This model generated summary measures of connectivity strength that accurately predicted a residual measure of cognitive reserve in unseen participants. The theoretical validity of these measures was established via a positive correlation with a socio‐behavioural proxy of cognitive reserve  and a positive correlation with global cognition, independent of brain structure. This fitted model was then applied to external test data: resting‐state functional connectivity data from The Irish Longitudinal Study on Ageing . The network‐strength predicted measures were not positively associated with a residual measure of cognitive reserve nor with measures of verbal intelligence and global cognition. The present study demonstrated that task‐based functional connectivity data can be used to generate theoretically valid measures of cognitive reserve. Further work is needed to establish if, and how, measures of cognitive reserve derived from task‐based functional connectivity can be applied to independent resting‐state data.Cognitive reserve supports cognitive function in the presence of pathology or atrophy. Functional neuroimaging may enable direct and accurate measurement of cognitive reserve which could have considerable clinical potential. The present study aimed to develop and validate a measure of cognitive reserve using task‐based fMRI data that could then be applied to independent resting‐state data. Connectome‐based predictive modelling with leave‐one‐out cross‐validation was applied to predict a residual measure of cognitive reserve using task‐based functional connectivity from the Cognitive Reserve/Reference Ability Neural Network studies ( Task‐based fMRI may enable more accurate direct measurement of cognitive reserve (CR) but rs‐fMRI can be more widely used. Connectome‐based predictive modelling was applied to task‐based functional connectivity in a training dataset to predict a CR residual. The task‐based predicted values were validated as measures of CR but the task‐based model did not generalize to resting‐state data in an independent test dataset. CPMconnectome‐based predictive modellingCR/RANNCognitive Reserve/Reference Ability Neural Network studiesDMNdefault mode networkEPIecho‐planar imagingfMRIfunctional magnetic resonance imagingFPNfrontoparietal networkFWDframewise displacementLOOCVleave‐one‐out cross‐validationMAEmean absolute errorMNIMontreal Neurological InstituteMPRAGEmagnetization‐prepared rapid gradient echoNARTNational Adult Reading Testrs‐fMRIresting‐state functional magnetic resonance imagingSALsalience networkTEecho timeTILDAThe Irish Longitudinal Study on AgeingTRrepetition time1Cognitive reserve (CR) refers to a property of the brain that enables better‐than‐expected cognitive function given the degree of age‐related brain changes and brain injury or disease  that reflect the degree of exposure to various lifetime experiences thought to contribute to CR  and two other components: a measure of brain structure/pathology and a measure of cognitive function  provides a means of measuring global patterns of connectivity in generic or task‐invariant CR networks. In contrast to task‐fMRI, rs‐fMRI is unaffected by various individual‐level factors, including task difficulty Stern, , motivatVarious studies have identified associations between resting‐state connectivity in specific networks and CR proxies as well as protective effects on cognition. Educational attainment has been positively associated with connectivity of the frontoparietal network  studies , a nationally representative longitudinal cohort study of community‐dwelling older adults in Ireland . In addition to 200 volumes, four dummy volumes were acquired at the start of the rs‐fMRI scan and automatically discarded. Structural MRI data were acquired using a 3D T1 MPRAGE scan with the following parameters: field of view = 240 × 240 × 162 mm2.3https://github.com/rorytboyle/fMRI_QC.Each dataset was preprocessed separately with the same pipeline. Functional and structural images were manually reoriented to ensure approximately similar orientation in Montreal Neurological Institute (MNI) space. Images were visually inspected for artefacts, data quality issues, possible lesions, and severe atrophy. Images were preprocessed using SPM12 and fMRI images were corrected for slice‐timing and head motion. Nuisance regressors consisted of six motion estimates, mean white matter signal, mean cerebrospinal fluid signal, and mean global signal, and the derivatives, quadratic terms, and squares of derivatives of these nine parameters , 63 nodes within the cerebellum and brainstem were removed from all participants in each dataset . CPM consisted of the following steps: edge selection, network strength calculation, model fitting, model application, model evaluation as detailed in Figure R2) from a linear regression, and the mean absolute error (MAE), in line with best‐practice guidelines for predictive modelling in neuroimaging  was applied to the training set  from Step 1 to Step 2, and from Step 2 to Step 3 in linear regression models were used to assess the size of the independent and moderation effects of CR proxies, respectively. This analysis was conducted in Python .To assess the theoretical validity of the network strength predicted CR measures, their face validity and protective effects on cognition were investigated. Face validity was assessed by establishing if there was a positive association with a CR proxy, verbal intelligence, using Pearson's correlation. The protective effect was assessed by establishing whether they a) moderated the relationship between mean cortical thickness and global cognition , or b) were positively associated with global cognition, independent of mean cortical thickness . In hierarchical linear regressions, global cognition was regressed on age, sex, and mean cortical thickness in Step 1, with network strength predicted CR added as an independent variable in Step 2, and the interaction term for mean cortical thickness and network strength predicted CR included as an independent variable in Step 3. The change in 2.9R2, and MAE. Finally, as described above for the training set, the predicted CR values were assessed with respect to their theoretical validity as measures of CR.To evaluate if network strength predicted CR generalised to independent data, the trained CPM from CR/RANN was applied to TILDA data. First, positive and negative network strength values were computed by summing the positive and negative edges selected in each iteration of the LOOCV in the training set and dividing the sums by two to account for the symmetrical matrix. Combined network strength was computed as positive network strength minus negative network strength. Second, the regression parameters fitted in the training set were averaged across all iterations of the LOOCV and applied to their respective network strength values to calculate network strength predicted CR values. Third, these values were evaluated with respect to their predictive accuracy of the CR residual, using Pearson's correlation, 2.10The ‘36 Parameter’ preprocessing pipeline used here has been shown to attenuate motion‐related artefacts and noise in the data .The connectome‐based predictive models significantly predicted the CR residuals of novel participants  from task‐based functional connectivity data in the training set  and 12 edges  selected in every iteration of the positive and negative network, respectively  were significantly positively correlated with the CR residual.A negative correlation between network strength predicted CR values and observed values  is interpreted as a failure to explain any variance in the observed values  also failed to generalize , but not when applied to independent test sets  of the training set, nodes within the cerebellum and brainstem were removed from the functional connectivity matrices. This was necessary to avoid a drastic reduction in training set sample size but it reduced the number of edges in each connectivity matrix by 58%, from 35,778 to 20,910. The loss of this information in the training set, from a region that has been previously associated with CR  and socio‐economic diversity that may have influenced results. Given the recent finding that predictive modelling of brain‐phenotype relationships fails when applied to individuals who do not fit the stereotypical profile of the sample  that are significantly associated with a CR residual, positively correlated with a CR proxy, and demonstrate a protective effect on cognition, beyond the effects of brain structure. These findings were demonstrated on unseen data within the training set . However, the findings were not replicated when the model was applied to the test set . Recent developments in methods for relating functional connectivity to cognition include calculating latent functional connectivity using both task‐based fMRI and rs‐fMRI  show that the CR residuals are approximately normally distributed. Scatterplots with regression lines (bottom row) show significant positive relationships between CR residuals and NART scores, demonstrating the face validity of CR residuals as CR measures.Table S2 Results of multiple regressions used to create CR residuals in the training and test datasets.Table S3 Hierarchical regression results demonstrating average additional variance explained in global cognition across datasets.Table S4. Positive CR network functional neuroanatomy with nodes sorted by degree strength.Table S5. Negative CR network functional neuroanatomy with nodes sorted by degree strength.Table S6 CPM performance for prediction of CR residuals in both datasets using k‐fold cross‐validation in the training set.Table S7 Correlation of selected edges with CR residual in test set.Table S8 CPM performance for prediction of CR residuals in both datasets using an age‐restricted sample in the training set.Table S9 CPM performance and validation of network strength measures in the training set using less conservative edge selection threshold.Click here for additional data file.


