Due to the highly infectious nature of the novel coronavirus (COVID‐19) disease, excessive number of patients waits in the line for chest X‐ray examination, which overloads the clinicians and radiologists and negatively affects the patient's treatment, prognosis and control of the pandemic. Now that the clinical facilities such as the intensive care units and the mechanical ventilators are very limited in the face of this highly contagious disease, it becomes quite important to classify the patients according to their severity levels. This paper presents a novel implementation of convolutional neural network (CNN) approach for COVID‐19 disease severity classification (assessment). An automated CNN model is designed and proposed to divide COVID‐19 patients into four severity classes as mild, moderate, severe, and critical with an average accuracy of 95.52% using chest X‐ray images as input. Experimental results on a sufficiently large number of chest X‐ray images demonstrate the effectiveness of CNN model produced with the proposed framework. To the best of the author's knowledge, this is the first COVID‐19 disease severity assessment study with four stages  using a sufficiently large number of X‐ray images dataset and CNN whose almost all hyper‐parameters are automatically tuned by the grid search optimiser. Based on the official data reported over the past year, the number of people infected and died of COVID‐19 has exceeded 77 and 1.7 million, respectively 9 disease. All humIdentifying the COVID‐19 patients who need intensive clinical care using automated severity assessment methods by deep learning becomes very urgent within the pandemic. Timely assessment of COVID‐19 patients at an early stage is now an urgent task if disease progression, triage time and mortality rate are desired to be minimised. Nevertheless, accurately staging the disease severity from radiographic images is very challenging. Some researchers found that most of the COVID‐19 patients have non‐severe (mild or moderate) symptoms . There aThe objective and motivation of this study are to designate a fully automatic convolutional neural network (CNN) model for multi‐classification of the COVID‐19 disease severity using large publicly available datasets. To the best of the author's knowledge, this is the first attempt of COVID‐19 disease severity classification  from the largest publicly available chest X‐rays datasets until the writing of this paper, using CNN whose almost all hyper‐parameters are automatically tuned by the grid search optimiser. The rest of this paper is organised as follows. Section 22.1Despite many scientific papers published about COVID‐19 using deep learning over the past year, most of them are about COVID‐19 disease detection rather than severity assessment , 12, 13.2.2Deep learning‐based disease severity assessment is more objective and quantitative in comparison to radiologist assessment, which is qualitative reports. Despite highly promising findings of deep learning methods for COVID‐19 disease severity assessment on chest X‐ray images, just a few studies related to this subject have been reported. For instance, He et al.  suggeste33.1Finding a research dataset to be used for COVID‐19 disease researches is very challenging now that this disease is a quite newly emerged type of coronaviruses. Despite the lack of COVID‐19 data in the literature, nine datasets from different publicly available sources are carefully collected and used in this study. The first dataset is called the COVID‐19 Image Data Collection by Cohen et al.  and inclHigh accuracies from training and validation phases are not meaningful without testing the trained and hyper‐parameter‐tuned CNN on predicting unseen samples. Therefore, a test dataset is randomly assigned and separated along with training and validation datasets to test the performance of trained CNN on predicting samples; otherwise, the high accuracy may be due to biased dataset assignment (e.g. obvious images with strong characteristics from severe COVID‐19 patients). All the datasets used in this study are publicly available, and the corresponding websites are given in the reference section of this paper. It is planned to collect the largest possible number of publicly available X‐ray images of COVID‐19 that exist in the literature until the writing of this paper. Figure 3.2The experiments of this study are performed on an NVIDIA GeForce GTX‐850 GM107 with 16 GB RAM and Intel Core i7 GPU 2.6 GHz, whereas the software environment consists of Windows 10 and MATLAB R2019a. The time spent to train the deep learning model (2608 images) was 12 min.3.3Staging lung diseases severity using radiologist scoring is commonly the standard approach used for lung diseases severity assessments . Not onlOpacity degree has been computed between 0 and 3 for each lung separately (left lung and right lung) and assigned as 0 if there is no opacity, 1 if ground‐glass opacity exists, 2 if there is consolidation in the lung and 3 if white‐out exists in the lung.Lung involvement score is computed between 0 and 4 for each lung based on ground‐glass opacity and consolidation and assigned as 0 if there is no involvement, 1 if 0%–25% involvement exists, 2 if 25%–50% involvement exists, 3 if 50%–75% involvement exists and 4 if 75%–100% involvement exists.The total lung severity score has been computed between 0 and 14 by summing up the opacity (0–6) and involvement scores (0–8), which is computed from each lung separately and added together. Figure 3.4CNN approach is one of the most popular and efficient type of deep learning methods. Unlike ANN, which uses matrix multiplication, at least one of the CNN layers uses convolution (circulation of filters for feature extraction on input) instead of matrix multiplication. CNNs generally consist of multiple trainable layers placed one after the other. Convolutional and pooling layers are the leading layers of CNN architectures, whereas fully connected (FC) and classification layers are the final stage layers. The training process is started by performing layer‐by‐layer operations just after CNN receives the input data. Finally, a final output is given to compare with the correct  result. The differences between the estimated and the actual results produce an error, which is transferred to all weights by the backpropagation algorithm. Weights are updated with each iteration to reduce the error.This study aims to design and propose a fully automatic CNN model using large clinical chest X‐ray images for COVID‐19 disease severity assessment. Grid search optimisation is employed to decide the hyper‐ and architectural parameters of the CNN model. The proposed CNN architecture classifies the chest X‐ray images of COVID‐19 patients into four severity stages, that is, mild, moderate, severe and critical. The proposed CNN model has 16 weighted layers  as can be seen in Figure 44.1The parameter of a deep CNN whose value must be set before the learning process is initiated is called a hyper‐parameter. Different methods have been widely used for hyper‐parameter setting, which is often a time‐consuming process. Hyper‐parameter tuning is simply the process of selecting a set of hyper‐parameters for a learning framework. With the deepening of the architectures developed to achieve more successful results and the higher quality of the images used, more computational costs arise. Both the reduction of these calculation costs and the achievement of successful results depend on the use of powerful hardware and optimising the hyper‐parameters of the established network.It is important to take into account not only the number of hyper‐parameters but also the hyper‐parameters value range while choosing the CNN hyper‐parameters optimisation method. However, when the number of hyper‐parameters to be optimised increases in addition to the specified wide parameter value ranges, the required computation time becomes excessively high, which makes the optimisation process unpractical from the computation point of view. The grid search optimisation method is an efficient alternative for hyper‐parameter optimisations of CNN's when the value range is a small search space. Grid search, which is typically an exhaustive searching through a manually specified range of hyper‐parameter space of a learning framework, has been recently adopted in machine learning as a hyper‐parameter tuning tool. The grid search aims to select the best combination of which the network is trained in all specified range combinations.2 regularisation (L2R), momentum (M), mini‐batch size (MBS) and learning rate (LR)). The NF, FS, AF, FCL, CML form the most effective architectural hyper‐parameters, whereas L2R, M, MBS and LR form the most effective fine adjustment hyper‐parameters of CNN models in terms of classification accuracy and efficiency. Once the architectural hyper‐parameters are tuned, fine adjustment hyper‐parameters are tuned based on the architectural hyper‐parameters. Algorithm In this study, the CNN hyper‐parameters needed to be optimised are grouped in two categories: Architectural hyper‐parameters , number of FC layers (FCL), number of filters (NF), filter sizes (FS), activation function (AF)) and fine adjustment hyper‐parameters ‐assisted deep learning‐based study, a novel CNN method is developed and validated to classify the COVID‐19 infected patients according to their severity levels as mild versus moderate versus severe versus critical. Experimental results suggest that the proposed method can accurately predict disease severity in COVID‐19 patients using X‐ray imaging, offering promise for clinical diagnosis and early treatment. Many other authors have also detected the COVID‐19 disease through CNN recently. However, the number of images used to train and test the CNN in this proposed study is higher than the number of images used in the previously published studies. For a valid machine learning study, there must be a high number of images to train the neural network. In addition to this, a separate testing dataset has to be used along with training and validating datasets to test the performance of the trained CNN on predicting unseen samples for detecting COVID‐19. Therefore, a test dataset having 652 images is randomly assigned and separated along with a training dataset having 652 images and a validation dataset having 1956 images to comprehensively test the performance of trained CNN on predicting samples. Experimental results on the sufficiently large number of chest X‐ray images demonstrate the effectiveness of the CNN model produced with the proposed framework.The method proposed in this paper has other aspects that are superior to similar methods in the literature. To compare the proposed model with other deep learning models and to show the worth of the work, the same experiments are conducted using ResNet‐101, ResNet‐34, AlexNet, Visual Group Geometry‐16 (VGG16), and the results are compared with the results of the proposed model. Compared with other supervised AI‐assisted predictive models, the proposed model outperforms other deep learning models in terms of accuracy and AUC as shown in Table The proposed study also differs from other methods in that the CNN hyper‐parameters are automatically optimised. Optimising the hyper‐parameters based on the input images is very important for computation efficiency. In this study, the important hyper‐parameters are automatically tuned using grid search. It is worth to note that observing the trends of grid search is more important than focusing on the only best performing result while deciding the configuration values. That is why reviewing all grid search results should be adopted. A general opinion should be created rather than trying to looking for the best fit values for hyper‐parameters. This should be followed by observing fixed intervals and the relationships or trends among the parameters, which will result in a subset of the dataset that saves time in the long‐timed training process. Elapsed time to train the different CNN models and the proposed CNN model is