Search

According to the World Health Organisation and European Commission definitions, substances shall be considered as having endocrine disrupting properties if they show adverse effects, have endocrine activity and the adverse effects are a consequence of the endocrine activity (using a weight-of-evidence approach based on biological plausibility), unless the adverse effects are not relevant to humans or non-target organisms at the (sub)population level. To date, there is no decision logic on how to establish endocrine disruption via the thyroid modality in non-mammalian vertebrates. This paper describes an evidence-based decision logic compliant with the integrated approach to testing and assessment (IATA) concept, to identify thyroid-mediated effect patterns in aquatic vertebrates using amphibians as relevant models for thyroid disruption assessment. The decision logic includes existing test guidelines and methods and proposes detailed considerations on how to select relevant assays and interpret the findings. If the mammalian dataset used as the starting point indicates no thyroid concern, the Xenopus Eleutheroembryonic Thyroid Assay allows checking out thyroid-mediated activity in non-mammalian vertebrates, whereas the Amphibian Metamorphosis Assay or its extended, fixed termination stage variant inform on both thyroid-mediated activity and potentially population-relevant adversity. In evaluating findings, the response patterns of all assay endpoints are considered, including the direction of changes. Thyroid-mediated effect patterns identified at the individual level in the amphibian tests are followed by mode-of-action and population relevance assessments. Finally, all data are considered in an overarching weight-of-evidence evaluation. The logic has been designed generically and can be adapted, e.g. to accommodate fish tests once available for thyroid disruption assessments. It also ensures that all scientifically relevant information is considered, and that animal testing is minimised. The proposed decision logic can be included in regulatory assessments to facilitate the conclusion on whether substances meet the endocrine disruptor definition for the thyroid modality in non-mammalian vertebrates., Competing Interests: Declaration of competing interest Administrative support, article publishing charges and the fees for writing assistance were provided by CropLife Europe. The employment affiliation of the authors is listed on the cover page. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Swimming bacteria navigate chemical gradients using temporal sensing to detect changes in concentration over time. Here we show that surface-attached bacteria use a fundamentally different mode of sensing during chemotaxis. We combined microfluidic experiments, massively parallel cell tracking and fluorescent reporters to study how Pseudomonas aeruginosa senses chemical gradients during pili-based 'twitching' chemotaxis on surfaces. Unlike swimming cells, we found that temporal changes in concentration did not induce motility changes in twitching cells. We then quantified the chemotactic behaviour of stationary cells by following changes in the sub-cellular localization of fluorescent proteins as cells are exposed to a gradient that alternates direction. These experiments revealed that P. aeruginosa cells can directly sense differences in concentration across the lengths of their bodies, even in the presence of strong temporal fluctuations. Our work thus overturns the widely held notion that bacterial cells are too small to directly sense chemical gradients in space., (© 2024. The Author(s).)

Background: Sustainable career advancement opportunities for pharmacy technicians will be a critical part of patient-centered community pharmacy environments as the role of the pharmacist provider expands., Objectives: (1) To determine the impact of a Pharmacy Technician Certification Board pharmacy (PTCB) certification on career advancement and professional growth metrics; (2) To assess technicians' role in advanced pharmacy services before and after certification; and (3) To identify changes in pharmacist services when a certified pharmacy technician (CPhT) was added to the provider team., Methods: A 73-question web-based survey was distributed to all PTCB certified pharmacy technicians (CPhT) in the United States, Washing D.C., Puerto Rico, Guam, and the US Virgin Islands. The survey was distributed by PTCB in April 2021 with a 28-day collection period. The survey included multiple choice, rating scale, and free text questions centered on five domains: Practice experience, Career aspirations, Compensation, Pharmacy practice motivations, and Impact of COVID-19 pandemic., Results: 23,007 CPhTs completed the survey. Respondents were primarily female (85.5%), age 30-39 (32.8%), and ≥ 10 years CPhT experience (42.8%). The majority of respondents cited improvement of patient health (77.4%), career advancement opportunities (53.5%), the ability to expand their role during emergencies (e.g., COVID-19) (52.6%), and future career advancement opportunities (51.7%) as benefits of CPhT certification. Increases in job responsibility after certification included changes occurring in roles related to clinical pharmacy services, patient education, preventive health services, provider communication, and staff training. Respondents agreed that PTCB-certification allowed for the expansion of pharmacists' services where they practiced, including clinical services (18.5%), patient education (18.3%), and preventive health services (18.1%)., Conclusion: CPhT's value certification for its benefits on career advancement, personal growth, and salary enhancement. Affirmation of skill and training through certification is also recognized to positively influence patient care and the pharmacy's ability to provide advanced patient care and services., (Copyright © 2024. Published by Elsevier Inc.)

