This study aims to increase understanding of the relationship between heavy episodic drinking (HED) and fathers' involvement in parenting in five countries. The potential moderating effect of fathers' experiences of childhood trauma is also studied, controlling for the possible confounding of the effect of HED by father's attitudes toward gender equality, father's age and father's education.United Nations Multi‐Country Study on Men and Violence (UNMCS) survey data from 4562 fathers aged 18–49 years from Cambodia, China, Indonesia and Papua New Guinea (PNG) and Sri Lanka were used to assess the relationship between fathering involvement  and self‐reported HED of 6+ drinks in one occasion vs. non‐HED and abstaining. Moderating effects of a 13‐item fathers' childhood trauma (FCT) scale were tested and analyses were adjusted for gender‐inequitable attitudes using the Gender‐Equitable Men scale score. Bivariate and adjusted individual participant meta‐analyses were used to determine effect estimates for each site and across all sites.p = 0.07).Fathers' HED was associated with less positive parental involvement after adjusting for gender‐equitable attitudes, FCT, age and education. No overall interaction between HED and FCT was identified. Gender equitable attitudes were associated with fathering involvement in some countries but not overall  expression and protein levels were highly induced by binge ethanol. We generated CYP2B10‐knockout mice and found that they exhibit increased levels of liver injury after chronic‐plus‐binge ethanol administration. CYP2B10 plays a protective role in ethanol‐induced liver injury by indirectly increasing ethanol metabolism and altering liver metabolites. Fathers around the world are increasingly involved in children's development Gerson, . FatheriStudies have focused on the role of problematic alcohol and its impact on intimate and family relationships, children's emotional development and subsequent alcohol use  in the Asia Pacific region, we test the key hypothesis that fathers' current HED is associated with less involvement in parenting, taking into account the possible moderating effect of fathers' childhood trauma (FCT) and controlling for gender inequitable attitudes, as well as men's age and education.The present study uses the individual‐level data from the United Nations Multi‐Country Study on Men and Violence (UNMCS) data  was assessed with three items measured on a 4‐point Likert scale , asking the participant about time spent: playing with or participating in activities with his children; discussing personal matters with his children; and helping children with their homework  Scale . The youngest age group only contained 180 fathers and was combined, creating two age groups: 18–34 years (1) and 35–49 years (0).Finally, it is important to control for social status , which analyses the individual, site, and country level data, and pools the data from all sites. The ipdmetan adjusts for individual level and group level effects, thereby in the analysis acting as a form of multi‐level analysis, adjusting for both individual and country level effects. The random effects meta‐analysis allows for variability across sites and countries while increasing power through pooled sample size. Analyzing individual sites or countries may result in underpowered analyses, while the meta‐analytic approach increases power to detect an effect, and the random effects account for some of the site‐specific and country‐specific sources of variation. Ipdmetan is a useful tool for adjusting for multiple studies while allowing analysis of multiple surveys gathered using the same survey tools, where the individual data are available for secondary data analysis. Random effects individual‐level participant meta‐analysis was employed because, while the survey items were identical, the studies varied by cultural background and sample composition ; however, there was considerable variability among countries and sites within countries.Analysis of the relationship between scores on gender‐equitable attitudes and fathering involvement found more gender equitable attitudes were generally linked to more involved parenting , and in Cambodia , Indonesia  and PNG . Non‐significant effects were found for China  and Sri Lanka . Father's education was also significant with any high school education associated with increased engagement with children overall  and in Cambodia  and Indonesia  but not in China , PNG  or Sri Lanka .Younger fathers (18–34 years) reported significantly less involvement with their children than older fathers (35–49 years) overall , and this relationship varied only slightly (the effect size increased to −0.26) with the inclusion of fathers' gender‐equitable attitudes, experience of childhood trauma, father's age and education.We analyzed the relationship between HED and fathering involvement, including gender equitable attitudes, FCT, father's age and low education in the model  in PNG.Previous research has found that HED is related to other aspects of men's lives, including their parenting  countries are very rare. Thus, although the relationship between heavy drinking and less parental involvement was weak and not evident in all countries, it provides important directions for future research. This could include more in‐depth measures of parental involvement than was possible in this survey that covered many topics, including assessing different behaviors by age of the children. It would also be valuable to explore the relationship of drinking with intensity of both positive and negative parental involvement – that is, while parental involvement is seen as a positive father behavior, some parental involvement can be controlling and negative.Notwithstanding the fact that some fathers involved in parenting may also be violent, our findings on heavy drinking and less involvement with parenting fit with a spectrum of evidence wherein less positive and more negative parenting, including child maltreatment, are associated with HED. More than 10 years ago, research identified paternal alcoholism, depression and marital satisfaction as important factors in parenting. Since then, alcohol and parenting literature has rarely focused on what it is about drinking in problematic ways that might make men less involved with their children . In some countries, specifically, in China and Sri Lanka, men with more gender equitable attitudes were significantly more likely to be involved in parenting. Given that the country‐level effect estimates were all positive, except in Cambodia where the result was marginally negative (−0.01), future research that includes a larger number of countries may find stronger evidence of a direct relationship.We explored the relationship between fathering involvement and gender‐inequitable attitudes and a weak effect was found overall  changes in the effect estimates for the relationship of fathering involvement with both HED and gender‐equitable attitudes. This somewhat contrasts with previous research with young people (not fathers), where masculine norms have explained patterns of problematic drinking among men  may produce more robust measures of masculinity. The CMNI is multi‐dimensional and has been found to be positively and negatively associated with various alcohol outcomes  and in Cambodia. These results are presented in Table The AUDIT , worldviews  and expectations within these countries. These are important factors within Asian countries and should be considered for inclusion in future UNMCS surveys, particularly given specific cultural values may be protective and linked to fathers' involvement with their children.Despite these limitations and given cross‐cultural detailed studies of parenting involvement are rare, especially for the countries included in these analyses, this study provided a unique opportunity to explore drinking and fathering involvement. Overall, the primary effects were relatively small and future studies using larger surveys, in depth interviews and ethnographic studies would add further explanations of country‐level differences.This study provides evidence that fathers' HED is associated with less involvement in parenting. These findings suggest that reducing men's HED (and increasing gender‐equitable attitudes in some countries) may increase men's positive involvement in parenting.Laslett was funded by the Australian Research Council Grant DE190100329 and veski. The Victorian Near‐miss Award Pilot is being administered by veski for the Victorian Health and Medical Research Workforce Project on behalf of the Victorian Government and the Association of Australian Medical Research Institutes. Funding for the Pilot has been provided by the Victorian Department of Jobs, Precincts and Regions. The Victorian Near‐miss Awards are provided to eligible individuals who narrowly missed out on the 2021 NHMRC Investigator Grant funding in the Emerging Leaders 2 stream.None.Appendix S1Click here for additional data file.


