Diuris brumalis, a nonrewarding species, pollinated by bees via mimicry of the rewarding pea plant Daviesia decurrens. When distant from the pea plant, Diuris was hypothesized to enhance pollinator attraction by exaggeratedly mimicking the floral ultraviolet (UV) reflecting patterns of its model. By experimentally modulating floral UV reflectance with a UV screening solution, we quantified the orchid pollinia removal at a variable distance from the model pea plants. We demonstrate that the deceptive orchid Diuris attracts bee pollinators by emphasizing the visual stimuli, which mimic the floral UV signaling of the rewarding model Daviesia. Moreover, the exaggerated UV reflectance of Diuris flowers impacted pollinators' visitation at an optimal distance from Da. decurrens, and the effect decreased when orchids were too close or too far away from the model. Our findings support the hypothesis that salient UV flower signaling plays a functional role in visual floral mimicry, likely exploiting perceptual gaps in bee neural coding, and mediates the plant pollinia removal at much greater spatial scales than previously expected. The ruse works most effectively at an optimal distance of several meters revealing the importance of salient visual stimuli when mimicry is imperfect.Flowers have many traits to appeal to pollinators, including ultraviolet (UV) absorbing markings, which are well‐known for attracting bees at close proximity . While striking UV signals have been thought to attract pollinators also from far away, if these signals impact the plant pollinia removal over distance remains unknown. Here, we report the case of the Australian orchid  Donkey orchids mimic and exaggerate UV reflectance signals of rewarding model pea plants to attract pollinators. The ruse works exclusively from afar when the orchid is at an optimal distance away from the pea it mimics. Our findings explain the adaptive significance of salient UV display in long‐range plant‐bee communication and why deceptive plants succeed despite imperfect floral mimicry. Mimicry, a form of deception, allows individuals to conceal their identity and avoid recognition by (more or less) closely imitating the behavior or resembling the appearance of their models  of the floral signal display that Trichocolletes bees normally encounter in the rewarding Daviesia peas. We expected that modulating the exaggerated UV signals of Diuris over a spatial scale would affect pollinia removal when orchids are relatively distant from their model food plants because pollinators are more likely to mistake the orchid for the rewarding model when afar. In order to setup the UV modulation experiments on the distance range that is ecologically relevant for the orchid mimicry success, our study firstly describes the function of pollinia removal in orchids according to their distance from the model pea plants.Salient UV signals against the background may be particularly relevant for increasing long‐distance attractiveness in plants that employ flower mimicry Dyer, , but the22.1Di. brumalis produces yellow–brown nectarless flowers between July and August and is pollinated via mimicry of rewarding pea plants (Daviesia spp.) by native Trichocolletes (Colletidae) bees  feeder on pea flowers and display a distinctive and identical behavior on both orchids and peas, confirming that it is successfully deceived. The orchid mimics the papilionaceous flower typical of the pea model and while the visible spectrum differs between the mimic and model flower, they are likely to look similar through a bee visual model  for both orchid and pea plants using a Cary 4000 UV–Vis spectrophotometer (Agilent Technologies) and calculating the average spectral reflectance for each floral part.To test the hypothesis that the two outer petals of Diuris and Daviesia  and the circle (green), respectively  in 10 plants of both a Figure , Data S1a Figure   on the number of  Methods ; Data S3Diuris flowers by free‐foraging bees when the mimicking orchid occurred inside [IN] and outside [OUT] the 30 × 30 m patch of model plants  only when orchids are out of the patch of model pea plants as we expected that when orchids are relatively distant from their model food plant pollinators are more likely to mistake the orchid for the rewarding model per conditioning effect. Accordingly, we quantified the number of pollinia removed from Daviesia's attractive UV reflectance, Diuris benefits from pollinators that mistake it for the rewarding model from afar. We quantified pollinia removal within 63 orchid groups randomly selected across three large orchid populations  was balanced by removing flowers in excess to make the sample size the same. This was made randomly to compare always the same floral display between treated and untreated orchid clumps and to control potential bias due to the attraction to an unbalanced floral display. Within each group, the UV filter solution was sprayed on the outer petals of one clump  and at the base of the corolla on the other clump  as in the previous experiment (same treatment and plant visitation timing). Prior to the UV filter application, the treated and untreated plants were numbered, tagged, and the number of pollinia removed per flower/per plant was recorded. Pea plant flower range was uniform among plants at the time of the experiment  and “u” (ultraviolet) sectors of the Hexagon color space related to the excitation of bee photoreceptors and subsequent bee neural coding of information  while it was found a positive logarithmic dependency with the number of orchids' flowers .Mimic‐model distance on large scale revealed that the number of pollinia removed from the orchid flowers decreased significantly with the distance between orchid and pea Figure , Data S43.3Di. brumalis are located in the bee‐perceived “g” (green) Hexagon sector and according to Scaccabarozzi et al. . There was no difference in the pollinia removal of Diuris whose outer petals had been treated with the UV filter [IN‐T] compared with untreated control orchids [IN‐C] inside the patches of model plants  and the covariate was subsequently removed. We detected no effect of UV reflectance on Diuris pollinia removal when the orchids were closer than a few meters to their model pea plants  neurons that permit an association between flower and reward with a sustained spiking response of about 15 s  but within a maximum distance of 10 m from the model patch. Because the pollinia removal of deceptive species can be subject to both competition and facilitation effects depending on the density of rewarding ; data curation (lead); funding acquisition ; investigation (lead); methodology ; resources ; supervision ; validation ; visualization ; writing – original draft (lead); writing – review and editing . Klaus Lunau: Conceptualization ; data curation ; methodology ; writing – original draft ; writing – review and editing . Lorenzo Guzzetti: Data curation ; formal analysis ; writing – review and editing . Salvatore Cozzolino: Conceptualization ; methodology ; supervision ; visualization ; writing – original draft ; writing – review and editing . Adrian G. Dyer: Conceptualization ; methodology ; validation ; visualization ; writing – review and editing . Nicola Tommasi: Methodology ; writing – review and editing . Paolo Biella: Writing – review and editing . Andrea Galimberti: Methodology ; validation ; visualization ; writing – review and editing . Massimo Labra: Validation ; writing – review and editing . Ilaria Bruni: Writing – review and editing . Giorgio Pattarini: Methodology ; writing – review and editing . Mark Brundrett: Methodology ; writing – review and editing . Monica Gagliano: Conceptualization ; methodology ; supervision ; validation ; writing – original draft ; writing – review and editing .The authors declare no competing interests.Appendix S1Click here for additional data file.Data S1Click here for additional data file.Data S2Click here for additional data file.Data S3Click here for additional data file.Data S4Click here for additional data file.Data S5Click here for additional data file.Data S6Click here for additional data file.


The incidence of stroke after coronary artery bypass grafting (CABG) is around 1.3% in the Society of Thoracic Surgeons database but carries a mortality of almost 20%.The case by Osorio–Jaramillo published in this issue of the journal reignites the discussion on the value of computerized tomographic  (CT) imaging as a routine preoperative investigation before cardiac surgery.Atheromatous disease of the aorta not only increases the risk of perioperative stroke but also impacts upon long term mortality.Preoperative CT has been used in the past predominantly in the re‐operative setting. Studies comparing patients undergoing reoperative surgery have reported a reduction in stroke rates in patients undergoing preoperative CT scans.While the usefulness of preoperative CT scans is intuitive, robust data on improvement with this strategy is sparse, especially in routine or low‐risk patients. In high‐risk patients use of preoperative CT scans in patients undergoing cardiac surgery has been shown to be associated with a reduction in stroke rates as well as mortality.The concerns with using preoperative CT scans include radiation exposure, contrast‐induced nephropathy, additional cost, and utilization of resources which may be an important consideration in resource‐depleted countries and state‐funded healthcare systems. Even though, ultra‐low‐dose CT scanning without contrast enhancement can satisfactorily identify an atheromatous aorta thus ameliorating some of the concerns the benefit of preoperative CT scan is still not established. Studies that have compared the role of preoperative CT in improving outcomes, especially in primary surgery are few and suffer from considerable heterogeneity.While some of the studies have used contrast‐enhanced CT scans others use non‐contrast CT for reporting outcomes. Considerable variability also exists in the case‐mix with CABG, valve surgeries, and CABG with concomitant valve surgery being included in varying proportions in different studies all of which further muddy the water. Mortality has been defined at 30‐day in some and as in‐hospital in others making a comparison across studies extremely unreliable. The definition of stroke in these studies still needs to be standardized. The current definition of stroke as recommended by the new American Heart Association/American Stroke Association statement has modified the definition such that in addition to clinical features of stroke, evidence of cerebral emboli by diffusion‐weighted magnetic resonance imaging also constitutes stroke.Preoperative CT scans have shown potential and should not be dismissed, however, large scale randomized studies would be needed to confirm its place in routine preoperative evaluation of cardiac surgical procedures. The results of “Ultra low‐dose chest CT with iterative reconstructions as an alternative to conventional chest X‐ray before heart surgery (CRICKET study)” are awaited (NCT02173470). The study is a multi‐centric randomized controlled trial comparing preoperative chest X‐rays and those undergoing an additional preoperative noncontrast‐enhanced chest CT among patients undergoing cardiac surgery.The authors declare no conflicts of interest.


