To use data from electronic health records (EHRs) to describe the demographic, clinical and functional correlates of childhood sexual abuse (CSA) in patients with severe mental illness (SMI), and compare their clinical outcomes (admissions and receipt of antipsychotic medications) to those of patients with no recorded history of CSA.We applied a string‐matching technique to clinical text records of 7000 patients with SMI (non‐organic psychotic disorders or bipolar disorder), identifying 619 (8.8%) patients with a recorded history of CSA. Data were extracted from both free‐text and structured fields of patients’ EHRs.Comorbid diagnoses of major depressive disorder, post‐traumatic stress disorder and personality disorders were more prevalent in patients with CSA. Positive psychotic symptoms, depressed mood, self‐harm, substance use and aggression were also more prevalent in this group, as were problems with relationships and living conditions. The odds of inpatient admissions were higher in patients with CSA than in those without , and they were more likely to have spent more than 10 days per year as inpatients . Patients with CSA were more likely to be prescribed antipsychotic medications  and be given over 75% of the maximum recommended daily dose .Data‐driven approaches are a reliable, promising avenue for research on childhood trauma. Clinicians should be trained and skilled at identifying childhood adversity in patients with SMI, and addressing it as part of the care plan. The rates of CSA recorded in electronic health records of people with SMI are considerably lower than self‐reported rates found in previous studies.Exposure to CSA is associated with more severe psychiatric symptomatology, impaired functioning and higher rates of comorbid major depressive disorder, post‐traumatic stress disorder and personality disorders.Higher odds and longer duration of inpatient admissions, as well as higher dosage of antipsychotic medication, are evident in people with SMI and a history of CSA as compared to those without such a documented history.A string‐matching technique was used to identify cases of CSA in clinical text notes. While the positive predictive value was high, this does not account for the possibility that some cases may have been missed.Patients with more or longer admissions might have had more opportunities to have CSA recorded in their EHRs, partially explaining some of the associations found in this study.Our search strategy did not allow us to extract information on the age or duration of sexual abuse, variables which have been shown to be associated with the clinical presentation of psychotic disorders.1There are many definitions of childhood sexual abuse (CSA), encompassing a range of sexually abusive acts towards children. These include sexual assault, rape, incest and the commercial sexual exploitation of children.Consistent evidence suggests that there is an association between childhood trauma (CT), particularly sexual and physical abuse, and later psychotic disorders.Exposure to CT among people with severe mental illness (SMI)—namely schizophrenia, bipolar disorder and other non‐organic psychotic disorders—is associated with a range of negative outcomes.The majority of previous studies used structured questionnaires, such as the Childhood Trauma Questionnaire,1.1We aim to describe the clinical and functional characteristics of patients with SMI and a documented history of CSA, and compare their clinical outcomes (admissions and record of antipsychotic medications) to those of patients with no recorded history of childhood sexual abuse in a large mental healthcare provider in the United Kingdom. We hypothesise that patients with SMI and a history of CSA will have more severe psychiatric symptoms and functional impairment, higher rates of comorbidities and psychiatric admissions, and higher prescribed dosages of antipsychotic medication than patients without a history of CSA.22.1Data for this study were obtained from Camden & Islington NHS Foundation Trust (C&I NHS FT) using the Clinical Record Interactive Search (CRIS) tool.For purposes of this study, we identified patients with non‐organic psychotic disorders or bipolar disorder (ICD‐10 diagnosis of F20‐F29 or F30‐31) who were in contact with services in the years 2009–2017 and had at least one year of follow‐up data available. Additionally, only patients with at least one recorded assessment using the Health of the Nation Outcome Scales (HoNOS) were included in the study.2.2String matching was used to identify a list of key phrases depicting CSA in free‐text fields. Initially, a group of clinical experts defined relevant search terms. We then used an iterative process, whereby a sample of records produced by the string‐matching process was reviewed and additional key phrases were extracted from the text and added to the search strategy. Additionally, to refine the search strategy, exclusion rules were added in a similar way.Key phrases used in the string matching process included terms such as ‘childhood sexual abuse’, ‘history of sexual abuse’, ‘csa’, ‘sexual abuse at age X’, ‘sexually abused between the ages of X‐Y’, ‘sexually abused as a child’, ‘childhood Hx of sexual abuse’ and ‘childhood experiences of sexual abuse'. Exclusion rules included phrases negating a history of CSA such as ‘no CSA’, ‘nil csa’, ‘denied a childhood history of sexual abuse’, as well as those suggesting a possible history of CSA. The full list of terms used for the identification of CSA is presented in Appendix 2.3Demographic variables, including sex, ethnicity and marital status, were extracted from structured fields within CRIS.Social deprivation was estimated using The Index of Multiple Deprivation (IMD). This is a measure that combines national census information from 38 indicators into seven domains of deprivation , to create an individual score of deprivation for each area.Additional clinical and functional variables were extracted from the HoNOS—a validated instrument routinely used by professionals to describe recent health and functioning in individuals with mental health problems.Finally, we extracted information from ICD‐10‐structured fields on comorbid psychiatric diagnoses, including major depressive disorder, post‐traumatic stress disorder and personality disorders.2.4The two primary clinical outcomes were inpatient admission to a psychiatric ward and receipt of antipsychotic medication. Data for all admissions were extracted from structured fields within CRIS to derive two binary variables: yes/no admission; and among those with at least one inpatient admission – number of admission days per year above or below the cohort median (10 days).The use of antipsychotic medication was identified through the Natural Language Processing (NLP) application for ‘medication’ developed by the South London and Maudsley NHS Foundation Trust Biomedical Research Centre.The percentage of the maximum recommended daily dose was calculated for all instances of antipsychotic medication identified through NLP. Maximum recommended daily doses were extracted from the British National Formulary2.5We compared the demographic, clinical and functional characteristics of patients with and without a history of CSA using chi‐square tests. Next, logistic regression models were fitted for each of the outcome variables . Analyses were adjusted for sex, age at first presentation and ethnicity. Associations were expressed as odds ratios (OR) and their corresponding 95% confidence intervals (CI). Data were analysed using SPSS version25.0.3We identified 7030 patients with SMI who were in contact with services at C&I NHS FT in the years 2009–2017 and had at least one recorded HoNOS assessment. Fifteen patients were removed from the cohort as they were missing information on the date of first contact with C&I NHS FT, and hence, follow‐up time could not be calculated. An additional 15 were removed as they had a mention of ‘historical sexual abuse’ in their EHR where age at the time of the abuse could not be confirmed, and hence could not be classified as definite childhood events. Hence, the final analytic cohort included 7000 patients with SMI, of which 619 (8.8%) had a recorded history of CSA.Patients with a recorded history of CSA were more likely to be female, single, of white ethnic origin than their counterparts without CSA , and they were more likely to have spent above 10 days a year as inpatients . Similarly, patients with a history of CSA were more likely to be prescribed antipsychotic medication during the follow‐up period , and more likely to receive over 75% of the maximum recommended daily dosage  as compared to patients with SMI and no recorded history of CSA .Our study has several limitations. First, the data were obtained from routine electronic clinical records and were not collected for research purposes. Second, we used a simple string‐matching technique to identify cases of CSA in free‐text fields of EHRs. While the PPV of our search algorithm was high, this does not account for the possibility that some cases may have been missed . It is possible that there are additional search terms that were not used in this study, which may have led to the identification of additional cases. The under‐reporting and/or under‐recording of CSA in EHRs may have led to an underestimation of the true association between CSA and the outcomes described in this study. Third, patients with more or longer admissions might have had more opportunities to have CSA recorded in their EHRs, partially explaining this association. However, this cannot be true for the increased antipsychotic prescribing, dose and HoNOS items. Finally, our search strategy did not allow us to extract information on the age or duration of sexual abuse, variables which have been shown to be associated with the clinical presentation of psychotic disorders.To conclude clinicians working with patients with SMI  should be trained and skilled at assessing childhood adversity as this may have prognostic and treatment implications. While the observational nature of this study does not allow us to make treatment recommendations, clinicians and researchers should consider evidence‐based trauma‐focused interventions, such as eye movement desensitisation and reprocessing (EMDR) and cognitive analytic therapy (CAT), when forming treatment plans for people with a history of CSA. These interventions have been proven to be effective in reducing trauma symptoms,This study demonstrates the potential of using novel approaches for identification of CSA in routinely collected electronic clinical records. The secondary use of data collected in EHRs can dramatically increase the breadth and depth of information available for research.https://publons.com/publon/10.1111/acps.13302.The peer review history for this article is available at