Although endoscopic screening for esophageal cancer has been performed in high‐risk areas in China for decades, there is limited and inconsistent evidence regarding the starting age for individuals participating in screening. The aim of this study is to investigate the optimal starting age of esophageal cancer screening.This study is based on a multicenter prospective cohort consisting 338,017 permanent residents aged 40–69 years in six high‐risk areas of esophageal cancer in China. The participation rate, detection rate, hazard ratios (HRs), cumulative incidence and mortality and number needed to screen (NNS) were calculated in each age group. Screening burden, benefit and risk were compared among screening strategies with different initiation ages to explore the optimal starting age for population‐based screening in high‐risk areas.Individuals aged 50–69 had a higher participation rate, a higher detection rate and improved screening effectiveness than those aged 40–49. The endoscopic screening had no significant effect on reducing the incidence of esophageal cancer in individuals under 55 and mortality in individuals under 45. Increasing the starting age to 50 years reduced the screening demand and NNS by 40% and 55%, and resulted in 12% of detectable positive cases, 16% of preventable incident cases, and 14% of preventable deaths being missed.Postponing the starting age of endoscopic screening to 50 years might yield a more‐favorable balance between screening benefit and burden in high‐ risk areas with limited resources. Compared with the unscreened group, initiation of screening after 50 years was associated with a greater reduction in cumulative incidence and mortality in 10 years follow‐up compared with initiation before 50 years. According to estimates from the GLOBOCAN project, there were more than 604,000 new cases and 544,000 cancer deaths worldwide in 2020.Accumulating evidence has demonstrated that endoscopic examination is an effective tool for screening and can provide long‐term protection from esophageal cancer occurrence and death in high‐risk areas in China.There is no guideline for esophageal cancer screening worldwide. The current screening program conducted in high risk areas of esophageal cancer in China recommended all permanent residents aged 40–69 years old to take at least one endoscopy.Given the limited and inconsistent evidence on the optimal starting age for esophageal cancer screening,22.1This study was based on data from a multi‐center population‐based screening cohort. The details on population selection have been described previously.2.2A once‐only endoscopic examination was offered to participants who agreed to take screening. The screening was done in local hospital by well‐trained doctors according to the screening protocol for upper‐gastrointestinal cancer in China.People diagnosed with severe dysplasia and above were advised to undergo surgery or endoscopic therapy. For high‐grade dysplasia, carcinoma in situ and intramucosal carcinoma, local therapies were used, including endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), multiring banded mucosal excision (MBM), or radiofrequency ablation (RFA). For submucosal cancers (infiltration depth ≥ 200 μm) and advanced esophageal cancers, esophagectomy, radiotherapy, and other conventional treatments were used for treatment. For individuals diagnosed with mild or moderate dysplasia, endoscopic surveillance was recommended after 3–5 years or 1 year, respectively.All individuals participated in the screening took a risk factor survey before endoscopy by trained investigators using a uniform questionnaire. In the first year of screening, 20% of the individuals in the unscreened group were invited to complete the same questionnaire.2.3The primary outcomes were the detection of esophageal cancer and its precancerous lesions within 1 year after baseline screening (screen‐detected cases), and the occurrence and death of esophageal cancer during follow‐up (follow‐up detected cases). We re‐classified precancerous lesions into low‐grade intraepithelial neoplasia (LGIN) and high‐grade intraepithelial neoplasia (HGIN) in accordance with diagnostic terms recommended by the International Agency for Research on Cancer.The demographic information of the target population, including gender and date of birth, was derived from the household registration system. The information on cancer incidence and mortality were obtained by matching the target populations with the cancer registration and death surveillance database. All participants were followed up to 31 December 2015.2.4Multiple indicators related with outcomes were evaluated in the analysis. The participation rate, biopsy rate, and detection rate were described as proportions. The follow‐up time was defined from cohort entry date to the date of outcome onset, death or the end of follow‐up. For the screened individuals, the cohort entry date was the screening date, and for those who refused to screen, the invitation date was used as the cohort entry date. We used the Cox proportional hazards regression model to calculate the hazard ratios (HRs) and 95%CIs. The number needed to screen was calculated as the inverse of risk difference to measure the effect of screening strategy.Statistical analysis was completed using STATA V.14.0 . The study was approved by the independent ethics committee of Cancer Hospital Chinese Academy of Medical Sciences .3The baseline characteristics of study population are summarized in Table p < 0.001) (Table The detection rates of positive cases diagnosed with HGIN and EC increased significantly with age (1) Table . They rap < 0.001) and 48%  in those undertaking screening. Compared with unscreened group, initiation of endoscopic screening after 55 years was associated with a reduced risk of incident esophageal cancer, and initiation of endoscopic screening after 45 years was associated with a reduced risk of death from esophageal cancer. The results of propensity score‐matched analysis were consistent with those of the primary analysis  had one time endoscopy at their 50 years since the 50–59 age group had a lower NNSThe benefits of improving screening age can be attribute to increased participant rate, detection rate, and screening effect. Participation rate is an important determinant of the effectiveness in population‐based screening. Our findings suggested that older people (50–69 years old) had a higher participation rate than younger people (40–49 years old), which were consistent with the results of previous studies.The risk of increasing the screening age is the reduced number of individuals who are prevented from esophageal cancer through early detection and early treatment. Decision makers should consider the tradeoff between benefit and risk based on the local health resources and social‐economic level in determination of the target age for screening. Screening at the age of 40 instead of 50 gains more benefits by detecting and preventing more cases. However, in areas with limited resources, we recommend that the starting age of screening could be defined as 50 years based on the following reasons: (1) Starting screening at the age of 50 instead of 40 can reduce a great number of demands for screening, while the loss of benefit is relatively small. When the screening age is increased to 50, the demand for screening can be reduced by 40%, with the sacrifice of 12% of detectable positive cases, 16% of preventable incident cases and 14% of preventable deaths. (2) A huge gap was observed in NNS between individuals who were in their 40 s and 50 s. The NNS to prevent one incident case esophageal cancer is 4703 and 2634 in individuals aged 40–44 and 45–49, respectively, while it is 925 and 214 in individuals aged 50–54 and 55–59, respectively. (3) Screening has limited effect on people aged 40–49 but could cause additional risk such as complications. Increasing the starting age to 50 can avoid the unnecessary endoscopic examinations and improve the effectiveness of screening.The existing guidelines for population‐based endoscopic screening are for gastric cancer and their recommendation on starting age are different. In Japan, the latest guideline for gastric cancer screening suggests that individuals start a biennial or triennial endoscopic screening at the age of 50,The screening program evaluated in this study consisted of one‐time screening at baseline and endoscopic surveillance for positive cases. Repeated screening of individuals diagnosed with mild or moderate dysplasia could help monitor disease progression, guide early diagnosis and treatment, and further reduced the incidence and mortality of esophageal cancer. A total of 5180 individuals took at least one endoscopic follow‐up during the study period, accounting for 4.6% of screened individuals, which contributed to the reduction on incidence and mortality. Health economic studiesIn addition, the estimation of the follow‐up time and the method of follow‐up may also have an impact on the results. Since we used the invitation date as the cohort entry date for the unscreened group, which was usually earlier than the date of screening, the median follow‐up time was longer for the unscreened group than for the screened group. This would overestimate the follow‐up duration for the unscreened group, resulting in low calculated incidence and mortality rates, and would overestimate the effectiveness of screening. We conducted passive follow‐up based on the cancer registry system, so that the incidence and mortality outcomes of all screened and unscreened individuals could be tracked. However, there is often a significant delay and more missed diagnosis for passive matching to cancer registry compared to active follow‐up to ascertain the outcomes. Therefore, the lack of active follow‐up in the unscreened group might lead to missed diagnoses, resulting in overestimation of screening effectiveness.To our knowledge, this is the first study to evaluate the impact of starting age of endoscopic screening for esophageal cancer based on data from a large sample multicenter cohort. The strength of this study is the comprehensive evaluation of multiple outcomes, including participation rate, detection rate, incidence, mortality, cumulative incidence and mortality, as well as estimated indicators such as diagnostic yield, HR and NNS. Compared to modeling studies, the present results provide real‐world evidence that can be used directly as well as important data that can be used for subsequent simulation‐based cost‐effectiveness analyses.There are several limitations in this study. First, this study is based on real‐world data, and there is inevitable selection bias and information bias. Due to the lack of risk factors for all unscreened individuals, we could only compare the risk factors between screened and unscreened groups in a limited sample Table . The resIn conclusion, this study provides evidence‐based recommendations on starting age of esophageal cancer screening in high‐risk areas. The findings could be used to guide the individuals to participate in screening, and help to improve the efficiency of screening and avoid overscreening.Ru Chen: Conceptualization (lead); formal analysis (lead); writing – original draft (lead); writing – review and editing (lead). Lizhou Dou: Conceptualization ; writing – original draft . Jiachen Zhou: Formal analysis (supporting). Guohui Song: Data curation . Bianyun Li: Data curation . Deli Zhao: Data curation . Zhaolai Hua: Data curation . Xinzheng Wang: Data curation . Jun Li: Data curation . Changqing Hao: Data curation (supporting). Yanyan Li: Data curation . Xiang Feng: Data curation . Lin Li: Data curation . Wenqiang Wei: Conceptualization (lead); supervision (lead); writing – original draft (lead); writing – review and editing (lead). Guiqi Wang: Conceptualization (lead); supervision (lead); writing – original draft (supporting); writing – review and editing (supporting).This study is supported by National Natural Science Foundation of China , Beijing Natural Science Foundation (7204294), National Science & Technology Fundamental Resources Investigation Program of China (2019FY101101), and the Chinese Academic of Medical Sciences Innovation Fund for Medical Sciences (2021‐I2M‐1‐013).The authors disclose no conflicts.Appendix S1Click here for additional data file.