Revised information requirements for endocrine disruptor (ED) assessment of chemicals under the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation have been proposed. Implementation will substantially increase demands for new data to inform ED assessment. This article evaluates the potential animal use and financial resource associated with two proposed ED policy options, and highlights areas where further clarification is warranted. This evaluation demonstrates that studies potentially conducted to meet the proposed requirements could use tens of millions of animals, and that the approach is unlikely to be feasible in practice. Given the challenges with implementing either policy option and the need to minimise the reliance on animal testing, further consideration and clarification is needed on several aspects prior to implementation of the requirements. This includes how testing will be prioritised in a proportionate approach; how to harness new approach methodologies to waive higher-tier animal testing; and need for provision of clear guidance particularly in applying weight-of-evidence approaches. There is now a clear opportunity for the European Commission to lead the way in developing a robust and transparent ED assessment process for industrial chemicals which fully implements replacement, refinement, and reduction of the use of animals (the 3Rs)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rebeccca J Brown, Rhiannon Smith reports financial support was provided by Corteva Agriscience and Concawe. L. Kent and J.R. Wheeler are affiliated to companies that develop and manufacture agrochemicals. S. Marty and N. Wang are affiliated to companies that develop and manufacture industrial chemicals. G. Guerrero-Limón and L.J. Saunders are affiliated to an organization primarily funded by the fuel manufacturing industry. Authors’ affiliations do not imply competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Ensuring pharmacy technicians are adequately trained and prepared to enter the workforce is an important first step in addressing technician staff shortages. How pharmacy technician learners perceive their experiences after completion of a training program remains unknown. This study evaluated participant outcomes and self-efficacy ratings for common technician competencies after completion of a pharmacy technician training program., Methods: Between December 2021 and March 2023, we distributed a survey to participants who successfully completed the program approximately 3 months after their estimated completion date. The survey assessed 6 domains: enrollment and academic progression, utilization of educational resources, self-perceived proficiency on core competencies of a pharmacy technician, employment information, program recommendations, and student demographics., Results: Thirty-six participants completed the survey, corresponding to a 60% response rate. Participants were attracted to the pharmacy technician program due to its affiliation with a college of pharmacy, online format, and affordability. Half of respondents were actively employed as pharmacy technicians, and the self-reported certification exam passage rate slightly exceeded national averages (78% vs 70% to 71%). Participants' self-efficacy ratings for pharmacy technician competencies were high (mean rating of 4.12 out of 5). Overwhelmingly, 97% of participants agreed that the program prepared them well for becoming a pharmacy technician., Conclusion: A pharmacy technician training program housed within a college of pharmacy presents one potential solution in addressing pharmacy technician workforce shortages. Participants positively viewed their training experience, with high self-efficacy ratings for pharmacy technician competencies. Moreover, national certification exam results were slightly better than national averages., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5'-diphospho-glucuronosyltransferase (UDPGT) induction. In total, 22 chemicals identified as thyroid-active or -inactive in Amphibian Metamorphosis Assays (AMAs) were tested using the XETA OECD Test Guideline. The comparison showed that both assays are highly concordant in identifying chemicals with mechanisms of action related to THR agonism, DIO inhibition, and GR agonism. They also consistently identified the UDPGT inducers as thyroid inactive. NIS inhibition, investigated using sodium perchlorate, was not detected in the XETA. TPO inhibition requires further mechanistic investigations as the reference chemicals tested resulted in opposing response directions in the XETA and AMA. This study contributes refining the applicability domain of the XETA, thereby helping to clarify the conditions where it can be used as an ethical alternative to the AMA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Du Pasquier, Benoit Salinier, Gregory Lemkine, Barbara Robin-Duchesne reports financial support was provided by CropLife Europe. Laurent Lagadic reports a relationship with Bayer CropScience AG that includes: employment. This work was supported by CropLife Europe as a Company Investment Project and research and development funds from Corteva Agriscience USA. The employment affiliation of the authors is listed on the cover page. BRD, BS, DDP and GL are affiliated to Laboratoire WatchFrog, developer of the Xenopus Eleutheroembryonic Thyroid Assay (XETA) and coordinator of the validation of OECD TG 248. AJ, JL, JRW, KKC, LL, LW and OK are affiliated to companies that manufacture agrochemicals, some of which having been used in the present study. There are no other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Amphibians are currently considered to be covered by pesticide Environmental Risk Assessment schemes by surrogacy assumptions of exposure and susceptibility based on typical laboratory test species such as fish, mammals, and birds. While multiple reviews have shown for this approach to be adequate in the case of aquatic stages, the same cannot be definitively stated for terrestrial stages. Concerns have risen that exposure of amphibians is likely to be highly influenced by dermal absorption, primarily due to the high permeability of their skin and the lack of a protective layer, such as fur or feathers. It is thus hypothesized that dermal uptake could be a significant route of exposure. Consequently, it is necessary to determine the relative importance of different exposure routes that might affect the integrated toxicity outcome for terrestrial amphibian life-stages. Here, a one-compartment Toxicokinetic model was derived and tested using a publicly available dataset containing relevant exposure and uptake information for juvenile anurans exposed to 13 different pesticides. Modelled body burdens were then compared to measured burdens for a total of 815 individuals. Overall, a good concordance between modelled and measured values was observed, with the predicted and measured body burdens differing by a factor of 2 on average (overall R 2 of 0.80 and correlation coefficient of 0.89), suggesting good predictivity of the model. Accordingly, the model predicts realistic body burdens for a variety of frog and toad species, and overall, for anurans. As the model includes rehydration (implicit in the evaluated studies) but currently does not account for metabolism, it can be seen as a worst-case assessment. We suggest toxicokinetic models, such as the one here presented, could be used to characterize dermal exposure in amphibians, screen for pesticides of concern, and prioritize risk assessment efforts, whilst reducing the need for de novo vertebrate testing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Valentin Mingo reports a relationship with Corteva Agriscience that includes: employment. James R. Wheeler reports a relationship with Corteva Agriscience that includes: employment. Manousos Foudoulakis reports a relationship with Corteva Agriscience that includes: employment. VM, JRW and MF are full time employees for Corteva Agriscience. The authors declare no conflicts of interest. We are grateful for the thoughtful comments of Vince Kramer, John Marton and Marina Lauck, that greatly improved the manuscript. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dengue fever, a prevalent and rapidly spreading arboviral disease, poses substantial public health and economic challenges in tropical and sub-tropical regions worldwide. Predicting infectious disease outbreaks on a countrywide scale is complex due to spatiotemporal variations in dengue incidence across administrative areas. To address this, we propose a machine learning ensemble model for forecasting the dengue incidence rate (DIR) in Brazil, with a focus on the population under 19 years old. The model integrates spatial and temporal information, providing one-month-ahead DIR estimates at the state level. Comparative analyses with a dummy model and ablation studies demonstrate the ensemble model's qualitative and quantitative efficacy across the 27 Brazilian Federal Units. Furthermore, we showcase the transferability of this approach to Peru, another Latin American country with differing epidemiological characteristics. This timely forecast system can aid local governments in implementing targeted control measures. The study advances climate services for health by identifying factors triggering dengue outbreaks in Brazil and Peru, emphasizing collaborative efforts with intergovernmental organizations and public health institutions. The innovation lies not only in the algorithms themselves but in their application to a domain marked by data scarcity and operational scalability challenges. We bridge the gap by integrating well-curated ground data with advanced analytical methods, addressing a significant deficiency in current practices. The successful transfer of the model to Peru and its consistent performance during the 2019 outbreak in Brazil showcase its scalability and practical application. While acknowledging limitations in handling extreme values, especially in regions with low DIR, our approach excels where accurate predictions are critical. The study not only contributes to advancing DIR forecasting but also represents a paradigm shift in integrating advanced analytics into public health operational frameworks. This work, driven by a collaborative spirit involving intergovernmental organizations and public health institutions, sets a precedent for interdisciplinary collaboration in addressing global health challenges. It not only enhances our understanding of factors triggering dengue outbreaks but also serves as a template for the effective implementation of advanced analytical methods in public health., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey C. Wolf reports financial support was provided by Corteva Agriscience. Jeffrey C. Wolf reports a relationship with Corteva Agriscience that includes: consulting or advisory., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Total elbow replacement (TER) is an accepted treatment for complex intra-articular distal humerus fractures in elderly patients. Distal humeral hemiarthroplasty (HA) is also a potential surgical option for unreconstructable fractures and avoids the concerns regarding mechanical wear and functional restrictions associated with TER. In the current literature, there are limited data available to compare the revision rates of HA and TER for the treatment of fracture. We used data from a large national arthroplasty registry to compare the outcome of HA and TER undertaken for fracture/dislocation and to assess the impact of demographics and implant choice on revision rates., Methods: Data obtained from the Australian Orthopaedic Association National Joint Replacement Registry from May 2, 2005, to December 31, 2021, included all procedures for primary elbow replacement with primary diagnosis of fracture or dislocation. The analyses were performed using Kaplan-Meier estimates of survivorship and hazard ratios (HRs) from Cox proportional hazards models., Results: There were 293 primary HA and 631 primary TER procedures included. The cumulative percentage revision (CPR) rate at 9 years was 9.7% for HA (95% confidence interval [CI] 6.0, 15.7), and 11.9% (95% CI 8.5, 16.6) for TER. When adjusted for age and gender, there was a significantly higher risk of revision after 3 months for TER compared to HA (HR 2.47, 95% CI 1.22, 5.03, P = .012). There was no difference in the rate of revision for patients aged <55 years or ≥75 years when HA and TER procedures were compared. In primary TER procedures, loosening was the most common cause of revision (3.6% of primary TER procedures), and the most common type of revision in primary TER involved revision of the humeral component only (2.6% of TER procedures). TER has a higher rate of first revision for loosening compared to HA (HR 4.21, 95% CI 1.29, 13.73; P = .017). In HA procedures, instability (1.7%) was the most common cause for revision. The addition of an ulna component was the most common type of revision (2.4% of all HA procedures)., Conclusion: For the treatment of distal humerus fractures, HA had a lower revision rate than TER after 3 months when adjusted for age and gender. Age <55 or ≥75 years was not a risk factor for revision when HA was compared to TER. Loosening leading to revision is more prevalent in TER and increases with time. In HA, the most common type of revision involved addition of an ulna component with preservation of the humeral component., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rebeccca J Brown, Grace Panter reports financial support was provided by Bayer AG. E.R. Salinas, L. Weltje, J.R. Wheeler, Y. Wolf, B. Holmes, and L. Lagadic are affiliated to companies that develop and manufacture agrochemicals. Authors’ affiliations do not imply competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitellogenin (VTG), a biomarker for endocrine activity, is a mechanistic component of the regulatory assessment of potential endocrine-disrupting properties of chemicals. This review of VTG data is based on changes reported for 106 substances in standard fish species. High intra-study and inter-laboratory variability in VTG concentrations was confirmed, as well as discrepancies in interpretation of results based on large differences between fish in the dilution water versus solvent control, or due to the presence of outlier measurements. VTG responses in fish were ranked against predictions for estrogen receptor agonist activity and aromatase inhibition from bioactivity model output and ToxCast in vitro assay results, respectively. These endocrine mechanisms explained most of the VTG responses in the absence of systemic toxicity, the magnitude of the VTG response being proportional to the in vitro potency. Interpretation of the VTG data was sometimes confounded by an alternative endocrine mechanism of action. There was evidence for both false positive and negative responses for VTG synthesis, but overall, it was rare for substances without endocrine activity in vitro to cause a concentration-dependent VTG response in fish in the absence of systemic toxicity. To increase confidence in the VTG results, we recommend improvements in the VTG measurement methodologies and greater transparency in reporting of VTG data (including quality control criteria for assay performance). This review supports the application of New Approach Methodologies (NAMs) by demonstrating that endocrine activity in vitro from mammalian cell lines is predictive for in vivo VTG response in fish, suggesting that in vitro mechanistic data could be used more broadly in decision-making to help reduce animal testing., Competing Interests: Declaration of competing interest The employment affiliation of the authors is listed on the cover page. Rebecca J. Brown and Grace H. Panter are affiliated to wca environment Ltd., an independent consultancy providing objective advice on the risk assessment of chemicals in the environment and the workplace. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rebecca J Brown and Grace H. Panter both report financial support was provided by Bayer AG. Natalie Burden is affiliated to NC3Rs, an independent scientific organisation, tasked by Government with supporting the UK science base through the application of the 3Rs. Edward R. Salinas, Lennart Weltje, James R. Wheeler, Yvonne Wolf, and Laurent Lagadic are affiliated to companies that develop and manufacture agrochemicals, some of which having been included in the present review., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The burden from medication costs for treating heart failure can be financially toxic for uninsured/underinsured patients and their families. Prescription discount cards, which offer cash price reductions, may decrease out-of-pocket costs for patients without prescription benefits, but the degree to which they offer financial relief remains unclear. Our objective was to assess the financial burden for uninsured/underinsured patients prescribed a drug from each of the 4 standard classes of medications for heart failure with reduced ejection fraction. A second objective assessed whether discounts varied across economically and geographically diverse regions in Tennessee., Methods: This was a cross-sectional pricing analysis of guideline-directed medical therapy heart failure with reduced ejection fraction regimens utilizing prescription discount cards. Between February 9 and March 31, 2022, we conducted searches on 3 discount card websites (GoodRx, NeedyMeds, and Blink Health) for the prices of 30- and 90-day supplies of select guideline-directed medical therapy heart failure regimens for 6 Tennessee ZIP codes. Prices were compared with Amazon and Redbook prices., Results: Monthly costs among discount card services varied from $10.58 to $30.86 for a generic 3-drug regimen consisting of beta blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. With the addition of a sodium-glucose cotransporter-2 inhibitor, prices increased to $540.32 to $593.74. The ideal 4-drug regimen (beta blocker, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter-2 inhibitor) ranged from $1188.31 to $1464.54. When compared with Amazon cash prices, the cards offered an average discount of 65% on a generic 3-drug regimen; when brand-name medications were added, discounts were modest (<12%). There were no significant variations in pricing based on ZIP codes in differing economic and geographic regions., Conclusions: Although prescription discount cards offered significant savings on generic medications, brand-name drug discounts were small and overall costs remained high. These findings highlight the potential for unequal access to life-saving therapies for heart failure with reduced ejection fraction., Competing Interests: Disclosures Dr Hauptman serves on the Clinical Events Committee for the ANTHEM HFrEF study (https://www.clinicaltrials.gov; Unique identifier: NCT03425422) sponsored by LivaNova, the Steering Committee for REALM-DCM (https://www.clinicaltrials.gov; Unique identifier: NCT03439514), a rare diseases study sponsored by Array Biopharma/Pfizer, and a working group evaluating best practices concerning digoxin toxicity sponsored by BTG Inc. The other authors report no conflicts.