also shown in Table Another method rather than the AI‐assisted methods in the literature for predicting the severity classification of COVID‐19 disease is the radiological severity scoring method, which is based on the radiologist's manual assigning a severity score to each image. This is a subjective method that relies on the experience and expertise of the radiologist. The proposed deep learning method is also superior to this radiological severity scoring method, as the deep learning model eliminates the time‐consuming and subjective severity assignment. Compared with other subjective radiological severity scoring methods, the proposed method not only saves radiologists and clinicians a great deal of time by eliminating the huge workload of the manual annotating the lesion, but it also enables radiologists and clinicians to handle effectively and quickly in dealing with pandemic emergencies.5.1As stated previously in the related work section, many of the deep learning‐based COVID‐19 studies have been reported since the outbreak over the past year. Most of them are about COVID‐19 disease detection, with only some specifically designed for severity classification (assessment). Among the COVID‐19 disease severity assessment studies using deep learning methods, the disease severity has been divided into severe and non‐severe, reducing the severity assessment into a binary classification. For example, He et al.  proposedIn summary, most of the deep learning‐based COVID‐19 disease studies belong to disease detection. The remaining related literature shows that the COVID‐19 disease severity assessment is generally about binary classification (severe vs. non‐severe) rather than multi‐classification of COVID‐19 disease severity. It is also quite obvious that the number of images is not high enough to comprehensively train the deep learning models and prevent a biased dataset assignment effect on the CNN to ensure comprehensively testing the CNN model.Considering the literature carefully, to the best of the author's knowledge, the main advantages and contributions of the proposed approach in this paper are as follows:Many other authors have also detected the COVID‐19 disease through CNN recently; however, the number of images used to train and test the CNN in this proposed study is higher than the number of images used in previous studies. In addition, the proposed study differs from other disease detection studies as it not only makes COVID‐19 disease detection but also achieves the disease severity assessment.This is the first COVID‐19 disease severity assessment study with four stages  from chest X‐ray images using CNN whose almost all hyper‐parameters are automatically tuned by the grid search optimiser.Thanks to the proposed novel CNN model for COVID‐19 disease severity assessment, multi‐classification of patients’ severity can be achieved with a high classification result such as 95.52%.Comparing with COVID‐19 disease assessment studies based on deep learning approaches, this study eliminates the big workload of segmenting the lesions, which saves time and increases the capacity of clinicians to quickly and effectively handle the COVID‐19 pandemic.On the contrary of time‐consuming and subjective radiological severity scoring methods in which radiologist manually assigns a severity score to each X‐ray image, the proposed fully automatic CNN method is more objective, faster, non‐invasive and does not depend on expertise and experience.n = 2). The consistency of the severity score should be validated with more experienced readers in the future work. Moreover, since this study focuses only on COVID‐19 disease pneumonia and lacks to be applied to assess other pneumonias, the study will be extended to classify other pneumonia severity in the future work. Finally, it will be interesting to construct a cloud‐based publicly available website that uses the proposed system, which can be helpful for researchers to fight and handle the COVID‐19 pandemic.There are several limitations to this study. For instance, the lung disease severity score has been computed with a small group of radiologists (6Now that the radiologists differ in skills and experience, an incorrect staging of the disease severity can lead to more deaths of the COVID‐19 patients. This paper suggests a novel implementation of CNN approach to divide COVID‐19 patients into four severity stages: Mild versus moderate versus severe versus critical with an average accuracy of 95.52%. It is believed that this study has a great potential to lighten the workload of the overloaded frontline radiologists and accelerate the diagnosis, treatment of patients, and thus ease the control of the pandemic.


The shorter analogue 6 employs 9,10‐anthracene as the linker and demonstrates the importance of an adequate linker length with a certain level of flexibility by exhibiting generally lower binding affinities than 3–5. Pronounced aggregation–deaggregation processes are observed in fluorimetric titration experiments with DNA for compounds 3 and 5. Molecular modelling of complexes of 5 with AT‐DNA, suggest the minor groove as the dominant binding site for monomeric 5, but demonstrate that dimers of 5 can also be accommodated. Strong SERS responses for 3–5 versus a very weak response for 6, particularly the strong signals from anthracene itself observed for 5 but not for 6, demonstrate the importance of triple bonds for strong Raman activity in molecules of this compound class. The energy of the characteristic stretching vibration of the C≡C bonds is significantly dependent on the aromatic moiety between the triple bonds. The insertion of aromatic moieties between two C≡C bonds thus offers an alternative design for dual Raman and fluorescence chromophores, applicable in multiplex biological Raman imaging.We report four new luminescent tetracationic bis‐triarylborane DNA and RNA sensors that show high binding affinities, in several cases even in the nanomolar range. Three of the compounds contain substituted, highly emissive and structurally flexible bisarene linkers arene linkers and are strongly fluorescent and highly Raman active. Fluorimetric titration experiments reveal distinct aggregation–deaggregation processes for two of the compounds, and molecular modelling of complexes of the compounds with DNA illustrates and corroborates the experimental findings. One of the most essential tasks of living organisms is the reproduction of their own genome.There are three main binding modes, namely intercalation, groove binding and external binding Figure ./[DNA]>0.25, followed by a gradual blue shift of the emission maximum back to 520 nm for ratios r[5]/[poly(dAdT)2]<0.25. This again suggests aggregation along the polynucleotide helix for comparatively high dye concentrations and redistribution of the dye molecules into separate binding sites for an excess of polynucleotide. For the titration with poly(rA)–poly(rU), such an aggregation‐deaggregation process was not observed. Only one binding process was observed, as indicated by a systematic shift of the emission maximum toward 550 nm, even at a large excess of RNA (r5]/[poly(A)–poly(U)]/[DNA]/[DNA]/[ctDNA]=0.2, and not observed at all at the molar ratio r[compound]/[ctDNA]=0.1  and at 1557 and 1257 cm−1 (5/ctDNA) were selectively enhanced  was attributed to stretching of the aromatic moieties, and the latter (1258/1257 cm−1) to in‐plane deformation of the aromatic CH groups. Both bands, in essence, originate from arene ring vibrations and can be easily associated with three phenyl substituents as well. Thus, it can be assumed that, upon binding with the nucleic acid, either the central part of the molecule  or the phenyl moieties linked to boron were placed closer and/or more perpendicular towards the enhancing silver surface. New bands originating from the nucleic acid were not observed in the SERS spectra of the complexes.Furthermore, the SERS spectra of 1 Figure . Presuma Figures  and c. T3–6. Three of them contain long bis(phenylethynyl)aryl  linkers between the two boryl moieties and can be considered as dual Raman and fluorescence chromophores, while the short analogue 6 possesses only an anthracene moiety as the linker and can be considered a fluorophore probe. Analysis of the solid‐state structures of the neutral precursors to 3 and 4 reveal a high level of flexibility for ethynyl‐containing aryl linkers. Concentration‐ and temperature‐dependent UV/Vis and fluorescence experiments suggest a tendency of compounds 3 and 5 to aggregate, increasing with the ionic strength of the solution. Thermal denaturation experiments revealed strong stabilization of dsDNA/RNA for complexes formed with compound 3–5, similar to that observed for our previously studied compounds 1 and 2. The very weak stabilization observed for compound 6 demonstrates that a certain length and flexibility of the aromatic linker need to be exceeded for efficient thermal stabilization to occur. All four compounds bind to dsDNA/RNA and ssDNA/RNA with similar affinities; this contrasts with the fact that binding affinities for single‐stranded polynucleotides are typically 2–3 orders of magnitude lower than for double‐stranded polynucleotides. This is consistent with our previous studies[We have successfully extended our novel class of tetracationic bis‐triarylborane DNA and RNA sensors by four molecules s studies88, 896 to the polynucleotides tested is somewhat weaker than that of the other compounds, which agrees nicely with the thermal denaturation experiments and, again, demonstrates the importance of the linker length and flexibility. For compounds 3 and 5, aggregation–deaggregation processes were observed in fluorimetric titration experiments with DNA and RNA. Thus, at an excess of dye, an aggregation of the dye along the helical axis of the polynucleotide or in dimeric form inside a groove is suggested, while at an excess of polynucleotide, the molecules are separated and are each transferred to separate binding sites. Based on all of our experimental data, including CD results, we suggest the minor groove as the dominant binding site for dsDNA and the major groove for dsRNA for compounds 3, 4 and 6. This is in accordance with our previous findings for compounds 1 and 2.[5, the CD results suggest an unwinding of the helical structure of the polynucleotide upon binding and very uniform orientation with respect to the helical axis for all ds‐polynucleotides tested containing A, T and U base pairs. A molecular modelling study on complexes of compound 5 with AT‐DNA also suggests the minor groove as the dominant binding site and that even dimers of 5 can be accommodated by the minor groove, whereas their binding into the major groove is much less efficient. Strong SERS responses were obtained for 3–5 at low concentrations. For compound 6, weak SERS signals were observed only at the highest concentration measured. This confirms the important role of the triple bonds for strong Raman scattering and demonstrates that the insertion of aromatic moieties between two triple bonds, by which the absorption and emission properties of a molecule can be conveniently tuned, is a feasible alternative for the design of dual Raman and fluorescence chromophores. In addition, the energy of the stretching vibration of the characteristic C≡C bonds was found to be significantly dependent on the aromatic moiety between the triple bonds. In analogy to a variation of the length of the poly‐yne chain,In general, binding of compound  1 and 2.88, 89The authors declare no conflict of interests.