In 2021 the UK government announced a new obesity policy requiring large out‐of‐home food outlets to provide mandatory in‐store calorie labeling on food and drink items. Public acceptability and engagement with obesity policies could influence the level of impact on wider public health particularly with population‐level policies such as calorie labeling. This study aimed to examine public responses and awareness of the policy using social media (Twitter) comments and Google trends data.This study examined responses to social media posts on Twitter (tweets) from the UK Department of Health and Social Care detailing the policy, implementation date and post‐implementation information about the policy's enforcement. The sentiments of the tweets were coded and the number of likes and replies extracted. This study utilized google trends to examine public awareness of the policy by extracting weekly relative search volume for relevant phrases such as “calorie labeling.”N = 197/71.4%). There were fewer tweets expressing a positive sentiment (N = 25/8.7%) and a neutral/no sentiment (N = 54/19.6%). There was no difference in the number of “likes” or retweets between tweets expressing positive or negative sentiments. Five themes were identified expressing negative sentiments (most common being negative impacts on eating disorders). Google trends data revealed increased searches for “calorie labels/labeling” during the week of the policy enforcement compared to previous weeks in the last 5 years but no significant differences in searches for specific menu calorie labeling.From the 276 replies/quote‐tweet extracted, the majority expressed a negative sentiment toward the policy (This analysis revealed negative sentiment toward and increased searching of calorie labeling information during the announcement and implementation of the 2021 mandatory calorie labeling policy in England. A greater understanding of public responses to calorie labeling policies may help tailor future policies and public communication strategies. In 2021 the UK government announced a new obesity policy requiring large out‐of‐home food outlets to provide mandatory in‐store calorie labeling on food and drink items. This study examines public responses and awareness of the policy pre and post‐implementation using Twitter comments and Google trends data. The wider food environment, particularly the OHFS, is thought to be a key contributing factor to increased prevalence of overweight and obesity both globally,appear to be helping improve public health without having to do very much.”mandatory calorie labeling policy requiring large‐scale food businesses (>250 employees) in England, to provide calorie labeling on food and non‐alcoholic drink items to address public health and combat rising obesity with the policy coming into effect in April 2022. The policy requires outlets in England selling food for immediate consumption  to provide calorie labeling on all unpackaged food and non‐alcoholic drink items on the menu for more than 30 days per year, alongside contextual information on recommended calorie consumption. Guidelines state that labeling should be clearly presented, legible and provided for all eligible food and drink items.In 2011 the UK public health responsibility deal was established by the UK government, in collaboration with members of the food industry, to address public health and combat rising obesity. A key component of this deal was for businesses to voluntarily provide calorie information on menus for food and non‐alcoholic drinks. Whilst several restaurants and cafes signed the calorie labeling pledge, a 2018 assessment found that less than 20% of UK restaurants provided any in‐store calorie content information.Similar policies have recently been passed in the USA,Positive public perceptions, awareness and engagement with health policies, particularly ones such as calorie labeling that rely on consumers noticing and use of provided information, may prove vital for a wider impact on public health and obesity levels.Some researchers have suggested that calorie labeling will be ineffective due to a lack of awareness or the noticing of the nutritional information by consumers.The Government should insist that restaurants and takeaways give information on the fat and calorie content of foods,” which supports findings from other countries . Google trends allows researchers to measure information seeking and consumer search behaviorStudies that use these methods could result in socially desirable responses and self‐selection of participants into studies.In the present research, online data sources from Twitter and Google were used to examine online public sentiment and awareness  of the 2021 national calorie labeling policy implemented in England. Twitter replies to three policy announcement tweets made by the government department responsible for its introduction , concerning mandatory calorie labeling policy were both quantitatively and qualitatively analyzed. Moreover, Google trends data in the weeks following the announcements were examined to explore potential changes in (i) public awareness of the policy and (ii) interest in the calorie content of menus in food outlets affected by the policy.22.12.1.1On two occasions prior to the policy implementation (May 2021), the UK DHSC sent tweets detailing the policy and when it would be implemented. Post‐implementation (April 2022) a further tweet was sent stating the policy was now enforced. The UK DHSC has a large , active (tweeting multiple times per day), and publicly accessible Twitter account.In line with previous research2.1.2https://trends.google.com/), allowing users to examine the relative search frequency of daily Google search terms. This can be tailored to a specific location  as well as time periods, and which Google product is used to search . Search results are normalized to represent a 0–100 scale, whereby each search term examined is divided by the total searches in that topic area during the specified time range; otherwise known as the relative search volume (RSV). Searches for a given topic have been used as a proxy for increased public awareness, for example, increased public awareness of Tuberculosis following World Tuberculosis Day.Google Trends is a publicly accessible online tool provided by Google Inc . This time period was also descriptively compared to equivalent time periods of previous years.To examine public awareness of the policy weekly RSV values for the terms “calorie labeling,” “calorie labels” were first extracted from Google trends over a 5‐year period (week commencing 2 July 2017 until the week commencing 18 June 2022). During these time periods we also searched “kcal labeling” and “kcal labels” however there was no search information for these. The RSV were then averaged across both search terms before From today, large UK restaurants and cafes have to display calorie counts on their menus as part of the government's drive to tackle obesity”—https://www.theguardian.com/society/2022/apr/06/calorific‐which‐high‐street‐meals‐are‐the‐most‐and‐least‐fattening), BBC news  and Daily Mail . The study focused on popular, well‐known businesses  to ensure individuals would likely be searching for information on these businesses. A mix of typical fast food and counter service restaurants were chosen, with different types of food served. Our searches included: McDonald's, KFC, Burger King, Nandos, Pizza Hut, Leon, Bella Italia, Starbucks, and Subway. Our search strategy was limited to two weeks prior to the policy implementation date (23 March 2022 to 05 April 2022) and two weeks following the implementation (06 April 2022 to 19 April 2022).To examine public interest in the calorie content of menus subjected to the policy the search terms were extracted from Google trends for 10 businesses with >250 employees that would be subject to the policy, followed by the word “calories.” It was reasoned this was a good proxy for awareness of the policy, as on the days following implementation the policy was covered in a number of large media sources including The Guardian , whereas negative tweets had to communicate a negative appraisal of the policy or the proposed effects . Tweets that were neutral in sentiment or did not have clear sentiment were coded as such. There was a high degree of agreement between the two coders (>90%). All disagreements were resolved between AJ and MP. Differences in the number of likes and retweets between tweets expressing positive and negative sentiment using Mann‐Whitney tests were also examined.For each tweet, or quote tweet the sentiment of the tweet was coded using the same guidelines as Stautz et al.Following sentiment analyses, Thematic AnalysisIn line with guidelines by Rivers and Lewis,2.2.2p‐value from the Z score of week of interest. The RSVs for “[restaurant name] calories” were then extracted during the search period 23 March 2022 to 19 April 2022. This provided us with 10 restaurants × 28 days = 280 RSV data points. To compare search volumes, the 2 weeks prior to the policy and post‐policy implementation were split and the search volumes compared using the Mann‐Whitney test. The RSVs were also combined for each out‐of‐home establishment on a daily basis (Averaging RSV across the 10 restaurants) and correlated this time (day 1–28) using Spearman's correlation. Data and analysis code is available on the Open Science Framework (https://osf.io/bu5jw/).Using the “gtrendR” R package33.1N = 197/71.4%). A much smaller number expressed a positive sentiment (N = 25/8.7%), and neutral/no‐sentiment tweets (N = 54/19.6%). There was no difference in the number of “likes” for tweets expressing negative  versus positive sentiment . There was also no difference in the number of retweets of tweets expressing a negative sentiment  versus positive sentiment The original DHSC tweets received a total of 186 likes, as of June 2022. From the 276 replies/quote‐tweets the majority expressed a negative sentiment . Five themes were identified expressing negative sentiment toward the policy, including: “Impact on eating disorders,” “Ignoring experts,” “Nanny state,” “Calorie counting,” and “Ineffective/Doesn't go far enough/Will be ignored.”Negative sentiment was related to the potential adverse effect of calorie labeling on individuals with eating disorders, with concerns that calorie labeling will increase the prevalence of eating disorders, impact recovery, and increase the likelihood of relapse. UK eating disorder charities have expressed concerns about the policies effect on people with eating disorders and this sentiment is largely reflected in the Twitter responses. “Beat,” the UK eating disorder charity argues against the implementation of mandatory calorie labeling after warning that calorie labeling “risks exacerbating all eating disorders.”In relation to this, a second theme identified was that the policy will be “ineffective/doesn't go far enough/will be ignored.” Multiple tweets expressed negative sentiments reflecting the potential harm toward individuals with eating disorders combined with the view that the policy will be ineffective at achieving aims to reduce obesity levels. This is in line with qualitative evidence in which individuals reported support for calorie labeling policies, but scepticism regarding their effectiveness.calorie counting” included tweets that expressed concerns that the policy approach may be oversimplistic as “calories in, calories out” is not a useful explanation of obesity.Similarly, the theme “In summary, most tweets expressed negative sentiments discussing calorie labeling policy with the overarching theme that the policy will be inefficient in reducing obesity levels. However, a minority of tweets (8.7%) were positive toward calorie labeling and there was no difference in how frequently negative versus positive tweets were endorsed by others online. Because polarized opinions  are more likely to be shared on social media, the tendency for Twitter responses to the policy to be largely negative is to be largely expected. Research examining the spread of information on Twitter found that increased negativity (but not positivity) predicted content sharing on Twitter when examining political content.Data from Google trends indicated that there was an overall increase in searches for calorie labeling around the period of policy enactment, specifically in relation to similar time periods in previous years (likely due to media coverage). However, the policy announcement did not significantly increase interest in calorie content of menu items in food outlets affected by the policy. This alongside research that has found low levels of noticing of calorie information in restaurants may indicate a lack of public interest in calorie content of labeled menu items.To our knowledge, this study is the first to examine public responses to the implementation of the 2022 calorie labeling policy in England. The data utilized offers a novel insight into online public responses without requiring participants to self‐select into a study (selection bias) or answer questions in a socially desirable way. However, it should be noted that tweets themselves are limited in length, and often contain unconventionally written expressions that can make it difficult to portray an in‐depth opinion or sentiment.Furthermore, a limitation is the inability to determine the demographics of the sample and therefore conclusions cannot be drawn on the representativeness or generalizability. The sample utilized was comprised of a small proportion of Twitter and internet users selected for inclusion based on engagement with the identified tweets (and presumably directly following or following others who follow the UK DHSC). Research suggests that men and people from densely populated areas are over‐represented on Twitter and user ethnicities proportions are not representative of the general population.Additionally, Twitter replies may provide a useful insight into immediate reactions to presented information, however they do not provide information on the deliberation time before the response or if the individual's opinion altered after more in‐depth deliberation. Evidence suggests that Twitter tends to have more negative communications,Twitter replies and Google trends data can offer valuable insight into public interest and opinions on health policies. In the present study, several negative themes were identified relating to the announcement and implementation of the 2021 mandatory calorie labeling policy in England when examining social media data. The study also found that although internet searches for calorie labeling increased upon implementation, there was no evidence suggesting that searches for calorie content information of OHFS foods increased. Future research is required to investigate whether the policy leads to a longer‐term increase in public interest of OHFS food calorie content. Furthermore, research should examine whether public perceptions of calorie labeling affects the level of reach and impact of the policy on public health.Conceptualization and methodology design contributions and project administration contributions were made by Megan Polden, Andrew Jones and Eric Robinson. The formal analysis, data curation, and original draft preparation contributions were made by Megan Polden and Andrew Jones. Supervision and funding acquisition were conducted by Andrew Jones and Eric Robinson. All authors contributed to revising the manuscript. All authors read and agreed to the published version of the manuscript.The authors declare no conflict of interest.