Background: Reconstruction techniques after subtotal colectomy (STC) and end ileostomy for ulcerative colitis (UC), include ileal pouch-anal anastomosis (IPAA), ileorectal anastomosis (IRA) and continent ileostomy. Aim: To assess surgical strategies and outcomes after subtotal colectomy for UC by calculating the proportions of patients who had further surgery 10 years post-STC and those who did not undergo surgery but who were under surveillance, and histological analysis of pathology specimens from STC and proctectomy. Methods: Patients who had STC for UC from 2002 to 2018 were identified. Variables of interest were extracted from electronic records. Survival analysis on reconstruction surgery was performed using Kaplan-Meier curves. Curves were censored for loss from follow-up and death. Subtotal colectomy and proctectomy specimens were assessed by a pathologist for acute inflammation at the distal resection margin and within the resected bowel, and for dysplasia or cancer. Results: One hundred and ninety-two patients were included. Eighty-nine (46.3%) underwent proctectomy: eight had panproctocolectomy; thirty had completion proctectomy and the remaining fifty-one of the eighty-nine patients (27%) had IPAA. One patient who did not undergo a proctectomy had an ileorectal anastomosis. Sixty-one (69%) proctectomy specimens had active inflammation, with 29 (48%) including the resection margins. Of the 103 patients who did not have completion surgery, 72 (69%) were under surveillance as of August 2021. No patients in this non-operative group had developed cancer of the residual rectum at follow up. Conclusions: At 10 years after STC for UC, eighty-nine (46.4%) patients had proctectomy, of which fifty-two had IPAA (27%). However, no inflammation was found in the proctectomy specimen in one third of these patients. Therefore, it is possible that IRA may still have a role in the occasional patient with UC.

