Guidance on the use of complex systems models for economic evaluations of public health interventions.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.

Hearing outcome measures for conductive and mixed hearing loss treatment in adults: a scoping review.

OBJECTIVE: Rehabilitation options for conductive and mixed hearing loss are continually expanding, but without standard outcome measures comparison between different treatments is difficult. To meaningfully inform clinicians and patients core outcome sets (COS), determined via a recognised methodology, are needed. Following our previous work that identified hearing, physical, economic and psychosocial as core areas of a future COS, the AURONET group reviewed hearing outcome measures used in existing literature and assigned them into different domains within the hearing core area. DESIGN: Scoping review. STUDY SAMPLE: Literature including hearing outcome measurements for the treatment of conductive and/or mixed hearing loss. RESULTS: The literature search identified 1434 studies, with 278 subsequently selected for inclusion. A total of 837 hearing outcome measures were reported and grouped into nine domains. The largest domain constituted pure-tone threshold measurements accounting for 65% of the total outcome measures extracted, followed by the domains of speech testing (20%) and questionnaires (9%). Studies of hearing implants more commonly included speech tests or hearing questionnaires compared with studies of middle ear surgery. CONCLUSIONS: A wide range of outcome measures are currently used, highlighting the importance of developing a COS to inform individual practice and reporting in trials/research.

Breast conservation versus mastectomy in patients with T3 breast cancers (> 5 cm): an analysis of 37,268 patients from the National Cancer Database.

PURPOSE: Breast conservation therapy (BCT) is standard for T1-T2 tumors, but early trials excluded breast cancers > 5 cm. This study was performed to assess patterns and outcomes of BCT for T3 tumors. METHODS: We reviewed the National Cancer Database (NCDB) for noninflammatory breast cancers > 5 cm, between 2004 and 2011 who underwent BCT or mastectomy (Mtx) with nodal evaluation. Patients with skin or chest wall involvement were excluded. Patients having clinical T3 tumors were analyzed to determine outcomes based upon presentation, with those having pathologic T3 tumors, subsequently assessed, irrespective of presentation. Overall survival (OS) was analyzed using multivariable Cox proportional hazards models, with adjusted survival curves estimated using inverse probability weighting. RESULTS: After exclusions, 37,268 patients remained. Median age and tumor size for BCT versus Mtx were 53 versus 54 years (p < 0.001) and 6.0 versus 6.7 cm (p < 0.001), respectively. Predictors of BCT included age, race, location, facility type, year of diagnosis, tumor size, grade, histology, nodes examined and positive, and administration of chemotherapy and radiotherapy. OS was similar between Mtx and BCT (p = 0.36). This held true when neoadjuvant chemotherapy patients were excluded (p = 0.39). BCT percentages declined over time (p < 0.001), while tumor sizes remained the same (p = 0.77). Median follow-up was 51.4 months. CONCLUSIONS: OS for patients with T3 breast cancers is similar whether patients received Mtx or BCT, confirming that tumor size should not be an absolute BCT exclusion. Declining use of BCT for tumors > 5 cm in younger patients may be accounted for by recent trends toward mastectomy.

Which Two-dimensional Radiographic Measurements of Cam Femoroacetabular Impingement Best Describe the Three-dimensional Shape of the Proximal Femur?