During recent years, it was discovered that hematopoietic stem and progenitor cells may also accumulate genetic aberrations with advancing age, resulting in clonal expansion of mutated cells: a process now referred to as clonal hematopoiesis (CH).The acronym “Clonal Hematopoiesis of Indeterminate Potential” (CHIP) was first proposed to describe the presence of CH in otherwise healthy individuals, at a VAF ≥2%.2When we detect clonal mutations in a patient with a blood count abnormality and a non‐diagnostic bone marrow, the question may be raised whether this indicates an early sign of a developing malignancy.Clonal dynamics, external pressures and progression to malignancy.Graphical illustration of clonal expansion potential and risk of malignancy development associated with recurrent gene mutations in the general population. Purple, DNA damage response genes; green, RNA splicing; blue, epigenetic regulators (including DNA methylation and histone modification); red, signal transduction.3Knowledge about the clonal dynamics over time and selective pressures that may drive clonal expansion is crucial for our understanding of the natural history of CH. The first studies on mutational data generated from longitudinal sampling have recently been published. Gene‐specific fitness effects determining clonal outgrowth were shown in the Lothian Birth Cohort.4Next to the presence of peripheral blood cytopenia or cytosis, increased clonal expansion, reflected by a higher clone size or VAF, has been associated with myeloid neoplasm risk and adverse health events across numerous studies.5Apart from gene‐specific trajectories, there is still considerable inter‐individual variation in growth trajectories, even when such individuals carry the exact same mutation. Bona fide driver mutations do not always lead to considerable expansion,6Recent work has refined our knowledge about the dynamics of clonal hematopoiesis in healthy individuals. Driver mutations are important determinants in the trajectory of clonal evolution—both in terms of expansion and risk of incident malignancy—and should be used to define a consensus spectrum of high‐risk CHIP or CCUS. Identification of extrinsic factors that can modulate clonal expansion may provide rationales for intervention studies.The authors declare no conflict of interest.


Readers of JCPP Advances known that the dominant classification system  in psychiatry and psychology conceptualizes psychopathology as discrete diagnostic categories. This measurement model builds on a strong assumption of a clear discontinuity between individuals who meet criteria for a diagnosis and those who don't fulfill diagnostic criteria. During the past decades we have seen huge efforts to test this assumption and explore alternative models, such as research from the hierarchical taxonomy of psychopathology consortia. Key findings of these efforts are reviewed and discussed in the December issue of JCPP Advances. JCPP Advances aims to lead and influence the field of child psychology and psychiatry. We are committed to stimulate discussion around fundamental questions via editorials, commentaries, and reviews. The review papers from Lahey et al.  and PlomReaders of JCPP Advances know that the dominant classification system  in psychiatry and psychology conceptualizes psychopathology as discrete diagnostic categories. This measurement model builds on a strong assumption of a clear discontinuity between individuals who meet criteria for a diagnosis and those who don't fulfill diagnostic criteria. During the past decades we have seen huge efforts to test this assumption and explore alternative models, such as research from the hierarchical taxonomy of psychopathology consortia , comorbidity  and developmental change  than the categorical model based on DSM. Finally, Lahey et al.  and Sonuga‐Barke (2022) highlight that the societal implications and clinical utility of replacing the available categorical model with dimensions remain unclear. Their insightful discussion covers two important themes that needs careful deliberation, discussion and further research. The first theme covers questions related to stigma. For example: Does diagnosis necessarily always increase stigma? What terminology should be used to minimize stigma related to psychopathology? The second theme deal with problems related to implementation of a substantially different diagnostic system for psychopathology. For example: Can clinical decision making about psychopathology ever be anything other than categorical? What cost would be associated with replacing the categorical system with a dimensional approach? Will replacing the available diagnostic nosology with a dimensional model improve the care provided to people in the clinic? How do we keep up a strong link between science and clinical practice to facilitate translational impact? As noted by others  at the top and several specific factors at lower levels such as neurodevelopmental, externalizing and internalizing problems  of cognitive abilities that accounts for the positive correlations among scores on the subtests of intelligence (Caspi & Moffitt, First, research have convincingly demonstrated that almost all forms of psychopathology are positively correlated with high rates of comorbidity. This observation challenges the assumption that different diagnoses are distinct and indicate that they may have common underlying causes. Research at the phenotypic symptom/trait level suggest that the correlated nature of psychopathology can be adequately captured by a hierarchical model that include a general factor of psychopathology (Second, a substantial number of behavioral genomic studies indicate that comorbidity is mostly genetic in origin and that genetic overlap among different conditions might reflect, at least partly, a transdiagnostic, genetically influenced general factor of psychopathology. Plomin  predictsThe dominant classification system in psychiatry and psychology conceptualizes psychopathology as discrete diagnostic categories. A substantial number of studies have asked fundamental questions about the nature of psychopathology related to dimensionality and the underlying structure. Findings from these studies challenge critical assumptions of this categorical model. Further developments of a theory‐based classification system that better align the nosology with data on the actual structure and etiology of psychopathology is, therefore, an important scientific goal.Henrik Larsson: Writing – original draft; Writing – review & editing. Erik Pettersson: Writing – original draft; Writing – review & editing.Henrik Larsson reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; and sponsorship for a conference on attention‐deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. Henrik Larsson is editor‐in‐chief of JCPP Advances. Erik Pettersson serves on the Editorial Advisory Board for JCPP Advances.


