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Abstract Background Germ-line mutations in the BRCA1 and BRCA2 genes are major contributors to hereditary breast/ovarian cancer. Large rearrangements are less frequent in the BRCA2 gene than in BRCA1. We report, here, the first total deletion of exon 3 in the BRCA2 gene that was detected during screening of 2058 index cases from breast/ovarian cancer families for BRCA2 large rearrangements. Deletion of exon 3, which is in phase, does not alter the reading frame. Low levels of alternative transcripts lacking exon 3 (Δ3 delta3 transcript) have been reported in normal tissues, which raises the question whether deletion of exon 3 is pathogenic. Methods Large BRCA2 rearrangements were analysed by QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments) or MLPA (Multiplex Ligation-Dependent Probe Amplification). The exon 3 deletion was characterized with a "zoom-in" dedicated CGH array to the BRCA2 gene and sequencing. To determine the effect of exon 3 deletion and assess its pathogenic effect, three methods of transcript quantification were used: fragment analysis of FAM-labelled PCR products, specific allelic expression using an intron 2 polymorphism and competitive quantitative RT-PCR. Results Large rearrangements of BRCA2 were detected in six index cases out of 2058 tested (3% of all deleterious BRCA2 mutations). This study reports the first large rearrangement of the BRCA2 gene that includes all of exon 3 and leads to an in frame deletion of exon 3 at the transcriptional level. Thirty five variants in exon 3 and junction regions of BRCA2 are also reported, that contribute to the interpretation of the pathogenicity of the deletion. The quantitative approaches showed that there are three classes of delta3 BRCA2 transcripts (low, moderate and exclusive). Exclusive expression of the delta3 transcript by the mutant allele and segregation data provide evidence for a causal effect of the exon 3 deletion. Conclusion This paper highlights that large rearrangements and total deletion of exon 3 in the BRCA2 gene could contribute to hereditary breast and/or ovarian cancer. In addition, our findings suggest that, to interpret the pathogenic effect of any variants of exon 3, both accurate transcript quantification and co-segregation analysis are required.

Abstract Background Techniques based on radio frequency (RF) energy have many applications in medicine, in particular tumour ablation. Today, mammography screening detects many breast cancers at an early stage, facilitating treatment by minimally invasive techniques such as radio frequency ablation (RFA). The breast cancer is mostly surrounded by fat, which during RFA-treatment could result in preferential heating of the tumour due to the substantial differences in electrical parameters. The object of this study was to investigate if this preferential heating existed during experimental in vitro protocols and during computer simulations. Methods Excised breast material from four patients with morphologically diagnosed breast cancers were treated with our newly developed RFA equipment. Subsequently, two finite element method (FEM) models were developed; one with only fat and one with fat and an incorporated breast cancer of varying size. The FEM models were solved using temperature dependent electrical conductivity versus constant conductivity, and transient versus steady-state analyses. Results Our experimental study performed on excised breast tissue showed a preferential heating of the tumour, even if associated with long tumour strands. The fat between these tumour strands was surprisingly unaffected. Furthermore, the computer simulations demonstrated that the difference in electrical and thermal parameters between fat and tumour tissue can cause preferential heating of the tumour. The specific absorption rate (SAR) distribution changed significantly when a tumour was present in fatty tissue. The degree of preferential heating depended on tissue properties, tumour shape, and placement relative to the electrode. Temperature dependent electrical conductivity increased the thermal lesion volume, but did not change the preferential heating. Transient solutions decreased the thermal lesion volume but increased the preferential heating of the tumour. Conclusion Both the computer model and the in vitro study confirmed that preferential heating of the tumour during RFA exists in breast tissue. However, the observed preferential heating in the in vitro studies were more pronounced, indicating that additional effects other than the difference in tissue parameters might be involved. The existing septa layers between the cancer tissue and the fatty tissue could have an additional electrical or thermal insulating effect, explaining the discrepancy between the in vitro study and the computer model.

A poorly understood factor that may influence differences in the accumulation of a xenobiotic among fishes is interspecies differences inphysiology. We have extensively studied the uptake, distribution, and excretion kinetics of the lipophilic herbicide trifluralin (TF) in fish, using a static water exposure system and compartmental toxicokinetic models. We obtained quantitative estimates of physiologically based toxicokinetic parameters such as uptake clearance, apparent volume of distribution, and elimination clearance due to xenobiotic metabolism, in rainbow trout, channel catfish, and bluegill sunfish at twoacclimation temperatures. In these and other species (largemouth bass, gizzard shad, fathead minnows, and lake sturgeon), oxygen consumption rate, total lipid content, plasma protein binding, and in vitro biotransformation rates from liver homogenates were determined and examined for their capacities to predict toxicokinetic parameter values.The uptake clearance of TF was predictable based on the oxygen consumption rate, and in vitro TF biotransformation rate was a useful predictor of the in vivo metabolic clearance of TF. Lipid content, however, did not predict the apparent volume of distribution of TF. Values of uptake and metabolism clearance were predicted in largemouth bass,gizzard shad, fathead minnows, and lake sturgeon, using the oxygen consumption and the in vitro TF biotransformation rates. These predicted parameters were then used to successfully simulate the toxicokinetics of TF in these species. [ABSTRACT FROM AUTHOR]