Heatwaves cause excess mortality and physiological impacts on humans throughout the world, and climate change will intensify and increase the frequency of heat events. Many adaptation and mitigation studies use spatial distribution of highly vulnerable local populations to inform heat reduction and response plans. However, most available heat vulnerability studies focus on urban areas with high heat intensification by Urban Heat Islands (UHIs). Rural areas encompass different environmental and socioeconomic issues that require alternate analyses of vulnerability. We categorized Nebraska census tracts into four urbanization levels, then conducted factor analyses on each group and captured different patterns of socioeconomic vulnerabilities among resultant Heat Vulnerability Indices (HVIs). While disability is the major component of HVI in two urbanized classes, lower education, and races other than white have higher contributions in HVI for the two rural classes. To account for environmental vulnerability of HVI, we considered different land type combinations for each urban class based on their percentage areas and their differences in heat intensifications. Our results demonstrate different combinations of initial variables in heat vulnerability among urban classes of Nebraska and clustering of high and low heat vulnerable areas within the highest urbanized sections. Less urbanized areas show no spatial clustering of HVI. More studies with separation on urbanization level of residence can give insights into different socioeconomic vulnerability patterns in rural and urban areas, while also identifying changes in environmental variables that better capture heat intensification in rural settings. Despite similar incidence rates, Heat Vulnerability Index (HVI) in rural areas is under studied in comparison to urban areasThe environmental vulnerability variables in rural areas are dissimilar to urban areas, so we applied different variables to calculate themWe found different organization of socioeconomic variables in calculated HVIs, suggesting separate heat strategies for urbanization levels ADCM pr2.4Local Indicators of Spatial Association (LISA) was used to analyze the hotspots, cold spots, and outlier census tracts of total vulnerabilities in each urban class of Nebraska Anselin, . This me3More than 90% of total land area in Nebraska consists of Grassland or Cultivated Crops Table . While tWe reconfigured the RUCA tracts in Nebraska to combine classes Table . The revPairplots of socioeconomic and environmental variables for urban and non‐urban areas show considerable difference in the correlations Figures  and 4. TThe results of factor analyses show differences in the combinations and coefficients of variables for each urban classification Tables  and 4. MThe results of the highest urbanized areas were mapped separately for clarity. Mapping values of each HVI for each tract shows patterns of high vulnerabilities in Omaha area Figure . VulneraThe spatial distribution of three HVI values in Small Metro tracts do not appear to follow any specific pattern and are not similar in any of the three Figure . Even arFigure The results of LISA analysis for Omaha area shows clusters of High‐High and Low‐Low total HVI Figure . This coLISA analysis for Rural class did not show any significant classification of clustering or outlier that could be expected from Figure 4To our knowledge, this is the first study to show that separating census tracts into different categories based on urbanization levels results in different combinations of socioeconomic variables in calculated HVIs. For example, disability contributes highest in HVI factors in both more urbanized groups‐ Medium Metro and Small Metro‐, while it only appears in the last HVI factors for the two higher rural areas–Micropolitan and Rural with the lowest coefficients compared to other variables. On the other hand, race other than white is the most contributing socioeconomic variable in two higher rural areas, which is not the case for two more urbanized classes. We also found that both the structure of land cover types used as environmental variables–and their contributions in HVI factors vary for different urban classes, suggesting different potential mitigation strategies for each group. And finally, our hotspot analysis showed clusters of high HVI and low HVI concentration in the highest urban level class, but no such pattern was distinguished in the other three classes.Reid et al.  suggest We suspect that rural areas may contain socioeconomic variables that were used in a limited fashion in similar studies focusing on urban areas. For example, we investigated the percentage of outdoor workers in our different urban types but could not find any significant differences, therefore we did not include it in our study. Another example can be inclusion of tribal communities as sources of increased adaptive capacities due to the support they provide to their vulnerable population in rural areas that include such social ties.Sheridan and Dolney  found co5Heatwaves are expected to become increasingly dangerous for human health. Many studies focus on the effect of heatwaves in urban areas or use one model to map related vulnerabilities in urban areas and their surrounding less urbanized regions. We showed that separating heterogeneous study areas into different groups can reveal different structures of socioeconomic variables in the development of HVIs, so that including them in one model may be misleading and neglecting less urbanized areas. In our analysis, we have considered these groups based on their urbanization levels and the expert suggestions on how they can fit into groups. These results can better help decision makers at various levels to focus on customized solutions for each urbanization level of residence. This study focuses on Nebraska as a state with large rural areas and a small percentage of urban systems. We suggest that similar frameworks can be applied to other regions that contain similar heterogeneity.The authors declare no conflicts of interest relevant to this study.Supporting Information S1Click here for additional data file.


To the Editor,There is temporal variation in mortality that may complicate any conclusions made. The authors conducted an electronic search to include articles from the inception of the pandemic to November 12, 2020. However, mortality rates in the early stages of the pandemic in March 2020 differed significantly from mortality rates later on in October and November 2020.In addition, socioeconomic and sociocultural variations in mortality rates exist across countries. The hygiene hypothesis featured prominently during the early phase of the pandemic. Data from India's first COVID‐19 surge in October 2020 noted that infected individuals were protected from severe manifestations of the disease and experienced reduced mortality rates compared to Western nations due to cross‐immunity from other pathogens, which was confirmed serologically.The authors did not control for continuation or discontinuation of the ACEIs/ARBs after discharge from the hospital. A French study established a causal link between out‐of‐hospital cardiac arrest or out‐of‐hospital sudden death and COVID‐19 in the early pandemic, during March to April 2020 and some Indian studies found an increase in mortality associated with the administration of ACEIs/ARBs in hospitalized COVID‐19 patients in the early phase of the pandemic.We read with great pleasure the article by Jia, et al., titled “Influence of angiotensin converting enzyme inhibitors/angiotensin receptor blockers on the risk of all‐cause mortality and other clinical outcomes in patients with confirmed COVID‐19: A systemic review and meta‐analysis,” which found that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were not associated with in‐hospital mortality in COVID‐19 patients from March to November 2020.Despite these limitations, the findings of the systematic review discussed does warrant further investigation, especially as the full breadth of COVID‐19‐related side‐effects is currently not understood. In developing nations, such as India, ACEIs/ARBs are not routinely given to hospitalized patients unless previously prescribed to the patients due to limitations on available medical resources,The authors declare that they have no conflicts of interests.


Obesity prevalence is increasing globally. Bariatric surgery is an effective treatment for severe and complex obesity resulting in significant and sustained weight loss. In Sweden, most bariatric surgery patients are referred by primary care physicians. We aimed to explore barriers for physicians to refer patients with severe and complex obesity for bariatric surgery.A questionnaire survey was in 2019 emailed to 1100 primary care physicians in the Skåne and Kronoberg regions in south Sweden. The survey focused on referral patterns, knowledge and attitudes towards bariatric surgery and concerns about postoperative complications. We created different statistical indices for referral patterns, knowledge, attitudes and concerns about bariatric surgery. To analyze the correlation between these indices, we did Spearman’s correlations and regression analyses.Of 1100 email respondents, we received 157 (14%) completed surveys. Among 157 physician respondents, 73% answered that they had good knowledge about the referral criteria for bariatric surgery, whereas 55 and 60% answered correctly to two items on criteria for bariatric surgery. A majority of respondents (84%) stated that their patients initiated referral to bariatric surgery. Half of the respondents had concerns about postoperative medical and surgical complications, but another half had a positive attitude to bariatric surgery as a treatment for obesity comorbidities. Almost half of the respondents (44%) answered that they needed to learn more about bariatric surgery.p < 0.001) and positive attitudes  respectively. We found significant reverse correlations between concerns and referral patterns  and between positive attitudes and concerns . In logistic regression high levels of concerns explained low willingness to refer for bariatric surgery .We found significant positive correlations between high knowledge and referral patterns (r = 0.292, According to this Swedish survey among primary care physicians, high levels of concerns about bariatric surgery among physicians seemed to be a barrier to refer patients with severe and complex obesity for bariatric surgery. Since high knowledge about obesity and bariatric surgery correlated negatively to concerns and positively to favorable attitudes to bariatric surgery, more knowledge about obesity and bariatric surgery is warranted.The online version contains supplementary material available at 10.1186/s12902-021-00723-8. According to WHO, BMI ≥ 40 kg/m2 is classified as obesity class III, in this article defined as severe and complex obesity.The prevalence of obesity is increasing globally, and half of the population aged 16–84 years in Sweden was overweight or obese in 2018 [An increased BMI is a risk factor for several comorbidities such as diabetes type 2, obstructive sleep apnea, cardiovascular diseases, infertility in women, several types of cancer and depression . ObesityBariatric surgery has shown positive effects on morbidity and mortality in individuals with severe and complex obesity and is an effective treatment resulting in significant and sustained weight loss –11. Bari2 or a BMI ≥ 35 kg/m2 in addition to a major obesity-related comorbidity, are eligible for bariatric surgery paid for by public health care [According to Swedish national guidelines, individuals who do not lose weight by nonsurgical obesity treatment and have a BMI ≥ 40 kg/mlth care .Although severe and complex obesity is equally common among men and women in Sweden , the majIn 2007 an obesity task force was created on behalf of the Swedish National Board of Health, the Swedish Municipalities & Counties and the Swedish Medical Association . The obeConsidering the relatively small proportion of eligible patients that undergo bariatric surgery, it is important to understand barriers to the treatment. In a systematic review it was seen that both patients and referring physicians had considerable concerns about the outcomes and safety of bariatric surgery, and the physicians acknowledged that they had limited knowledge about obesity treatment alternatives . A DanisIn Sweden, the majority of patients are referred to bariatric surgery by primary care physicians. The results of a survey from USA showed that the probability that primary care patients would seriously consider bariatric surgery was five times higher if their physicians recommended bariatric surgery . HoweverOur primary aim of the current study was to assess referral patterns, knowledge, attitudes and concerns about bariatric surgery for patients with obesity among primary care physicians through an electronic questionnaire. Our secondary aim was to explore potential barriers for referral of patients to bariatric surgery by investigating possible correlations between the physicians’ knowledge, attitudes and concerns about bariatric surgery, and if these factors might influence the suggested referral patterns. Our hypothesis was that low knowledge about obesity and bariatric surgery in primary care physicians might correlate to negative attitudes or concerns, which consequently would be associated with less referral for bariatric surgery for patients with severe and complex obesity.An electronic questionnaire survey was in 2019 emailed to all primary care physicians with potentially available email addresses in Skåne and Kronoberg regions in south Sweden. We chose Skåne and Kronoberg regions since the authors worked in these two regions and had access to primary care physicians’ email addresses. Skåne is Sweden’s third most populated region and Kronoberg represents a 2% cross section of Sweden both regarding population demographics and surface area. We had access to the email addresses through the regional councils.The potential participants were informed briefly about obesity, the purpose of the study and that their participation was voluntary and that responses were collected anonymously and could not be traced back to any of the