Immunological mechanisms have come into the focus of current translational stroke research, and the modulation of neuroinflammatory pathways has been identified as a promising therapeutic approach to protect the ischemic brain. However, stroke not only induces a local neuroinflammatory response but also has a profound impact on systemic immunity. In this review, we will summarize the consequences of ischemic stroke on systemic immunity at all stages of the disease, from onset to long‐term outcome, and discuss underlying mechanisms of systemic brain‐immune communication. Furthermore, since stroke commonly occurs in patients with multiple comorbidities, we will also overview the current understanding of the potential role of systemic immunity in common stroke‐related comorbidities, such as cardiac dysfunction, atherosclerosis, diabetes, and infections. Finally, we will highlight how targeting systemic immunity after stroke could improve long‐term outcomes and alleviate comorbidities of stroke patients. This Review discusses the impact of ischemic stroke on systemic immunity, its interaction with common comorbidities, and the underlying mechanisms of systemic brain‐immune communication. AtherosclerosisThe clogging or hardening of arteries caused by atheromatous plaques .Cardioembolic strokeA subtype of ischemic stroke caused by a blood clot that forms in the heart and travels through the bloodstream to the brain.ComorbidityAny coexisting health condition in addition to a primary disease.Cryptogenic strokeA subtype of ischemic stroke of unknown etiology .CytokinesSoluble mediators (peptide or protein) that are used for cell–cell communication between immunocompetent cells; directs their cell function and proliferation.DiabetesDisorder of the carbohydrate metabolism characterized by impaired ability of the body to produce or respond to insulin and thereby maintain physiological blood glucose levels.Endovascular therapyTherapeutic approach for cardiovascular diseases that uses minimally invasive, catheter‐based procedures to remove obstructive clots from inside the artery.Intraparenchymal hemorrhageA type of bleeding that occurs within the brain parenchyma.Ischemic strokeThe most common type of vascular brain injury; brain lesion is caused by occlusion of a brain‐supplying artery.Lymphopenia/lymphocytopeniaA condition of pathologically reduced blood lymphocyte counts.RecanalizationSpontaneous or induced restoration of the blood flow in an occluded vessel or artery.Subarachnoid hemorrhageA type of bleeding that occurs in the subarachnoid space, the space between the membranous layers of the arachnoid mater and the pia mater surrounding the brain.Sympathetic hyperactivityIncreased activity of the sympathetic nervous system.et al, et al, Stroke is a major public health concern with a vast socioeconomic burden . Both types of therapies aim at restoring blood flow to the hypo‐perfused brain tissue and need to be applied to patients as early as possible after stroke onset. This narrow therapeutic time window and several medical contraindications seriously reduce the number of stroke patients who currently can benefit from these recanalization therapies; hence, new treatment strategies are still urgently needed. As alternative methods to treat ischemic stroke, many neuroprotective agents have been evaluated during past decades to minimize the destructive pathophysiology of stroke and protect the ischemic brain . The proteolytic degradation of the tight junction protein complexes and basement membranes, the loss of vascular cells and the increase in transcytosis of leukocytes are key factors contributing to the opening of the BBB, and thus facilitating a passive exit of brain‐derived DAMP as early as within hours after stroke onset  to Type 2 (Th2) helper T cell ratio. This phenomenon represents the disbalance between proinflammatory and cellular (Th1) and anti‐inflammatory and humoral (Th2) predominant mechanisms and is reflected by an increase in the circulating levels of anti‐inflammatory cytokines, such as IL‐10 and IL‐4, and a consequent reduction of pro‐inflammatory factors, including IFN‐γ and TNF‐α, among others  and pathogen recognition ability (TLR genes)  Fig . In the et al, et al, et al, Beyond the SNS, the (over)activation of the hypothalamic pituitary adrenal (HPA) axis also has been proposed to participate in triggering immunosuppression after stroke. In a similar manner to catecholamines, high levels of glucocorticoids after stroke further contribute to lymphocyte apoptosis in spleen  might also participate in promoting this immunosuppressive state. Although less well characterized than the SNS, the parasympathetic activity also increases after stroke  cells in blood 2 months after ischemic stroke . Plasma IL‐6 levels were found to be substantially increased in patients 6 months after mild TBI, compared to orthopedic injury controls , in diverse cerebrovascular diseases. The recent SCIL‐STROKE and SCIL‐SAH trials  two small single‐center double‐blind randomized phase 2 trials, demonstrated the efficacy of subcutaneous IL‐1Ra administration in reducing the peripheral inflammatory response, evaluated by plasma IL‐6 and CRP levels, in acute ischemic stroke and SAH, respectively , a multinational double‐blind phase III study, was also designed to target inflammation in patients with established atherosclerotic disease who had prior myocardial infarction and high residual systemic inflammatory state (measured by high‐sensitivity CRP levels >2 mg/L)—comparable to the chronic inflammatory state after stroke (Ridker et al, et al, et al, et al, et al, et al, Beyond IL‐1β, other anti‐inflammatory strategies are also now under investigation to lower inflammation and prevent cardiovascular events. This is the case of colchicine, a widely available, safe, and low‐cost anti‐inflammatory drug currently used as a treatment for gout, Behçet's disease and familiar Mediterranean fever. Mechanistically, colchicine is known to inhibit tubulin polymerization and microtubule generation, which primarily impairs cell mitosis and motility. Moreover, colchicine has also been known to interfere with the inflammatory process by inhibiting the synthesis of pro‐inflammatory factors, including TNF‐α, COX‐2, and E‐ and P‐selectin expression, among others, and impairing the activity of the NLRP3 inflammasome by blocking its oligomerization (Martínez Taken together, the existing first clinical data from studies targeting systemic inflammation in multiple inflammation‐related diseases suggest that systemic inflammation is as an important driver of secondary vascular events in patients with underlying vascular comorbidities and preceding ischemic events. The currently ongoing and newly planned studies aiming at preventing vascular events after stroke by means of anti‐inflammatory strategies further highlight that the relevance of systemic inflammation after stroke has been already recognized by the large stroke research field, and will likely motivate further trials to test alternative anti‐inflammatory approaches and drugs for the prevention of post‐stroke comorbidities.In recent years, systemic immunity has gained significant importance as a key player in the stroke pathology. Despite its increasing relevance, no consideration is yet given to systemic inflammation for the management of stroke patients in the clinical practice. Solid evidence points toward a tight connection between poststroke systemic inflammation and secondary complications, including infections and diverse cardiovascular pathologies. This emerging concept suggests that inflammation could be a potential target for intervention in stroke patients to improve stroke outcomes and avoid secondary complications at the same time. Particularly, targeting IL‐1β has shown promising results so far. The CANTOS study laid the foundation for the prevention of cardiovascular comorbidities by minimizing systemic inflammation and showed a clear benefit for patients with a high‐risk cardiovascular profile. Similarly, the beneficial effects of Colchicine for preventing secondary vascular events also support the promising potential of anti‐inflammatory agents as therapeutic approaches to minimize the incidence of cerebrovascular and cardiovascular diseases in patients of high risk. Several clinical trials for anti‐inflammatory strategies in stroke are currently recruiting and we can expect increasing interest in the systemic immune response as a therapeutic target. This development gives hope for a paradigm shift from a neuro‐centric view on stroke therapy toward the recognition of systemic effects as important elements in the personalized treatment of stroke patients.Alba Simats: Conceptualization; writing – original draft; writing – review and editing. Arthur Liesz: Conceptualization; writing – original draft; writing – review and editing.CRediT author contributions listed above, the contributions in detail are:In addition to the AS and AL contributed to the conception, writing, and editing of the manuscript.The authors declare that they have no conflict of interest.iwww.heart.orgAmerican Heart Association is a voluntary organization dedicated to fighting heart disease and stroke—iiClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world—www.clinicaltrials.goviiihttps://immunostroke.deImmunoStroke consortium: DFG‐funded consortium for analyzing brain‐immune interaction in stroke—Uncovering the source of increased systemic pro‐inflammatory mediators across time after ischemic stroke and their association with stroke severity and etiology.Understanding in detail the impact of each specific chronic pro‐inflammatory mediator on the pre‐existing or acquired comorbidities after ischemic stroke.Understanding the interaction between primary immunological mechanisms after stroke with other pathways such as stress response or neurohumoral signals in modulating post‐stroke immunity.Elucidating the effect of targeting systemic inflammation as a therapeutic approach to minimize the incidence of secondary comorbidities chronically after stroke.Table EV1Click here for additional data file.