BACKGROUND: Many two-dimensional (2-D) radiographic views are used to help diagnose cam femoroacetabular impingement (FAI), but there is little consensus as to which view or combination of views is most effective at visualizing the magnitude and extent of the cam lesion (ie, severity). Previous studies have used a single image from a sequence of CT or MR images to serve as a reference standard with which to evaluate the ability of 2-D radiographic views and associated measurements to describe the severity of the cam lesion. However, single images from CT or MRI data may fail to capture the apex of the cam lesion. Thus, it may be more appropriate to use measurements of three-dimensional (3-D) surface reconstructions from CT or MRI data to serve as an anatomic reference standard when evaluating radiographic views and associated measurements used in the diagnosis of cam FAI. QUESTIONS/PURPOSES: The purpose of this study was to use digitally reconstructed radiographs and 3-D statistical shape modeling to (1) determine the correlation between 2-D radiographic measurements of cam FAI and 3-D metrics of proximal femoral shape; and 2) identify the combination of radiographic measurements from plain film projections that were most effective at predicting the 3-D shape of the proximal femur. METHODS: This study leveraged previously acquired CT images of the femur from a convenience sample of 37 patients (34 males; mean age, 27 years, range, 16-47 years; mean body mass index [BMI], 24.6 kg/m, range, 19.0-30.2 kg/m) diagnosed with cam FAI imaged between February 2005 and January 2016. Patients were diagnosed with cam FAI based on a culmination of clinical examinations, history of hip pain, and imaging findings. The control group consisted of 59 morphologically normal control participants (36 males; mean age, 29 years, range, 15-55 years; mean BMI, 24.4 kg/m, range, 16.3-38.6 kg/m) imaged between April 2008 and September 2014. Of these controls, 30 were cadaveric femurs and 29 were living participants. All controls were screened for evidence of femoral deformities using radiographs. In addition, living control participants had no history of hip pain or previous surgery to the hip or lower limbs. CT images were acquired for each participant and the surface of the proximal femur was segmented and reconstructed. Surfaces were input to our statistical shape modeling pipeline, which objectively calculated 3-D shape scores that described the overall shape of the entire proximal femur and of the region of the femur where the cam lesion is typically located. Digital reconstructions for eight plain film views (AP, Meyer lateral, 45° Dunn, modified 45° Dunn, frog-leg lateral, Espié frog-leg, 90° Dunn, and cross-table lateral) were generated from CT data. For each view, measurements of the α angle and head-neck offset were obtained by two researchers (intraobserver correlation coefficients of 0.80-0.94 for the α angle and 0.42-0.80 for the head-neck offset measurements). The relationships between radiographic measurements from each view and the 3-D shape scores (for the entire proximal femur and for the region specific to the cam lesion) were assessed with linear correlation. Additionally, partial least squares regression was used to determine which combination of views and measurements was the most effective at predicting 3-D shape scores. RESULTS: Three-dimensional shape scores were most strongly correlated with α angle on the cross-table view when considering the entire proximal femur (r = -0.568; p < 0.001) and on the Meyer lateral view when considering the region of the cam lesion (r = -0.669; p < 0.001). Partial least squares regression demonstrated that measurements from the Meyer lateral and 90° Dunn radiographs produced the optimized regression model for predicting shape scores for the proximal femur (R = 0.405, root mean squared error of prediction [RMSEP] = 1.549) and the region of the cam lesion (R = 0.525, RMSEP = 1.150). Interestingly, views with larger differences in the α angle and head-neck offset between control and cam FAI groups did not have the strongest correlations with 3-D shape. CONCLUSIONS: Considered together, radiographic measurements from the Meyer lateral and 90° Dunn views provided the most effective predictions of 3-D shape of the proximal femur and the region of the cam lesion as determined using shape modeling metrics. CLINICAL RELEVANCE: Our results suggest that clinicians should consider using the Meyer lateral and 90° Dunn views to evaluate patients in whom cam FAI is suspected. However, the α angle and head-neck offset measurements from these and other plain film views could describe no more than half of the overall variation in the shape of the proximal femur and cam lesion. Thus, caution should be exercised when evaluating femoral head anatomy using the α angle and head-neck offset measurements from plain film radiographs. Given these findings, we believe there is merit in pursuing research that aims to develop the framework necessary to integrate statistical shape modeling into clinical evaluation, because this could aid in the diagnosis of cam FAI.

Do Your Routine Radiographs to Diagnose Cam Femoroacetabular Impingement Visualize the Region of the Femoral Head-Neck Junction You Intended?