participants. They were also informed that they could terminate their participation at any time. A survey response by the physicians was considered as a consent to participate. According to Swedish legislation, application to the Ethical Review Authority (EPM) was not required, as the survey was anonymous and did not contain what the EPM considers as sensitive data.We, the authors, discussed barriers affecting physicians’ decision making to refer potential patients to bariatric surgery. The discussion was based on our own experiences and those from other primary care colleagues.We searched the literature for other questionnaire surveys that had one or more items of interest for our study and found four studies , 24–26. We translated items from other questionnaire surveys from English to Swedish and from Swedish back to English consecutively by two independent researchers to ensure that the meaning of the items did not alter after the translation.We invited 20 primary care physicians to answer and give comments on the first version of the survey in order to assess the content and the face validity of the survey.We altered the survey based on the comments, which were found to be applicable to the purpose of the study.The final version of the questionnaire contained 59 items and was created electronically in REDCap®, a web application for handling electronic questionnaires.In order to check if the survey link worked properly, we sent the survey to the authors and a sample of 10 email addresses of colleagues at our clinic. This sample of 10 emaila ddresses were not included in the final mail list used for collecting the survey data.We designed the electronic questionnaire by taking the following steps:The final version of the questionnaire was electronically sent out to all physicians, with available email addresses, working in primary care in Skåne and Kronoberg regions in south Sweden. The survey was sent out the first time in July 2019. We send out two reminders, one in August and one in October 2019. The total duration of the study was 4 months.The questionnaire contained demographic information such as age, gender, years of experience, and medical specialization.p < 0.05 was considered statistically significant.Data were analyzed and estimated by descriptive statistics and regression analyses. We developed indices for items regarding referral patterns items 7–10), knowledge items 23–41), attitudes  and concerns (items 42–46) about bariatric surgery. A detailed description of how the indices were developed is presented in Additional file 0, knowle3–41, attn = 65) were male and 58% (n = 91) female (1 missing). Most of the respondents  claimed to be specialists in general practice and 53 of them answered that they had worked more than ten years in primary care. Most of the respondents  worked in public primary care and 23% (n = 36) worked in private primary care, see Table The questionnaire survey was emailed to 1100 primary care physicians in Skåne and Kronoberg regions and 157 responded (14%). A total of 11 questionnaires were not complete and had internal missing answers for 1–4 items. Of the 157 respondents, 41%  stated that they agreed or strongly agreed to referring patients to bariatric surgery if patients met the required national referral criteria. Only 7% (n = 11) of physicians actively suggested bariatric surgery to patients with obesity (item 10) whereas 84% (n = 132) answered that it is most often the patients that request referral to bariatric surgery (item 9), see Fig. Most of the physicians n = 11, 71% sn = 89, 57%) of the physicians stated that they predominantly referred women for bariatric surgery. Many physicians  suggested that the gender difference was explained by women requesting referral for surgery more often than men.More than half  met 1–2 patients per month that could be a candidate for bariatric surgery and 64% (n = 100) had referred 1–5 patients for bariatric surgery in the last five years. However, 11% (n = 17) answered that they had not referred anyone for bariatric surgery during the last five years (item 21).More than half of the physicians  had refused to refer patients to bariatric surgery despite the patient’s wish, whereas 29% (n = 45) had never denied a patient a referral. Most of the physicians  had denied referral for bariatric surgery due to non-eligibility for bariatric surgery, 25% (n = 39) had denied referral due to uncertainty if the patient could follow the postoperative advices, and 19% (n = 30) had denied referral due to patients’ cognitive problems (item 57).More than half of the physicians (n = 115) agreed or strongly agreed to having good knowledge about the referral criteria for bariatric surgery, whereas 55% (n = 86) and 60% (n = 94) answered correctly to the two items on BMI criteria for bariatric surgery (items 35 and 36).A majority of respondents  agreed or strongly agreed that bariatric surgery had positive effects on type 2 diabetes, obstructive sleep apnea , hypertension  and joint pain  see Fig. Most respondents  stated that diet and exercise are effective methods for sustained weight loss in patients with severe and complex obesity, only 25% (n = 39) stated that they agreed or strongly agreed that bariatric surgery is the only effective treatment for sustained weight loss in patients with severe and complex obesity (item 24). In response to the item about mortality associated to bariatric surgery, 57% (n = 89) answered correctly that perioperative mortality is < 1% (item 40).While more than half of the physicians  indicated that they needed more education about obesity and bariatric surgery. Most of the physicians  stated that they felt competent to discuss bariatric surgery as an alternative treatment for their patients with severe and complex obesity and 63% (n = 99) felt competent to take care of patients after bariatric surgery (items 49 and 50).Nearly half of the physicians  had a positive attitude to bariatric surgery as a treatment for obesity related disease. According to 46% (n = 72) of the physicians the advantages of bariatric surgery outweigh the risks (item 51).Nearly half of the physicians (n = 64) stated that they disagreed or strongly disagreed, while 26% (n = 41) stated that they agreed or strongly agreed (item 48).When respondents were asked if they were confident to prescribe non-surgical treatment for weight management among patients with severe and complex obesity, 41%  stated that they were not concerned about the risks associated with bariatric surgery. Half of the physicians were concerned about postoperative medical  and surgical complications , and 46% (n = 71) stated that they were concerned about psychiatric side effects after bariatric surgery, see Fig. Nearly half of the physicians  and between high knowledge and positive attitudes towards bariatric surgery  i. e. high knowledge was associated with higher willingness to refer and more positive attitudes to bariatric surgery.High knowledge was defined when the respondents answered correctly to the items regarding knowledge (items 23–41). We found significant positive correlations between high knowledge and referral patterns  and between knowledge and concerns , i. e. poor knowledge was associated with more concerns, and more concerns was associated with lower referral to bariatric surgery. More correlations are presented in Table We found significant reverse correlations between concerns and referral patterns . Female physician gender was associated with more concerns .There was a positive correlation between physician age and referral pattern  and physician age and attitude . Table Additionally, we dichotomized the variables concerns and referral patterns and used the highest quartiles in logistic regression analyses showing that high levels of concern were associated with low willingness to refer for bariatric surgery  . High leThe results of our study showed a significant positive correlation between high knowledge and referral and a significant negative correlation between high knowledge and concerns. This indicates that knowledge about obesity and bariatric surgery among primary care physicians is a factor that might affect referral patterns and concerns. Our data also showed that high knowledge correlated with a positive attitude. Almost half of the respondents stated that they needed more education about bariatric surgery. Two earlier studies reported that poor knowledge about bariatric surgery among primary care physicians seemed to be a barrier for bariatric surgery referral , 37. SomOne limitation of this study is the low response rate of 14% which is however similar to that of many other email surveys  and coulOne strength of this study is that it is the first Swedish survey about bariatric surgery attitudes in primary care physicians. Another strength is the analysis of correlation between knowledge, concerns, attitudes and referral patterns. The survey items were formulated both negatively and positively in order to reduce an acquiescence response set. Some of the survey items were used in other survey studies which make them comparable and they were translated from English to Swedish and back translated from Swedish to English by two independent researchers to ensure that the meaning of the items was not lost in translation. The researchers were fluent in both languages.This survey study reveals novel information about primary care physicians’ knowledge, attitudes and concerns about bariatric surgery, in two regions in the south of Sweden. The physicians’ knowledge about obesity and bariatric surgery was related to concerns and attitudes about bariatric surgery and high levels of concerns and negative attitudes seemed to be a barrier for referring patients with severe and complex obesity to bariatric surgery.Since there is evidence showing increased life expectancy after bariatric surgery, primary care physicians need to be more aware of benefits of surgical treatment and should consider the bias that they meet more patients in daily practice with postoperative complications and unsuccessful results rather than patients who do not encounter much problems and where benefits outweighs the complications. Primary care physicians should also be more active to suggest surgery as obesity treatment for their patients, especially male patients who are not usually the main drivers in requesting bariatric surgery. More evidence-based education and training in the field of obesity and its treatment is probably warranted.Additional file 1: Appendix 1. How we developed the indicesAdditional file 2: Appendix 2. English translation of the questionnaire


We report the case of a 22‐year‐old man with a diagnosis of dihydropteridine reductase (DHPR) deficiency who progressively developed movement disorders and epilepsy. Despite L‐Dopa supplementation the patient continued to show high prolactin levels, with a discrepancy between the neurological clinical picture and the hormonal biochemical levels. For this reason, other potential causes were ruled out by performing a cerebral magnetic resonance imaging, which demonstrated a solid lesion in the pituitary gland strongly suggestive of a prolactinoma. As the association between metabolic disorders affecting biogenic amine synthesis and prolactinoma has not been previously reported in humans, this report suggests that a critical evaluation of the use of prolactin as a guide for therapy dosage should be made in patients with DHPR deficiency disorders. It is characterized by an elevation of phenylalanine (Phe) and low levels of biogenic amines.Dihydropteridine reductase (DHPR) deficiency is the second most frequent autosomal recessive disorder of tetrahydrobiopterin . Due to side effects, l‐dopa and 5‐HT should be started in a low dose and increased gradually.Phe levels are controlled by low Phe diet life long, while biogenic amine replacement therapy is given as l‐dopa deficiency due to its reverse feedback with l‐dopa synthesis.Monitoring cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA) as a marker of dopamine turnover and 5‐hydroxyindoleacetic acid (5‐HIAA) for serotonin metabolism is not feasible in clinical practice due to the need of repeating lumbar puncture, which is an invasive procedure. Hence, prolactin plasma level may be useful in monitoring Treatment with folinic acid is also needed to prevent folate deficiency.2QDPR gene ; hence, a diagnosis of variant hyperphenylalaninemia due to DHPR deficiencyA 22‐year‐old man was initially diagnosed with phenylketonuria (PKU) during newborn metabolic screening; after 2 months, due to the