Spatiotemporal modulation of growth factors directs the generation of multilineage mouse embryonic stem cell-derived mammary organoids.

Ectodermal appendages, such as the mammary gland (MG), are thought to have evolved from hair-associated apocrine glands to serve the function of milk secretion. Through the directed differentiation of mouse embryonic stem cells (mESCs), here, we report the generation of multilineage ESC-derived mammary organoids (MEMOs). We adapted the skin organoid model, inducing the dermal mesenchyme to transform into mammary-specific mesenchyme via the sequential activation of Bone Morphogenetic Protein 4 (BMP4) and Parathyroid Hormone-related Protein (PTHrP) and inhibition of hedgehog (HH) signaling. Using single-cell RNA sequencing, we identified gene expression profiles that demonstrate the presence of mammary-specific epithelial cells, fibroblasts, and adipocytes. MEMOs undergo ductal morphogenesis in Matrigel and can reconstitute the MG in vivo. Further, we demonstrate that the loss of function in placode regulators LEF1 and TBX3 in mESCs results in impaired skin and MEMO generation. In summary, our MEMO model is a robust tool for studying the development of ectodermal appendages, and it provides a foundation for regenerative medicine and disease modeling.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Lumbar Level Significantly Influences Postoperative Global Sagittal Balance Following Pedicle Subtraction Osteotomy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: The current evidence regarding how level of lumbar pedicle subtraction osteotomy (PSO) influences correction of sagittal alignment is limited. This study sought to investigate the relationship of lumbar level and segmental angular change (SAC) of PSO with the magnitude of global sagittal alignment correction. METHODS: This study retrospectively evaluated 53 consecutive patients with adult spinal deformity who underwent lumbar PSO at a single institution. Radiographs were evaluated to quantify the effect of PSO on lumbar lordosis (LL), thoracic kyphosis (TK), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), T1-spinopelvic inclination (T1SPI), T1-pelvic alignment (TPA), and sagittal vertical axis (SVA). RESULTS: Significant correlations were found between PSO SAC and the postoperative increase in LL (r = 0.316, P = .021) and PT (r = 0.352, P = .010), and a decrease in TPA (r = -0.324, P = .018). PSO level significantly correlated with change in T1SPI (r = -0.305, P = .026) and SVA (r = -0.406, P = .002), with more caudal PSO corresponding to a greater correction in sagittal balance. On multivariate analysis, more caudal PSO level independently predicted a greater reduction in T1SPI (ß = -3.138, P = .009) and SVA (ß = -29.030, P = .001), while larger PSO SAC (ß = -0.375, P = .045) and a greater number of fusion levels (ß = -1.427, P = .036) predicted a greater reduction in TPA. CONCLUSION: This study identified a gain of approximately 3 degrees and 3 cm of correction for each level of PSO more caudal to L1. Additionally, a larger PSO SAC predicted greater improvement in TPA. While further investigation of these relationships is warranted, these findings may help guide preoperative PSO level selection.

Impact of Lower Extremity Arthroplasty on Improvement of Quality-of-Life Outcomes Following Lumbar Fusion.