Ataxia–telangiectasia (A‐T) is a complex inherited disease associated with an increased risk of malignancy. Surveillance guidelines have demonstrated significant health benefits in other cancer predisposition syndromes. However, evidence‐based guidelines for cancer screening are not currently used in the United Kingdom for people affected by A‐T. This study aims to understand how people with A‐T and their parents feel about cancer surveillance using whole‐body magnetic resonance imaging (MRI) to inform the future development of cancer surveillance guidelines.We conducted semistructured interviews with people affected by A‐T. Data were analysed inductively using thematic analysis.Nine parents of children with A‐T and four adults with A‐T were interviewed. Five main themes emerged from the data, including (1) cancer screening was considered invaluable with the perceived value of early detection highlighted; (2) the cancer fear can increase anxiety; (3) the perceived limitations around current practice, with the responsibility for monitoring falling too strongly on parents and patients; (4) the need for effective preparation for cancer screening, including clear communication and (5) the challenges associated with MRI screening, where specific recommendations were made for improving the child's experience.This study suggests that stakeholders are positive about the perceived advantages of a cancer screening programme. Ongoing support and preparation techniques should be adopted to maximise adherence and minimise adverse psychosocial outcomes.People with A‐T and parents of people with A‐T were actively involved in this study by giving their consent to be interviewed. An independent parent representative contributed to the study, supporting the research team in interpreting and commenting on the appropriateness of the language used in this report. Therefore, this study seeks to understand the views of people with A‐T and their parents regarding the idea of an MRI‐based cancer surveillance programme before a planned feasibility trial of WB‐MRI scans for cancer screening in children and young people with A‐T.22.1The target sample size was 15 participants to capture a diverse range of views and ensure data saturation.Participants with A‐T were included if they had a formal diagnosis of A‐T and were over the age of 12. The inclusion criterion for parents was to have, or have had, a child with A‐T. This study was approved by the University of Nottingham Research Ethics Committee (Ref: 2787), and participants gave electronic consent before the interview.2.2The semi‐structured interviews were conducted by two research team members (R. N. and B. D. P.). The interviews were directed by a topic guide, which was tailored to parents of people with A‐T and people affected by A‐T  for parents and 9–20 min mean =  15) for adults with A‐T. The participants' characteristics are described in Table 5 for aduFive themes were identified from the data collected: (1) Cancer screening is ‘invaluable’, 2) Cancer fear can increase anxiety, (3) Current practice for caring for people with A‐T has limitations, (4) Effective preparation is essential for the cancer screening and (5) MRI screening presents challenges. Five subthemes were identified from four of the five main themes . In addition, some parents considered the regular monitoring that the cancer surveillance offers as proactive care, which is how they would like to see the health system working (quote#2). The families expressed positive views about the safety of MRI, in terms of avoiding the use of ionising radiation (quote#3).3.1.1Early detection was the main anticipated advantage of cancer screening mentioned by most participants, on the assumption that it could lead to earlier treatment and improved outcomes. Participants emphasised that if cancer is detected too late, the person with A‐T could experience worse health outcomes (quote#4). Participants reported that cancer surveillance might lead to the detection of other pathologies that might not be related to cancer, which was seen as an advantage of cancer surveillance (quote#5).3.2This theme captured the strength of fear participants felt about the risk of cancer associated with A‐T (quote#6).3.2.1Participants reported that a diagnosis of A‐T is a stressful and life‐changing event on its own. In addition, with this diagnosis comes the awareness of the increased risk of cancer associated with A‐T and the lack of treatment options. Therefore, parents are constantly worrying about cancer (quote#7).3.2.2When discussing the implications of having a cancer screening programme in place, the participants explained how they would experience some anxiety before the diagnostic test, not only because of the implications of the results but also because it is a reminder of the A‐T condition itself (quote#8 and quote#9). The participants discussed the fact that they could experience anxiety waiting for the results of the cancer screening. However, because they need to attend several medical appointments for other A‐T‐related issues, some participants mentioned that anxiety is often present in their lives and thus they have learned how to deal with these feelings (quote#10).3.3Participants discussed a range of medical specialists involved in the care of people with A‐T but reported a lack of oncological support (quote#11). The parents (particularly) reported constantly looking after their children's health, suggesting that they felt as if they were acting as doctors (quote#12).3.4This theme captured the need for tailored communication with age‐appropriate education and information before cancer screening.The participants believed that attending a medical centre/hospital for cancer screening would be acceptable for people with A‐T as they are used to having medical appointments. However, they reported the need to improve awareness about cancer screening. Parents need to be provided with information and education about the purpose of the screening before the MRI scan. Parents reflected that the support given to people with A‐T should be tailored to their age, experience, knowledge and background. Therefore, the information should be provided in layperson's terms (quote#13). When asked about what information should be provided, the participants highlighted the importance of knowing the technical aspects associated with cancer surveillance (such as the range of cancers that can be detected), the frequency of screening and the length of time to receive the results (quote#14).3.4.1Participants identified critical aspects that can help people with A‐T to undergo an MRI scan: the use of a mock scan, listening to music, watching a movie and allowing their parents in the MRI room. They indicated that the medical staff should be friendly and calm. An adult with A‐T reflected upon her experience having an MRI scan, which was improved by having frequent communication with the radiographer during the scan (quote#15). The influence of past experience on how the person with A‐T would feel about having an MRI scan was discussed, with most having previously had a scan, which might make them feel more comfortable with the procedure. However, the medical team should be aware of this to ensure they provide the necessary support (quote#16). Regarding blood tests, participants discussed that people with A‐T have regular blood tests and thus they learn how to tolerate these tests. They believed that healthcare professionals should be experienced with the procedure and explain how the blood test will be performed (quote#17).3.5This theme captured the challenges and some concerns regarding the practical and emotional aspects of the MRI scan.The participants expressed some concerns related to the practical aspects of having an MRI scan, such as claustrophobia, laying still, the noise, the length of the scan and the need for anaesthesia for some people (quote#18). Particularly, a participant with A‐T felt that from personal experience, people with A‐T should have the option to be anesthetised as it was quite difficult for her to lay still in the MRI scan, as the results could be inconclusive due to excessive movement (quote#19). However, the parents expressed worries related to the implications of being anaesthetised, which for them is one of the most concerning aspects of the cancer surveillance programme (quote#20).3.5.1Participants expressed that having the MRI available locally would provide a better experience by minimising the challenges of travelling to a distant centre. Nevertheless, they reported that they would be willing to travel far if that ensured they could have the cancer screening (quote#21).4This study explored the views and feelings of both people with A‐T and parents of children with A‐T regarding the use of WB‐MRI for cancer surveillance in A‐T. Our results show that cancer screening in A‐T is perceived as valuable and desirable by people with A‐T and their families. The participants highlighted early cancer detection as the main perceived advantage of cancer screening protocols, which could allow earlier initiation of treatment. Participants mentioned the emotional comfort that comes with proactive, regular medical checks, and feeling they are doing something positive for their health or their child's health. This is important because they feel there is a lack of support in A‐T regarding oncology. This could be particularly relevant following the COVID‐19 pandemic, where medical consultations are increasingly being performed remotely as telephone or video consultations, reducing the opportunity for a medical professional to physically examine the person with A‐T. These results align with previous studies that evaluate the psychosocial impact of cancer surveillance in people affected with Li‐Fraumeni. They indicated that overall participation in the cancer surveillance programme does not bring additional psychosocial burdens to people with LFS.Participants felt that screening could temporarily increase their levels of anxiety before the screening test, during the scan and while waiting for the MRI results. This was balanced by the recognition that living with A‐T is already emotionally demanding and as a result, they had built up the resilience needed to cope with any additional short‐term anxiety. These results are in accordance with previous studies showing that the highest anxiety levels are at baseline but then are reduced a few weeks after the scan, especially after getting the results.Some potential strategies to manage the anxiety and concerns associated with cancer surveillance protocols were identified. Participants highlighted the importance of having continuous communication and support from their medical team, which should be tailored to their knowledge and experience. An important note that needs to be considered is that the speech in people with A‐T is often affected, therefore the medical consultation should not be time restricted and perhaps should have a family member or a friend who can facilitate the communication. The participants mentioned the importance of ongoing education and information about the cancer risk in A‐T and the advantages of adhering to cancer screening guidelines. This is in line with previous studies that mentioned regular appointments as an opportunity for families affected by LFS to express their worries and to receive appropriate support.Parents in this study reported that they face difficulties knowing when and how to discuss the cancer risk associated with A‐T with their children. It is therefore important that health professionals are able to make use of the best practice to build parents’ confidence. For example, the World Health Organisation guideline for HIV counselling has highlighted the psychological and health benefits of disclosure to children and outlines evidence‐based strategies to improve the disclosure process.Participants suggested that detailed information about technical aspects of a cancer screening programme, such as the frequency of screening, the length of time to receive the results and the diagnosis performance of WB‐MRI scans, needs to be discussed before participation in a cancer screening programme. This information would help to reduce the anxiety levels experienced before participation and enable informed decision‐making. These results are highlighted in previous trials that study the psychosocial impact of using WB‐MRI for cancer surveillance in people with LFS.The participants mentioned challenges associated with WB‐MRI, such as the length of the scan, the noise of MRI scans and the need for anaesthesia for some people. They emphasised that preparation is the key to helping their children to undergo the MRI scan. The value of adequate preparation for children undergoing MRI scans is confirmed in the literature.4.1This study has limitations that should be considered. First, the adults with A‐T interviewed were all female, so our study does not have the perspectives of male adults with A‐T. Second, we did not have the chance to assess the feelings of children with A‐T between twelve and eighteen years old about cancer surveillance. Our difficulty recruiting people with A‐T in this age group may have been due to parental reluctance to bring their children into discussions on this sensitive and potentially upsetting topic. Thirdly, overall recruitment was lower than expected, possibly due in part to the COVID‐19 pandemic, as we had hoped to recruit through parent workshops and A‐T family events. Although online interviews offered convenience, and participants were provided with details of additional support in our patient information sheet, it may have been more acceptable and appropriate to recruit to face‐to‐face interviews in supportive settings. However, a sample size of 13 exceeds the suggested minimum of 12 interviews necessary to ensure data saturation (39).5In summary, our results suggest that WB‐MRI for cancer screening will be accepted and welcomed by people with A‐T and their families. The responsibility and pressure of managing a life‐limiting condition such as A‐T was acknowledged by participants in this study, and our results suggest that parents and people with A‐T perceive that the benefits of early cancer detection would outweigh the additional psychological burdens of screening. In addition, parents and adults with A‐T were able to suggest strategies to reduce the psychological impact of a cancer surveillance programme, including ongoing clinical support and continuous communication to provide psychosocial care.Study conception and design: Robert A. Dineen, Cris Glazebrook, Rafal Panek, Sophie Wilne, Mohnish Suri, William Whitehouse, Sumit Jagani, Madhumita Dandapani. Recruitment: Renata Neves, Blanca de Dios Perez, Tierney Tindall. Data collection: Renata Neves, Blanca de Dios Perez, Tierney Tindall. Analysis and interpretation of results: Renata Neves, Blanca de Dios Perez, Madhumita Dandapani, Robert A. Dineen, Cris Glazebrook. Draft manuscript preparation: Renata Neves. Manuscript review and editing: Renata Neves, Robert A. Dineen, Cris Glazebrook, Rafal Panek, Sophie Wilne, Mohnish Suri, William Whitehouse, Sumit Jagani, Madhumita Dandapani, Blanca de Dios Perez, Tierney Tindall, Natasha Schneider Fernandez.The authors declare no conflict of interest.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.