In this study, we constructed an up‐to‐date GPR40 ligand dataset for training models and performed a systematic optimization of the ensemble model, resulting in a powerful ensemble model (ROC AUC: 0.9496) for distinguishing GPR40 agonists and non‐agonists. The ensemble model is divided into three layers, and the optimization process is carried out in each layer. We believe that these results will prove helpful for both the development of GPR40 agonists and ensemble models. All the data and models are available on GitHub. ( Various GPR40 agonists and non‐agonists for model training and evaluation were collection and used for building and systematically optimizing an ensemble model for predicting GPR40 agonists. The ensemble model was built based on 20 baseline models, which were consisting of different algorithms and molecular representations. And the ensemble model showed greater performance than the performance of any baseline model. Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by reduced insulin sensitivity, which results in the inability to maintain glucose homeostasis. It is the most prevalent type of diabetes, accounting for over 90 % of all diabetes cases worldwide.2+ oscillations and agonist‐induced protein kinase C (PKC)/(PKD) activation enhances downstream secretory mechanisms that are independent of Ca2+ oscillations.), offering a potential new way to treat T2DM.G protein‐coupled receptor 40 (GPR40), named fatty acid receptor 1 (FFAR1), is a type of G protein‐coupled receptor that is highly expressed in pancreatic β‐cells.The development of GPR40 agonists is hindered by both the time‐consuming and labor‐intensive nature of traditional experimental methods and the low selectivity, high toxicity, or low efficiency of certain GPR40 agonists.Ensemble learning involves combining multiple models (such as machine learning model and deep learning model) to solve a computational intelligence problem and has emerged as an effective way to improve model performance.This study describes a novel predictive ensemble model combining ML and DL for identifying GPR40 agonists and non‐agonists. Initially, GPR40 data points were collected from ChEMBLInitially, we built 151 baseline models using 6 different algorithms and 25 molecular representations. The D‐MPNN algorithm  can be trained solely based on the input of the compound's SMILES, without relying on additional molecular representations as input. These models were evaluated on both the test set and the external dataset. The performance of top 20 baseline models in 5‐fold cross‐validation are shown in Table As illustrated in Supplementary Tables Here, we investigated the impact of the number of top baseline models in layer 1 on the performance of the ensemble model. Table In layer 2, the impact of binarizing the predictive scores of the baseline models on the ensemble model by setting various thresholds  for binarization was investigated. As shown in Table The output from layer 2 was processed in layer 3 using two methods: voting and stacking. As shown in Table In this experiment, the number of nodes was set to 800, and various numbers of top baseline models were selected to construct the ensemble model. To identify its performance, we removed compounds from the external dataset based on their similarity to the compounds in the main set. As shown in Table In this study, we also performed molecular docking by AutoDock Vina software and evaluated its performance in terms of ROC AUC.The GPR40 receptor contains at least three allosteric binding sites, and two of them  have the potential to be developed as drugs to treat T2DM, as reported.To explain the output of the ensemble model, we apply the Shapley Additive exPlanations (SHAP)50 value of existing active compounds , the threshold for distinguishing agonists from non‐agonists was determined to be 1 μM and the further details about their measurements can be found in paragraph 1 (supporting information).[Firstly, we extracted two datasets from two public databases (ChEMBLrmation).7e, 7hA baseline model consists of an algorithm and a molecular representation. While ML continues to advance rapidly, traditional ML algorithms may struggle to achieve desirable results when handling imbalanced, high‐dimensional data. On the other hand, DL can extract abstract features from a training set and effectively process complex and heterogeneous data structures.The XGBoost (XGB) algorithm is widely utilized in various fields and provides state‐of‐the‐art results on multiple problems.Logistic Regression (LR) is a widely used machine learning method with a long history of development.A single decision tree usually can't provide a good performance in prediction and combining the results of multiple models may yield better result. Random forest (RF) is a traditional machine learning algorithm which is composed of a collection of decision trees. And RF uses a special bagging strategy to construct this ensemble model, which is characterized by selecting a subset of features to build decision trees. Because of this feature randomness, the decision trees of RF have low correlation in their compositions. The assembly of the decision trees also minimizes their individual errors. In terms of applications, RF is always used for classification, regression, and feature selection. For example, Cano et al. discussed the approach based on RF to improve the performance of selecting molecular descriptors.Support vector machine (SVM) algorithm has a long history of development which was created in 1963 and developed rapidly in 1990s. In the case of binary classification problem, SVM searches for a hyperplane which is able to separate two classes with different labels. But there are a lot of hyperplanes that can finish this job and it chooses the best hyperplane forming the largest separation between the different classes.With comparison to other DL algorithms, fully connected neural network (FCNN) has the simplest structure and the longest history. Compared with ML models, it has a better ability to process high‐dimensional feature data.Directed message passing neural network (D‐MPNN), developed in 2019, has become an effective tool for predicting molecular properties. Although D‐MPNN is similar to the message passing neural network, the main difference is that D‐MPNN employs messages related to directed bonds instead of atoms.In this study, 151 baseline models were constructed by combining an algorithm and a molecular representation. The stacking strategy or voting was employed to build ensemble models based on varying numbers of these baseline models. As illustrated in Figure In this paper, models’ reliability and predictive power were evaluated in two ways, including 5‐fold cross‐validation and external validation, which is performed using an external validation data set. We employed several performance indicators to quantify the performance of the baseline classifiers and the ensemble classifier, including ROC AUC, precision, F1 score, ACC, and MCC.Where TP (true positive) is the number of the agonists that are correctly predicted, TN (true negatives) represents the number of the non‐agonists that are correctly predicted, FN  is the number of agonists that are mistakenly predicted as non‐agonists, FP  is the number of the non‐agonists that are mistakenly predicted as agonists.For prediction of GPR40 agonists, we initially collected data records from ChEMBL and BindingDB, totaling 2038 data points, and curated 1689 GPR40 agonists and 175 non‐agonists from patents and literature. Next, we proposed an ensemble model for prediction of GPR40 agonists based on both ML and DL techniques. The architecture of the ensemble model can be classified as 3 layers. After optimizing each layer systematically, the ensemble model was significantly improved with an AUC‐ROC of 0.9496. The optimal architecture for the best ensemble model: using the top 20 baseline models as the models in layer 1, without binarizing probabilities in layer 2, and both a single hidden layer with 800 nodes and the Adam optimizer were used for the FCNN in layer 3. We believe that this work affords an ensemble model capable of accurately predicting GPR40 agonists and will contribute to the development of drugs for the treatment of diabetes.Our research also has limitations, which need to be addressed in the future. Currently, there are two types of GPR40 agonists that bind to different pockets due to the fact that different pockets of the protein may produce different functions: partial agonists and full agonists.24, 50https://github.com/Jiamin‐Yang/ensemble_model)The Supporting Information provides detailed information on various aspects including the data processing procedure, the GPR40 agonist and non‐agonist frameworks, principal component analysis of the training and external datasets using six molecular properties, AtomPairFP and MorganFP, information and sources of various molecular representations, a comparison of our ensemble model with the top 20 baseline models using various evaluation metrics, the impact of chiral fingerprints on the overall performance of the models, the influence of optimizer and hidden layer structure on FCNN performance, and additional information on the measurement of compound activity. All the data and models are opened via GitHub.  should be addressed to the authors.Supporting InformationClick here for additional data file.


The aim of this study was to use recent evidence to investigate and update volume–outcome relationships after open surgical repair (OSR) and endovascular repair (EVAR) of abdominal aortic aneurysm in England.Hospital Episode Statistics (HES) data from April 2006 to March 2018 were obtained. The primary outcome was in‐hospital death. Other outcomes included duration of hospital stay, readmissions within 30 days, and critical care requirements. Case‐mix adjustment included age, sex, HES year, deprivation index, weekend admission, mode of admission, type of procedure and co‐morbidities.P < 0·001) but not for EVAR (P = 0·169 for emergency and P = 0·363 for elective). The effect appeared to extend beyond 60 repairs per year to volumes above 100 repairs per year. There was no significant relationship between volume and duration of hospital stay or 30‐day readmissions. In patients receiving emergency OSR, higher volume was associated with longer stay in critical care.Annual volume of all repairs combined appeared to be an appropriate measure of volume. After case‐mix adjustment, a significant relationship between volume and in‐hospital mortality was seen for OSR (Higher annual all‐procedure volumes were associated with significantly lower in‐hospital mortality for OSR, but such a relationship was not significant for EVAR. There was not enough evidence for a volume effect on other outcomes. However, the definition of volume differed between studiesThere is variation in abdominal aortic aneurysm (AAA) care internationally, especially regarding AAA size thresholds for offering repair, and availability and use of endovascular options to treat AAA. A recent reviewversus OSR, elective versus all repairs) in more detail to identify the most relevant measure of volume and its impact on outcomes16. Current data show that there has been a major shift, and that most elective AAA repair is performed using EVAR, whereas OSR remains the main method of repair for ruptured AAA,,,There are several concerns, however, with the evidence from previous studies and the implications for minimum volume. The data used in most of these studies were from the first decade of the current millennium when most elective AAA repairs were undertaken using open surgical repair (OSR). Some studies using recent data have not investigated the type of volume (such as endovascular aneurysm repair (EVAR) The purpose of this study was to evaluate the impact of volume on outcomes in AAA surgery using more recent evidence from HES and improved methods. The impact of different definitions of volume on the results was examined. The volumes used to examine outcomes in this study included all repairs, elective repairs, emergency repairs, all EVAR and all OSR. The outcomes measured were in‐hospital mortality, duration of hospital stay, 30‐day readmissions and use of critical care in the index admission. The study reports on all repairs of infrarenal AAA from April 2006 to March 2018.,AppendixHES patient care data with linkages to national mortality data from 1 April 2006 to 31 March 2018 were acquired. Inpatient episodes for patients with AAA