BACKGROUND: Both hip-spine and knee-spine syndromes can significantly impact a patient's quality of life; however, few studies have investigated their effect on postoperative outcomes following lumbar fusion. OBJECTIVE: Our study aimed to evaluate the impact of a prior lower extremity arthroplasty on the improvement of patient-reported outcome measures (PROMs) following lumbar fusion surgery. METHODS: Patients undergoing primary, single, or multilevel lumbar interbody fusion were retrospectively reviewed. Patients missing preoperative PROMs were excluded. PROMs were collected preoperatively and postoperatively and included the Oswestry Disability Index (ODI), 12-Item Short Form Physical Component Summary, Patient-Reported Outcomes Measurement Information System Physical Function, and visual analog scale (VAS). A minimum clinically important difference (MCID) was calculated. Patients were categorized based on a history of hip/knee arthroplasty and propensity score matched. Intragroup improvement of PROM scores and intergroup differences in mean scores were evaluated using a paired t test and linear regression. MCID achievement differences were evaluated using logistic regression. RESULTS: A total of 335 patients were included, with 25 having a history of hip/knee arthroplasty. Arthroplasty patients were significantly older (P = 0.001) and typically had a higher Charlson Comorbidity Index (P ≤ 0.003, both). Patients differed in spinal pathology of degenerative spondylolisthesis (P = 0.049). Nonarthroplasty patients demonstrated significant improvements in all PROMs by 2 years (P < 0.001, all). The arthroplasty group demonstrated significant improvements in all PROMs by 1 year (P < 0.031, all). Preoperative VAS back was significantly worse for nonarthroplasty patients (P = 0.035). MCID achievement did not significantly differ between groups except at 6 months for ODI (P = 0.035). CONCLUSION: Following lumbar fusion, patients with a past surgical history did not demonstrate differences in outcome measures or MCID from those without. These results suggest that comorbid orthopedic conditions requiring surgery do not negatively impact the ability of patients to improve following lumbar fusion. CLINICAL RELEVANCE: Prior surgical history of lower extremity arthroplasty should not discourage the use of lumbar fusion when properly indicated, as patients reported clinical improvement regardless of history of hip or knee arthroplasty.

Abrogation of Rb Tumor Suppression Initiates GBM in Differentiated Astrocytes by Driving a Progenitor Cell Program.

Glioblastoma (GBM) remains lethal with no effective treatments. Despite the comprehensive identification of commonly perturbed molecular pathways, little is known about the disease's etiology, particularly in early stages. Several studies indicate that GBM is initiated in neural progenitor and/or stem cells. Here, we report that differentiated astrocytes are susceptible to GBM development when initiated by perturbation of the RB pathway, which induces a progenitor phenotype. In vitro and in vivo inactivation of Rb tumor suppression (TS) induces cortical astrocytes to proliferate rapidly, express progenitor markers, repress differentiation markers, and form self-renewing neurospheres that are susceptible to multi-lineage differentiation. This phenotype is sufficient to cause grade II astrocytomas which stochastically progress to GBM. Together with previous findings, these results demonstrate that cell susceptibility to GBM depends on the initiating driver.

The diabetes community exercise programme plus usual care versus usual care in patients with type 2 diabetes: A randomised, two-arm, parallel, open-label trial.

Background: Exercise is important in type 2 diabetes (T2D) management. Focussing on Maori and Pacific people and those from deprived circumstances, the Diabetes Community Exercise Programme (DCEP) was developed to engage people with T2D in exercise. We report the evaluation of whether being offered DCEP (plus usual care) was more effective than usual care in improving glycaemic control at 1-year. Methods: A randomised, two-arm, parallel, open-label trial with blinding of outcome assessor and data analyst. Adults (age ≥35 years) with T2D recruited from two New Zealand (NZ) communities were randomised, using opaque sealed envelopes and stratified by centre with random block lengths, to DCEP or usual care. DCEP comprises twice-weekly, two-hour sessions of exercise and education over 12-weeks, followed by a twice-weekly maintenance exercise class. The primary outcome was between-group differences in mean changes of glycated haemoglobin (HbA1c) from baseline to 1-year follow-up with intention-to treat analysis. This trial is registered with the Australian NZ Clinical Trials Registry (ANZCTR): ACTRN12617001624370p and is closed to new participants. Findings: From 2018 - 2019, of 294 people screened, 165 (mean age 63·8, SD16·2 years, 56% female, 78·5% European, 14% Maori, 6% Pacific, 27% most deprived) were baseline evaluated, randomised, and analysed at study end (DCEP = 83, control = 82). Multimorbidity (≥2) and polypharmacy (>5 medications) were high (82%, 69%). We found no statistically significant between-groups differences in HbA1c (mmol/mol) change at 15 months (mean 3% higher in DCEP, 95% CI 2% lower to 8% higher, p = 0·23). Twelve-week intervention adherence was good (41% attended >80% available sessions). No adverse events were reported. Interpretation: DCEP was not effective in improving glycaemic control, possibly due to insufficient exercise intensity. Our attendance demonstrated DCEP's cultural accessibility. DCEP might be good to engage in exercise marginalised people with high Hb1Ac levels, multimorbidity, and high polypharmacy. Funding: Health Research Council of New Zealand.

Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers.

Antibody-based therapies designed for human use frequently fail to cross-react with the murine isoform of their target. Because of this problem, preclinical studies of antibody-based mesothelin (Msl)-targeted therapeutics in immunocompetent systems have been limited by the lack of suitable mouse models. Here, we describe two immunocompetent humanized mesothelin transgenic mouse lines that can act as tolerant hosts for C57Bl/6-syngeneic cell lines expressing the human isoform of mesothelin. Thyroid peroxidase (TPO) mice have thyroid-restricted human mesothelin expression. Mesothelin (Msl) mice express human mesothelin in the typical serosal membrane distribution and can additionally be utilized to assess on-target, off-tumor toxicity of human mesothelin-targeted therapeutics. Both transgenic strains shed human mesothelin into the serum like human mesothelioma and patients with ovarian cancer, and serum human mesothelin can be used as a blood-based surrogate of tumor burden. Using these models, we examined the on-target toxicity and antitumor activity of human mesothelin-targeted recombinant immunotoxins. We found that immunotoxin treatment causes acute and chronic histologic changes to serosal membranes in Msl mice, while human mesothelin-expressing thyroid follicular cells in TPO mice are resistant to immunotoxin despite excellent drug delivery. Furthermore, poor delivery of immunotoxin to syngeneic orthotopic human mesothelin-expressing pancreatic adenocarcinoma limits antitumor activity both alone and in combination with immune checkpoint inhibition. In summary, we have developed two high-fidelity, immunocompetent murine models for human cancer that allow for rigorous preclinical evaluation of human mesothelin-targeted therapeutics.

Identifying the axillary nerve during shoulder surgery: an anatomic study using advanced imaging.

BACKGROUND: The axillary nerve (AXN) is one of the more commonly injured nerves during shoulder surgery. Prior anatomic studies of the AXN in adults were performed using cadaveric specimens with small sample sizes. Our research observes a larger cohort of magnetic resonance imaging (MRI) studies in order to gain a more representative sample of the course of the AXN and aid surgeons intraoperatively. METHODS: High-resolution 3T MRI studies performed at our institution from January 2010 to June 2019 were reviewed. Four blinded reviewers with musculoskeletal radiology or orthopedic surgery training measured the distance of the AXN to the surgical neck of the humerus (SNH), the lateral tip of the acromion (LTA), and the inferior glenoid rim (IGR). Intraclass correlation coefficient was calculated to assess reliability between reviewers. The nerve location was assessed relative to rotator cuff tear status. RESULTS: A total of 257 shoulder MRIs were included. Intraclass correlation coefficient was excellent at 0.80 for the SNH, 0.90 for the LTA, and 0.94 for the IGR. All intraobserver reliabilities were above 0.80. The mean distance from the AXN to SNH was 1.7 cm (range, 0.7-3.1 cm; interquartile range, 1.38-2.00) and that from the AXN to IGR was 1.6 cm (range, 0.6-2.6 cm; interquartile range, 1.33-1.88). The mean AXN to LTA distance was 7.1 cm, with a range of 5.2-9.0 cm across patient heights; there was a large effect size related to the LTA to AXN distance and patient height with a correlation of r = 0.603 (P < .001). Rotator cuff pathology appears to affect nerve location by increasing the distance between the AXN and SNH (P = .027). DISCUSSION/CONCLUSION: The AXN is vulnerable to injury during both open and arthroscopic shoulder procedures. This injury can be either a result of direct trauma to the nerve or secondary to traction placed on the nerve with reconstructive procedures that distalize the humerus. Our study demonstrates that the AXN can be found as little as 5.6 mm from the IGR and 6.9 mm from the SNH. In addition, we illustrate the relationship between patient height and the LTA to AXN distance and complete rotator cuff tears and the SNH to AXN distance. Our study is the first to demonstrate the nerve's proximity to important surgical landmarks of the shoulder using a large sample size of high-resolution images in living human shoulders.

