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Pharmaceuticals and personal care products (PPCPs) are an indispensable component of a healthy society. However, they are well‐established environmental contaminants, and many can elicit biological disruption in exposed organisms. It is now a decade since the landmark review covering the top 20 questions on PPCPs in the environment (Boxall et al., 2012). In the present study we discuss key research priorities for the next 10 years with a focus on how regions where PPCPs pose the greatest risk to environmental and human health, either now or in the future, can be identified. Specifically, we discuss why this problem is of importance and review our current understanding of PPCPs in the aquatic environment. Foci include PPCP occurrence and what drives their environmental emission as well as our ability to both quantify and model their distribution. We highlight critical areas for future research including the involvement of citizen science for environmental monitoring and using modeling techniques to bridge the gap between research capacity and needs. Because prioritization of regions in need of environmental monitoring is needed to assess future/current risks, we also propose four criteria with which this may be achieved. By applying these criteria to available monitoring data, we narrow the focus on where monitoring efforts for PPCPs are most urgent. Specifically, we highlight 19 cities across Africa, Central America, the Caribbean, and Asia as priorities for future environmental monitoring and risk characterization and define four priority research questions for the next 10 years. Environ Toxicol Chem 2024;43:575–588. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

How can data on the occurrence of pharmaceuticals and personal care products (PPCPs) in the environment and the quality of ecosystems exposed to PPCPs be used to determine whether current regulatory risk assessment schemes are effective? This is one of 20 "big questions" concerning PPCPs in the environment posed in a landmark review paper in 2012. Ten years later, we review the developments around this question, focusing on the first P in PPCPs, that is, pharmaceuticals, or more specifically the active ingredients included in them (active pharmaceutical ingredients, APIs). We illustrate how extensive data on both the occurrence of APIs and the ecotoxicological sensitivity of aquatic species to them can be used in a retrospective risk assessment. In the Netherlands, current regulatory risk assessment schemes offer insufficient protection against direct ecotoxicological effects from APIs: the toxic pressure exerted by the 39 APIs included in our study exceeds the policy‐related protective threshold of 0.05 (the "95%‐protection level") in at least 13% of sampled surface waters. In general, anti‐inflammatory and antirheumatic products (e.g., diclofenac, ibuprofen) contributed most to the overall toxic pressure, followed by sex hormones and modulators of the genital system (e.g., ethinylestradiol) and psychoanaleptics (e.g., caffeine). We formulated three open questions for future research. The first relates to improving the availability and accessibility of good‐quality ecotoxicity data on pharmaceuticals for the global scientific, regulatory, and general public. The second relates to the adaptation of regulatory risk assessment frameworks for developing regions of the world. The third relates to the integration of effect‐based and ecological approaches into regulatory risk assessment practice. Environ Toxicol Chem 2024;43:611–622. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Organic wheat production systems have lower yields compared with intensive conventional production and often do not achieve the grain protein content and quality thresholds set by millers and bakers. In contrast, organic production methods were reported to result in higher concentrations of nutritionally desirable micronutrients and lower concentrations of the toxic metal Cd in wheat grain and wholegrain flour. However, although N-availability and variety characteristics are known to affect both gain yields and bread-making quality, the exact reasons for the yield gap and differences in grain processing and nutritional quality between organic and conventional spring wheat production in the UK are poorly understood. The overall aim of this study was therefore to determine to what extent changes in variety choice and fertilization regimes may reduce the yield gap and improve processing quality without affecting nutritional quality in organic spring wheat production. To achieve this aim, we compared crop health, yield, grain processing, and nutritional quality parameters in spring wheat produced using (i) six contrasting spring wheat varieties grown with a standard fertilization regime and (ii) one variety widely used by organic farmers (Paragon) with nine different fertilization regimes in (iii) three UK sites/farms with contrasting pedoclimatic conditions. Significant differences in foliar disease severity, grain yield, and quality parameters were detected between six contrasting spring wheat varieties when grown under organic management regimes. Specifically, the varieties Paragon and Tybalt were identified as the best-performing varieties with respect to foliar disease resistance and grain yield under organic farming conditions and also produced high processing and nutritional quality across the three UK sites. However, the highest grain yields were obtained by Paragon at the Gilchester site and Tybalt at the Sheepdrove and Courtyard sites, while the highest protein contents were produced by Tybalt at the Gilchester site and Paragon at the Sheepdrove and Courtyard sites, which suggests that there is a need for site-specific wheat variety selection in the UK organic sector. Although organic fertilizer input type and level also affected wheat performance, differences between fertilization regimes were smaller than those observed between the five contrasting varieties, which suggests that improvements in spring wheat breeding/selection have a greater potential for increasing crop yield and quality in the organic sector compared with changes to fertilization practices. Overall, results suggest it is feasible to breed/select spring wheat varieties that combine high protein, vitamin E, and micronutrients with low toxic metal (Cd, Pb) concentrations when produced under organic farming conditions. These findings also support the hypothesis that differences in variety choice by organic and conventional farmers have contributed to the differences in nutritional quality between organic and conventional wheat products reported in previous studies. [ABSTRACT FROM AUTHOR]