We previously characterized the toxicokinetics of trifluralin (TF) in rainbow trout (Oncorhynchus mykiss) and found a large steady-state volume of distribution (Vss) that was attributed to a large, poorly perfused peripheral storage compartment. Because adipose tissue was expected to be an important peripheral storage tissue for this lipophilic herbicide, we studied its toxicokinetics in trout that differed in body fat content. Large, hatchery-reared rainbow trout and adult summer-run steelhead trout were fitted with an aortic cannulaand given a 1-mg/kg dose of TF. The steelhead were studied approximately 3 weeks prior to spawning and after a 9-month fasting period. The total lipid content of the steelhead after removal of the reproductive organs averaged 1.2% of body weight, whereas that of the hatcherytrout was 8%. Toxicokinetic analysis of the plasma concentration-time profile using a three-compartment model found the Vss insteelhead to be reduced significantly (p< 0.01) compared with the hatchery trout (1.3 vs. 5.7 L/kg). Other parameters that differed were the maximum plasma concentration, which was higher in steelhead (p< 0.05), and the elimination t1/2,beta and mean residence time, which were reduced (p< 0.05) in steelhead. Although several physiological factors are probably involved, examination of the relationship between Vss and lipid content supported the hypothesis that the distribution of TF in trout was largely influenced by the lipid content of the fish. [ABSTRACT FROM AUTHOR]

In classical pharmacology, oral bioavailability of a toxicant is defined as that fraction of an orally administered dose reaching the systemic circulation of the animal. The present study estimates the bioavailability of methylmercury in channel catfish (1clalurus punctatus)by comparing concentrations in the blood through time after oral andintra-arterial (IA) administration. Catfish were carmulated in the dorsal aorta and gavaged a pelleted feed that had been spiked with methylmercury. Each catfish was gavaged an increasing amount of spiked feed. Following oral dosing, serial blood samples were removed for more than 1,500 h. One month after removal of the last blood sample, thesame fish were injected IA with methylmercury and serial blood samples were removed for more than 3,000 h. The area under the curve of the blood concentration-time curve extrapolated to infinity (AUC) was calculated from fish dosed orally and IA using both noncompartmental (trapezoidal) and compartmental methods. Bioavailability was estimatedas the ratio of the dose-corrected oral AUC0_. to the IA AUC. Average bioavailability estimates from this approach were 33% using noncompartmental (range 14-55%) and 29% using compartmental (range 12-42%) methods and were correlated with the amount of food gavaged to the fish (r' = 0.95, p = 0.026). Bioavailability estimates using the presentmethods were much lower than estimates using more conventional methods (i.e., assimilation efficiency estimates using mass balance), suggesting that conventional methods may overestimate the true bioavailability of toxicants in fish. [ABSTRACT FROM AUTHOR]

A mid-infrared laser absorption sensor was developed for gas temperature and carbon oxide (CO, CO) concentrations in high-enthalpy, hydrocarbon combustion flows. This diagnostic enables non-intrusive, in situ measurements in harsh environments produced by hypersonic propulsion ground test facilities. The sensing system utilizes tunable quantum cascade lasers capable of probing the fundamental mid-infrared absorption bands of CO and CO in the 4-5 µm wavelength domain. A scanned-wavelength direct absorption technique was employed with two lasers, one dedicated to each species, free-space fiber-coupled using a bifurcated hollow-core fiber for remote light delivery on a single line of sight. Scanned-wavelength modulation spectroscopy with second-harmonic detection was utilized to extend the dynamic range of the CO measurement. The diagnostic was field-tested on a direct-connect scramjet combustor for ethylene-air combustion. Simultaneous, laser-based measurements of carbon monoxide and carbon dioxide provide a basis for evaluating combustion completion or efficiency with temporal and spatial resolution in practical hydrocarbon-fueled engines. [ABSTRACT FROM AUTHOR]

Background : Sex-based differences in mortality have been previously observed in patients with surgically treated infective endocarditis. We sought to evaluate the risk factors leading to this difference. Methods : A retrospective cohort from three centers in Israel comprising 376 surgically treated patients, comparing short- and long-term mortality rates and risk factors between female and male patients. Results : Compared to male patients, female patients had higher rates of hypertension (62% vs. 48%), higher rates of Gram-negative infections (20% vs. 11%), and more mitral valve replacement (55% vs. 42%). Diabetes and age were the most significant predictors for mortality and did not differ between female and male patients. In-hospital mortality rates did not differ between female and male patients (29% vs. 26%), and the difference in long-term mortality was not statistically significant (46% vs. 36% p = 0.088). Conclusions : No statistical difference was observed in short- and long-term mortality between female and male patients, most likely due to a lack of difference in the rates of important risk factors such as diabetes and age. Mortality rates decreased in the last 10 years, and a good prognosis is observed for patients surviving the initial 30 days after surgery.

Background: Acellular dermal matrices (ADMs) are sometimes used in implant-based breast reconstructions (IBR), but long-term ADM-related evaluations are scarce. In this study, we evaluated early and late complications and patient-related outcomes (PROs) over an 8-year postoperative period in women who had undergone immediate IBR following risk-reducing mastectomy with bovine ADM (SurgiMend)., Methods: This prospective observational single-center analysis involved 34 women at high risk for breast carcinoma. Complications were prospectively recorded during the first year, followed by 4 years of postoperative retrospective chart reviews. Long-term evaluations were done using a questionnaire. Preoperative, 1 year, and 5- to 8-year postoperative PRO assessments were obtained based on results from the BREAST-Q questionnaire., Results: In 56 breasts, complications after a mean of 12.4 months follow-up included implant loss (7.1%), implant change (1.8%), hematoma (7.1%), breast redness (41.1%), and seroma (8.9%). Most breasts (80.3%) were graded Baker I/II, which indicated a low capsular contracture incidence. After a mean of 6.9 years, the total implant explantation rate was 33.9%, and the revision surgery rate was 21.4%. Two cases of breast cancer were reported during the long-term evaluation. BREAST-Q results indicated significantly decreased satisfaction with outcome ( P  = 0.024). A positive trend regarding psychosocial well-being and declining trend regarding satisfaction with both breast physical- and sexual well-being parameters were reported., Conclusions: The observed complication rates agree with previous findings concerning ADM-assisted IBR. A high demand for revision surgery exists, and PROs remain relatively stable over time., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. The acellular dermal matrix used in this study, SurgiMend, was obtained from the manufacturer, TEI Biosciences (Boston, Mass.) as an educational grant. TEI Biosciences had no role in study design, data interpretation, or article preparation., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Radiotherapy is important in breast cancer treatment. A side effect of the treatment is fibrosis that decreases the possibility for a successful breast reconstruction with expanders and with high patient satisfaction with the result. The most common option for mastectomized, irradiated women wishing for a breast reconstruction is autologous tissue transplantation. However, some patients are not suitable for flap surgery. Fifty mastectomized and irradiated women were included in a randomized controlled trial. They underwent breast reconstruction with expanders and were allocated 1:1 to either receive pre-treatment with autologous fat transplantation (AFT) or not. Primary outcomes were frequency of reoperations and complications. Secondary outcomes were number of days in hospital, number of outpatient visits to surgeon or nurse and patient reported outcome as reported with Breast Q. Follow-up time was 2 years. Fifty-two per cent of the intervention group and 68% of the controls underwent reoperations (p = 0.611). Thirty-two per cent of the intervention group and 52% of the controls had complications (p = 0.347). The median number of consultations with the nurse was four in the intervention group and six in the control group (p = 0.002). The AFT patients were significantly more satisfied with their breasts and psychosocial well-being after 2 years. They also had higher increase in satisfaction with breasts, psychosocial well-being, and sexual well-being when comparing baseline with 2 years postoperatively. This randomized controlled trial indicates benefits of AFT prior to breast reconstruction with expanders, especially on patient reported outcome even if the study sample is small.