Short communication: Characterizing ovine serum stress biomarkers during endotoxemia.

Breeding stress-resilient livestock is a potential strategy to help mitigate the negative effect of environmental and pathogenic stressors. The hypothalamic-pituitary-adrenal axis and immune system are activated during stress events and release mediators into the circulation that help restore physiological homeostasis. The purpose of this study was to assess a comprehensive set of circulatory mediators released in response to an acute immune stress challenge to identify candidate biomarkers that can be used for the selection of stress-resilient animals. Fifteen female lambs were stress challenged with an intravenous bolus of lipopolysaccharide (LPS; 400 ng/kg), and blood was collected from the jugular vein at 0, 2, 4, and 6 h after LPS challenge to identify and monitor candidate stress biomarkers; temperature was also recorded over time. Biomarker responses were evaluated with a repeated-measures model to compare time points with baseline values. As expected, all sheep had a monophasic febrile response to LPS challenge, and cortisol increased and returned to baseline by 6 h. The cytokines tumor necrosis factor-α, IL-6, IFN-γ (proinflammatory), and IL-10 (anti-inflammatory) increased, but only tumor necrosis factor-α returned to baseline during the monitoring period. The cytokines IL-1α, IL-1ß, IL-17α (proinflammatory), and IL-4 (anti-inflammatory) did not respond to LPS challenge. All chemokines (CCL2, CCL3, CCL4, CXCL10, and IL-8) responded to LPS challenge; however, only CCL2, CCL3, CCL4, and CXCL10 increased over time, and only CCL3, CCL4, and CXCL10 returned to baseline during the monitoring period. MicroRNA (miR-145, miR-233, and miR-1246) also increased and remained elevated during the study. In summary, the LPS challenge induced a strong stress response in Rideau-Dorset sheep that could be monitored with a distinct profile of circulatory biomarkers.

Vismodegib for periocular basal cell carcinoma: an international multicentre case series.

INTRODUCTION: Vismodegib (Erivedge, Genentech) is a first-in-class inhibitor of the hedgehog (Hh) pathway, which is licensed for use in locally advanced basal cell carcinoma (BCC) and metastatic BCC. The National Institute for Health and Care Excellence withdrew recommendation for use of vismodegib secondary to a lack of data comparing vismodegib to standard supportive care. The purpose of this multicentre, international case series is to report outcomes of patients with locally advanced periocular BCC who have been treated with vismodegib. METHODS: The medical records of all patients treated with vismodegib were retrospectively reviewed across seven institutions in the United Kingdom, Australia, and New Zealand. RESULTS: Thirteen patients were identified. Seven (54%) patients were male. All BCCs were ill-defined, with seven (58%) having orbital involvement at presentation. Median treatment time was 7 months (range 2-36 months). Eleven out of 13 patients developed side effects, the most common being fatigue in six patients (46%). Median follow-up was 24 months (range 12-48 months). Complete response was found in 5/13 patients (38%) and a partial response in 8/13 patients (62%). Six patients had further surgery after vismodegib, with three classed as globe-sparing operations. Three patients developed recurrence (23%). Three patients (23%) ultimately underwent exenteration. DISCUSSION: This study demonstrates vismodegib to be a well-tolerated treatment which may, in some cases, facilitate globe-sparing surgery and hence avoid disfiguring operations such as exenteration. Uncertainty does remain regarding the long-term outcomes of patients treated with vismodegib.

Thoracic Idiopathic Scoliosis Severity Is Highly Correlated with 3D Measures of Thoracic Kyphosis.