Diffuse midline gliomas (DMGs) are pediatric high-grade brain tumors in the thalamus, midbrain, or pons; the latter subgroup are termed diffuse intrinsic pontine gliomas (DIPG). The brain stem location of these tumors limits the clinical management of DIPG, resulting in poor outcomes for patients. A heterozygous, somatic point mutation in one of two genes coding for the noncanonical histone H3.3 is present in most DIPG tumors. This dominant mutation in the H3-3A gene results in replacement of lysine 27 with methionine (K27M) and causes a global reduction of trimethylation on K27 of all wild-type histone H3 proteins, which is thought to be a driving event in gliomagenesis. In this study, we designed and systematically screened 2′-O-methoxyethyl phosphorothioate antisense oligonucleotides (ASOs) that direct RNase H–mediated knockdown of H3-3A mRNA. We identified a lead ASO that effectively reduced H3-3A mRNA and H3.3K27M protein and restored global H3K27 trimethylation in patient-derived neurospheres. We then tested the lead ASO in two mouse models of DIPG: an immunocompetent mouse model using transduced mutant human H3-3A cDNA and an orthotopic xenograft with patient-derived cells. In both models, ASO treatment restored K27 trimethylation of histone H3 proteins and reduced tumor growth, promoted neural stem cell differentiation into astrocytes, neurons, and oligodendrocytes, and increased survival. These results demonstrate the involvement of the H3.3K27M oncohistone in tumor maintenance, confirm the reversibility of the aberrant epigenetic changes it promotes, and provide preclinical proof of concept for DMG antisense therapy. Combatting pediatric glioma: Diffuse intrinsic pontine gliomas (DIPG) are pediatric high-grade brain tumors located in the brainstem, which limits treatment options and thus leads to poor patient outcomes. These tumors often have point mutations in histone H3.3, which represents a potential target for treatment. Here, Zhang et al. have generated and screened antisense oligonucleotides (ASOs) in H3.3 mutant DIPG patient cells to directly target and inhibit glioma growth. They treated patient-derived neurospheres and two DIPG mouse models with their lead ASO, which led to reduced tumor growth, cell differentiation, and increased survival, suggesting ASOs as a promising therapy for DIPG that requires further study. —DH [ABSTRACT FROM AUTHOR]

CRISPR/Cas9‐driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame‐shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss‐of‐function studies. However, how CRISPR/Cas9 influences gain‐of‐function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β‐catenin) results in exon skipping and generates gain‐of‐function isoforms in vivo. CRISPR/Cas9‐mediated exon skipping of Ctnnb1 induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping‐induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon‐skipped β‐catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon‐skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β‐catenin‐related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain‐of‐function mutations of oncogenes in cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

"M&M" conferences have traditionally been the means for addressing medical errors, but too often they have focused on assigning individual blame rather than identifying root causes within systems. [ABSTRACT FROM AUTHOR]