Sexual antagonism is thought to be an important selective force in multiple evolutionary processes, but very few examples of the genes involved are known. Such a deficit of loci could partially be explained by the lack of overlap in terminology between scientific disciplines. Following a similar review in humans, we searched systematically for studies that described genes with sexually antagonistic or sex‐opposite effects in any taxa, using terms designed to capture alternative descriptions of sexual antagonism. Despite drawing on a potentially very large pool of studies we found only eight articles, which between them described seven candidate variants, five of these were gene knockouts. In every case, the variants had net negative effects on the focal trait. One locus was independently validated between studies, but in comparison to previous data on variants in humans and the fruit‐fly, the studies generally suffered from small sample sizes, with concomitant high variance. Our review highlights the radically different effects that gene deletions can have on males and females, where the beneficial effects seen in one sex may facilitate the evolution of gene loss. We searched systematically for genetic variants with sexually antagonistic or sex‐opposite effects in any taxa. Of 2116 articles, we found seven candidate variants, five of which were gene knockouts. Our review highlights the radically different effects that gene deletions can have on males and females, where the beneficial effects seen in one sex may facilitate the evolution of gene loss. We searched systematically for genetic variants with sexually antagonistic or sex‐opposite effects in any taxa. Out of 2116 articles, we found 7 candidate variants, five of which were gene knockouts. Our review highlights the radically different effects that gene deletions can have on males and females, where the beneficial effects seen in one sex may facilitate the evolution of gene loss. Studies were required to report in non‐human specific genes or genetic variants with opposite effects in the two sexes. The search terms used were designed to include papers from biomedical and ecological fields that may not have reported their findings using terms normally found within the evolutionary biology literature . Full texts of these candidate papers were then reviewed in detail. Papers were included in the final list if they described a sex‐opposite or SA effect linked to a specific genetic locus, loci, or gene, and reported the effect to be statistically significant in both sexes . Studies that only reported significant sex‐by‐variant effects were not automatically included unless they also satisfied the criteria above.The abstracts of the papers from this search were then examined, and any papers that had the possibility of reporting an opposite effect of a specific genetic locus on a trait were considered for further screening. This screening produced a shortlist of 97 candidate papers (d) quantifying the magnitude of how a given variant affects the studied trait expressed in the given sex. Specifically, Cohen's d was computed based on the reported descriptive statistics  or by conversion from other effect sizes (Odds ratio) and test statistics  using formulas reported elsewhere . These cases, and the figures the values were extracted from, are detailed in the Data Drosophila melanogaster derived from sex‐specific effect sizes reported in Ruzicka et al.   and more variable  than those found in either humans   Figure  of synth) Figure . DisentaArp53D in D. melanogaster, where loss of the gene significantly improved male fertility as well as reproductive success under competitive conditions (possibly mediated by faster sperm production) but was found to reduce female fertility, through a combination of maternal and zygotic effects on embryonic development  knockout in mice, where effects on villi length were replicated in two independent studies from the same laboratory  mucosal growth in the mouse gut during aging  that have been studied in detail at a genetic level for decades, then this large literature may potentially yield numerous examples of genes with sex‐opposite or sexually antagonistic effects ; data curation (lead); formal analysis (lead); investigation ; methodology ; visualization (lead); writing – original draft (lead), writing – review and editing . Edward Morrow: Conceptualization ; data curation (supporting); formal analysis ; funding acquisition (lead); investigation (supporting); methodology (supporting); supervision (lead); visualization (supporting); writing – original draft (supporting); writing – review and editing .The authors declare no conflict of interest.Appendix S1.Click here for additional data file.Data S1.Click here for additional data file.


It is widely acknowledged that negative body image perception is linked to anxiety, depression, and body dysmorphic disorder. However, there is no gold standard, body image related patient reported outcome measure in use, specific for dermatologic disease, despite evidence to suggest a high prevalence of mental health problems relating to body image in this group of patients.The aim of this study was to perform a review of body image Patient Reported Outcome Measures (PROMs) used in dermatology and to evaluate their effectiveness.Searches were performed in the major databases. Two investigators independently performed full text evaluation by applying an established checklist to evaluate the conceptual model, content validity, reliability, construct validity, scoring and interpretability and respondent burden.Six different PROMs were identified of which only one was fully validated. There was a significant lack of patient involvement in the development of PROMs in this context.We therefore encourage further research in this field to improve the quality of evidence to better understand the relationship between mental health and dermatologic disease. SIGNIFICANCE: Many dermatological conditions can have a detrimental impact on patients' perception of their body image and can contribute to mental health problems such as anxiety, depression, and body dysmorphic disorder. A systematic review was performed and identified six PROMs within this context. Unfortunately, only one of these were fully validated while the remaining had significant shortcomings in particular with regard to a lack of patient involvement during development. This calls for more work to do/be done to help researchers and clinicians evaluate the mental health effects dermatologic conditions may have on this patient cohort. This is important as a deranged body image can lead to Body Dysmorhic Dysorder. Not all PROMs are validated properly and patient participation during construction was not always the case. This could be unethical and should be corrected in future work on these PROMs.Body image is a multidimensional construct that can be defined as the subjective emotions surrounding the degree of satisfaction an individual has with their appearance.To date, no study has assessed which body image scoring tool is most reliable and fit for purpose and currently there are a variety of tools being adopted in the study of this topic which has resulted in a significant heterogeneity in data interpretation.We set out to evaluate which body image Patient Reported Outcome Measure (PROM), relating to dermatological disease, reported within the published literature over the last 10 years, have undergone a validation process, as well as a critical appraisal.This paper will highlight the current strengths, weaknesses and shortcomings in PROMs used to measure body image in dermatology patients which may inform future study design and clinical mental health evaluation of this high‐risk group.2The methods for this systematic review were developed according to the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta Analyses Protocol (PRISMA‐P) statement.We planned to search several databases. We concentrated on generic (or if possible) specific instruments measuring body image in dermatologic diseases. The second aim was to perform a quality appraisal of all the discovered instruments. To avoid a subjective and to obtain an objective evaluation we chose to use the COSMIN approach EMBASE, Scopus, PSYCH Info and Cochrane Library databases using Medical Subject Headings (Mesh) ‘body image’, combined with ‘skin diseases’, ‘dermatology patients’, ‘PROMS’, ‘surveys’ and ‘questionnaires’. We chose studies that had been published between 2010 and present and stratified the results according to the PRISMA flow chart  test‐retest measures. (2) Internal consistency (or reliability) is often measured using Cronbach's alfa. As this measure is influenced by the number of items, users of this test have to be aware of questionnaires with redundant questions. Alfa should be not lower than 70 and not higher than 90.Validity describes the extent to which an instrument measures what it purports to measure. This is specific to the population and setting. (1) Construct validity signifies that the items provide distinctive clinical information. This is often explored using factor analysis and correlation coefficients. ‘Face validity’ is often used instead. (2) Criterion validity: This can be described as (a) predictive validity which means ability to predict response to treatment and clinical outcome and (b) concurrent validity where the correlation with another previously validated instrument is explored.Sensitivity means that the items should be able to discriminate between different groups of patients, between patients and controls, it should be able to give meaningful results in clinical trials, be able to measure wanted or unwanted effects, measure active versus placebo. Sensitivity is crucial when treatment effects are small.Sensibility . The instrument should be easy to use, be short, use the right wording, be calibrated, and facilitate patient‐clinician interaction.As previously mentioned, we adopted a modified COSMIN approach.As the COSMIN approach was found to be too complex to use without modifications. Instead, the simplified version incorporates the critical features highlighted in COSMIN and other relevant literatureThe quality of the individual papers can be judged indirectly from the scoring list Table .3Table The literature search is summarized in the PRISMA diagram Figure .We found six PROMS published in 17 papers and validated in 10 papers. One PROM was specific to dermatology, while the other five were generic.The main properties of each PROM were extracted, and the results are presented in the text.Their psychometric properties are presented in Table The main properties and uses of each PROM will be presented in the following.The Cutaneous Body Image Scale (CBIS) is a 7‐item (10 point) Likert scale from 0 ‘not at all’ to 9 ‘very markedly’. ‘I like the overall appearance of my skin’. The CBIS has been used and validated in multiple skin diseases by the construction teamThe Japanese version of CBIS has been used in dermatitis, acne, alopecia, psoriasis, and skin tumours.The Body Image Quality of Life Inventory (BIQLI)The BIQLI has been adapted to Danish.The Body Image scale (BIS)The Portuguese version of BIS has been used in skin tumours and breast cancer.The Appearance Schema's Inventory Revised (ASI‐R) is a 20 item, 5‐point Likert scale from 1 (strongly disagree) to 5 (strongly agree). It contains two subscales. (1) Self‐evaluative salience and (2) Motivational salience.The Body Image State Scale (BISS) is a Likert scale with six nine‐point items.The Spanish version of BISS was thoroughly validated in diverse groups and compared to other questionnaires.The Body‐Self Relations Questionnaire (BSRQ) contains 10 subscales and consists of 69 Likert type items with five grades from 1 ‘never’ to 5 ‘very often’. The questionnaire is available in a shorter version containing only five subscales with 35 items.4The aim of this systematic review was to identify and evaluate the Body Image PROMS used in studies involving dermatologic conditions. In general, there is a paucity of studies investigating body image in dermatology and hence scarcer those fully evaluating the use of PROMs in this domain. A total of five PROMs were reported more than once within a 10‐year period. One instrument used only once was chosen as it was previously validated.However, there were few descriptions of item development, and in three cases factor analysis was not performed.An evaluation of expected differences between known groups was not undertaken in four proms. There was a lack of sensibility in everyday practical use of the PROMs regarding patient involvement in study design. A plan for missing scores were found only in two cases. Time to complete was not stated in any but had to be derived from the number of items. The literacy level of the PROM was only measured in three cases. Only one PROM (The BIS) ticked all the boxes in Table One of the main limitations in this study was the use of the COSMIN checklist. Several reviews have used the Cosmin approachThis study has highlighted that patient involvement in development of PROMs should be encouraged. Use of PROMs without patient input is increasingly being viewed as unwise and perhaps unethical.In conclusion, this study has demonstrated the limitations in data interpretation of studies investigating the effect of body image perception in dermatologic disease and calls for further research in the field. This will rely on the development of high‐ quality validated PROMs with patient involvement which can extend to specific psychological conditions such as Body Dysmorphic Disorder. Ultimately further research will equip clinicians with a better understanding of the relationship in the context of dermatologic disease and enable timely treatment and support for this high‐risk group of patients.Johannes Kjeldstrup Kristensen: Conceptualization (lead); Data curation (lead); Formal analysis (lead); Funding acquisition ; Investigation (lead); Methodology (lead); Project administration (lead); Resources ; Software ; Supervision (lead); Validation (lead); Visualization (lead); Writing – original draft (lead); Writing – review & editing . Corina Nielsen: Conceptualization ; Data curation ; Formal analysis ; Funding acquisition ; Investigation ; Methodology ; Project administration (supporting); Resources (supporting); Software (supporting); Supervision (supporting); Validation (supporting); Visualization ; Writing – original draft (supporting); Writing – review & editing (supporting). Nora Haloob: Conceptualization (supporting); Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology ; Project administration ; Resources ; Software ; Supervision ; Validation (supporting); Visualization ; Writing – original draft (supporting); Writing – review & editing .None to declare.


