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Highlights: [•] Feasibility of the threshold approach for formulated PPPs fish acute toxicity tests. [•] Database analysis demonstrates that a reduction of approximately 38% of the fish might be achieved. [•] Proposal for the threshold approach in the development of a regulatory dataset. [Copyright &y& Elsevier]

• The Amphibian Metamorphosis Assay (AMA) and Fish Short Term Reproduction Assay (FSTRA) are standardized regulatory tests used to determine if a chemical might affect the hypothalamic-pituitary-thyroid (HPT) axis or hypothalamic-pituitary-gonadal (HPG) axis, respectively. • Histopathology historical control data were assembled and evaluated from 55 AMA and 45 fathead minnow FSTRA studies. • Historical control data were found useful for investigating the existence of outlier results and aberrant control groups, identifying potential confounding variables, providing context for rare diagnoses, differentiating endocrine from non-endocrine effects, identifying background lesions, and helping to determine if specific improvements to established test guidance may be warranted. The Amphibian Metamorphosis Assay (AMA) is used to determine if a tested chemical has potential to impact the hypothalamic-pituitary-thyroid (HPT) axis of Xenopus laevis tadpoles, while the Fish Short Term Reproduction Assay (FSTRA) assesses potential effects on the hypothalamic-pituitary-gonadal (HPG) axis of fish such as the fathead minnow (Pimephales promelas). Several global regulatory programs routinely require these internationally validated tests be performed to determine the potential endocrine activity of chemicals. As such, they are conducted in accordance with standardized protocols and test criteria, which were originally developed more than a decade ago. Sizeable numbers of AMA and FSTRA studies have since been carried out, which allows for the mining of extensive historical control data (HCD). Such data are useful for investigating the existence of outlier results and aberrant control groups, identifying potential confounding variables, providing context for rare diagnoses, discriminating target from non-target effects, and for refining current testing paradigms. The present paper provides histopathology HCD from 55 AMA studies and 45 fathead minnow FSTRA studies, so that these data may become publicly available and thus aid in the interpretation of future study outcomes. Histopathology is a key endpoint in these assays, in which it is considered to be one of the most sensitive indicators of endocrine perturbation. In the current review, granular explorations of HCD data were used to identify background lesions, to assess the utility of particular diagnostic findings for distinguishing endocrine from non-endocrine effects, and to help determine if specific improvements to established regulatory guidance may be warranted. Knowledge gleaned from this investigation, supplemented by information from other recent studies, provided further context for the interpretation of AMA and FSTRA histopathology results. We recommend HCDs for the AMA and FSTRA be maintained to support the interpretation of study results. [ABSTRACT FROM AUTHOR]

Purpose: There is no consensus in the literature regarding the association between operative blood loss and postoperative outcomes in colorectal surgery, despite evidence suggesting a link. Therefore, this systematic review assesses the association between operative blood loss, perioperative and long-term outcomes after colorectal surgery. Methods: A literature search of MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane was performed to identify studies reporting on operative blood loss in colorectal surgery. Results: The review included forty-nine studies reporting on 61,312 participants, with a mean age ranging from 53.4 to 78.1 years. The included studies demonstrated that major operative blood loss was found to be a risk factor for mortality, anastomotic leak, presacral abscess, and postoperative ileus, leading to an increased duration of hospital stay. In the long term, the studies suggest that significant blood loss was an independent risk factor for future small bowel obstruction due to colorectal cancer recurrence and adhesions. Studies found that survival was significantly reduced, whilst the risk of colorectal cancer recurrence was increased. Reoperation and cancer-specific survival were not associated with major blood loss. Conclusion: The results of this systematic review suggest that major operative blood loss increases the risk of perioperative adverse events and has short and long-term repercussions on postoperative outcomes. Laparoscopic and robotic surgery, vessel ligation technology and anaesthetic considerations are essential for reducing blood loss and improving outcomes. This review highlights the need for further high quality, prospective, multicentre trials with a greater number of participants, and accurate and standardised methods of measuring operative blood loss. [ABSTRACT FROM AUTHOR]

Background: The purpose of this systematic review and meta-analysis was to determine the prevalence of the number of sigmoid arteries (SA) and variations in their origins.Methods: A thorough systematic search of literature through February 2020 was conducted on major electronic databases to identify eligible studies. Data were extracted and pooled into a meta-analysis using Metafor package in R. The primary outcome was the variations in the SA origin (according to modified Zebrowski classification), and the secondary outcome was the prevalence of the number of SA.Results: A total of 22 studies (n = 2653 patients) were included. Type 1 modified Zebrowski (separated origins or common trunk of the SA originating from descending recto-sigmoid trunk (DRST)) was the most common origin type of the SA (pooled prevalence estimate (PPE) = 49.67% (95% CI 32. 67- 66.71)), while type 3 (separated origins or common trunk of 1 or 2 SA originating from DRST or superior rectal artery (SRA) and 1 or 2 SA originating from DRST or SRA) was the least common (PPE = 0.18%; 95% CI 0.00-2.82)). Of the Type 1 variants, the not specified (N.S) variant was by far the most prevalent. The number of SA ranged from one to five, with three being the mode (PPE = 42.3%).Conclusion: This is the most comprehensive analysis of arterial vascular anatomy of the sigmoid colon. In light of the highly variable anatomical pattern displayed by the SA, thorough pre-operative knowledge of their anatomy can be crucial in minimizing incidences of iatrogenic injury. [ABSTRACT FROM AUTHOR]