In most superconductors electrons form Cooper pairs in a spin-singlet state mediated by either phonons or by long-range interactions such as spin fluctuations. The superconductor UTe2 is a rare material wherein electrons are believed to form pairs in a unique spin-triplet state with potential topological properties. While spin-triplet pairing may be mediated by ferromagnetic or antiferromagnetic fluctuations, experimentally, the magnetic properties of UTe2 are unclear. By way of muon spin rotation/relaxation (μSR) measurements on independently grown UTe2 single crystals we demonstrate the existence of magnetic clusters that gradually freeze into a disordered spin frozen state at low temperatures. Our findings suggest that inhomogeneous freezing of magnetic clusters is linked to the ubiquitous residual linear term in the temperature dependence of the specific heat (C) and the low-temperature upturn in C/T versus T. The omnipresent magnetic inhomogeneity has potential implications for experiments aimed at establishing the intrinsic low-temperature properties of UTe2. UTe2 receives significant attention as it may be an example of a spin-triplet superconductor but many features of this material are still to be fully understood. Here, the authors use muon spin rotation to investigate the existence of low-temperature magnetic clusters in single crystals of UTe2 and discuss the potential relationship with the temperature dependent behaviour of the specific heat. [ABSTRACT FROM AUTHOR]

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I have a busy morning during clinic, and I realize that a new patient has been added to my late afternoon schedule because of back pain, headache, abdominal pain, fatigue, and difficulty sleeping. A brief review of the medical record reveals that over the past years, this 32-year-old patient has been seen by primary care physicians, numerous specialists, and even in emergency medicine settings for various ongoing symptoms, including headache, neck pain, diffuse body aches, urinary frequency, dysuria, generalized fatigue, brain fog, and anxiety. Despite multiple investigations with negative results, the patient does not appear to have received any definitive diagnoses. Experiencing a moment of dread and anticipating a difficult patient encounter, I vent my frustration to my colleague, knowing that I will unlikely be able to offer any useful tests, explanations, or acceptable treatment recommendations. My colleague suggests that central sensitization could be a useful concept in understanding and explaining my new patient's various types of chronic pain. [ABSTRACT FROM AUTHOR]

Large-scale biodiversity monitoring remains a challenge in science and policy. 'Biodiversity Observation Networks' provide an integrated infrastructure for monitoring biodiversity through timely discovery, access, and re-use of data, but their establishment relies on an in-depth understanding of existing monitoring effort. We performed a scoping review and network analysis to assess the scope of available data on amphibians and reptiles in the UK and catalogue the mobilisation of information across the data landscape, thereby highlighting existing gaps. The monitoring portfolio has grown rapidly in recent decades, with over three times as many data sources than there are amphibian and reptile species in the UK now available. We identified 45 active sources of 'FAIR' ('Findable', 'Accessible', 'Interoperable' and 'Reusable') data. The taxonomic, geographic and temporal coverage of datasets appears largely uneven and no single source is currently suitable for producing robust multispecies assessments on large scales. A dynamic and patchy exchange of data occurs between different recording projects, recording communities and digital data platforms. The National Biodiversity Network Atlas is a highly connected source but the scope of its data (re-)use is potentially limited by insufficient accompanying metadata. The emerging complexity and fragmented nature of this dynamic data landscape is likely to grow without a concerted effort to integrate existing activities. The factors driving this complexity extend beyond the UK and to other facets of biodiversity. We recommend integration and greater stakeholder collaboration behind a coordinated infrastructure for data collection, storage and analysis, capable of delivering comprehensive assessments for large-scale biodiversity monitoring. [ABSTRACT FROM AUTHOR]

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing. [ABSTRACT FROM AUTHOR]

Wheat yields in organic production are significantly lower than those achieved in conventional farming systems and in Northern Europe organic farmers also struggle to achieve the processing quality levels demanded by millers and bakers, especially in winter-wheat crops. Here, we report the findings of a 3-year pilot study which investigated the potential of increasing grain yields and both standard processing (e.g., grain protein levels and specific weights) and selected nutritional (tocopherol and tocotrienol isomers) quality parameters via (i) changes in the management of clover crops grown before wheat (Rhizobium seed inoculation, application of greenwaste compost to clover swards) and (ii) use of new varieties developed in both the UK and continental Europe. Results indicate that the use of compost amendment to preceding clover swards significantly increased the grain protein levels in the three winter-wheat, but not the four spring-wheat varieties, and also significantly increases grain yields in one winter-wheat variety (Greina). In contrast, the use of Rhizobium-inoculation was found to significantly reduce protein concentrations in the winter-, but not spring wheat varieties, and had no significant effect on grain yields in both winter and spring wheat. However, analysis of variance detected significant interactions between Rhizobium seed inocula in clover pre-crops and (a) compost application for grain specific weights in winter-wheat and grain hardness in spring wheat crops and (b) variety for grain protein content in spring wheat crops. No significant effect of clover pre-crop management on tocopherol and tocotrienol isomer profiles could be detected, although significant differences between varieties were detected in both winter and spring wheat. Results of this pilot study need to be confirmed in future trials, but indicate that both (a) changes in clover-management practices and (b) the selections of wheat varieties that are more suitable for organic farming systems has the potential to increase grain yield and allow organic farmers to more frequently achieve baking or milling grade quality. [ABSTRACT FROM AUTHOR]