Background: The European Society of Plastic, Reconstructive and Aesthetic Surgery (ESPRAS) comprises 40 national societies across Europe. In addition to ESPRAS, there are 8 different European Plastic Surgery societies representing Plastic Surgeons in Europe. The 4 th European Leadership Forum (ELF) of ESPRAS, held under the motto "Stronger together in Europe" in Munich in 2023, aimed to collect and disseminate information regarding the national member societies of ESPRAS and European societies for Plastic Surgeons. The purpose was to identify synergies and redundancies and promote improved cooperation and exchange to enhance coordinated decision-making at the European level., Material and Methods: An online survey was conducted regarding the organisational structures, objectives and challenges of national and European societies for Plastic Surgeons in Europe. This survey was distributed to official representatives (Presidents, Vice Presidents and General Secretaries) and delegates of national and European societies at the ELF meeting. Missing information was completed using data obtained from the official websites of the respective European societies. Preliminary results were discussed during the 4 th ELF meeting in Munich in March 2023., Results: The ESPRAS survey included 22 national and 9 European Plastic Surgery societies representing more than 7000 Plastic Surgeons in Europe. Most national societies consist of less than 500 full members (median 182 members (interquartile range (IQR) 54-400); n=22). European societies, which covered the full spectrum or subspecialities, differed in membership types and congress cycles, with some requiring applications by individuals and others including national societies. The main purposes of the societies include research, representation against other disciplines, specialisation and education as well as more individual goals like patient care and policy regulation., Conclusion: This ESPRAS survey offers key insights into the structures, requirements and challenges of national and European societies for Plastic Surgeons, highlighting the relevance of ongoing close exchange between the societies to foster professional advancement and reduce redundancies. Future efforts of the ELF will continue to further explore strategies for enhancing collaboration and harmonisation within the European Plastic Surgery landscape., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Evidence on the learning curve associated with robotic-arm-assisted total knee arthroplasty (ra-TKA) is scarce and mostly based on operative time. Thus, the objective of this study was to assess a surgeon's learning experience based on accuracy to reach planned limb alignment and its impact on surgical-characteristics, limb-alignment, and perioperative-outcomes. A retrospective chart review was conducted on a consecutive series of 204 primary ra-TKAs (patients), performed by a single surgeon in a single institution (3/7/2018-to-6/18/2019). Cumulative summation control sequential analysis was used for the assessment of the learning curve using accuracy of reaching the planned limb alignment establishing that surgeries had an initial-learning-phase, followed by a second-consolidation-phase. Baseline demographics, operative/tourniquet times, prosthesis type, and limb alignment were compared between these two phases. Length of stay, discharge disposition, complications, reoperation/readmission (90 days), and total morphine equivalents (TMEs) prescribed were compared between phases. Independent sample t -tests, and chi-squared analyses were performed. ra-TKA demonstrated a learning curve of 110 cases for reaching planned limb alignment ( p  = 0.012). Robotic experience resulted in significantly more proportion of knees in neutral-axis postoperatively ( p  = 0.035) and significant reduction in TMEs prescribed ( p  = 0.04). The mean operative and tourniquet time were found to be significantly lower in second-phase versus the first-phase ( p for both < 0.0001). ra-TKA has a significant learning curve in clinical practice. A surgeon can reach the planned limb alignment with increased accuracy over time (110-cases). Progressive robotic learning and associated operative time efficiency can lead to significantly lower opioid consumption in patients undergoing TKA., Competing Interests: C.A.H. reports personal fees and other from KCI, other from PSI, other from CD Diagnostics, Cymedica, Ferring Pharmaceuticals, Lyfstone, OREF, Orthofix, Inc., Stryker, Zimmer, other from American Journal of Orthopedics, Journal of Arthroplasty, Journal of Hip Surgery, Journal of Knee Surgery, other from American Association of Hip and Knee Surgeons, Mid-American Orthopaedic Association, Musculoskeletal Infection Society, outside the submitted work. Dr. Barsoum reports Royalties from a company or supplier: Thieme, Stryker, Shukla Medical, Exactech. Inc.; Speakers bureau/paid presentations for a company or supplier: Stryker; Paid consultant for a company or supplier: Stryker, Peerwell; Stock or stock options in a company or supplier: Custom Orthopaedic Solutions, Capsico Health, Peerwell, PT Genie, Sight Medical, Health XL; Research support: Zimmer, Third Frontier, Stryker, Orthosensor, NIH, DJO, Inc.; Other financial or material support from a company or supplier: Thieme; Royalties, financial or material support from publishers: Thieme; Editor in Chief: Journal of Hip Surgery. P.D.P. reports Paid consultant for a company or supplier: Stryker, Zimmer. The rest of the authors declare no conflict of interest., (Thieme. All rights reserved.)

Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5'/3' splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs. We gathered a curated set of 4616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. The Bayesian analysis provided us with the number of control variants, that is, variants without impact on splicing, to mimic the deluge of variants from high-throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, better than SpliceAI and SQUIRLS (0.965 and 0.766) for the same data set. SPiP lends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: https://sourceforge.net/projects/splicing-prediction-pipeline/., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Mohs micrographic surgery is the preferred surgical option for high-risk basal cell carcinomas. In our institution, the method is exclusively used for the treatment of aggressive and recurrent facial tumours selected via multidisciplinary team meetings and consistently managed using a multidisciplinary approach. The aim of this retrospective patient-record study was to examine the outcomes for basal cell carcinomas managed with Mohs micrographic surgery and to present our experience from multidisciplinary team meetings and interdisciplinary collaborations. All patients treated between September 2009 and March 2019 at Karolinska University hospital were included. In a total of 143 facial basal cell carcinomas in 138 patients, 86 primary and 57 recurrent, the recurrence rate was 4.9% after a median follow-up of 24 months. In regions, where highly specialised Mohs surgeons performing all the steps of the procedure are limited, interdisciplinary collaboration can be an effective strategy for appropriate patient selection and for performing all steps of Mohs surgery with dermatosurgeons eradicating the tumour, pathologists evaluating the histopathology, followed by reconstructive surgery by plastic surgeons. The approach we present here provides a robust and functioning Mohs surgical service during the build-up of the organisation, while providing the opportunity to train new surgeons. Once the clinic has been set up, the multidisciplinary approach should always be considered and applied when dealing with complex cases., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of interestNone declared.

Abstract: In 2011, the U.S. National Science Foundation created the Innovation Corps (I-Corps) program in an effort to explore ways to translate the results of the academic research the agency has funded into new products, processes, devices, or services and move them to the marketplace. The agency established a 3-tier structure to support the implementation of the I-Corps concept. Selected I-Corps teams consisting of the principal investigator, an entrepreneurial lead, and an industry mentor participate in a 7-week accelerated version of the Lean Launchpad methodology that was first developed by Steve Blank at Stanford University. Participating teams engage in talking to potential customers, partners, and competitors and address the challenges and the uncertainty of creating successful ventures. I-Corps sites were set up to promote selected aspects of innovation and entrepreneurship ecosystems at the grantee institutions. I-Corps Regional Nodes were charged with recruiting I-Corps teams in a larger geographical area as well as stimulating a new culture of academic entrepreneurship in the institutions in their area of influence. This Topical Review describes the experiences and the impact of the New York City Regional Innovation Node, which is led by the City University of New York, in partnership with New York University and Columbia University., Competing Interests: Conflict of interestAll three authors contributed equally to this manuscript. The three authors declare that they have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2022.)

Purpose: Overall survival in breast cancer patients receiving a delayed deep inferior epigastric perforator (DIEP) flap breast reconstruction is better than in those without delayed breast reconstruction. This study aimed at determining the impact of socioeconomic status (SES) and comorbidity on these observations., Materials and Methods: This matched cohort study included all consecutive women undergoing a delayed DIEP flap reconstruction at Karolinska University Hospital, Sweden, between 1999 and 2013. Controls had not received any delayed breast reconstruction and were relapse-free after a corresponding follow-up interval. Matching was by year of and age at mastectomy, tumour stage and lymph node status. Charlson Comorbidity Index (CCI) and socioeconomic data were obtained from national registers. Associations with breast cancer-specific (BCSS) and overall survival (OS) were investigated by Kaplan-Meier survival estimates and Cox proportional hazard regression analysis., Results: Women in the DIEP group (N = 254) more often continued education after primary school (88.6% versus 82.6%, P = 0.026), belonged to the high-income group (76.0% versus 63.1%, P < 0.001), were in a partnership (57.1% versus 55.7%, P = 0.024) and healthier (median CCI 1.00 (range 0-13) versus 2.00 (range 0-16), P = 0.021) than the control group (N = 729). After adjustment for tumour and treatment factors, SES and comorbidity, OS remained significantly better for the DIEP group than the control group (HR 2.27, 95% CI 1.44-3.55)., Conclusion: Women with a delayed DIEP flap reconstruction are a subgroup of higher socioeconomic status and better health. Higher survival estimates for the DIEP group persisted after adjusting for those differences, suggesting the presence of further unmeasured covariates., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5' region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families., Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing., Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1 , fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin., Conclusions: Taken together, our results firmly establish that the BRCA1 5' region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