Abstract: Ecotoxicity testing of pesticide active ingredients and formulated plant protection products (PPPs) prior to their commercial use is required by authorities around the world. Such studies are important for the conduct of risk assessments to protect wildlife and the environment, but they should only be conducted when their use is scientifically justified. One test of questionable scientific merit is the chronic fish toxicity test when conducted with formulated PPPs, which is a potential requirement under European legislation: chronic exposure to the formulated product per se rarely occurs in the environment and therefore it is generally not possible to use the data from chronic formulation studies in a meaningful risk assessment. A recent survey of European crop protection companies to explore the scientific merits and regulatory drivers for chronic fish toxicity studies has shown that current practice in deciding on the need for chronic fish toxicity testing of formulated PPPs varies substantially between companies. The most commonly cited reason for conducting such studies was solely to meet regulatory requirements. We conclude that chronic formulation testing is rarely if ever scientifically justified, and recommend that the forthcoming revision of the EU Aquatic Toxicology Guidance Document takes account of this by including a requirement that justification must be provided for conducting the test, rather than the current situation where the onus is on the registrant to provide a justification for not conducting the test. [ABSTRACT FROM AUTHOR]

Wood structure and function of juvenile wood from 18 conifer species from four conifer families (Araucariaceae, Cupressaceae, Pinaceae and Podocarpaceae) were examined for a trade-off between wood reinforcement and hydraulic efficiency. Wood density and tracheid ‘thickness-to-span’ ratio were used as anatomical proxies for mechanical properties. The thickness:span represented the ratio of tracheid double wall thickness to lumen diameter. Hydraulic resistivity (R) of tracheids on a cross-sectional area basis (RCA) increased over 50-fold with increasing density and thickness:span, implying a strength versus efficiency conflict. The conflict arose because density and thickness:span were increased by narrowing tracheid diameter rather than by thickening walls, which may be developmentally difficult. In the Pinaceae and Cupressaceae species, density and thickness:span correlated strongly with protection from drought-induced embolism, suggesting that mechanical strength was required in part to withstand tracheid collapse by negative sap pressure. These species showed a corresponding trade-off between increasing RCA and embolism protection. In contrast, species of Podocarpaceae and Araucariaceae were overbuilt for their embolism protection and were hydraulically inefficient, having greater density, thickness:span and RCA, none of which were correlated with vulnerability to embolism. [ABSTRACT FROM AUTHOR]

The hydraulic resistivity (R, pressure gradient/flow rate) through end walls of xylem conduits was estimated in seven species of diverse anatomy and affinity including a vessel-bearing fern, a tracheid-bearing gymnosperm, and angiosperms with versus without vessels. Conduit lengths were measured with a silicone injection method which was easier and more accurate than the usual paint injection. TheRdeclined linearly with the removal of end walls as stems were shortened from 10 to 0.3 cm. This relationship gave the minimumRwith no end walls present, or the lumen resistivity (RL). This was indistinguishable from the Hagen–Poiseuille value. The maximumRwith all end walls present gaveRC, the resistivity of end wall and lumen in series. Average end-wall resistivity (RW) was the differenceRC − RL and the‘wall fraction’ wasRW/ RC. Wall fraction was approximately constant, averaging 0.54 ± 0.07. This suggests that end wall and lumen resistivities are nearly co-limiting in vascular plants. Average conduit length was proportional to the diameter squared across species (r2 = 0.94). Together with a constant wall fraction, this was consistent with the end wall resistance (rw, pressure difference/flow rate) being inversely proportional to conduit length. Lowerrw in longer conduits is consistent with their having more end wall pits than shorter conduits. [ABSTRACT FROM AUTHOR]

The Amphibian Metamorphosis Assay (AMA) is used to identify substances that potentially interfere with the normal function of the hypothalamic-pituitary-thyroid (HPT) axis. Although numerous AMA studies have been performed since the establishment of this assay a decade earlier, a comprehensive, large-scale examination of histopathology data obtained from control larvae has not been performed. The current investigation reviewed 51 AMA experiments conducted at 7 different laboratories in Europe and North America. Dilution water control and/or solvent control specimens from each study (1,335 animals total) had been evaluated microscopically by one of eight anatomic pathologists. In order of descending frequency, the most common findings in prometamorphic Xenopus laevis controls were the core criteria of follicular cell (FC) hypertrophy, FC hyperplasia, thyroid hypertrophy, and thyroid atrophy, respectively. Less frequently recorded were non-core and ad hoc diagnoses, the toxicological relevance and utility of which were in some cases uncertain. As anticipated, the prevalence of FC hypertrophy and FC hyperplasia diagnoses were at least partially dependent on the Nieuwkoop and Faber (NF) stage at sacrifice. The recorded frequencies of each of the four core diagnoses also differed according to pathologist, which suggests that pathologist diagnostic interpretation is a potential source of variability across AMA study outcomes. Based on the current examination of the AMA historical data, and further hands-on experience with this assay, diagnostic approaches to evaluating the histopathology endpoint are discussed, and several recommendations are proposed for the refinement of core diagnostic criteria assessment. [ABSTRACT FROM AUTHOR]