During their production, use, and disposal, active pharmaceutical ingredients (APIs) are released into aquatic systems. Because they are biologically active molecules, APIs have the potential to adversely affect nontarget organisms. We used the results of a global monitoring study of 61 APIs alongside available ecotoxicological and pharmacological data to assess the potential ecotoxicological effects of APIs in rivers across the world. Approximately 43.5% (461 sites) of the 1052 sampling locations monitored across 104 countries in a recent global study had concentrations of APIs of concern based on apical, nonapical, and mode of action–related endpoints. Approximately 34.1% of the 137 sampling campaigns had at least one location where concentrations were of ecotoxicological concern. Twenty‐three APIs occurred at concentrations exceeding "safe" concentrations, including substances from the antidepressant, antimicrobial, antihistamine, β‐blocker, anticonvulsant, antihyperglycemic, antimalarial, antifungal, calcium channel blocker, benzodiazepine, painkiller, progestin, and lifestyle compound classes. At the most polluted sites, effects are predicted on different trophic levels and on different endpoint types. Overall, the results show that API pollution is a global problem that is likely negatively affecting the health of the world's rivers. To meet the United Nations' Sustainable Development Goals, work is urgently needed to tackle the problem and bring concentrations down to an acceptable level. Environ Toxicol Chem 2022;41:2008–2020. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Introduction: We sought to evaluate the reporting and methodological quality of cost evaluations of physician continuing professional development (CPD). Methods: We conducted a systematic review, searching MEDLINE, Embase, PsycInfo, and the Cochrane Database for studies comparing the cost of physician CPD (last update 23 April 2020). Two reviewers, working independently, screened all articles for inclusion. Two reviewers extracted information on reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), and on methodological quality using the Medical Education Research Study Quality Instrument (MERSQI) and a published reference case. Results: Of 3338 potentially eligible studies, 62 were included. Operational definitions of methodological and reporting quality elements were iteratively revised. Articles reported mean (SD) 43% (20%) of CHEERS elements for the Title/Abstract, 56% (34%) for Introduction, 66% (19%) for Methods, 61% (17%) for Results, and 66% (30%) for Discussion, with overall reporting index 292 (83) (maximum 500). Valuation methods were reported infrequently (resource selection 10 of 62 [16%], resource quantitation 10 [16%], pricing 26 [42%]), as were descriptions/discussion of the physicians trained (42 [68%]), training setting (42 [68%]), training intervention (40 [65%]), sensitivity analyses of uncertainty (9 [15%]), and generalizability (30 [48%]). MERSQI scores ranged from 6.0 to 16.0 (mean 11.2 [2.4]). Changes over time in reporting index (initial 241 [105], final 321 [52]) and MERSQI scores (initial 9.8 [2.7], final 11.9 [1.9]) were not statistically significant (p ≥ 0.08). Discussion: Methods and reporting of HPE cost evaluations fall short of current standards. Gaps exist in the valuation, analysis, and contextualization of cost outcomes. [ABSTRACT FROM AUTHOR]

Domestic violence and sexual abuse advocates, mental health clinicians, and other professionals are painfully aware of both the pervasiveness and insidiousness of child sexual abuse. Despite the herculean efforts made by advocacy groups to publicize this issue, protect children, and offer healing experiences to victims, in reality child sexual abuse persists at alarmingly high levels. Worse, even within the criminal justice system, not to mention the general public, there is a lack of suffi cient understanding of the subtle dynamics, such as grooming techniques, victims’ reluctance to report, the keeping of family secrets, and the perpetrator’s “nice guy” image, among others, that enable these crimes to remain hidden and to go unpunished. Here, the authors address ten elements that are typically present in cases of intra-familial sexual abuse. Were this information to be widely disseminated and understood, those who perpetrate these heinous crimes could be more easily and quickly identifi ed and brought to justice, thus preventing them from further perpetration, which would, in turn, diminish the number of victims suffering from the lifelong deleterious impacts of such violations. [ABSTRACT FROM AUTHOR]