For bone preparation, several maceration techniques are available; however, gentle defleshing and soft tissue removal from bones without damaging the bone surface remains a challenge. The study aims to develop a novel, inexpensive, rapid, and resource-saving maceration technique that does not lead to bone surface changes and allows the study of signs of violence on the bone surface. Pig ribs and femurs were covered in aluminum foil and treated in the oven for 5 h at different temperatures with and without detergent. Additionally, femurs were placed in hot non-boiling water containing household bleach and detergents for 1 h. Examinations using macro photography, stereo and fluorescence microscopy, and micro-computed tomography showed no surface changes after treatment at 100 °C, such as flakes or bone cracks, on the ribs. The femurs showed surface changes after incubation in water, such as roughening., Competing Interests: Conflicts of interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Completion lymph node dissection (CLND) for malignant melanoma is performed for regional cancer control and is associated with a high complication rate. It is unknown whether post-operative complications influence cancer recurrence or survival. Our aim was to evaluate the risk factors for short- and long-term complications after CLND, and to determine whether complications affect recurrence or survival., Method: We performed a retrospective cohort study including all melanoma patients who underwent CLND in the Stockholm region during 2005-2014. Patient and cancer characteristics were collected from medical records, as were clinical outcomes. Assessment was performed by multivariate logistic regression., Results: Among 144 patients, the risk of any post-operative one year complication was 68.8%. Lymphedema (41.0%), infection (37.5 %), and seroma (31.3 %) were the most common complications. Diabetes and inguinal CLND were associated with nine- and ten-fold increased risks of post-operative complications (p<0.05), respectively. Complications were linked to an increased risk of recurrent cancer (p<0.05), median follow-up time of 49 months, but did not appear to affect five-year survival., Conclusion: Post-operative complications are common in melanoma patients undergoing CLND. Strong risk factors for complications are diabetes and inguinal CLND. Post-operative complications appear to be associated with increased risks of recurrent cancer, but the mechanism is unknown., Competing Interests: Conflicts of interest None declared, (Copyright © 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Branch points (BPs) map within short motifs upstream of acceptor splice sites (3'ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3'ss., Results: We used a large set of constitutive and alternative human 3'ss collected from Ensembl (n = 264,787 3'ss) and from in-house RNAseq experiments (n = 51,986 3'ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3'ss (99.48 and 65.84% accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17%., Conclusions: Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3'ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area.

Endogenous estrogens play major roles in many aspects of female reproductive development in fish. In order to develop a relatively high-throughput assay to determine the potential impact on reproductive development, vitellogenic rainbow trout ovarian follicles were exposed to a suite of contaminants in vitro and then assessed for the ability to produce estradiol-17β (E2) after a 500 ng/ml salmon gonadotropin (sGTH) challenge. There was a positive correlation between ovarian follicle size and E2 production, but an inverse correlation between size and responsiveness to sGTH. Significant impacts on E2 levels were observed following treatment with different endocrine disrupting chemicals, such as 17α-ethinylestradiol (EE2), prochloraz, or trenbolone. EE2 was remarkably potent and significantly reduced ovarian follicle responsiveness to sGTH at concentrations as low as 0.1 nM. Of the other contaminants tested, only tamoxifen impacted E2 levels, and only at concentrations near the limits of solubility. Flutamide, fluoxetine, 4-hydroxy tamoxifen, hydroxyflutamide, and norfluoxetine had little or no impact. Quantitative PCR analyses of steroidogenesis-related genes were carried out on EE2 treated ovarian follicles, but significant transcriptional responses to EE2 were not observed. Overall, this study suggests that xenoestrogens and anti-estrogens are more likely to interfere with ovarian E2 synthesis than other classes of EDCs. This also provides a template for further testing of the effects of EDCs on ovarian function., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: A sentinel lymph node (SLN) biopsy is a common surgical procedure for cutaneous melanoma. Our aim was to evaluate risk factors for early post-operative complications after SLN biopsy and to examine the impact of complications on health care resource utilisation., Methods: We performed a retrospective cohort study including all adult patients who underwent a SLN biopsy for cutaneous melanoma in the Stockholm region from 2006 to 2014. Data of patient and tumour characteristics were collected from medical records, as well as information on complications and outpatient visits within 30 days from surgery. Risk factors were evaluated through logistic regression., Results: Out of 886 patients who underwent SLN biopsy during the study period, 109 (12.3%) had one or several post-operative complications. The most common complication was a wound infection (7.7%), followed by seroma (6.4%). The risk of a post-operative complication was increased in patients with diabetes (odds ratio (OR) = 10.0, 95% confidence interval (CI) 4.0-24.6), who had inguinal location of SLN (OR = 2.7, 95% CI 1.7-4.3), who were male (OR = 1.9, 95% CI 1.2-2.9) and who had ulceration of the primary tumour (OR = 1.6, 95% CI 1.0-2.6). Individuals with post-operative complications had more visits to the outpatient clinic (p < 0.05)., Conclusion: Complications after SLN biopsy affect 12.3% of patients. Our results suggest that patients with diabetes, who had inguinal SLN biopsy and who were male have increased risk, and this might warrant more intense post-operative surveillance., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Autologous fat transplantation (AFT) is being increasingly used to improve the results after breast-conserving surgery and breast reconstruction. However, studies on patient-reported outcomes (PROs) and health-related quality of life (HRQoL) after AFT are scarce. The aim of this prospective longitudinal case-series study was to assess PRO in women who had undergone AFT after surgery for breast cancer or risk-reducing mastectomy., Methods: Fifty women, who had undergone breast-conserving surgery or breast reconstruction, needing corrective surgery, were consecutively included between 2008 and 2013. A 20-item study-specific questionnaire (SSQ) and the Short Form Health Survey (SF-36) were used pre-operatively and 6 months, 1 year and 2 years post-operatively, to evaluate PRO and HRQoL., Results: The patients underwent three (1-4) AFT procedures, with the injection of 164 ml (median) (range 40-516) fat. Thirty-eight and 34 patients completed the study-specific questionnaire and the SF-36, respectively, both pre-operatively and after 2 years. Sixteen of the 20 items in the SSQ were improved after 2 years, including breast size (p < 0.0001), shape (p < 0.0001), appearance (p < 0.0001), softness of the breast (p = 0.001), pain in the region (p = 0.005), scarring from previous breast surgery (p < 0.001) and willingness to participate in public physical activities (p < 0.001). HRQoL did not largely differ before and after AFT, or between the study group and a reference population., Conclusions: AFT alone or in combination with other corrective surgical procedures, improved PRO after breast-conserving surgery and breast reconstruction in both irradiated and non-irradiated women.