PURPOSE: To use computer models and image analysis to identify the position on the head-neck junction visualized in 10 radiographic views used to quantify cam morphology. METHODS: We generated 97 surface models of the proximal femur from computed tomography scans of 59 control femurs and 38 femurs with cam morphology-a flattening or convexity at the femoral head-neck junction. Each model was transformed to a position that represents the anteroposterior, Meyer lateral, 45° Dunn, modified false-profile, Espié frog-leg, modified 45° Dunn, frog-leg lateral, cross-table, 90° Dunn, and false-profile views. The position on the head-neck junction visualized from each view was identified on the surfaces. This position was then quantified by a clock face generated on the plane of the head-neck junction, in which the 12-o'clock position indicated the superior head-neck junction and the 3-o'clock position indicated the anterior head-neck junction. The mean visualized clock-face position was calculated for all subjects. Analysis was repeated to account for variability in femoral version. A general linear model with repeated measures was used to compare each radiographic view and anteversion angle. RESULTS: Each radiographic view provided visualization of the mean clock-face position as follows: anteroposterior view, 12:01; Meyer lateral view, 1:08; 45° Dunn view, 1:40; modified false-profile view, 2:01; Espié frog-leg view, 2:14; modified 45° Dunn view, 2:35; frog-leg lateral view, 2:45; cross-table view, 3:00; 90° Dunn view, 3:13; and false-profile view, 3:44. Each view visualized a different position on the clock face (all P < .001). Increasing simulated femoral anteversion by 10° changed the visualized position of the head-neck junction to a more clockwise position (range, 0:07 to 0:29; all P < .001), whereas decreasing anteversion by 10° visualized a more counterclockwise position (range, -0:23 to -0:08; all P < .001). CONCLUSIONS: Ten common radiographic views used to identify cam morphology visualized different clock-face positions of the head-neck junction. Our data will help clinicians to understand the position of the head-neck junction visualized for each radiographic view and make educated decisions in the selection of radiographs acquired in the clinic. CLINICAL RELEVANCE: Our findings will aid clinicians in choosing a set of radiographs to capture cam morphology in the assessment of patients with hip pain.

Assessment of Acetabular Morphology Using the Acetabular Anterior Center-Edge Angle on Modified False-Profile Radiographs.

PURPOSE: To compare radiographic parameters of acetabular morphology between standard and modified false-profile (FP) radiographs. METHODS: Standard and modified FP radiographs were obtained in 225 hips in 200 consecutive patients evaluated for hip pain and suspected femoroacetabular impingement. Radiographs were retrospectively reviewed by 2 readers to determine the anterior center-edge angle (ACEA), as assessed to the sourcil and to the bone edge. Inter-rater reliability of radiographic measurements was assessed using the intraclass correlation coefficient. Measurements were evaluated for normality with the Shapiro-Wilk test, averaged between the 2 readers, and compared between views using the paired Wilcoxon test. RESULTS: The intraclass correlation coefficient values for standard and modified FP views were 0.923 and 0.932, respectively, measuring to the sourcil and 0.867 and 0.896, respectively, measuring to the lateral bone edge. The median difference in ACEA measurements to the sourcil was 1° between the standard and modified FP view (45° vs 44°, P < .001). The median difference in ACEA measurements to the bone edge was 2° (34° vs 32°, P < .001). CONCLUSIONS: Thirty-five degrees of femoral internal rotation for a modified FP hip radiographic view provides similar clinical information regarding acetabular morphology to that of the standard FP view. Given that the modified FP view also provides better visualization of the anterosuperior head-neck junction cam lesion, the modified FP view may be preferred over the standard FP view in evaluation of hip pain in the young patient. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Modified False-Profile Radiograph of the Hip Provides Better Visualization of the Anterosuperior Femoral Head-Neck Junction.

PURPOSE: The purpose of this study was to quantify the amount of internal femur rotation required to visualize the 12 to 3 o'clock positions of the femoral head-neck junction as seen on the false-profile radiograph. METHODS: Computed tomography (CT) images of the femur were retrospectively reviewed from control subjects and cam femoroacetabular impingement (FAI) patients. Using an automatically determined clockface, the positions between 12 and 3 o'clock were determined. The optimal femoral rotation angle to visualize each clockface position on the femoral head-neck junction was calculated based on the CT surface data. RESULTS: Fifty-nine control subjects and 38 cam FAI patients were evaluated for this study. The mean (95% confidence interval) internal femur rotation needed to optimally visualize the clockface positions of the femoral head-neck junction on the modified false-profile radiograph were 0.9° (0.8°-1.0°) for 3:00, 10.3° (10.0°-10.6°) for 2:30, 21.6° (21.0°-22.1°) for 2:00, 34.3° (33.6°-35.1°) for 1:30, 49.6° (48.6°-50.4°) for 1:00, 68.4° (67.7°-69.0°) for 12:30, and 90.1° (89.9°-90.4°) for 12:00. CONCLUSIONS: Internal femur rotation of 35° during the false-profile radiograph may better visualize the femoral head-neck junction in the anterosuperior (1 to 2 o'clock) region commonly associated with the cam lesion. From this view, rotation angles between 0° and 90° can be used to visualize other regions of the anterosuperior femoral head-neck junction. CLINICAL RELEVANCE: The internal rotation of the affected femur for a modified false-profile radiograph may provide a new radiographic view that can be used to quantify anterosuperior femoral head-neck morphology.