Aim: The incidence of benign colonic anastomotic stricture is approximately 2% in patients undergoing left hemicolectomy or anterior resection and as high as 16% in patients undergoing low anterior or intersphincteric resection. In the majority, rather than complete occlusion, a stenosis forms, which can be managed with endoscopic balloon dilatation, a self-expanding metallic stent or endoscopic electroincision. In the less common scenario of a completely occluded colonic anastomosis, surgery is often required. In this study, we aim to describe the technique we used to treat this condition non-operatively METHOD: We describe a case series of three patients with benign complete occlusion of their colorectal anastomosis and how we managed them nonoperatively with a colonic/rectal endoscopic ultrasound (EUS) anastomosis technique and a Hot lumen-apposing metallic stent., Results: We demonstrate that the technical and clinical success for this technique is 100%., Conclusions: We believe that the technique we describe is effective and safe. It should be widely reproducible in centres with expertise in interventional EUS, given the similarity to well-established procedures such as EUS-guided gastroenterostomy. Patient selection and timing of reversal of ileostomy need careful consideration, especially in patients with a history of keloid formation. Given the shorter hospital stay and reduced invasiveness of this technique, we believe it should be considered for all patients who have complete benign occlusion of a colonic anastomosis. However, given the small number of cases and short period of follow-up, the long-term outcome of this technique is not known. More studies with higher power and a longer period of follow-up should be conducted to further ascertain the effectiveness of this technique., (© 2023 Association of Coloproctology of Great Britain and Ireland.)

The toxicity and ecotoxicity of pesticide active ingredients are evaluated by a number of standardized test methods using vertebrate animals. These standard test methods are required under various regulatory programs for the registration of pesticides. Over the past two decades, additional test methods have been developed with endpoints that are responsive to endocrine activity and subsequent adverse effects. This article examines the available test methods and their endpoints that are relevant to an assessment of endocrine-disrupting properties of pesticides. Furthermore, the article highlights how weight-of-evidence approaches should be applied to determine whether an adverse response in (eco)toxicity tests is caused by an endocrine mechanism of action. The large number of endpoints in the current testing paradigms for pesticides make it unlikely that endocrine activity and adversity is being overlooked. Integr Environ Assess Manag 2023;19:1089-1109. © 2023 Bayer CropScience and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2023 Bayer CropScience and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

The amphibian metamorphosis assay (AMA) is a key in vivo endocrine screen to investigate chemicals with potential thyroid activity. The test guidelines and associated guidance consider that treatment-related effects on thyroid gland histomorphology automatically result in the assay being considered positive for thyroid activity, independent of the direction of change or conflicting results in the other biological endpoints. An AMA study was conducted with five different feeding rations equivalent to 50%, 30%, 20%, 10%, and 5% of the recommended feeding rate. Biological endpoints relating to growth and development, including thyroid gland histopathology, were evaluated, and the specificity of these endpoints for the determination of thyroid activity was assessed. There was no effect on survival or clinical signs of toxicity. Effects related to feed reduction generally occurred in a feeding ration-response manner and included reduced development stage; reduced body weight and body length metrics; decreased prevalence of thyroid follicular cell hyperplasia and hypertrophy, and the occurrence of thyroid atrophy; reduced liver vacuolation; and the occurrence of liver atrophy. The results indicate that treatment-related histopathological changes in the AMA can be induced by Non-chemical factors; therefore histopathological results are not necessarily diagnostically specific for chemically induced thyroid endocrine activity. Consequently, the interpretation of data from AMA studies should be adjusted accordingly. We recommend that the decision logic presented in the test guidelines and associated guidance be changed to reflect a requirement for directional agreement between the thyroid histopathology findings and the growth and developmental endpoints before it is concluded that a test substance has thyroid endocrine activity. Environ Toxicol Chem 2023;42:1061-1074. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

In order to protect European Union (EU) drinking water resources from chemical contamination, criteria for identifying persistent, mobile, and toxic (PMT) chemicals and very persistent and very mobile (vPvM) chemicals under the EU REACH Regulation were proposed by the German Environment Agency (Umweltbundesamt-UBA). Additionally, new hazard classes for PMT and vPvM substances in the revised EU classification, labeling, and packaging (CLP Regulation) are intended. Therefore, a reliable approach in the identification of potential drinking water resource contaminants is needed. The scientific basis of the property-based PMT/vPvM criteria, focusing on mobility, which dictates the migration of chemical drinking water sources, was evaluated, and a critical analysis of the deviation of sorption metrics from simple behavior was carried out. Based on our evaluation, a K oc may be used for nonionic substances on a screening level only, requiring a higher tier assessment. It is considered inappropriate for hydrophilic and ionizable chemicals, particularly for soils with low organic carbon contents. The nonextractable residue formation is complex and not well understood but remains significant in limiting the mobility of chemicals through soils and sediments. In order to inform the EU commission's work on the introduction of new hazard classes for PMT and vPvM substances into the European legislation, the derivation of a tiered approach is proposed, which utilizes the weight of evidence available, with adoption of appropriate higher tier models commensurate with the nature of the substance and the data available. Integr Environ Assess Manag 2023;19:775-791. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Objective: To assess pharmacy student responses to medication problems with and without clinical decision support (CDS) alerts during simulated order verification., Methods: Three classes of students completed an order verification simulation. The simulation randomized students to a different series of 10 orders with varying CDS alert frequency. Two of the orders contained medication-related problems. The appropriateness of the students' interventions and responses to the CDS alerts were evaluated. In the following semester for 2 classes, 2 similar simulations were completed. All 3 simulations contained 1 problem with and 1 without an alert., Results: During the first simulation, 384 students reviewed an order with a problem and an alert. Students exposed to prior inappropriate alerts within the simulation had less appropriate responses (66% vs 75%). Of 321 students who viewed a second order with a problem, those reviewing an order lacking an alert recommended an appropriate change less often (45% vs 87%). Among 351 students completing the second simulation, those who participated in the first simulation appropriately responded to the alert for a problem more often than those who only received a didactic debrief (95% vs 87%). Among those completing all 3 simulations, appropriate responses increased between simulations for problems with (n = 238, 72-95-93%) and without alerts (n = 49, 53-71-90%)., Conclusions: Some pharmacy students displayed baseline alert fatigue and overreliance on CDS alerts for medication problem detection during order verification simulations. Exposure to the simulations improved CDS alert response appropriateness and detection of problems., (Copyright © 2023 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide. New approach methodologies (NAMs) hold great promise to identify molecular, cellular, and tissue changes that can be used to predict effects reliably and more efficiently at the individual level (and potentially on populations) while reducing the number of animals used in (eco)toxicological testing for endocrine disruption. In a collaborative effort, experts from government, academia, and industry met in 2020 to discuss the current challenges of testing for endocrine activity assessment for fish and amphibians. Continuing this cross-sector initiative, our review focuses on the current state of the science regarding the use of NAMs to identify chemical-induced endocrine effects. The present study highlights the challenges of using NAMs for safety assessment and what work is needed to reduce their uncertainties and increase their acceptance in regulatory processes. We have reviewed the current NAMs available for endocrine activity assessment including in silico, in vitro, and eleutheroembryo models. New approach methodologies can be integrated as part of a weight-of-evidence approach for hazard or risk assessment using the adverse outcome pathway framework. The development and utilization of NAMs not only allows for replacement, reduction, and refinement of animal testing but can also provide robust and fit-for-purpose methods to identify chemicals acting via endocrine mechanisms. Environ Toxicol Chem 2023;42:757-777. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Objective. To survey pharmacists, including those who make or contribute to hiring decisions, regarding certificate training programs and specifically about a primary care certificate for pharmacists. Methods. We conducted a cross-sectional survey of pharmacist registrants of the Office of Continuing Professional Development at the University of Tennessee Health Science Center College of Pharmacy's listserve, including both hiring and non-hiring pharmacists. The 40-question survey probed perceptions of various types of postgraduate training and the design of a primary care certificate training program for pharmacists. Data were collected between November and December 2020. Results. A total of 230 pharmacists participated in this study (14% response rate), and most reported practicing in the community (n=126, 57%). Nearly half of the respondents reported making or contributing to hiring decisions of other pharmacists (n=94, 41%), and, of those, most reported that completion of a primary care certificate program by a candidate would increase their likelihood of hiring that candidate (n=50, 78%). Both groups (hiring and non-hiring pharmacists) most commonly reported that a primary care certificate training program should be 30 hours total and 12 weeks in length, ranked communication as the most important topic to be included, and indicated the didactic and simulation/experiential components should be similarly weighted. Conclusions. Pharmacists, including those who make or contribute to hiring decisions, reported valuing certificate training programs. Developing a certificate training program that is at least 30 hours in length over 12 weeks may serve as an opportunity to address gaps in primary care in the United States., (© 2023 American Association of Colleges of Pharmacy.)