The amphibian metamorphosis assay (AMA; US Environmental Protection Agency [USEPA] test guideline 890.1100 and Organisation for Economic Co‐Operation and Development test guideline 231) has been used for more than a decade to assess the potential thyroid‐mediated endocrine activity of chemicals. In 2013, in the context of the Endocrine Disruptor Screening Program of the USEPA, a Scientific Advisory Panel reviewed the results from 18 studies and recommended changes to the AMA test guideline, including a modification to a fixed‐stage design rather than a fixed‐time (i.e., 21‐d) design. We describe an extended test design for the AMA (or EAMA) that includes thyroid histopathology and time to metamorphosis (Nieuwkoop–Faber [NF] stage 62), to address both the issues with the fixed‐time design and the specific question of thyroid‐mediated adversity in a shorter assay than the larval amphibian growth and development assay (LAGDA; Organisation for Economic Co‐Operation and Development test guideline 241), using fewer animals and resources. A demonstration study was conducted with the EAMA (up to NF stage 58) using sodium perchlorate. Data analyses and interpretation of the fixed‐stage design of the EAMA are more straightforward than the fixed‐time design because the fixed‐stage design avoids confounded morphometric measurements and thyroid histopathology caused by varying developmental stages at test termination. It also results in greater statistical power to detect metamorphic delays than the fixed‐time design. By preferentially extending the AMA to NF stage 62, suitable data can be produced to evaluate thyroid‐mediated adversity and preclude the need to perform a LAGDA for thyroid mode of action analysis. The LAGDA remains of further interest should investigations of longer term effects related to sexual development modulated though the hypothalamus–pituitary–gonadal axis be necessary. However, reproduction assessment or life cycle testing is currently not addressed in the LAGDA study design. This is better addressed by higher tier studies in fish, which should then include specific thyroid‐related endpoints. Environ Toxicol Chem 2021;40:2135–2144. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

: ObjectiveTo determine the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).: DesignRandomized, double-blind, placebo-controlled, multicenter metabolic and osteoporosis substudy of the Women''s Health, Osteoporosis, Progestin, Estrogen (Women''s HOPE) study.: SettingNineteen study centers across the United States.: Patient(s)Healthy, postmenopausal women (n = 822) with an intact uterus were recruited.: Intervention(s)Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 using a centralized protocol.: Main outcome measure(s)Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed estrogen (E).: Result(s)No cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence rates from 3.17% (CEE 0.3 mg) to 27.27% (CEE 0.625 mg) was seen at 2 years. The number of cases increased from year 1 to year 2. For the CEE-alone groups, the incidence rates and types of hyperplasia diagnosed varied among the pathologists.: Conclusion(s)Two years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These regimens should be considered for postmenopausal women who are candidates for hormone therapy. [Copyright &y& Elsevier]

Describes how a more advanced bootstrap methodology may be applied to derive better point estimates and confidence intervals for species sensitivity distribution (SSD) estimates of safe environmental concentrations. Generic problems with fitting an SSD; Use of the basic bootstrap.

Presents a study which described a method for selecting the appropriate form of prior information through the procedure of iterative image reconstruction by using the information derived from boundary measurements in electrical impedance tomography. Principle in which the method is based; Details of the application of incompatible prior information for image reconstruction.

Introduction: Colorectal cancer (CRC) is the fourth leading cause of death with 1.4 million new cases occurring annually worldwide. High-quality clinical practice guidelines are needed to tailor high-quality individualized treatment. The aim of the present study was to evaluate the methodological quality of the current guidelines for the management of acute malignant left-sided colonic bowel obstruction. Methods: A systematic search of the literature was carried out using electronic databases. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument was used to assess the quality of each guideline. Results: Search results returned a total of 14 guidelines appropriate for assessment. Both domain I (scope and purpose) and domain VI (editorial independence) were assessed with the same median score of 83%. The lowest scoring domain was domain V (applicability), scoring only 43%. The 2 guidelines that had the highest score were the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN), each scoring 100%. However, there were significant variations in terms of quality. The NICE and New Zealand guidelines were voted unanimously for use unchanged, whilst 8 other guidelines were voted for use with modifications. Conclusion: Variation in guideline quality in CRC is a concern despite some clearly excellent published guidelines. All guidelines score poorly when it comes to describing how the guidelines could be applied. Lack of patient participation in guideline development is also a shortcoming that requires urgent redress. [ABSTRACT FROM AUTHOR]

Summary The coexistence of cutaneous and extra-cutaneous malignancies within one family could be explained by shared genetic mechanisms such as common tumor suppressor gene mutations or oncogene activation, as well as mutations in DNA repair genes. Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir–Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations. Colonic and endometrial tumors from HNPCC patients exhibit microsatellite instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from cancer prone families to determine if MSI is found in benign and malignant skin lesions and to assess whether MSI in the skin is predictive of genomic instability with susceptibility to tumors characteristic of HNPCC. One hundred and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone families were analyzed. Thirteen benign skin lesions from three individuals belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were found in two of the three individuals with RER + skin lesions. We found MSI in non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found in skin lesions within other family cancer syndromes. These results have important clinical implications as the detection of MSI in prevalent readily accessible skin lesions could form the basis of noninvasive screening for HNPCC families. It may also be a valuable tool in the search for new mismatch repair genes. [ABSTRACT FROM AUTHOR]