Three-dimensional femoral head coverage in the standing position represents that measured in vivo during gait.

Individuals with over- or under-covered hips may develop hip osteoarthritis. Femoral head coverage is typically evaluated using radiographs, and/or computed tomography (CT) or magnetic resonance images obtained supine. Yet, these static assessments of coverage may not provide accurate information regarding the dynamic, three-dimensional (3-D) relationship between the femoral head and acetabulum. The objectives of this study were to: (1) quantify total and regional 3-D femoral head coverage in a standing position and during gait, and (2) quantify the relationship between 3-D femoral head coverage in standing to that measured during gait. The kinematic position of the hip during standing and gait was measured in vivo for 11 asymptomatic morphologically normal subjects using dual fluoroscopy and model-based tracking of 3-D CT models. Percent coverage in the standing position and during gait was measured overall and on a regional basis (anterior, superior, posterior, inferior). Coverage in standing was correlated with that measured during gait. For total coverage, very little change in coverage occurred during gait (range: 35.0-36.7%; mean: 36.2%). Coverage at each time point of gait strongly correlated with coverage during standing (r = 0.929-0.989). The regions thought to play an important role in weight bearing (i.e. anterior, superior, posterior) were significantly correlated with coverage in standing during the stance phase. Our results suggest that coverage measured in a standing position is a good surrogate for coverage measured during gait. Clin. Anat. 31:1177-1183, 2018. © 2018 Wiley Periodicals, Inc.

Implementing a Breastfeeding Toolkit for Nursing Education.

All health professional organizations recommend exclusive breastfeeding for at least 6 months, with continued breastfeeding for 1 year or more after birth. Women cite lack of support from health professionals as a barrier to breastfeeding. Meanwhile, breastfeeding education is not considered essential to basic nursing education and students are not adequately prepared to support breastfeeding women. Therefore, a toolkit of comprehensive evidence-based breastfeeding educational materials was developed to provide essential breastfeeding knowledge. A study was performed to determine the effectiveness of the breastfeeding toolkit education in an associate degree nursing program. A pretest/posttest survey design with intervention and comparison groups was used. One hundred fourteen students completed pre- and posttests. Student knowledge was measured using a 12-item survey derived with minor modifications from Marzalik's 2004 instrument measuring breastfeeding knowledge. When pre- and posttests scores were compared within groups, both groups' knowledge scores increased. A change score was calculated with a significantly higher mean score for the intervention group. When regression analysis was used to control for the pretest score, belonging to the intervention group increased student scores but not significantly. The toolkit was developed to provide a curriculum that demonstrates enhanced learning to prepare nursing students for practice. The toolkit could be used in other settings, such as to educate staff nurses working with childbearing families.

Land-use influences phosphatase gene microdiversity in soils.

Phosphorus cycling exerts significant influence upon soil fertility and productivity - processes largely controlled by microbial activity. We adopted phenotypic and metagenomic approaches to investigate phosphatase genes within soils. Microbial communities in bare fallowed soil showed a marked capacity to utilise phytate for growth compared with arable or grassland soil communities. Bare fallowed soil contained lowest concentrations of orthophosphate. Analysis of metagenomes indicated phoA, phoD and phoX, and histidine acid and cysteine phytase genes were most abundant in grassland soil which contained the greatest amount of NaOH-EDTA extractable orthophosphate. Beta-propeller phytase genes were most abundant in bare fallowed soil. Phylogenetic analysis of metagenome sequences indicated the phenotypic shift observed in the capacity to mineralise phytate in bare fallow soil was accompanied by an increase in phoD, phoX and beta-propeller phytase genes coding for exoenzymes. However, there was a remarkable degree of genetic similarity across the soils despite the differences in land-use. Predicted extracellular ecotypes were distributed across a greater range of soil structure than predicted intracellular ecotypes, suggesting that microbial communities subject to the dual stresses of low nutrient availability and reduced access to organic material in bare fallowed soils rely upon the action of exoenzymes.

Impact of rheumatoid arthritis on radiation-related toxicity and cosmesis in breast cancer patients: a contemporary matched-pair analysis.