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Most children globally are not breastfed to recommendations. Medical practitioners are frequently visited in the first 6 months post‐partum, and the interaction at such visits significantly influences subsequent infant feeding decisions. Medical practitioners report that clinical practice in lactation is often disproportionately reliant on personal experience. This systematic review synthesises the literature on lactation health interventions used to support clinical decision making by medical practitioners. MEDLINE, Embase, PsycINFO, Scopus and Cochrane Library databases were searched for peer‐reviewed empirical studies published after 2000. Two reviewers independently screened and then assessed full‐text articles against inclusion criteria. Quality of reporting and risk of bias were independently assessed using three validated tools. No conclusions can be made regarding the success or failure of implementation strategies used or the outcomes of putting them into effect due to problems with study methodology, intervention reporting and risk of bias. Good‐quality research, which follows proven implementation frameworks, is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants. Breastfeeding is not meeting recommendations globally with inconsistent advice contributing to early weaning.Medical practitioners influence infant feeding decisions but report reliance on personal experience for clinical decision making.Health interventions deliver evidence‐based decision support and improve consistency of care, but few lactation interventions are used by medical practitioners.No conclusions can be made regarding implementation strategies and outcomes of those reported due to poor study quality and bias.Good‐quality research is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants.1Human lactation is well established as a foundation for human health  methodology with checklist available as an additional file Appendix . The pro2.2A search strategy was devised in consultation with a health and medical sciences librarian from J Robin Warren Library at The University of Western Australia. Search terms and Medical Subject Headings (MeSH) chosen were those relevant to ‘doctor’ AND ‘lactation’ AND ‘intervention’. Databases searched were MEDLINE, Embase, PsycINFO, Scopus and Cochrane Library Appendix . The sea2.3Publications were selected on the basis of the PICOS  outlined below  classification of health workers WHO, . General2.3.2Based on the WHO International Classification of Health Interventions WHO, , the int2.3.3The comparator was ‘usual practice’. Usual practice was indicated by no health intervention targeted to the medical practitioner to change current practice with respect to lactation.2.3.4Understanding implementation processes is assisted by conceptualising implementation outcomes  web‐based systematic review software.Data were independently abstracted by two reviewers (M. B. and N. S.) using a series of forms applied through DistillerSR. These forms were used to extract data regarding study design, implementation strategy, implementation outcome variables, quality of study methodology, quality of health intervention reporting and risk of bias. Forms were each piloted independently using three articles from the included references with disagreements discussed and resolved by consensus. If consensus could not be achieved, a third researcher (R. C.) was available for mediation. The two reviewers then independently extracted data from the remaining included articles for each form. Disagreements were resolved by discussion and moderation.The form used for categorising study design was based on the Cochrane EPOC classification of study designs for evaluating the effect of healthcare interventions EPOC, .Implementation science taxonomies are helpful to articulate both the strategies used to deliver a health intervention as well as the results of putting a health intervention into effect   tool  or critical (too problematic to provide useful evidence of intervention effect) within all included studies Figure . ConfounThus, the outcomes of these studies are unlikely to be reliable.4The findings of this systematic review highlight a need for high‐quality implementation research on lactation interventions for medical practitioners caring for breastfeeding families. The limited studies reporting on lactation interventions all identified a need for medical practitioner lactation education, but poor quality of study methodology and reporting and serious to critical risk of bias precluded further conclusions from being made. As evidence‐based knowledge has been shown to improve consistency of medical care and optimise outcomes . Use of three validated tools to comprehensively assess the quality of included studies allowed detailed insight into the strength of evidence reported.Conclusions were limited by the presence of serious to critical risk of bias in all studies, which was compounded by poor quality in study methodology and intervention reporting. Although this meant that there was little to inform specific implementation strategies for LactaMap, the value of using theory‐based models or frameworks to help inform study design and mitigate the challenges of complex intervention development and evaluation was highlighted Nilsen, .5This systematic review highlighted the deficit in medical practitioner lactation interventions and indicates an urgent need for high‐quality research on their uptake in practice. No conclusions can be made regarding the success or failure of implementation strategies used or the outcomes of putting them into effect due to problems with study methodology, intervention reporting and risk of bias.This has several implications for further research. Breastfeeding mothers and infants are not meeting recommendations globally. Medical practitioners supporting them are reporting that clinical practice is overly reliant on personal experience and social networks, which is likely contributing to inconsistent care. Few lactation interventions have been implemented to support clinical decision making. Good‐quality research, which follows proven implementation frameworks, is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants (Pérez‐Escamilla & Odle, The authors declare that they have no conflicts of interest.MB developed the search question and strategy with considerable input and supervision from RC, DP and RP‐E. MB conducted the search. MB and NS selected full‐text articles for eligibility, abstracted data and assessed quality of evidence of the selected articles. MB wrote the manuscript and developed figures and tables with review and input from RC, DP and RP‐E. All authors gave final approval of drafts and final version of this manuscript.


The nutritional requirements of adolescence and the reported poor UK eating behaviours of young people are a significant public health concern. Schools are recognised as an effective ‘place’ setting to enable improvement to nutrition outcomes. The COVID‐19 pandemic resulted in UK school closures from March 2020. In re‐opening in September 2020, schools were required to meet guidelines to ensure the minimised impact of COVID‐19 on the population (DfE 2020). We aimed to evaluate the impact of COVID‐19 school guidelines on secondary and post‐16 (16–18 years) food provision. An online survey was posted on 8th October to 1st December 2020, targeted at young people, parents and staff of secondary/post‐16 education establishments in the UK. Two hundred and fifty‐two responses were received, of which 91% reported a change in their school food provision, 77% reported time for lunch was shortened and 44% indicated the provision was perceived as less healthy during September 2020 (post‐lockdown school return) compared with March 2020 (pre‐lockdown). Analyses demonstrated that time, limited choice and healthiness impacted negatively upon young people's school food experience. The COVID‐19 pandemic has presented a huge challenge to the delivery of healthy school food to young people. Therefore, schools require more support in following national food standards and incorporating nutrition education and behaviour change strategies within current guidelines. The critical and rapid cognitive, emotional and physical developmental changes experienced during adolescence require a high quality of nutrition . The Government guidance on re‐opening provided information which would support schools in delivering school meals whilst ensuring year groups did not mix, and that each year group would remain in a ‘bubble’ DfE,  must be A cross‐sectional online survey Table  was deveData collection took place between 8th October and 1st December 2020. A survey was developed (hosted on Jisc Online Surveys), and a snowball method was used through social media . The survey was also shared via email .The survey comprised of 11 closed questions to identify the participants’ demographic information Table . The then = 152, 60%), followed by staff  and young people . Although responses were gained from a range of ethnicities across the UK, the majority of responses were received from white British citizens, largely residing in the North East of England. Half of the survey respondents specified secondary academy as their education establishment, 36% indicated secondary school, with 16% from college or post‐16 setting. Of the 252 respondents, 248 indicated lunch was provided in their education establishment. In the current study, an adapted socioecological model to include various levels of school food influences was used to describe and understand the views and perceptions of survey respondents , when compared to March 2020 (pre‐lockdown). Twenty‐three respondents stated no change, and of these six added comments suggesting improvements could be made to their school food provision, with regard to time, healthier or specific dietary choices and dining room arrangements.Ninety‐one per cent of respondents stated that their school food I don't think there has been any changes in terms of nutrition and availability, it was poor before Covid and continues to be poor after. Sadly what is served in the school canteen does not mirror the messages delivered in food lessons… ID: 6522729 (staff)More healthy choices. Needs to be more choice for vegetarians/vegans ID: 7433009 (parent)More gluten free options. Food available at break times. ID: 8500995 (parent)Statements or suggestions from respondents who indicated ‘no change’ to school food provision as a result of COVID‐19 guidelines.Where respondents reported change, 77% indicated that lunchtime had been shortened in September 2020, with 44% reporting that school food provision was less healthy, and 50% reporting no change to the healthiness to school food provision between March and September 2020.n = 21 students, n = 107 parents, n = 35 staff). More choice was a common factor, holding most importance to students in this section of the survey . Creating more time to consume lunch was of particular importance to parents (34%) with staff showing equal concern in relation to time and choice, closely followed by ‘more healthy options’ (22%). Parents referred to their child missing lunch or swapping to home brought packed lunches often (32%). Students were concerned about time to a lesser degree, with healthier options factored as being more important (25%), followed by ‘more veggie/vegan options’ and time as equal priorities (20%).Three main themes emerged from the overall survey data: ‘longer time to eat’, ‘reduced menu and grab items’, ‘could be healthier’, as shown in Figure n = 12 students, n = 73 parents, n = 27 staff). The limited menus and choice as a result of COVID‐19 guidelines featured as the most adverse aspect of the changes to all three categories of respondents . Poor nutritional quality as a result of the changes to school meals was secondary to ‘choice’ for all respondents, and most frequently mentioned by staff respondents (30%) followed by students (25%) and parents (23%).Table Student respondents valued choice as the most important factor, with healthy options and time as secondary factors. Interestingly, time was deemed as the most important factor by parent respondents in question 13 My daughter now eats pizza at morning break because it's hot and it takes so long to get food at lunchtime by the time she's finished lunch is over… lunch is now a packet of crisps which is pretty awful… ID: 6193639 (parent)Due to shorter lunch times ‐ child now going without school lunch ID: 6145187 (parent)Parents expressed