Vitellogenin (VTG) is a biomarker for possible endocrine activity of chemicals acting via the estrogen, androgen, or steroidogenesis pathways. VTG is assessed in standardised fish guideline studies conducted for regulatory safety assessment of chemicals. VTG data can be highly variable leading to concerns for potential equivocal, false positive and/or negative outcomes. Consequently, additional fish testing may be required to address uncertainties in the VTG response, and possibly erroneous/missed identification of endocrine activity. To better understand the technical challenges of VTG assessment and reporting for regulatory purposes, a survey was sent to 27 testing laboratories performing these analyses. The survey results from 16 respondents (6 from the UK, 3 from the USA, and 7 from the EU) were analysed and discussed in a follow-up webinar. High variability in background VTG concentrations was widely acknowledged and thought to be associated with fish batch, husbandry, laboratory practices, and several methodological aspects. These include sample collection and storage, VTG quantification, data handling, and the benchmarks used for data acceptability. Information gathered in the survey provides a basis for improving and harmonizing the measurement of VTG in fish, and an opportunity to reassess the suitability of current acceptability criteria in test guidelines. • Vitellogenin (VTG) is an endocrine activity biomarker in fish regulatory studies. • A survey of laboratories revealed technical challenges for VTG assessment. • These include methodological, data handling and data acceptability issues. • The results provide a basis for improving and harmonizing the measurement of VTG. • Implementation of the recommendations will support decision-making processes. [ABSTRACT FROM AUTHOR]

This is a summary of the history of the Association of Coloproctology of Great Britain and Ireland from its inception in the late 1980s to the present day. [ABSTRACT FROM AUTHOR]

A machine learning approach is applied to Raman spectra of cells from the MIA PaCa-2 human pancreatic cancer cell line to distinguish between tumor repopulating cells (TRCs) and parental control cells, and to aid in the identification of molecular signatures. Fifty-one Raman spectra from the two types of cells are analyzed to determine the best combination of data type, dimension size, and classification technique to differentiate the cell types. An accuracy of 0.98 is obtained from support vector machine (SVM) and k-nearest neighbor (kNN) classifiers with various dimension reduction and feature selection tools. We also identify some possible biomolecules that cause the spectral peaks that led to the best results. [ABSTRACT FROM AUTHOR]

Fish acute toxicity tests are conducted as part of regulatory hazard identification and risk‐assessment packages for industrial chemicals and plant protection products. The aim of these tests is to determine the concentration which would be lethal to 50% of the animals treated. These tests are therefore associated with suffering in the test animals, and Organisation for Economic Co‐operation and Development test guideline 203 (fish, acute toxicity) studies are the most widely conducted regulatory vertebrate ecotoxicology tests for prospective chemical safety assessment. There is great scope to apply the 3Rs principles—the reduction, refinement, and replacement of animals—in this area of testing. An expert ecotoxicology working group, led by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research, including members from government, academia, and industry, reviewed global fish acute test data requirements for the major chemical sectors. The present study highlights ongoing initiatives and provides an overview of the key challenges and opportunities associated with replacing, reducing, and/or refining fish acute toxicity studies—without compromising environmental protection. Environ Toxicol Chem 2020;39:2076–2089. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Background: appendiceal tumours are rare, they may be encountered unexpectedly in any acute or elective abdominal operation, many of these tumours are not appreciated intraoperatively and are diagnosed only during formal histopathological analysis of an appendicectomy specimen. Herein we present a case of appendiceal adenocarcinoma presenting as left-sided large bowel obstruction, we also review the literature of unusual presentations of appendiceal tumours. Case Presentation: we report a case of left sided large bowel obstruction found to be secondary to an appendiceal adenocarcinoma. The patient presented with abdominal pain, distension and constipation, CT scan showed large bowel obstruction thought to be due to a sigmoid tumour, on laparotomy the appendix was also noted to be abnormal. A low Hartman's was performed with enbloc total hysterectomy and bilateral salpigo-oophorectomy. A separate ileocaecal resection with end ileostomy was also performed, pathology specimens showed that the primary neoplasm was the appendix with metastasis to the distal sigmoid. Conclusion: appendiceal tumours are rare, they usually present as acute appendicitis, other presentations are far less common. [ABSTRACT FROM AUTHOR]

It is unclear to what extent cerebellar networks show long-term plasticity and accompanied changes in cortical structures. Using drumming as a demanding multimodal motor training, we compared cerebellar lobular volume and white matter microstructure, as well as cortical thickness of 15 healthy non-musicians before and after learning to drum, and 16 age matched novice control participants. After 8 weeks of group drumming instruction, 3 ×30 minutes per week, we observed the cerebellum significantly changing its grey (volume increase of left VIIIa, relative decrease of VIIIb and vermis Crus I volume) and white matter microstructure in the inferior cerebellar peduncle. These plastic cerebellar changes were complemented by changes in cortical thickness (increase in left paracentral, right precuneus and right but not left superior frontal thickness), suggesting an interplay of cerebellar learning with cortical structures enabled through cerebellar pathways. [ABSTRACT FROM AUTHOR]

