association slightly stronger for processed (risk increase per one SD increase in percent density (95 % CI): 1.55 (1.29, 1.85)) and "analogue-like" raw (1.52 (1.28, 1.80)) than for raw (1.35 (1.14, 1.60)) images. LIBRA percent density produced weaker associations with risk, albeit stronger for processed (1.32 (1.08, 1.61)) than raw images (1.17 (0.99, 1.37)). The percent density values yielded by the various density assessment/type of image combinations had similar ability to discriminate between patients and controls (area under the receiving operating curve values for percent density, age, BMI, parity and menopausal status combined ranged from 0.61 and 0.64). CONCLUSIONS: The findings showed that Cumulus can be used to measure density on all types of digital images. They also indicate that LIBRA may provide a valid fully automated alternative to the more labour-intensive Cumulus. However, the same digital image type and assessment method should be used when examining mammographic density across populations, or longitudinal changes in density within a single population.

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

E11/Podoplanin Protein Stabilization Through Inhibition of the Proteasome Promotes Osteocyte Differentiation in Murine in Vitro Models.

The transmembrane glycoprotein E11 is considered critical in early osteoblast-osteocyte transitions (osteocytogenesis), however its function and regulatory mechanisms are still unknown. Using the late osteoblast MLO-A5 cell line we reveal increased E11 protein/mRNA expression (P < 0.001) concomitant with extensive osteocyte dendrite formation and matrix mineralization (P < 0.001). Transfection with E11 significantly increased mRNA levels (P < 0.001), but immunoblotting failed to detect any correlative increases in E11 protein levels, suggestive of post-translational degradation. We found that exogenous treatment of MLO-A5 and osteocytic IDG-SW3 cells with 10 µM ALLN (calpain and proteasome inhibitor) stabilized E11 protein levels and induced a profound increase in osteocytic dendrite formation (P < 0.001). Treatment with other calpain inhibitors failed to promote similar osteocytogenic changes, suggesting that these effects of ALLN rely upon its proteasome inhibitor actions. Accordingly we found that proteasome-selective inhibitors (MG132/lactacystin/ Bortezomib/Withaferin-A) produced similar dose-dependent increases in E11 protein levels in MLO-A5 and primary osteoblast cells. This proteasomal targeting was confirmed by immunoprecipitation of ubiquitinylated proteins, which included E11, and by increased levels of ubiquitinylated E11 protein upon addition of the proteasome inhibitors MG132/Bortezomib. Activation of RhoA, the small GTPase, was found to be increased concomitant with the peak in E11 levels and its downstream signaling was also observed to promote MLO-A5 cell dendrite formation. Our data indicate that a mechanism reliant upon blockade of proteasome-mediated E11 destabilization contributes to osteocytogenesis and that this may involve downstream targeting of RhoA. This work adds to our mechanistic understanding of the factors regulating bone homeostasis, which may lead to future therapeutic approaches.

Physician versus non-physician delivery of alcohol screening, brief intervention and referral to treatment in adult primary care: the ADVISe cluster randomized controlled implementation trial.