BACKGROUND: Loss of thoracic kyphosis has been associated with thoracic idiopathic scoliosis. Modern 3-dimensional (3D) imaging systems allow more accurate characterization of the scoliotic deformity than traditional radiographs. In this study, we utilized 3D calculations to characterize the association between increasing scoliosis severity and changes in the sagittal and axial planes. METHODS: Patients evaluated in a scoliosis clinic and determined to have either a normal spine or idiopathic scoliosis were included in the analysis. All underwent upright, biplanar radiography with 3D reconstructions. Two-dimensional (2D) measurements of the magnitude of the thoracic major curve and the thoracic kyphosis were recorded. Image processing and MATLAB analysis were utilized to produce a 3D calculation of thoracic kyphosis and apical vertebral axial rotation. Regression analysis was performed to determine the correlation of 2D kyphosis, 3D kyphosis, and apical axial rotation with the magnitude of the thoracic major curve. RESULTS: The 442 patients for whom 2D and 3D data were collected had a main thoracic curve magnitude ranging from 1° to 118°. Linear regression analysis of the 2D and 3D T5-T12 kyphosis versus main thoracic curve magnitude yielded significant models (p < 0.05). The 2D model had a minimally negative slope (-0.07), a small R value (0.02), and a poor correlation coefficient (-0.14). In contrast, the 3D model had a strongly negative slope (-0.54), a high R value (0.56), and a strong correlation coefficient (-0.75). Curve magnitude also had a strong correlation with loss of 3D T1-T12 kyphosis and increasing apical axial rotation. CONCLUSIONS: Segmentally calculated 3D thoracic kyphosis had a strongly negative correlation with the magnitude of the main thoracic curve. With near uniformity, 3D thoracic kyphosis progressively decreased as scoliosis magnitude increased, at a rate of more than half the increase in the main thoracic curve magnitude. Analysis confirmed a surprisingly strong correlation between scoliosis severity and loss of 3D kyphosis that was absent in the 2D analysis. A similarly strong correlation between curve magnitude and apical axial rotation was evident. These findings lend further credence to the concept that scoliosis progresses in the coronal, sagittal, and axial planes simultaneously. CLINICAL RELEVANCE: The findings of this study suggest that 3D assessment is critical for adequate characterization of the multiplanar deformity of idiopathic scoliosis and deformity in the sagittal plane is linked to deformity in the coronal plane. Increasing severity of coronal plane curvature is associated with a progressive loss of thoracic kyphosis that should be anticipated so that the appropriate intraoperative techniques for correction of idiopathic scoliosis can be applied in all 3 planes.

A Novel Method for Estimating Three-Dimensional Apical Vertebral Rotation Using Two-Dimensional Coronal Cobb Angle and Thoracic Kyphosis.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVES: To use a large cohort of three-dimensional (3D) spinal reconstructions to create a simple mathematical formula capable of estimating 3D apical vertebral rotation (AVR) based on the correlation with routinely obtained two-dimensional (2D) measurements of scoliosis. SUMMARY OF BACKGROUND DATA: Quantification of vertebral rotation in AIS using 2-dimensional (2D) imaging is inherently challenging as the axial plane cannot be directly visualized. METHODS: A database of 279 3D spinal reconstructions was queried for patients with thoracic major adolescent idiopathic scoliosis (AIS). 2D thoracic Cobb angle, T5-T12 thoracic kyphosis, pelvic incidence, sacral slope, and pelvic tilt were recorded. 3D AVR was calculated for each patient from 3D reconstructions. Patients were divided into development (n = 186) and validation (n = 93) cohorts. Within the development cohort, univariate analysis was performed between 2D measurements and 3D AVR with significance set at p < .05 for inclusion in multivariate analysis. In multivariate analysis, significance was set at p < .01 for inclusion in the final model. Model performance was tested in development and validation cohorts. RESULTS: Only 2D thoracic Cobb and T5-T12 thoracic kyphosis had significance in univariate (p < .05) and multivariate analyses (p < .01), meriting inclusion in the final model. 3D AVR (°) = 0.26*(T5-T12 kyphosis) + 0.34*(coronal Cobb) - 5.38. In the development cohort, the model performed well (R = 0.739, r2 = 0.54). In testing with the validation cohort, the model proved generalizability (R = 0.703) and had a mean absolute error <5°. CONCLUSIONS: This model is capable of estimating 3D AVR given 2D thoracic Cobb and T5-T12 kyphosis. The accuracy of this method is comparable to previously reported methods of 2D axial rotation measurement. However, this model provides 3D axial rotation and requires no physical instruments, non-standard measurements, or software programs. Such a model is valuable for both routine evaluation of AIS and operative preparation. LEVEL OF EVIDENCE: Level II, diagnostic.