Pharmaceutical contamination of the environment is recognized as a global problem although most research has focused on Europe and North America to date, and there remains a dearth of information for developing countries, including those in Africa. To address this data gap, the occurrence of 37 pharmaceuticals belonging to 19 therapeutic classes was monitored in surface water and effluents in Lagos State, Southwest Nigeria. Samples were collected quarterly between April 2017 and March 2018 from 22 sites, and 26 compounds were detected at least once, many in the µg/L range. Maximum concentrations for those compounds detected ranged from 75 to 129 µg L−1, and even mean concentrations for 13 compounds were in the order of µg L−1. These values are among the highest ever measured globally. Sewage effluent was more important than drug manufacturing waste in polluting rivers, although there are likely to be numerous unregulated sources of effluent being discharged to rivers that require further study, including urban waste collection areas and vacuum trucks that collect effluent. Seasonal trends in the data were complex, with some compounds being found at higher concentrations in the dry season and, conversely, others being greater during the wet period; this variation potentially relates to the variety of pollution sources in the catchment. Pharmaceuticals are indispensable to human health, although their usage and discharge into the aquatic environment may lead to ecological problems and antibiotic resistance. The data we present indicate that pharmaceutical pollution of freshwaters is a serious issue in Nigeria, and management efforts are needed to improve this problem. Environ Toxicol Chem 2022;41:551–558. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

The sixth UN Sustainable Development Goal, Clean Water and Sanitation, directly underpins other goals of Health, Life in Water and Sustainable Cities. We highlight that poor sanitation, exemplified through some of the highest concentrations of pharmaceuticals ever detected in rivers, will amplify societal and environmental stress where climate-induced reductions in flow are predicted. Rapidly growing urban centres with inadequate water treatment works will need to prioritise water quality improvement before supply reductions become a reality. For 23 river locations within Kathmandu City and the Annapurna region, Nepal, we show the presence of 28 of 35 monitored human-use pharmaceuticals. Concentrations of antibiotics measured in this sampling campaign in both Kathmandu City (sulfamethazine, metronidazole and ciprofloxacin) and rural locations (ciprofloxacin) are in excess of predicted no effect concentrations, suggesting these sites are at risk of proliferating antimicrobial resistance as well as affecting other ecotoxicological endpoints. It is anticipated that climate-induced reductions in flow combined with contaminated river systems will amplify future societal and environmental stress. [ABSTRACT FROM AUTHOR]

Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world’s rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC. [ABSTRACT FROM AUTHOR]

In this study, we describe two novel adenoviruses isolated from (i) a common lizard (Zootoca vivipara) found dead and examined post-mortem and (ii) pooled samples from free-living sand lizards (Lacerta agilis agilis). Sequencing indicated the two were closely related atadenovirus strains which were distinct from previously recorded adenoviruses in lizards. Adenoviruses are not always associated with disease in squamates, but morbidity and mortality have been reported. These are the first known cases of adenovirus infection in free-living native British lizards, and further monitoring will be necessary to elucidate the implications of these possible pathogens for vulnerable populations of native reptiles. [ABSTRACT FROM AUTHOR]