BACKGROUND: Unhealthy alcohol use is a major contributor to the global burden of disease and injury. The US Preventive Services Task Force has recommended alcohol screening and intervention in general medical settings since 2004. Yet less than one in six US adults report health care professionals discussing alcohol with them. Little is known about methods for increasing implementation; different staffing models may be related to implementation effectiveness. This implementation trial compared delivery of alcohol screening, brief intervention and referral to specialty treatment (SBIRT) by physicians versus non-physician providers receiving training, technical assistance, and feedback reports. METHODS: The study was a cluster randomized implementation trial (ADVISe [Alcohol Drinking as a Vital Sign]). Within a private, integrated health care system, 54 adult primary care clinics were stratified by medical center and randomly assigned in blocked groups of three to SBIRT by physicians (PCP arm) versus non-physician providers and medical assistants (NPP and MA arm), versus usual care (Control arm). NIH-recommended screening questions were added to the electronic health record (EHR) to facilitate SBIRT. We examined screening and brief intervention and referral rates by arm. We also examined patient-, physician-, and system-level factors affecting screening rates and, among those who screened positive, rates of brief intervention and referral to treatment. RESULTS: Screening rates were highest in the NPP and MA arm (51 %); followed by the PCP arm (9 %) and the Control arm (3.5 %). Screening increased over the 12 months after training in the NPP and MA arm but remained stable in the PCP arm. The PCP arm had higher brief intervention and referral rates (44 %) among patients screening positive than either the NPP and MA arm (3.4 %) or the Control arm (2.7 %). Higher ratio of MAs to physicians was related to higher screening rates in the NPP and MA arm and longer appointment times to screening and intervention rates in the PCP arm. CONCLUSION: Findings suggest that time frames longer than 12 months may be required for full SBIRT implementation. Screening by MAs with intervention and referral by physicians as needed can be a feasible model for increasing the implementation of this critical and under-utilized preventive health service within currently predominant primary care models. TRIAL REGISTRATION: Clinical Trials NCT01135654.

Digital mammographic density and breast cancer risk: a case-control study of six alternative density assessment methods.

INTRODUCTION: Mammographic density is a strong breast cancer risk factor and a major determinant of screening sensitivity. However, there is currently no validated estimation method for full-field digital mammography (FFDM). METHODS: The performance of three area-based approaches (BI-RADS, the semi-automated Cumulus, and the fully-automated ImageJ-based approach) and three fully-automated volumetric methods (Volpara, Quantra and single energy x-ray absorptiometry (SXA)) were assessed in 3168 FFDM images from 414 cases and 685 controls. Linear regression models were used to assess associations between breast cancer risk factors and density among controls, and logistic regression models to assess density-breast cancer risk associations, adjusting for age, body mass index (BMI) and reproductive variables. RESULTS: Quantra and the ImageJ-based approach failed to produce readings for 4% and 11% of the participants. All six density assessment methods showed that percent density (PD) was inversely associated with age, BMI, being parous and postmenopausal at mammography. PD was positively associated with breast cancer for all methods, but with the increase in risk per standard deviation increment in PD being highest for Volpara (1.83; 95% CI: 1.51 to 2.21) and Cumulus (1.58; 1.33 to 1.88) and lower for the ImageJ-based method (1.45; 1.21 to 1.74), Quantra (1.40; 1.19 to 1.66) and SXA (1.37; 1.16 to 1.63). Women in the top PD quintile (or BI-RADS 4) had 8.26 (4.28 to 15.96), 3.94 (2.26 to 6.86), 3.38 (2.00 to 5.72), 2.99 (1.76 to 5.09), 2.55 (1.46 to 4.43) and 2.96 (0.50 to 17.5) times the risk of those in the bottom one (or BI-RADS 1), respectively, for Volpara, Quantra, Cumulus, SXA, ImageJ-based method, and BI-RADS (P for trend <0.0001 for all). The ImageJ-based method had a slightly higher ability to discriminate between cases and controls (area under the curve (AUC) for PD = 0.68, P = 0.05), and Quantra slightly lower (AUC = 0.63; P = 0.06), than Cumulus (AUC = 0.65). CONCLUSIONS: Fully-automated methods are valid alternatives to the labour-intensive "gold standard" Cumulus for quantifying density in FFDM. The choice of a particular method will depend on the aims and setting but the same approach will be required for longitudinal density assessments.

There's no place like home: boarding surgical ICU patients in other ICUs and the effect of distances from the home unit.