Recent regulatory testing programs have been designed to evaluate whether a chemical has the potential to interact with the endocrine system and could cause adverse effects. Some endocrine pathways are highly conserved among vertebrates, providing a potential to extrapolate data generated for one vertebrate taxonomic group to others (i.e., biological read‐across). To assess the potential for biological read‐across, we reviewed tools and approaches that support species extrapolation for fish, amphibians, birds, and reptiles. For each of the estrogen, androgen, thyroid, and steroidogenesis (EATS) pathways, we considered the pathway conservation across species and the responses of endocrine‐sensitive endpoints. The available data show a high degree of confidence in the conservation of the hypothalamus–pituitary–gonadal axis between fish and mammals and the hypothalamus–pituitary–thyroid axis between amphibians and mammals. Comparatively, there is less empirical evidence for the conservation of other EATS pathways between other taxonomic groups, but this may be due to limited data. Although more information on sensitive pathways and endpoints would be useful, current developments in the use of molecular target sequencing similarity tools and thoughtful application of the adverse outcome pathway concept show promise for further advancement of read‐across approaches for testing EATS pathways in vertebrate ecological receptors. Environ Toxicol Chem 2020;39:739–753. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Background: The number of harvested lymph nodes (LNs) in colorectal cancer surgery relates to oncologic radicality and accuracy of staging. In addition, it affects the choice of adjuvant therapy, as well as prognosis. The American Joint Committee on Cancer defines at least 12 LNs harvested as adequate in colorectal cancer resections. Despite the importance of the topic, even in high-volume colorectal centres the rate of adequacy never reaches 100%. The aim of this study was to identify factors that affect the number of harvested LNs in oncologic colorectal surgery.Materials and Methods: We prospectively collected all consecutive patients who underwent colorectal cancer resection from January 1st 2013 to December 31st 2017 at Emergency Surgery Unit St Orsola University Hospital of Bologna.Results: Six hundred and forty-three consecutive patients (382 elective, 261 emergency) met the study inclusion criteria. Emergency surgery and laparoscopic approach did not have a significant influence on the number of harvested LNs. The adequacy of lymphadenectomy was negatively affected by age >80 (OR 3.47, p < 0.001), ASA score ≥3 (OR 3.48, p < 0.001), Hartmann's or rectal resection (OR 3.6, p < 0.001) and R1-R2 resection margins (OR 3.9, p = 0.006), while it was positively affected by T-status ≥3 (OR 0.33 p < 0.001).Conclusion: Both the surgical technique and procedure regimen did not affect the number of lymphnodes retrieved. Age >80 and ASA score ≥3 and Hartmann's procedure or rectal resection showed to be risk factors related to inadequate lymphadenectomy in colorectal cancer surgery. [ABSTRACT FROM AUTHOR]

An important goal in toxicology is the development of new ways to increase the speed, accuracy, and applicability of chemical hazard and risk assessment approaches. A promising route is the integration of in vitro assays with biological pathway information. We examined how the adverse outcome pathway (AOP) framework can be used to develop pathway‐based quantitative models useful for regulatory chemical safety assessment. By using AOPs as initial conceptual models and the AOP knowledge base as a source of data on key event relationships, different methods can be applied to develop computational quantitative AOP models (qAOPs) relevant for decision making. A qAOP model may not necessarily have the same structure as the AOP it is based on. Useful AOP modeling methods range from statistical, Bayesian networks, regression, and ordinary differential equations to individual‐based models and should be chosen according to the questions being asked and the data available. We discuss the need for toxicokinetic models to provide linkages between exposure and qAOPs, to extrapolate from in vitro to in vivo, and to extrapolate across species. Finally, we identify best practices for modeling and model building and the necessity for transparent and comprehensive documentation to gain confidence in the use of qAOP models and ultimately their use in regulatory applications. Environ Toxicol Chem 2019;38:1850–1865. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this review is to (1) provide information concerning the opioid crisis including origins, trends, and some important related laws/policies; and (2) summarize the current involvement and impact of pharmacists in helping to address the crisis, as well as examine practices in other healthcare disciplines from which pharmacists might derive guidance and strategies. Summary Contributors to the opioid crisis included campaigns to treat pain as a fifth vital sign and to use opioids in treatment of non-cancer-related pain, as well as aggressive marketing of opioid analgesics by pharmaceutical companies. To address the crisis, numerous strategies have been implemented at the policy/legislative, health-system, and patient levels, such as prescription drug monitoring programs (PDMPs), increased regulation of pain clinics, and expanded use of naloxone. Pharmacists have a critical role to play in interventions to address opioid misuse and reduce harm resulting from misuse. Such interventions include patient screening and risk stratification, patient and community education and outreach concerning appropriate pain management, medication reviews/medication therapy management, education on safe storage and disposal, distribution of naloxone/opioid rescue kits and training on their proper use, and referral of patients to addiction treatment, among other strategies. Conclusion Pharmacists have multiple, complex roles in addressing the opioid crisis. Outcomes of several studies provide substantial evidence that pharmacists can make an impact through appropriate pain management, use of PDMPs, opioid overdose prevention training, and medication reviews and counseling, among other interventions. [ABSTRACT FROM AUTHOR]

Abstract The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity. [ABSTRACT FROM AUTHOR]

The ongoing debate concerning the regulation of endocrine disruptors, has increasingly led to questions concerning the current testing of chemicals and whether this is adequate for the assessment of potential endocrine disrupting effects. This paper describes the current testing approaches for plant protection product (PPP) active substances in the European Union and the United States and how they relate to the assessment of endocrine disrupting properties for human and environmental health. This includes a discussion of whether the current testing approaches cover modalities other than the estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, sensitive windows of exposure, adequate assessment of human endocrine disorders and wildlife species, and the determination of thresholds for endocrine disruption. It is concluded, that the scope and nature of the core and triggered data requirements for PPP active substances are scientifically robust to address adverse effects mediated through endocrine mode(s) of action and to characterise these effects in terms of dose response. [ABSTRACT FROM AUTHOR]

Avian reproduction studies are a regulatory requirement for pesticides in many regions. The data often require careful interpretation due to the nature of the study design. Here we present the historical control dataset for bobwhite quail and mallard duck reproduction studies performed at the Evans Analytical Group LLC avian toxicology laboratory over the period 1985–2016. The analysis demonstrates the stability of reproductive parameters over time and good agreement to normal control ranges as required by the regulatory test guidelines. The major source of variation is shown to be within study variation. Power analyses confirm the generally good power properties of the test design. Recommendations for the use of historical control data for the interpretation of avian reproduction studies are made. We believe the analysis and evaluation presented here can facilitate the development of practical guidance that can be implemented in regulatory programmes requiring this test. [ABSTRACT FROM AUTHOR]