concerns about time in response to the question around ‘how to improve the food experience’. Concerns about shortened lunchtimes and the impact of late lunches caused some young people to change to packed lunches brought from home or skipping lunch altogether.Longer periods of time to eat. Bubbles are rushed through in 5 mins and some getting pushed out after just arriving in the dinner hall. Pupils could take their lunch back to bubble locations then outside. ID: 6127271 (staff)Lunch time has been reduced to 30 mins and only Year 7 and 6th form students are now entitled to a hot lunch…needs to be extended as students do not have time to eat, fill up water bottles and/or use the toilets… ID: 6582219 (staff)Shorter time to each. VI formers encouraged to go off site which often means they are eating fast food and energy drinks’ ID: 6141434Of the staff who provided free text responses, time was a concern due to rushing the students to eat lunch quickly to make sure everyone eats in their respective bubbles, and that time for cleaning was factored in.Longer lunch breaks. Currently 30 mins, with 20 mins stood queueing for food ID: 6122858 (student)Extend lunch time as queuing takes up half of the lunch time then you don't have long to eat ID: 7568429 (student)The student respondents, in contrast to parents and staff, commented on time to a lesser degree than choice and healthiness; however, frustrations with queuing and suggestions for a longer lunchtime were expressed in the data.Choice was the most prevalent theme across all three categories of respondents . Some respondents, in receipt of free school meals, suggested that the new options changing from a hot meal to only a sandwich were not filling or acceptable, perceiving a packed lunch from home would be better for the student.The choices were so poor that we moved the children onto packed lunches’ ID: 8316115 (parent)Due to the staggered time for lunch, at least once and sometimes twice a week there is not sufficient choice for my child and she goes without any lunch! ID: 6118633 (parent)Child will only eat pizza which is poor in terms of nutrition. Complains there is very limited menu. ID: 6217013 (parent)Parents expressed concerns over limited choices, poor quality, convenience foods offered and less availability for those eating at the later lunchtimes. Students often chose to take in a packed lunch or skipped lunch. Suggestions for improvement included: offering more sit‐down meals at staggered lunchtimes and preordering. A few comments suggested that young people were happier with pre‐packaged fast food/HFSS options.Better quality of food needed. Meals need more flavour. Portions are too small. Not enough choice. Pupils with disabilities need a hot dessert or a soft one. ID: 6434587 (staff)Some areas have full kitchens and can serve a full range of hot food such as chips and veg where the “pop up” kitchens have limited range ID: 7518875 (staff)More choice for pupils who eat last…they are left with the things no‐one else wants. ID: 7456126 (staff)Lack of choice, even poorer quality of produce which I didn't think was possible Bland taste. Food is often cold by the time pupils get it… ID: 6434587 (staff)Staff respondents demonstrated a shared priority of choice and time in their concerns arising from changes in the school food provision, with smaller portions also mentioned and one member of staff suggesting that those children living with a disability were not catered for due to the changes. Sit‐down meals were also mentioned, with some concerns raised about the difference in experience within school due to the logistics of year group bubbles, and staggered lunchtimes. For example, where student's dietary needs were not being met, or the choice/quality of lunch was dependent on the time or location students were eating their lunch.So the school has cut all hot meals. And it's only a sandwich as I receive free school meals I don't get as much anymore I can only get a sandwich. ID: 7703286 (student)More choice bigger portions ID: 7898716 (student)there could be more options for vegans and vegetarians ID: 7739163 (student)Student respondents demonstrated a higher emphasis on choice and variety through the free text responses, with four students suggesting more vegetarian/vegan or dairy free should be available. A student eligible for free school meals commented on having ‘only a sandwich’ as hot meals have been removed in the school they attend.Healthy food doesn't look appealing ID: 6132328 (parent)more healthy choices. Less availability of unhealthy food as this is what they will choose everyday ID: 6289888 (parent)My son's school offers bacon rolls or pizza as a snack at break time. These are not a snack. ID: 6304103 (parent)Child will only eat pizza which is poor in terms of nutrition. ID: 6217013 (parent)My son's bubble was sent home… to self‐isolate…The head teacher dropped a bag a food off which was kind but misguided. The bag contained apples and brown pitta, all good. But it also contained a 6 pack of crisps and a 5 pack of chocolate bars. I don't buy these items myself. Hardly nutritious for other families who may struggle to buy healthy food. In addition, the main food source was a box of soup sachets containing just under 100 kcals, again not sufficient as a meal. Being poor should not equal eating poor food… And school cooks also need more training. ID: 6304103 (parent)Respondents commenting on nutrition or healthy options expressed a frustration with reduced nutritional quality and suggested improvements to include more fruit and vegetables and a reduction in HFSS options. Forty‐four per cent of respondents thought that school food was less healthy than pre‐COVID‐19. The percentage of respondents who requested healthier options Table  was closMore nutritious options. There is one main meal choice at our school now instead of three. Other hot food served is pizza, pastry products, pasta pots with limited veg and covered in cheese. Cold options consist mainly of sandwiches with a high proportion of mayonnaise and very limited salad options. ID: 6211006 (staff)Lots of HFHS options, no fish, pizza served most days and Chips once a week. Slush puppies served…Cheap sausage and bacon sandwiches available every day. Poor quality in my opinion. ID: 6522729 (staff)Too limited to non‐nutritious quick options like pizza slices ID: 6223679 (staff)Staff comments reflect their view that schools could provide healthy options, despite the COVID‐19 guidelines. The limited salad, fruit and vegetable options, and the increased fast food options were expressed by staff respondents as a concern. The range of comments of this type was from a range of geographical locations, demonstrating this is not a geographical issue. One staff respondent commented that as a food teacher they had ‘no information on canteen’.Offer more nutritional food such as fruit or vegetables. Reward individuals for choosing healthier options within the current food selection. ID: 8554800 (student)the vegetarian is limited and we find lunch options aren't as good or healthy ID: 6134576 (student)In my school, there is less cold food and in the hot food section it's lukewarm instead of hot. Furthermore there is more unhealthy food at the counter which concludes in us getting a bit more fatter. ID: 6528383 (student)Of those students who responded to the free text questions, most noted they would like to see ‘more healthy options’.It is better than pre Covid due to staggered lunch breaks and most taking packed lunch, there's no queue ID: 6127806 (parent)The changes have actually worked better for my fussy kids with hot sandwiches and burgers, jackets ID: 6186929 (parent)My eldest was going into town for lunch so actually has to make healthier choices now they have to remain in school ID: 6118251 (parent)School has just introduced last week a pasta bar so various pasta and sauces/toppings, they love it! ID: 6297408 (parent)My daughter's school does a takeaway lunch one day a week for each year group…There is not as much choice as previously but it doesn't seem to be an issue, she still eats something. If anything it has made her try new things. ID: 7450620 (parent)Some parents and staff added comments to express their views that schools were doing their best to at least offer something within the COVID‐19 guidelines, with one parent preferring that their children like the newly introduced fast food options. There is evidence to suggest schools are varied in their approaches, and the data show good practice examples in finding other ways to keep healthful but convenient options, such as introducing a pasta bar with various toppings.More participant views are displayed in Table This study suggests that COVID‐19 has presented further challenges to improving the nutrition intake of young people in a school setting. A clear pattern, revealed in the national survey data, indicated that a significant number of secondary or post‐16 establishments may have been further from the School Food Standards DfE,  before tEvidence suggests that mal/undernourishment results in a weakened immune function, and those with obesity and co‐morbidities such as type 2 diabetes are more likely to suffer worsened outcomes from COVID‐19 GNR, . The panThe current findings demonstrate that cleaning procedures and the logistics of keeping year groups apart as set out in the COVID‐19 guidance DfE,  have negThese data highlight the significant challenge the COVID‐19 guidelines have posed to effectively delivering a positive dining experience, and nutritionally balanced school food, with 44% of respondents stating the school food is less healthy than pre‐COVID‐19. The survey responses in the current study demonstrated the perceived increase in fast unhealthy food choices in schools since September 2020. The limited choice of school food options as a direct result of insufficient space or cooking areas, and a need to feed young people ‘something’ in limited time frames may have compromised the nutrient content of many school food offerings, with pizza, paninis and bacon rolls commonly featured. Parents who responded were in general agreement that all choices should be healthy, as they perceived young people would choose the unhealthy option. All respondents (regardless of category) suggested less HFSS and more fruits and vegetables should and could be available. The concern that we are moving further away from ‘the healthy choice being the easiest choice’ and the target of reducing obesity levels requires urgent attention, as eating habits developed by or during adolescence are likely to remain through adulthood CSJ, .Adolescent eating behaviours are highly complex, and the cognitive development of food familiarity is of significant interest with regard to taste preferences towards HFSS options ;e.g. a pasta, rice/wrap station which has a variety of toppings);offering choices which provide nutritious options . This may include overnight oat pots with a choice of toppings and rice dishes;be smart and inclusive with food choices which meet specific dietary requirements and incorporate . Where external catering contracts are used by schools, guidance specifies the School Food Standards should be included within the catering contract or service level agreement and stipulates regular evidence of compliance to be supplied to the school's governing body DfE, .In addition, it may be useful at national level to supply schools with resources for the educating of young people on the importance of good immune health. Future research to examine the nutritional content of school food provision, and adherence to national school food policy may provide further insight into the effectiveness of school food provision in the UK.None.This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving research study participants were approved by the School of Health and Life Sciences research ethics sub‐committee at Teesside University (Ref: 2020 Sep 1325 Rose). Written informed consent was obtained from all subjects.Tables S1‐S2Click here for additional data file.