were extracted. The episodes were then sorted chronologically and grouped into continuous inpatient stays (CIPS). The CIPS was used to define a hospital admission for volume–outcome analyses. The index admission was defined as the admission where patients received their first AAA repair. The methods used to identify the different case‐mix groups, including elective, emergency intact and ruptured AAA, have been reported in previous studiesFor each HES year in the data set, the volume per hospital for the different types of AAA repair was calculated. The hospitals performing AAA repair were identified using provider and treatment site codes as well as the postcode of the treatment site. These codes were used to account for any variation in the data because of movement of sites or change in provider name. The problem of using the provider code only was that one provider could have multiple sites that provided vascular services over the years. A unique classification system was developed to accurately identify vascular sites at which AAA repairs were performed over the study period.It was necessary to account for the observed time trend in data on in‐hospital mortality  in the volume–outcome analysis. In addition, because of the substantial service reconfigurations that took place during the study interval, annual volume was used for each specific year rather than average annual volume across the years. In this way, the same vascular unit providing AAA repair could be observed to have different volumes across the years. The main volume measure comprised all repairs . Several alternative definitions of volume were tested, based on counting elective repairs only, emergency repairs only, OSR only and EVAR only.2 test was used to investigate the impact of volume on binary outcomes  and the Mann–Whitney–Wilcoxon test for continuous outcomes . Baseline differences between data quintiles are presented in Table S1 . Volume data are presented by quintiles. The data were divided into five equal portions so that each data group contained a similar number of observations. The short‐term outcomes were then summarized for each data quintile. Using the first quintile as the reference for comparison with the other quintiles, the χTable S1 .,AppendixThe volume and in‐hospital mortality relationship was first investigated without adjusting for confounding factors. Then logistic regression models were used to adjust for age, sex, HES year of data, deprivation index, weekend admission, mode of admission, type of procedure and co‐morbidities. Patient co‐morbidities were identified using a modified version of the Charlson co‐morbidity categoriesTable Between April 2006 and March 2018, a total of 72 022 patients had AAA repairs. The largest group comprised 28 656 patients who underwent elective EVAR (39·8 per cent). Some 21 694 patients had elective OSR (30·1 per cent), 15 953 had emergency OSR (22·2 per cent), and the smallest group included 5719 patients who had emergency EVAR (7·9 per cent). Table Fig. There was a total of 150 unique hospital sites (differentiated by postcodes) which performed at least five AAA repairs per year within the study interval. Through the time span, some sites were only active in a few years owing to service reconfiguration, and some new sites appeared. The number of active sites was 136 in 2006–2007 and 68 in 2017–2018. The total annual volume  of procedures at each site was counted for each HES year. Higher annual volume of AAA repair  was significantly associated with lower in‐hospital mortality after OSR (both elective and emergency); there was a trend with increasing benefit beyond the current recommended threshold of 60 repairs per year, which appeared to extend beyond 100 repairs per year. There was no statistically significant relationship between volume and in‐hospital mortality for EVAR (both elective and emergency).Table A consistent volume–outcome relationship was not observed for duration of hospital stay or 30‐day readmissions, although volume was associated with a slightly shorter hospital stay for elective operations above a volume of about 100 repairs per year. A statistically significant relationship between volume and duration of critical care stay in index admissions was observed for the emergency OSR group: higher volume was associated with higher critical care. Such a relationship was not observed in other case‐mix groups  and elective OSR . However, there was no significant relationship for emergency EVAR  or elective EVAR . OR values of less than 1·00 indicate a negative association between volume and in‐hospital mortality. The negative relationship means that, as volume increases, the odds of in‐hospital death decrease by a factor equal to the OR. A more intuitive illustration of these results is provided in AppendixAppendixTable P value was 0·060. The volume–outcome relationship following elective EVAR was not statistically significant across all definitions of volume. This suggests an absence of evidence for such a relationship. The volume–outcome relationship after emergency EVAR was not statistically significant across all definitions of volume, except for OSR‐specific volume; there was a significant association between higher OSR volume and lower EVAR mortality (P = 0·033).The impact of different volume definitions on the relationship between volume and in‐hospital mortality was analysed by changing the definition of the volume co‐variable in each regression model from all repairs to elective‐only and emergency‐only repair, and open or endovascular procedures. Different definitions of volume affected the volume–outcome relationship  between 2001 and 2008, hospital volume was minimally associated with in‐hospital mortality after EVAR, whereas no such association was observed for surgeon volume.In agreement with previous studies in the UK22 and from the most recent version of a document from the Vascular Society of Great Britain and Ireland28 on the provision of vascular services suggests that centres should perform a minimum of 60 AAA repairs per year. The evidence presented here suggests that there would continue to be improvements in outcome if this threshold were increased to above 100 repairs per year. This may be related to the increased proportion of patients treated by EVAR, which may limit experience in OSR. These findings are important and could help in updating national and international guidelines for service reconfiguration,,The present study also evaluated whether there is a volume threshold to guide service reconfiguration. Current guidance from the service specification for vascular servicesFor other short‐term outcomes – duration of hospital stay and 30‐day readmissions – there was not enough evidence for significant volume–outcome relationships, although volume seemed to be associated with a slightly shorter stay for elective procedures if the volume of repairs exceeded about 100 per year. Another finding is the statistically significant relationship between volume and duration of critical care in admissions after emergency OSR; higher volume was associated with longer critical care stay. This could be related to the lower mortality observed in higher‐volume centres, where more patients survived at the expense of greater critical care requirements. Such a relationship between volume and critical care was not observed in other case‐mix groups. The findings regarding overall duration of hospital stay and critical care use may have implications in relation to service reconfiguration and resource constraints.This study used improved methods for analysing administrative data for patients treated for AAA in the National Health Service (NHS) in England. The improved methods increased the validity of case identification and classification, as well as identification of sites. The EVAR procedures in this study were identified more completely than those in previous smaller studies. The study time frame covered a period of vascular services' reconfiguration in England that was driven by previous volume–outcome studies using the NHS administrative data set. The range of short‐term outcomes examined was also extended to include duration of hospital stay, 30‐day readmission and need for critical care.,23 and may be selecting patients with more complex anatomy for EVAR, and emergency data do not take account of selection that may take place in turning down patients for emergency procedures24. Although no relationship between volume and EVAR outcomes was observed, there may be competing effects as higher‐volume centres may be undertaking more complex EVAR procedures, a trend suggested by the recent National Vascular Registry report23. The recent increases in complex EVAR procedures, and differences in definitions between the National Vascular Registry and HES, require further investigation to understand the changes in patient selection and tertiary referrals, and the effect on cost and longer‐term outcomes. Emergency procedures (and elective ones to an extent) can also be confounded by turndown rates; only the effect on operated patients was evaluated here, and there is evidence of turndown rates being related to overall volumes and other factors, such as sex, with higher‐volume centres turning down fewer patients24.Case‐mix adjustment was made for possible factors that could influence outcomes, including age, sex, year of data, deprivation index, weekend admission, mode of admission, type of procedure, and co‐morbidities evaluated using a modified version of the Charlson co‐morbidity categoriesper se, associated with lower inpatient mortality, critical care use and duration of hospital stay, economic modelling suggests that the reduced initial resource use and health benefits of this may be outweighed by higher overall costs and poorer long‐term outcomes29. Future research should investigate these relationships further and examine factors beyond volume to improve the quality of AAA surgical services.This study only examined the relationships between volume and short‐term outcomes for patients who received repairs in hospitals; little is known about the impact of merging vascular centres and the effect that this has on long‐term outcomes, practice and patient selection. Although higher‐volume centres tend to have higher rates of EVAR, which are, znaa179_Supplementary_DataClick here for additional data file.


Estimates of species geographic ranges constitute critical input for biodiversity assessments, including those for the International Union for the Conservation of Nature (IUCN) Red List of Threatened Species. Area of occupancy (AOO) is one metric that IUCN uses to quantify a species’ range, but data limitations typically lead to either under‐ or overestimates (and unnecessarily wide bounds of uncertainty). Fortunately, existing methods in which range maps and land‐cover data are used to estimate the area currently holding habitat for a species can be extended to yield an unbiased range of plausible estimates for AOO. Doing so requires estimating the proportion of sites (currently containing habitat) that a species occupies within its range . Multiplying a quantification of habitat area by prevalence yields an estimate of what the species inhabits . For species with intense sampling at many sites, presence–absence data sets or occupancy modeling allow calculation of prevalence. For other species, primary biodiversity data (records of a species’ presence at a point in space and time) from citizen‐science initiatives and research collections of natural history museums and herbaria could be used. In such cases, estimates of sample prevalence should be corrected by dividing by the species’ detectability. To estimate detectability from these data sources, extensions of inventory‐completeness analyses merit development. With investments to increase the quality and availability of online biodiversity data, consideration of prevalence should lead to tighter and more realistic bounds of AOO for many taxonomic groups and geographic regions. By leading to more realistic and representative characterizations of biodiversity, integrating maps of current habitat with estimates of prevalence should empower conservation practitioners and decision makers and thus guide actions and policy worldwide. Quantifications of biodiversity and its change over time are key for answering outstanding questions in basic science and guiding policy regarding important applied issues   associations  Table  Brooks . AnalogoNevertheless, even with appropriate consideration