For individuals living with debilitating hereditary diseases, therapies that can modify a person’s genome (genomic therapies) hold the promise to shift treatment outlooks from a lifetime of chronic disease management to a cure . We now Unfortunately, the first generation of genomic therapies have entered the market with price tags up to $3.5 million per treatment Table , with reFor diseases disproportionately affecting marginalized communities  is highly prevalent in Navajo and Apache communities ), affordEven more troubling are signs that traditional for-profit pharmaceutical companies may be unsuitable for delivering genomic therapies for rare diseases. Orchard Therapeutics secured a license to commercialize a gene therapy for SCID but returned the license to the University of California due to manufacturing issues . BluebirIn a for-profit context, deprioritization of genomic therapies for rare diseases is logical because commercialization is only feasible if the economics are positive. With small patient populations, the revenue expected from rare genomic therapies, even when highly priced, may be insufficient for commercial entities to justify the considerable upfront investment . Given tTo investigate the underlying drivers of high prices and explore alternative pathways to development, the Innovative Genomics Institute (IGI) launched an expert Affordability Task Force in January 2022. The 35-member task force is evaluating business models and funding, manufacturing challenges, intellectual property, health insurance and health policy. While the task force’s work will not be completed until early 2023, here we present its early findings.Box 1 Value based pricing and payment modelsValue-based pricing attempts to reconcile prices with the value provided to patients and health systems, and thus creates an added incentive to produce highly effective drugs. A push for value-based pricing and payment models has been observed in recent years as overpriced, under-performing drugs, like Aduhelm for Alzheimer’s, draw public scrutiny . HoweverIn a purely value-based pricing system, reduced drug production costs are unlikely to significantly reduce prices since the value of a drug is wholly separate from input costs. Technological improvements that lower development costs, may increase profits for companies while not improving affordability for patients. Thus, value-based payment models  do not sThe path to market for new drugs has remained virtually unchanged for decades: governments and philanthropies fund early-stage research at academic institutions with the technology then licensed by for-profit companies who further develop, clinically evaluate, and bring drug candidates through regulatory approvals. These companies take on the risk of failure at the clinical and regulatory stages. Fig.  9].Fig..Fig.9].FToday, an increasing number of government and philanthropy programs are challenging this traditional pipeline by not only funding early-stage research, but also funding clinical trials and providing regulatory support to accelerate promising new drugs . This moTo address this challenge, the IGI has assembled an expert Affordability Task Force composed of interdisciplinary scholars and practitioners with insights into all aspects of drug development and healthcare economics. Working with the IGI team, the task force is generating a roadmap of concrete strategies to increase the likelihood that genomic therapies developed by the IGI and other academic institutions are affordable and accessible . We aim The task force is divided into four sub-groups addressing specific aims critical to affordability and accessibility Fig. . The firTo the best of our knowledge, this effort represents the most comprehensive attempt to understand and develop solutions to the affordability crisis facing new genomic therapies.The current drug development system is centered on commercialization tied to for-profit pharmaceuticals. However, real-world examples of alternative organizational models have emerged in recent years that exemplify different incentive structures. First passed into law in 2010 in Maryland, a Public Benefit Corporation is a type of for-profit corporate entity legally permitted to consider social goals rather than only shareholder value, and may be well-suited for drug development. United Therapeutics and Audacity Therapeutics are already using this model for drug development, relying on investors with a shared social vision, such as venture philanthropy.Nonprofit drug organizations, like CivicaRx, have also emerged as potential models. In 2018, a group of health systems and philanthropies founded and financed CivicaRx to address generic drug pricing and shortage issues. Instead of separating investors and customers, CivicaRx is pioneering a Health Care Utility Model where the purchasers of the products fund the company . This moOrganizational models focusing on the role of government and public funds may also be an effective approach. Frustrated by prices preventing access to necessary drugs, the state of California recently allocated $100 million to acquire and manufacture an insulin biosimilar with the goal of providing low-cost insulin to residents . SeparatAlthough CIRM supports genomic therapies, it functions more as a funder than an organization that creates and distributes drugs. Most examples of alternative models for commercialization or distribution of drugs focus on generics or