A Weight-of-evidence (WoE) evaluation should be applied in assessing all the available data for the identification of endocrine disrupting (ED) properties of chemicals. The European Commission draft acts specifying criteria under the biocidal products and plant protection products regulations require that WoE is implemented for the assessment of such products. However, only some general considerations and principles of how a WoE should be conducted are provided. This paper reviews WoE approaches to distil key recommendations specifically for the evaluation of potential ED properties of chemicals. In a manner, which is consistent with existing, published WoE frameworks, the WoE evaluation of ED properties can be divided into four phases: 1) Definition of causal questions and data gathering and selection, 2) Review of individual studies, 3) Data integration and evaluation, and 4) Drawing conclusions based on inferences. Recommendations are made on how to conduct each phase robustly and transparently to help guide the WoE evaluation of potential endocrine disrupting properties of chemicals within a European regulatory context. [ABSTRACT FROM AUTHOR]

Multiple neoadjuvant therapy strategies have been used and compared for rectal cancer and there has been no true consensus as to the optimal neoadjuvant therapy regimen. The aim is to identify and compare the neoadjuvant therapies available for stage II and III rectal cancer. A systematic literature review was performed, from inception to August 2022, of the following databases: MEDLINE, EMBASE, Science Citation Index Expanded, Cochrane Library. Only randomized controlled trials comparing neoadjuvant therapies for stage II and III rectal cancer were considered. Stata was used to draw network plots, and a Bayesian network meta-analysis was conducted through models utilizing the Markov Chain Monte Carlo method in WinBUGS. A total of 58 articles were included based on 41 randomised controlled trials, reporting on 12,404 participants that underwent 15 neoadjuvant treatment regimens. No significant difference was identified between treatments for major or total postoperative complications, anastomotic leak rates, or sphincter-saving surgery. Straight to surgery (STS) ranked as best treatment for preoperative toxicity but ranked worst treatment for positive resection margins and complete response. STS had significantly increased positive resection margins compared to long-course chemoradiotherapy with short-wait (LCCRT-SW) or long-wait (LCCRT-LW) to surgery, or short-course radiotherapy with short-wait (SCRT-SW) or immediate surgery (SCRT-IS). LCCRT-SW or LCCRT-LW resulted in significantly increased complete response rates compared to STS. LCCRT-LW significantly improved 2-year overall survival compared to STS, SCRT-IS, SCRT-SW. Total neoadjuvant therapy regimes with short-course radiotherapy followed by consolidation chemotherapy (SCRT-CT-SW), induction chemotherapy followed by long-course chemoradiotherapy (CT-LCCRT-S), long-course chemoradiotherapy followed by consolidation chemotherapy (LCCRT-CT-S), significantly improved positive resection margins, complete response, and disease-free survival compared to STS. Chemotherapy with monoclonal antibodies followed by long-course chemoradiotherapy (CT+MAB-LCCRT+MAB-S) significantly improved complete response and positive resection margins compared to STS, and 2-year disease-free survival compared to STS, SCRT-IS, SCRT-SW, SCRT-CT-SW, LCCRT-SW, LCCRT-LW. CT+MAB-LCCRT+MAB-S ranked as best treatment for disease-free survival and overall survival. Conventional neoadjuvant therapies with short-course radiation or long-course chemoradiotherapy have oncological benefits compared to no neoadjuvant therapy without increasing perioperative complication rates. Prolonged wait to surgery may improve oncological outcomes. Total neoadjuvant therapies provide additional benefits in terms of complete response, positive resection margins, and disease-free survival. Monoclonal antibody therapy may further improve oncological outcomes but currently is only applicable to a small subgroup of patients and requires further validation. • Neoadjuvant therapy does not significantly increase perioperative complications. • Short-course radiation or long-course chemoradiation improve oncological outcomes. • Prolonged wait to surgery improves outcomes without increasing complications. • Total neoadjuvant therapy improves complete response rate and disease-free survival. • Monoclonal antibodies may improve oncological outcomes but not widely applicable. [ABSTRACT FROM AUTHOR]

Photocatalytically generated gold on carbon and TiO 2 composites were used for acetylene hydrogenation in excess ethylene, in a way close to current industrial practices. The crystalline effect of TiO 2 and the addition of Pd to supported Au catalysts on acetylene hydrogenation were investigated. Carbon and amorphous TiO 2 supported Au were highly active, selective, and stable and possessed the highest ethylene yield of 83% at 210 °C with a H 2 /C 2 H 2 ratio of 2/1 for selective hydrogenation of acetylene to ethylene. With further addition of Pd to the supported Au catalyst, ethylene yield reached a maximum value of 57% at 30 °C with a H 2 /C 2 H 2 ratio of 2/1. The enhanced performance originated from small neutral Au nanoparticles and the formation of bimetallic Au–Pd catalyst. This report opens up promising possibilities for the design of highly efficient heterogeneous supported gold catalysts. [ABSTRACT FROM AUTHOR]