KRAS‐type traditional serrated adenoma. It has also been reported that SuSA may have malignant potential.A new subtype of serrated lesions, superficially serrated adenoma (SuSA), has been proposed as a lesion that histopathologically exhibits the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one. SuSA has been elucidated to be a precursor lesion of H pit pattern and the flattened area had a stellate to slightly elongated type IIIH pit pattern diagnosed based on Kudo's classification and other pit pattern classification systems. Ki67‐positive cells were distributed in the basal and middle layers of the gland in the flattened elevated area. Genetic analysis results were positive for KRAS mutation and negative for BRAF mutation. Histopathological examination revealed a traditional serrated adenoma in the pinecone‐like structure and SuSA in the adjacent flattened elevated area.We report a case treated with endoscopic submucosal dissection and detailed observation. Endoscopy revealed a raised lesion with a two‐tier raised appearance in the sigmoid colon: a tall pinecone‐like reddish structure and flattened whitish elevation on white light imaging. Magnifying narrow‐band imaging revealed conspicuous blood vessels in the pinecone‐like structure and slightly dilated reticular vessels in the flattened area. Crystal violet staining showed that the pinecone‐like structure had a type IV KRAS‐subtype traditional serrated adenoma (TSA), it may have malignant potential.Superficially serrated adenoma (SuSA) was proposed as a new subtype of serrated lesions by Hashimoto et al.To date, there are still few reports on the clinicopathologic features and detailed endoscopic findings of SuSA. Herein, we report a case of TSA with SuSA carefully detected by colonoscopy and treated with endoscopic submucosal dissection, wherein an immunohistochemistry analysis was performed.A 74‐year‐old woman was referred to our hospital for endoscopic resection of a polyp in the sigmoid colon. Colonoscopy showed a raised lesion, approximately 25 mm in size, with a two‐tier raised appearance in the sigmoid colon, consisting of a tall pinecone‐like structure and a flattened elevation Figure . The pinH‐type pit pattern, diagnosed based on Kudo's classificationH‐type pit pattern  revealed conspicuous blood vessels in the pinecone‐like structure Figure  and slign Figure .Based on these findings, endoscopic submucosal dissection was performed, considering the TSA in the pinecone‐like structure and adenoma or SuSA in the adjacent flattened structure. The patient underwent an en‐bloc resection without any adverse events.Histopathological examination revealed a dense proliferation of the glandular ducts with pseudostratified nuclei and a serrated surface around the TSA lesion, forming tall ridges Figure .Immunohistochemical staining showed that CK20 was expressed in the upper layer of the flattened structure adjacent to the TSA lesion Figure .Ki‐67 and MYC expressions were distributed in the basal and middle layers of the flattened structure Figure . AdditioKRAS mutation and negative for BRAF mutation. No tests could be performed for RSPO fusions. The histopathological findings and KRAS mutation strongly suggested the possibility of TSA with SuSA.Genetic analysis revealed positive results for In 2018, a new subtype of serrated lesions, SuSA, has been proposed as a new subtype of serrated lesions that manifests the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one.RSPO mutation/overexpression in 95% of both TSA and SuSA components and KRAS mutations in all patients.In a report examining 21 cases of TSA with SuSA by Mizuguchi et al., the median age was 67 years, of which the majority was female. All lesions were located in the sigmoid colon or rectum and had a median diameter of 15 mm. Genetic analysis results showed Endoscopic findings revealed a two‐tier raised elevation, with a flat portion (SuSA) and a taller elevated portion (TSA). The SuSA portion appeared white, whereas the TSA portion appeared reddish on white‐light imaging.H pit pattern in the SuSA areas.Although the NBI findings clearly showed blood vessels in the TSA area, none were observed in most SuSA areas. Chromoendoscopy revealed a type IIIKRAS and BRAF mutations. They found that all TSA with associated lesions showing KRAS mutations were located in the distal colon. These lesions were considered SuSA‐like lesions and reported to show a type IIL pit pattern in the associated portion without endoscopic mucus signs or II‐Open pit pattern.Tanaka et al. studied the histopathology of TSA and its associated lesions according to L. All these lesions had KRAS mutations without BRAF ones and were reported to be similar to SuSAs.RSPO fusion/overexpression at a high rate in both TSA and SuSAs in these reports, TSA presenting with a two‐stage elevation in the distal colon with KRAS mutations may be considered associated with SuSAs.All lesions in previous reports were located in the distal colon and had sessile‐elevated central components resembling mixed adenomatous morphology and included various pit patterns such as typeIV with serration, type II, and type IIIIn our case, the flattened component of the two‐stage elevated lesion, the SuSA, showed a type II pit pattern, a stellate cap with an elongated type II pit pattern, and a partially branching pit pattern. In addition, the flattened component showed a network pattern of vessels on NBI.Although vascular structures have not been reportedly recognized in approximately 80% of SuSA lesions, vessels could be seen in our case, and the caliber of the vessels in the flattened component was similar to that in the surrounding normal mucosa. Therefore, this lesion was diagnosed as similar to type I according to the Japan NBI Expert Team classification.KRAS mutations in both lesions, without performing analysis for RSPO fusions, as the RSPO gene fusion test could only be performed in a limited number of facilities.Genetic analysis showed Since the SuSA may not only be a precursor lesion of TSA but also have malignant potential,None.


Authors declare no conflict of interests for this article.To editor:Tan and colleagues summarized real‐world clinical data on the adverse events associated with the use of cryoballoon catheters for atrial fibrillation.The rate of procedure‐related complications is supposed to decline with the innovation of novel devices and improvements in procedural techniques. In another large‐scale study, the procedure‐related complication rate decreased significantly from the early era (2013 and 2017) to the late era (2018 and 2022).Phrenic nerve palsy and cardiac tamponade are well‐known procedure‐related complications. Most paralysis is transient. Thus, the novelty of the authors' study is unclear. For example, an intra‐age comparison of the procedure‐related complication rates may be interesting to demonstrate the feasibility of this treatment in elderly patients. A previous study demonstrated a comparable procedure‐related complication rate in elderly patients to the young patients. Observation of natural breathing during the procedure may be a key to early detection of phrenic nerve palsy.