Aim: 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., Design: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Children and young people in contact with forensic child and adolescent mental health services present with more complex needs than young people in the general population. Recent policy in child and adolescent mental health has led to the implementation of new workstreams and programmes to improve service provision. This research examines the characteristics of children and young people referred to recently commissioned Community Forensic Child and Adolescent Services (F:CAMHS) and service activity during the first 24 months of service. The study is a national cohort study to describe the population and investigate service provision and access across England. Secondary data on 1311 advice cases and 1406 referrals are included in analysis. Findings show that 71.9% of the sample had accessed mainstream CAMHS before their referral, 50.9% had experienced/witnessed multiple traumatic events and 58.4% of young people presented with multiple difficulties. The results of the study highlight the complexity of the cohort and a need for interagency trauma-informed working. This is the first study to describe the characteristics of children and young people referred to Community F:CAMHS and provides valuable information on pathways and needs to inform service policy and provision., (© 2021. The Author(s).)

Bacteria commonly live in surface-associated communities where steep gradients of antibiotics and other chemical compounds can occur. While many bacterial species move on surfaces, we know surprisingly little about how such antibiotic gradients affect cell motility. Here, we study the behaviour of the opportunistic pathogen Pseudomonas aeruginosa in stable spatial gradients of several antibiotics by tracking thousands of cells in microfluidic devices as they form biofilms. Unexpectedly, these experiments reveal that bacteria use pili-based ('twitching') motility to navigate towards antibiotics. Our analyses suggest that this behaviour is driven by a general response to the effects of antibiotics on cells. Migrating bacteria reach antibiotic concentrations hundreds of times higher than their minimum inhibitory concentration within hours and remain highly motile. However, isolating cells - using fluid-walled microfluidic devices - reveals that these bacteria are terminal and unable to reproduce. Despite moving towards their death, migrating cells are capable of entering a suicidal program to release bacteriocins that kill other bacteria. This behaviour suggests that the cells are responding to antibiotics as if they come from a competing colony growing nearby, inducing them to invade and attack. As a result, clinical antibiotics have the potential to lure bacteria to their death., (© 2022. The Author(s).)

Background: Different techniques exist for the imaging of lateral lymph nodes in rectal cancer., Objective: This study aimed to compare the diagnostic accuracy of pelvic MRI, 18 F-FDG-PET/CT, and 18 F-FDG-PET/MRI for the identification of lateral lymph node metastases in rectal cancer., Data Sources: Data sources include PubMed, Embase, Cochrane Library, and Google Scholar., Study Selection: All studies evaluating the diagnostic accuracy of pelvic MRI, 18 F-FDG-PET/CT, and 18 F-FDG-PET/MRI for the preoperative detection of lateral lymph node metastasis in patients with rectal cancer were selected., Interventions: The interventions were pelvic MRI, 18 F-FDG-PET/CT, and/or 18 F-FDG-PET/MRI., Main Outcome Measures: Definitive histopathology was used as a criterion standard., Results: A total of 20 studies (1,827 patients) were included out of an initial search yielding 7,360 studies. The pooled sensitivity of pelvic MRI was 0.88 (95% CI, 0.85-0.91), of 18 F-FDG-PET/CT was 0.83 (95% CI, 0.80-0.86), and of 18 F-FDG-PET/MRI was 0.72 (95% CI, 0.51-0.87) for the detection of lateral lymph node metastasis. The pooled specificity of pelvic MRI was 0.85 (95% CI, 0.78-0.90), of 18 F-FDG-PET/CT was 0.95 (95% CI, 0.86-0.98), and of 18 F-FDG-PET/MRI was 0.90 (95% CI, 0.78-0.96). The area under the curve was 0.88 (95% CI, 0.85-0.91) for pelvic MRI and was 0.83 (95% CI, 0.80-0.86) for 18 F-FDG-PET/CT., Limitations: Heterogeneity in terms of patients' populations, definitions of suspect lateral lymph nodes, and administration of neoadjuvant treatment., Conclusions: For the preoperative identification of lateral lymph node metastasis in rectal cancer, this review found compelling evidence that pelvic MRI should constitute the imaging modality of choice. In contrast, to confirm the presence of lateral lymph node metastasis, 18 F-FDG-PET/MRI modalities allow discarding false positive cases because of increased specificity., Prospero Registration Number: CRD42020200319., (Copyright © The ASCRS 2022.)