The current study examines changes in awareness and health beliefs from baseline to 12 months post-intervention following receipt of one of two colorectal cancer (CRC) educational interventions that aimed to promote CRC screening among a racially and ethnically diverse and medically underserved population. Participants (N = 270) were enrolled in a randomized controlled trial to increase CRC screening and completed both baseline and 12-month follow-up assessments. Participants were aged 50-75, at average CRC risk, not up-to-date with CRC screening guidelines, and receiving care at one of three community-based clinics. Participants were randomized to receive either a targeted, low-literacy intervention informed by the Preventive Health Model [PHM] (photonovella and DVD plus fecal immunochemical test [FIT]) or a non-targeted intervention (standard educational brochure plus FIT). Changes in CRC awareness and health beliefs from baseline to 12 months were examined both within and between intervention groups using Student's t tests. Participants in both intervention conditions demonstrated an increase in CRC awareness, PHM social influence, and trust in the healthcare system (all p's < .0001), with no significant between-group differences. Among those receiving the targeted intervention, there also was an increase in PHM salience (p < .05). Among individuals receiving the non-targeted intervention, there was an increase in PHM response efficacy (p < .01) and PHM self-efficacy (p < .0001). Both CRC screening interventions promoted positive changes in awareness and several health beliefs from baseline to 12 months, suggesting important benefits of CRC education. Regardless of whether education was targeted or non-targeted, providing CRC screening education successfully promoted durable changes in awareness and health beliefs.

Background: To reduce colorectal cancer (CRC) screening disparities, it is important to understand correlates of different types of cancer worry among ethnically diverse individuals., Objectives: The current study examined the prevalence of three types of cancer worry (i.e., general cancer worry, CRC-specific worry, and worry about CRC test results) as well as sociodemographic and health-related predictors for each type of cancer worry., Methods: Participants were aged 50-75, at average CRC risk, nonadherent to CRC screening guidelines, and enrolled in a randomized controlled trial to increase CRC screening. Participants completed a baseline questionnaire assessing sociodemographics, health beliefs, healthcare experiences, and three cancer worry measures. Associations between study variables were examined with separate univariate and multivariable logistic regression models., Results: Responses from a total of 416 participants were used. Of these, 47% reported experiencing moderate-to-high levels of general cancer worry. Predictors of general cancer worry were salience and coherence (aOR = 1.1, 95% CI [1.0, 1.3]), perceived susceptibility (aOR = 1.2, 95% CI [1.1, 1.3), and social influence (aOR = 1.1, 95% CI [1.0, 0.1]). Fewer (23%) reported moderate-to-high levels of CRC-specific worry or CRC test worry (35%). Predictors of CRC worry were perceived susceptibility (aOR = 1.4, 95% CI [1.3, 1.6]) and social influence (aOR = 1.1, 95% CI [1.0, 1.2]); predictors of CRC test result worry were perceived susceptibility (aOR = 1.2, 95% CI [1.1, 1.3) and marital status (aOR = 2.0, 95% CI [1.1, 3.7] for married/partnered vs. single and aOR = 2.3, 95% CI [1.3, 4.1] for divorced/widowed vs. single)., Discussion: Perceived susceptibility consistently predicted the three types of cancer worry, whereas other predictors varied between cancer worry types and in magnitude of association. The three types of cancer worry were generally predicted by health beliefs, suggesting potential malleability. Future research should include multiple measures of cancer worry and clear definitions of how cancer worry is measured.

The current study examined the sociodemographic and psychosocial variables that predicted being at risk for low health literacy among a population of racially and ethnically diverse patients accessing primary care services at community-based clinics. Participants (N = 416) were aged 50-75 years, currently not up-to-date with colorectal cancer (CRC) screening, at average CRC risk, and enrolled in a randomized controlled trial (RCT) aimed at promoting CRC screening. Participants completed a baseline interview that assessed health literacy as measured by Rapid Estimate of Adult Literacy in Medicine-Revised, sociodemographic factors, and psychosocial variables (e.g., health beliefs) prior to randomization and receipt of an intervention. Thirty-six percent of the participants were found to be at risk for low health literacy. Sociodemographic and psychosocial variables were assessed as predictors of being at risk for low health literacy using logistic regression. In the final model, predictors were male gender, being from a racial/ethnic minority group, being unable to work, having higher social influence scores, and having higher religious belief scores. These findings suggest several patient characteristics that may be associated with low health literacy, and highlight the importance of supporting all patients through simplified and clear communications and information to improve understanding of CRC screening information.