Gallbladder neuroendocrine carcinomas (NECs) are a rare but important differential diagnosis of gallbladder cancer. This case report highlights the importance of pathological diagnosis and the efficiency of endoscopic ultrasound‐guided fine‐needle aspiration. Pathological diagnosis should be attempted because the treatment of gallbladder NEC differs from that of gallbladder adenocarcinoma, especially in unresectable cases. A woman in her 70s, with obstructive jaundice and left periclavicular lymph node (LN) enlargement, was referred to our hospital for further examination. Duke Pancreatic Monoclonal Antigen Type 2 (DUPAN‐2) levels were elevated to 434 U/mL, while carcinoembryonic antigen and carbohydrate antigen 19–9 levels were within the normal range. Contrast‐enhanced computed tomography revealed a hypovascular tumor of the gallbladder fundus with a well‐defined margin accompanied by an intact overlying mucosa, liver invasion  with a poorer prognosis than that of gallbladder adenocarcinoma.EUS‐FNA is considered an efficient and safe diagnostic modality for the evaluation of pancreaticobiliary diseases.In conclusion, gallbladder NECs are a rare but important differential diagnosis of gallbladder cancer. Pathological diagnosis should be attempted because the treatment of gallbladder NEC differs from that of gallbladder adenocarcinoma, especially in unresectable cases.Written informed consent was obtained from the patient for the publication of this case report and accompanying images.


The COVID‐19 pandemic has affected women and children globally, disrupting antiretroviral therapy (ART) services and exacerbating pre‐existing barriers to care for both pregnant women and paediatric populations.We used the Spectrum modelling package and the CEPAC‐Pediatric model to project the impact of COVID‐19‐associated care disruptions on three key populations in the 21 Global Plan priority countries in sub‐Saharan Africa: (1) pregnant and breastfeeding women living with HIV and their children, (2) all children (aged 0–14 years) living with HIV (CLWH), regardless of their engagement in care and (3) CLWH who were engaged in care and on ART prior to the start of the pandemic. We projected clinical outcomes over the 12‐month period of 1 March 2020 to 1 March 2021.Compared to a scenario with no care disruption, in a 3‐month lockdown with complete service disruption, followed by 3 additional months of partial (50%) service disruption, a projected 755,400 women would have received PMTCT care (a 21% decrease), 187,800 new paediatric HIV infections would have occurred (a 77% increase) and 516,800 children would have received ART (a 35% decrease). For children on ART as of March 2020, we projected 507,200 would have experienced ART failure (an 80% increase). Additionally, a projected 88,400 AIDS‐related deaths would have occurred (a 27% increase) between March 2020 and March 2021, with 51,700 of those deaths occurring among children engaged in care as of March 2020 (a 54% increase).While efforts will continue to curb morbidity and mortality stemming directly from COVID‐19 itself, it is critical that providers also consider the immediate and indirect harms of this pandemic, particularly among vulnerable populations. Well‐informed, timely action is critical to meet the health needs of pregnant women and children if the global community is to maintain momentum towards an AIDS‐free generation. For somWhile lockdowns have been lifted, permitting travel to healthcare facilities, the pandemic has strained global supply chains, contributing to increased ART costs. These strains also put countries at risk for ART stockouts , with foWe used the Spectrum software package and the Cost‐Effectiveness of Preventing AIDS Complications Pediatric (CEPAC‐P) model to project the potential impact of service interruptions on key outcomes for children at risk for or living with HIV.2Spectrum is a modelling package that generates estimates of HIV‐related measures. For model inputs, Spectrum uses country‐specific surveillance, survey and programme data, such as the number of children receiving ART and cotrimoxazole and the number of women receiving antiretroviral prophylaxis by regimen. Results from scientific studies are used to inform parameters for which country‐specific estimates do not exist, such as MTCT rates by regimen and mother's CD4 count, and the effect of ART on mortality .The CEPAC‐P model is a clinically detailed microsimulation model of paediatric HIV acquisition, disease progression and treatment. CEPAC‐P was initially populated, validated and calibrated using cohort data from the International epidemiology Databases to Evaluate AIDS (IeDEA) East African cohort. The model was then calibrated to match pooled UNAIDS data from eight sub‐Saharan African countries to ensure generalizability of results to the broader region . These dDrawing on the respective strengths of these models, we simulated three separate populations likely to be affected by COVID‐19‐associated care disruptions in the 21 Global Plan priority countries in sub‐Saharan Africa . Using SWe then projected clinical outcomes from 1 March 2020 to 1 March 2021. We first modelled a comparator scenario with no service interruption. In all disruption scenarios, we modelled time‐limited disruption of ART access. Disruption duration varied between scenarios: all included 3 months of complete lockdown, with 100% of the population unable to access ART; for the subsequent 3 months of disruption, we varied the proportion of the population that remained unable to access services . Following these modelled 6‐month disruptions, we assumed a full return to pre‐disruption access to care.Of the overall paediatric cohort, 65% were modelled as virologically suppressed pre‐disruption . Upon re3If there had been no service interruption due to COVID‐19, we projected that between March 2020 and March 2021 within the 21 priority countries in sub‐Saharan Africa, 959,200 women would have received PMTCT care, 106,200 new paediatric HIV infections would have occurred and 796,700 children would have received ART  service disruption, we projected 755,400 women would have received PMTCT care (a 21% decrease), 187,800 new paediatric HIV infections would have occurred (a 77% increase) and 516,800 children would have received ART  for women, or pandemic‐spurred economic hardships that may have put women at increased risk for HIV infection , 21, altThis analysis has two important limitations. First, we provide aggregate estimates for 21 countries, which necessarily exclude key differences in HIV care coverage pre‐COVID‐19, as well as in the length and severity of pandemic‐related care interruptions. Following international guidance, we examined the impact of uncertainty in these parameters by varying the length and extent of the modelled disruption, the most influential and uncertain input . Second,Many questions remain about the COVID‐19 pandemic, including when it will subside. It is likely that programmes providing care for people living with HIV – and other illnesses – will be affected by pandemic‐associated service disruptions for some time to come . In ordeThese findings suggest an increase in projected new paediatric HIV infections, with more infants born with HIV to women temporarily disengaged from PMTCT programmes. Reports on the impact of COVID‐related service disruptions show that several countries experienced declines in both rates of HIV testing in antenatal clinics and in antiretroviral prophylaxis to prevent vertical transmissions in 2020 . Many ofAs re‐opening progresses in many countries, meeting the needs of pregnant women and CLWH should be a top priority. This will require enhanced action and thoughtful solutions. COVID‐19 has presented an opportunity to rethink traditional care delivery in favour of more innovative solutions. Differentiated service delivery (DSD) may help to minimize the risk of COVID‐19 exposure while continuing to meet the healthcare needs of pregnant women and CLWH , 31. TheAny potential solutions – self‐testing, service bundling, ART delivery, electronic symptom monitoring and other creative approaches , 31 – sh4While efforts will continue to curb the rising death tolls stemming directly from COVID‐19, providers must not lose sight of the immediate and indirect harms of this pandemic, particularly among vulnerable populations. Well‐informed timely action is critical to meet the health needs of pregnant women and children if the global community is to maintain momentum towards an AIDS‐free generation.The authors have no competing of interests to report.All authors discussed the results and contributed to the final version of this short report. NM conducted the CEPAC‐P model projections. JS conducted the Spectrum model projections. CFF and ALC had the initial idea for this analysis. CFF wrote the report.Support for CEPAC‐P model development was provided by the US National Institutes of Health (NICHD R01 HD079214 to ALC). Support for the Spectrum model was provided by the Bill & Melinda Gates Foundation (OPP1191665).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Bill & Melinda Gates Foundation or the United States Government.