Many radioisotopes with potential medical applications are difficult to produce routinely, especially those on the proton-rich side of the valley of stability. Current production methods typically use light-ion (protons or deuteron) reactions on materials of similar mass to the target radioisotope, which limits the elemental target material available and may require the use of targets with poor thermal properties (as is the case for the production of radiobromine). These reactions may also create significant amounts of proton-rich decay products which require chemical separation from the desired product in a highly radioactive environment. A promising alternative method using heavy-ion fusion-evaporation reactions for the production of the medically relevant bromine radioisotopes 76Br (t1/2 = 16.2 h) and 77Br (t1/2 = 57.0 h) is presented. Heavy-ion beams of 28Si and 16O were used to bombard natural chromium and copper targets just above the Coulomb barrier at the University of Notre Dame's Nuclear Science Laboratory to produce these bromine and precursor radioisotopes by fusion-evaporation reactions. Production yields for these reactions were measured and compared to PACE4 calculations. In addition to using more robust targets for irradiation, a simple physical–chemical separation method is proposed that will lead to very high radiopurity yields. A summary of accelerator facility requirements needed for routine production of these radioisotopes is also presented. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a heterogeneous group of conditions related to specific biologic and cellular abnormalities that are not fully understood. Psychological factors do not cause IBS, but many people with IBS also have anxiety or depressed mood, a history of adverse life events, or psychosocial stressors. Physicians must understand the fears and expectations of patients and how they think about their symptoms and should also respond empathetically to psychosocial cues. Anxiety related to the unpredictability of symptoms may have a greater effect on quality of life than the symptoms themselves. Patients in generally good health who have ongoing or recurrent gastrointestinal symptoms and abnormal stool patterns most likely have IBS or another functional gastrointestinal disorder. Patients who meet symptom-based criteria and have no alarm features may be confidently diagnosed with few, if any, additional tests. Patients may not completely understand the diagnostic process; asking about expectations and carefully explaining the goals and limitations of testing leads to more effective care. There is no definitive treatment for IBS, and recommended treatments focus on symptom relief and improved quality of life. Trusting patient-physician interactions are essential to help patients understand and accept an IBS diagnosis and to actively engage in effective self-management. [ABSTRACT FROM AUTHOR]

This article addresses the challenge to professionalised practices of reading represented by the oeuvre of Alfred Starr Hamilton (1914–2005), with broader implications for the contested category of Outsider Writing. Drawing on the author's experience, three types of early life encounter with poetry are specified, guided to its objects by cultural and parental authority and later reaction against them: a fetish of the book and representations of the poet, oral pleasure, and the magic of the word as an illimitably productive and plastic material. These are linked to encounter with Hamilton's poetry, at once unrelentingly repetitive, and sponsored and structured by a small seedbank of magic words, occasioning the sudden florescence of beauty. To read Hamilton requires a feline practice of submitting to reverie while registering disturbance and aesthetic shock precisely. [ABSTRACT FROM AUTHOR]

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene–environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation. [ABSTRACT FROM AUTHOR]

This article explores ideas of abstraction developed in the visual art and poetry produced in the artistic centre of St Ives in Cornwall during the mid-twentieth century. The first part briefly explores the St Ives milieu, the second offers a detailed reading of W.S. Graham's poem WYNTER AND THE GRAMMARSOW in relation to the painting and other artwork of Graham's friend Bryan Wynter, while the third considers how the practices of both poet and painter eventuate in works which remain 'adrift stationary'. [ABSTRACT FROM AUTHOR]

Dysphagia is common but may be underreported. Oropharyngeal dysphagia manifests as coughing, choking, aspiration, or difficulty initiating swallowing, and is most often caused by chronic neurologic conditions. Patients with esophageal dysphagia may report a sensation of food getting stuck after swallowing. This condition is most commonly caused by gastroesophageal reflux disease and functional esophageal disorders. Esophagogastroduodenoscopy is recommended for the initial evaluation of esophageal dysphagia, with barium esophagography as an adjunct. Testing for esophageal cancer or other serious conditions may be deferred in low-risk patients while a four-week trial of acid suppression therapy is undertaken. Diagnosis of oropharyngeal dysphagia in frail older adults should prompt a discussion about goals of care before considering potentially harmful interventions. Dysphagia is common but may be underreported. Specific symptoms, rather than their perceived location, should guide the initial evaluation and imaging. Obstructive symptoms that seem to originate in the throat or neck may actually be caused by distal esophageal lesions. Oropharyngeal dysphagia manifests as difficulty initiating swallowing, coughing, choking, or aspiration, and it is most commonly caused by chronic neurologic conditions such as stroke, Parkinson disease, or dementia. Symptoms should be thoroughly evaluated because of the risk of aspiration. Patients with esophageal dysphagia may report a sensation of food getting stuck after swallowing. This condition is most commonly caused by gastroesophageal reflux disease and functional esophageal disorders. Eosinophilic esophagitis is triggered by food allergens and is increasingly prevalent; esophageal biopsies should be performed to make the diagnosis. Esophageal motility disorders such as achalasia are relatively rare and may be overdiagnosed. Opioid-induced esophageal dysfunction is becoming more common. Esophagogastroduodenoscopy is recommended for the initial evaluation of esophageal dysphagia, with barium esophagography as an adjunct. Esophageal cancer and other serious conditions have a low prevalence, and testing in low-risk patients may be deferred while a four-week trial of acid-suppressing therapy is undertaken. Many frail older adults with progressive neurologic disease have significant but unrecognized dysphagia, which significantly increases their risk of aspiration pneumonia and malnourishment. In these patients, the diagnosis of dysphagia should prompt a discussion about goals of care before potentially harmful interventions are considered. Speech-language pathologists and other specialists, in collaboration with family physicians, can provide structured assessments and make appropriate recommendations for safe swallowing, palliative care, or rehabilitation. (Am Fam Physician. 2021;103(2):97–106. Copyright © 2021 American Academy of Family Physicians.) [ABSTRACT FROM AUTHOR]