Although Cognitive Behavioural Therapy (CBT) is effective for 60% of adolescents with anxiety disorders, only 36% are in remission post‐intervention. This indicates that more effective treatments are needed which should be reflected in the NICE guidelines. We hypothesised that Single‐case experimental designs (SCEDs) may provide a framework for accelerating the development of novel interventions. The primary purpose of this review was to investigate whether SCEDs are currently followed by randomised controlled trials (RCTs) of CBT intervention for adolescent anxiety disorders named in the NICE guidelines. The secondary objective was to investigate whether using SCEDs prior to RCTs could be a helpful approach.For the primary search of SCEDs five databases were used . Nineteen articles met eligibility criteria including a total of 107 participants. For the secondary search of RCTs named in the NICE guidelines for adolescent anxiety disorders 53 articles met inclusion criteria and were included in the systematic review.The 19 SCED studies included in the review were conducted with participants with a diverse range of anxiety disorders and across a range of CBT formats. Two of the SCEDs were followed by RCTs, but neither of these were named in the NICE guidelines for anxiety disorders. All of the SCEDs identified were rated as low quality with none meeting the criteria for the highest or second highest quality rating. From the secondary searches, none of the RCTs named in the NICE guide were preceded by SCEDs.It was concluded that currently SCEDs were not followed by RCTs of CBT interventions named in the NICE guidelines for adolescent anxiety disorders. However, it was suggested that SCEDs may provide an important framework for the development of more effective interventions for adolescents with anxiety. Cognitive Behavioural Therapy (CBT) is effective for 60% of adolescents with anxiety disorders, but only 36% are in remission post‐intervention. This suggest that more effective treatments are needed.Historically it takes an average of 7 years from grant application to randomised controlled trials (RCT) publication and 17 years for research evidence to reach clinical practice.We suggested that SCEDs could be used to identify interventions most likely to be efficacious and prioritise them for RCT funding, accelerating the process of treatment development.We found that currently SCEDs are not being routinely used prior to RCTs of CBT interventions for adolescent anxiety disorders named in the NICE guidelines.However, we found evidence that SCEDs were being used to provide high‐quality evidence for a diverse range of CBT interventions for adolescent anxiety. This included groups of young people for whom RCT evidence is unavailable.This study demonstrated that using SCEDs prior to RCTs of CBT interventions for adolescent anxiety is a helpful approach and could lead to more effective treatments for young people with anxiety disorders. This finding has significant implications for research policy and clinical practice.Cognitive Behavioural Therapy (CBT) is an evidence‐based treatment for anxiety and related disorders in children and adolescence  Smith, . In the Similarly to case studies, SCEDs are also relatively low‐cost and can be conducted on a far smaller scale than RCT designs. The methodological strengths of the SCED approach also means that they are considered higher quality evidence than case series on the NICE hierarchy and of sufficient quality to influence guidelines development To investigate whether SCEDs were currently followed by RCTs of CBT interventions named in the NICE guidelines for child and adolescent anxiety disorders. The primary method will be a systematic search of databases for SCEDs of CBT interventions for adolescent anxiety disorders. This will be supplemented by a secondary backwards search of RCTs currently cited in the NICE guidelines. These results will then be cross‐referenced with the identified SCEDs.B)1)Are there high‐quality SCEDs of CBT interventions for adoelscent anxiety disorders in the literature?2)Do SCEDs of CBT interventions for adolescent anxiety disorders lead to subsequent RCTs of the intervention?3)Is SCED study quality predictive of whether there is a subsequent RCT?4)Are SCED results predictive of subsequent outcomes in RCTs, where an RCT has followed a SCED?To assess whether it would be useful to use SCEDs prior to RCTs by answering the following questions:The purpose of this systematc review is:https://www.crd.york.ac.uk/prospero/) on 28.04.22. Registration number: CRD42022320071.The conduct and reporting of this systematic review is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement  of CBT interventions for adolescent anxiety disorders.The study had to be published in English, or with an English translation available.Peer‐reviewed journal articles and unpublished manuscripts were included. The rationale for the latter was that SCEDs may be used in early stage treatment development and therefore not published in peer‐reviewed journals.The study reports the results of a Single‐Case Experimental Design (SCED) as defined by the methodology Smith, . SCEDs aThe study population is adolescents. As with other meta‐analyses of adolescent anxiety disorders  framework as defined by the study team. Meaning that any interventions where the authors used the term “CBT”, “cognitive behavioural therapy” or similar terminology were included. Where this was unclear the description of the intervention was reviewed to ascertain whether it was based upon cognitive behavioural therapy principles  and examined by a second independent researcher. The inter‐rater agreement was 96.25%. Any conflicts of opinion regarding study eligibility were discussed until a consensus reached. Sixty‐eight articles then received a full‐text review for eligibility. Nineteen articles were included in the systematic review which included a total of 107 participants. 10%  and were screened by the second independent researcher for suitability, with inter‐rater agreement of 100%. Of the 45 excluded papers, 1 was excluded as the paper could not be accessed and the author did not respond to an email requesting the paper. Fourty‐four papers were excluded as they did not meet eligibility criteria.Articles were identified, screened and then assessed following PRISMA guidelines  in order to minimise the probability of errors. Socio‐demographic and clinical characteristics were extracted from the eligible studies. Whether the SCEDs were followed by an RCT was also determined by doing a ‘cited by’ search in the databases. Based on the assumption that if there was a subsequent RCT, it would cite the prior SCED. This was reported as a binary outcome (Yes/No). If an RCT was conducted, this was then cross‐referenced with the list of RCTs reported under the ‘Evidence’ section of each of the NICE guidelines for anxiety disorders and it was recorded whether the RCT was named in the NICE guidelines (Yes/No). Whether the results of the SCED was predictive of the RCT outcome was also reported, defined as a binary outcome (Congruent/Incongruent). It was recorded as congruent if both the SCED and RCT reported the same outcome, that is, that the intervention was effective or non‐effective. It was not possible to report and compare effect sizes, as the required information was not included in the SCED studies.a)Participant sampleb)Participant mean agec)Participant age ranged)Participant gender composition e)Sample sizef)Target anxiety disorderg)Delivery method of CBT intervention h)Outcome measure used for repeated measurementi)Was the SCED followed by an RCT (Yes/No). If so:i)Were the results of the SCED predictive of the RCT outcome? (Congruent/Incongruent). Operationalised as whether both reported the same outcome regarding the interventions efficacy. Whether a SCED was classified as efficacious was determined by the results of Tau‐U analysis Was the RCT named in the NICE guidelines for child and adolescent anxiety disorders (Yes/No)The data extracted included:If data were not reported  it was calculated by the primary researcher where possible. If data was not available then this is indicated by ‘– ‘in the table. No effect sizes were calculated as this is not typical within the SCED approach, with the studies also not giving sufficient information to allow for effect size calculation.The RoBiNT scale  named in the NICE guidelines for anxiety disorders. The search included all RCTs named in the ‘evidence’ section of the relevant NICE guidelines as of April 12The study had to be published in English, or with an English translation available.The study reports a randomised controlled trial (RCT)The study was conducted with adolescents. Defined as ages 11–18 (as above).The intervention is based within a Cognitive Behavioural Therapy (CBT) framework as defined by the study team.The study is listed under the “Evidence” section for one of the NICE guidelines for generalised anxiety disorder (GAD) and panic disorder NICE, , PTSD N, SAD NI and OCD Inclusion/exclusion criteria:The source of the information was the ‘Evidence’ sections of the NICE guidelines for anxiety disorders. This included the guidelines for GAD and panic disorder NICE, , PTSD N, SAD NI, and OCDwww.random.org) and examined by a second independent researcher. The inter‐rater agreement was 100%. Ninety articles then received a full‐text review for eligibility, with 52 articles meeting criteria for inclusion in the systematic review. 10% of these articles were selected at random using a random number generator (www.random.org) and were screened by the second independent researcher for suitability, with inter‐rater agreement of 100%. 37 Articles were excluded. Six due to inaccessibility and 31 not meeting inclusion criteria.The RCTs were then systematically screened to identify eligible studies. See Figure A)Participant mean ageB)Participant age rangeC)Target anxiety disorderD)Was there a previous SCED (Yes/No)Data were extracted and brief socio‐demographic and clinical characteristics were reported. Whether there was a previous SCED was determined by a search of the manuscript, on the assumption that if there was it would be cited. The characteristics reported included:The studies included within the systematic review were synthesised before being summarised narratively. This approach follows published guidelines Whether SCEDs of CBT interventions for adolescent anxiety disorders are followed by RCTs, and whether these RCTs are named in the NICE guidelines.2)a)Are SCED results predicitve of subsequent outcomes in RCTs?b)Are there high‐quality SCEDs of CBT interventions for adoelscent anxiety disorders in the literature?c)Is SCED study quality predictive of whether there is a subsequent RCT?Whether it would be useful to use SCEDs prior to RCTs by answering the following questions:Therefore, the synthesis covered the following categories:It was not expected that there would be a sufficient number of homogeneous studies to conduct a meta‐analysis. Within the SCED approach it is not typical to report effect sizes and so this was not included, with the studies also not giving sufficient information to allow effect size calculation.M = 13.70% and 40.3% of the total sample were male. The target anxiety disorder of the interventions varied, GAD (n = 2), OCD (n = 3), PTSD (n = 4), Phobia (n = 1) and Hoarding (n = 1). Several of the studies did not specify a specific anxiety disorder and used the term “anxiety” or “childhood anxiety” more generally (n = 3) whilst others reported on participants with multiple comorbid anxiety disorders (n = 5).In total 19 SCED studies met inclusion criteria. Table n = 45) with the others being RCTs of CBT interventions for SAD (n = 5), childhood anxiety (n = 1) and OCD (n = 1).Fifty‐Two RCTs also met the inclusion criteria of the backwards searches and are reported in Appendix Are SCEDs of CBT interventions for adolescent anxiety disorders followed by RCTs? Are SCED results predictive of RCT outcomes? And are these RCTs