repurposed pharmaceuticals. Compared to these small molecule drugs, genomic therapies represent cutting edge technologies with valuable IP and a complex manufacturing process. Existing alternative models may need to be adapted to consider the unique properties of genomic therapies. A model that leverages the existing ecosystem of public dollars, grants, and philanthropy could make use of the unique expertise and manufacturing capacity of academic medical centers to create centers of excellence through strategic partnerships and operate under a nonprofit or public benefit designation.To ensure affordability and access, universities, particularly those with a public mission, should consider integrating affordability and accessibility clauses into licensing agreements along with tracking and enforcement mechanisms. Resources such as the Master Alliance Provisions Guide (MAPGuide)  and MediWhile pricing and access are concerns for genomic therapies here in the US and in other high income countries, these concerns are compounded when considering whether and how these therapies will reach low and middle income countries. Medicines Patent Pool (MPP) was created to address this very type of challenge through non-exclusive voluntary licensing. MPP negotiates and manages licensing pools for IP, which makes achieving equitable access easier for patent holders who wish to reach a more global market but are not prepared to develop manufacturing and distribution infrastructure in developing countries on their own. The effectiveness of this approach was recently published, showing that upon inclusion in MPP, patents see “an immediate and large increase in licensing” and lead to an increase in product sales .In addition to non-exclusive licensing, universities could include provisions in exclusive licenses that request or mandate companies to provide an agreed upon number of doses to low-income individuals, provide the product or sub-license the technology at reduced cost for those serving low and middle income countries, or require the creation of an accessibility and affordability plan with mechanisms for enforcement such as claw-back provisions.Manufacturing costs and compliance with US regulations present a major bottleneck. The cost of building a dedicated current good manufacturing practice (cGMP) facility for a specific drug product is on the order of billions of dollars and any organization pursuing this approach needs significant upfront capital investment. Distributed manufacturing models may lower the cost of cell-based therapies  and haveDespite all its advantages, point-of-care manufacturing models are difficult to implement in the US given FDA requirements. Lowering the cost of CRISPR-based therapies may necessitate regulatory streamlining. One proposed path is to minimize requirements for cGMP grade reagents in investigational new drug (IND)-enabling and clinical studies. In the context of editing autologous cells, the Cas protein and guide RNA become diluted and degraded before the cell product is returned to the patient , 25. TheAdvances in manufacturing, delivery, and regulatory frameworks will be necessary to lower the cost of goods for genomic therapies and increase potential for administration, but these advances are insufficient if they are not paired with mechanisms to lower prices and create new models of commercialization see Box .Conventional approaches to pricing—based on what the market can bear—have led to historically high prices. Most alternative methods identified by our Task Force aim to lower prices by tethering the final price of the product to the cost to develop and deliver the drug. Simple cost-plus models that calculate the cost of goods, labor, plus some predetermined profit margin are one approach that have been discussed in the literature . The priDespite their benefits, simplified cost-plus approaches have drawbacks that prevent organizations from easily adapting to market systems unique to innovative genomic therapies. Our task force members are developing a dynamic pricing model that includes the cost of drug development, number of patients requiring treatment, insurance coverage, market conditions, and the cost of capital. Under various modeling scenarios this dynamic cost-plus model yielded prices significantly less, in some cases up to 10x less than genomic therapies currently on the market, whilst still supporting a sustainable business.Any new low-cost genomic therapy also needs to fit into the larger healthcare ecosystem. In some cases, misaligned incentives within the system may lead to higher prices for patients; for example, pharmacy benefit managers and hospitals are paid a percentage of the total cost of administering a drug, therefore drugs priced significantly lower than a competitor’s may be unattractive. Models such as CivicaRx may help address some of these issues through direct partnerships with health systems. Any entity seeking to establish a new/alternative structure will need to consider all the major healthcare system players  and ideally negotiate contracts prior to release to ensure a smooth transition and guarantee market share.Concerns over cost and distribution of benefits have been at the forefront of every debate since CRISPR genome editing was first developed, yet no substantive action has occurred. This project takes a first step toward developing a practical roadmap for academic institutions as the engines of genomic innovation.