Esophageal motility disorders can cause chest pain, heartburn, or dysphagia. They are diagnosed based on specific patterns seen on esophageal manometry, ranging from the complete absence of contractility in patients with achalasia to unusually forceful or disordered contractions in those with hypercontractile motility disorders. Achalasia has objective diagnostic criteria, and effective treatments are available. Timely diagnosis results in better outcomes. Recent research suggests that hypercontractile motility disorders may be overdiagnosed, leading to unnecessary and irreversible interventions. Many symptoms ascribed to these disorders are actually due to unrecognized functional esophageal disorders. Hypercontractile motility disorders and functional esophageal disorders are generally self-limited, and there is considerable overlap among their clinical features. Endoscopy is warranted in all patients with dysphagia, but testing to evaluate for less common conditions should be deferred until common conditions have been optimally managed. Opioid-induced esophageal dysmotility is increasingly prevalent and can mimic symptoms of other motility disorders or even early achalasia. Dysphagia of liquids in a patient with normal esophagogastroduodenoscopy findings may suggest achalasia, but high-resolution esophageal manometry is required to confirm the diagnosis. Surgery and advanced endoscopic therapies have proven benefit in achalasia. However, invasive interventions are rarely indicated for hypercontractile motility disorders, which are typically benign and usually respond to lifestyle modifications, although pharmacotherapy may occasionally be needed. [ABSTRACT FROM AUTHOR]

Recent ordination controversies have served as barometers for how denominations have addressed matters of human sexuality, and LGBTQ sexuality in particular. Using the Presbyterian Church (U.S.A.)'s fifty-year narrative as a case study, this article traces developments in thought and shifts in perspective, from language that calls "homosexual acts" sin to actions that move from apology to celebration. The essay follows decades of intense debate and conflict to reflect on the implications when a church changes its mind. [ABSTRACT FROM AUTHOR]

An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden. [ABSTRACT FROM AUTHOR]

Pregnancy causes a series of cellular and molecular changes in mammary epithelial cells (MECs) of female adults. In addition, pregnancy can also modify the predisposition of rodent and human MECs to initiate oncogenesis. Here, we investigate how pregnancy reprograms enhancer chromatin in the mammary epithelium of mice and influences the transcriptional output of the oncogenic transcription factor cMYC. We find that pregnancy induces an expansion of the active cis-regulatory landscape of MECs, which influences the activation of pregnancy-related programs during re-exposure to pregnancy hormones in vivo and in vitro. Using inducible cMYC overexpression, we demonstrate that post-pregnancy MECs are resistant to the downstream molecular programs induced by cMYC, a response that blunts carcinoma initiation, but does not perturb the normal pregnancy-induced epigenomic landscape. cMYC overexpression drives post-pregnancy MECs into a senescence-like state, and perturbations of this state increase malignant phenotypic changes. Taken together, our findings provide further insight into the cell-autonomous signals in post-pregnancy MECs that underpin the regulation of gene expression, cellular activation, and resistance to malignant development. Mammary epithelial cells are epigenetically modified during pregnancy, these changes can influence the pre-disposition to cancer. Here, the authors examine the epigenetic landscape of mammary epithelial cells pre and post pregnancy and identify changes to the epigenetic landscape, which can protect mice from Myc induced cancer. [ABSTRACT FROM AUTHOR]