PURPOSE: To evaluate the impact of rheumatoid arthritis (RA) on toxicity and cosmesis in women undergoing radiotherapy for breast cancer. METHODS: We queried an institutional database for women with RA treated with external beam radiotherapy for breast cancer between 1981 and 2016. Matching each patient to three controls without RA was attempted. Radiation toxicity was graded using CTCAE 4.0. Cosmesis was graded using the Global Harris Scoring System of Excellent, Good, Fair, or Poor. Grade 2+ (G2+) acute and late toxicities were compared between women with RA and their matched pairs using a generalized estimating equation (GEE). Wilcoxon test and mixed effects model were used to compare the cosmesis between two groups. RESULTS: Forty women with RA at time of radiation were matched to 117 controls. The median radiation dose was 60 Gy (50-66 Gy) and the median follow-up was 94 months (1-354 months). When comparing the women with RA to their matched pairs, there was no significant difference in the rates of G2+ acute toxicity (25.0 vs. 13.7%, O 2.1, CI 0.91-4.9) or G2+ late toxicity (7.5 vs. 4.3%, OR 1.8, CI 0.48-6.8). Mean cosmesis was between Good and Excellent for both groups of patients, although women with RA were less likely to get Excellent cosmesis compared to their matched pairs (OR 0.35, CI 0.15-0.84). CONCLUSIONS: Among women with RA, radiation for breast cancer was well tolerated without significantly increased toxicity. Their cosmesis was generally Good to Excellent, although they might be less likely to get Excellent cosmesis compared to their matched pairs.

Does Removal of Subchondral Cortical Bone Provide Sufficient Resection Depth for Treatment of Cam Femoroacetabular Impingement?

BACKGROUND: Residual impingement resulting from insufficient resection of bone during the index femoroplasty is the most-common reason for revision surgery in patients with cam-type femoroacetabular impingement (FAI). Development of surgical resection guidelines therefore could reduce the number of patients with persistent pain and reduced ROM after femoroplasty. QUESTIONS/PURPOSES: We asked whether removal of subchondral cortical bone in the region of the lesion in patients with cam FAI could restore femoral anatomy to that of screened control subjects. To evaluate this, we analyzed shape models between: (1) native cam and screened control femurs to observe the location of the cam lesion and establish baseline shape differences between groups, and (2) cam femurs with simulated resections and screened control femurs to evaluate the sufficiency of subchondral cortical bone thickness to guide resection depth. METHODS: Three-dimensional (3-D) reconstructions of the inner and outer cortical bone boundaries of the proximal femur were generated by segmenting CT images from 45 control subjects (29 males; 15 living subjects, 30 cadavers) with normal radiographic findings and 28 nonconsecutive patients (26 males) with a diagnosis of cam FAI based on radiographic measurements and clinical examinations. Correspondence particles were placed on each femur and statistical shape modeling (SSM) was used to create mean shapes for each cohort. The geometric difference between the mean shape of the patients with cam FAI and that of the screened controls was used to define a consistent region representing the cam lesion. Subchondral cortical bone in this region was removed from the 3-D reconstructions of each cam femur to create a simulated resection. SSM was repeated to determine if the resection produced femoral anatomy that better resembled that of control subjects. Correspondence particle locations were used to generate mean femur shapes and evaluate shape differences using principal component analysis. RESULTS: In the region of the cam lesion, the median distance between the mean native cam and control femurs was 1.8 mm (range, 1.0-2.7 mm). This difference was reduced to 0.2 mm (range, -0.2 to 0.9 mm) after resection, with some areas of overresection anteriorly and underresection superiorly. In the region of resection for each subject, the distance from each correspondence particle to the mean control shape was greater for the cam femurs than the screened control femurs (1.8 mm, [range, 1.1-2.9 mm] and 0.0 mm [range, -0.2-0.1 mm], respectively; p < 0.031). After resection, the distance was not different between the resected cam and control femurs (0.3 mm; range, -0.2-1.0; p > 0.473). CONCLUSIONS: Removal of subchondral cortical bone in the region of resection reduced the deviation between the mean resected cam and control femurs to within a millimeter, which resulted in no difference in shape between patients with cam FAI and control subjects. Collectively, our results support the use of the subchondral cortical-cancellous bone margin as a visual intraoperative guide to limit resection depth in the correction of cam FAI. CLINICAL RELEVANCE: Use of the subchondral cortical-cancellous bone boundary may provide a method to guide the depth of resection during arthroscopic surgery, which can be observed intraoperatively without advanced tooling, or imaging.