are named in the NICE guidelines?Of the 19 SCEDs included in the review, two had subsequent RCTs (Farrell et al., Are there high‐quality SCEDs of CBT interventions for adolescent anxiety disorders in the literature?The total RoBiNT (Tate et al., Is SCED study quality predictive of whether there is a subsequent RCT?T‐test to further examine the relationship between study quality and whether there was a subsequent RCT.No clear evidence of a relationship between SCED quality and recency of publication was identified. Within the internal validly subscale, which is used to calculate the RoBiNT quality level, the lack of blinding and ratings of interrater agreement and treatment adherence were significant areas of weakness. The two studies which had subsequent RCTs had RoBiNT ratings of 15 (Kane & Kendall, This systematic review identified 19 SCEDs of CBT interventions for adolescent anxiety disorders that were published over a 31‐year period. Nineteen eligible studies are relatively few, suggesting that the methodology has yet to become commonplace for the evaluation of CBT interventions for adolescent anxiety disorders. However, 13 of the 19 studies identified were published since 2010, which may indicate that the approach is beginning to increase in popularity.Of the 19 SCEDs, only two resulted in RCTs of the intervention (Farrell et al., Another finding was that neither of the RCTs that were conducted following SCEDs were named in the NICE guidelines. However, there is a recent addition to the literature (Farrell et al., This finding is surprising due to the clear rationale for this approach and because one of the SCEDs identified (Kane & Kendall, There are several possible reasons for the finding that SCEDs are not typically being followed by RCTs, including the low quality scores identified on the RoBiNT scale. However, caution should be taken when interpreting these ratings. Although the RoBiNT is specifically designed for SCED studies, historically SCEDs have primarily been used within the field of behavioural and educational interventions Smith, , rather Although this review found that SCEDs are not routinely used prior to RCTs of CBT interventions for adolescent anxiety disorders, there was evidence to suggest that this approach could be helpful. The SCEDs identified targeted a range of anxiety difficulties. This included CBT therapy for populations that have not yet had interventions evaluated in RCTs, for example, adolescent hoarders (Knight et al., A limitation of this review is that there are inconsistencies in the terminology used within the literature to describe the SCED approach. Therefore, it is possible that there may be some SCEDs not identified during the searches that would meet the criteria for this review. A second limitation was that inter‐rater percentage agreement was used instead of Cohen's Kappa due to the small sample size. Furthermore, the main finding that SCEDs are not used prior to RCTs of CBT interventions named in the NICE guidelines for adolescent anxiety disorders was based upon searches of the current literature. However, on average there is a 7 years delay from RCT grant application to publication (Riley William et al., Approximately 60% of adolescents report improvements in anxiety following CBT treatment (James et al., The primary purpose of this systematc review was to investigate whether SCEDs of CBT interventions for adolescent anxiety and related disorders were followed by RCTs named in the NICE guidelines. The secondary objective was to assess whether it would be helpful to use SCEDs prior to RCTs in this population. It was found that there were 19 SCEDs of CBT interventions for adoelscent anxiety and related disorders, however only two had subsequent RCTs and these were not named in the NICE guidelines. It was also identified that no RCTs named in the relevant NICE guidelines were preceeded by SCEDs. However, evidence that this approach could be helpful was also found. SCEDs had been used to evaluate a diverse range of interventions for adolecent anxiety and related disorders in a range of real‐world settings. This included populations whereby SCEDs were being used to providde evidence of sufficent quality to be used as the basis for treatment recommendations NICE,  when RCTTom Cawthorne: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Writing – original draft. Anton Käll: Conceptualization; Formal analysis; Methodology; Supervision; Writing – review & editing. Sophie Bennett: Conceptualization; Investigation; Methodology; Project administration; Supervision; Visualization; Writing – review & editing. Elena Baker: Data curation; Formal analysis; Project administration. Emily Cheung: Data curation; Project administration. Roz Shafran: Conceptualization; Formal analysis; Methodology; Supervision; Writing – review & editing.The authors have declared that they have no competing or potential conflicts of interest.Ethical approval was not required for this research review.Supporting Information S1Click here for additional data file.


Adolescent and young adult (AYA) cancer patients and survivors face significant mental health challenges throughout their cancer journey that are different to those faced by children and older adults. Patient‐reported outcome measures (PROMs) can be used to explore the experiences of AYAs, and to identify important issues and areas for potential improvement in quality of life.We aimed to compare patient reported mental health outcomes between AYAs diagnosed with cancer and non‐cancer controls.We built on a larger systematic review of AYA cancer PROMs which searched PubMed, EMBASE, CINAHL and PsychINFO. This review identified 175 articles, which were filtered to those reporting on mental health and including a non‐cancer control group.We identified 12 eligible studies. Seven studies (58%) found those diagnosed with cancer reported poorer mental health than the non‐cancer controls. The remaining five (42%) studies found no significant difference in severity or prevalence of mental health between the AYA cancer cohort and the healthy control group. Most (83%) were cross‐sectional studies, highlighting the need for further longitudinal assessment of this group throughout their journey.The mental health outcomes feature conflicting results and illustrate the need for larger studies to characterise discrepancies. They are often taking on educational challenges; they are developing key relationships and forming their identity. A diagnosis of cancer and the treatment it entails, can disrupt their goals, tear social bonds, affect family lives, lead to increased dependence on caregivers and even lead to the loss of reproductive capacity.Survivors of AYA cancer are at risk of mental health challenges including anxiety, depression and other mood disorders.One form of investigating outcomes, often used in cancer patients, is through patient‐reported outcome measures (PROMs). PROMs are instruments or tools used to collect information on patient outcomes, as directly reported by the patient through questionnaires.This study builds on the work of a systematic review that identified the PROM domains measured and PROM tools used in AYA cancer patients to understand various outcomes and challenges.2An initial systematic review was undertaken, the full details of which are described elsewhere.Inclusion criteria were, AYA focused ; diagnosed with a malignant neoplasm; and PROM as a central outcome. Publications that reported on PROM validation studies, protocols or outcomes for family or caregivers only were excluded.Manuscripts first underwent a title and abstract review, conducted independently by two out of three reviewers . Consensus was obtained via discussion at a team meeting with all three authors. Cohen's Kappa for title and abstract review was 0.59, representing moderate agreement. Manuscripts subsequently underwent a full‐text review, at which time additional exclusion criteria were applied: inability to identify full text; not written in English; or review article. Again, this was undertaken independently by two out of three researchers . Consensus was again obtained via discussion at a team meeting with these reviewers. Cohen's Kappa for the full‐text review was 0.69, representing substantial agreement. The final papers underwent data extraction for the relevant information.mental component summary (MCS), measures of self‐reported mental health as an outcome or measures of self‐reported anxiety or depression. Other components of psychological wellbeing such as distress, stress or emotional function were considered as separate domains, and were therefore not included as part of this review. All identified mental health manuscripts were then re‐reviewed for the specific exclusion and inclusion criteria. Only studies with a cancer‐free AYA comparison group were included. For this review, a cancer‐free AYA comparison group included either a separate control group of cancer‐free peers that were studied, or AYA population norms. Studies using a cross‐sectional comparison between the groups were included regardless of the number of comparison time points. A reverse reference search of all identified manuscripts was undertaken to identify additional relevant studies that may have been missed in the initial review. Finally, the included manuscripts underwent further data extraction which included additional details of the mental health measures along with the outcomes for both AYAs with and without cancer.Manuscripts identified during the data abstraction phase that used a PROM tool to measure a mental health outcome were considered for inclusion in this systematic review. These included—measures of Two authors assessed each study for risk of bias using the risk of bias in non‐randomised studies of interventions (ROBINS‐I) tool.33.1Twelve articles met the inclusion criteria and were included in the final review Figure . A reverThree studies used the Short‐Form‐12 Scale (SF‐12).Four of the studies limited their inclusion criteria to certain types of cancer. One specifically looked at breast cancer.The complete assessment of the risk of bias among the included studies is presented in Table 3.2The three BRFSS papers studied 8375,Due to the overlap in samples, the following patient characteristics will only be reported from the nine non‐BRFSS studies. In total, 2974 participants were included in the other studies. This includes participants who were AYA cancer patients at the time of the study, and individuals who were longer term survivors following a diagnosis of cancer in their AYA years.Four studies reported mean age both at diagnosis and time of study.The sex of participants was reported in all studies. There were a total of 1821 (61.2%) women and 1153 (38.8%) men.3.3Two of the studies used country specific population norms—one was age‐matched,3.43.4.1Five studies found no significant difference in severity or prevalence of anxiety and depression between the AYA cohort and the healthy control group.p < 0.001).The three studies that used the BRFSS survey data all found that the number of poor mental health days per month was higher in survivors of AYA cancer than in control groups.Three studies identified that survivors reported worse mental health, in terms of both self‐perception of mental health and in anxiety and mood disorders diagnosed by a healthcare professional.A further study found that the AYA patients scored statistically significantly lower  than the AYA‐specific age‐matched US norm on the mental health aspect of the SF‐12 survey, but only in the age groups of 25–34 and 35–41 year‐olds, and not among 18–24 year‐olds, where a statistically significant difference was not found.3.4.2p = 0.001).p = 0.008).Three studies compared mental health outcomes between males and females, focused on survivors of AYA cancer.Sociodemographic factors that were associated with worse mental health in female survivors included having a migration background,The impact of age on mental health outcomes in this group compared to cancer‐free peers was