Purpose: Our purposes are to compare the accuracy of RaySearch's analytical pencil beam (APB) and Monte Carlo (MC) algorithms for clinical proton therapy and to present clinical validation data using a novel animal tissue lung phantom. Methods: We constructed a realistic lung phantom composed of a rack of lamb resting on a stack of rectangular natural cork slabs simulating lung tissue. The tumor was simulated using 70% lean ground lamb meat inserted in a spherical hole with diameter 40 ± 5 mm carved into the cork slabs. A single‐field plan using an anterior beam and a two‐field plan using two anterior‐oblique beams were delivered to the phantom. Ion chamber array measurements were taken medial and distal to the tumor. Measured doses were compared with calculated RayStation APB and MC calculated doses. Results: Our lung phantom enabled measurements with the MatriXX PT at multiple depths in the phantom. Using the MC calculations, the 3%/3 mm gamma index pass rates, comparing measured with calculated doses, for the distal planes were 74.5% and 85.3% for the APB and 99.1% and 92% for the MC algorithms. The measured data revealed up to 46% and 30% underdosing within the distal regions of the target volume for the single and the two field plans when APB calculations are used. These discrepancies reduced to less than 18% and 7% respectively using the MC calculations. Conclusions: RaySearch Laboratories' Monte Carlo dose calculation algorithm is superior to the pencil‐beam algorithm for lung targets. Clinicians relying on the analytical pencil‐beam algorithm should be aware of its pitfalls for this site and verify dose prior to delivery. We conclude that the RayStation MC algorithm is reliable and more accurate than the APB algorithm for lung targets and therefore should be used to plan proton therapy for patients with lung cancer. [ABSTRACT FROM AUTHOR]

The objective was to quantitatively evaluate clinician characteristics associated with unwarranted practice variation, and how clinical care algorithms influence this variation. Participants (142 physicians, 53 nurse practitioners, and 9 physician assistants in family medicine, internal medicine, and cardiology) described their management of 4 clinical vignettes, first based on their own practice (unguided), then using care algorithms (guided). The authors quantitatively estimated variation in management. Cardiologists demonstrated 17% lower variation in unguided responses than generalists (fold-change 0.83 [95% confidence interval (CI) 0.68, 0.97]), and those who agreed that practice variation can realistically be reduced had 16% lower variation than those who did not (fold-change 0.84 [CI, 0.71, 0.99]). A 17% reduction in variation was observed for guided responses compared with baseline (unguided) responses (fold-change 0.83 [CI, 0.76, 0.90]). Differences were otherwise similar across clinician subgroups and attitudes. Unwarranted practice variation was similar across most clinician subgroups. The authors conclude that care algorithms can reduce variation in management. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to validate the RayStation Monte Carlo (MC) dose algorithm using animal tissue neck phantoms and a water breast phantom. Methods: Three anthropomorphic phantoms were used in a clinical setting to test the RayStation MC dose algorithm. We used two real animal necks that were cut to a workable shape while frozen and then thawed before being CT scanned. Secondly, we made a patient breast phantom using a breast prosthesis filled with water and placed on a flat surface. Dose distributions in the animal and breast phantoms were measured using the MatriXX PT device. Results: The measured doses to the neck and breast phantoms compared exceptionally well with doses calculated by the analytical pencil beam (APB) and MC algorithms. The comparisons between APB and MC dose calculations and MatriXX PT measurements yielded an average depth difference for best gamma agreement of <1 mm for the neck phantoms. For the breast phantom better average gamma pass rates between measured and calculated dose distributions were observed for the MC than for the APB algorithms. Conclusions: The MC dose calculations are more accurate than the APB calculations for the static phantoms conditions we evaluated, especially in areas where significant inhomogeneous interfaces are traversed by the beam. [ABSTRACT FROM AUTHOR]

Examines the changes in mood and performance among pursuit cyclists in response to high-intensity, short-duration overtraining and a subsequent taper in the U.S. Effect of overtraining on cycling performance; Correlation between mood and performance; Factors affecting overtraining syndrome.