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice.

Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

Diffuse optical spectroscopic imaging of subcutaneous adipose tissue metabolic changes during weight loss.

BACKGROUND: Changes in subcutaneous adipose tissue (AT) structure and metabolism have been shown to correlate with the development of obesity and related metabolic disorders. Measurements of AT physiology could provide new insight into metabolic disease progression and response to therapy. An emerging functional imaging technology, diffuse optical spectroscopic imaging (DOSI), was used to obtain quantitative measures of near infrared (NIR) AT optical and physiological properties. METHODS: Ten overweight or obese adults were assessed during 3 months on calorie-restricted diets. DOSI-derived tissue concentrations of hemoglobin, water and lipid and the wavelength-dependent scattering amplitude (A) and slope (b) obtained from 30 abdominal locations and three time points (T0, T6, T12) were calculated and analyzed using linear mixed-effects models and were also used to form 3D surface images. RESULTS: Subjects lost a mean of 11.7±3.4% of starting weight, while significant changes in A (+0.23±0.04 mm(-1), adj. P<0.001),b (-0.17±0.04, adj. P<0.001), tissue water fraction (+7.2±1.1%, adj. P<0.001) and deoxyhemoglobin (1.1±0.3 µM, adj. P<0.001) were observed using mixed-effect model analysis. DISCUSSION: Optical scattering signals reveal alterations in tissue structure that possibly correlate with reductions in adipose cell volume, while water and hemoglobin dynamics suggest improved AT perfusion and oxygen extraction. These results suggest that DOSI measurements of NIR optical and physiological properties could be used to enhance understanding of the role of AT in metabolic disorders and provide new strategies for diagnostic monitoring of obesity and weight loss.

Radiation exposure to comforters and carers during paediatric molecular radiotherapy.

BACKGROUND: To show whether the incidental radiation exposure received by comforters and carers of children undergoing molecular radiotherapy was kept as low as reasonably achievable and was within English national dose constraints. PROCEDURE: The radiation exposure of adult comforters and carers was routinely monitored with a whole body personal dose meter while the child was in hospital. Data were collected on iodine-131 meta-iodobenzylguanidine (131 I-mIBG), lutetium-177 DOTATATE (177 Lu-DOTATATE), and iodine-131 sodium iodide (131 I-NaI) treatments. RESULTS: Data were available for 50 treatments with high-administered activity double-infusion 131 I-mIBG and 12 single administrations; 15 177 Lu-DOTATATE treatments and 28 131 I-NaI administrations. The median age was 7 years (1-18). The median administered activity of: 131 I-mIBG was 16.2 GBq (6.8-59 GBq) for double infusion patients and 8.1 GBq (5.26-16.25 GBq) for single administrations; 177 Lu-DOTATATE was 7.2 GBq (2.5-7.5 GBq); and 131 I-NaI was 3 GBq for thyroid remnant ablation and 5.5 GBq for cancer therapy. The median number of comforters and carers for all administrations was 2 (range 1-9). The median exposure values for comforters and carers for high-administered activity 131 I-mIBG administrations was 302 µSv (0-5282 µSv); for single fraction 131 I-mIBG 163 µSv (3-3104 µSv); 177 Lu-DOTATATE 6 µSv (1-79 µSv); and 131 I-NaI 37 µSv (0-274 µSv). Only one of the comforters and carers exceeded the dose constraint of 5 mSv. CONCLUSIONS: Doses to comforters and carers were in all but one case within the dose constraint nationally recommended by the Health Protection Agency, now part of Public Health England. New evidence is presented which show that comforter and carer radiation exposure levels from paediatric molecular radiotherapy in routine clinical practice are acceptably low. Pediatr Blood Cancer 2015;62:235-239. © 2014 Wiley Periodicals, Inc.

Characterization and anti-settlement aspects of surface micro-structures from Cancer pagurus.