of variables reflecting land cover, range maps typically lead to biased, implausible overestimates of the sites a species is projected to occupy. Species are absent from many currently suitable areas within their ranges for a variety of reasons. These include hunting and overharvesting, unconsidered biotic interactors, inadequate patch size, high isolation of patches, and environmental and population‐demographic stochasticity. Accordingly, IUCN guidelines call for considering the proportion of habitat that the species is projected as very likely to occupy IUCN, . HoweverUnbiased values of AOO can be achieved by estimating a species’ prevalence and using that information to extend existing methods that quantify current habitat Figure . The IUCencounter rate) will be biased—lower than reality—for species that are hard to detect; such biases falsely indicate species as rarer than they really are  Figure . In the In the third case of groups of species where sampling not only has low spatial density but also varies in intensity across sites, future methodological development merging information from inventory‐completeness analyses could allow the use of data from citizen‐science initiatives and the research collections of natural history museums and herbaria  lists of the particular species observed and the level of inventory completeness . Prevalence (including information regarding detectability) generally is estimated at the scale of a site. Hence, before being used to convert the quantification of habitat area into AOO, estimates of prevalence must be transformed from the proportion of sites occupied into the proportion of 2×2 km cells occupied. With extremely dense sampling (many sites in each 2×2 km grid cell), even low values of site‐level prevalence will correspond to 100% grid‐cell prevalence, a strong mismatch between scales. At the other extreme, with sparse sampling (the vast majority of 2×2 km cells lacking any sampling), site‐level prevalence will approximate that of grid cells. Fortunately, the species most needing consideration of prevalence  correspond to the latter situation in which estimates of prevalence at the site‐ and grid‐cell scales converge.Heteromys teleus) is a forest‐restricted species occurring in a region with high deforestation and sparse biological sampling  to 18,544 km2 as an upper bound provided by a habitat‐masked range map from a statistical model (with uncharacterized uncertainty) . However, it surely underestimates the lower bounds of AOO, given the extremely low spatial density of sampling in the region. In contrast, the upper‐bound estimate would correspond only to near‐threatened (B2). Although prevalence and detectability for H. teleus remain unknown, the species has not been observed frequently via sampling in suitable areas . However, a moderately higher hypothetical value of 0.30 (and 90% CI of 0.25−0.35) would generate an AOO best estimate of 5563 km2 and a plausible range of 4636−6490 km2, far above the threshold for any threatened category.The prevalence‐based conversion method could improve the assessment of  B IUCN,   illustrates the value of stratifying calculations by suitability level. A comparison of suitable areas before and after masking by forest cover indicates a 53% decline, which would (barely) qualify the species as endangered . However, most deforestation within the species’ range has affected extensive areas of low modeled suitability (Kass et al., In comparison with current methods for calculating AOO, two general tendencies should emerge with the prevalence‐based conversion of areal quantifications derived from habitat‐masked range maps Figures . First, Although most of the underlying methodologies highlighted here already exist, widespread implementation of the prevalence‐based conversion method will involve surmounting challenges related to methodological development as well as data quality and availability. For some taxonomic groups and geographic regions, appropriate data from high‐intensity sampling allow immediate use. For others, where sampling intensity varies greatly, future development is needed to calculate detectability based on primary biodiversity data and inventory‐completeness analyses. In addition, the conservation need for IUCN Red List assessments provides tangible justification for investments to improve the quality and availability of online primary biodiversity data. Relevant efforts include ongoing digitization, further georeferencing, and improved taxonomic identifications—with quantifications of the uncertainty associated with the latter two (Anderson et al., Such analytical and data‐related advancements for biodiversity conservation should also promote a positive feedback loop with basic science. Improved range estimates would facilitate many uses in macroecology and biogeography and applications to other problems of importance to society, for example, invasive species and zoonotic diseases (Graham et al.,


However, the practical application of photocatalyst‐promoting CRR  requires significant improvement of their conversion efficiency. Accordingly, extensive research is being conducted toward improving semiconductor photocatalysts, as well as cocatalysts that are loaded as active sites on the photocatalysts. In this review, we summarize recent research and development trends in the improvement of cocatalysts, which have a significant impact on the catalytic activity and selectivity of photocatalytic CRR. We expect that the advanced knowledge provided on the improvement of cocatalysts for CRR in this review will serve as a general guideline to accelerate the development of highly efficient CRR photocatalysts.Suppressing the amount of carbon dioxide in the atmosphere is an essential measure toward addressing global warming. Specifically, the photocatalytic CO Catalytic CRRiteria: This review summarizes recent research and development trends in the improvement of cocatalysts, which have a significant impact on the catalytic activity and selectivity of photocatalytic carbon dioxide reduction reaction (CRR). It provides advanced knowledge on the improvement of cocatalysts for CRR, serving as a general guide to accelerate the development of highly efficient CRR photocatalysts. In addition, given the current situation in which it is not possible to promptly and completely stop the use of fossil fuels and shift to a society that uses alternative greener fuels  as its energy source, it is essential to establish means to reduce CO2 concentration in the atmosphere in parallel with reducing the use of fossil resources. As a strategy to reduce atmospheric CO2 concentration, a technology to capture and bury emitted CO2 underground has been established and is currently being applied. Alternatively, as a more efficient strategy, the emitted CO2 could be recycled (carbon cycle) through its conversion into carbon monoxide (CO) and organic compounds . The use of fossil fuels generates nitrides and sulfides, which are harmful to the ecosystem, cause air pollution, and increase greenhouse gas emissions , which ultimately lead to climate change. Therefore, reducing the use of fossil fuels and thereby suppressing CO2 to useful compounds (CO2 reduction reaction (CRR)), photochemical reduction using sunlight and water (H2O) and electrochemical reduction using H2O are attracting attention as clean and sustainable technologies. However, between these two technologies, photochemical reduction, termed artificial photosynthesis, is more advantageous as it does not require complex device design or detailed components and it is therefore less expensive to implement. Consequently, photochemical methods are gaining more interest as an environmentally sustainable means of CRR. However, high conversion efficiencies from sunlight are yet to be achieved for CRR by artificial photosynthesis,To reduce CO1.2−) with reduction power and excited holes (h+) with oxidizing power  surface atoms and electronic states are created that are suitable for adsorption and desorption of the substrate, thereby improving the reactivity and selectivity of CRR. In addition, loading of the cocatalyst is effective in preventing self‐deactivation of the photocatalyst caused by its reducing or oxidizing power, thereby improving the durability of the photocatalyst.In CRR, semiconductor photocatalysts absorb light energy and generate excited electrons  and is therefore a very stable molecule. As CO2 is more energetically stable than methanol , methane , or ethylene , the CRR process is an uphill reaction and reduction is thus difficult to proceed. Limitation 2 is related to the fact that the reduction potentials of CO2 and H2O are comparable to each other. This causes a competitive H2 evolution reaction (HER) to occur, in which H2O is reduced to H2, in parallel with CRR, making it difficult to only obtain the desired CO2‐reduced species with a high selectivity  and other substances produced in O2 evolution reaction (OER) are present in the system, a reverse reaction to CO2 can also occur upon reaction of these products and substances. Limitation 3 is related to the fact that there are various reducing species of CRR , formaldehyde (HCHO), acetic acid, CH4, and C2H4). Once such mixtures are obtained, their separation requires a great amount of energy. To overcome these challenges and realize artificial photosynthesis with high efficiency, high selectivity, and high durability, it is essential to improve the cocatalyst.Currently, the CRR process has the following limitations: 1) the reaction is difficult to proceed; 2) side reactions and reverse reactions are likely to occur; and 3) the selectivity of the reduction products is low. Limitation 1 is related to the fact that COy Figure . In addi1.3As described above, the improvement of cocatalysts plays an important role in the engineering of highly functional photocatalysts. Therefore, we have conducted extensive research on improving the cocatalysts on photocatalysts.In Section 2, the mechanism of CRR with semiconductor photocatalysts is described in detail, followed by a discussion on the characteristics and types of semiconductor photocatalysts used in CRR in Section 3. In Section 4, we describe examples of previous studies and findings on controlling the properties of cocatalysts, which is the subject of this review. Section 5 provides a summary of insights gained to date and an outlook on future prospects in this area.The focus of the present review is on the control of cocatalyst particles in CRR using semiconductor photocatalysts. Therefore, readers interested in improving CRR photocatalysts using surface plasmon resonance,22.12O or in a vapor atmosphere. CRR proceeds according to the following three major steps  and excited h+ in the valence band (VB); Step 2) the excited e− and h+ diffuse to the photocatalyst surface and, when a cocatalyst is present, further migrate to the cocatalyst; and Step 3) CRR [Eqs. (1)–(5)] or OER [Eq. (6)] proceeds on the cocatalyst or on the photocatalyst surface.Photocatalytic CRR generally proceeds in Hs Figure :. This is because of the high stability of CO2 that requires a large reducing power of −1.9 eV ; at pH 7) for its conversion into an anion radical species. Such a large reduction power is difficult to generate with visible‐light‐driven semiconductor photocatalysts. In contrast, in multi‐electron reactions using H+ [Eqs. (1)–(5)], HCOOH, CO, HCHO, CH3OH, and CH4 are the reaction products. The reduction potential required for these reactions to proceed is much lower than that in one‐electron reactions . Therefore, most CRR processes that employ semiconductor photocatalysts are designed as multi‐electron reaction systems using H+.In a typical CRR, a proton (H2.22. OER proceeds when the VB maximum edge (VBM) of the semiconductor photocatalyst is more positive than the oxidation potential of H2O  accounts for about 43 % of sunlight. Therefore, it is indispensable to make effective use of sunlight using photocatalysts with small BGs, which can absorb visible light , for engineering semiconductor photocatalysts with high efficiencies. However, it is difficult to achieve appropriate CBM and VBM positions simultaneously in such semiconductor photocatalysts. Therefore, only a limited number of one‐step photocatalytic materials  of the semiconductor photocatalyst is more negative than the reduction potential of COO Figure . Controls Figure  that can− and h+; Figure In contrast, CRR can also proceed according to a two‐step reaction mechanism involving a semiconductor