Ostrea edulis collected using video transects, we used an ensemble modeling technique to model and predict current and recent distribution of O. edulis along the Swedish west coast where its distribution is, in relative terms, still rather unaffected. We could detect a recent change in the distribution of O. edulis along the coast which to a large extent could be attributed to a change in depth distribution, suggesting that the population of O. edulis have a slightly shallower distribution today than in the past. Although a potential mismatch between living and dead assemblages, caused by a complex combination of biological and environmental conditions, needs to be considered in the interpretations drawn, it may be a way around the lack of suitable background data in management decisions. This provides important information for management and conservation of the native oyster beds. Furthermore, this study illustrates a method for identifying recent changes in species distribution using dead assemblages of bivalves.Marine coastal areas are increasingly affected by human activities resulting in changes in species and habitat distributions. Understanding these patterns and its causes and consequences is important for conservation and restoration of such changing habitats. One habitat that has been heavily affected by human use are the North Sea oyster beds which once were abundant but have lost large parts of its coastal distribution due to overexploitation. Based on data of living and dead assemblages of  Ostrea edulis collected using video transects, we used an ensemble modeling technique to model and predict current and recent distribution of O. edulis along the Swedish west coast. We could detect a recent shift in distribution of O. edulis along the coast which to a large extent could be attributed to a change in‐depth distribution suggesting that the population of O. edulis have a slightly shallower distribution today than in the past.Based on data of living and dead assemblages of  We also demonstrate a potential new method for predicting short‐term changes in species distribution based on species distribution modeling technique and field data on living and dead shells. For these purposes, we generated two models, using a similar approach as Bergström et al.  but which now have none.The aim of the study was to investigate similarities and differences in predictive models and predicted distribution of adult living m et al. , to (a) 22.1Ostrea edulis and dead shells was extracted from the studies performed by Thorngren et al.  were selected for the modeling. The candidate predictors were based on the general relevance for species distribution in marine environment, their availability as full covering raster layers for the investigated area, and the results obtained by Bergström et al. . Wave exm et al.  were usem et al. , here we2.3Ostrea edulis than single algorithm models. Models were built using a 100‐fold cross‐validation and randomly splitting the data into training (70%) and test data (30%) for respective model calibration and testing. This splitting procedure permit evaluation of model accuracy and predictive performance when data are non‐independent.We fitted an ensemble species distribution model based on nine commonly used algorithms: four machine learning methods, Artificial Neural Networks  was assessed using the area under receiver curve  living oysters (LO) or high‐density (>1 ind. m−2) dead shells (EOS), was further explored using partial dependence plots. The predictors that most strongly influence the model were determined using variable importance assuming that the most important variables are the ones with a relative importance above the mean of the predictor variables within each subset. Variable importance was estimated using the built‐in function in the BIOMOD2 package  raster layers of the environmental variables to generate probability maps of occurrences . These probability maps were translated into presence–absence distribution using the threshold  calculated by BIOMOD2 where all areas (15 × 15 m raster cells) with a predicted probability above the threshold (>cut‐off) grouped into “present,” whereas lower suitability values were grouped into “absent.” The observed results were then analyzed visually to identify areas of high interest for further studies on changes in the distribution of living oysters along the Swedish coast. Since areas based on cut‐offs optimized using Youdens index  for each model are not easily comparable between models, we also used a more “decision‐analytic approach” where the same cut‐off values were used for both models. This allowed us to estimate areal extent of LO and EOS plus overlapping areas, under conditions where the criteria for classification are equal for LO and EOS models.33.1−2) of living oysters, dead shells, or both. Of these 59 sites, 52 had high densities of dead shells and 27 had high densities of living oysters. Thirty‐two sites had only high densities of dead shells while only seven sites displayed high densities of living oyster without at the same time having high densities of dead shells. The remaining 20  sites with high densities of living oysters also had high densities of dead shells in its assemblages. The average depth of the sampling sites was 4.41 m (±2.65) while the mean salinity for the sites was 17.3 (±4.0). After recalculating the exposure accounting for depth at the individual sites, the observed average depth‐attenuated exposure was 13302 .Of the total 452 sites investigated, 59 sites had high densities  and the correlation plot showed no strong relationship among the predictors, with all VIF values just above 1  and only weak correlations between variables Figure . The str3.2Ostrea edulis and empty O. edulis shells resulted from ensemble forecasting parameterizing TSS >0.6 for 900 individual models (100 runs of nine methods). Figure The predicted distribution maps of both living Upon building the ensemble models, GL, RF, GAM, GBM, MARS, FDA, ANN, and CTA models were included in the ensemble model of living oysters while RF, GAM, GAM, and CTA models were used for the model for dead assemblages. The two ensemble models, one for living oysters (LO) and one for dead assemblages (EOS), were generally very accurate with AUC scores >0.9 for both LO and EOS models and TSS scores between 0.76 and 0.99 Table . The modAnalysis of variable importance for the ensemble models shows that depth has the strongest influence on the ensemble model for both models (LO and EOS). For the LO model, depth was followed by depth‐attenuated exposure and salinity being the least importance variable, while for the EOS model, exposure and salinity were in the reverse order of importance Table . However3.3As illustrated by the partial plots in Figure In order to estimate the overall areal extent and map the locations of living oysters (LO) and empty shells (EOS), we utilized predictions of high densities of living oyster and empty shells. The areal extents were predicted using both model‐specific optimized cut‐offs (Youdens index) and the decision analytic approach of equal cut‐offs. These analyses showed that the predicted areal extent of living oysters and empty shells was largely sensitive to cut‐off values Table . Using m4Ostrea edulis, see Allison et al., Ostrea edulis and empty shells, this study demonstrates an example of how empty shells of living organisms can be used for prediction of recent (8–15 years) changes in spatial distribution. The results found in this study also provide important information on the current distribution of Ostrea edulis and how the distribution has changed during recent years toward slightly more shallow areas. We also note that exposure and salinity are more important in determining the distribution of empty shells than they are for explaining the distribution of living oysters. It gives insights into the development of tools for management of oyster beds and for planning and management of the coastal environment.For meaningful targets for conservation and restoration, it is vital with baseline information on the status of the community/species before a recent and/or rapid change NRC, . HoweverOstrea edulis population, the use of methods utilizing dead assemblages might be the only way to obtain some scientifically based baseline information for future management of the population. As in the case of Ostrea edulis, heavier shells require a much higher water movement energy for transportation, making them more suitable for utilization of recent changes in spatial distribution than lighter shells such as blue mussel (Mytilus edulis) shells which are more easily transported away from its origin.For environmental assessment, the mismatch between living and dead assemblages is not perfect, as there are some overlap between dead assemblages and pristine areas and the assemblages of dead shells may represent a range of time spans depending on local biological and environmental conditions. Often these assemblages of dead shells include a majority of relatively recent deaths and a long tail of rare shells from individuals that died at increasingly earlier time. Given these time spans, the distribution of dead shells may not be a perfect indicator of present or past habitats, restricting the interpretations and conclusions that can be drawn from the mismatch in distribution between living and dead assemblages  are inhibited by increased resuspension due to decreased ingestion and dilution of food with inorganics  areas along the Swedish coast  in most of the investigated area. However, in cases of applying the demonstrated technique for species with lighter shells, shells more likely to be transported by wave energy, such considerations are increasingly important. Furthermore, the distinction between areas containing empty shells only and those with both living and dead help identify areas where there are no longer living oysters but where they previously thrived. However, modeled estimates of areal extents of dead and living oysters are very sensitive to cut‐off values ; Formal analysis (lead); Methodology (lead); Writing – original draft (lead); Writing – review & editing . Linnea Thorngren: Data curation (lead); Funding acquisition (supporting); Writing – original draft (supporting); Writing – review & editing . Mats Lindegarth: Funding acquisition (lead); Methodology (supporting); Resources (lead); Writing – original draft (supporting); Writing – review & editing .The 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.