Objectives: To compare minimal trauma hip fractures (MTHF) between older Indigenous and non-Indigenous Australians., Methods: Epidemiological study of retrospective New South Wales hospitalisation data (2005-2016) for MTHF among Indigenous and non-Indigenous Australians over 40 years of age., Results: Estimated age-standardised rates of MTHF were lower among Indigenous Australians than non-Indigenous Australians (142.2 vs. 161.7 per 100,000) with a direct standardised rate ratio of 0.887 (95%CI 0.78-0.99, p = 0.031). However, for both male and female Indigenous Australians, MTHF occur at a younger age than in non-Indigenous Australians (age 40-74: 52% vs. 19%, p < 0.001). Proportions of MTHF are higher among women and were almost double among rural Indigenous Australians compared with rural non-Indigenous Australians (59% vs. 31%, p < 0.001)., Conclusions: New South Wales Hospitalisation data showed that estimated age-standardised rates of MTHF appear lower among Indigenous Australians than in non-Indigenous Australians but also occur at a younger age for Indigenous people. MTHF are more common among rural Indigenous Australians and women., (© 2022 The Authors. Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Background: Ensuring opportunities exist to dispose of unused or unwanted drugs that are appropriate, accessible, and affordable is critical to avoid misuse and lasting harm to the environment., Objective: The objectives of this study were to identify state statutes promulgated in all 50 states and the District of Columbia (DC) facilitating disposal of unused or unwanted drugs in the community setting and assess their characteristics., Methods: A retrospective review of state statutes in all 50 U.S. states and DC between October 2020 and May 2022 was conducted. Statutes using terms "drug and disposal or collection" and that were intended to facilitate disposal of unused or unwanted drugs were included. Drug donation programs or repositories, drug returns to the pharmacy, charitable clinics, and others not intended to dispose or unused or unwanted drugs were excluded. Publicly available resources and Westlaw, a legal resource, were used to identify state statutes. Descriptive statistics were used to describe the findings., Results: Of the 50 U.S. states and DC, we found that most states enacted a statute pertaining to drug disposal (63%; n = 32) as of May 2022. Of states with a drug disposal statute, few had funding mechanisms or required pharmacy participation. Most statutes specified the type of product that may be accepted for disposal, what site may accept them, and who may dispose of the product. Few states specified which health care provider or other individual may accept the product(s) for disposal., Conclusion: Most states have enacted statutes facilitating drug disposal, but their characteristics varied widely. Opportunities may exist at the state level to further incentivize proper drug disposal, and further research is needed to measure possible effects of these state statutes., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: As the pharmacy profession transforms toward practice centered around direct patient care and clinical services, upskilling the existing workforce may be required for pharmacists to take on expanded roles, especially in an increasingly competitive job market., Objective: To explore pharmacist employer perceptions of a primary care certificate training program including its design, value, and relevance and to develop and implement a pharmacist primary care certificate training program based on study results., Methods: Focus groups were conducted to a point of saturation in December 2020 via video conference. Participants were identified via the study institution's continuing professional development registrant listserv and invited to participate via self-selection. Interviews were recorded, transcribed, and underwent inductive thematic analysis., Results: Four focus groups were conducted with 15 pharmacist employers. Employers perceived primary care certificate training as valuable, helping pharmacists sustain shifting roles and increasing opportunities in a competitive job market. A combination of clinical and practice management topics with emphasis on an experiential component was recommended to achieve expected competency levels and favorably influence hiring decisions. The primary care certificate was specifically recommended to pharmacists aiming to transition into primary care or for pharmacists who did not complete residency training., Conclusions: This study's findings informed development of a pharmacist primary care certificate program containing didactic and experiential training on a variety of key topics. As pharmacists' roles evolve, this program may prepare pharmacists to engage in direct patient care and develop skills and expertise necessary to succeed in outpatient primary care., Competing Interests: None., (© 2022 The Authors.)

Background: The impact of body mass index (BMI) on long-term survival outcomes after colorectal cancer surgery is debated., Design: A systematic literature review and meta-analysis was performed to compare long-term survival outcomes of patients of different BMI categories after colorectal cancer surgery., Results: Of the 2588 articles screened, 56 articles met the inclusion criteria, reporting on 72,582 participants. Patients with BMI &lt;18.5 had significantly worse overall survival [hazard ratio (HR) 1.91; P &lt; 0.0001], cancer-specific survival (HR = 1.91; P &lt; 0.0001), disease-free survival (HR = 1.50; P &lt; 0.0001) and recurrence-free survival (HR = 1.13; P = 0.007) compared to patients with a BMI of 18.5-25. There was no significant difference between those with BMI 25-30 and 18.5-25 in overall survival, cancer-specific survival, disease-free survival and recurrence-free survival, except for the subgroup of patients with colon cancer where patients with BMI 25-30 had significantly improved overall survival (HR = 0.90; P = 0.05) and disease-free survival (HR = 0.90; P = 0.04). Patients with BMI &gt;30 had significantly worse disease-free survival (HR = 1.05; P = 0.03) compared to patients with a BMI of 18.5-25, but no significant difference in overall survival, cancer-specific survival and recurrence-free survival. Patients with BMI &gt;35 compared to 18.5-25 had significantly worse overall survival (HR = 1.24; P = 0.02), cancer-specific survival (HR = 1.36; P = 0.01), disease-free survival (HR = 1.15; P = 0.03) and recurrence-free survival for colon (HR = 1.11; P = 0.04) and rectal (HR = 4.10; P = 0.04) cancer., Conclusions: Being underweight (BMI &lt; 18.5) or class II/III obese (BMI &gt; 35) at the time of colorectal cancer surgery may result in worse long-term survival outcomes, whereas being overweight (BMI 25-30) may improve survival in a subgroup of patients with colon cancer. Optimising BMI may preoperatively improve long-term survival after surgery for colorectal cancer., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The present case-series describes the first full-robotic colorectal resections performed with the new CMR Versius platform (Cambridge Medical Robotics Surgical, 1 Evolution Business Park, Cambridge, United Kingdom) by an experienced robotic surgeon., Methods: In a period between July 2020 and December 2020, patients aged 18 years or older, who were diagnosed with colorectal cancer and were fit for minimally invasive surgery, underwent robotic colorectal resection with CMR Versius robotic platform at "Casa di Cura Cobellis" in Vallo della Lucania,Salerno, Italy. Three right colectomies, 2 sigmoid colectomies and 1 anterior rectal resection were performed. All the procedures were planned as fully robotic. Surgical data were retrospectively reviewed from a prospectively collected database., Results: Four patients were male and 2 patients were female with a median (range) age of 66 (47-72) years. One covering ileostomy was created. Full robotic splenic flexure mobilization was performed. No additional laparoscopic gestures or procedures were performed in this series except for clipping and stapling which were performed by the assistant surgeon due to the absence of robotic dedicated instruments. Two ileocolic anastomoses, planned as robotic-sewn, were performed extracorporeally. One Clavien-Dindo II complication occurred due to a postoperative blood transfusion. Median total operative time was 160 (145-294) min for right colectomies, 246 (191-300) min for sigmoid colectomies and 250 min for the anterior rectal resection., Conclusions: The present series confirms the feasibility of full-robotic colorectal resections while highlighting the strengths and the limitations of the CMR Versius platform in colorectal surgery. New devices will need more clinical development to be comparable to the current standard., (© 2022. The Author(s).)