photocatalyst capable of instigating both CRR and OER. These reactions function by combining a photocatalyst, which causes CRR and OER, and a redox couple (mediator), which is responsible for the transfer of excitons (e33N4),Since Honda and colleagues reported using a semiconductor for CRR in 1979,2 form a strong bond, metal oxides are highly stable in air and H2O. Therefore, metal oxides are often used as photocatalytic materials for the fabrication of semiconductor photocatalysts. Among the range of metal oxides available, those containing d0 metal elements , zirconium ion (Zr4+), niobium ion (Nb5+), tantalum ion (Ta5+), vanadium ion (V5+), tungsten ion (W6+), and cerium ion (Ce4+)) and d10 metal elements , indium ion (In3+), gallium ion (Ga3+), germanium ion (Ge4+), tin ion (Sn4+), and antimony ion (Sb5+)) can function as CRR photocatalysts . e Figure . The obt3 ⋅ xH2O/AgNPs/Ga2O3 was prepared at Ag : Cr ratios of 1 : 1 and 2) the highest CO evolution rate (525.3 μmol h−1) and selectivity (85.2 %) were obtained for photocatalysts loaded with Ag and Cr both at 0.25 wt%. Examination of the chemical composition and shape of the Cr shell on the photocatalyst revealed that Cr(OH)3 ⋅ xH2O was transformed to Cr(OH)x(CO3)y during the photocatalytic reaction  surfaces are suitable cocatalysts for CRR. In the PtCu alloy cocatalyst, exposure of the PtCu(730) surface leads to highly efficient and selective CHSuppression of the competing HER or the reverse reaction improves the activity and selectivity of CRR. In particular, the formation of shell layers can be effectively used to suppress these reactions.Given the knowledge gained to date, further areas remain to be explored, as summarized below, to guide the development of future CRR photocatalysts.CRR is a multi‐electron reaction that employs several electrons simultaneously, and a longer charge separation lifetime contributes significantly to the activity. It is expected that the carrier lifetimes of various photocatalysts will be elucidated by fluorescence lifetime measurements, TA spectroscopy,Previous studies have demonstrated that the catalytic activity can be enhanced when cocatalysts are loaded on suitable crystal facets for the reduction and oxidation reactions.46 ThereIt is expected that the geometric structure of highly active and selective cocatalysts will be revealed at the atomic level by aberration‐corrected TEM and STEMAtomically precise metal nanoclusters (NCs),DFT calculations are important for understanding the rate‐limiting step of a reaction.It is expected that researchers in the field of photocatalysis, as well as those in the fields of metal NC chemistry,2 increases year by year, the current state of the art is uneven. Namely, of the previous studies, some do not satisfy the requirements of the field of photocatalytic conversion of CO2. The important requirements are as follows: 1) isotope experiments should show the carbon source of the reduction product to be CO2 (not contamination); 2) the competing H2 production must also be analyzed accurately, and the number of excited electrons consumed in the production of the CO2 reduction products must be greater than those in H2 production; 3) the oxidation product  must be analyzed accurately, and the ratio of excited electrons to holes consumed in the reaction must be 1. In future studies, these requirements are expected to be inevitably satisfied to avoid misunderstanding and thereby establish clear design guidelines for high‐performance CRR photocatalysts.Although the number of published papers on the photocatalytic conversion of COThere are no conflicts to declare.6Tokuhisa Kawawaki is a Junior Associate Professor in the Department of Applied Chemistry at Tokyo University of Science. He received his Ph. D. degree in applied chemistry from the University of Tokyo in 2015. In 2016, he worked as a Japan Society for the Promotion of Science (JSPS) postdoctoral fellow at the University of Melbourne. He then worked as a JSPS super postdoctoral fellow at Kyoto University. In 2019, he moved to his current University. His current research topics include the synthesis of metal nanoparticles and nanoclusters in solution and their application in photoelectrochemistry and photocatalysis.Yuki Akinaga is a masters student in the Negishi group at Tokyo University of Science. He received his B. Sc. degree in chemistry from Tokyo University of Science in 2021. His main research focuses on the development of high‐performance water‐splitting and CRR photocatalysts using metal clusters and single atoms as cocatalysts.Daichi Yazaki is a masters student in the Negishi group at Tokyo University of Science. He received his B. Sc. degree in chemistry from Tokyo University of Science in 2021. His main research interest is the development of high‐performance water‐splitting photocatalysts using atomically precise metal clusters as cocatalysts.Hinano Kameko is a masters student in the Negishi group at Tokyo University of Science. She received her B. Sc. degree in chemistry from Tokyo University of Science in 2022. Her research focuses on the development of high‐performance water‐splitting and CRR photocatalysts by using metal clusters and single atoms as cocatalysts.Daisuke Hirayama is a masters student in the Negishi group at Tokyo University of Science. He received his B. Sc. degree in chemistry from Tokyo University of Science in 2022. His main research interest is on the development of high‐performance water‐splitting photocatalysts by using atomically precise metal clusters as cocatalysts.Yuichi Negishi is a professor in the Department of Applied Chemistry at Tokyo University of Science. He received his Ph. D. degree in chemistry in 2001 under the supervision of Prof. Atsushi Nakajima from Keio University. Before joining Tokyo University of Science in 2008, he was employed as an assistant professor at Keio University and at the Institute for Molecular Science. His current research interests include the precise synthesis of stable and functionalized metal nanoclusters for use in energy‐ and environmental‐related application areas.


The occurrence of a large pericardial effusion is not a commonly noted adverse event associated with pembrolizumab and our report demonstrates that a rapid development can be diagnosed with close monitoring and triage to acute medical settings.Pembrolizumab is an immune checkpoint inhibitor used in various types of cancers. Pericardial tamponade is a rare side effect reported in only very few case reports. Early recognition and therapeutic intervention is vital in all cases. We report a case of a 54‐year‐old male with Stage 3 lung adenocarcinoma who developed cardiac tamponade secondary to pembrolizumab and subsequently required pericardial window. More specifically, it is a monoclonal antibody targeted against programmed death receptor‐1 (PD‐1) on lymphocytes.2A 54‐year‐old male with unresectable Stage 3 non‐small cell lung cancer (NSCLC) adenocarcinoma (T3N3) of the right upper lobe of the lung (PD‐L1 30% positive), diagnosed 3 months prior, started on carboplatin, pemetrexed, and pembrolizumab therapy with the third cycle completed 17 days prior to admission, presented to the emergency department (ED). His visit was prompted by a critical finding found on computerized tomography (CT) scan of the chest performed for monitoring of disease progression as an outpatient and for evaluation of 3 days worsening dyspnea. The patient was ultimately instructed to present to the ED by his oncologist after the imaging revealed a large pericardial effusion Figures .On arrival, vital signs revealed a temperature of 97.4°F, a heart rate of 89 beats per minute, a respiratory rate of 24 breaths per minute, a blood pressure of 128/38 mmHg, and an oxygen saturation of 100% on 2 L nasal cannula. An electrocardiogram revealed sinus tachycardia with low voltage QRS intervals throughout  in a meta‐analysis performed on 5090 patients.The incidence of irAEs from pembrolizumab resulting in death was found to be 0.89 (95% CI, 00.49; 1.62, Previous case reports of pembrolizumab‐induced pericardial effusion causing cardiac tamponade in the literature were first reported in 2016 with most cases requiring pericardiocentesis, pericardial window, withdrawal of pembrolizumab, and steroid treatment.Pericardial effusion secondary to an immune checkpoint inhibitor such as pembrolizumab is also a diagnosis of exclusion. The diagnosis is nested primarily in a temporal relationship between the onset of symptoms and the initiation of the agent, the absence of another identifiable causes, and resolution once the agent has been discontinued.Additionally, a biopsy of the pericardium revealed only minimal chronic inflammation on histopathological assessment with no evidence of malignant cells, suggesting the process was acute and unrelated to involvement by the patient's malignancy. The pericardium also stained negative for TTF‐1 and CK7, which also further supports evidence against a carcinogenic etiology of the effusion.Unfortunately, the exact pathophysiologic mechanism behind this patient's irAE remains unclear and no gold standard diagnostic test exists to aid the diagnosis, but further descriptions of pembrolizumab‐induced cardiac tamponade in the literature may eventually detail the pathologic process definitively in the future and lead to the development of such a modality.Furthermore, only after considering the time frame, lack of evidence for more common etiologies of cardiac tamponade and the absence of pericardial effusion recurrence with withdrawal of pembrolizumab has this diagnosis of pembrolizumab‐induced cardiac tamponade been reached as a diagnosis of exclusion.4In conclusion, as immune checkpoint inhibitors increasingly become the mainstay of treatment for a growing number of cancers, so should an increased level of awareness with regard to possible life threatening irAEs. The occurrence of a large pericardial effusion is not a commonly noted adverse event associated with pembrolizumab and our report demonstrates that a rapid development can be diagnosed with close monitoring and triage to acute medical settings. However, more common additional diagnoses must be ruled out including infection, trauma, metastasis, and acute cardiac dysfunction before considering this diagnosis. Henceforth, imaging patients prior to the use of pembrolizumab could possibly be a preventive strategy to avoid this potentially lethal sequalae. However, more defined guidelines for significant effusions, time frame of development of the effusion and indications for definitive withdrawal of the checkpoint inhibitor must be further identified in a coordinated clinical trial setting. Therefore, in the interim, if clinical criteria alongside radiographic evidence correlates with a life threatening irAE such as cardiac tamponade, all measures should be taken to discontinue the offending agent and coordinate surgical intervention.Dariusz Uczkowski: Conceptualization; writing – original draft; writing – review and editing. Hamza Ashraf: Conceptualization; writing – original draft; writing – review and editing. Arunabh Sekhri: Formal analysis; investigation; supervision; writing – review and editing. Arbaz Samad: Data curation; resources; supervision; validation.No financial support was necessary for the preparation of this manuscript or acquiring data.All authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Extensive resection of the infected calcified annulus and the reconstruction with a pericardial patch for the debrided annulus is an effective surgical option for the treatment of infectious endocarditis in patients with mitral annular calcification.A 78‐year‐old woman was referred to our hospital because of left‐sided hemiparesis. During the treatment for cerebral infarction, the patient became feverish and lost consciousness. Transthoracic echocardiography revealed mitral annular calcification and a tumor‐like mass on the posterior leaflet despite no findings of mitral regurgitation. She underwent successful mitral valve replacement with debridement of the infected mitral annulus and reconstruction of the posterior annulus (annuloplasty) with bovine pericardium after removal of the mitral annular calcification. There was an inhomogeneous mass with calcification attached to the posterior annulus, which caused the embolization and it was considered for surgical intervention. Magnetic resonance imaging (MRI) of the brain revealed multiple cerebral infarctions in the right hemisphere. The source of embolization