Reversing epithelial-to-mesenchymal transition (EMT) in cancer cells has been widely considered as an approach to combat cancer progression and therapeutic resistance, but a limited number of broadly comprehensive investigations of miRNAs involved in this process have been conducted. In this study, we screened a library of 1120 miRNA for their ability to transcriptionally activate the E-cadherin gene CDH1 in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing miRNA. miR-520f expression was sufficient to restore endogenous levels of E-cadherin in cancer cell lines exhibiting strong or intermediate mesenchymal phenotypes. In parallel, miR-520f inhibited invasive behavior in multiple cancer cell systems and reduced metastasis in an experimental mouse model of lung metastasis. Mechanistically, miR-520f inhibited tumor cell invasion by directly targeting ADAM9 , the TGFβ receptor TGFBR2 and the EMT inducers ZEB1, ZEB2 , and the snail transcriptional repressor SNAI2 , each crucial factors in mediating EMT. Collectively, our results show that miR-520f exerts anti-invasive and antimetastatic effects in vitro and in vivo , warranting further study in clinical settings. Cancer Res; 77(8); 2008-17. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: The objective of the current study was to improve colorectal cancer (CRC) screening uptake with the fecal immunochemical test (FIT). The current study investigated the differential impact of a multicomponent, targeted, low-literacy educational intervention compared with a standard, nontargeted educational intervention., Methods: Patients aged 50 to 75 years who were of average CRC risk and not up-to-date with CRC screening were recruited from either a federally qualified health center or a primary care community health clinic. Patients were randomized to the intervention condition (targeted photonovella booklet/DVD plus FIT kit) or comparison condition (standard Centers for Disease Control and Prevention brochure plus FIT kit). The main outcome was screening with FIT within 180 days of delivery of the intervention., Results: Of the 416 participants, 54% were female; the participants were racially and ethnically diverse (66% white, 10% Hispanic, and 28% African American), predominantly of low income, and insured (the majority had county health insurance). Overall, the FIT completion rate was 81%, with 78.1% of participants in the intervention versus 83.5% of those in the comparison condition completing FIT (P =  .17). In multivariate analysis, having health insurance was found to be the primary factor predicting a lack of FIT screening (adjusted odds ratio, 2.10; 95% confidence interval, 1.04-4.26 [P =  .04])., Conclusions: The multicomponent, targeted, low-literacy materials were not found to be significantly different or more effective in increasing FIT uptake compared with the nontargeted materials. Provision of a FIT test plus education may provide a key impetus to improve the completion of CRC screening. The type of educational material (targeted vs nontargeted) may matter less. The findings of the current study provide a unique opportunity for clinics to adopt FIT and to choose the type of patient education materials based on clinic, provider, and patient preferences. Cancer 2017;123:1390-1400. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background and Purpose: Image guided adaptive brachytherapy (IGABT) using intracavitary applicators (IC) has led to a significant improvement of local control in locally advanced cervical cancer (LACC). Further improvement has been obtained with combined intracavitary/interstitial (IC/IS) applicators. The aim of this analysis was to evaluate the impact on local control and late morbidity of application of combined IS/IC brachytherapy in a large multicentre population., Material/methods: 610 patients with LACC from the retroEMBRACE study were included. Patients were divided into an IC group (N=310) and an IC/IS group (N=300). The IC/IS group was defined from the time point, when a centre performed IC/IS brachytherapy in more than 20% of cases., Results: With systematic usage of IC/IS the D90 of CTV HR increased from 83±14Gy to 92±13Gy (p<0.01). No difference in doses to organs at risk was found. The 3-year local control rate in patients having a CTV HR volume⩾30cm 3 was 10% higher (p=0.02) in the IC/IS group. No difference was found for CTV HR <30cm 3 (p=0.50). No significant difference in late morbidity was found between the IC/IS group and IC group., Conclusion: Combined IC/IS brachytherapy improves the therapeutic ratio in LACC by enabling a tumour specific dose escalation resulting in significantly higher local control in large tumours without adding treatment related late morbidity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Autologous fat transplantation (AFT) to the breast can correct defects and be a part of a breast reconstruction to achieve a better aesthetic result. The impact of AFT on the radiological evaluation and detection of cancer remains unclarified. The aim of this study is to investigate whether AFT induces lasting modifications., Methods: In the present study, a valuation was performed of 44 breasts from 37 patients examined with mammography and ultrasound before and after autologous fat transplantation. Breast radiologists evaluated the images using a study specific protocol., Results: AFT did not hinder post-operative assessment of mammograms or ultrasound. No detectable changes with serious clinical impact were found after injections of mean 177 ml (34-516) of fat in one to four sessions. The rate of oil cysts was significantly higher after AFT than pre-operatively (2.3 vs. 34.1 % p = 0.0013). Significantly more post-operative oil cysts were detected after injection of larger volumes of fat (144 vs. 243 ml, p = 0.013). No significant differences were found in the post-operative images regarding age at surgery, follow-up time, or time from previous breast surgery., Conclusion: AFT does not impair assessment of mammograms and ultrasound in patients who have a history of breast cancer surgery or prophylactic mastectomy.

Hypoxia in solid tumors remains a challenge for conventional cancer therapeutics. As a source for resistance, metastasis development and drug bioprocessing, it influences treatment results and disease outcome. Bioreductive platinum(iv) prodrugs might be advantageous over conventional metal-based therapeutics, as biotransformation in a reductive milieu, such as under hypoxia, is required for drug activation. This study deals with a two-step screening of experimental platinum(iv) prodrugs with different rates of reduction and lipophilicity with the aim of identifying the most appropriate compounds for further investigations. In the first step, the cytotoxicity of all compounds was compared in hypoxic multicellular spheroids and monolayer culture using a set of cancer cell lines with different sensitivities to platinum(ii) compounds. Secondly, two selected compounds were tested in hypoxic xenografts in SCID mouse models in comparison to satraplatin, and, additionally, (LA)-ICP-MS-based accumulation and distribution studies were performed for these compounds in hypoxic spheroids and xenografts. Our findings suggest that, while cellular uptake and cytotoxicity strongly correlate with lipophilicity, cytotoxicity under hypoxia compared to non-hypoxic conditions and antitumor activity of platinum(iv) prodrugs are dependent on their rate of reduction.

Several population-based and family-based studies have demonstrated that germline mutations of the PALB2 gene (Partner and Localizer of BRCA2) are associated with an increased risk of breast cancer. Distinct mutation frequencies and spectrums have been described depending on the population studied. Here we describe the first complete PALB2 coding sequence screening in the French population. We screened the complete coding sequence and intron-exon boundaries of PALB2, using the EMMA technique, to assess the contribution of pathogenic mutations in a set of 835 familial breast cancer cases and 662 unrelated controls from the French national study GENESIS and the Paul Strauss Cancer Centre, all previously tested negative for BRCA1 and BRCA2 pathogenic mutations. Our analysis revealed the presence of four novel deleterious mutations: c.1186insT, c.1857delT and c.2850delC in three cases, c.3418dupT in one control. In addition, we identified two in-frame insertion/deletion, 19 missense substitutions (two of them predicted as pathogenic), 9 synonymous variants, 28 variants located in introns and 2 in UTRs, as well as frequent variants. Truncating PALB2 mutations were found in 0.36% of familial breast cancer cases, a frequency lower than the one detected in comparable studies in other populations (0.73-3.40%). This suggests a small but significant contribution of PALB2 mutations to the breast cancer susceptibility in the French population.