also examined and the findings suggest that the 20‐ to 29‐year‐old age group is the most vulnerable. One study found that age played a role, with the poorest mental health found in survivors aged 20–29 years old.p = 0.021) for depression and 3.1 (p = 0.010) for anxiety,p < 0.001) overall.Health and cancer factors were also found to affect mental health in AYAs. Tumour type, for example, made a difference, with one study finding that patients with germ cell tumours were more likely to have favourable mental health outcomes than lymphoma patients.4In this systematic review of 12 studies, we provided a comprehensive overview of self‐perceived mental health among AYA cancer patients and survivors compared with healthy peers. A small majority of these studies (7/12) found statistically significantly worse mental health outcomes among the cancer cohort compared to their cancer‐free peers; the remaining five studies did not find a statistically significant difference in mental health between the two groups. The paucity of studies in this area and the inconsistent findings leave a sense that more research is needed to confirm the nature of AYA cancer survivor and patient‐reported mental health. Furthermore, most of the research identified by this systematic review was cross‐sectional; there is scope for further work in the form of longitudinal and longer term studies.Despite the broad inclusion criteria of the initial study, only a single longitudinal cohort study was identified that measured mental health over time in this group of interest. It followed patients only in the first 2 years of diagnosis, and not over the longer term.A recent systematic review into adolescent and AYA cancer survivors over the long term identified five longitudinal studies that investigated psychological health as a primary outcome, and two that investigated it as a secondary outcome.We identified three papers that reported statistically significantly worse mental health and increased rates of anxiety and mood disorders in AYA survivors in a study population, compared with cancer‐free controls. Covering more than 1200 cancer survivors, these papers had a substantial sample size. This is supported by a further three papers that used the BRFSS data to illustrate that survivors are more likely to have ≥15 days of poor mental health per month than cancer‐free peers. The remaining four studies that covered AYA survivors found no statistically significant difference in mental health between survivors and controls. No studies found a difference in the other direction to suggest that AYA survivors may have better mental health than their cancer‐free counterparts. Overall, then, the evidence favours the idea that AYA survivors have poorer mental health outcomes than their cancer‐free peers, though this area would benefit from further comparative research.It was interesting that AYA patients receiving chemotherapy and radiation therapy had worse mental health than those who only underwent surgery in one study,The systemic effects of chemotherapy and radiation therapy could also explain the association between being still on treatment and having worse mental health outcomes compared with survivors found by that paper,Small sample sizes and the selection of study participants indicates that more rigorous research with larger studies would be of benefit. The three studies that found no difference in levels of anxiety or depression between the AYA group and the control group had small sample sizes, with 43, 36 and 335 participants. Furthermore, in one of these studies, participants were selected from a university survey. Cancer survivors who can attend university may be higher functioning in everyday life, and have a lower residual burden, such that they can cope with the demands of university. As a result, it is possible they are not representative of the wider population of AYA cancer patients and survivors.The incongruence discovered with these outcomes illustrates the importance of this review. Such discrepancies demonstrate the need to further characterise the mental health outcomes of, and areas of difficulty faced by, AYAs with cancer compared to their healthy peers.All three studies that compared both sexes showed women having poorer mental health outcomes than men and being more likely to experience anxiety and depression. This finding is in line with research that has identified that female cancer patients report the lower quality of life outcomes compared to their male counterparts.Several studies found that age played a role in poorer mental health outcomes, though the findings were not unanimous. Our results overall suggest that there is a significant period of mental health vulnerability in the early AYA period that is not as prominent in the later years. More research would be useful to further characterise the differences in age groups.4.1This review has some limitations. First, the scope of mental health for the purposes of the review was specific; for example, it did not encompass wider definitions of stress, or psychological concepts such as growth or life outlook. Those aspects were coded differently in the scoping review and may be subject to a systematic review of their own.Furthermore, we limited our search to full‐text English language articles. Studies in other languages may contribute additional knowledge but was missed by this search exclusion.The use of population norm values as a control group by a handful of the studies is a further limitation. Research has found that it is difficult to compare the SF‐36 responses of a group with an illness to a population normative data.4.2Overall, there is little consensus as to whether AYA cancer patients have worse mental health outcomes than their healthy peers. It may be that the mental health challenges in all people in this age group are so significant that the addition of a cancer diagnosis, followed by improvement and recovery from cancer, does not add a greater burden. There is a gender difference, with most studies finding that women are worse off than men. There is an age element as well, with younger patients more at risk. Young women are a particularly vulnerable group and may benefit from further investigation into how these poor mental health outcomes can be improved. There is also scope for more longitudinal research into this vulnerable group, to further characterise their mental health challenges and experiences and improve outcomes in this population.Sarah Tanner: Data curation ; formal analysis ; methodology ; writing – original draft ; writing – review and editing . Teyl Engstrom: Data curation ; investigation ; methodology ; project administration ; writing – review and editing . Wen Ray Lee: Data curation ; formal analysis ; writing – review and editing . Cheryl Forbes: Data curation ; formal analysis ; writing – review and editing . Rick Walker: Investigation ; writing – review and editing . Natalie Bradford: Investigation ; writing – review and editing . Jason D. Pole: Conceptualization ; investigation ; methodology ; supervision ; writing – review and editing .The authors received no specific funding for this work.The authors declare no potential conflicts of interest.We identified twelve eligible studies, seven (58%) of which found those diagnosed with cancer reported poorer mental health than the non‐cancer controls; the remaining five (42%) studies found no significant difference in severity or prevalence of mental health between the groups. The mental health outcomes feature conflicting results and illustrate the need for larger studies to characterise discrepancies.


Dispersal, the movement of individuals across space, has long been recognized as a fundamental process influencing the assembly of plants and animals Ronce, . In contBefore looking forward, we discuss our current understanding of microbial dispersal. While an exhaustive review is beyond the scope of this article  parameters are solely responsible for the patterns. That said, the large body of studies coming to the same conclusion is powerful evidence that microbes are dispersal limited  are assessed in microcosms with and without the addition of cells from an assembled source pool. These studies find that dispersal can affect microbial evolution, community assembly, and community functioning. Further, the effects of dispersal vary based on a range of factors including the size, timing, and composition of the dispersing community  What rate are microbes moving? (2) Where are they coming from? and (3) How far are they moving?In the following sections, we describe how established approaches are starting to be combined in novel ways to answer these questions in free‐living (i.e. non‐host associated) environments. Only by quantifying these components of dispersal  can we begin to integrate dispersal into more predictive models and eventually, applications.Dispersal rate can be measured as the number of individuals immigrating into a defined area per unit time. This measure is analogous to propagule pressure in invasion biology, a measurement describing the number of individuals entering a new habitat per unit time  and the physical vector  used to transfer individual cells  of specific dispersal routes. For instance, sequential exclusion of individual dispersal routes has been accomplished by using a series of cages varying in mesh size or orientation. Vannette and Fukami  caged Mis et al.  manipulaThese studies are rare examples of how dispersal routes can be isolated and assessed in the field and can serve as inspiration for similar assessments in other systems. Among other benefits, identifying important dispersal routes would aid in predicting a microbial community's ability to respond to future global changes , and then follow its spread following reintroduction in the field. Although theoretically possible, this method is not currently practical due to technical limitations in re‐isolating the same strain from the environment. We propose that an alternative, more practical approach to quantifying microbial dispersal is to consider whole community dispersal rates. In this case, the dispersal kernel reflects the probability of any individual from the community emigrating a certain distance from a source of interest Figure .To understand how one might investigate whole microbial community dispersal kernels in the field, consider a hypothetical landscape Figure . In thisStudying the movement of microscopic organisms is undeniably challenging. However, this difficulty should not dissuade us from trying to quantify the basic properties of dispersal  in environmental ecosystems. The studies highlighted above give hints at the future: research in this area will move away from the lab and inference‐based observations and towards field‐based experiments. This will happen not only through technical advances in sequencing, but through clever experimental designs that permit us to measure and manipulate microbial dispersal in the environment. These future studies will yield field‐informed dispersal parameters that can be incorporated into conceptual and predictive models of microbial communities to address far‐reaching questions such as: How do antibiotic‐resistant bacteria or plant pathogens move through a landscape? Can translocation of microbial communities help to restore native plant communities or improve agriculture soils in the face of global change? and Will microbial dispersal allow ecosystems to adapt to future climate change?Kristin Barbour: Conceptualization ; writing – original draft (lead); writing – review and editing (lead). Alberto Barron Sandoval: Conceptualization ; writing – original draft (supporting); writing – review and editing (supporting). Kendra E. Walters: Conceptualization ; writing – original draft (supporting); writing – review and editing (supporting). Jennifer B. H. Martiny: Conceptualization ; supervision (lead); writing – original draft (supporting); writing – review and editing (supporting).The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.