onset of sialorrhea more complete metabolic evaluation was conducted, including biochemical screening , enzymatic assay , and genetic analysis  performed at that stage showed multiple bilateral subcortical white matter lesions consistent with hypoxic‐ischemic lesions; a possible cardiac arrest as a trigger of the status epilepticus was hypothesized, but never documented on clinical or instrumental grounds. He recovered from mechanical ventilation after 2 months, but he was left with motor aphasia, right hemiparesis, and cognitive impairment.During the follow‐up, he showed plasma Phe and the ratio of Phe/tyrosine within the normal range. Despite this metabolic stability and ongoing antiseizure treatment, he progressively developed drug‐resistant epilepsy, with daily focal to bilateral tonic‐clonic seizures, tonic seizures, and electroencephalography (EEG) findings, suggesting epileptic encephalopathy. Clinically, he showed a spastic tetraparesis, with superimposed dystonic movements of upper and lower limbs as well as cervical dystonia.l‐dopa (melevodopa/carbidopa 100/250 mg three times a day).His treatment consisted in antiseizure drugs , hydroxytryptophan, folinic acid, l‐dopa daily dose was progressively increased. We also determined plasma prolactin levels, as suggested from literature: prolactin, physiologically, is inversely related to dopamine levels, so it can be considered a marker to guide the doses of dopamine replacement therapy, rather than using more invasive approaches .Patient was referred to our Adult Hereditary Metabolic Clinic at the age of 20: he was wheelchair bound, alert but unable to communicate verbally, could perform some simple motor commands, and showed no rest tremor but diffuse muscular rigidity, so that Prolactin plasmatic level measurements at different times are reported in Figure l‐dopa dosage adjustment (up to melevodopa/carbidopa 100/25 mg five times a day), the clinical picture showed a patterned stiffening and hyperextension of the upper right limb, sometimes involving the lower right limb or contralateral one, lasting about 20 seconds. Sweating and redness in the face were also present, while sphincteric release or tongue biting were not observed. The frequency of these episodes, which were consistent with dystonic posturing, was higher at night (up to 20 per night). All these symptoms were unmodified despite benzodiazepine administration. The frequency of epileptic seizures remained unchanged. The patient underwent long‐term monitoring video‐EEG to better evaluate these episodes and cerebral MRI , prolactin levels did not decrease as expected after adequate l‐dopa administration.Following I Figure . The EEGl‐dopa deficiency. Moreover, the detection of cerebral bilateral hemispheric ischemic lesions explained the presence of tetraparesis.The MRI showed the presence of bihemispheric large malacic lesions in the subcortical white matter, mostly in the semi‐oval centers and fronto‐parietal subcortical regions, more on the left side. Other bilateral cerebellar ischemic lesions were evident. As compared to previous MRI scan, signs of cortical atrophy were more pronounced and a moderate enlargement of ventricles was also present. In the left sector of the pituitary gland, a hypointense 5 mm area determining a slight salience of the pituitary profile was shown, being consistent with a pituitary adenoma. We therefore hypothesized that the patient's hyperprolactinemia was caused by a previously undiagnosed prolactinoma and not by l‐dopa was reduced to 400 mg a day. The new treatment progressively reduced dystonic movements. After 4 months, prolactin levels returned within normal limits. At the last evaluation, the patient showed a good clinical picture, with a reduction of neurological signs.The patient was then treated with cabergoline (0.5 mg ½ cp twice a week) and 3QDPR gene, leading to a deficient q‐dihydropteridine reductase activity: this causes an absolute reduction in tetrahydrobiopterin (BH4) levels,DHPR deficiency OMIM#261630) is a rare recessive metabolic disease caused by biallelic mutations in the 61630 is 4 deficit syndromes) due to a potential increased in 7,8‐dihydrobiopterin (BH2) production and a decreased BH4/BH2 ratio resulting in a worsening of clinical symptoms; however, guidelinesl‐dopa (the direct dopamine precursor), while restricting dietary phenylalanine intake (to avoid its toxic accumulation in the brain). The effect of l‐dopa supplementation may be monitored clinically or biochemically by determining biogenic amine levels in the CSF. The need for a noninvasive marker has led to hypothesize the use of plasma prolactin levels; in fact, its strong, negative correlation to dopamine levels may be used for both diagnosis and follow‐up.Sapropterin dihydrochloride  therapy is controversial in DHPR deficiency  seemed not to correlate with high prolactin levels (that are considered a marker of dopamine deficiency). The discrepancy between the clinical picture and the presence of an inappropriately elevated prolactin level suggested the need for a deeper investigation on the possible causes of the latter condition. Indeed, the MRI demonstrated the presence of a pituitary prolactinoma.4 metabolism disorders, while in mice,The association between metabolic disorders affecting biogenic amine synthesis and prolactinoma has not been previously reported in humans affected by BHDespite the lack of a human model, we could hypothesize that the association described in our patient may reflect the same pathological pathway described by Hnasko and colleagues: a possible chronic endogenous dopamine deficiency that leads to a lack in D2R simulation may augment the risk of oncogenic mutation and promote pituitary tumor growth. Interestingly, in animal models, estrogen secretion is needed to promote the development of prolactinoma, while our male patient did not show pathological estrogen levels.4‐deficiency disorders. The role of prolactin as a marker of dopamine deficiency, and its use as a guide for therapy dosages should be critically revised as pointed by the present clinical case, not only at the time of disease diagnosis but also during follow‐up. Variations in prolactin levels inconsistent with patient's clinical picture or not responsive to l‐dopa dosage modifications must be carefully monitored and evaluated to rule out underlying potentially curable endocrine conditions.The possible association between DHPR deficiency and prolactinoma poses a clinical challenge in managing BH44 deficiency disorders should be critically reconsidered when a metabolic disorder of biogenic amine synthesis and prolactinoma coexist.The present clinical case suggests that the measurement of prolactin as a guide for therapy dosages in the treatment of BHThe authors declare that they have no conflict of interest.Nicola Vitturi made metabolic evaluation of the patient and wrote the text; Livia Lenzini and Angelo Avogaro revised the manuscript; Concetta Luisi and Miryam Carecchio made the neurological evaluation of the patient; Giorgia Gugelmo and Francesco Francini‐Pesenti followed the nutritional care of the patient.


We report a 15‐year‐old male with hypoplastic left heart syndrome (HLHS) after Fontan operation with recurrent, drug‐resistant atrial tachycardia. With the use of electro‐anatomical mapping system (EnSite) an atrial flutter (AFl) with reentry activation around the tricuspid valve was diagnosed. Successful radiofrequency catheter ablation (RFCA) was performed. Since its inception, the procedure has undergone a lot of modifications to improve hemodynamics, which resulted in longer life expectancy of these patients. Despite the improvement in surgical and interventional techniques, many patients after Fontan operation develop atrial tachycardia (AT) with increasing frequency of arrhythmia episodes during the follow‐up that poorly respond to pharmacological treatment. Although radiofrequency catheter ablation (RFCA) could be an optimal invasive treatment for supraventricular tachyarrhythmias, the limited access because of multiple surgical interventions in patients with complex congenital heart diseases may be a challenge.We report a case of a child with lateral tunnel Fontan and an epicardial pacemaker who underwent RFCA for drug resistant atrial flutter (AFl).2A 15‐year‐old child with complex congenital heart disease, after multiple hospitalizations because of persistent, drug resistant supraventricular tachyarrhythmia was admitted to a high‐volume tertiary care university center presenting atrial tachycardia with ventricle response of about 130 bpm. He had been diagnosed as a newborn with a hypoplastic left heart syndrome, mitral stenosis, and aorta atresia, initially palliated with a modified Norwood operation in 2003, followed by Rashkind operation and balloon angioplasty of coarctation of the aorta 3 months later. Then he underwent hemi‐Fontan and Fontan operation followed by tricuspid valve and left pulmonary artery plasty. Because of a Fontan operation, he developed sick sinus syndrome which was treated by epicardiac dual chamber pacemaker implantation in September 2018.2 saturation of 93%. In the ECG the atrial tachycardia with a ventricular rate of 130 bpm was observed  was cut off and connected to the pulmonary artery—the new vascular canal was also connected with right atrium (RA) via fenestrations. Because of the atresia of femoral veins, a hydrophilic leader and a long vascular sheet were used to reach the vascular canal. With the use of Lasso catheter, the canal was reconstructed (on the EnSite Cardiac Mapping System) and atrial reference signals  were recorded. Subsequently, with the use of transseptal sheet, the RA (via fenestrations) was reached to create an activation and potential map of RA. A reentrant tachycardia (AFl with the cycle of 300 ms) around the tricuspid valve, with the isthmus between the tricuspid valve and the scar that was created by the excision of the SVC and creation of the vascular canal during the second Fontan procedure was found Figure . The appDuring 20 months of follow‐up the patient was in general good condition, without any syncope and remained free of arrhythmia.3Atrial arrhythmias following Fontan‐type surgery are very common and increase in the postoperative time reaching about 50% of patients during 20 years of follow‐up and are associated with significant morbidity and mortality. Furthermore, almost half (47%) of these tachyarrhythmias are resistant to antiarrhythmic drugs.Several isthmuses of tachycardia could be developed by anatomical sectors made by the orifices of vena cave, coronary sinus, suture lines of atriopulmonary anastomosis, or lateral tunnel repair. Catheter ablation in post‐Fontan patients is challenging because of distorted anatomy of the heart after multiple surgical interventions consequently barriers to access the native atrial tissue, limited access to the heart or possible hemodynamic instability. It is even more challenging in patients with lateral tunnel or extracardiac conduit because the caval veins are not directly connected to the heart and the access to the heart is possible only through the fenestration if present.Furthermore, the acute and long‐term results of RFCA in Fontan patients are significantly worse than in other congenital heart diseases with a high risk of recurrent tachycardia, which reaches 40%. For these reasons, RFCA in these group of patients is not very common. There is a case report of a 7‐year‐old boy with HLHS after Fontan procedure who required RFCA because of drug resistant reentry atrial tachycardia. The ablation electrode could not have been inserted through small fenestration. After dilatation with the use of angioplasty balloon, the RFCA was successfully performed. Other case report of a 24‐year‐old female after Fontan operation has shown efficacy of RFCA for paroxysmal AF. However, pulmonary vein stenosis was developed as a consequence of the ablation procedure. Moore et al. observed that AT of extracardiac total cavopulmonary connection (E‐TCPC) in 36 patients was treated with success via catheter ablation in 83% of the cases.4Radiofrequency catheter ablation with the use of electro‐anatomical mapping system could be effective and feasible treatment of drug resistant atrial flutter in pediatric patients with hypoplastic left heart syndrome after Fontan operation.Ewa Jędrzejczyk‐Patej and Radosław Lenarczyk—consultant fees from Medtronic, Biotronik, Abbott, and Boston Scientific. Beata Średniawa—consultant: Medtronic, Zoll, Bayer, lectures fee for: Boehringer‐Ingelheim, Bayer, Pfizer.