was atrial fibrillation at that time; therefore, a direct oral anticoagulant was initiated. She had no murmurs on auscultation and was afebrile. On Day 16 of cerebral infarction treatment, she suddenly became feverish and lost consciousness. Antibiotic treatment started 11 days before the surgical treatment. Brain MRI showed only an atypical small cerebral hemorrhage. Transthoracic echocardiography revealed MAC and a tumor‐like mass on the posterior leaflet; however, there was no evidence of mitral stenosis or regurgitation Figure .Cardiopulmonary bypass was performed through ascending aortic cannulation and bicaval drainage. Cardiac arrest was achieved with aortic cross‐clamping and the administration of blood cardioplegia. Mitral valve exposure was achieved through a superior transseptal approach. A friable mass was observed on the posterior annulus, which included a severely calcified bar Figure . The mas3MAC is known to be associated with cardiovascular events and mortality. The Framingham Heart Study demonstrated that MAC was associated with an increased risk of incident cardiovascular disease (hazard ratio [HR] 1.5), cardiovascular mortality (HR 1.6), and all‐cause mortality (HR 1.3).There are several surgical treatment methods for patients with MAC, including mitral valve surgery (repair or replacement), with or without annular calcium debridement, and edge‐to‐edge repair. It is generally considered that debridement of the MAC may lead to cardiac rupture at the atrioventricular junction and circumflex artery injury. However, some surgeons consider that complete resection of debris and reconstruction of the annulus are essential for the treatment of endocarditis in patients with MAC.4MAC was the most conceivable cause of endocarditis and cerebral infarction in this case. Extensive resection of infected calcified annulus is a surgical option for the treatment of infectious endocarditis in patients with MAC. And the postoperative use of the IABP is a considerable option for the prevention of left ventricle rupture after extensive resection of infected calcified annulus.Tatsuya Horibe: Writing – original draft. Hideaki Hidaka: Writing – review and editing. Ryosuke Numaguchi: Writing – review and editing. Jun Takaki: Writing – review and editing. Kosaku Nishigawa: Writing – review and editing. Takashi Yoshinaga: Writing – review and editing. Toshihiro Fukui: Writing – review and editing.The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


The interplay of students’ ethnic and national identity moderated the relationship of social identity threat and sense of belonging. The relationship was particularly negative for students who endorsed either ethnic or national identity. However, it was less negative for students with integrated multiple social identities and non-significant for students who identified neither with the ethnic nor the national group. Results generalized for social approach motivation towards ethnic majority and minority classmates. These patterns were only found for social approach motivation in face-to-face contact situations, but not in online situations. We discuss these findings in light of the literature on social identity threat and multiple social identities. Practical implications include measures to foster students’ sense of belonging and to reduce social identity threat.The integration of ethnic minority youth can only be successful if they are motivated to establish and maintain social relationships in important institutions such as school. At the same time, worries about negative stereotypes about one’s ethnic group can undermine ethnic minority students’ motivation to approach others. In the present study, we tested whether social identity threat predicts ethnic minority adolescents’ social approach motivation via reduced sense of belonging. We also examined whether multiple social identities  buffer against the negative effects of social identity threat. In a sample of 426 ethnic minority students from 36 9 Germany is a multicultural country and ethnic heterogeneity is present in the educational system as approximately 40% of children and adolescents below the age of 15 have a migration background . Concerning motivation to approach ethnic minority members, two opposing predictions can be made. On the one hand, the negative effect of social identity threat might not extend to ethnic minority members, as minority members turn towards ethnic ingroup members in the face of possible social rejection by majority members  interactions with ethnic minority vs. majority members  and (b) face-to-face vs. online interactions . Concerning group membership, studies on ethnic homophily have shown that people tend to befriend others who are culturally similar to themselves  and their ethnic group of origin . The interaction of ethnic and national identity moderates the relationship of social identity threat and sense of belonging. The relationship is non-significant for students with a strong ethnic and a strong national identity (H2). We explore whether social approach motivation differs towards ethnic minority vs. majority members and in face-to-face vs. online contact situations. We explore to which extent sense of belonging to the class and the school, or perceived acceptance by teachers play a mediating role in the relationship between social identity threat and social approach motivation. Because we assess social approach motivation towards peer students within the classroom, we expect that sense of belonging to the class plays a stronger mediating role than sense of belonging to the school or perceived acceptance by teachers. The pre-registration, materials, data, and analysis scripts are available on the Open Science Framework ) and dual identity  = 5.33, p < .001, d = 0.27, 95% CI ). Dual identity was endorsed more strongly than national identity (t(382) = 11.45, p < .001, d = 0.58, 95% CI ). Exploratory investigation of the interrelations of multiple social identities showed that ethnic identity was not significantly associated with both national and dual identity, whereas national and dual identity were positively associated.Descriptive statistics and bivariate correlations are depicted in Table To examine H1 – sense of belonging mediates the relationship of social identity threat and social approach motivation – we computed a path model with indirect effects including social identity threat as the predictor variable, sense of belonging to class as the mediator, and the four measures of social approach motivation  as the outcome variables. As a measure of social approach motivation towards ethnic minority members, we computed the mean of social approach motivation towards students from one’s own group of origin and social approach motivation towards students with other non-German backgrounds in the class, as 30% of the sample indicated that there were no other students with the same group of origin than themselves in their class. We therefore opted for averaging the items targeted towards students of one’s own culture of origin and students of other non-German groups of origin as the best approximation for social approach motivation towards ethnic minority members.The path model was fully identified as all possible direct and indirect effects of social identity threat on the four measures of social approach motivation via sense of belonging were included. Results Table  showed tp < .001, CFI = 0.94, TLI = 0.88, RMSEA = 0.10, SRMR = 0.09. Modification indices suggested that fit could be improved by including direct paths from ethnic identity and national identity to the four outcome variables of social approach motivation. These additional direct effects were included in a modified model, which showed good model fit (χ²(16) = 25.31; p = .065, CFI = 1.00, TLI = 0.99, RMSEA = 0.04, SRMR = 0.03). Results are displayed in Table To examine H2 – the interaction of ethnic and national identity moderates the relationship of social identity threat and sense of belonging – we computed a moderated mediation path model by introducing ethnic and national identity as well as all two-way interactions and the three-way interaction with social identity threat on sense of belonging as additional paths. All predictors involving the interactions were standardized. Fit indices for this model showed insufficient fit, χ²(24) = 133.92; Simple slopes analyses Fig.  revealedThe current research investigated the indirect relationship of social identity threat with social approach motivation for ethnic minority adolescents in German secondary schools. Results replicated previous findings with ethnic minority adults in Norway showing an indirect effect of social identity threat on social approach motivation via reduced sense of belonging  indirect effect was not significant. Although online interactions with peers are frequent  were also susceptible to the consequences of social identity threat in the social domain. Only identifying with the cultural group of Germans and not with the ethnic culture of origin might represent a strategy of social mobility . However, the effect size was smaller than for students endorsing one identity strongly and the other one weakly. Compared to results from Froehlich et al.  with aduResults of the current study have implications for schools and educational practice. There are several routes through which ethnic minority students can be supported in order to reduce ethnic disparities based on stereotypes and stereotype threat. One route would be to decrease the salience of ethnic group memberships and the activation of ethnic stereotypes in the school context. For example, teachers could contribute to blurring ethnic group boundaries by creating a common ingroup identity among students for example as members of the same school or classroom , contexts  and methods (experiments and surveys), results for the direct effect of social identity threat on social approach motivation were mixed with sometimes negative and sometimes positive relationships (Froehlich et al., Peer relationships are relevant for the educational success of ethnic minority students from negatively stereotyped countries of origin Raabe, , who und


Adverse events are a key issue when considering the prescription of medications for children with cerebral palsy. The study by Li et al. is the first large study of adverse events following injection of Lanbotulinumtoxin‐A in children with cerebral palsy (CP). The rate of adverse events following injection of Lanbotulinumtoxin‐A was similar to that following injection of Onabotulinumtoxin‐A (aka Botox) at 12% versus 14% respectively.These findings are important because Lanbotulinumtoxin‐A is significantly cheaper than Onabotulinumtoxin‐A. The costs of botulinum neurotoxin‐A have posed a significant restraint on the use of the neurotoxin in many countries. The availability of a less‐expensive neurotoxin‐A product with a comparable safety profile is potentially good news for children with CP and their parents/guardians who may pay for toxin injections in some jurisdictions, as well as for global healthcare funding systems looking to constrain or reduce pharmaceutical costs. However, this simple conclusion is not based on clinical outcomes data.Clinically relevant outcome measures were not included in this study by Li et al., who investigated adverse events in isolation. Current literature shows that it is becoming as difficult to find a black cat in a dark room as to demonstrate objective, clinically verifiable, positive outcomes from botulinum toxin therapy in children with CP.The most frequently injected muscles sites in the Li et al. study were gastrocnemius and soleus.In a more recent study, Schwartz et al. estimated the short‐term effectiveness of 13 common orthopaedic and neurological treatments at four different levels of outcome in children with CP.When outcomes are subjective, such as goal attainment scaling, or if spasticity is inappropriately linked as a causal factor in activity or participation restrictions, the benefits of neurotoxin injections may be overestimated. When objective gait laboratory measures are used, the benefits of neurotoxin injection are undetectable or insignificant.This study confirms a comparable safety profile between Lanbotulinumtoxin‐A and Onabotulinumtoxin‐A for children with CP. As Lanbotulinumtoxin‐A provides a cheaper alternative, it may become more widely available. This is an opportunity to design robust studies with objective, verifiable, and clinically meaningful outcomes.