Prospectively gated 64‐slice CT coronary angiography (CTCA) may be contraindicated for heart rates (HRs) over 65 beats per minute (bpm) due to reduced diagnostic sensitivity. Newer CT scanners typically provide 128 or more slices and superior temporal resolution compared with older models; consequently, diagnostic accuracy for current technology prospectively gated CTCA may be adequate at HRs above 65 bpm. The aim of this systematic review was to investigate the diagnostic accuracy of CTCA using 128‐slice or greater CT technology when compared with conventional coronary angiography for patients with HRs >65 bpm.A systematic search of PubMed, CINAHL, EMBASE and Scopus was performed as well as unpublished databases, sources and reference lists. Titles and abstracts were screened by two independent reviewers. Full‐text screening was then performed. Studies that determined diagnostic accuracy of coronary artery stenosis in adult patients with high heart rates utilising prospectively gated 128 detector or greater scanners were included. Studies that were included in the review underwent critical appraisal using the QUADAS‐2 tool.Ten studies were included in the systematic review, with nine of these included in a diagnostic test accuracy meta‐analysis, including six of which reported data at the patient level. Meta‐analysis indicated very high pooled sensitivity 100% ; however, pooled specificity was less at 79% .Prospectively gated CT coronary angiography may be justifiable at heart rates above 65 bpm if performed on a 128‐slice or greater CT unit. Caution regarding the implication of a positive result is recommended due to reduced specificity. Further evidence is required before consideration of a new higher heart threshold. High heart rates create challenges for prospectively‐gated CT coronary angiography. A systematic review and meta‐analysis were undertaken to identify the effect of high heart rate (>65 bpm) on diagnostic accuracy. The review found diagnostic sensitivity remains high at higher heart rates 100% , however, specificity was shown to be less reliable at 79% . Where standard heart rate control is contraindicated or ineffective, prospectively‐gated CT coronary angiography using 128‐slice or greater CT scanners may be justifiable. Computed tomography coronary angiography (CTCA) is a well‐established test, primarily due to its excellent negative predictive value in the context of ruling out the presence of coronary artery stenosis.Current recommendations for the performance of CTCA, which are based on data from studies performed using 64‐slice CT technology, include preferential use of a prospectively gated axial scan technique because the radiation dose delivered to the patient is considerably less than that for retrospectively gated helical CTCA. However, prospectively gated CTCA may not be appropriate for patients with high heart rates due to reduced sensitivity resulting from motion artefacts. Thus, current performance guidelines recommend pharmaceutical intervention to maintain heart rate below 65 beats per minute (bpm) during imaging.Several important technical innovations have been made clinically available over the past decade, which may mitigate the challenges of high heart rate CTCA with 64‐slice CT. These include new iterations of dual‐source technology, as well as other technical improvements such as increased detector coverage and faster gantry rotation speeds. Proprietary software algorithms have also been designed to reduce effects from cardiovascular motion The review included all study design types describing adult participants (>18 years) with heart rates greater than 65 bpm that did not directly evaluate the effect of known confounding factors such as atrial fibrillation, obesity or intraluminal stents for coronary artery bypass grafts.Studies that related to the use of MDCT with ≥128 detector rows as the index test and that utilised a prospective‐ECG‐gating mechanism were included. Scans performed using single or multi‐beat reconstructions and any level of temporal padding were included, provided the scan was ostensibly acquired in a prospective ECG  scan mode. Where possible, radiation dose and padding data were collected for comparative purposes. Study cohorts that did not describe traditional or common practices, such as those that looked at novel ECG‐gating techniques, dual‐energy acquisitions or low dose examinations, were excluded. Where a study compared a novel technique to a control arm, only data from the control were included. Where a recognised post‐processing motion correction technique was directly compared with original image data using the same patient group, the former group was included. Only studies that directly compared CTCA with conventional coronary angiography as the reference standard were included.For the purposes of this review, significant coronary artery disease was defined as a 50% or greater narrowing of a coronary artery segment based on the American Heart Association definition.PubMed, CINAHL, EMBASE and Scopus databases were reviewed using a carefully constructed search string. Further to the formal strategy, we also performed searches of ProQuest dissertation database and Google Scholar, and contacted key authors for recommendations. The reference lists of included papers were also screened to identify additional relevant studies that were not discovered during the database searches. Search limits included English language studies only, and dates were limited to 2007 as the technology in question was not clinically available prior to this time. A pragmatic updated search of PubMed conducted on 11/01/2021 did not yield further results.An assessment of the diagnostic quality of included studies was conducted using the QUADAS‐2 risk of bias and applicability instrument by two of the authors (GTWM and CJS). The assessment was performed independently, and results compared as per the design of the QUADAS‐2 tool.a priori.Data were extracted from all included papers by the lead reviewer (GTWM). The data extracted included specific details about the tests, populations, study methods and diagnostic accuracy outcomes at patient, vessel and segment levels. The data to be extracted were defined in the review protocol Data were synthesised narratively, and results pooled through proportional paired meta‐analyses.Meta‐analysis was conducted using a subscription‐based online software package (JBI SUMARI).Summary receiver operating characteristic (SROC) curves were not produced as the review focussed on a single diagnostic threshold, reported 50 per cent narrowing. Summary ROC curves are used in systematic reviews of diagnostic accuracy where diagnostic thresholds vary. Instead, the reviewers felt it was more appropriate to use paired forest plots to determine summary estimates of sensitivity and specificity. Therefore, the summary estimates provided in this review may not be representative if other diagnostic thresholds are used in practice.Furthermore, positive and negative predictive values were not reported in this review. Whilst the negative predictive value for CTCA is high and is commonly referred to when highlighting the value of the test, care should be taken when interpreting negative predictive values. Predictive values are directly affected by the prevalence of disease in the sample and therefore are not the preferred method of reporting when the reference standard does not necessarily reflect the prevalence expected in clinical practice. For this reason, only sensitivity and specificity values were reported. Sensitivity and specificity are not affected (at least directly) by the prevalence of positive cases in the sample and are therefore considered a more global measure of the true accuracy of CTCA when conventional coronary angiography is used as the reference standard.Further sensitivity and subgroup analyses were then created using a separate package . Paired forest plots were generated for these analyses; however, pooled summary estimates were not created for sensitivity and specificity as there were insufficient data to perform this.Database searches identified 1689 records  scanners, two studies that utilised Revolution CT  scanners, four studies that described Somatom Definition Flash  scanners and one study that assessed a Brilliance iCT  scanner. All studies reported prospective‐ECG acquisition techniques; however, the level of temporal padding employed differed between studies, as did corresponding median dose‐length product (DLP) values for each study.Table All studies reported significant coronary artery disease as >50% stenosis. Only data at this diagnostic cut point were included in the analysis. The reported sensitivity and specificity for each included study at patient, vessel and segment levels are included in Table Overall, methodological quality was rated as high. Issues associated with the flow and timing of the study design and patient selection were noted. Proportional results for the methodological assessment are shown in Figure All included studies were cross‐sectional designs. The majority of studies performed the ICA prior to CTCA as this ensured that only patients receiving both tests were being independently assessed for diagnostic accuracy.Four primary studies directly analysed the diagnostic accuracy of patients undergoing CTCA with high HRs.Four studies that reported patient‐level diagnostic accuracy data were included in the review.The remaining two studies included in the review reported diagnostic accuracy at segment level only. Gang and colleagues enrolled consecutive patients with high‐risk coronary artery disease to receive clinically mandated CTCA and then ICA.Wang and colleagues reported segment‐level data in their assessment of patients with various heart rates.Overall, the literature provides evidence of high sensitivity results for patients with high heart rates with point estimates of sensitivity varying between 87.8% and 100%. Specificity is more variable, with included studies reporting estimates between 63% and 100%.Diagnostic accuracy at the vessel‐ and segment‐level accuracies is summarised in Table Nine of the 10 included studies provided sufficient data to perform meta‐analysis. Insufficient data were provided by one study, and it was therefore excluded from the analysis.n = 450), vessel (n = 1229) and segment levels (n = 8144). Overall sensitivity was 100%  and specificity 79% . For the vessel‐level analysis, sensitivity was 96%  and specificity 93% . For the segment‐level analysis, sensitivity was 91%  and specificity 96% . The paired meta‐analyses are included as Figure Paired proportional meta‐analysis was performed for all included data at the patient  and specificity of 96% . Compared with the all‐inclusive sensitivity and specificity values of 91% and 96%, respectively, this adjusted result does not indicate a substantial variation in the summary estimates provided. Furthermore, where data were re‐analysed incorporating only studies that had excluded indeterminate segments from the analysis, sensitivity was 93% , and specificity was 98% . Again, no substantial difference exists.A subgroup analysis was originally planned to assess for the effect‐specific heart rate had on test accuracy. However, there were insufficient individual data points to perform this analysis. Instead, a subgroup analysis based on the minimum heart rate reported for each of the primary studies was included Figure .Scanner make and model subgroup analysis performed and provided as Figure Several previous systematic reviews have assessed diagnostic accuracy of CTCA;A 2013 systematic review investigated the diagnostic accuracy of CTCA across several ‘difficult‐to‐image’ patient groups.Although the subgroup analysis did not have statistical power to provide a definitive conclusion on the value of particular scan technologies on the diagnostic accuracy at high heart rates, the results reported by each of the individual studies were similar, indicating that each individual scan technology is valuable to ensure accuracy at higher heart rates. However, further study is needed to provide a definitive result for each group.Whilst the included padding and subsequent dose‐length product (DLP) values for included studies were summarised, they were not a primary outcome of the review. It is assumed that the amount of padding, and therefore dose, incorporated will increase the likelihood of a more accurate outcome; however, the relationship is unlikely to be linear, due to several other confounding factors. The amount of padding used in the included varies between studies and is likely to be higher than that commonly encountered in clinical practice.It is recognised that the reported sensitivity and specificity are different for patient‐, artery‐ and artery segment‐level analyses. This is explainable by the nature of how each group are calculated. That is, only one of three arteries needs to have a significant stenosis present to report a positive finding for a patient. In comparison, at the vessel–segment level a positive can only be recorded where there is disease in that segment. This effect increases the sensitivity (true positive rate) and decreases the specificity (true negative rate) of patient‐level analyses relative to the vessel–segment analyses, and the phenomena have been reported previously.A limitation in this review was a paucity of individual data points that could be extracted from the primary studies to allow for a more comprehensive assessment of the effect of heart rates on diagnostic accuracy. Considerable effort was made to contact each study author to enquire about how certain variables, such as the discrete heart rates and padding used, differed between study participants. However, without this information, the scope of the review was limited to determining the current state of play in accurate diagnosis of CTCA, rather than exploring in further detail the strength of particular factors, such as the effect of discrete heart rates and vendor‐specific technology on test accuracy.As only 6 studies were included in the patient‐level meta‐analysis, comment is made that the results may be limited. However, due to the similarity in the individual study results and relatively small confidence intervals in the summary estimates, it is surmised there is sufficient statistical power to produce a meaningful and accurate result. Furthermore, a lack of primary data is a limitation of the level of exploration of this field of study, rather than a limitation of the review methodology itself. We therefore recommend further research to explore the effect of high heart rates on the accuracy of diagnosis.The temporal padding differed significantly between and within studies. Whilst this has the potential to increase heterogeneity of the review, the reviewers felt variation in the amount of padding used was primarily controllable by the staff performing the scan. Consequently, it is expected to vary across patients. Likewise, the radiation dose, measured as the dose‐length product, was also considered to have too many resulting factors to consider this a significant source of clinical heterogeneity between the studies.Studies based on retrospectively gated helical CTCA were excluded from this systematic review. Although helical CTCA using 128‐slice or greater CT may show similar, or even better diagnostic accuracy compared with prospectively gated axial CTCA at high heart rates, the decision to exclude helical CTCA from this study was made to provide a more focussed discussion of diagnostic accuracy between older and newer CT technologies.Whilst studies that exclusively studied difficult‐to‐image patients were excluded, it was not necessarily clear that, for example, coronary calcium blooming or heart rate variability was not still a cause for misdiagnosis in the data. This is a concern in all data sets where CTCA accuracy is being assessed; consequently, it can be assumed it would not have a significant impact on the results presented here.There was a significant degree of complexity in selecting included participants for this review. Although several of the included studies directly identified the diagnostic accuracy of high heart rates within their studies, studies were also included where only a small subgroup of patients who underwent the test had high heart rates. Additionally, because the review excluded scans that were performed using retrospective ECG gating, only data where it was clear prospective‐gating had been used (with or without padding) were included.The inclusion of the study by Nerlekar and ColleaguesFinally, there was some concern regarding the populations of three studies initially included in the review by Liang and Colleagues.Scanning at high heart rates using retrospectively gated axial acquisition on 128‐slice or greater MDCT is appropriate and the diagnostic value maybe non‐inferior to imaging at low heart rates. However, consideration must be given to a likely decrease in resultant specificity for high heart rate patients. Therefore, scanning at high heart rates should still only be considered where appropriate heart rate lowering medications is inappropriate and where the scan is used to rule out rather than evaluate clinically significant coronary artery stenoses.This systematic review describes high level accuracy for patients undergoing CTCA with high heart rates, when comparing against ICA as the reference standard. Diagnostic test accuracy paired meta‐analysis produced sensitivity and specificity summary estimates of 99%  and 79%  for patient level, 96%  and 93%  for vessel level, and 91%  and 96%  for segment level.Further study is required to better understand the effect that individual vendor‐specific technologies have on diagnostic performance, particularly for historically difficult‐to‐image groups such as patient with high HR.CJS is a current employee of Philips Australia and New Zealand. No further conflicts of interest are identified.


Deer are regarded to be a keystone species as they play a crucial role in the way an ecosystem functions. Most deer–forest interaction studies apply a single scale — process of analyzing ecological interactions by only taking into account one dependent variable — to understand how deer browsing behavior shapes different forest components, but they overlook the fact that forests respond to multiple scales simultaneously. This research evaluates the effect of browsing by wild deer on temperate and boreal forests at different scales by synthesizing seminal papers, specifically (a) what are the effects of deer population density in forest regeneration? (b) What are the effects of deer when forests present diverging spatial characteristics? (c) What are the effects on vegetation at different temporal scales? and (d) What are the hierarchical effects of deer when considering other trophic levels? Additionally, a framework based on modern technology is proposed to answer the multiscale research questions previously identified. When analyzing deer–forest interactions at different scales, the strongest relationships occur at the extremes. For example: when deer assemblage occurs in low or high density and is composed of a mix of small and large species. As forests on poor soils remain restrained in size, isolated and chronically browsed. When forests harbor incomplete trophic levels, the effects spill over to lower trophic levels. To better understand the complexities in deer–forest interactions, researchers should combine technology‐based instruments like fixed sensors and drones with field‐tested methods such observational studies and experiments to tackle multiscale research questions. When analyzing deer–forest interactions at different scales, the strongest relationships occur at the extremes: when deer assemblage occurs in low or high density and is composed of a mix of small and large species. As forests on poor soils remain restrained in size, isolated and chronically browsed. When forests harbor incomplete trophic levels, the effects spill over to lower trophic levels. At this point, deer effects in forest might be irreversible. To overcome the challenge of understanding how vegetation responds to deer browsing and trampling at multiple scales, combining modern technology with field‐tested methods could provide a holistic insight into deer–forest interactions. Deer interact with forest directly by browsing, trampling, fraying, and stripping vegetation and indirectly by seed dispersing and defecating  in the northern hemisphere have increased in abundance  and bottom‐up control mechanisms . Top‐down control by predation and culling directly reduces deer density  and forest composition  can provide a competitive advantage to either plants or herbivores, thus having the potential to entirely shift deer–forest interactions. To contextualize their effect, experiments can be conducted in controlled environments that isolate deer mechanism from the confounding factors that are present in forests Putman, . For exa7.22 for red deer) typically exceeds the study area for vegetation surveys, it is necessary to survey vegetation at a landscape level to better understand deer–forest interactions  smans Gill, . This cans Gill, ; and (d)ns Gill, .As previously stated, scaling‐up and scaling‐down approaches are highly recommended for ecological research in the 21st century because by downscaling, the mechanisms unveil, while upscaling tests whether these mechanisms are still ecologically relevant in the field. Combining a multiscale approach demands a substantial increase in human effort and capital investment and thus, this approach can be challenging to implement in practice. New and affordable technology may thus allow to overcome these scaling challenges by reducing the time needed to collect reliable and systematic information.7.3The largest obstacle within this field of research is acquiring systematic and replicable information that accurately represents deer–forest interactions Gill, . TechnolThe Internet of Things—objects that are embedded with all sorts of monitors that are connected by wireless networks with the purpose of exchanging information in a near real time—might be the platform that links the previously described sensors while transmitting the information to a data processing center. At this stage, the greatest bottleneck is processing large amounts of data in short periods of time, and Machine Learning is the option forward. There are numerous applications where The Internet of Things has been used to better understand ecological systems, including the underground behavior of rodents and movement of birds, and also to monitor the Qinling Mountain reserve and help preserve its endemic species  embedded in a large and heterogeneous experimental forests  and mounting sensors that track ecosystem properties, but also specimens belonging to different trophic levels . By doing so, researchers can quantify the interactions among members of the forest community but also, with their environment, even when the system is characterized for being cryptic and highly dynamic.No conflict of interest to declare.Juan Ignacio Ramirez: Conceptualization (lead); Formal analysis (lead); Funding acquisition (lead); Investigation (lead); Project administration (lead); Validation (lead); Visualization (lead); Writing‐original draft (lead); Writing‐review & editing (lead).