Tuning surface and material properties to inhibit or prevent settlement and attachment of microorganisms is of interest for applications such as antifouling technologies. Here, optimization of nano- and microscale structures on immersed surfaces can be utilized to improve cell removal while reducing adhesion strength and the likelihood of initial cellular attachment. Engineered surfaces capable of controlling cellular behaviour under natural conditions are challenging to design due to the diversity of attaching cell types in environments such as marine waters, where many variations in cell shape, size and adhesion strategy exist. Nevertheless, understanding interactions between a cell and a potential substrate for adhesion, including topographically driven settlement cues, offers a route to designing surfaces capable of controlling cell settlement. Biomimetic design of artificial surfaces, based upon microscale features from natural surfaces, can be utilized as model surfaces to understand cell-surface interactions. The microscale surface features of the carapace from the crustacean Cancer pagurus has been previously found to influence the rate of attachment of particular organisms when compared to smooth controls. However, the nature of microscale topographic features from C. pagurus have not been examined in sufficient detail to allow design of biomimetic surfaces. In this work, the spatial distribution, chemical composition, size and shape descriptors of microscale surface features from C. pagurus are characterized in detail for the first time. Additionally, the influence of topography from C. pagurus on the settlement of marine diatoms is examined under field conditions.

A comparison of fibrin sealant versus standard closure in the reduction of postoperative morbidity after groin dissection: A systematic review and meta-analysis.

BACKGROUND: Groin dissection is commonly performed in patients with lower limb malignant conditions such as malignant melanoma, vulvar, penile, anal and scrotal carcinomas with an associated high complication rate. Numerous surgical strategies have been suggested to reduce morbidity. We aimed to systematically review one of those methods - fibrin sealant (FS) - in comparison to standard closure (SC) in reducing postoperative morbidity from groin dissection. METHODS: A systematic search of the literature, study selection and data extraction using an independent screening process, assessment of risk of bias and statistical data analysis was performed. Only randomised controlled trials (RCTs) comparing fibrin sealant to standard care in patients with malignant disease undergoing groin dissection reporting at least one outcome measure relating to postoperative complications were included in the review. RESULTS: A total of 6 RCTs were included. There were no statistically significant differences in postoperative surgical site infection (SSI) rates between FS and SC. The overall incidence of wound infection in the FS group was 32% (43/133) compared to 34% (45/132) in the SC group. (Pooled risk ratio = 0.0.94 [0.68, 1.32]; 95% CI; P = 0.74). The incidence of seroma for the FS group (30/133) and the SC group (30/132) did not differ (Pooled risk ratio = 1.03 [0.67, 1.58]; 95% CI; P value = 0.90). Complication rates were similar between groups. CONCLUSION: Based on current evidence, fibrin sealant does not significantly reduce morbidity in patients undergoing groin dissection for the management of malignant disease when compared to standard closure techniques.

U-shaped relationship between tissue docosahexaenoic acid and atrial fibrillation following cardiac surgery.

BACKGROUND/OBJECTIVES: Randomised controlled trials (RCTs) evaluating the effect of fish oil supplementation on postoperative atrial fibrillation (POAF) following cardiac surgery have produced mixed results. In this study, we examined relationships between levels of red blood cell (RBC) n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and the incidence of POAF. SUBJECTS/METHODS: We used combined data (n=355) from RCTs conducted in Australia and Iceland. The primary end point was defined as POAF lasting >10 min in the first 6 days following surgery. The odds ratios (ORs) for POAF were compared between quintiles of preoperative RBC n-3 LC-PUFA levels by multivariable logistic regression. RESULTS: Subjects with RBC docosahexaenoic acid (DHA) in the fourth quintile, comprising a RBC DHA range of 7.0-7.9%, had the lowest incidence of POAF. Subjects in the lowest and highest quintiles had significantly higher risk of developing POAF compared with those in the fourth quintile (OR=2.36: 95% CI; 1.07-5.24 and OR=2.45: 95% CI; 1.16-5.17, respectively). There was no association between RBC eicosapentaenoic acid levels and POAF incidence. CONCLUSIONS: The results suggest a 'U-shaped' relationship between RBC DHA levels and POAF incidence. The possibility of increased risk of POAF at high levels of DHA suggests an upper limit for n-3 LC-PUFAs in certain conditions.