Is there sufficient Ensifer and Rhizobium species diversity in UK farmland soils to support red clover (Trifolium pratense), white clover (T. repens), lucerne (Medicago sativa) and black medic (M. lupulina)?

Rhizobia play important roles in agriculture owing to their ability to fix nitrogen through a symbiosis with legumes. The specificity of rhizobia-legume associations means that underused legume species may depend on seed inoculation with their rhizobial partners. For black medic (Medicago lupulina) and lucerne (Medicago sativa) little is known about the natural prevalence of their rhizobial partner Ensifer meliloti in UK soils, so that the need for inoculating them is unclear. We analysed the site-dependence of rhizobial seed inoculation effects on the subsequent ability of rhizobial communities to form symbioses with four legume species (Medicago lupulina, M. sativa, Trifolium repens and T. pratense). At ten organic farms across the UK, a species-diverse legume based mixture (LBM) which included these four species was grown. The LBM seed was inoculated with a mix of commercial inocula specific for clover and lucerne. At each site, soil from the LBM treatment was compared to the soil sampled prior to the sowing of the LBM (the control). From each site and each of the two treatments, a suspension of soils was applied to seedlings of the four legume species and grown in axenic conditions for six weeks. Root nodules were counted and their rhizobia isolated. PCR and sequencing of a fragment of the gyrB gene from rhizobial isolates allowed identification of strains. The number of nodules on each of the four legume species was significantly increased when inoculated with soil from the LBM treatment compared to the control. Both the proportion of plants forming nodules and the number of nodules formed varied significantly by site, with sites significantly affecting the Medicago species but not the Trifolium species. These differences in nodulation were broadly reflected in plant biomass where site and treatment interacted; at some sites there was a significant advantage from inoculation with the commercial inoculum but not at others. In particular, this study has demonstrated the commercial merit of inoculation of lucerne with compatible rhizobia.

Breast conservation versus mastectomy for patients with T3 primary tumors (>5 cm): A review of 5685 medicare patients.

BACKGROUND: Although breast conservation therapy (BCT) is standard for breast cancer treatment, patients with tumors measuring >5 cm have been excluded from clinical trials. Nevertheless, only a few small retrospective series to date have compared BCT with mastectomy for tumors measuring >5 cm. The current study was performed to determine whether survival is equivalent for BCT versus mastectomy using a large national data set. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked cases were identified for patients aged ≥ 66 years undergoing breast conservation for invasive, noninflammatory, nonmetastatic breast cancer between 1992 and 2009. Propensity score-based adjustment was used to account for demographics and tumor and treatment factors. RESULTS: A total of 5685 patients with tumors measuring >5.0 cm underwent breast surgery, with 15.6% receiving BCT. Mean ages of the patients and tumor sizes were similar. Predictors of BCT included neoadjuvant chemotherapy and postoperative radiotherapy use, higher income, breast cancer as a first malignancy, and a higher Charlson Comorbidity Index. Predictors of mastectomy included younger age, nonductal histology, higher grade, numbers of lymph nodes examined and found to be positive, American Joint Committee on Cancer stage III disease, postoperative chemotherapy use, and residential region of the country. Adjusted overall and breast cancer-specific survival were not different between patients treated with BCT and mastectomy (hazard ratio, 0.934; 95% confidence interval, 0.791-1.103 [P = .419] for overall survival; and subdistribution hazard ratio, 1.042; 95% confidence interval, 0.793-1.369 [P = .769] for breast cancer-specific survival), with each improving over time. The median follow-up was 7.0 years. CONCLUSIONS: For Medicare patients with tumors measuring >5 cm, survival is similar between those treated with BCT and mastectomy as for patients with smaller primary tumors. Despite exclusion from randomized trials, BCT may remain an option for patients with larger tumors when deemed clinically and cosmetically amenable to surgical resection.

Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.

BACKGROUND: The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. METHODS: Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. FINDINGS: 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. INTERPRETATION: In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. FUNDING: Takeda Development Center Americas.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes.

BACKGROUND: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. METHODS: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

The role of adjuvant radiation in lymph node positive endometrial adenocarcinoma.

OBJECTIVES: The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer. METHODS: We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS. RESULTS: The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS. CONCLUSIONS: In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings.