This hiThis valve was developed for the treatment of aortic insufficiency and to serve as a prototype to test the possibility that a valvular prosthesis would satisfactorily function within the cardiovascular system.”As Hufnagel himself stated: “The operation to implant the Hufnagel prosthesis was performed through a standard posterolateral thoracotomy incision through the 5th intercostal space with the patient placed in the right lateral decubitus. As described by Hufnagel himself, the prosthesis was implanted in the descending aorta just below the takeoff of the left subclavian artery.Hufnagel reported in 1976 a series of 5 patients operated between 1953 and 1959.In 1975, Fishbein and Roberts described the clinical and pathological observations in 2 patients who died between 11 and 13 years following implantation of a Hufnagel prosthesis.all of the aortic leaks” because the poorly functioning native aortic valve remained untouched; nevertheless, in many patients clinical improvement occurred even at long‐term follow‐up.The Hufnagel caged‐ball prosthesis was viewed more like an aortic‐assist device, since it did not replace the aortic valve, but was mainly designed with the aim of assisting patients with significant aortic valve incompetence; indeed, it reduced significantly aortic regurgitation but could not completely control “Interestingly, 40 years later, the Hufnagel principle was revitalized by Cale et al.The first aortic and mitral caged‐ball mechanical prostheses were implanted in orthotopic position in 1960 and dramatically changed the outlook of patients with cardiac valve disease.The authors declare no conflict of interest.


Biodiversity data records contain inaccuracies and biases. To overcome this limitation and establish robust geographic patterns, ecologists often curate records keeping those that are most suitable for their analyses. Yet, this choice is not straightforward and the outcome of the analysis may vary due to a trade‐off between data quality and volume. This problem is particularly recurrent for less‐studied groups with patchy sampling effort. The latitudinal pattern of mosses richness remains inconsistent across studies and these may emerge purely from sampling artefacts. Our main objective here is to assess the effect of different curation criteria on this spatial pattern in the Temperate Northern Hemisphere (above 20° latitude). We contrasted the geographical distribution of moss species records and the latitude‐species richness relation obtained under different data curation scenarios. These scenarios comprehend five sources of taxonomical standardisations and eight data cleaning filters. The analyses are based on the selection of well‐surveyed cells at 100 km cell resolution. The application of some ‘data curation scenarios’ severely affects the number of records selected for analysis and substantially changes the proportion of richness per cell. The sensitivity to data curation becomes detectable at regional and at the cell scales showing a large shift in the latitudinal richness peak in Europe, from 60° N to 45° N latitude, when only preserved specimens are selected and duplicates based on date of collection and coordinates are excluded. Our results stress the importance of justifying the criteria used for filtering biodiversity data retrieved from biodiversity databases to avoid detecting misleading patterns. Curating records under particular criteria compromises the information in some areas displaying different spatial information of mosses. This problem can be ameliorated if data filtering is combined with identifying well‐surveyed cells, render relatively constant results under different combinations of filtering even for less well‐known groups such as mosses. To overcome any biodiversity data limitation and establish robust geographic patterns, ecologists have to curate records. However, the application of some ‘data curation scenarios’ may severely affect the number of records selected for analysis and substantially changes the proportion of richness per cell. This study stresses the importance of justifying the criteria used for filtering biodiversity data retrieved from biodiversity databases to avoid detecting misleading patterns. HoweverSome challenges come from the dynamic nature of the species nomenclature which usually entails an overdescription in highly surveyed areas, different taxonomic treatments between regions or alternative spellings between databases , a relatively poorly studied group of non‐vascular plants that has been unevenly sampled across regions  To what extent do different baseline data used for standardising species names affect the observed spatial patterns of species richness?; (2) To what extent do the geographical distribution of the number of records and species change using different criteria for filtering by (i) duplicate records, (ii) basis of records (i.e. field observation or existence of herbarium voucher) and (iii) temporal coverage; (3) To what extent do different filtering criteria affect the spatial coverage of well‐sampled cells?; (4) How do data curation scenarios affect the observed latitudinal gradient of richness at both regional and across study area?22.1https://www.gbif.org/), Consortium of North American Bryophyte Herbaria . We then retained those records placed in the same country referenced in ‘countryCode’ field  or nearby the country border. Finally, we discarded records placed in country centroids, nearby GBIF headquarters in Copenhagen or biodiversity institutions  covering our study region. The area was divided into three regions corresponding to North America, Europe and North Africa  and Asia. We generated 49 latitudinal bands dissolving each row from the grid (hereby numbered from ‘1’ to ‘49’ towards north) , World Flora Online , Missouri Botanical Garden's Tropicos database  using TNRS web application setting ‘Tropicos’ option and Taxonomic Name Resolution Service . This procedure resulted in five different lists of accepted species names (shortened to only genus and specific epithet). We created a consensus species list from them as a conservative way to avoid taxonomic conflicts between those lists. Only those species names presented in at least three out of the five lists were selected generating the ‘taxConsensus’ dataset.After pre‐processing the records, we extracted a list of unique scientific names . We standardised all names using five commonly used taxonomic databases for nomenclatural standardisation and harmonisation of plants , we quantified the proportion of species names observed by cell for each of the five taxonomic databases compared with the consensus list. We also calculated for each taxonomic database and region the proportion of cells for which the number of species names decrease, increase or remain unchanged compared with the consensus list.2.3We selected eight filters generating the corresponding subsets from the ‘taxConsensus’ dataset. These filters have been used previously in ecology studies Table . They de2.4We calculated the inventory completeness with the ‘KnowBR’ package  can be considered well‐sampled after applying at least one of the eight cleaning filters proposed  Figure . Remarka4The criteria used to clean species occurrence records of mosses have a significant impact on the final data used in analyses and the associated results. Further, such impact may vary depending on the region or the temporal and spatial scale considered. Severe loss of information on the perceived species richness occurred at small scale, but it did not impact the large‐scale perception of latitudinal gradient considering well‐surveyed cells. The selection of source for taxonomic standardisation and data cleaning filters  presented a trade‐off between getting suitable data and the limited number of records available with these characteristics. Our results showed that publicly available data on mosses is unevenly distributed across the temperate region of the Northern Hemisphere, a pattern that was also observed in previous studies with other groups . In this region, most of the information was recorded as observations. Thus, selecting only preserved specimens shifted the peak of richness from ~60° N of latitude towards the south to ~45° N Figure . FilteriAnother crucial aspect to consider when filtering records is the selection of a particular temporal coverage. Data‐driven uncertainty increases as records get older  is often challenging. Therefore, all the ‘data curation scenarios’ chosen for analysing the latitudinal gradients of richness filters records with the same date of collection, coordinates and species name.We showed that observed species richness by region or cell is sensitive to the choice of the reference baseline data by using five different sources of taxonomic standardisation. For example, we found that GBIF backbone presented a lower number of accepted species than the others, but generated higher values of observed richness in some areas Figure . Each taExpert knowledge is key when selecting the taxonomic reference for standardisation  global latitudinal gradient of moss species richness. The latitudinal region exhibiting the highest richness peak of differed between North America, Europe/N. Africa and Asia. This peak, however, did not change significantly with the use of different ‘data curation scenarios’. In Asia the peak in species richness was placed further south compared to Europe or North America, although this observation should be interpreted with caution due to the limited number of cells included in the analysis. However, this result seems robust as it was maintained despite filter combinations and it was also consistent with previous analyses of the latitudinal biodiversity gradients in mosses ecologists and biogeographers should consider public data limitations such as survey effort, inconsistent taxonomic information or quality of digitalization by different sets of researchers when modelling and evaluating diversity patterns. This implies that studies using biodiversity data records should detail and justify how they filter and standardise the taxonomy of species occurrences, as well as spatial data quality and accuracy ; data curation (lead); formal analysis (lead); methodology (lead); software (lead); visualization (lead); writing – original draft (lead). Juliana Stropp: Conceptualization ; formal analysis (supporting); supervision ; validation (supporting); visualization (supporting); writing – original draft (supporting); writing – review and editing . Nagore G. Medina: Methodology (supporting); supervision (supporting); validation (supporting); writing – review and editing . Joaquin Hortal: Conceptualization ; formal analysis (supporting); funding acquisition (lead); methodology (supporting); project administration (lead); supervision (supporting); validation (supporting); visualization (supporting); writing – original draft (supporting); writing – review and editing .All authors declare that they have no conflicts of interest.Appendix S1.Click here for additional data file.