Background: The opioid epidemic continues to have a significant negative impact on public health in the United States. Community pharmacies represent an important care setting in confronting the opioid epidemic. However, they continue to be an underutilized care access point. Pharmacy technicians are often the first and most frequent pharmacy personnel to interact with people receiving a prescription for opioid medications. There is a paucity of studies conducted with pharmacy technicians as it pertains to interactions with these patients., Objectives: To explore community pharmacy technicians' roles and their personal experiences when interacting with patients who are receiving a prescription for opioid medications., Methods: A qualitative design was employed in use of focus groups (FGs) conducted virtually across several regions of the United States. Audio recordings of U.S. FGs were transcribed verbatim and imported via Dedoose (v2.0, Dedoose, Manhattan Beach, CA,) for further data assessment using thematic analysis. The researchers used the Consolidated Criteria for Reporting Qualitative Research., Results: In total, 46 pharmacy technicians participated in 8 FGs. The average length of time for FG was 56 minutes. The mean for the work experience was 7 years, with a range of 1 to 44. Of 46 subjects, 34 were working in a community setting, and the rest were in a hospital setting. Most of the subjects practiced in Tennessee and California at the time of the study. Two themes emerged from the data: "Interactions between pharmacy technicians and patients who are using opioid prescriptions," and "Interactions between pharmacy technicians and the pharmacy team while dispensing opioid prescriptions.", Conclusion: Pharmacy technicians serve as a key health care system touchpoint in the community pharmacy. Although pharmacy technicians are exposed to people receiving a prescription for opioid medications, they feel under-resourced and ill-quipped to adequately serve this patient population., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Microfluidic devices are widely used in many fields of biology, but a key limitation is that cells are typically surrounded by solid walls, making it hard to access those that exhibit a specific phenotype for further study. Here, we provide a general and flexible solution to this problem that exploits the remarkable properties of microfluidic circuits with fluid walls─transparent interfaces between culture media and an immiscible fluorocarbon that are easily pierced with pipets. We provide two proofs of concept in which specific cell subpopulations are isolated and recovered: (i) murine macrophages chemotaxing toward complement component 5a and (ii) bacteria ( Pseudomonas aeruginosa ) in developing biofilms that migrate toward antibiotics. We build circuits in minutes on standard Petri dishes, add cells, pump in laminar streams so molecular diffusion creates attractant gradients, acquire time-lapse images, and isolate desired subpopulations in real time by building fluid walls around migrating cells with an accuracy of tens of micrometers using 3D printed adaptors that convert conventional microscopes into wall-building machines. Our method allows live cells of interest to be easily extracted from microfluidic devices for downstream analyses.

Many regulations are beginning to explicitly require investigation of a chemical's endocrine-disrupting properties as a part of the safety assessment process for substances already on or about to be placed on the market. Different jurisdictions are applying distinct approaches. However, all share a common theme requiring testing for endocrine activity and adverse effects, typically involving in vitro and in vivo assays on selected endocrine pathways. For ecotoxicological evaluation, in vivo assays can be performed across various animal species, including mammals, amphibians, and fish. Results indicating activity (i.e., that a test substance may interact with the endocrine system) from in vivo screens usually trigger further higher-tier in vivo assays. Higher-tier assays provide data on adverse effects on relevant endpoints over more extensive parts of the organism's life cycle. Both in vivo screening and higher-tier assays are animal- and resource-intensive and can be technically challenging to conduct. Testing large numbers of chemicals will inevitably result in the use of large numbers of animals, contradicting stipulations set out within many regulatory frameworks that animal studies be conducted as a last resort. Improved strategies are urgently required. In February 2020, the UK's National Centre for the 3Rs and the Health and Environmental Sciences Institute hosted a workshop ("Investigating Endocrine Disrupting Properties in Fish and Amphibians: Opportunities to Apply the 3Rs"). Over 50 delegates attended from North America and Europe, across academia, laboratories, and consultancies, regulatory agencies, and industry. Challenges and opportunities in applying refinement and reduction approaches within the current animal test guidelines were discussed, and utilization of replacement and/or new approach methodologies, including in silico, in vitro, and embryo models, was explored. Efforts and activities needed to enable application of 3Rs approaches in practice were also identified. This article provides an overview of the workshop discussions and sets priority areas for follow-up. Integr Environ Assess Manag 2022;18:442-458. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Professional surgical societies recommend the identification and treatment of pre-operative anaemia in patients scheduled for abdominal surgery. Our aim was to determine if pre-operative iron allows correction of haemoglobin concentration and decreased incidence of peri-operative blood transfusion in patients undergoing major abdominal surgery. MEDLINE, Embase and CENTRAL were searched for RCTs written in English and assessing the effect of pre-operative iron on the incidence of peri-operative allogeneic blood transfusion in patients undergoing major abdominal surgery. Pooled relative risk (RR), risk difference (RD) and mean difference (MD) were obtained using models with random effects. Heterogeneity was assessed using the Q-test and quantified using the I 2 value. Four RCTs were retained for analysis out of 285 eligible articles. MD in haemoglobin concentration between patients with pre-operative iron and patients without pre-operative iron was of 0.81 g/dl (3 RCTs, 95% CI 0.30 to 1.33, I 2 : 60%, p = 0.002). Pre-operative iron did not lead to reduction in the incidence of peri-operative blood transfusion in terms of RD (4 RCTs, RD: - 0.13, 95% CI - 0.27 to 0.01, I 2 : 65%, p = 0.07) or RR (4 RCTs, RR: 0.57, 95% CI 0.30 to 1.09, I 2 : 64%, p = 0.09). To conclude, pre-operative iron significantly increases haemoglobin concentration by 0.81 g/dl before abdominal surgery but does not reduce the need for peri-operative blood transfusion. Important heterogeneity exists between existing RCTs in terms of populations and interventions. Future trials should target patients suffering from iron-deficiency anaemia and assess the effect of intervention on anaemia-related complications., (© 2022. The Author(s).)

Schools and colleges of pharmacy are optimally positioned to train the entire pharmacy team, including pharmacists and pharmacy support personnel, because they can provide comprehensive workforce development, utilize established faculty expertise, harness existing infrastructure, afford opportunities for intraprofessional education, and support institutional growth and reputability. As the emphasis of training shifts towards team-based approaches and expanded responsibilities, ensuring the existing and future pharmacy workforce is equipped to serve their communities becomes increasingly important. Thus, schools and colleges of pharmacy should consider offering a pharmacy technician training program to meet the needs of their community and the profession., (© 2022 American Association of Colleges of Pharmacy.)

Introduction: This How-I-Do-It article presents a modified Deloyers procedure by mean of the case of a 67-year-old female with adenocarcinoma extending for a long segment and involving the splenic flexure and proximal descending colon who underwent a laparoscopic left extended hemicolectomy (LELC) with derotation of the right colon and primary colorectal anastomosis., Background: While laparoscopic extended right colectomy is a well-established procedure, LELC is rarely used (mainly for distal transverse or proximal descending colon carcinomas extending to the area of the splenic flexure). LELC presents several technical challenges which are demonstrated in this How-I-Do-It article., Technique and Methods: Firstly, the steps needed to mobilize the left colon and procure a safe approach to the splenic flexure are described, especially when a tumor is closely related to it. This is achieved by mobilization and resection of the descending colon, while maintaining a complete mesocolic excision to the level of the duodenojejunal ligament for the inferior mesenteric vein and flush to the aorta for the inferior mesenteric artery. Subsequently, we depict the adjuvant steps required to enable a primary anastomosis by trying to mobilize the transverse colon and release as much of the mesocolic attachments at the splenic flexure area. Finally, we present the rare instance when a laparoscopic derotation of the ascending colon is required to provide a tension-free anastomosis. The resection is completed by delivery of the fully derotated ascending colon and hepatic flexure through a suprapubic mini-Pfannenstiel incision. The primary colorectal anastomosis is subsequently fashioned in a tension-free way and provides for a quick postoperative recovery of the patient., Results: This modified Deloyers procedure preserves the middle colic since the fully mobilized mesocolon allows for a tension-free anastomosis while maintaining better blood supply to the mobilized stump. Also, by eliminating the need for a mesenteric window and the transposition of the caecum, we allow the small bowel to rest over the anastomosis and the mobilized transverse colon and reduce the possibility of an internal herniation of the small bowel into the mesentery., Conclusions: Laparoscopic derotation of the right colon and a partial, modified Deloyers procedure preserving the middle colic vessels are feasible techniques in experienced hands to provide primary anastomosis after LELC with improved functional outcome. Nevertheless, it is important to consider anatomical aspects of the left hemicolectomy along with oncological considerations, to provide both a safe oncological resection along with good postoperative bowel function., (© 2021. The Author(s).)