Recently, non‐B non‐C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5‐5‐500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non‐B non‐C cirrhosis and HCC, are highlighting the importance of peri‐transplant management of patients with various comorbidities. The post‐LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome‐related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome‐related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post‐LT outcomes. Patient management in the peri‐transplant period as well as risk assessment for LT are key to improving post‐LT outcomes in the era of a growing number of cases of LT for non‐B non‐C liver diseases. Recently, the cases of LT for non‐B non‐C cirrhosis and HCC have been increasing in Japan as well as worldwide. Perioperative management of non‐B non‐C liver disease is problematic due to various risk factors, including alcohol consumption and metabolic syndrome‐related risks, such as obesity and diabetes mellitus. This article aims to review the current status and issues of LT focusing on non‐B non‐C liver diseases, including HCC." cd_value_code="text Liver transplantation (LT) for HCC is an effective curative therapy that can simultaneously replace not only the tumors but also the damaged liver parenchyma from which the tumors originate. In recent years, there has been a global shift in the causes of chronic liver injury and the resulting HCC, leading to changing trends in the management of LT.The causes of liver injury and systemic comorbidities that underlie non‐B non‐C liver diseases are diverse, frequently overlapping and further complicating the prognostic impact after LT. In addition, the concept of metabolic dysfunction‐associated fatty liver disease (MAFLD) has been proposed as a fatty liver disease associated with metabolic dysfunction due to obesity, diabetes, and metabolic syndrome‐related abnormalities, which is independent from the conventional definition of alcoholic intake.Thus, patient management and education in the peri‐transplant period as well as the indication and risk assessment for LT are key to improving the post‐LT outcomes in the era of a growing number of cases of LT for non‐B non‐C etiologies. This article aims to review the current status and issues of LT focusing on non‐B non‐C liver diseases, including HCC.2LT provides a good treatment option for selected patients with HCC, achieving long‐term survival without cancer recurrence due to efforts to establish appropriate indications. In 1996, Mazzaferro et al proposed the Milan criteria , which has been widely accepted as a global gold standard.Similar to the Milan criteria, tumor burdens have been principally used for indications with modest modification, including the University of California San Francisco (UCSF) criteria,In Japan, unlike in Europe and the United States, living donor (LD) is the mainstay of donor sources for LT due to the critical shortage of deceased donor livers, and thus the eligibility of patients with HCC for LT are limited to those with decompensated cirrhosis.Thus, efforts to expand the indications of LT for patients with HCC and to improve the outcomes by reducing the risk of tumor recurrence have established liver transplantation as one of the curative therapeutic options for HCC. Alternatively, most of the abovementioned criteria incorporated only HCC‐specific factors and did not sufficiently take into account outcomes other than cancer recurrence. In particular, the prognosis of non‐B non‐C HCC with underlying diseases such as ALD and NAFLD/NASH might be affected by cardiovascular diseases, de novo malignancies, and other etiology‐related sociomedical backgrounds of patients. Recent reports have proposed a prognostic model after liver transplantation for HCC that takes into consideration not only HCC‐related variables but also non‐HCC‐specific factors such as age, renal function, and etiology .Considering the significantly high risk of cardiovascular events in recipients with NAFLD/NASH, pre‐LT evaluation and management of metabolic risk factors, including central obesity, type 2 diabetes, hypertension and dyslipidemia, are of key importance. Screening of cardiovascular and renal function is also recommended.In patients with NAFLD/NASH who have persistent risks of metabolic syndrome, it is important to adopt strategies of management and treatment that focus on improving and controlling the metabolic complications depending on the individual risk factors while avoiding increasing the metabolic risk factors by appropriate immunosuppressive regimens. High‐dose corticosteroids are associated with the risk for metabolic syndrome, and protocols for early reduction and withdrawal of steroids are preferable.Recurrence of NAFLD/NASH is often problematic after LT, and it is important to control weight gain and metabolic syndrome‐related risk factors in the peri‐transplant period. NAFLD recurrence and de novo NAFLD  are seen in more than half of patients at 1 year after LT. NASH recurrence also occurs frequently , while the incidence of de novo NASH is reportedly relatively low .N = 26). Those for de novo NAFLD and de novo NASH were 23%, 31%, 37%, and 40% and 13%, 16%, 18%, and 22%, respectively, in non‐NASH recipients, including ALD (N = 52) and cryptogenic (N = 23) cases  from 1996 to 2020 at Kyoto University Hospital, Japan. For definitive diagnosis of NASH recurrence, liver biopsy was performed in patients with abnormal liver function after LT or those with fatty liver indicated by imaging studies, including ultrasonography and/or computed tomography. The diagnosis of NAFLD/NASH was proven based on pathological findings.6HCC recurrence after liver transplantation peaks within 2 to 3 years after LT. The most common recurrence pattern is extrahepatic metastasis in lung and bone. Early recurrence within 1 year after LT could occur due to undetected extrahepatic metastasis that might present prior to transplantation or circulating cancer cells engrafting and growing in the target sites.Immunosuppressive regimens after LT are associated with HCC recurrence. CNIs are one of the standard agents used after LT; however, from an oncological point of view, CNIs reportedly promote tumor growth.There is no sufficient evidence of the efficacy of adjuvant therapy after LT for HCC. For example, adjuvant therapy using sorafenib did not contribute to recurrence‐free or overall survival, showing that its benefits were limited.The effectiveness of surgical resection, locoregional therapy including transcatheter arterial chemoembolization and radiofrequency ablation, and systemic therapy such as sorafenib has been reported as treatment after recurrence.Immune checkpoint inhibitors (ICIs) have made remarkable progress in recent years as a treatment option for advanced HCC; on the other hand, ICIs increase the risk of rejection and graft loss after LT, and there is no evidence that the antitumor effect outweighs the risk of rejection.7Recently, the cases of LT for non‐B non‐C cirrhosis and HCC have been increasing in Japan as well as worldwide. Perioperative management of non‐B non‐C liver disease is problematic due to various risk factors, including alcohol consumption and metabolic syndrome‐related risks, such as obesity and diabetes mellitus. Stratifying the indications for LT in individual etiology based on the risk assessment for recurrence of the primary disease remains a future challenge.Conflict of Interest: The authors declare no conflicts of interest for this article.Ethical Approval: The analysis of human data in this study was performed in accordance with the ethical guidelines for epidemiological research in Japan and was approved by the Ethics Committee of the Kyoto University Graduate School and Faculty of Medicine . Written informed consent was obtained from all study patients.


New York State Department of Environmental Conservation (NYSDEC) has developed a robust citizen science macroinvertebrate sampling method. The metric relies on the presence and not the absence of key macroinvertebrates and therefore is resistant to collection and sorting errors. It identifies unimpaired streams with high confidence (0.1% type 1 errors) and at a reasonable efficiency compared to NYSDEC’s multimetric index of biological integrity (54%). We rank remaining stream samples for further investigation using a calculated probability of impairment. This method is valuable as a tool for large monitoring programs with limited resources for quality assurance checks. The value of this method goes beyond data collection, however, as data of known quality is an effective communication tool between citizen scientists and state regulatory agencies and/or local decision makers. Benthic macroinvertebrates are well documented biological indicators in rivers and streams because they are ubiquitous, abundant, diverse, and sensitive to chemical and physical environmental impacts  similar to Connecticut’s approach and a metric that uses threshold probabilities of impairment (TPI) based on the presence of these taxa. The New York State Department of Environmental Conservation (NYSDEC) used these results to design the Water Assessments by Volunteer Evaluators (WAVE) program. Our primary objective was to create a volunteer monitoring program that produced data of known quality to enable clear communication of stream health in support of state and local efforts to protect New York’s water resources.To develop both metrics, we used the historic NYSDEC macroinvertebrate data set to (1) identify indicator macroinvertebrates, (2) generate distribution frequencies for each indicator organism / water quality condition combination, and (3) used these indicators and frequencies to calculate and assess the two metrics. To prevent bias, we separated the historic data set into a training data set and a test data set. Steps 1 and 2 were accomplished using the training data set and step 3 was performed on the test data set.The NYSDEC collects water quality data and information in streams and rivers on a statewide, 5‐year cycle. This includes benthic macroinvertebrate samples to estimate water quality impacts on aquatic life. For this project, the focus was on wadeable streams and rivers sampled using a traveling kick method which consisted of a one‐time, 5‐m diagonal transect sample through a riffle area over 5 min. Samplers kick the bottom substrate and collect the dislodged organisms in a 0.25 m X 0.5 m, 900 µm mesh net held downstream. Sampling occurs during the July to September index period. From each sample, a random 100-organism subsample is removed and each individual specimen is identified to the lowest possible taxonomic resolution, typically genus or species  score, to summarize benthic macroinvertebrate data and report water quality impacts on aquatic life. For the traveling kick method, individual component metrics of the BAP include species richness, Hilsenhoff’s biotic index (Hilsenhoff Chironomus spp. (Diptera: Chironomidae) at genus because they are generally identified by their red coloration.We used the training data set to identify indicators of impaired and unimpaired biological conditions. Taxonomic resolution was reduced to family level (with five exceptions), reflecting the extent a volunteer would likely be able to visually distinguish taxonomic differences in the field. This decision was based on our experience identifying organisms in the field without a microscope as well as interaction with a broad range of volunteers. Exceptions included Pelecypoda, Hirudinea, and Turbellaria which were reduced to class and Amphipoda to order because of difficulty distinguishing these organisms in the field. We kept n = 406) to identify indicators of unimpaired biological condition. All moderately and severely impacted (n = 287) macroinvertebrate community samples (BAP < 5.0) were used to represent the impaired condition due to the limited number of severely impacted samples (BAP < = 2.5). We calculated the Sørensen index to estimate community similarity within each category and calculated the relative contribution of each taxon. The Sørensen index is the most commonly used index in community ecology to compare populations using presence/absence data  with the test data set. We calculated the frequency at which 3, 4, 5, 6, and 7 minimum indicator taxa correctly or incorrectly (type 1 errors) identified samples collected from unimpaired streams (BAP > 5) or samples from impaired streams (BAP ≤ 5).We assessed five possible metrics using the TPI also with the test data set. For each sample in the test data set, we calculated the probability of biological impairment and the probability biological condition is unimpaired using a modified Naïve Bayes equation Eqs. . Using tWe identified indicator taxa for both unimpaired and impaired biological condition categories Table . The 32 The PTIT metric was successfully able to match both impaired and unimpaired biological condition categories for all five taxa threshold iterations. The percent of samples with matching condition categories decreased when we increased the required number of indicator taxa Tables  and 3. EThe TPI metric was successfully able to match impaired and unimpaired biological condition categories for all five probability threshold iterations Tables  and 3. ABoth metrics performed better at capturing unimpaired compared to impaired biological conditions Fig.  and 3. BMacroinvertebrate sampling is a common method used by citizen science programs sampling rivers and streams  with negligible type 1 errors  at negligible type 1 error rates (0.1%) to be valuable as a monitoring tool alone Table , is deliThe NYSDEC launched the WAVE program in 2012 and the program has collected 1343 samples in total, 33% of which indicated unimpaired biological conditions and 7.5% of which launched further investigations of possible impairment. The frequency of unimpaired samples is lower than the 54% in the test data set and is most likely caused by sampling and handling errors that result in no conclusion but, importantly, not erroneous results. WAVE plays an efficient regulatory role because it requires minimal staff time, and the method is robust to most errors. NYSDEC included WAVE sample results in Clean Water Act section 305b reporting.It is possible to increase the efficiency of WAVE assessments by directing samplers to undisturbed watersheds since the method is more efficient in less disturbed streams Fig. . ConnectCitizen scientists transition from data collection to participation in restoration and preservation efforts at multiple levels. With state monitoring programs, citizen scientists can highlight waterbodies that they feel deserve attention and participate in watershed planning efforts supporting those waterbodies . Several organizations use WAVE as part of a larger education/stewardship program and appreciate that the data can serve both educational and state monitoring objectives. Most WAVE participants, however, indicate that they are sampling primarily to support NYSDEC efforts. Therefore, it is important that we are transparent about the value and application of the data collected to best take advantage of this opportunity to foster stewardship and educate the participants about stream ecosystems and the NYSDEC efforts to conserve and protect these resources. After receiving his results, one WAVE participant wrote, “My family has lived on the banks of Fish Creek since 1866. Helping to assess its health is very rewarding for me” .Previous research highlights that citizen science has the potential to improve environmental decision making, but few studies indicate that the data collected changed management decisions (Conrad and Hilchey Presence only metrics are valuable tools for large volunteer programs because they are robust to sampling variability and therefore programs require fewer quality assurance checks to ensure the integrity of the data produced. The NYSDEC WAVE program uses a presence only metric that is not vulnerable to collection and sorting variability thereby removing the major sources of uncertainty. This metric identifies samples from unimpaired streams and we rank the remaining samples for potential follow up investigations using a calculated probability of impairment based on presence only macroinvertebrate types. The benefits of this method go beyond data collection alone. The data is of known quality and thresholds for response are clearly defined which enables clear communication between citizen monitoring groups and NYSDEC and/or local decision makers.