This review starts off outlining the control of Insulin-like growth factor I (IGF-I) kinetics in Nature and by virtue of a complex system of 6 binding proteins controlling half-life and tissue distribution of this strong anabolic peptide. In addition, alternative splicing is known to result in IGF-I variants with modulated properties in vivo and this insight is currently translated into advanced IGF-I variants for therapeutic use. Insights into these natural processes resulted in biomimetic strategies with the ultimate goal to control pharmacokinetics and have recently propelled new developments leading to optimized pharmaceutical performance of this protein in vivo. Aside from parenteral administration routes, IGF-I was successfully delivered across various epithelial barriers from liquid as well as from solid pharmaceutical forms opening novel and more convenient delivery modalities. IGF-I decoration yielded effective targeting upon systemic administration expanding the options for optimally deploying the growth factor for therapy. This review summarizes the exciting biotechnological and pharmaceutical progress seen for IGF-I delivery in recent years and critically discusses outcome in light of translational application for future IGF-I therapeutics., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: There is controversy surrounding the impact of workplace interventions aimed at improving social support and supervisory quality on absenteeism, productivity and financial outcomes., Objective: To determine the value of social support interventions for work outcomes., Methods: Databases were searched for systematic reviews between 2000 and 2012 to complete a synthesis of systematic reviews guided by the PRISMA statement and the IOM guidelines for systematic reviews. Assessment of articles for inclusion and methodological quality was conducted independently by at least two researchers, with differences resolved by consensus., Results: The search resulted in 3363 titles of which 3248 were excluded following title/abstract review, leaving 115 articles that were retrieved and underwent full article review. 10 articles met the set inclusion criteria, with 7 focusing on social support, 2 on supervisory quality and 1 on both. We found moderate and limited evidence, respectively, that social support and supervisory quality interventions positively impact workplace outcomes., Conclusion: There is moderate evidence that social support and limited evidence that supervisory quality interventions have a positive effect on work outcomes.

Background: Hypoxic and necrotic regions that accrue within solid tumors in vivo are known to be associated with metastasis formation, radio- and chemotherapy resistance, and drug metabolism. Therefore, integration of these tumor characteristics into in vitro drug screening models is advantageous for any reliable investigation of the anticancer activity of novel drug candidates. In general, usage of cell culture models with in vivo like characteristics has become essential in preclinical drug studies and allows evaluation of complex problems such as tumor selectivity and anti-invasive properties of the drug candidates., Materials and Methods: In this study, we investigated the anticancer activity of clinically approved, investigational and experimental drugs based on platinum (cisplatin, oxaliplatin and KP1537), gallium (KP46), ruthenium (KP1339) and lanthanum (KP772) in different cell culture models such as monolayers, multicellular spheroids, as well as invasion and metastasis models. Results Application of the Alamar Blue assay to multicellular spheroids and a spheroid-based invasion assay resulted in an altered rating of compounds with regard to their cytotoxicity and ability to inhibit invasion when compared with monolayer-based cytotoxicity and transwell assays. For example, the gallium-based drug candidate KP46 showed in spheroid cultures significantly enhanced properties to inhibit protrusion formation and fibroblast mediated invasiveness, and improved cancer cell selectivity., Conclusion: Taken together, our results demonstrate the advantages of spheroid-based assays and underline the necessity of using different experimental models for reliable preclinical investigations assessing and better predicting the anticancer potential of new compounds.

Background: Patients with cutaneous melanoma (CM) on the trunk have a worse prognosis than those with extremity CM. One reason could be multiple or uncommon (outside axilla or groin) sentinel node locations (SNLs)., Methods: We identified 859 patients who underwent sentinel node biopsy for trunk (n = 465) or extremity (n = 394) CM in three Swedish healthcare regions from 2000 to 2008. We collected patient, tumor, and sentinel node characteristics through clinical registers and medical records. We investigated the distribution of SNLs in a logistic regression model, and risk of overall and melanoma-specific death through 2011 in a multivariable Cox regression model., Results: Trunk CM was associated with multiple SNLs (31 vs. 7 %; odds ratio [OR] 7.1; 95 % confidence interval [CI] 4.6-11.5; p < 0.001) but not uncommon SNLs (8 vs. 7 %; OR 1.1; 95 % CI 0.6-1.9; p = 0.75) compared with extremity CM. The increased risk of melanoma-specific death was confirmed for trunk CM (hazard ratio [HR] 1.9; 95 % CI 1.3-2.9; p = 0.003), especially on the upper back (HR 2.3; 95 % CI 1.4-3.6; p < 0.001) compared with extremity CM. Uncommon SNLs (HR 0.5; 95 % CI 0.2-1.4; p = 0.21) or multiple SNLs (HR 1.1; 95 % CI 0.4-2.9; p = 0.81) were not associated with melanoma-specific death compared with those with common/single SNL., Conclusions: Trunk melanomas were associated with multiple lymph drainage, but the worse prognosis of trunk melanomas could not be explained by the increased frequency of multiple or uncommon SNLs.

The rainbow trout endocrine system is sensitive to changes in annual day length, which is likely the principal environmental cue controlling its reproductive cycle. This study focuses on the endocrine regulation of vitellogenin (Vg) protein synthesis, which is the major egg yolk precursor in this fish species. We present a model of Vg production in female rainbow trout which incorporates a biological pathway beginning with sex steroid estradiol-17β levels in the plasma and concluding with Vg secretion by the liver and sequestration in the oocytes. Numerical simulation results based on this model are compared with experimental data for estrogen receptor mRNA, Vg mRNA, and Vg in the plasma from female rainbow trout over a normal annual reproductive cycle. We also analyze the response of the model to parameter changes. The model is subsequently tested against experimental data from female trout under a compressed photoperiod regime. Comparison of numerical and experimental results suggests the possibility of a time-dependent change in oocyte Vg uptake rate. This model is part of a larger effort that is developing a mathematical description of the endocrine control of reproduction in female rainbow trout. We anticipate that these mathematical and computational models will play an important role in future regulatory toxicity assessments and in the prediction of ecological risk.