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., (© 2021. Crown.)

Background: Opioid use disorder affects millions of Americans, but only a fraction receive treatment. This may be due in part to inaccurate information available about buprenorphine waivered practitioners (waivered practitioners) and Opioid Treatment Programs (OTPs) on public, federally-sponsored locator databases. We aimed to assess the accuracy of publicly-listed locator information for waivered practitioners and OTPs across the US. Methods: Using a cross-sectional study design, we randomly sampled waivered practitioners ( n  = 253; 0.5%) and licensed OTPs ( n  = 165; 10%) that were publicly-listed on a federally-sponsored database. We used a three-pronged approach to assess the accuracy of the information available by concurrently administering a phone survey (making up to 3 attempts to contact), conducting online searches, and reviewing provider information on state board websites (practitioners only) between August and November 2020. We used descriptive analyses and inferential statitistics to analyze the data. Results: Among n  = 418 waivered practitioners and OTPs sampled, many were located in the South and in an urban area. For the phone survey, researchers were able to reach OTPs nearly twice as often as waivered practitioners. Of those reached, n  = 19 waivered practitioners and n  = 40 OTPs agreed to participate, and we found most had up-to-date contact information. OTPs yielded significantly more online search results and matching contact information than waivered practitioners ( p  < 0.001). Most waivered practitioners were located on state licensing board websites, but few had contact information listed, and only one listed the practitioner's waiver status. Conclusions: Waivered practitioners and OTPs were difficult to reach via phone but easier to find online and on state licensing board websites; when they were reached via phone, their contact information was very accurate. Whether challenges locating a waivered practitioner or OTP is associated with lower treatment utilization should be evaluated.

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., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Introduction: Young people in contact with forensic child and adolescent mental health services present with more complex needs than young people in the general population. Recent policy has led to the implementation of new workstreams and programmes to improve service provision for this cohort. This paper aims to present the protocol for a national study examining the impact and implementation of Community Forensic Child and Adolescent Mental Health Services (F:CAMHS). Methods and analysis: The study will use a mixed-methods Realist Evaluation design. Quantitative service activity and feedback data will be collected from all 13 sites, as well as questionnaires from staff. Non-participant observations and qualitative interviews will be conducted with staff, young people and parents/guardians from four focus study sites. An economic evaluation will examine whether Community F:CAMHS provides good value for money. The results will be triangulated to gain an in-depth understanding of young people's, parents/guardians' and staff experiences of the service. Ethics and dissemination: Ethical approval was granted by the Health Research Association and UCL Ethics. The results will be disseminated via project reports, feedback to sites, peer-reviewed journal publications and conference presentations., Competing Interests: DL was employed by MindMonkey Associates. WR and RU were employed by company Riches and Ullman LLP. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lane, D'Souza, Livanou, Jacob, Riches, Ullman, Rashid, Singleton, Wheeler, Fuggle, Bevington, Deighton, Law, Fonagy, Hindley, White and Edbrooke-Childs.)

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.

Background: We describe a clinic-randomized trial to improve chronic kidney disease (CKD) care through a CKD-clinical decision support (CKD-CDS) intervention in primary care clinics and the challenges we encountered due to COVID-19 care disruption., Methods/design: Primary care clinics (N = 32) were randomized to usual care (UC) or to CKD-CDS. Between April 17, 2019 and March 14, 2020, more than 7000 patients had accrued for analysis by meeting study-eligibility criteria at an index office visit: age 18-75, laboratory criteria for stage 3 or 4 CKD (eGFR 15-59 mL/min/1.73 m 2 ), and one or more opportunities algorithmically identified to improve CKD care such as blood pressure (BP) or glucose control, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use, discontinuance of a nonsteroidal anti-inflammatory drug (NSAID), or nephrology referral. At CKD-CDS clinics, CDS provided individualized treatment suggestions that were printed for patients and clinicians at the start of office encounters and were viewable within the electronic health record. By initial design, the impact of the CKD-CDS intervention on care gaps was to be assessed 12 months after the index date, but COVID-19 caused major disruptions to care delivery during the intervention period. In response to disruptions, the intervention was temporarily suspended while we expanded CDS use for telehealth encounters and programmed new criteria for displaying the CKD-CDS to intervention patients due to clinic closures and scheduling changes., Discussion: We describe a NIH-funded pragmatic trial of web-based EHR-integrated CKD-CDS and modifications necessary mid-study to complete the study as intended in the face of COVID-19 pandemic challenges., (Copyright © 2021. Published by Elsevier Inc.)

Bioaccumulation (B) assessment is challenging because there are various B-metrics from laboratory and field studies, multiple criteria and thresholds for classifying bioaccumulative (B), very bioaccumulative (vB), and not bioaccumulative (nB) chemicals, as well as inherent variability and uncertainty in the data. These challenges can be met using a weight of evidence (WoE) approach. The Bioaccumulation Assessment Tool (BAT) provides a transparent WoE assessment framework that follows Organisation for Economic Co-operation and Development (OECD) principles for performing a WoE analysis. The BAT guides an evaluator through the process of data collection, generation, evaluation, and integration of various lines of evidence (LoE) (i.e., B-metrics) to inform decision-making. Phenanthrene (PHE) is a naturally occurring chemical for which extensive B and toxicokinetics data are available. A B assessment for PHE using the BAT is described that includes a critical evaluation of 74 measured in vivo LoE for fish and invertebrate species from laboratory and field studies. The number of LoE are reasonably well balanced across taxa (i.e., fish and invertebrates) and the different B-metrics. Additionally, in silico and in vitro biotransformation rate estimates and corresponding model-predicted B-metrics are included as corroborating evidence. Application of the BAT provides a consistent, coherent, and scientifically defensible WoE evaluation to conclude that PHE is not bioaccumulative (nB) because the overwhelming majority of the bioconcentration, bioaccumulation, and biomagnification metrics for both fish and invertebrates are below regulatory thresholds. An analysis of the relevant data using fugacity ratios is also provided, showing that PHE does not biomagnify in aquatic food webs. The critical review identifies recommendations to increase the consistency of B assessments, such as improved standardization of B testing guidelines, data reporting requirements for invertebrate studies, and consideration of temperature and salinity effects on certain B-metrics. Integr Environ Assess Manag 2021;17:911-925. © 2021 Concawe. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2021 Concawe. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)