The European Plant Protection Products Regulation 1107/2009 requires that registrants establish whether pesticide metabolites pose a risk to the environment. Fish acute toxicity assessments may be carried out to this end. Considering the total number of pesticide (re-) registrations, the number of metabolites can be considerable, and therefore this testing could use many vertebrates. EFSA's recent “Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters” outlines opportunities to apply non-testing methods, such as Quantitative Structure Activity Relationship (QSAR) models. However, a scientific evidence base is necessary to support the use of QSARs in predicting acute fish toxicity of pesticide metabolites. Widespread application and subsequent regulatory acceptance of such an approach would reduce the numbers of animals used. The work presented here intends to provide this evidence base, by means of retrospective data analysis. Experimental fish LC 50 values for 150 metabolites were extracted from the Pesticide Properties Database ( http://sitem.herts.ac.uk/aeru/ppdb/en/atoz.htm ). QSAR calculations were performed to predict fish acute toxicity values for these metabolites using the US EPA's ECOSAR software. The most conservative predicted LC 50 values generated by ECOSAR were compared with experimental LC 50 values. There was a significant correlation between predicted and experimental fish LC 50 values (Spearman r s = 0.6304, p < 0.0001). For 62% of metabolites assessed, the QSAR predicted values are equal to or lower than their respective experimental values. Refined analysis, taking into account data quality and experimental variation considerations increases the proportion of sufficiently predictive estimates to 91%. For eight of the nine outliers, there are plausible explanation(s) for the disparity between measured and predicted LC 50 values. Following detailed consideration of the robustness of this non-testing approach, it can be concluded there is a strong data driven rationale for the applicability of QSAR models in the metabolite assessment scheme recommended by EFSA. As such there is value in further refining this approach, to improve the method and enable its future incorporation into regulatory guidance and practice. [ABSTRACT FROM AUTHOR]

Amphibians are currently the most threatened and rapidly declining group of vertebrates and this has raised concerns about their potential sensitivity and exposure to plant protection products and other chemicals. Current environmental risk assessment procedures rely on surrogate species (e.g. fish and birds) to cover the risk to aquatic and terrestrial life stages of amphibians, respectively. Whilst a recent meta-analysis has shown that in most cases amphibian aquatic life stages are less sensitive to chemicals than fish, little research has been conducted on the comparative sensitivity of terrestrial amphibian life stages. Therefore, in this paper we address the questions “What is the relative sensitivity of terrestrial amphibian life stages to acute chemical oral exposure when compared with mammals and birds?” and “Are there correlations between oral toxicity data for amphibians and data for mammals or birds?” Identifying a relationship between these data may help to avoid additional vertebrate testing. Acute oral amphibian toxicity data collected from the scientific literature and ecotoxicological databases were compared with toxicity data for mammals and birds. Toxicity data for terrestrial amphibian life stages are generally sparse, as noted in previous reviews. Single-dose oral toxicity data for terrestrial amphibian life stages were available for 26 chemicals and these were positively correlated with LD50 values for mammals, while no correlation was found for birds. Further, the data suggest that oral toxicity to terrestrial amphibian life stages is similar to or lower than that for mammals and birds, with a few exceptions. Thus, mammals or birds are considered adequate toxicity surrogates for use in the assessment of the oral exposure route in amphibians. However, there is a need for further data on a wider range of chemicals to explore the wider applicability of the current analyses and recommendations. [ABSTRACT FROM AUTHOR]

Radar backscatter from forest canopies is related to forest cover, canopy structure and aboveground biomass (AGB). The S-band frequency (3.1-3.3 GHz) lies between the longer L-band (1-2 GHz) and the shorter C-band (5-6 GHz) and has been insufficiently studied for forest applications due to limited data availability. In anticipation of the British built NovaSAR-S satellite mission, this study evaluates the benefits of polarimetric S-band SAR for forest biophysical properties. To understand the scattering mechanisms in forest canopies at S-band the Michigan Microwave Canopy Scattering (MIMICS-I) radiative transfer model was used. S-band backscatter was found to have high sensitivity to the forest canopy characteristics across all polarisations and incidence angles. This sensitivity originates from ground/trunk interaction as the dominant scattering mechanism related to broadleaved species for co-polarised mode and specific incidence angles. The study was carried out in the temperate mixed forest at Savernake Forest and Wytham Woods in southern England, where airborne S-band SAR imagery and field data are available from the recent AirSAR campaign. Field data from the test sites revealed wide ranges of forest parameters, including average canopy height (6-23 m), diameter at breast-height (7-42 cm), basal area (0.2-56 m2/ha), stem density (20-350 trees/ha) and woody biomass density (31-520 t/ha). S-band backscatter-biomass relationships suggest increasing backscatter sensitivity to forest AGB with least error between 90.63 and 99.39 t/ha and coefficient of determination (r2) between 0.42 and 0.47 for the co-polarised channel at 0.25 ha resolution. The conclusion is that S-band SAR data such as from NovaSAR-S is suitable for monitoring forest aboveground biomass less than 100 t/ha at 25 m resolution in low to medium incidence angle range. [ABSTRACT FROM AUTHOR]

Fish bioconcentration test guidelines generally require that bioconcentration factors (BCFs) are determined at two exposure concentrations. However, recent revisions to the OECD test guideline for bioconcentration testing (TG 305) provide the option to use only one exposure concentration, when justification is provided, although two concentrations may still be required for some regulatory purposes. Recently, this justification has been demonstrated for plant protection product active ingredients. To determine whether this justification has a broader validity for general chemicals, an analysis of 236 BCF studies on general chemicals was conducted. The results presented here again demonstrate that BCF values do not significantly differ between concentrations when more than one concentration is used. This relationship is particularly strong for BCFs ⩾1000 L/kg, which is beneficial, since only chemicals with BCFs >2000 L/kg may require regulatory action. This analysis therefore provides a data-driven rationale for using the one test concentration approach for general chemical substances and thus could contribute to a substantial reduction in the use of fish in bioconcentration tests. [ABSTRACT FROM AUTHOR]