Subcutaneous immunotherapy (SCIT) requires patients to regularly visit their doctors and receive injections at weekly or monthly intervals for at least 3 years. However, the ongoing COVID‐19 pandemic has influenced the routine for SCIT and impacted adherence to SCIT to a large degree.Vaccination is considered as an effective strategy to prevent COVID‐19 infection and ameliorate its outcome. Thus far, two mRNA‐based vaccines, three inactivated‐virus vaccines and two adenovirus‐vector vaccines have mainly been used in countries worldwide. COVID‐19 vaccines are promoted to general people and more than 78 billion vaccine doses have been administered globally at the time of writing this paper. This situation raises new concerns about the relationship between COVID‐19 vaccination and SCIT for both allergists and patients undergoing SCIT. Although the European Academy of Allergy and Clinical Immunology recommended that AIT should be separated from vaccination for infectious diseases by at least 1 week,A web‐based survey was conducted from 21 June to 23 July 2021. Patients who received regular SCIT in the Allergy Department at Peking Union Medical College Hospital (PUMCH) were invited to participate in an electronic questionnaire  received two doses of inactivated COVID‐19 vaccine  during their SCIT schedule.Among the vaccinated patients, 57 (40%) had anxiety about negative interference between their vaccine and SCIT/allergic disease. Ninety‐seven (68%) patients consulted an allergist about whether they could be vaccinated and whether an intermission for SCIT was needed during vaccination. As a result, 66 (46%) patients stopped SCIT during vaccination, of whom 56 patients stopped SCIT for 1 week before and after vaccination as recommended by an allergist based on the guidelines.In a recent survey conducted on 56 doctors with experience of AIT management, 77% did not stop AIT before vaccination and 70% considered that COVID‐19 vaccines were similar to vaccines for other infectious diseases.To summarize, the safety of inactivated COVID‐19 vaccines in patients undergoing SCIT is similar to that in the general population and patients without interruption of SCIT during COVID‐19 vaccination do not exhibit increased adverse reactions to the vaccines.None of the authors has potential conflict of interest related to this manuscript.Yingyang Xu has made substantial contributions to design of the study, acquisition of data, analysis and interpretation of data, and drafting the article. Kai Guan has made substantial contributions to design of the study, acquisition of data, and giving final approval of the version to be submitted.


Obesity is a major public health crisis for children and adults across the world (Karnik 2012). Since 1980, the prevalence of overweight and obesity has increased remarkably in developed countries; 23.8% (22.9–24.7) of boys and 22.6% (21.7–23.6) of girls were overweight or obese in 2013, compared with 16.9% (16.1–17.7) of boys and 16.2% (15.5–17.1) of girls in 1980 (Ng 2014). Data from the National Health and Nutrition Examination Survey (NHANES) over a 25 year period (from 1988 to 2014) reported that in United States, obesity in children aged 2‐11 years continued to rise until 5‐8 years ago but has then plateaued . HoweverThere is considerable evidence to show that childhood obesity is a risk factor for type 2 diabetes, hypertension, coronary heart disease and stroke in adulthood (hazard ratios ranging from 1.1‐5.4)  Global Strategy on Diet, Physical Activity and Health”, which encourages use of healthy diets and regular physical activity (WHO 2014). WHO developed the “Global Action Plan for the Prevention and Control of Non‐communicable Diseases 2013‐2020” which aims to achieve nine global non‐communicable diseases (NCD) targets by 2025, including a hold in rise of global obesity to match the rates of 2010. Obesity is caused by several modifiable and non‐modifiable risk factors . Non‐modVarious lifestyle, pharmacological and surgical interventions have been advocated to prevent and manage obesity in children and adolescents . Schools► Dietary intervention: Dietary interventions have been a mainstay for prevention and management of childhood and adolescent obesity. These interventions include dietary education and balanced meal provision.▷Dietary education: Educating children and/or their parents regarding healthy dietary behaviours has been a corner stone of several interventions that have targeted obesity in children and adolescents. It involves any combination of educational strategies, accompanied by environmental supports, designed to facilitate voluntary adoption of food choices and other food‐ and nutrition‐related behaviours conducive to health and well‐being. Nutrition lessons have been offered to participants along with their parents to motivate weight monitoring or reduction : Low dietary intake of fruits and vegetables is closely related to obesity and non‐communicable diseases , Peer‐Enhanced Adventure Therapy (PEAT), Social Cognitive Therapy and Cue Exposure Therapy, to improve psychological awareness of current health and associated risks with obesity . The theLifestyle modifications can be effective in preventing and managing obesity along with its associated morbidity in children and adolescents . This tiDietary intervention:Dietary intervention intends to reduce total calorie consumption. This allows the body to utilise energy stored as fat, leading to weight loss. It plays a role in both the prevention as well as management of obesity. Long term adverse effects, like cholelithiasis, and gastrointestinal distress have been noticed with extremely low calorie diets which are hence is not recommended . Diets cBalanced diets can ensure an adequate supply of required nutrients during the growth phase in childhood and adolescence while maintaining negative energy balance to loose fats and assist weight management. Low glycaemic diet causes reduction of the overall consumption of energy rich items . DiscourPhysical activity:Theoritically, when the energy expenditure is equal to the energy intake, body weight should be maintained, which is the goal for preventing weight gain. However, if the intention is to loose weight, there is a need to decrease the energy intake and/or increase energy expenditure. Physical activity aims to increase calorie expenditure by the body. Increased calorie demand will lead to consumption of the stored excessive body fat and result in weight loss. It also avoids loss of lean muscle tissue in children and adolescent . ExercisBehavioural therapy:Behavioural interventions develop the understanding and response of an individual towards obesity and health . Self‐moObesity is associated with significant morbidity, hence accounting for a notable health care and economic burden . MultiplWe intend to assess the effectiveness of interventions along with various contextual factors that could potentially impact the uptake and effectiveness of these interventions based on the Social Ecological Model adapted from the Centers for Disease Control and Prevention (CDC) framework for addressing obesity disparities (CDC). The objective of this review is to assess the impact of lifestyle interventions  along with the contextual factors to prevent and manage childhood and adolescent obesity.We will include primary studies using experimental and quasi‐experimental study designs that allow for causal inference. We will include non‐randomised studies with a control group in order to include large‐scale program evaluations so to capture important evidence on the effectiveness of lifestyle interventions from large scale programs and hence we would include the following study designs:► Randomised controlled trials: Studies where participants are randomly assigned, individually or in clusters, to intervention and comparison groups► Quasi‐experimental : Studies where non‐random assignment to intervention and comparison groups is based on other known allocation rules, including a threshold on a continuous variable (regression discontinuity designs) or exogenous geographical variation in the treatment allocation ► Controlled before‐after (CBA) studies: Studies in which allocation to intervention and control groups was not made by study investigators, and outcomes were measured in both intervention and control groups at baseline and endline.► Interrupted time series (ITS): Studies in which outcomes were measured in the intervention group at least three time points before the intervention was implemented and at least three time points after.Participants will be children from 0‐9 years of age and adolescents 10‐19 years of age. We will include studies from both high income countries (HIC) and LMIC. Studies including only a subset of eligible participants will be included if the review provides separate results for the eligible subgroup. We will exclude studies conducted among hospitalised children and children and adolescents with any pre‐existing health conditions  because these types of interventions are not generalizable but provide information for the specific target groups.We will include the following interventions targeting children and adolescents:► Dietary interventions▷ Dietary education ▷ Provision of balanced meals (school or community)► Physical activity▷ Promoting physical exercise▷ Reducing sedentary behaviour► Behavioural Therapy► Combination of any of the above interventionsWe will analyse the above mentioned single interventions separately and studies assessing combinations of these interventions would be analysed separately. The above interventions could be compared against no intervention, standard of care (whatever is applicable in the study setting) or a combination of the above mentioned interventions. We will not include studies comparing one intervention with the other from the above list of intervention. In case of studies with multiple intervention arms, we will only include study arms that meet the inclusion criteria.We will not use the list of outcomes as criteria for including studies.Primary outcomes► BMI (defined as weight in kilograms (kg) divided by height in meters squared)► BMI z‐scores (defined as a BMI measures of relative weight adjusted for child age and sex)► Change in body weight (change in weight in kg)► Adverse events Secondary outcomes► Prevalence of overweight and obesity► Percentage body fat change► Skin Fold Thickness► Circumference▷ Waist▷ Hip► Health‐related quality of life and self esteem (as defined by study authors)► Cost effectiveness of the interventionExplanatory Secondary Outcomes:► Physical Activity intensity► Total Caloric consumptionWe will only include studies with a minimum duration of 12 weeks for intervention and follow‐up.Studies conducted in any settings including schools, community or within family settings.We will use a comprehensive search strategy to identify eligible studies regardless of date of publication, language or publication status.Electronic searcheshttp://www.who.int/nutrition/databases/en/), Social Science Index, and Dissertation Abstracts International. The trials registry Clinicaltrials.gov will be searched for ongoing trials. We will search Google along with key nutrition agencies databases such as Nutrition International, the Global Alliance for Improved Nutrition, the World Food Programme, and HarvestPlus to search for non‐indexed, grey literature to locate relevant programme evaluations and any additional trials.We will search the following electronic databases: Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, the WHO nutrition databases , we will ensure that all articles reporting on the same study are appropriately linked. To ensure independence and appropriate combination of outcome constructs, syntheses will be conducted according to the type of interventions specified above. If multi‐arm studies are included, intervention groups will be combined or separated into different forest plots, and we will ensure that there is no double counting of participants. If an outcome is reported in several different metrics, we will perform unit conversions in order to pool the data. We do anticipate differences in the types of literature and we will ensure that any analysis will take possible sources of dependency into account by grouping papers into studies and ensuring that no double counting of evidence takes place when synthesizing across studies.Two review authors will independently assess potential study eligibility using predefined screening criteria. Any studies considered obviously irrelevant from screening the titles and/or abstracts will be excluded at the first level. Any uncertainties at the first level screening will be re‐assessed on the basis of full text in the second level of screening. For any discrepancies that may occur between the two reviewers, a third reviewer's opinion will be sought. We will resolve any disagreements through discussion until a consensus is reached. Reasons for exclusion of studies will be documented.Two review authors (ZH and KRN) will extract data independently and a third review author (JKD) will check for reliability and resolve any conflicts. We will check primary study data for accuracy and extract the following information in duplicate for each of the included studies:► Background: time period when study took place, type of publication , study country or countries, funding source(s), and conflicts of interest► Population and setting: population age and setting► Methods: Study design, description of study arms, unit of allocation, sample or cluster size per study arm , start and end date, follow up► Participants: total number randomised, sample representativeness, baseline characteristics, number of withdrawals, socio‐demographic data.