Long-Term Impact of Field Applications of Sewage Sludge on Soil Antibiotic Resistome.

Land applications of municipal sewage sludge may pose a risk of introducing antibiotic resistance genes (ARGs) from urban environments into agricultural systems. However, how the sewage sludge recycling and application method influence soil resistome and mobile genetic elements (MGEs) remains unclear. In the present study, high through-put quantitative PCR was conducted on the resistome of soils from a field experiment with past (between 1994 and 1997) and annual (since 1994) applications of five different sewage sludges. Total inputs of organic carbon were similar between the two modes of sludge applications. Intrinsic soil resistome, defined as the ARGs shared by the soils in the control and sludge-amended plots, consisted of genes conferring resistance to multidrug, ß-lactam, Macrolide-Lincosamide-Streptogramin B (MLSB), tetracycline, vancomycin, and aminoglycoside, with multidrug resistance genes as the most abundant members. There was a strong correlation between the abundance of ARGs and MGE marker genes in soils. The composition and diversity of ARGs in the five sludges were substantially different from those in soils. Considerable proportions of ARGs and MGE marker genes in the sludges attenuated following the application, especially aminoglycoside and tetracycline resistance genes. Annual applications posed a more significant impact on the soil resistome, through both continued introduction and stimulation of the soil intrinsic ARGs. In addition, direct introduction of sludge-specific ARGs into soil was observed especially from ARG-rich sludge. These results provide a better insight into the characteristics of ARG dissemination from urban environment to the agricultural system through sewage sludge applications.

The Importance of the Microbial N Cycle in Soil for Crop Plant Nutrition.

Nitrogen is crucial for living cells, and prior to the introduction of mineral N fertilizer, fixation of atmospheric N2 by diverse prokaryotes was the primary source of N in all ecosystems. Microorganisms drive the N cycle starting with N2 fixation to ammonia, through nitrification in which ammonia is oxidized to nitrate and denitrification where nitrate is reduced to N2 to complete the cycle, or partially reduced to generate the greenhouse gas nitrous oxide. Traditionally, agriculture has relied on rotations that exploited N fixed by symbiotic rhizobia in leguminous plants, and recycled wastes and manures that microbial activity mineralized to release ammonia or nitrate. Mineral N fertilizer provided by the Haber-Bosch process has become essential for modern agriculture to increase crop yields and replace N removed from the system at harvest. However, with the increasing global population and problems caused by unintended N wastage and pollution, more sustainable ways of managing the N cycle in soil and utilizing biological N2 fixation have become imperative. This review describes the biological N cycle and details the steps and organisms involved. The effects of various agricultural practices that exploit fixation, retard nitrification, and reduce denitrification are presented, together with strategies that minimize inorganic fertilizer applications and curtail losses. The development and implementation of new technologies together with rediscovering traditional practices are discussed to speculate how the grand challenge of feeding the world sustainably can be met.

Soil pH determines microbial diversity and composition in the park grass experiment.

The Park Grass experiment (PGE) in the UK has been ongoing since 1856. Its purpose is to study the response of biological communities to the long-term treatments and associated changes in soil parameters, particularly soil pH. In this study, soil samples were collected across pH gradient (pH 3.6-7) and a range of fertilizers (nitrogen as ammonium sulfate, nitrogen as sodium nitrate, phosphorous) to evaluate the effects nutrients have on soil parameters and microbial community structure. Illumina 16S ribosomal RNA (rRNA) amplicon sequencing was used to determine the relative abundances and diversity of bacterial and archaeal taxa. Relationships between treatments, measured soil parameters, and microbial communities were evaluated. Clostridium, Bacteroides, Bradyrhizobium, Mycobacterium, Ruminococcus, Paenibacillus, and Rhodoplanes were the most abundant genera found at the PGE. The main soil parameter that determined microbial composition, diversity, and biomass in the PGE soil was pH. The most probable mechanism of the pH impact on microbial community may include mediation of nutrient availability in the soil. Addition of nitrogen to the PGE plots as ammonium sulfate decreases soil pH through increased nitrification, which causes buildup of soil carbon, and hence increases C/N ratio. Plant species richness and plant productivity did not reveal significant relationships with microbial diversity; however, plant species richness was positively correlated with soil microbial biomass. Plants responded to the nitrogen treatments with an increase in productivity and a decrease in the species richness.