Regular exercise training has potent and powerful protective effects against the development of cardiovascular disease. These cardioprotective effects of regular exercise training are partly explained through the effects of exercise on traditional cardiovascular risk factors and improvement in cardiac and vascular health, which take several weeks to months to develop. This review focuses on the observation that single bouts of exercise may also possess an underrecognized, clinically useful form of immediate cardioprotection. Studies, performed in both animals and humans, demonstrate that single or short‐term exercise‐induced protection (SEP) attenuates the magnitude of cardiac and/or vascular damage in response to prolonged ischaemia and reperfusion injury. This review highlights preclinical evidence supporting the hypothesis that SEP activates multiple pathways to confer immediate protection against ischaemic events, reduce the severity of potentially lethal ischaemic myocardial injury, and therefore act as a physiological first line of defence against injury. Given the fact that the extent of SEP could be modulated by exercise‐related and subject‐related factors, it is important to recognize and consider these factors to optimize future clinical implications of SEP. This review also summarizes potential effector signalling pathways (i.e. communication between exercising muscles to vascular/cardiac tissue) and intracellular pathways (i.e. reducing tissue damage) that ultimately confer protection against cardiac and vascular injury. Finally, we discuss potential future directions for designing adequate human and animal studies that will support developing effective SEP strategies for the (multi‐)diseased and aged individual.Single or short‐term exercise‐induced protection (SEP) attenuates the magnitude of cardiac and/or vascular damage in response to prolonged ischaemia and reperfusion injury (IR injury).SEP activates multiple pathways to confer cardiac protection, which develops remotely at the site of the activated muscle by release of circulating molecules, which transfer towards activation of intramyocardial signalling that promotes cell survival during episodes of IR injury.SEP represents an attractive intervention in aged individuals and in those with co‐morbidities. The immediate protection, low cost and simplicity to increase the ‘dose’ of SEP offers unique opportunities in the clinical applications of SEP. Abstract figure legend Single to short‐term exercise preconditioning (SEP) stimulates the release of circulating factors and activation of intramyocardial signalling, resulting in attenuated severity of myocardial ischaemia reperfusion (IR) injury. As opposed to SEP, regular exercise  also prevents IR injury episodes by inhibiting the development and/or progression of atherosclerosis. This process is mediated by cardiovascular structural and functional changes and reductions in cardiovascular risk factors following regular exercise. Cardiovascular disease (CVD) continues to be the leading cause of morbidity and mortality worldwide  injury represents a major contributor to cardiovascular‐related morbidity and mortality , although more research would be required to validate this observation. Similar monophasic protection by short‐term repeated exercise has been observed against neurovascular injury and brain infarct size following stroke in rats undergoing high‐intensity interval training (HIIT) . This method induces impairments in brachial artery function as measured by flow‐mediated dilatation (FMD)  cardiac and vascular injury. The efficacy of SEP in ageing and diseased populations suggests that SEP may be a more robust stimulus as compared to IPC. Evidence is appearing that repeated bouts of continuous exercise, as demonstrated in heart failure patients, bolster the protective effects of SEP. Although larger and more heterogenous human studies of SEP are required, especially for understanding the time course of exercise‐induced cardioprotection, single or short‐term exercise may represent a powerful tool for cardioprotection.The strength of SEP may depend on factors related to the exercise stimulus itself or to subject‐related factors Fig. . Below, et al. et al. et al. In line with preclinical data in preconditioning, the presence of cardiovascular risk factors or disease can attenuate the efficacy of SEP. This is important because loss of efficacy of the preconditioning stimulus predominates the lack of translation to clinical implementation. For example, the benefits of acute exercise against ischaemic injury were absent in spontaneously hypertensive rats as opposed to healthy rat hearts in an isolated Langendorff‐perfused heart model , intermediate (7–14 days) and extended (28 days) voluntary wheel running, male mice showed improved tolerance to IR by 7 days, with no further improvements with increasing duration or volume of exercise . The contribution of humoral factors in exercise preconditioning has been sparsely investigated. In isolated Langendorff‐perfused rabbit hearts perfused with human plasma dialysate, Michelsen et al.  family, was recently reported to lower cardiac IR injury in response to 4 weeks of exercise training  formation  are a set of enzymes that convert arginine to nitric oxide, which is a multi‐faceted cellular cross‐talk molecule related to vasodilatory response, thrombogenicity, proliferation, inflammation, contractility and mitochondrial function. The significance of NOS for SEP was demonstrated in C57BL/6 mice undergoing 7 days of exercise  acts as a signalling molecule for cellular ion homeostasis, calcium handling, contractile function and cardioprotection. In the early window following one and seven bouts of exercise, it appears that PKC isoforms are bi‐directionally modulated in rat hearts  cover a large family of molecular chaperones that are triggered by exposure to stress. Studies have reported increased HSP70/72 expression by exercise as a potential source for cardioprotection following training .Peer Review HistoryClick here for additional data file.


Atrial fibrillation (AF) is the most common arrhythmia and a growing health problem worldwide. The number of AF patients is increasing constantly, which can be attributed to the better detection of AF, the increase in life expectancy, and corresponding risk comorbidities predisposing to AF.Another very good example of its efficacy is the present report “Midterm Outcomes of Concomitant Cox‐Maze IV: Results from a Multicenter Prospective Registry,” in which Gerdisch and colleagues describe their results from a routine performance of a standardized Cox‐Maze IV (CMIV) procedure concomitant to cardiac surgery.Despite these excellent results, concomitant AF ablation during cardiac surgery was recently downgraded from a Class IA recommendation


A trial comparing prenatal with postnatal open spina bifida (OSB) repair established that prenatal surgery was associated with better postnatal outcome. However, in the trial, fetal surgery was carried out through hysterotomy. Minimally invasive approaches are being developed to mitigate the risks of open maternal–fetal surgery. The objective of this study was to investigate the impact of a novel neurosurgical technique for percutaneous fetoscopic repair of fetal OSB, the skin‐over‐biocellulose for antenatal fetoscopic repair (SAFER) technique, on long‐term postnatal outcome.This study examined descriptive data for all patients undergoing fetoscopic OSB repair who had available 12‐ and 30‐month follow‐up data for assessment of need for cerebrospinal fluid (CSF) diversion and need for bladder catheterization and ambulation, respectively, from eight centers that perform prenatal OSB repair via percutaneous fetoscopy using a biocellulose patch between the neural placode and skin/myofascial flap, without suture of the dura mater (SAFER technique). Univariate and multivariate logistic regression analyses were used to examine the effect of different factors on need for CSF diversion at 12 months and ambulation and need for bladder catheterization at 30 months. Potential cofactors included gestational age at fetal surgery and delivery, preoperative ultrasound findings of anatomical level of the lesion, cerebral lateral ventricular diameter, lesion type and presence of bilateral talipes, as well as postnatal findings of CSF leakage at birth, motor level, presence of bilateral talipes and reversal of hindbrain herniation.A total of 170 consecutive patients with fetal OSB were treated prenatally using the SAFER technique. Among these, 103 babies had follow‐up at 12 months of age and 59 had follow‐up at 30 months of age. At 12 months of age, 53.4% (55/103) of babies did not require ventriculoperitoneal shunt or third ventriculostomy. At 30 months of age, 54.2% (32/59) of children were ambulating independently and 61.0% (36/59) did not require chronic intermittent catheterization of the bladder. Multivariate logistic regression analysis demonstrated that significant prediction of need for CSF diversion was provided by lateral ventricular size and type of lesion (myeloschisis). Significant predictors of ambulatory status were prenatal bilateral talipes and anatomical and functional motor levels of the lesion. There were no significant predictors of need for bladder catheterization.Children who underwent prenatal OSB repair via the percutaneous fetoscopic SAFER technique achieved long‐term neurological outcomes similar to those reported in the literature after hysterotomy‐assisted OSB repair. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. abstract to view the translations.This article's abstract has been translated into Spanish and Chinese. Follow the links from the here to view the Correspondence.Linked article: There is a comment on this article by Macedo Jr and Leal da Cruz. Click  What are the novel findings of this work?The majority of children who had undergone percutaneous fetoscopic open spina bifida repair did not require a ventriculoperitoneal shunt or third ventriculostomy within the first 12 months of age (53%), were ambulating independently at 30 months of age (54%) and did not require chronic intermittent catheterization of the bladder at 30 months of age (61%).What are the clinical implications of this work?Long‐term neurological outcomes after percutaneous fetoscopic open spina bifida repair are similar to those after hysterotomy‐assisted repair.vs 80%) by the age of 12 months and a 50% increase in the rate of ambulation without the need for orthotics (42% vs 21%) by 30 monthsThe Management of Myelomeningocele Study (MOMS) reported that prenatal repair of open spina bifida (OSB) through maternal hysterotomy, compared to postnatal repair, was associated with a 50% reduction in the ventricular shunt rate , Los Angeles (USA), Petah Tikva (Israel), Santiago (Chile), London (UK), Milan , Miami (USA) and New York (USA)) were examined. Of note, use of the biocellulose patch was not approved in Miami, Los Angeles and New York, so a dural substitute was instead used in these centers. First, we used data from children at 12 months of age or older to determine the need for CSF diversion by 12 months of age; CSF diversion was defined as either insertion of a ventriculoperitoneal shunt or endoscopic third ventriculostomy. Second, we used data from children at 30 months of age or older to determine the rate of and risk factors for the ability to ambulate without the need for an assistive device and the need for chronic intermittent bladder catheterization. Information on ambulation and need for chronic intermittent catheterization of the bladder was obtained from the attending physician, medical records and/or parents. The study (NCT04356703) was approved by the institutional review boards (IRB) of the Hospital Israelita Albert Einstein, São Paulo, Brazil (SGPP number: 2973‐17 on 1 April 2017), Keck School of Medicine, Los Angeles, CA, USA (IRB number: HS‐18‐00591 on 9 June 2018), Rabin Medical Center, Petah Tikva, Israel (IRB number: 0295‐19‐RMC on 21 May 2019), Clinica Universidad Los Andes, Santiago, Chile  and King's College Hospital, London, UK .2; and maternal diabetes or hypertension. After completion of the CECAM  trialThe diagnosis of OSB with hindbrain herniation was established via preoperative ultrasound, and pre‐ and postoperative fetal magnetic resonance imaging was performed. Hindbrain herniation was defined as the cerebellar tonsils below the foramen magnum. Initially, the inclusion criteria were as follows: gestational age from 19 + 0 to 27 + 6 weeks; lesion level T1 to S1; hindbrain herniation; no other major anomaly; and normal karyotype. Exclusion criteria were: multiple gestation; previous uterine surgery; fetal kyphosis > 30°; cervical length < 2 cm; complete anterior placenta; low‐lying placenta; placental abruption; history of preterm birth; history of cervical incompetence; alloimmunization; positive maternal viral load for hepatitis and/or human immunodeficiency virus; large uterine fibroids; body mass index > 35 kg/mLateral ventricular diameter was measured on ultrasound before surgery, and the larger of the two sides was used for the study. The anatomical level of the lesion was categorized as low if the lesion was at L5 or lower, intermediate if the lesion started at L3–L4 and high if the lesion was at or above L2. We now use motor level, rather than anatomical level, as an inclusion criterionAfter discussion of all management options, patients who elected to proceed with fetoscopic treatment gave written informed consent and signed the IRB‐approved study consent forms. The technical issues of percutaneous fetoscopic OSB repair have been reported in detail previouslyDelivery was advised at 39 weeks' gestation, and Cesarean section was initially mandated based on the first version of the protocol. Vaginal delivery was allowed from Case 27 onwards. In cases of preterm prelabor rupture of membranes (PPROM) before 34 weeks' gestation, corticosteroids, intravenous ampicillin plus erythromycin for 2 days followed by oral amoxicillin plus erythromycin for 5 days, and a vaginal antimicrobial agent (miconazole and tinidazole) every 3 days was given until delivery. In cases of PPROM, elective delivery was recommended at 34 weeks' gestation. After birth, if a bilaminar patch was used, it was kept in place and protected using a Mepilex® wound dressing . Sutures were removed after spontaneous detachment of the silicone layer from the dermal matrix was noted. The dressing was changed at least every 2–3 days, until complete skin secondary intention healing was achieved. Daily assessments for CSF leakage from the surgically repaired site were performed while the neonate was admitted in the hospital. Leakage of CSF was defined as dripping from the lesion site and/or as a finding of persistent wet drapes. Postnatal motor level was assessed by a neurosurgeon and/or physiatrist at discharge and/or at outpatient visits, and the most recent findings were used. Functional motor level determined by ultrasound was divided into three categories: high (L1–L2), intermediate (L3–L4) and low (L5–S1).vs endoscopic third ventriculostomy was at the discretion of the attending pediatric neurosurgeon.Need for placement of a ventriculoperitoneal shunt or endoscopic third ventriculostomy was at the discretion of the attending pediatric neurosurgeon. Initially, we used the protocol established during the MOMS trial which was later modified in 2015At birth, motor level was assigned from T12 to S2 using a more detailed clinical evaluation: muscle strength and tone; deep tendon reflexes; and coordination and movements. If the level was asymmetric, the ‘worse’ level was consideredChronic intermittent bladder catheterization was defined as urethral clean catheterization for emptying the bladder every 3–4 h. The criteria for such treatment vary between centers. Some centers use a proactive approach for bladder catheterization, meaning that all spina bifida babies are initiated on chronic intermittent catheterization in the neonatal period. Only the Albert Einstein Hospital and the Milan center used a conservative approachThe need to untether the spinal cord was based solely on the presence of clinical symptoms including loss of an acquired function (worsening or loss of gait), worsening of neurogenic bladder, local back pain and/or progressive scoliosis.U‐test for continuous variables and Fisher's exact test for categorical variables, with post‐hoc Bonferroni correction. Univariate and multivariate logistic regression analyses, with Firth's penalization when required, were used to determine which factors among prenatal and postnatal findings were significant predictors of outcome. The variance inflation factor (VIF), which represents the factor by which the variance is inflated, was used to assess multicollinearity; VIF values > 4 require further investigation, whereas VIF values > 10, which are a sign of serious multicollinearity, require correction. We used a non‐automated backwards elimination strategy to select variables included in the final model. All variables that were significant in the adjustment were included in the final model. The best model was selected using the Akaike information criterion. Significance was set at P < 0.05.Descriptive data were assessed for all patients undergoing fetoscopic OSB repair with available 12‐month follow‐up for assessment of CSF diversion and 30‐month follow‐up for assessment of bladder catheterization and ambulation. Comparisons between groups were performed using the Mann–Whitney We conducted statistical analyses using package R softwareBy 1 June 2020, 170 consecutive patients had undergone prenatal OSB repair using the SAFER technique in the eight different centers: 116 cases in São Paulo, 18 in Los Angeles, 10 in Petah Tikva, nine in Santiago, eight in London, five in Milan, three in Miami and one in New York.in utero in Brazil.In 54 of the 170 cases, fetal surgery was carried out less than 12 months prior to the time of writing. Of, the remaining 116, three cases were excluded because prenatal repair could not be completed; two of these were due to loss of access to the uterine cavity as a result of gas leaking to the maternal abdomen, and, in the third case, there was massive