► Intervention group details: number randomised to group, description of intervention, duration and follow‐up, timing, delivery of intervention, providers and their training. In case of studies with multiple intervention arms, we will describe all arms in the tables of included studies, while we will only report the arms that meet the inclusion criteria.► Comparison group details: number randomised to group, description of comparison, duration and follow‐up, timing, providers and their training► Outcomes: measurement tool, validation of the tool, total number in intervention and comparison groups, change indicated at each time point. In case if multiple measures are reported for the same outcome construct, we will use the one pre‐specified in our protocol.► Contextual factors:► Individual level factors: demographics, psychosocial, knowledge and skills, gene‐environment interactions and food preferences► Environmental level factors: homes, early care and education, schools, worksites, recreational facilities, food service and retail establishments and other community settings► Socio‐cultural level factors: belief systems, traditions, heritage, religion, priorities, lifestyle and body image► Multi‐sectoral level factors: government, organizations and business industries.Additionally, we will use PROGRESS  checklist to record whether outcome data were reported by socio‐demographic characteristics known to be important from an equity perspective and to assess whether studies included specific strategies to address diversity or disadvantage (O'Neill 2014).We will convert data to useable form and also contact authors for missing information. We will also examine any relevant retraction statements and errata for information.Two review authors will independently assess quality of studies and risk of bias for each study. For randomised studies, we will use the Cochrane Risk of Bias tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions , which aWe will summarise the quality of evidence according to the outcomes as per Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria . A gradeWe will perform statistical analysis using RevMan 5 (Revman 2014). We will analyse dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). For continuous data, we will use the mean difference (MD) with 95% CI, if outcomes are measured in the same way between trials. We will use the standardized mean difference (SMD) with 95% CI to combine trials that measure the same outcome but use different methods of measurement.Where trials have used clustered randomisation, we anticipate that study investigators would have presented their results after appropriately controlling for clustering effects . If it is unclear whether a cluster‐ randomised controlled trial has appropriately accounted for clustering, the study investigators will be contacted for further information. Where appropriate controls for clustering were not used, we will request an estimate of the intra‐class correlation coefficient. The data will be re‐analysed using multi‐level models which control for clustering. Following this, effect sizes and standard errors will be meta‐analysed in RevMan using the generic inverse method a. They wIf the outcome of interest does not include data on all participants, we will first contact the trial authors via email to inquire about data for the missing cases. Missing data if found will be re‐included in the analysis. If unable to find missing data we will analyse data for only those participants whose results are available, and address the impact of the missing data in the assessment of risk of bias.2, Q, and tau2 for all random‐effects meta‐analyses.We will assess heterogeneity among studies in two ways. Firstly, we will assess heterogeneity at face value: heterogeneity in population, interventions, or outcomes. Secondly, heterogeneity between trial results will be tested using a standard Chi² test, to assess whether observed differences in results are compatible with chance alone . We willIf there are 10 or more studies in a meta‐analysis, we will investigate reporting biases using funnel plots. If the plots are asymmetrical, we will consider various explanations such as publication bias, poor study design etc.We will pool data from studies we judge to be clinically homogeneous. If more than one study provides usable data in any single comparison, we will perform a meta‐analysis. We will conduct separate meta‐analysis based on the interventions . Separate meta‐analysis will be conducted for each intervention, outcome and study design . We will standardize all the reported effect sizes as RRs for the dichotomous outcome and synthesize all effect sizes as a common metric and synthesized together.We will carry out statistical analysis using the Review Manager software (Revman 2014). We will use random‐effects meta‐analysis for combining data to produce an overall summary, since we expect reasonable clinical heterogeneity in interventions, comparisons, outcomes, or settings within the studies included. The random‐effects summary will be treated as the average of the range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.For each comparison, we will descriptively summarise the findings from the contextual factors at the individual, environmental, socio‐cultural and multi‐sectorial levels based on our logic model to assess their impact on the implementation and effectiveness of each intervention.Where data will allow, we will perform the subgroup analyses listed below, to explore substantial and considerable heterogeneity across studies:► Age (e.g. 0‐9 year versus 10 to 19 years of age)► HIC versus LMIC► Duration or intensity of intervention ► Study setting, school, community etc.► Methodological quality of the included studies (Low risk of bias versus high risk of bias)2 statistic for subgroup differences that describes the percentage of the variability in effect estimates from different subgroups due to genuine subgroup differences rather than sampling error. We will not conduct meta‐regression.We will assess difference in subgroups based on the methodology described in the Cochrane Handbook  by usingThe potential effects of biases on the quality of the included trials will be assessed by sensitivity analysis. We will exclude studies at high risk for selection and attrition bias (> 20%) from the analysis to assess the difference on the pooled result.We do not plan to include qualitative research.1 SU adolescent OR SU child OR SU infant OR kid* OR child* OR pediat* OR baby OR babies OR infan* OR paed* OR pediat* OR teen*2 adolescen* OR pubescen* OR juvenil* OR youth OR young* OR pubert* OR preschool* OR toddler*3 1 OR 24 SU obesity OR SU pediatric obesity OR SU overnutrition OR SU overweight OR SU body mass index OR SU body weight changes OR obes* OR overweigh* OR over weigh* OR overnutrition OR over nutrition OR increas* weigh*5 weigh* gain* OR weigh* loss OR over‐weigh* OR over‐nutriti* OR fat* OR body fat* OR BMI OR Body mass index OR circumferenc*6 4 OR 57 SU psychotherapy OR SU motor activity OR SU exercise OR SU diet OR SU eating OR SU food OR behavio* therap* OR counsel* OR famil* therap* OR soci* support* OR exercis* OR exercis* therap*8 physical* educat* OR health promot* OR lifestyle OR healthy nutrit* OR educat* OR physical* OR activ* OR walk* OR jog* OR swim* OR danc* OR weigh* lift*9 aerobic* OR train* OR aware* OR behav* educat* OR physical* activ* OR diet* OR diet* therap* OR health* educat* OR diet* educat* OR nutrition* OR food* OR eat*10 food intake OR overeating OR balance* meal OR balance* diet* OR physical* train* OR game* OR psychotherap* OR peer* support* OR group therap* OR cognit* therap* OR psycholog* therap*11 7 OR 8 OR 9 OR 1012 3 AND 6 AND 1113 randomi* control* trial OR Quasi randomi* OR Quasirandomi* OR Quasi‐randomi* OR before after Stud* OR before‐after Stud* OR Interrupt* time ser* OR control* Stud* OR control* trial OR randomi* OR placebo OR control* group14 12 AND 13Lead review author: The lead author is the person who develops and co‐ordinates the review team, discusses and assigns roles for individual members of the review team, liaises with the editorial base and takes responsibility for the on‐going updates of the review.recommended optimal review team composition.Please give a brief description of content and methodological expertise within the review team. It is recommended to have at least one person on the review team who has content expertise, at least one person who has methodological expertise and at least one person who has statistical expertise. It is also recommended to have one person with information retrieval expertise. Please note that this is the Content: Rehana A Salam (RAS), Jai K Das (JKD) and Zulfiqar A Bhutta (ZAB)Systematic review methods: RAS, JKDStatistical analysis: RAS, JKD, Zahra Hoodbhoy (ZH), Karim Rizwan Nathani (KRN)Information retrieval: ZH, KRNDescribe the source(s) of financial and other support for the proposed review.None to declare: RAS, JKD, ZH, KRN, ZABApproximate date for submission of the systematic review. 31 January 2019Reviews should include in the protocol specifications for how the review, once completed, will be updated. This should include, at a minimum, information on who will be responsible and the frequency with which updates can be expected.Rehana A Salam will be responsible for updating this review and the review will be update every two years after publication date.By completing this form, you accept responsibility for preparing, maintaining and updating the review in accordance with Campbell Collaboration policy. Campbell will provide as much support as possible to assist with the preparation of the review.A draft review must be submitted to the relevant Coordinating Group within two years of protocol publication. If drafts are not submitted before the agreed deadlines, or if we are unable to contact you for an extended period, the relevant Coordinating Group has the right to de‐register the title or transfer the title to alternative authors. The Coordinating Group also has the right to de‐register or transfer the title if it does not meet the standards of the Coordinating Group and/or Campbell.You accept responsibility for maintaining the review in light of new evidence, comments and criticisms, and other developments, and updating the review at least once every five years, or, if requested, transferring responsibility for maintaining the review to others as agreed with the Coordinating Group.The support of the Coordinating Group in preparing your review is conditional upon your agreement to publish the protocol, finished review, and subsequent updates in the Campbell Library. Campbell places no restrictions on publication of the findings of a Campbell systematic review in a more abbreviated form as a journal article either before or after the publication of the monograph version in Campbell Systematic Reviews. Some journals, however, have restrictions that preclude publication of findings that have been, or will be, reported elsewhere and authors considering publication in such a journal should be aware of possible conflict with publication of the monograph version in Campbell Systematic Reviews. Publication in a journal after publication or in press status in Campbell Systematic Reviews should acknowledge the Campbell version and include a citation to it. Note that systematic reviews published in Campbell Systematic Reviews and co‐registered with Cochrane may have additional requirements or restrictions for co‐publication. Review authors accept responsibility for meeting any co‐publication requirements.I understand the commitment required to undertake a Campbell review, and agree to publish in the Campbell Library. Signed on behalf of the authors:


As a result, self‐powered electronic system could be constructed by integrating printed paper batteries with solar cells and light‐emitting diodes. The result highlights the feasibility of hydrogel reinforced paper for ubiquitous flexible and eco‐friendly electronics.Paper electronics offer an environmentally sustainable option for flexible and wearable systems and perfectly fit the available printing technologies for high manufacturing efficiency. As the heart of energy‐consuming devices, paper‐based batteries are required to be compatible with printing processes with high fidelity. Herein, hydrogel reinforced cellulose paper (HCP) is designed to serve as the separator and solid electrolyte for paper batteries. The HCP can sustain higher strain than pristine papers and are biodegradable in natural environment within four weeks. Zinc‐metal (Ni and Mn) batteries printed on the HCP present remarkable volumetric energy density of ≈26 mWh cm Hydrogel reinforced cellulose paper presents enhanced mechanical and conductivity properties that make them suitable as the separator and quasi‐solid electrolyte for paper batteries. The printed zinc batteries (Mn–Zn and Ni–Zn) are flexible, cuttable, and potentially integrable with other paper electronics. Burgeoning development of flexible electronics not only poses severe challenges to traditional manufacturing methods, but also raises further concerns on sustainability, in terms of the waste disposal and recyclability at the end of product life. Cellulose paper, derived from abundant natural biomass on earth, presents an ideal building block for developing flexible and environmentally sustainable electronics. Because of its portability, renewability and function tuneability, paper electronics could be the raising star of next‐generation functional devices, especially in the field of paper‐based flexible batteries, sensors, circuits, and diagnostic equipment. Imagine if these devices can be integrated on a piece of paper, it will greatly facilitate the application scenarios and enhance the commercial values. Meanwhile, the compatibility of paper to printing techniques allows facile ink printing of a wide variety of source materials, further flourishing the paper electronics.As fifth generation (5G) broadband has been set for commercial availability since 2020, full potential of Internet of Things (IoT) technology will be released by allowing the interconnection and communication of massive amount of IoT devices.1, 2 Compared with conventional lithium‐ion batteries, aqueous zinc‐ion batteries hold the advantages of low cost, high theoretical volumetric capacity (5854 Ah L–1), good rechargeability, and safe chemistry. Paper‐based zinc‐ion batteries are mainly shown in two categories. One is assembling active materials on the surface of cellulose fibers paper or directly fabricating freestanding active material films as paper‐like electrodes. This method hinders the printability of paper, making it almost impossible to use printing technology to fabricate batteries. The other type of paper zinc‐ion batteries employs the paper only as the substrate, in which the batteries are in‐plane printed on one side and present interdigitated configuration. Printing electrode inks on both sides is challenging because it may cause short of the battery due to the rough and permeable surface of paper. Accordingly, the printed micro‐batteries on paper deliver limited areal capacity and volumetric energy density (up to ≈10 mWh cm–3). The above limitations of energy storage components impede the integration and reliability of paper electronics.Among these printed paper devices, batteries are considered as the heart of paper electronics.19 Com but the electrode materials cannot be printed on the composite. In addition, the compatibility of the paper batteries with flexible circuits and devices allows the construction of a self‐powered paper system that integrates printed battery with circuit lines and solar cells. This work demonstrates the possibility of printed paper batteries and integration with flexible electronics toward the new era of paper electronics.Herein, we propose a new hydrogel reinforced cellulose paper (HCP) for printable zinc batteries and paper electronics. By combining the characteristics of cellulose paper and hydrogel, the composite paper presents favorable mechanical and conductivity properties that are suitable to its function as the separator and electrolyte for quasi‐solid zinc batteries. The anode and cathode materials are printed on the front and back of the paper, respectively. This is different from previous nano‐cellulose/hydrogel composites where the composites were employed only as the separator for energy devices,31 but2FigureTo fabricate the HCP, commercial cellulose filter paper (CP) was pre‐immersed in acrylamide solution with initiator and crosslinking agent. After heating under inert atmosphere, polyacrylamide (PAAM) hydrogel was polymerized among the fiber gaps in CP Figure1a. SincScanning electron microscopy (SEM) images in Figure  After four weeks, HCP are completely degraded while the CP takes six weeks for full degradation. Hygroscopicity of hydrogel greatly facilitates the growth and reproduction of microorganism. For comparison, Celgard separator  and other three typical polymer separators (cellulose acetate (CA), polyethersulfone (PES) and polytetrafluoroethylene (PTFE)) retained their original shape after the same burial time , both CP and HCP became fractured after two weeks of burial Figure . PAAM an33 AftIt is worth noting that the HCP only expands itself in longitudinal direction , and presents neglectable expansion in the lateral direction when it is immersed and swollen in electrolyte solution. This can be attributed to the anisotropic expansion of hydrogel which is constrained in the laminate stacking frame structure of cellulose fibers. This property guarantees the integrity of the printed electrode films during the activation of HCP electrolyte. As a proof of concept, radio‐frequency identification (RFID) antenna patterns were printed with a commercial printer on two pieces of HCP with the same size of 30 mm × 30 mm. One patterned HCP was swollen in liquid electrolyte. As shown in Figure −1 from the impedance measurement , which can be rooted to the lower content of hydrogel in HCP. Compared with aqueous electrolyte in pure cellulose paper, the HCP electrolyte shows highly stable Zn plating/stripping behavior and smaller polarization ,37 whin Figure . This enFigure2 and MnO2 were synthesized by a facile co‐precipitation method  powders with a certain amount of carbon black and PVDF. The carbon black enhances the electronic conductivity of the printed electrode, and the PVDF additive improves the bonding of electrodes and HCP substrate. The cathode and anode inks are printed on the front and back of HCP, respectively  according to discharge curves, respectively, which is equal to volumetric capacity of 20 and 27.5 mAh cm−3 (including the entire device volume). These values are significantly higher than previous flexible Ni–Zn batteries (4.4 mAh cm−3) and Mn–Zn batteries (3.3 mAh cm−3) under similar measured current densities. The plateaus in the charge and discharge curves correspond to the peaks in the cyclic voltammetry curves 2. When the current density is five times higher (from 1 to 5 mA cm−2), the capacity of Ni–Zn battery slightly drops to ≈0.7 mAh cm−2, retaining 84% of the initial capacity. This rate capability is much better than that of Mn–Zn batteries (34% capacity retention when current density increases from 1 to 5 mA cm−2). The resistance of the two battery systems were also investigated using impedance spectra . They are also much higher than the reported flexible NiCo‐Zn battery (8.0 mWh cm−3), Mn–Zn battery (12.0 mWh cm−3), and Ni–Fe battery (16.6 mWh cm−3). By evaluating the volumetric  energy and power densities, our printed paper batteries may represent the state‐of‐the‐art and supersede the commercial supercapacitors and lithium‐ion thin‐film batteries .40 The−2, the capacity of Ni–Zn and Mn–Zn batteries retained at ≈0.4 and 0.5 mAh cm−2, respectively. To prove the universality of the hydrogel reinforcement strategy, we also used commercial A4 copy paper for the fabrication of printed batteries  was employed and silver wires were printed on the same paper substrate to connect the electrodes to a red light‐emitting diode (LED). When the switch was turned on, the LED can emit light normally. As shown in FigureFor flexible energy devices composed of hydrogel electrolyte, safety, cuttability, and editability are their intrinsic features.58 To J–V curve is shown in Figure The best destination for the paper batteries should be in paper electronics. The integration of our battery and other flexible electronics on paper will promote the electronic system into a compact, lightweight, and convenient configuration. In principle, it is possible to achieve the all‐in‐one paper electronic system by integrating built‐in flexible solar cells, batteries, circuitry, and energy‐consuming electronics. This concept is schematically illustrated in Figure −2. The total energy released from the battery is ≈7.5 mAh , which is converted from light by the solar cell. Although we employed commercial solar cell in the experiment for conceptual demonstration, we are optimistic that with the fast advance in manufacturing technologies, more and more energy harvesting devices (such as solar cells and nanogenerators) can be printed on paper. Therefore, our printed zinc‐metal batteries may serve as reliable and low‐cost energy storage units in an all‐paper self‐powered system.To confirm the compatibility of the battery and solar cell on paper, the light charging performance of the integrated system was investigated. The battery was fully discharged first and stabilized for 10 min. Then the solar cell was illuminated by a standard solar simulator at one sun intensity Figure , and thelar cells61 and3In summary, we have realized zinc‐based paper batteries by printing electrode inks on biodegradable hydrogel reinforced cellulose paper. The hydrogel paper serves as both electrolyte and separator for printed batteries, for which the hydrogel significantly improves the mechanical strength of the cellulose fibers and maintains the ion conductivity of the composite. As a result, the printed batteries are cuttable and flexible without the risk of short of contact failure. In addition, they exhibit high volumetric capacity and energy density which outperform other paper based or thin‐film energy storage units. The facile synthesis and high performance may push forward the advance of paper batteries for applications in printed electronics and integrated paper circuits.The authors declare no conflict of interest.Supporting InformationClick here for additional data file.Supplemental Video 1Click here for additional data file.Supplemental Video 2Click here for additional data file.


Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre‐clinical drug screening platforms have identified genetic dependencies that can be exploited with drug therapy. These genetic dependencies can also be used as biomarkers to predict response to treatment. For many cancers, the identification of such biomarkers remains elusive. In this review, we discuss the development and characterization of models used to study human cancers, RNA interference and CRISPR screens to identify genetic dependencies, large‐scale pharmacogenomics studies and drug screening approaches to improve pre‐clinical drug screening and biomarker discovery. This Review provides an overview of currently used cancer models and genomics approaches to uncover genetic dependencies, identify novel therapeutic targets, and discover biomarkers that can predict response to drug therapy. Genotype–phenotype relationshipsThe association between a specific genotype  and the resulting phenotype . In cancer biology, this refers to how specific genetic alterations produce changes in the properties of tumour cells.Patient avatarsPatient‐derived tumour xenografts that are co‐treated with the same therapies as the patient to mimic changes that would occur in the patient in order to evaluate response to therapy and changes in clonal heterogeneity.Predictive biomarkerA marker  that can be used to predict the response of a tumour to a specific therapy.Spatiotemporal heterogeneityThis refers to the different clones (that harbour distinct genomic aberrations) present in different areas of a tumour and that appeared at different time points in disease progression.Targeted therapyDrug therapy directed at a specific gene product or pathway, as opposed to chemotherapy, which is less specific and targets all proliferating cells.Tumour microenvironmentInteractions between tumour cells and the cells and growth factors within its surrounding environment, such as stromal cells, blood vessels and infiltrating inflammatory cells.Rapidly developing sequencing technology, in conjunction with advances in computational analysis, has culminated in the genomic and transcriptomic characterization of individual patients’ tumours, bringing the possibility of precision‐medicine to the clinic. However, a remaining challenge is how to use this information to identify therapeutic targets and predictive biomarkers to guide clinical decision‐making about whether a particular drug is likely to be effective for the treatment of a specific patient’s disease.et al, et al, et al, de novo generation of drug‐resistant clones. To overcome these challenges, efforts have been taken to model cancer in different systems, study how specific genomic alterations result in changes to tumour growth, and test different therapies in these model systems as a surrogate readout for how the patient’s cancer will respond to treatment. These approaches offer the opportunity to uncover genetic dependencies, identify novel therapeutic targets and define mechanisms of drug resistance.There have been a number of notable successes in the development of targeted therapy. Some of these include the use of tyrosine kinase inhibitors such as Imatinib for chronic myelogenous leukaemia harbouring the BCR‐ABL translocation , and patient‐derived tumour xenografts (PDTXs). We will also review RNA interference (RNAi) and CRISPR technologies applied to functional genomic screens for the discovery of novel therapeutic targets, drug screens, and combination therapy screens using different cancer models in order to identify novel molecular biomarkers that can predict response to drug therapy.et al, et al, et al, et al, et al, et al, et al, et al, et al, Hundreds of human cancer cell lines have been established and are the most widely used to study cancer biology and drug screening. Resources with comprehensive genomic information about these cell lines include the Cancer Cell Line Encyclopedia  polymerase (PARP) inhibition in ovarian cancers with homologous DNA repair deficiency, there still appear to be a range of responses to appropriately selected therapy and the eventual development of drug resistance. Hence, there is value in the discovery of predictive biomarkers not only for other disease‐specific contexts where there are no reliable biomarkers to guide the choice of appropriate therapy, but also for the prediction of drug resistance, and the selection of appropriate therapy once this has developed.There are a number of approaches to discover novel biomarkers in cancer. These include genomic and transcriptomic profiling, proteomic approaches and metabolomic approaches, all of which are beyond the scope of our review but have been covered in detail elsewhere  and short interfering RNA (siRNA) sequences are designed to contain a short “seed sequence” that can bind to and downregulate mRNA to repress expression of the gene of interest  library on H23, a human lung adenocarcinoma cell line , a member of the COMPASS histone H3K4 methyltransferase complex, resulted in dramatic tumour growth arrest ‐promoter that is engineered to minimize leaky Cas9 expression for tight temporal control of Cas9 activity critical for avoiding aberrant genome‐editing activity, and the reverse tetracycline‐controlled transactivator (rtTA)‐V10 variant that displays increased sensitivity to low doxycycline concentrations in order to improve Cas9 expression in response to doxycycline treatment in vivo  responsible for a particular phenotype. These studies represent the majority of experimentally validated information on genotype–phenotype relationships. However, it is becoming readily apparent that genotype–phenotype relationships are exceedingly complex, and not limited to a single gene corresponding to a single phenotype, where certain genetic mutations do not consistently result in the same phenotype, due to factors such as incomplete penetrance, variable expressivity, and the multitude of interactions a single gene product can have  was developed by Corsello and colleagues. This approach increases the number of drug‐cell line combinations that can be tested simultaneously by labelling cancer cell lines each with a unique DNA sequence (or “barcode”), pooling the cell lines in equal proportions, and then using the barcodes (detected by DNA sequencing) as a surrogate readout for cellular viability after a period of in vitro drug screening and analysis methods will also help to reconcile the interpretation of drug sensitivities and genetic dependencies identified from these studies.Large‐scale pharmacogenomics studies are helpful to identify potential novel treatments for specific genetic alterations but must be followed by further validation studies. Standardization of in vitro, are amenable to high‐throughput analyses and are thought to be more representative of the cellular and mutational heterogeneity of the original patient’s disease. PDTOs have been used to test drug sensitivity in almost all tumour types, including colon  to PDTXs established from triple‐negative breast cancer and used the barcodes (quantified from DNA sequencing) to decode which cells received which chemotherapeutic agent, and the efficacy of each treatment  from AstraZeneca and Varsity Pharmaceuticals. The other author declares no conflict of interest.ihttps://caldaslab.cruk.cam.ac.uk/bcape/).An encyclopaedia of breast cancer patient‐derived tumour xenografts (iihttps://cancer.sanger.ac.uk/cosmic).COSMIC, a catalogue of somatic mutations in human cancer (iiihttps://web.expasy.org/cellosaurus/).Cellosaurus, a resource of information on cell lines from multiple species, not limited to human cancer (ivhttps://cellmodelpassports.sanger.ac.uk/).Cell Model Passports, which provides genomics information and functional datasets on human cancer cell lines and patient‐derived tumour organoid models .Cancer Therapeutics Response Portal (CTRP) from the Broad Institute that links the genetic information from human cancer cell lines with their response to small‐molecular therapies .Cancer Dependency Map (DepMap), an initiative from the Broad Institute and Wellcome Sanger Institute that aims to map all the genetic dependencies of human cancers (viihttps://www.cancerrxgene.org/).Genomics of Drug Sensitivity in Cancer (GDSC), collaboration between The Cancer Genome Project at the Wellcome Sanger Institute and the Center for Molecular Therapeutics to discover therapeutic biomarkers in human cancers (viiihttps://bioinformatics.mdanderson.org/public‐software/mclp/).MD Anderson Cell Lines Project (MCLP) provides protein expression data linked to genomic and transcriptomic data in human cancer cell lines (Determine whether ctDNA can be used to accurately assess drug response and changes in clonal heterogeneity of a patient’s tumour.Determine whether drug response and changes in clonal heterogeneity in PDTO and PDTX models of different human cancers correspond to that seen in similarly treated patients.Incorporate single‐cell genomic, transcriptomic, proteomic and epigenomic analysis into drug therapy screens in order to identify novel predictive biomarkers and therapeutic targets in human cancers.