A common finding in the aging literature is that of the brain's decreased within‐ and increased between‐network functional connectivity. However, it remains unclear what is causing this shift in network organization with age. Given the essential role of the ascending arousal system (ARAS) in cortical activation and previous findings of disrupted ARAS functioning with age, it is possible that age differences in ARAS functioning contribute to disrupted cortical connectivity. We test this possibility here using resting state fMRI data from over 500 individuals across the lifespan from the Cambridge Center for Aging and Neuroscience (Cam‐CAN) population‐based cohort. Our results show that ARAS‐cortical connectivity declines with age and, consistent with our expectations, significantly mediates some age‐related differences in connectivity within and between association networks . Additionally, connectivity between the ARAS and association networks predicted cognitive performance across several tasks over and above the effects of age and connectivity within the cortical networks themselves. These findings suggest that age differences in cortical connectivity may be driven, at least in part, by altered arousal signals from the brainstem and that ARAS–cortical connectivity relates to cognitive performance with age. A common finding in the aging literature is that of the brain's decreased within‐ and increased between‐network functional connectivity. However, it remains unclear what is causing this shift in network organization with age. Our findings suggest that age differences in cortical connectivity may be driven, at least in part, by altered arousal signals from the brainstem and that ARAS–cortical connectivity relates to cognitive performance with age. A diffuse set of neuronal projections from multiple brainstem nuclei stimulate the cerebral cortex via ascending pathways that project to the thalamus, posterior hypothalamus, basal forebrain, and directly to the cortex itself Jones, . These tDuring the aging process, there is a clear disruption to the ARAS, whereby loss of neurons and receptors is associated with a compensatory increase in neurotransmitter system activity along the ascending pathways  population‐based cohort. Previous studies examining age differences in functional connectivity of ARAS nuclei have reported a complex pattern of results, with some connections increasing with age and others decreasing depending on the brain area  was taken from the population‐derived Stage 2 sample of the Cambridge Center for Aging and Neuroscience (Cam‐CAN) project  approximately equally distributed across the lifespan remained. Demographic information of the current sample is provided in Table A sample of 644 participants  in a 3 T Siemens TIM Trio, with a 32‐channel head‐coil. For resting state, 261 volumes were acquired, each containing 32 axial slices (acquired in descending order), with slice thickness of 3.7 mm and interslice gap of 20%  T1 and T2 weighted structural images were also acquired to aid registration across participants  and the automatic analysis (AA) batching system (http://imaging.mrc-cbu.cam.ac.uk/imaging/), T1 and T2 structural images were coregistered. Unified segmentation was performed on the combined images . The second step to reduce the effects of motion and other noise confounds was to apply multiple regression of the six original motion parameters as well as average signals from white matter (WM), and cerebrospinal fluid (CSF). We also regressed out the signal of the fourth ventricle due to its proximity to the nuclei of the brainstem  . For each subject, the Pearson's correlation coefficients were calculated between the preprocessed fMRI time series of each ROI and the time courses of all other ROIs and transformed to Z‐values using the Fisher transformation  mean connectivity within the ARAS, and between the ARAS and other brain networks, (b) mean connectivity within and between cortical networks, and (c) the effect of age on ARAS and cortical network connectivity  for our functional connectivity analysis included the ARAS structures from the Harvard Ascending Arousal Network Atlas , as age differences in segregation are typically strongest for these networks  was used as a mediator, so only one mediator , and covariates of no interest  were used as independent variables and cognitive subject scores as a dependent variable.33.1The ARAS nuclei were all positively correlated with each other  and increased between‐network  functional connectivity  and the age‐related increase in connectivity between the DMN and SN . Additionally, we also found two effects that were significant at p < .05, but did not survive FDR correction: ARAS–DMN connectivity was associated with the age‐related increase in connectivity between the DMN and DAN , and ARAS–SN connectivity was associated with the age‐related decrease in connectivity between the SN and DAN . Table To determine whether some of the age‐related variance in functional connectivity within and between the association networks is shared with age‐related differences in ARAS–cortex connectivity, we performed a series of mediation analyses  and identified that higher levels of ARAS‐association network connectivity  was associated with better levels of performance in all the cognitive tasks , and the direction of the interaction was such that increasing age strengthened the relationship between ARAS connectivity and cognitive performance profiles. It is worth noting that age was a continuous variable in the analysis, although for clarity of illustration in Figure To determine whether connectivity between the ARAS and association networks relates to cognitive functioning, we ran a canonical correlation analysis to identify relationships between ARAS‐association network connectivity and cognitive performance across a range of tasks. The first canonical vector was significant  characterize functional connectivity patterns of all brainstem arousal system nuclei and age differences therein, (b) test whether age differences in connectivity within and between association networks relate to age differences in ARAS‐association network connectivity, and (c) evaluate the relationship between ARAS–cortical connectivity and cognitive performance. Our results show that the ARAS nuclei have positive intrinsic connections, as well as positive and negative connections to the cortex, particularly the default mode and salience networks. In general, aging was associated with reduced ARAS‐association network connectivity and, replicating previous work, decreased within‐network and increased between‐network functional connectivity in the cortex. Additionally, consistent with our predictions, we found that functional connectivity between the arousal system and association networks was significantly associated with age‐related differences in connectivity within and between association networks, suggesting that age differences in ARAS functioning may contribute to altered cortical connectivity with age. Finally, we also found that higher connectivity between the ARAS association networks relates to better cognitive performance, and that this relationship is moderate by age.4.1Advances in neuroimaging have allowed for the investigation of arousal system functioning in humans and its effects on cortical activity and cognition (Beissner, Schumann, Brunn, Eisenträger, & Bär, We also examined the effects of age on ARAS connectivity. Within the ARAS itself, we found that some connections increased with age, while others decreased. In contrast, the effect of age on ARAS–cortical connectivity mainly consisted of an increase in negative connections and a reduction in positive connections, which was particularly pronounced for connections to the DMN and SN. Further, the locus coeruleus, periaqueductal gray, and dorsal raphe nucleus appeared to show the strongest age‐related decline in connectivity to the cortex, which could reflect age‐related physiological disruptions in the noradrenergic and serotonergic neurotransmitter systems Mather, .While our aging results largely align with previous work (Bär et al., 4.2The ARAS plays a critical role in cortical activation (Aston‐Jones, Anatomically, the ARAS nuclei have widespread projections to cortical regions, synthesizing and releasing modulatory neurotransmitters that affect neural activity across the cortex. Many studies have shown that pharmacological interventions on these neurotransmitter systems result in diverse changes in cortical network states, by altering the strength and topography of functional connectivity (van den Brink et al., The aging process is associated with structural degeneration and functional disruptions in the arousal system, which is thought to contribute to age differences in circadian and sleep–wake regulation (Mander, Winer, & Walker, 4.3We tested the multivariate association between ARAS‐association network connectivity and age‐related changes in cognitive performance given that maintaining cortical‐wide connectivity is increasingly important for performance in old age (Bethlehem et al., Our findings from the moderation analysis suggested that maintaining youth‐like ARAS‐association network connectivity becomes progressively more important for maintaining cognitive functioning in old age. This is consistent with previous findings based on neuronal signatures of cortical connectivity from magnetoencephalography data (Bruffaerts et al., 5In this study we showed the arousal system is functionally connected to widespread cortical regions and mediates age‐related differences in cortical networks. However, this study is not without limitations. First, we recognize that our cross‐sectional design is not ideal for capturing the true effects of age. Relatedly, significant mediation effects based on cross‐sectional data cannot be used to infer causality; thus, our results should be interpreted with caution. Changes in cortical connectivity associated with age could also be affecting age‐related changes in ARAS–cortical connectivity. Another limitation is that the ARAS nuclei are small structures located in regions very susceptible to physiological noise. We included a number of procedures to control for motion and reduce physiological noise, but improved signal definition from these small ARAS nuclei [e.g., by using a high‐resolution probabilistic atlas (Ye et al., Age differences in cortical connectivity are now well documented, but we still lack a thorough understanding of the mechanisms underlying those differences. Technological and methodological innovations in data acquisition and analysis are allowing for non‐invasive studies of ARAS functioning in humans. The results of this study and others suggest that the ARAS might play a critical role in determining age differences in the cortex and cognitive health.The authors declare no conflicts of interest.Appendix S1: Supporting InformationClick here for additional data file.


Previously, tumor resistance to chemotherapy has typically been described as selection for resistant tumor cell populations. However, Peschke et al (2022) demonstrated that PDAC cells seemed to acquire resistance not only through genetic changes, but also through modifications in cellular plasticity leading to gene expression and metabolism changes. Thus, the study supports this type of platform for the identification of new therapeutic targets following standard‐of‐care treatments in PDAC.Standard‐of‐care regimens for pancreatic ductal adenocarcinoma (PDAC) include a combination of chemotherapies, which are associated with toxicity and eventually tumor resistance. The lack of relevant tool to identify and evaluate new therapies in PDAC necessitates the search for a model, especially for cases with treatment resistance to standard of care. In the study from Peschke  M. E. Fernandez‐Zapico, T. L. Horgenson, and S. Sandhya discuss advantages of a longitudinal platform using patient‐derived organoids to identify new treatment regimens for pancreatic ductal adenocarcinoma patients following standard‐of‐care chemotherapy treatment as reported by M. Reichert and colleagues, in this issue of EMBO Mol Med.  Early metastatic progression, highly resistance to all current standard‐of‐care therapies including radio‐, and chemotherapy, makes it a devastating disease  provide advantages by being evolved as a reliable model to predict the drug response in cells having characteristics of individual patient tumors. Also, these 3‐dimensional (3D) cultures have heterogeneous structures mimicking the et al  validated MEK inhibitor (MEKi) sensitivity in a larger cohort of patients and confirmed chemotherapy‐induced vulnerability of cells following neoadjuvant therapy. Using PDOs, this study identified treatment‐imposed cell plasticity with diverse response for polychemotherapy as well as relevant targeted therapies.Further analysis identified the FOLFIRINOX treatment generated a resistance phenotype by inducing changes in cellular plasticity leading to new drug sensitivities. Peschke et al  performeThe authors demonstrate a vulnerability of cancer cells following chemotherapy treatment that is independent of genetic mechanisms. This demonstrates a need for additional testing using PDOs to identify new treatment regimens for sensitivity that evaluate more than the genetic landscape of the tumor. Additional studies examining these new pathways altered following chemotherapy treatment could benefit PDAC treatment options. The PDO model used in the study makes it a highly reliable and specific model for studying these mechanisms. This demonstrates another potential use of PDOs for identifying new cancer therapies for PDAC patients.