BACKGROUND: Intensive care units (ICUs) function frequently at capacity, requiring incoming critically ill patients to be placed in alternate geographically distinct ICUs. In some medical ICU populations, "boarding" in an overflow ICU has been associated with increased mortality. We hypothesized that surgical ICU patients experience more complications when boarding in an overflow ICU and that the frequency of these complications are greatest in boarders farthest from the home unit (HU). METHODS: A 5-year (June 2005 to June 2010) retrospective review of a prospectively maintained ICU database was performed, and demographics, severity of illness, length of stay, and incidence of ICU complications were extracted. Distances between boarding patients' rooms and the HU were measured. Complications occurring in patients located in the same floor (BUSF) and different floor (BUDF) boarding units were compared and stratified by distance from HU to the patient room. Logistic regression was used to develop control for known confounders. RESULTS: A total of 7,793 patients were admitted to the HU and 833 to a boarding unit (BUSF, n = 712; BUDF, n = 121). Boarders were younger, had a lower length of stay, and Acute Physiology and Chronic Health Evaluation II and were more often trauma/emergency surgery patients. Compared with in-HU patients, the incidence of aspiration pneumonia (2.2% vs. 3.6%, p < 0.01) was greater in BUSF patients and highest in those farthest from the HU (odds ratio [OR], 2.39; p = 0.01). Delirium occurred less often in HU than in BUDF patients (3.3% vs. 8.3 %, p < 0.01), and both delirium (OR, 6.09, p < 0.01) and ventilator-associated pneumonia (OR, 4.49, p < 0.05) were more frequent in patients farther from the HU. CONCLUSION: Certain ICU complications occur more frequently in boarding patients particularly if they are located on a different floor or far from the HU. When surgical ICU bed availability forces overflow admissions to non-home ICUs, greater interdisciplinary awareness, education, and training may be needed to ensure equivalent care and outcomes. LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV.

Neuroprotective effects of progesterone in traumatic brain injury: blunted in vivo neutrophil activation at the blood-brain barrier.

BACKGROUND: Progesterone (PRO) may confer a survival advantage in traumatic brain injury (TBI) by reducing cerebral edema. We hypothesized that PRO reduces edema by blocking polymorphonuclear (PMN) interactions with endothelium (EC) in the blood-brain barrier (BBB). METHODS: CD1 mice received repeated PRO (16 mg/kg intraperitoneally) or vehicle (cyclodextrin) for 36 hours after TBI. Sham animals underwent craniotomy without TBI. The modified Neurological Severity Score graded neurologic recovery. A second craniotomy allowed in vivo observation of pial EC/PMN interactions and vascular macromolecule leakage. Wet/dry ratios assessed cerebral edema. RESULTS: Compared with the vehicle, PRO reduced subjective cerebral swelling (2.9 ± .1 vs 1.2 ± .1, P < .001), PMN rolling (95 ± 1.8 vs 57 ± 2.0 cells/100 µm/min, P < .001), total EC/PMN adhesion (2.0 ± .4 vs .8 ± .1 PMN/100 µm, P < .01), and vascular permeability (51.8% ± 4.9% vs 27.1% ± 4.6%, P < .01). TBI groups had similar a Neurological Severity Score and cerebral wet/dry ratios (P > .05). CONCLUSIONS: PRO reduces live pericontusional EC/PMN and BBB macromolecular leakage after TBI. Direct PRO effects on the microcirculation warrant further investigation.

Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development.

The function of Snail2 in mesenchymal tumors is, to date unknown. Using knockdown and overexpression studies, we show that Snail2 regulates migration and invasion of osteosarcoma cells. Knockdown resulted in significantly decreased motility, remodelling of the actin cytoskeleton, and loss of cellular protrusions. Over-expression increased motility, formation of actin-rich cellular protrusions, and altered expression of some non-canonical Wnt pathway components whilst decreasing expression of the adhesion molecule OB-cadherin. Unexpectedly, knockdown also resulted in significantly smaller tumors in an in vivo CAM assay. Therefore Snail2 may be a potential therapeutic target for clinical intervention of osteosarcoma.

Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development.

The Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs.