Impaired mental health status tends to be associated with poor academic performance, but few prospective studies have examined the association between mental health and academic performance among undergraduates while considering the interacting roles of multiple lifestyle behaviors.A total of 1823 Japanese undergraduate students (67% men) were followed up for 4 years. Their mental health status was measured by the six‐item Kessler Psychological Distress Scale (K6). We defined poor academic performance as a grade point average (GPA) <2.0. Cox proportional hazards models were used to determine the relationship between the students' mental health status and the incident risk of poor academic performance.Our analyses revealed that impaired mental health status in the first semester of university study significantly predicted an increased incident risk of poor academic performance during the overall undergraduate period. This association remained significant when the health lifestyle behaviors were adjusted, and the hazard ratio  for poor academic performance was 1.62 (1.18–2.23). This significant association disappeared in the low‐lifestyle‐behavior‐risk group.Impaired mental health status in the first semester significantly predicts an increased incident risk of poor academic performance during the undergraduate period. A systematic review estimated that 12%–46% of undergraduates are distressed by mental health issues  survey, which was performed from 2011 to 2015 among Japanese university students. The details of the EQUSITE survey have been described  assigned on a scale from 0.0 to 4.0 scores, with lower GPA scores indicating poorer academic performance. Each student's GPA score was calculated as the credit‐weighted sum of his or her grades for all courses divided by the total number of course credits. There is no value was defined as the normal cut‐off value of GPA scores, but earlier studies used the means of GPA scores . Each item uses a five‐point Likert scale ranging from 0 to 4 points. The possible number of total points ranges from 0 to 24 points, with a greater number of points indicating a higher‐level impaired mental health status . The computations were carried out using the computer resources offered under‐General Projects by the Research Institute for Information Technology, K. University.We first used the Cochran‐Armitage trend test and Jonckheere‐Terpstra trend test to calculate the trends of healthy lifestyle behaviors according to the three K6 groups. We then calculated the crude hazard ratios (HRs) and multi‐variable adjusted HRs with 95% confidence intervals (CIs) for the incident risk of poor academic performance according to K6 groups, using multiple Cox proportional hazard models. The same analysis protocol was repeated to explore the association between the three K6 groups and the incident risk of poor academic performance in the different healthy lifestyle behavior groups, as appropriate. A two‐sided 2.7The Ethics Committee of the Institutional Review Board of Health Science, K. University approved this study .3During the four‐year follow‐up period, with no participants dropping out, all 1823 participants were included in the final analysis. The trends of healthy lifestyle behavior variables at baseline according to the three K6 groups are shown in Table Figure The data clarifying the incident risk of poor academic performance classified according to the K6 groups are provided in Table Table Figure 4The results of this prospective study demonstrate that impaired mental health status in the first semester of university studies significantly predicted an increased incident risk of poor academic performance among undergraduates during their overall undergraduate period. This association remained significant even with adjustment for health lifestyle behaviors. However, the significant association between impaired mental health status and the increased incident risk of poor academic performance disappeared in the group of students with a low lifestyle behavior risk.A study of 1530 Canadian undergraduate students revealed that impaired mental health status in the first semester tended to account for lower GPAs at the end of the second semester , which suggested that the students classified in the low lifestyle behavior risk group  may have impaired mental health status. We thus also investigated whether being in the healthy lifestyle risk group moderated the association between mental health status and the incident risk of poor academic performance. The data in Table n = 49 vs. 357 and 563 in the other groups; Table Health lifestyle behaviors may not be strictly related to either mental health status or academic performance. Interestingly, in the present study, the health lifestyle behavior risk score and K6 points showed a weak significant positive association (Pearson correlation coefficient: 0.13, Our findings also draw attention to the Health Sciences and Counseling division of the university that the students were attending; this division is essential to attempts to determine and improve students' unhealthy lifestyle behaviors. It is might optimal for students to lessen their risk of poor academic performance at an early stage by seeking advice from on‐campus counselors.The results of this study strengthen the association between impaired mental health status and poor academic performance, as shown by a large sample of undergraduate students in a 4‐year follow‐up prospective study. Our findings are based on the objective academic performance data obtained from the university affairs division, which can be expected to be accurate. Nonetheless, some study limitations should be noted. First, although the K6 scale is widely used to estimate individuals' mental health status and the specificity of depression and anxiety, the K6 scale cannot be used for clinical diagnoses. Second, we did not collect the students' secondary‐school academic performance data, although this parameter might be a confounder variable that could have affected the students' academic performance during the undergraduate period. Finally, we defined the cut‐off value for poor academic performance based on a single university's regulation, and this cut‐off might not be applicable at other universities or in different countries.5Undergraduate students' impaired mental health status in the first semester significantly predicted an increased risk of poor academic performance during the undergraduate period. The significant association between impaired mental health status and the poor academic performance disappeared in the students with a low lifestyle behavior risk.Tianshu Chu contributed to the study conception, design, formal statistical analyses, interpretation, and drafting of the manuscript. Xin Liu contributed to the data interpretation and reviewed the analysis and the manuscript. Shigemi Takayanagi and Tomoko Matsushita contributed to the data preparation and interpretation. Hiro Kishimoto as the corresponding author conceptualized and supervised the entire study, was responsible for obtaining funding, provided guidance on methodology, performed the statistical analyses, interpreted the results, and critically reviewed the manuscript. Hiro Kishimoto and Tianshu Chu accessed and verified all of the data. All authors had final responsibility for the decision to submit the manuscript for publication.We have no conflicts of interest.


The distribution of species among spatially isolated habitat patches supports regional biodiversity and stability, so understanding the underlying processes and structure is a key target of conservation. Although multivariate statistics can infer the connectivity processes driving species distribution, such as dispersal and habitat suitability, they rarely explore the structure. Methods from graph theory, applied to distribution data, give insights into both connectivity pathways and processes by intuitively formatting the data as a network of habitat patches. We apply these methods to empirical data from the hydrothermal vent habitats of the Northwest Pacific. Hydrothermal vents are “oases” of biological productivity and endemicity on the seafloor that are imminently threatened by anthropogenic disturbances with unknown consequences to biodiversity. Here, we describe the structure of species assemblage networks at hydrothermal vents, how local and regional parameters affect their structure, and the implications for conservation. Two complementary networks were formed from an extensive species assemblage dataset: a similarity network of vent site nodes linked by weighted edges based on their pairwise assemblage similarity and a bipartite network of species nodes linked to vent site nodes at which they are present. Using these networks, we assessed the role of individual vent sites in maintaining network connectivity and identified biogeographic sub‐regions. The three sub‐regions and two outlying sites are separated by their spatial arrangement and local environmental filters. Both networks detected vent sites that play a disproportionately important role in regional pathways, while the bipartite network also identified key vent sites maintaining the distinct species assemblages of their sub‐regions. These regional connectivity pathways provide insights into historical colonization routes, while sub‐regional connectivity pathways are of value when selecting sites for conservation and/or estimating the multivent impacts from proposed deep‐sea mining. Hydrothermal vents are “oases” of biological productivity and endemicity on the seafloor that are imminently threatened by anthropogenic disturbances with unknown consequences to biodiversity. Here, we describe the structure of hydrothermal vent species assemblage networks, how local and regional parameters affect their structure, and the implications for conservation. Here, wHydrothermal vent species occurrence data have previously been used to detect biogeographic barriers within the Northwest Pacific  to ensure up‐to‐date nomenclature. All occurrences were associated with a named vent site in the InterRidge database  between vent sites, we created a network of vent sites in the Northwest Pacific. The similarity value was used as the weight of the edges that link the vent site nodes in this network, hereafter referred to as a “similarity network.” The “percolation threshold” of the similarity network was calculated following the methods of Rozenfeld et al.  using thWe used variance partitioning to determine the contribution of environmental and spatial parameters to explain the β‐diversity . This network approach has been implemented in various biogeographic studies  and participation coefficient (Pi) , “Module hubs” (zi > 2.5 and Pi < 0.62), “Connector nodes” (zi < 2.5 and Pi > 0.62), and “Network Hubs” (zi > 2.5 and Pi > 0.62). These metrics of module connectivity were calculated using the “rnetcarto” package in R  and participation coefficient (Pi), as well as their category of “universal cartographic roles” . Other than the outliers, the five vent sites with the highest participation coefficients are Myojin Knoll, Northwest Rota, and Myojinsho Caldera of the IBMa, and Daisan‐Kume Knoll and North Knoll, Iheya Ridge of the OT module. All vent sites of the MT had relatively low participation coefficients, with Forecast having the highest 0.21 The vent sites that only contain module endemics have the lowest participation coefficients of 0 and are referred to as “ultra‐periphery” nodes. There are 11 such ultra‐periphery nodes among the vent sites , with representation from each of the three sub‐regions.The distribution of vent sites in terms of within‐module degree .The explanatory variables used in the redundancy analysis  were able to explain 92.8% of the module grouping, with tectonic setting and broad‐scale dbMEM varying significantly between modules . Previous studies have used both network methods to study other ecosystems at various scales but not in combination. The discrete nature and dispersal processes that dictate connectivity at hydrothermal vents make them particularly suitable for the application of such network methods.4.1At the scale of the entire region, the structure of the similarity network has “small world” properties due to the presence of tight clusters of nodes with key connectivity pathways Figure  between The clustering that gives the similarity network its small world properties is evident in the spatial arrangement of nodes based on their shared edges Figure  and the The presence of Sumisu Caldera as an outlier was detected across all methods. The similarity network disconnected this vent site from the network during the thresholding stage Figure : SmsC anThere are minor discrepancies in group membership between the different methods. We prefer the results from the bipartite modularity analysis due to its objectivity compared with similarity network clusters and the additional insights it provides compared with the SIMPROF clusters  detected by the modularity analysis suggest the presence of connectivity barriers within the Northwest Pacific, an area previously classified as a single biogeographic region Bachraty et al., By contracting vent site nodes of each module into a single node Figure , it is cGandalfus yunohana  should be protected to preserve regional diversity because they may also be key to maintaining gene flow within a metacommunity context. In this context, Sakai (Saka), Alice Springs Field (AlSF), and Nikko volcano (Nkkv) should be prioritized for protection in their respective sub‐regions. Special consideration for conservation should be given to the outlier vent sites of Sumisu Caldera and Minami‐Ensei Knoll due to their high proportion of endemic species  explained much of the variation in species distribution data among vent sites Figure  and variThe two dbMEMs explain most of the species assemblage variation and represent their relative geographical position. The calculation of the fine‐scale dbMEM assumes that vent sites in the Okinawa Trough are disconnected from the rest of the regional network while the broad‐scale dbMEM assumes at least indirect connectivity among all vent sites in the Northwest Pacific. It is therefore unsurprising that the broad‐scale dbMEM explains more variation among sites (22% compared with 7%) as it takes into account the species turnover among vent sites of the entire region. Connectivity among vent sites in the Northwest Pacific via larval dispersal is theoretically possible under certain assumptions of larval dispersal behavior ; data curation (supporting); formal analysis (lead); methodology (lead); writing – original draft (lead); writing – review and editing . Chong Chen: Conceptualization (supporting); data curation ; writing – review and editing . Thomas Giguère: Data curation ; writing – review and editing . Shinsuke Kawagucci: Data curation ; writing – review and editing . Verena Tunnicliffe: Conceptualization (supporting); data curation ; supervision (supporting); writing – review and editing . Hiromi Kayama Watanabe: Conceptualization (supporting); data curation ; writing – review and editing . Satoshi Mitarai: Conceptualization ; supervision (lead); writing – review and editing .This article has earned Open Data, Open Materials and Preregistered Research Design badges. Data, materials and the preregistered design and analysis plan are available at [[insert provided URL(s) on the Open Research Disclosure Form]].Appendix S1Click here for additional data file.


Androgenetic alopecia (AGA) is the most common form of non‐scarring alopecia in humans. Several studies have used different laboratory models to study the pathogenesis and interventions for AGA. These study models have proved beneficial and have led to the approval of two drugs. However, the need to build on existing knowledge remains by examining the relevance of study models to the disease.We sought to appraise laboratory or pre‐clinical models of AGA.We searched through databases  for articles on AGA‐related studies from 1942 to March 2019 with a focus on study models.The search rendered 101 studies after screening and deduplication. Several studies (70) used in vitro models, mostly consisting of two‐dimensional monolayer cells for experiments involving the characterization of androgen and 5‐alpha reductase (5AR) and inhibition thereof, the effects of dihydrotestosterone (DHT) and biomarker(s) of AGA. Twenty‐seven studies used in vivo models of mice and monkeys to investigate DHT synthesis, the expression and inhibition of 5AR and hair growth. Only four studies used AGA‐related or healthy excisional/punch biopsy explants as ex vivo models to study the action of 5AR inhibitors and AGA‐associated genes. No study used three‐dimensional [3‐D] organoids or organotypic human skin culture models.We recommend clinically relevant laboratory models like human or patient‐derived 3‐D organoids or organotypic skin in AGA‐related studies. These models are closer to human scalp tissue and minimize the use of laboratory animals and could ultimately facilitate novel therapeutics. The current laboratory models of Androgenetic alopecia (AGA) are not representative of the disorder. Thus, this study evaluated all the laboratory models of AGA used in the last seven decades.This article recommends the use of patient‐derived 3‐D skin/ scalp cells or tissue culture models for future research studies on AGA instead of non‐representative 2‐D human and animal models. These models, though beneficial, have only resulted in two FDA‐approved drugs for the treatment of AGA, which may be partly due to the lack of disease‐related models.This systematic review summarizes published evidence of laboratory models used in AGA‐related research and revealed the scarcity of studies that use human or patient‐derived 3‐D tissue culture models. These models are more suitable and more physiologically representative than 2‐D cell culture and animal models for pre‐clinical research. Thus, this article could guide the selection of appropriate study models for future research, and thus facilitate research translation.2,,,,,Androgenetic alopecia (AGA) is the most common form of non‐scarring hair loss in humans.In the early 1940s, Hamilton proved that genetic predisposition and male hormone stimulation are prerequisites in AGA development.This systematic review aims to appraise all AGA‐related study models published to date for the testing of AGA interventions. However, not intended to evaluate the efficacy of AGA treatments.3http://www.crd.york.ac.uk/PROSPERO).The protocol for this study was registered and published in the International Prospective Register of Systematic Reviews  from January 1942 until March 2019. A search strategy was developed for PubMed and adapted as per the requirements of other databases. A hand search in Google Scholar and Science Direct supplemented the search. The review also looked at unpublished articles from conferences and libraries (dissertations).3.3The inclusion criteria for the articles selected are as follows: preclinical laboratory studies and models  published in the English language. Our search excluded all articles involving human, clinical, diagnostic, drugs/phytochemicals efficacy and hair or cell transplant studies. Search results were filtered to include the research studies relevant to this review as per the pre‐decided inclusion criteria.3.4We used a predesigned template adapted from Cochrane to populate the data extracted from the selected studies Table . We anal3.5Is the model used in the study appropriate or relevant ? Studies that used patient‐related or human tissue instead of animal tissue as models had high scores.Do the techniques and methods of analysis used in the study adequately address the research question?Are the results from the research study validated by more than one research technique and are the results reproducible ? Articles with results confirmed by three or more techniques, and a minimum of three independent experiments, scored higher than studies that used two or one methods.The selected articles' quality was assessed by two authors (SN and AA) using a predesigned template validated by three independent assessors Table . The quaThe maximum score per question was five points.44.1Our initial search rendered 1228 related articles after removing duplicates. A further review of the full‐text articles based on set eligibility criteria excluded 1128 and an additional two with the reason (spheroids but unrelated to AGA). Three more research papers retrieved from an updated hand search supplement the remaining 98 articles, thus bringing the entire selected research articles to 101. These articles included studies involving 70 in vitro, 4 ex vivo and 27 in vivo models  is illustrated Figure  and grou4.3The overall results show a relatively high percentage (62%) of articles with a middle‐risk score Figure . The eva5n = 70), ex vivo (n = 4) and in vivo (n = 27).This systematic review, which sought to appraise models used in preclinical AGA research, rendered three groups of models: in vitro  of immortalized or primary epithelial and mesenchymal cell lines. Immortalized cell lines are often used in research in the place of primary cells because they are cost‐effective, easy to use and provide an unlimited supply of material. These cells can also grow indefinitely in culture and bypass ethical concerns associated with animal and human tissue use. However, immortalized cell lines undergo significant mutations to become immortal, which can alter cellular physiology. Also, genetic changes can occur over multiple passages, leading to phenotypic differences among isolates and unreproducible experimental data.,,,,Examples of immortalized cells used in the reviewed articles were human prostate cancer (PC3) cells, human keratinocytes (HaCaTs), prostate adenocarcinoma (LNCaP) cells, human sebaceous gland (SZ95 sebocytes) cells, human melanoma cells, human embryonic kidney 293 cells and the Shionogi carcinoma‐115 cells.,,,Although the use of these epithelial cells provided useful data to study potential AGA therapeutics, they are not related to this disorder. Therefore, some studies used DPCs.5.2,,,,,,Twenty‐seven studies used either mice or rats and monkeys as in vivo models, the most common being C57BL/6, Kunming mice and male Sprague Dawley rats, male Wister/ST rats, C57BL/6NCrSlc strain mice, C3H/He strain mice, B6CBACF1/J female mice, male Swiss albino and human scalp hair grafted into nude mice .,,The stump‐tailed macaque monkey was the only primate‐related in vivo model used in the reviewed studies.5.3,,,Only four of the included studies were ex vivo, using either diseased (AGA) or normal excisional and punch biopsy explants (whole skin organ cultures).5.4A validity assessment evaluated the risk of bias in the models and experimental techniques used in the included studies. The overall results show a relatively high percentage of articles with a middle‐risk score. This observation may result from the low scores in the reliability of methods used and validation of results . Result validation is a critical component in method evaluation because it reveals the specificity, accuracy, precision and, ultimately, the data's reliability. Validation is also essential to demonstrate that the model and technique used is suitable for the intended use. Many of the included studies (76%) were not exhaustive, with only 24% using three or more techniques to validate their results. Therefore, there is a need for continuity in work already done and the development of models with more relevant technologies.Assessing the risk of bias of studies contained in the body of evidence is foundational and central to all systematic reviews to improve the transparency, consistency and scientific rigour of the research. Bias refers to factors that can confound the overall observations and conclusions of a study, which may lead to inappropriate recommendations. These discrepancies can result in wasted resources and loss of opportunities to discover effective therapies.6None of the included studies used 3‐D models of AGA. The use of 3‐D AGA models  has an advantage over 2‐D models. These models allow experimentation with human diseased tissues under controlled conditions than would be challenging to achieve in 2‐D models, which may prove unachievable with in vivo models, thus allowing for a more detailed cellular and molecular characterization. Interestingly, 2‐D models can be used to create 3‐D models. The 3‐D models can either be organoid cultures or be organotypic skin cultures. Organoids are in vitro‐derived 3‐D cell aggregates derived from primary tissue, which possess similar composition and architecture to primary tissue, and exhibit organ functionality. On the other hand, organotypic skin cultures use primary human cells, and cell culture inserts to recapitulate the stratified epidermal architecture of the skin to replicate the normal anatomy and physiology. This approach, especially with whole skin punch biopsies, allows for the in vitro maintenance of skin appendages, for example, hair follicles. Therefore, organotypic skin cultures may be instrumental in preclinical AGA research to validate the mechanisms of diseases and test the novel therapeutics.7There is substantial evidence on the use of various models in the study of many diseases, including AGA and the discovery of effective targeted therapies. AGA models to date have helped in the understanding of this disorder. Howbeit, most of these models are not ideal representatives of AGA in humans. Only four studies used whole human skin biopsies from patients , a closer approximation of AGA in humans. However, none of the studies used 3‐D organoids or organotypic skin culture models. Therefore, there is a need to improve these models with a focus on the use of diseased and healthy biopsies or cell lines isolated from these biopsies. These 3‐D models allow experimentation closer to humans, which may prove difficult or impossible with in vivo models while minimizing harm to animals. It is also vital to validate experiments with a minimum of three techniques. Finally, 3‐D experimental data should ultimately be tested in human clinical trials to achieve formidable progress towards fast and effective treatment solutions for AGA. A good translation of AGA preclinical research into human trials will ensure the discovery of new and more effective drugs.The authors have no conflict of interest to declare.Supplementary MaterialClick here for additional data file.


Perca flavescens) abundance occurred at in‐lake disturbance values less than the gradient mean, but decreased continuously from minimum watershed disturbance to higher values. Bands of optimum in‐lake conditions occurred throughout the eastern and western portions of the Lake Erie nearshore zone; some areas were less disturbed than desirable. However, watershed‐derived disturbance conditions were generally poor for Yellow Perch throughout the lake. In contrast, optimum Smallmouth Bass (Micropterus dolomieu) abundance occurred at in‐lake disturbance values greater than the gradient mean and continuously increased with increasing watershed disturbance. Smallmouth Bass responses to disturbance indicated that most of the nearshore zone was less disturbed than is desirable and were most abundant in areas that the Yellow Perch response indicated were highly disturbed. Mapping counts of species response models that agreed on the disturbance level in each spatial unit of the nearshore zone showed a fine‐scale mosaic of areas in which habitat restoration may benefit many or few species. This tool may assist managers in prioritizing conservation and restoration efforts and evaluating environmental conditions that may be improved.Disturbances to aquatic habitats are not uniformly distributed within the Great Lakes and acute effects can be strongest in nearshore areas where both landscape and within lake effects can have strong influence. Furthermore, different fish species respond to disturbances in different ways. A means to identify and evaluate locations and extent of disturbances that affect fish is needed throughout the Great Lakes. We used partial Canonical Correspondence Analysis to separate “natural” effects on nearshore assemblages from disturbance effects. Species‐specific quadratic models of fish abundance as functions of in‐lake disturbance or watershed‐derived disturbance were developed separately for each of 35 species and lakewide predictions mapped for Lake Erie. Most responses were unimodal and more species decreased in abundance with increasing watershed disturbance than increased. However, eight species increased in abundance with current in‐lake disturbance conditions. Optimum Yellow Perch ( Species‐specific non‐linear responses of abundance to Great Lakes disturbance indices for multiple fish species identifies multiscale distributions of disturbed habitat perceived by each species throughout the lakes. The degree of agreement among species was mapped. The results provide decision support for population and community conservation and restoration efforts. However, fish are threatened by numerous environmental disturbances and influenced by natural conditions  to map the distribution of disturbance and spatial agreement among species, providing a tool that highlights locations with habitat that may be considered for protection or restoration for multiple species.Our objectives were to (1) separate the “natural” influences from anthropogenic disturbances affecting fish abundances in the Great Lakes, (2) develop quantitative, species‐specific abundance models of response to multimetric indices that include all of the known significant disturbances to fish and fish habitats throughout Great Lakes nearshore zones, (3) use those models and the distribution of disturbances to predict abundance responses for each species at each location  within the Lake Erie nearshore zone, and (4) quantify species agreement about disturbance conditions in each location by an overlay of those species‐specific maps. The resulting species‐specific disturbance distributions and degrees of species agreement can assist managers with decisions about species on which to focus and in what locations to conduct restoration or protection activities.22.1The Great Lakes nearshore zone was defined as water of ~3–30 m depth, except in Lake Erie, where maximum nearshore zone depth was 15 m  and ln‐transformed. There were 4332 nearshore fish assemblage samples with matching habitat and disturbance values throughout the Great Lakes , and included 80 species, 35 of which occurred at least 100 times (Appendix Coregonus artedi), Bloater (Coregonus hoyi), Pygmy Whitefish (Prosopium coulterii), and Round Whitefish (Prosopium cylindraceum); Van Meter & Trautman, glfc.org), September 2021). Each fish species was also classified according to its general habitat usage .This empirical analysis was possible because of extensive databases from throughout the Great Lakes collected by many people and agencies. Fish data were provided by the US Geological Survey and collaborators using standardized trawl collections throughout the Great Lakes   because they explain the most variability Figure .2.4F‐test for model significance at the α = 0.05 level  were included in the ordinations. However, most species were rare and to help ensure detectable responses to habitat and disturbance conditions, only species which occurred at least 100 times in the dataset 35 species) were used to develop the quadratic response models. We used the CANOCO program to fit those quadratic models of the response of fish abundance (ln[CPUE]) for each species, separately to each composite disturbance gradient, assuming a Poisson distribution and using an  species t) and coded for display and quantification purposes as +3 (<−2 t), +2 (<−1 t to ≥−2 t), +1 (<−0.5 t to ≥−1 t), 0 (≤0.5 t to ≥−0.5 t), −1 (>0.5 t to ≤1 t), −2 (>1 t to ≤2 t), −3 (>2 t). This scale highlights small negative code values  as highly degraded, large positive numbers as hyperoptimal (defined here as less degraded than preferred), and 0 as preferred conditions . These relative measures of deviation from the optimum disturbance value were necessary because maximum abundance values and, thus, optimal disturbance values could occur anywhere along the disturbance gradients and differed by species. For best comparison, monotonic response model predictions of abundance were assigned to four similar disturbance classes, based on quintiles of the areas under those curves from the disturbance value associated with the maximum abundance value as follows: <20%, 20%–40%, 40%–80%, and >80%  to the values of the three original disturbance variables at each spatial location. These composite index values formed the independent variable data for quadratic model predictions and species‐specific abundance predictions were then made for each Lake Erie nearshore zone spatial unit (cell) for each disturbance gradient. To simplify interpretation and comparison of disturbance conditions between species and among geographic areas, predicted disturbance values were classified according to the number of relative deviation units of those values from the optimum disturbance gradient value . Unimodal responses of fish abundance were placed into associated disturbance classes of multiple tolerance units  and Smallmouth Bass (Micropterus dolomieu) were selected to illustrate how species may respond differently to levels and changes in anthropogenic disturbances because of their clearly opposing responses.Classified model predictions of disturbance at each spatial location within the Lake Erie nearshore zone were then used in a GIS to determine spatial distributions of disturbance. A separate map layer was generated for each species for each of the two disturbance gradients. Each spatial cell was colored coded according to the associated disturbance class label for a given species. Yellow Perch . All species‐specific maps of disturbance were geographically aligned such that the disturbance class value for each species at each 30‐m spatial location of the nearshore zone were stacked one on top of the other. Then, for each disturbance class, a count was made of the number of species in the stack whose predicted disturbance fell into that class at that location. Thus, the number of species associated with the most highly disturbed conditions (class −3) was recorded for a given spatial location. Then the number associated with moderately disturbed conditions (class −2) at that same location was recorded, and so forth for each disturbance class. The process was then repeated for every 30‐m spatial location. These counts of species agreement were made separately for each disturbance gradient and mapped to show the spatial distribution of high and low agreement about disturbance throughout Lake Erie's nearshore zone. The predictive models developed for the four species that do not exist in Lake Erie, but are present in other Great Lakes, were excluded from the counts of agreement for Lake Erie.3Environmental and anthropogenic disturbance index values were available for all of the >53 million 30‐m spatial cells throughout all of the Great Lakes nearshore zones. Anthropogenic disturbances were not uniformly distributed throughout the nearshore zones  and Bluegill (Lepomis macrochirus) have similar (but not the same) habitat optima, while Lake Whitefish (Coregonus clupeaformis) habitat conditions are quite different from Brook Trout  habitat. There was relatively strong separation by Great Lake based on distinct groups of species optima and associated conditions, with a clear gradient from Lake Ontario  to Lake Superior  along the second axis, but with Lake Erie being most distinct and located in the negative portion of the first axis and at approximately average values of the second axis.The full CCA ordination provided indications of the effects of “natural variability” on distributions and abundances of the fishes in the Great Lakes. The ordination explained 18.6% of total variation and >75% of fitted variation with the first two canonical axes Table . Species3.2G is the value of the GLEAM index, W is the value of the Wehrly index, and S is the value of the Coastal Modification index.Partial CCA filtered out the natural variability and determined how the remaining variability was affected by disturbance factors   and Bluegill in response to watershed disturbance, and Common Carp (Cyprinus carpio) in response to in‐lake disturbance. Seven of the remaining models were significant (p ≤ .05) as linear, but not quadratic models; all linear models had negative slopes, except that for Smallmouth Bass (Table p ≤ .05) quadratic models.Quadratic models fit responses of fish abundance to each disturbance gradient well for most of the 35 species that occurred at least 100 time in the dataset  and White Sucker (Catostomus commersonii) preferred high levels of in‐lake disturbance, but were among the most sensitive species to watershed disturbance. Round Goby (Neogobius melanostomus) and Channel Catfish  were among the most sensitive species to in‐lake disturbance, but preferred high levels of watershed disturbance. None of the species were classified into the same response class for both types of disturbance.Species were listed in order of sensitivity to each disturbance gradient, with relative sensitivity defined by location of maximum predicted abundance along the disturbance gradient and more sensitive species having maxima associated with lower disturbance values than less sensitive species Figure  and 4; m3.4Predictions from all successful models were used to map the spatial distributions of disturbance for each species Figures –S13. In We focus on two common and important fishery species from Lake Erie, Yellow Perch and Smallmouth Bass, and one extirpated species (Cisco) to illustrate differences in the association with disturbance conditions by different fish species in the nearshore zone. The Yellow Perch optimum (PRCH) in the partial CCA ordination space was located in the quadrant where values of each type of disturbance were less than the average (origin) Figures  and 7. TThe Smallmouth Bass optimum (SBAS) in the partial CCA ordination space was located in the quadrant where values of each type of disturbance were greater than the averages Figures  and 7. TInterest in Cisco restoration to Lake Erie makes identifying relationships between Cisco abundance and disturbance conditions highly desirable. The Cisco optimum (LKHR) in the partial CCA ordination space was also located in the quadrant with lower than average disturbances Figure . Its quaA cursory examination of general habitat use (pelagic vs benthic) showed a broad mixture of habitat use across the different responses to in‐lake disturbance. However, those species classified as generally pelagic were most sensitive  to watershed disturbance.3.5At any given location, predictions of species' abundance‐disturbance relationships will differ. Summing the number of species within a particular disturbance class at a particular location gives a measure of agreement among species about disturbance level. Twenty‐five of the 35 species that occurred >100 times in the dataset were native to Lake Erie, six were established exotics, one was extirpated (Cisco), and three never occurred in Lake Erie . Discarding species with parabolic models and those absent or extirpated, 25 species models remained for each of the disturbance gradients. Thus, if all species' responses indicated the same level of disturbance at a particular location, the agreement measure would be 25, the maximum number of species that could agree. Counts of species' agreement were determined for each of the seven disturbance classes for each disturbance gradient. For example, if 20 species' model predictions indicated that the most degraded watershed disturbance conditions existed within a spatial cell near Buffalo, NY . Agreement among species about where in‐lake disturbances were worst, ranged from 0 to 20 Figure . BetweenAgreement among species about where watershed‐derived disturbances were worst (−3) ranged from 0 to 23 Figure . Nearly Maps of species agreement counts for lesser degrees of disturbance (classes −2 and −1) showed similar patterns, but with different areal extents for different classes of species agreement Figures . A gener4That fish populations respond to both natural conditions and anthropogenic disturbance factors is well known. An extensive body of research shows that fish have organs to sense their environments and use that ability to select preferred conditions. Therefore, fish are expected to occur more frequently and in greater relative abundances in environments they perceive as desirable, among those that are available and accessible , and Brown Trout ) were prominent in the Lake Ontario assemblage, which also included American Eel (Anguilla rostrata), a native species unique within the Great Lakes to Lake Ontario. Conditions in Lake Erie were associated with the most diverse assemblage of species optima (29).The regionwide ordination (full CCA) of nearshore Great Lakes fish assemblages, constrained by natural environmental conditions, confirms that there are relatively distinct fish assemblages in each of the Great Lakes  and adjacent watersheds. Partial CCA filtered out the effects of “natural” habitat conditions and revealed the influences of anthropogenic disturbances derived from integrated variables of in‐lake, watershed, and shoreline perturbations on fish abundances. While the composite variables (CCA constructed) each combine all three original disturbance indices, the dominance of in‐lake (GLEAM) factors explaining most variation (Axis 1) and the greatest influence  by watershed (Wehrly index) factors, with a lesser universal influence by shoreline alterations, was clear. The overlap of sample points and species optima, regardless of the lake from which they were collected, suggests that disturbance effects on fish abundances were similar in all lakes Figure . SpeciesUnimodal responses to environmental conditions are common in nature Gause,  and quadPungitius pungitius)), while others perceived large areas of the lake to be far too pristine to be suitable . The distributions of those perceived conditions were also different between in‐lake‐ and watershed‐derived disturbances for most species. More species appear to be sensitive to elevated levels of watershed disturbance than those sensitive to in‐lake disturbance. A few species  from conservation of present conditions or rehabilitation of “degraded” conditions in specific locations or regions. For example, more than a dozen species indicated that conditions were highly degraded along the western and southern coasts of Lake Erie, again generally reflective of the distribution of known anthropogenic disturbance conditions. Concomitantly, few species perceived highly degraded conditions along the northern shore or open water areas of the western ALU. However, fine‐scale details of these distributions show differences between human and fish perceptions of disturbance.4.2Anthropogenic changes to the landscape affect physical structure, water quality, hydrology, thermal conditions, and sediment load of receiving waters . That approach detects effects of disturbance on assemblage richness and is particularly good for examining losses or persistence of rare species  disturbed conditions (at least within the range of disturbance conditions observed for this study). This species‐specific response has far reaching implications for managers attempting to “improve” habitat conditions for enhancement or recovery of selected species. Not all species will respond positively to reduced disturbance.The species‐specific aspects of this research also provide managers with information relevant to species‐specific management plans for fisheries and/or species of concern. Notable among the particularly sensitive species are the native Coregonine species .The extent of “natural” conditions suitable for each species may also be limited. The full CCA showed the great difference in optimal conditions for many species and the best combination of those natural factors may not exist in all parts of nearshore zones. Thus, even areas indicated as having optimal disturbance conditions might not have ideal (or even suitable) natural conditions for a given species. Thus, comparisons between the distributions of naturally suitable habitat conditions and perceived disturbance conditions identify overlap between optimal natural and disturbance conditions .Our approach may be expanded to other aquatic and marine systems, with appropriate data. More investigation at particular locations and comparison with our results would test model prediction reliability and the broader applicability of this method to natural conditions. Application of our findings will work best in comparison with predictions of the distributions of natural conditions likely to support each species or assemblage McKenna, in pressJames E. McKenna, Jr.: Conceptualization (lead); data curation (supporting); formal analysis (lead); methodology (lead); project administration ; resources ; software (lead); visualization ; writing – original draft (lead); writing – review and editing . Catherine Riseng: Conceptualization (supporting); data curation (lead); formal analysis (supporting); funding acquisition (lead); methodology (supporting); project administration (supporting); resources ; software (supporting); visualization ; writing – original draft (supporting); writing – review and editing . Kevin Wehrly: Conceptualization (supporting); data curation ; formal analysis (supporting); funding acquisition ; methodology (supporting); project administration ; resources ; software (supporting); visualization ; writing – original draft (supporting); writing – review and editing .None.Supplementary MaterialsClick here for additional data file.


A 70‐year‐old female diagnosed with duodenal cancer was referred to our hospital. Esophagogastroduodenoscopy revealed an 80 mm flat elevated lesion was located in the inner wall of the second part of the duodenum and the lesion completely involved major papilla. Endoscopic submucosal dissection (ESD) was performed and the lesion was resected in a single piece including the part of the major papilla. The pathological examination of the resected specimen showed moderately differentiated adenocarcinoma limited in the mucosa in most parts of the lesion, however, cancer cells invaded into the submucosal layer with an invasion depth of 100 μm in only a small area. Lymph ductal involvement was confirmed in that area. Two months after ESD, pylorus‐preserving pancreatoduodenectomy combined with extended lymph node dissection was additionally performed. The postoperative pathological examination revealed lymph ductal involvement was observed in the regional lymph node. While the postoperative clinical course was uneventful, systematic metastasis was pointed out 5 months after surgery. The patient was died 9 months after surgery. Due to its rarity, the natural history of duodenal cancer has been still unclear. In this case, even a lesion with only a localized small area of submucosal invasion developed systemic metastasis, indicating the high malignant potential of duodenal cancer. Duodenal cancer is relatively rare and its biological behavior has not been fully understood yet. Here, we report a case of large laterally spreading duodenal cancer with invasion into the submucosa. In this case, invasion depth was limited only to slight submucosa, however, the patient presented lymph ductal involvement and developed systemic metastasis relatively early after radical surgery.A 70‐year‐old female patient was referred to our hospital for the treatment of a large laterally spreading duodenal tumor. Esophagogastroduodenoscopy (EGD) for preoperative evaluation revealed the tumor was located at the inner part of the descending duodenum to the inferior duodenal angle Figure . The tumWith the spread of endoscopy for health care, the detection number of duodenal tumors has been increasing in recent years. Although the natural history of duodenal tumors is still unclear, the poor prognosis of duodenal cancer has been gradually recognized. In this case, only a localized small area of submucosal and lymph ducts invasion eventually led to systemic metastasis, and this case symbolically indicates the high biological malignancy of duodenal cancer. Recently, Yoshimizu et al. reported lymph nodes metastasis was presented in 46% of duodenal cancer with submucosal invasion.Most duodenal epithelial tumors are low‐grade adenoma without invasion and metastatic capability, and it is essential to differentiate the rare lesions with aggressive biological phenotype from these majority low‐grade lesions. In the gross appearance of superficial duodenal tumors, type 0‐Ⅰ and 0‐Ⅱc account for 20%, and type 0‐IIa accounts for 60% of the total.The guideline on superficial duodenal epithelial tumors published by the European Society for Endoscopy mentions that duodenal ESD needs to be considered carefully due to its high incidence of complications,In conclusion, this case suggests duodenal cancer has an extremely high biological malignancy once it invades the submucosal layer, and en bloc resection should be considered for accurate pathological examination if high‐grade histology is predicted based on endoscopic findings.The authors declare no conflicts of interest.Not applicable.None.


Despite the World Health Organization (WHO) recommendation that pregnant women be prioritised for seasonal influenza vaccination, coverage in the Western Pacific Region remains low. Our goal was to provide additional data for the Western Pacific Region about the value of maternal influenza vaccination to pregnant women and their families.We conducted a 16‐year retrospective cohort to evaluate risks associated with influenza‐associated maternal acute respiratory infection (ARI) in New Zealand. ARI hospitalisations during the May to September influenza season were identified using select ICD‐10‐AM primary and secondary discharge codes from chapter J00–J99 (diseases of the respiratory system). Cox proportional hazards models were used to calculate crude and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).We identified 822,391 pregnancies among New Zealand residents between 2003 and 2018; 5095 (0.6%) had ≥1 associated ARI hospitalisation during the influenza season; these pregnancies were at greater risk of preterm birth  and low birthweight  than pregnancies without such hospitalisations. We did not find an association between maternal ARI hospitalisation and fetal death  during the influenza season. Maternal influenza vaccination was associated with reduced risk of preterm birth , low birthweight  and fetal death .In this population‐based cohort, being hospitalised for an ARI during the influenza season while pregnant was a risk factor for delivering a preterm or a low birthweight infant and vaccination reduced this risk. For example, despite the WHO recommendation that pregnant women be prioritised for seasonal influenza vaccination, coverage in the Western Pacific Region remains suboptimal.22.1The study used New Zealand Ministry of Health National Collections datasets, which are used to support policy, funding and point‐of‐care decision‐making. Data from the National Health Index, National Immunisation Registry, National Maternity Collection, National Minimum Dataset, Mortality Collection and Pharmaceutical Collection were used in the study Table . Immunis2.2The study population included all women residents of New Zealand of reproductive age (15–49 years)To address the study objectives, we examined each individual pregnancy and its birth outcomes. Pregnancy was the unit of observation. We defined ARI as a maternal hospitalisation that took place during the influenza season with select respiratory illness ICD‐10‐AM  primary or secondary discharge codes as described below. A woman could have been pregnant more than once during the observation period and counted as having been hospitalised with influenza‐related ARI during one of her pregnancies and not during the other.For the mothers in the study, we first identified all hospital admissions at any gestation with primary and secondary ICD‐10‐AM discharge codes from chapter J00–J99 (diseases of the respiratory system). Second, we excluded hospitalisations due to chronic respiratory conditions 2.3SAS® statistical software Version 9.3  were used for all aspects of data analysis. Univariate analyses were used to describe the study population by demographic and other baseline characteristics . Individuals selected only one priority ethnicity  even if they identified with several so that the ethnicity used in analysis was prioritised. The New Zealand Deprivation Index 2013 (NZDep‐13) is a measure of socioeconomic status at the smallest geographic area called a ‘meshblock’ defined by Statistics New Zealand.Bivariate analyses were used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) to describe associations between baseline characteristics and maternal ARI hospitalisation (exposure). Baseline characteristics were assessed as potential effect modifiers and confounders in the relationship between exposure and outcomes of interest to adjust for in multivariate regression models. Variables that could be controlled for in the study included maternal age, ethnicity, deprivation index, region, prior births, sex of baby, smoking status and obesity status. Maternal age was first stratified into 5‐year age groups and age groups that did not have a statistically significant difference in maternal ARI hospitalisation risk were collapsed to improve study power and find meaningful associations between independent variables and outcomes. In New Zealand, women older than 35 years of age are considered to be at higher risk of developing pregnancy‐related complications.Hazard ratios and 95% CIs for maternal ARI hospitalisation and adverse outcomes were estimated using Cox proportional hazards models. Person‐time contributed to the follow‐up period was defined as the total person‐weeks a woman was pregnant and at risk of getting an influenza virus infection. The outcomes of interest were classified into those related to pregnancy  and birth (low birthweight). Fetal death was first identified using the National Maternity Collection and cross‐checked with deaths data from the National Mortality Collection. The same demographic and other baseline characteristics  used in the main analysis were considered prior to regression modelling. The primary model was adjusted for maternal age, ethnicity and smoking status. The PROC PHREG RANDOM statement was used to adjust for clustering due to between‐person correlation among pregnancies.2.4We conducted a supplemental analysis to examine the potential protective effect of maternal influenza immunisation on mothers and babies using data from years 2010 through 2018. Analysis was limited to pregnancies in 2010 through 2018, to coincide with the approval of government‐funded influenza vaccinations for pregnant women in New Zealand.2.5The study was approved by the University of Auckland Human Participants Ethics Committee (Protocol Number 021530).33.1We identified 822,391 pregnancies among New Zealand residents of reproductive age during 1 January 2003 to 31 December 2018. The average maternal age was 29 years . More than half of the study population (53%) reported being of European or other non‐Asian prioritised ethnicity, 27% Māori, 11% Asian and 10% Pacific. Twenty‐seven percent of pregnancies occurred in mothers of the highest levels of deprivation (NZDep‐13 Index Levels 9–10). Most of the pregnancies occurred in women living in the Northern, Midland and Central regions, with only 19% in the South Island. Approximately 19% of women reported smoking during pregnancy and 40% were primigravids. There were 483,792 women who were pregnant once, 238,290 women who were pregnant twice, 72,666 women who were pregnant thrice and 27,643 women who were pregnant four or more times during follow‐up Table . A total3.2Only 0.6% (n = 5095) of the pregnancies had at least one maternal ARI hospitalisation during the influenza season and 99.4% n = 817,296) did not . Smokers and women who were obese (BMI ≥ 30) before pregnancy had higher maternal ARI hospitalisations than non‐smokers and women with a BMI < 30 .3.3Maternal ARI hospital admission during influenza season was associated with a greater risk of adverse pregnancy and birth outcomes in multivariate adjusted models compared with pregnancies without maternal ARI hospitalisation during the influenza season Table . After c3.4We found an association between influenza vaccination status and adverse pregnancy and birth outcomes Table . After c4Our analysis of 16 years of New Zealand data demonstrates that pregnant women with ARI hospitalisation during the influenza season had a higher risk of adverse birth outcomes; conversely, pregnant women who were influenza vaccinated were at lower risk of experiencing these outcomes. Our study also explored the relationship between influenza vaccination during pregnancy and ARI hospitalisation during the influenza season, and adverse pregnancy and birth outcomes. Maternal influenza vaccination did not decrease the risk of ARI hospitalisation for pregnant women.The main limitation of this study is that although we were able to quantify the hazard of adverse pregnancy and birth outcomes among women hospitalised with ARI during the influenza season, we were unable to conduct similar analyses for women seeking care for ARI in ambulatory settings. It is possible that hospitalised pregnant women may be more likely to have gestational diabetes and other underlying medical conditions, which place them at risk for preterm delivery regardless of whether they are infected with a respiratory virus or not. We could not include underlying medical conditions other than obesity in the analyses because of data limitations. During epidemic periods, a greater proportion of hospitalised pregnant women could have had an influenza‐associated ARI, but it might be that their diabetes, and not the ARI, for example, placed them at higher risk of an adverse birth outcome. However, it is also possible that influenza virus infection triggered cytokine dysregulation and exacerbated underlying medical conditions that disproportionately affected pregnant women and led to hospitalisation.Another limitation of this study is that maternal ARI hospitalisations were not laboratory confirmed for influenza, and it is likely that our study captured ARI hospitalisations associated with other respiratory pathogens that co‐circulate during the influenza season, not just influenza. Less than half of specimens tested from patients hospitalised with ARI during the influenza season test positive for influenza, and the other half test positive for non‐influenza viruses, like adenovirus, respiratory syncytial virus and rhinovirus.This study provides comprehensive estimates of maternal ARI hospital admission rates during the influenza season among residents of New Zealand. We found significantly increased risk of maternal ARI hospitalisations among the older (45–49 years) age group. Pregnancies among women older than 35 years are regarded as more at risk of pregnancy‐related complications,et al observed a similar protective effect between seasonal influenza vaccination during pregnancy and adverse birth outcomes.Our finding that influenza‐vaccinated mothers had almost half the incidence of fetal death compared with unvaccinated mothers is consistent with that observed in Australia.Despite the WHO recommendation that pregnant women be prioritised for seasonal influenza vaccination, coverage in the Western Pacific Region remains suboptimal.This study used data on a national cohort of pregnant women over the span of 16 years available from New Zealand's Ministry of Health National Collection datasets. Our findings from this retrospective cohort analysis indicate that maternal ARI hospitalisations during the influenza season are associated with preterm birth and low birthweight and that influenza vaccination may help prevent these outcomes. Moreover, we found that maternal influenza vaccination was linked to lower rates of fetal death. Findings that support the morbidity, and fetal and infant mortality associated with ARI and influenza infection, along with the benefits of influenza vaccine in this group, are useful to better establish the value proposition of influenza vaccines in preventing respiratory illnesses and related complications. The value of influenza vaccination, in this case, goes beyond preventing mostly self‐limited ARIs and seems to extend to the prevention of expensive and potentially deadly birth outcomes during influenza epidemic periods. Improving understanding, access and provider recommendations relating to maternal influenza immunisation in New Zealand could prove useful in improving pregnancy and birth outcomes.Jazmin Duque: Conceptualization; formal analysis; investigation; methodology; project administration; resources; software; validation. Anna S. Howe: Conceptualization; formal analysis; investigation; methodology; resources; supervision; validation. Eduardo Azziz‐Baumgartner: Conceptualization; formal analysis; investigation; methodology. Helen Petousis‐Harris: Conceptualization; formal analysis; investigation; methodology; resources; supervision.H. Petousis‐Harris reports grant funding from the New Zealand Health Research Council, CDC and the New Zealand Ministry of Health outside this work. No other potential conflicts of interest were disclosed.https://publons.com/publon/10.1111/irv.13063.The peer review history for this article is available at Table S1. Total number of pregnancies per woman during the study periodTable S2. Plurality of pregnancies included in the studyClick here for additional data file.


To evaluate the relationship between Doppler and biometric ultrasound parameters measured at diagnosis and perinatal adverse outcome in a cohort of late‐onset growth‐restricted (FGR) fetuses.th percentile for gestational age or as reduction of the longitudinal growth of AC by over 50 percentiles compared to ultrasound scan performed between 18 and 32 weeks of gestation. We evaluated the association between sonographic findings at diagnosis of FGR and composite adverse perinatal outcome (CAPO), defined as stillbirth or at least two of the following: obstetric intervention due to intrapartum fetal distress, neonatal acidemia, birth weight < 3rd percentile and transfer to the neonatal intensive care unit (NICU).This was a multicenter retrospective study of data obtained between 2014 and 2019 including non‐anomalous singleton pregnancies complicated by late‐onset FGR (≥ 32 weeks), which was defined either as abdominal circumference (AC) or estimated fetal weight (EFW) < 10P = 0.01) and NICU admission (P < 0.01), while the mean UtA pulsatility index (PI) multiples of the median (MoM) > 95th percentile at diagnosis was associated independently with obstetric intervention due to intrapartum fetal distress (P = 0.01). The model including baseline pregnancy characteristics and the EFW percentile was associated with an area under the receiver‐operating‐characteristics curve of 0.889  for CAPO (P < 0.001). A cut‐off value for EFW corresponding to the 3.95th percentile was found to discriminate between cases with and those without CAPO, yielding a sensitivity of 58.5% , specificity of 69.6% , positive predictive value of 19.8%  and negative predictive value of 92.9% .Overall, 468 cases with complete biometric and umbilical, fetal middle cerebral and uterine artery (UtA) Doppler data were included, of which 53 (11.3%) had CAPO. On logistic regression analysis, only EFW percentile was associated independently with CAPO (th percentile at diagnosis is associated independently with intrapartum distress leading to obstetric intervention. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.Retrospective data from a large cohort of late‐onset FGR fetuses showed that EFW at diagnosis is the only sonographic parameter associated independently with the occurrence of CAPO, while mean UtA‐PI MoM > 95 What are the novel findings of this work?rd centile and transfer to the neonatal intensive care unit, while uterine artery pulsatility index multiples of the median > 95th percentile is associated with intrapartum fetal distress leading to obstetric intervention.The findings of this study show that, at the time of diagnosis of late‐onset fetal growth restriction (FGR), estimated‐fetal‐weight percentile is the only ultrasound parameter associated independently with composite adverse perinatal outcome, defined as stillbirth or at least two of the following: obstetric intervention due to intrapartum fetal distress, neonatal acidemia, birth weight < 3What are the clinical implications of this work?In this cohort study, including non‐anomalous singleton pregnancies defined as late‐onset FGR according to the study inclusion criteria, we observed a low frequency of maternal, perinatal and postnatal complications. Our data can be used for antenatal counseling of prospective parents.Fetal growth restriction (FGR) is a complex and multifactorial disorder affecting fetal development, which represents currently one of the leading causes of perinatal mortality and morbidity, including iatrogenic preterm deliveryAccording to the Delphi consensus criteria, FGR is differentiated into early‐ and late‐onset phenotypes, depending on whether it is identified before or after 32 weeks' gestationExcept for delivery, there is no effective treatment to reverse the course of FGR. However, while evidence for management of FGR with onset between 26 and 32 weeks' gestation has emerged from the TRUFFLE studyrd percentile, has also been proposed as an additional risk factor for fetal or neonatal complicationsSeveral studies have demonstrated a relationship between sonographic indicators of placental insufficiency, cerebral blood flow redistribution and adverse perinatal outcome in late‐onset FGRth percentile or as decrease in AC of > 50 percentiles from ultrasound scan at 18–32 weeks' gestation. Using the same diagnostic criteria adopted by the TRUFFLE group, in this study we aimed to evaluate the relationship between Doppler and biometric ultrasound parameters measured at diagnosis and adverse outcome at birth within a selected cohort of late‐onset FGR fetuses.The recently published data of the prospective observational feasibility study conducted by the TRUFFLE group has led to the identification of thresholds for umbilical and cerebral Doppler values which correlate most strongly with adverse outcomeThis was a retrospective study conducted at three tertiary academic units in Italy , including a consecutive series of non‐anomalous singleton pregnancies referred for expert ultrasound between 32 + 0 and 36 + 6 weeks of gestation due to suspected FGR, between January 2014 and December 2019. All pregnancies were dated based on first‐trimester crown–rump length.th percentile or decrease in AC of > 50 percentiles from the ultrasound scan performed between 18 and 32 weeks. For each pregnant woman, information concerning fetal biometry and maternal Doppler assessment at diagnosis (i.e. mean UtA pulsatility index (PI) and fetal  PI and the CPR) was recorded. EFW was computed by means of the Hadlock IV formulaAll non‐anomalous singleton pregnancies referred between 32 + 0 and 36 + 6 weeks due to suspected FGR were screened. Diagnosis of late‐onset FGR was made based on EFW or AC < 10Cases were excluded in the event of missing data for umbilical artery, MCA and UtA Doppler at the time of diagnosis of late‐onset FGR or perinatal outcome and in the event of postnatal diagnosis of malformation, chromosomal abnormality, genetic syndrome or congenital infection.th percentile, on a weekly basis in the case of CPR < 5th percentile or UtA‐PI > 95th percentile and on alternate days in the case of umbilical artery PI > 95th percentile. Induction of labor was recommended between 36 and 37 weeks in the case of umbilical artery PI > 95th percentile, at 37 weeks in the case of EFW or AC < 3rd percentile, between 37 and 38 weeks if signs of redistribution were noted (i.e. CPR < 5th percentile) and at 39–40 weeks in the absence of any of those risk factors for adverse perinatal outcome. The monitoring strategy also included cardiotocography (CTG), which was performed at each assessment. The finding of absent or reversed end‐diastolic (ARED) flow in the umbilical artery and spontaneous repetitive decelerations on CTG represented indication for immediate delivery by Cesarean section. Antenatal steroids for lung maturation were administered in all cases delivering before 34 + 6 weeksAs per management protocol, which was consistent in the three participating centers, follow‐up scans were arranged every 2 weeks in the absence of signs of cerebral redistribution, defined as CPR > 5In all cases referred for labor induction, cervical ripening was promoted either by means of a cervical ripening balloon or by vaginal administration of a slow‐release prostaglandin‐E2 pessary, which was followed by oxytocin infusion if the onset of labor did not occur. Cesarean section was performed electively in the presence of ARED flow in the umbilical artery, spontaneous repetitive decelerations on CTG monitoring or other obstetric indications. The clinicians responsible for the intrapartum care were not blinded to the antepartum findings. The diagnosis of intrapartum fetal distress was defined by the physician in charge of the patient care based on abnormal CTG tracing according to the FIGO classification systemInformation on maternal demographics and peripartum and neonatal outcome were collected from patient case notes. Neonatal outcome was assessed by examining birth weight and birth‐weight percentile corrected for genderrd percentile and transfer to NICU. Additionally, neonatal hypoglycemia, defined by two consecutive whole‐blood glucose measurements by glucometer or one plasma glucose measurement < 3.3 mmol/LThe primary aim of this study was to evaluate the relationship between sonographic parameters measured at diagnosis and the occurrence of CAPO, defined as stillbirth or at least two of the following: obstetric intervention due to intrapartum fetal distress, neonatal acidemia, defined by umbilical artery pHEthical approval for collection of the data for this study was granted by the local ethics committee of the involved centers.n (%) or median (range). Categorical variables were compared using the chi‐square or Fisher's exact test. Comparison of continuous variables was performed using the independent‐samples t‐test and two‐tailed t‐test. Logistic regression analysis was used to control for potential confounding variables and receiver‐operating‐characteristics (ROC)‐curve analysis was performed in order to evaluate the accuracy of the prediction of primary outcome. The method of DeLong et al.P < 0.05 was considered to be statistically significant. This study was conducted following the STROBE guidelinesStatistical analysis was performed using SPSS, version 20 . Data are shown as mean ± SD, th percentile, with no difference in terms of adverse outcome between those with birth weight above vs below the 10th percentile threshold  with late‐onset FGR defined according to the study inclusion criteria were retrieved, of which 468 were included for data analysis following evaluation of the exclusion criteria  and NICU admission (P < 0.01 for both), while mean UtA‐PI MoM > 95th percentile at diagnosis was associated independently with obstetric intervention due to intrapartum fetal distress (P = 0.01). When assessing the baseline risk for CAPO using logistic regression analysis and a model including maternal age, booking body mass index, ethnicity, parity, smoking status, presence of comorbidities and gestational age at ultrasound examination (pretest probability), the addition only of EFW percentile at diagnosis resulted in a significant increase in the area under the ROC curve  vs 0.803 ; P = 0.02) , over 2‐fold higher rate of NICU admission  and almost 2‐fold higher incidence of neonatal hypoglycemia . Furthermore, EFW < 3.95th percentile was associated with an increased rate of Cesarean section  and obstetric intervention due to intrapartum fetal distress , over 2‐fold higher frequency of delivery prior to 37 weeks' gestation  and longer neonatal hospitalization (6 (2–42) vs 3 (1–37) days; P < 0.01) , specificity of 69.6% , positive predictive value of 19.8%  and negative predictive value of 92.9% .An EFW cut‐off corresponding to the 3.95th percentile , preterm delivery prior to 37 weeks  and obstetric intervention , earlier gestational age at delivery  and lower 5‐min Apgar score (P < 0.01), when compared with cases that did not fulfill the Delphi diagnostic criteria for late‐onset FGR. Furthermore, late‐onset FGR fetuses defined according to the Delphi criteria showed an increased incidence of perinatal adverse outcomes, including NICU admission , need for respiratory support at birth  and CAPO  as well as longer neonatal hospitalization (5 (2–42) vs 3 (1–37) days; P < 0.01), when compared with cases that did not fulfill the Delphi diagnostic criteria for late‐onset FGR  of the included cases met the Delphi diagnostic criteria for late‐onset FGR. These cases showed an increased frequency of mean UtA‐PI MoM > 95GR Table .th percentile at the time of diagnosis of late‐onset FGR was the only ultrasound parameter associated independently with adverse perinatal outcomes, including prematurity and its potentially related complications, such as NICU admission, neonatal hypoglycemia and length of neonatal admission. Of note, the frequency of Cesarean section and obstetric intervention due to intrapartum fetal distress was shown to be almost 2‐fold higher among fetuses with EFW percentile < 3.95th percentile. This finding is consistent with previous studies demonstrating a correlation between the risk of poor neonatal outcome, including stillbirth, and the actual EFWThe findings of this cohort study demonstrate that non‐anomalous singleton pregnancies defined as late‐onset FGR, according to the study inclusion criteria, had a low frequency of maternal, perinatal and postnatal complications. Our data also show that EFW < 3.95th percentile and mean UtA‐PI MoM > 95th percentile at diagnosis did not prove to be associated independently with the occurrence of the primary outcome of this study. The finding of Doppler indicators of cerebral redistribution or UtA Doppler abnormalities has been suggested as a surrogate of clinical severity in the context of subclinical impairment of the placental function. On this basis, these parameters have been suggested to represent indication for elective delivery in the context of antenatally detected FGRper se represent a risk factor for perinatal complications in the context of antenatally suspected FGR.Unexpectedly, CPR MoM < 5th percentileth percentilevs those who did not fulfill the Delphi diagnostic criteria for late‐onset FGR.Several studies have demonstrated an association between reduced CPR and adverse outcome, including stillbirth, in fetuses with EFW < 10et al.et al.When looking at other perinatal outcomes, our data revealed an incidence of NICU admission of just above 1 in 4 cases, which is consistent with that reported in the studies of Figueras th percentile is likely to have resulted from the inclusion of fetuses considered at risk based on the longitudinal reduction of AC from mid‐trimester scan, which has been endorsed recently by the TRUFFLE groupth percentile birth‐weight threshold was not associated with increased incidence of adverse perinatal outcome or with difference in the rate of Doppler abnormalities at diagnosis. The findings from a recent retrospective study of Meler et al.th percentile in the absence of criteria of severity  results in perinatal outcome comparable to that in normally grown neonates. In our cohort, the comparison between the fetuses identified as FGR and those with normal growth could not be undertaken, however, our results support the concept that the absence of criteria of severity is associated with improved perinatal outcome in the context of FGR.Albeit within the limitations of the adoption of different antenatal and postnatal growth charts, the unexpectedly high rate of neonates with birth weight above the 10To our knowledge, this is the first study providing information on perinatal outcome of late‐onset FGR based on sonographic findings at diagnosis. The main strength of this study is represented by the large number of included cases and its multicenter design involving three referral academic units. Of note, the participating centers had similar protocols for the perinatal management of late‐onset FGR.On the other hand, the retrospective design is a major limitation of this study. Approximately one‐third of cases identified as late‐onset FGR were excluded due to incomplete/missing outcome or Doppler data. Another limitation is represented by the fact that there were no data concerning the indication for delivery other than for late‐onset FGR. More specifically, we reported a low incidence of HDP, diabetes mellitus/gestational diabetes and autoimmune disorders, potentially indicating elective delivery; however, we could not retrieve information on their co‐occurrence or on early delivery only for maternal indication. The antenatal care of FGR fetuses may be complicated by HDPIn conclusion, this study reports the maternal and perinatal outcomes of a selected cohort of late‐onset FGR fetuses identified on the basis of a biometric cut‐off or longitudinal growth criteria. While we report a low incidence of adverse perinatal events, we demonstrate that, when late‐onset FGR is diagnosed, EFW percentile at diagnosis represents the only sonographic parameter associated with composite adverse outcome and that abnormal UtA Doppler is associated with intrapartum fetal distress leading to obstetric intervention. These data can be used for antenatal counseling of prospective parents.Table S1 Maternal demographics, clinical characteristics and perinatal outcome of cases with and those without birth weight < 10th percentileClick here for additional data file.Table S2 Maternal demographics, clinical characteristics and perinatal outcome of cases fulfilling vs those not fulfilling the Delphi diagnostic criteria for late‐onset fetal growth restriction (FGR) at diagnosisClick here for additional data file.


Simulation‐based education is a significant aspect of teaching clinical skills in tertiary medical radiation science programmes, allowing students to experience the clinical setting in a safe environment. As an educational tool, simulation exists in many valid forms including role play, interprofessional simulation and virtual reality simulation. This scoping review looks at the current literature in this field to identify the evidence surrounding simulation‐based education for medical radiation students. The purpose of this review is to provide an evidence‐based guide for educators, identify gaps in the literature and suggest areas of future research. Data extraction was performed on 33 articles where the interventions could be categorised into either role play simulation, virtual simulation, simulation videos or online learning environments. Most studies demonstrated that simulation could improve clinical competence and increase preparedness and confidence for clinical placement. Student satisfaction remained high throughout the studies; however, it is the view of many that although simulation‐based education is a valid and effective tool, it is complementary to and not a replacement for clinical placement. This scoping review investigated the current literature in this field to identify the evidence surrounding simulation‐based education for medical radiation students. Student satisfaction remained high throughout the studies; however, it is the view of many that although simulation‐based education is a valid and effective tool, it is complementary to and not a replacement for clinical placement. Clinical education is a core component of medical radiation university programmes  with simulation recognised as an essential preparatory tool for work‐integrated learning and clinical practice. Over the course of their undergraduate studies, students are required to develop a solid grounding in academic knowledge together with the associated technical and patient‐centred capabilities to facilitate a holistic approach in their own discipline. Globally, there is increasing pressure for training institutions to develop the competency of their students without the negative impacts that may be associated with clinical placements. This has resulted in university educators reassessing how to best facilitate the development of practical clinical skills in effective, safe and supported learning environments. Students not only need to be academically prepared for placement, but also need opportunities to develop technical skills outside the clinical learning environment.Simulation‐based education is a highly effective tool for mimicking the clinical environment to teach skills to students and practitioners in healthcare.While virtual simulation has been successfully embedded within radiation therapy programs in Australia, the use of virtual simulation within diagnostic radiography has not been widely adopted despite some promising recent studies.Despite the recent studies conducted in this field, many educators continue to use conventional teaching methods rather than seeking the potential benefits that simulation has to offer. Student preparation for clinical practice is essential and should be conducted with the most appropriate teaching methods to achieve the best results. Several scoping reviews and meta‐analyses have been performed in the field of nursing and medicine. There is, however, a scarcity of comprehensive literature review on this contemporary pedagogical approach. It is also unknown if medical radiation simulation curricula have been designed according to current best practice guidelines incorporating the cycle of simulation phases. The aim of this scoping review is to provide a contemporary evidenced‐based guide to simulation‐based education in medical radiation programs.A scoping review was performed to assess the current literature on the use of simulation for medical radiation students in an academic setting. Our existing knowledgebase and initial literature review of this topic have discovered a wide variety of alternate approaches to simulation education in medical radiation science. These aspects differ particularly in terms of the setting, duration and technology utilised by educators. Scoping reviews are particularly useful in this case, especially as our topic exhibits a complex and heterogeneous nature not amenable to a more precise form of review.The organisational framework described by Arksey and O'MalleyThe intention of this scoping review is to answer the question, ‘What is the current literature on simulation‐based education for medical radiation students’? For this review, we refined our search strategy based on a PICO approach, where P (population) is the medical radiation student/curriculum, I (intervention) is simulation‐based education, C (comparator) is other forms of learning and O (outcome) is knowledge retention/satisfaction/perceptions/experiences.A scoping search was performed on three databases: PubMed, Scopus and Medline from 2010 to 2021. These databases were selected to capture the existing literature in allied health and higher education. To identify the search terms, a preliminary search was conducted in the Scopus and Medline databases. The following terms were entered: ‘simulation’, ‘simulated learning’, ‘computed tomography’, ‘medical radiation’, ‘medical imaging’, ‘radiation therapy’, ‘nuclear medicine’, ‘radiologic technology’ and ‘radiography’. Later, synonyms for each search term were used and applied with the Boolean operators ‘AND’ and ‘OR’ to capture all possible relevant articles , with Likert scale questionnaires being the most popular tool (n = 21). Only seven studies incorporated performance‐based measures to assess skills or knowledge in their data collection. In two of these studies, however, performance‐based assessments were not a prominent feature. Six studies also employed a control group which did not experience the simulation intervention, while one additional study utilised a crossover study approach. None of the studies with a control group employed blinding, though it is noted that effective blinding is largely inconceivable. The total sample size of participants across the studies was 2343, with individual sample sizes ranging from five to 293. ‘Radiography’ was the sole focus for 20 articles, while seven had an interprofessional focus. The remainder focused on a combination of ‘radiation therapy’ (n = 5) or ‘sonography’ (n = 1). Role play simulation was the most common intervention (n = 16) followed by virtual/digital simulation (n = 13). Two studies each used simulation video clips or online learning environments as interventions.Table The use of performance‐based outcome measures, as adjudicated by external observers or questionnaires was only a major part of the data collection in five studies.Seventeen of the nineteen studies analysing self‐reported quantitative data, demonstrated an increase in competence after completing the simulation intervention. Students reported benefits in areas including empathy, attitudes towards patients, preparedness, confidence, content knowledge, reflection and technical skills. A control group was not utilised in 95% of studies, with Shinern = 10), interviews (n = 8), focus groups (n = 7), observations (n = 1), with five studies employing a combination of methods. Their findings were supportive of the use of simulation, citing enhanced student knowledge, confidence, clinical competence and collaboration with others as positive outcomes. Students mentioned that the opportunity to perform activities relating to positioning, visualisation, communication, clinical preparation, patient care, collaborative learning and relationship‐building were particularly beneficial.The studies including qualitative findings used many methods during data collection, namely open‐ended questions ; the capacity of simulation to achieve a variety of outcomes ; the mode of delivery (e.g. self‐directed and teacher‐led) and student satisfaction.All studies included in this review explored simulation as a means for education in a tertiary setting for medical radiation sciences; however, two primary subgroups emerged with regard to the intervention used; role play simulations and virtual/digital simulation. Bleiker, KnappThe role play simulation studies can be broken down into further subgroups; practical targeted simulation and interprofessional simulation. For the purpose of this study, ‘practical targeted simulation’ will refer to any simulation‐based teaching approach that was given to a specific population of students, whereas ‘interprofessional simulation’ will refer to any simulation‐based teaching approach given to students as part of a multidisciplinary team. Practical targeted simulation was the intervention of choice for eleven studies, eight of which were specific to radiography participants. The other three studies included participants from radiation therapyn = 5), allowing the students to position patients and operate an X‐ray tube in a digitally simulated clinical environment. Similarly, four studies used virtual Computed Tomography (CT) software, three used VERTThe intervention that was most common among the virtual simulation studies was virtual radiography software , and this review only included English‐language studies. Publication of studies with more favourable results are more likely to be published than those with contrary findings, meaning that the literature available may overestimate the true value of simulation interventions. Real‐world outcomes such as cost were not reported in any included study. Data regarding costs of implementation and qualitative discussion concerning accessibility of resources would be advantageous in enabling financial and resource analysis of given interventions.It is evident that the use of simulation‐based education can have significant effects on the learning of students in medical radiation. Almost all studies included in this review viewed the use of simulation in Medical Radiation education positively. If implemented appropriately, simulation can provide students with opportunities to experience the clinical environment in a safe context and learn at their own pace. Both practical and virtual simulation have shown their potential in a variety of contexts in this review, with many students endorsing its use in medical radiation courses as a complementary learning tool rather than a replacement for clinical practice. Due to the small number of studies with objective performance‐based outcome measures and control arms, it is difficult to arrive at a reliable comparative evaluation of the relative benefits of simulation versus traditional teaching methods. Nevertheless, this review highlights the benefits of simulation in medical radiation education and outlines the shortcomings in recent literature. There is a need for further research into simulation using objective outcome measures and control arms, particularly concerning modalities such as CT and MRI.The authors declare no conflict of interest.