maternal gas embolism that prompted immediate delivery to ensure maternal safety. There was one fetal death, one pregnancy termination at the request of the parents, three prematurity‐related neonatal deaths and five additional deaths before the age of 12 months, of which three were infection‐related following insertion of a ventriculoperitoneal shunt. Thus, 103 cases were available for assessment of need for CSF diversion at 12 months of age: 87 cases from São Paulo, five from Petah Tikva, four from Milan, three from Santiago, two from Los Angeles, one from London and one from New York. A total of 60 cases should have been 30 months of age or older, but one died between 12 and 30 months, leaving 59 patients for assessment of independent ambulation and need for chronic bladder catheterization; all of these patients were treated Maternal and pregnancy characteristics of pregnancies assessed at 12 and 30 months after birth are summarized in Table Need for bladder catheterization at 30 months of age is summarized in Table Ambulatory outcome at 30 months of age is summarized in Table There are four main findings of this study of patients that underwent percutaneous fetoscopic OSB repair. First, at 12 months of age, 53.4% did not require ventriculoperitoneal shunt or third ventriculostomy. Second, at 30 months of age, 54.2% were ambulating independently and 61.0% did not require chronic intermittent catheterization of the bladder. Third, preoperative lateral ventricular diameter and presence of myeloschisis were prenatal predictors of the need of CSF diversion by 12 months of age. Fourth, significant prediction for ambulation at 30 months of age was provided by prenatal bilateral talipes and anatomical and functional motor level of the lesion. Gestational age at fetal surgery, before or after 26 weeks, and gestational age at birth were not predictive of the three outcome measures of this study, but a larger number of patients will need to be investigated before exclusion of such potential associations.vs 60% of cases, ambulation without orthotics in 54% vs 42% and no need for chronic intermittent bladder catheterization in 61% vs 62%et al. also showed that the fetoscopic approach provides at least similar long‐term outcomes as compared to hysterotomy‐assisted fetal surgery, with 48% requiring CSF diversion and 46% with independent ambulation at 30 months of ageet al.vs 36%The criteria and techniques for fetal surgery, as well as the definition of outcome measures, vary between studies, and, therefore, the conclusions that can be drawn from comparison of different series are limited. Nevertheless, the long‐term outcomes after percutaneous fetoscopic OSB repair compared favorably to previously published outcomes after hysterotomy‐assisted repairin utero. For example, traditional diaphragmatic hernia repair failed in utero due to the kink of the umbilical vein that occurred after the intestines were returned to the abdominal cavity; based on this understanding that the fetus is different from the neonate, the novel approach of tracheal occlusion resulted in relatively improved outcomeThe physiology of a fetus is quite different from that of a neonate; consequently, not all techniques used in postnatal repair can achieve the same performance when used A fundamental question that this study raises is why the minimally invasive SAFER approach provided apparently similar or better neurological outcome as compared to ‘classic’ neurosurgical closure, which is a three‐layer repair . One explanation is that, in the prenatal setting, primary closure of the dura with a suture may be detrimental to the neural elements due to reduced perfusion and to scar formation, as shown in our prior animal studies2 during fetoscopy, these short‐term outcomes significantly improved; mean gestational age at birth increased from 32.5 to 34.5 weeks, and the rate of PPROM decreased from 67% to 38%The main problem with the percutaneous fetoscopic OSB repair technique is the high rate of PPROM and low gestational age at delivery. However, recent alterations of the surgical technique (not reflected in this early cohort) have resulted in improved short‐term outcome. Preliminary data suggest that, for example, after we initiated humidification of the COThe optimal timing of prenatal surgery for OSB remains unknown. The upper gestational age at surgery for the MOMS trial was determined by the available information at that time, indicating no additional effect on the need for shunt when surgery was performed after 26 weeksThe main strength of this study is that it represents the first description of long‐term outcome after this novel neurosurgical approach using the SAFER technique for percutaneous fetoscopic OSB repair. The main limitation is the relatively small number of cases with 30‐month follow‐up. Another important weakness is that comparison with findings from the MOMS trialvice versa.The findings of this study suggest that children with OSB who had undergone prenatal repair using the percutaneous fetoscopic SAFER technique achieved neurological outcomes similar to, if not better than, those reported in the literature after hysterotomy‐assisted repair. Although a randomized trial may ultimately be needed to compare fetoscopic and open fetal surgery, this is unlikely to take place because both techniques are evolving and many fetoscopy centers do not offer an open fetal surgery approach and


Extensive DNA damage can cause changes to centrosomes—structures in the cytoplasm that prevent cell replication and the continuation of defective cell lines. The process, called DNA damage‐induced centrosome amplification (DDICA), is an emergency mechanism that prevents tumor formation.Breast cancer gene 1 (BRCA1) is a well‐known tumor suppressor. Mutations in the gene have been linked to the increased risk of breast cancer and ovarian cancer. Although BRCA1 is closely involved in the DDICA process, the exact mechanism by which it causes changes to centrosomes remains unknown.Qi et al. examined BRCA1 accumulation on centrosomes during the cell cycle after they used the DNA crosslinker cisplatin (CDDP) to induce DNA damage.Their study found that the centrosomal localization of BRCA1 increased markedly following damage to the DNA. This had two noteworthy consequences—an increase in the localization of the enzyme Aurora A and the activation of the enzyme PLK1 by Aurora A in the centrosome. It is known that the overactivation of PLK1 in turn affects centrosome maturation.They also found that concentrations of BRCA1 and Aurora A in the centrosome following DNA damage were significantly lowered when they performed the same experiment with cells expressing BRCA1 variants from a patient with cancer. This suggests that BRCA1 variants in patients with cancer fail to produce the DNA damage signal that triggers the BRCA1‐Aurora A‐PLK1 pathway.Damage to DNA is detected by ataxia telangiectasia mutated (ATM), a sensory protein that modifies BRCA1. As a result of this modification, BRCA1 seems to traverse the nuclear membrane and diffuse into the cytoplasm before entering the centrosome.The pathway uncovered by their study suggests that BRCA1 acts as an intracellular messenger. By travelling from the nucleus to the cytoplasm and affecting changes to the centrosome through Aurora A and PLK1, BRCA1 can arrest cell replication. Mutant BRCA1 in patients with cancer, however, seems to be incapable of such signaling. This study shows that, during DDICA, BRCA1 has a crucial role in centrosome regulation and DNA repair.https://onlinelibrary.wiley.com/doi/full/10.1111/CAS.15573Small interfering RNAs (siRNAs) are used for the treatment of multiple diseases, including cancer. Notably, siRNAs are susceptible to degradation inside cells due to their physiochemical properties, making their delivery difficult. Hence, lipid nanoparticles (LNPs) are generally used as carriers for the systemic delivery of siRNAs, due to their biocompatibility, low‐toxicity, and ability to encapsulate siRNA.The external surfaces of LNPs play a key role in differentiating between a normal physiological environment and a cancerous environment. An ideal LNP system should be able to recognize tumor‐specific conditions and deliver the required siRNA to the targeted tumor. Such LNPs typically consist of a pH‐responsive lipid which identifies the tumor environment, and a polyethylene glycol (PEG) lipid, which encapsulates the siRNA and delivers it to the target site. At present, these LNPs lack the ability to deliver siRNAs to tissues and organs other than the liver.In this issue, Sung et al. designed an LNP through surface modifications which allow the molecule to remain neutrally charged at a physiological pH of 7.4, but switch to a positive or cationic charge upon sensing the acidic pH of cancerous tissues in its vicinity. They hoped that the positive charge of the LNPs would allow them to target anionic cancerous tissues with high efficacy.To achieve this, they used an “ethylenediamine‐based polycarboxybetain” molecule as a “smart shell” for the LNPs, which demonstrated the ability to switch to cationic charge in response to acidic pH. This polycarboxybetain‐modified LNP could seamlessly circulate through the blood at physiological pH, while enhancing cellular uptake of siRNA in cancerous tissues and delivering required nucleic acids to solid tumors.In addition, it effectively targeted tumor cells in two in‐vitro tumor models, leading to tumor growth inhibition.Overall, this study demonstrates the potential of pH‐responsive polycarboxybetaine as a surface coating molecule for LNP, which can facilitate the effective and targeted delivery of nanomedicines like siRNAs. The polycarboxybetain‐modifed LNP designed by the authors offers promise as a delivery vehicle in the treatment of cancers and other inflammatory diseases that are characterized by an acidic microenvironment.https://onlinelibrary.wiley.com/doi/full/10.1111/CAS.15554Colorectal cancer (CRC) affects the large intestine and the rectum and is a major cause of cancer‐related deaths. Patients with late‐stage CRC have a poor prognosis and dismal survival outcomes. Notably, it has been observed that the survival rates of patients with right‐sided CRCs are lower as compared to those with left‐sided CRCs. Although scientists have uncovered several differences between right‐sided and left‐sided CRCs, the mechanisms underlying the poorer outcomes in patients with right‐sided CRCs are not well understood.Recently, Ma et al. compared the cell multiplication and invasion capabilities of left‐sided and right‐sided CRCs by observing patient‐derived organoids (PDO), which are in vitro three‐dimensional cultures of intestinal cells. Additionally, they compared the expression of 184 genes that have been linked to CRC prognosis.Their experiments revealed that cancer cells derived from right‐sided CRC PDOs demonstrated significantly higher proliferation and invasion than left‐sided CRC PDOs. Gene expression analysis further established that the expression of the tissue inhibitor matrix metalloproteinase 1 (TIMP1) gene was the highest in right‐sided CRC PDOs. Interestingly, lowering the expression of TIMP1 led to a decrease in the cell proliferation and invasion capabilities of right‐sided CRC PDOs. The researchers also observed that TIMP1 exerts its effects by regulating the expression of two proteins—pFAK and pAkt—via the FAK/Akt/Bad signaling pathway.TIMP1 had a significantly shorter survival than those with lower levels of TIMP1. These findings are also consistent with previous reports on the role of TIMP1 in other types of cancers.Further corroborating the experimental findings of this study, the researchers analysed The Cancer Genome Atlas database and found that patients with higher levels of Overall, this study offers novel molecular insights into the differences between right‐sided and left‐sided CRC, and sheds light on possible causative factors underlying the poor outcomes in patients with right‐sided CRC. Furthermore, it highlights potential therapeutic targets that may help improve the survival rates of patients with late‐stage right‐sided CRC.https://onlinelibrary.wiley.com/doi/full/10.1111/CAS.15567