Of note, in the trial by Richards et al. SP 16 sp , proportions of iron deficient-patients were of 28% and 29%, depending on the group." now reads: "As we have previously commented in relation to the PREVENTT trial SP 25 sp , this might lead to statistical underpowering of these trials in the evaluation of the effect of pre-operative iron." Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-022-05283-y, published online 09 February 2022 The original version of this Article contained an error in the Discussion section, "As we have previously commented in relation to the PREVENTT trial SP 25 sp , this might lead to statistical underpowering of these trials in the evaluation of the effect of pre-operative iron. [Extracted from the article]

Highlights: [•] We developed an individual-based zebrafish population model. [•] We investigated the population-level impact of two endocrine disrupting chemicals. [•] Acute exposure had no effects at the population-level. [•] Chronic exposure had significant effects at the population-level. [•] Ecological models can link individual-level effects to population-level impacts. [Copyright &y& Elsevier]

The relative sensitivity of amphibians to chemicals in the environment, including plant protection product active substances, is the subject of ongoing scientific debate. The objective of this study was to compare systematically the relative sensitivity of amphibians and fish to chemicals. Acute and chronic toxicity data were obtained from the U.S. Environmental Protection Agency (U.S. EPA) ECOTOX database and were supplemented with data from the scientific and regulatory literature. The overall outcome is that fish and amphibian toxicity data are highly correlated and that fish are more sensitive (both acute and chronic) than amphibians. In terms of acute sensitivity, amphibians were between 10- and 100-fold more sensitive than fish for only four of 55 chemicals and more than 100-fold more sensitive for only two chemicals. However, a detailed inspection of these cases showed a similar acute sensitivity of fish and amphibians. Chronic toxicity data for fish were available for 52 chemicals. Amphibians were between 10- and 100-fold more sensitive than fish for only two substances (carbaryl and dexamethasone) and greater than 100-fold more sensitive for only a single chemical (sodium perchlorate). The comparison for carbaryl was subsequently determined to be unreliable and that for sodium perchlorate is a potential artifact of the exposure medium. Only a substance such as dexamethasone, which interferes with a specific aspect of amphibian metamorphosis, might not be detected using fish tests. However, several other compounds known to influence amphibian metamorphosis were included in the analysis, and these did not affect amphibians disproportionately. These analyses suggest that additional amphibian testing is not necessary during chemical risk assessment. Environ. Toxicol. Chem. 2013;32:984-994. © 2013 SETAC [ABSTRACT FROM AUTHOR]

The authors present a method to predict fish survival under exposure to fluctuating concentrations and repeated pulses of a chemical stressor. The method is based on toxicokinetic-toxicodynamic modeling using the general unified threshold model of survival (GUTS) and calibrated using raw data from standard fish acute toxicity tests. The model was validated by predicting fry survival in a fish early life stage test. Application of the model was demonstrated by using Forum for Co-ordination of Pesticide Fate Models and Their Use surface water (FOCUS-SW) exposure patterns as model input and predicting the survival of fish over 485 d. Exposure patterns were also multiplied by factors of five and 10 to achieve higher exposure concentrations for fish survival predictions. Furthermore, the authors quantified how far the exposure profiles were below the onset of mortality by finding the corresponding exposure multiplication factor for each scenario. The authors calculated organism recovery times as additional characteristic of toxicity as well as number of peaks, interval length between peaks, and mean duration as additional characteristics of the exposure pattern. The authors also calculated which of the exposure patterns had the smallest and largest inherent potential toxicity. Sensitivity of the model to parameter changes depends on the exposure pattern and differs between GUTS individual tolerance and GUTS stochastic death. Possible uses of the additional information gained from modeling to inform risk assessment are discussed. Environ. Toxicol. Chem. 2013;32:954-965. © 2013 SETAC [ABSTRACT FROM AUTHOR]

Introduction: Optimal follow-up after colorectal resection for adenocarcinoma is yet to be determined. The aim of this study was to examine the role of a fifth-year surveillance Computed Tomography (CT) scan in detecting recurrence in our population. Method: A retrospective analysis of all patients who had undergone potentially curative resections of colorectal adenocarcinomas between 2003 and 2004 was performed using electronic and casenote records. Data analysis was performed using Microsoft Office Excel 2007 and GnuPSPP statistical software. Results: Two hundred and seven patients (111 male and 96 female) with a median age of 74 years (IQR 66-80) undergoing colorectal resections were studied. One hundred and twenty-one patients (58%) were alive and disease free at 5 years of whom 81 (67%) had received a fifth-year surveillance CT scan. Fifth-year scanning did not demonstrate any new colo-rectal metastases. However 6 (7%) scans revealed new, undiagnosed, non-colorectal malignancies. Thirty-four patients developed metastatic disease. All metastasis were diagnosed by 3% years of follow-up. Eleven of these 34 cases presented after their second-year surveillance CT scan. Those patients with asymptomatic metastasis at the time of their discovery demonstrated improved likelihood of five year survival. Conclusion: This study showed no role for a fifth-year surveillance CT scan in the detection of resectable metastases, however there was a 7% pick up rate for detecting new malig-nancies. CT scanning beyond 2 years was needed to identify about one-third of the recurrences reported in this study. [ABSTRACT FROM AUTHOR]