Stigma in mental health settings is described as a set of negative and unrealistic beliefs about those with mental illness. Authors suggest that stigma is consistently underdefined and overused, leading to resources toward preventing and managing this problem lacking intention and efficiency. Three interacting levels of stigma are defined: social, structural, and internalized or self-stigma. Internalized stigma refers to how people with mental illness see themselves as mentally unwell and, therefore, of lesser value.We aim to discuss the impact of internalized stigma on psychiatric patients and ways of prevention and stigma resistance.PubMed using the key words “internalized stigma” and “mental illness”.We performed a non-systematic literature review from the data base Internalized stigma is one of the major factors leading to delayed contact with psychiatric care up to two years in outpatients. In psychiatric patients, higher internalized stigma was associated with weakened social support and integration, hopelessness and lower self-esteem and sense of coherence. Low self-esteem is the most significantly associated factor and mediates lower quality of life and higher treatment avoidance. The risk of self-esteem loss seems higher in patients with more insight, especially if they also have a loss of valued social identity. Although some studies suggest higher levels of internalized stigma in female, single and lower educated patients, adjusted statistical analyses do not validate these sociodemographic variations. It is however more prevalent in those with depression and who had been hospitalized because of their mental illness. The impact of internalized stigma is often compared to the levels of the illness burden itself, leading to higher levels of depression and greater psychiatric symptom severity. Additionally, more self-stigma seems to predict suicidal ideation, particularly in young adults.The internalization of negative stereotypes undermines empowerment and negatively impacts the evolution and recovery of psychiatric patients. There’s strong evidence that general stigma constitutes a risk factor for poor biopsychosocial health outcomes. Programs addressing multiple stigma components seem to be most effective in improving suicide prevention. However, most self-stigma interventions involve groups, which can create barriers for people who are not comfortable disclosing a mental health condition to others. Anti-stigma programs are most effective when they involve people with lived experience of mental health conditions in all aspects of development. Interventions from a younger age should focus on prevention of general stigma by improving understanding of mental illness and reducing self and outwards discrimination. Working on professionals own stigmatizing behaviors is also key to improve the way we communicate and educate populations on how to internally process mental health problems.None Declared


Mental health conditions are common during pregnancy and the first year after childbirth. Early detection allows timely support and treatment to be offered, but identifying perinatal mental health conditions may be challenging due to stigma and under-recognition of symptoms. Asking about symptoms of mental health conditions during routine antenatal and postnatal appointments can help to identify women at risk. This study explores women’s awareness of perinatal mental health conditions, their views on the acceptability of being asked about mental health and any preference for specific assessment tools in two regions in India.Focus group discussions (FGDs) were conducted with pregnant, post-partum and non-perinatal women in Kangra, Himachal Pradesh (northern India) and Bengaluru, Karnataka (southern India). Settings included a hospital antenatal clinic and obstetric ward, Anganwadi Centres and Primary Health Centres. FGDs were facilitated, audio-recorded and transcribed. Narratives were coded for emerging themes and analysed using thematic analysis.Seven FGDs including 36 participants were conducted. Emerging themes were: manifestations of and contributors to mental health conditions; challenges in talking about mental health; and the acceptability of being asked about mental health. Difficult familial relationships, prioritising the needs of others and pressure to have a male infant were cited as key stressors. Being asked about mental health was generally reported to be acceptable, though some women felt uncomfortable with questions about suicidality. No preference for any specific assessment tool was reported.Women face many stressors during the perinatal period including difficult familial relationships and societal pressure to bear a male infant. Being asked about mental health was generally considered to be acceptable, but questions relating to suicidality may be challenging in a community setting, requiring sensitivity by the interviewer. Future studies should assess the acceptability of mental health assessments in ‘real world’ antenatal and postnatal clinics and explore ways of overcoming the associated challenges in resource-constrained settings.The online version contains supplementary material available at 10.1186/s12888-023-05323-5. Mental health conditions are the most common morbidities of pregnancy and the first year after childbirth . PrevaleIdentifying perinatal mental health conditions is challenging, however. Persisting stigma means women may find it difficult to disclose symptoms, while poor awareness around what constitutes a mental health condition may lead to under-recognition of symptoms , 6. UndeIn some countries including the UK and the USA, women are asked about symptoms of mental health conditions using standardised assessment tools during routine antenatal and postnatal appointments , 8. SystIn India, an estimated one in five pregnant women experiences a mental health condition and 7.6% of women experience suicidal ideation or suicidal behaviours in pregnancy , 13. TheThis was a qualitative study consisting of focus group discussions (FGDs) conducted in two diverse regions of India. The study represents the first phase of the Perinatal Mental Health Study (PMHS), which uses the Maternal and Perinatal Health Research Collaboration India (MaatHRI), a network of sixteen partner hospitals across six states in India , 18. TheFGDs were conducted with women at each study site. Women were eligible to take part if they were aged 18–45 years, could speak the study languages  and were either pregnant (at any stage of pregnancy), post-partum (had given birth within the past 12 months) or non-perinatal (not currently pregnant and had not given birth within the past 12 months). The reason for including non-perinatal women was to understand views from a wide range of women, not only those who were currently pregnant or had recently given birth. Recruitment was through convenience sampling.In HP, FGDs were conducted at the DRPGMC hospital antenatal clinic, the DRPGMC obstetric ward and at two Anganwadi Centres in villages approximately 30 km outside of Kangra. In the antenatal clinic, women attending a routine appointment on the day of the FGDs who met the eligibility criteria were invited to participate. On the obstetric ward, eligible women who were present on the ward on the day of the FGDs were invited to participate. At Anganwadi centres, eligible women were invited several days in advance by Anganwadi workers to attend the centre on the scheduled day if they were willing to take part.In Bengaluru, Karnataka, FGDs were conducted at the NIMHANS Centre for Wellbeing and at two Primary Health Centres. At the NIMHANS Centre for Wellbeing, women receiving care at the centre who met the eligibility criteria were invited a few days in advance to attend on the scheduled day. At Primary Health Centres, eligible women who were attending immunisation clinics on specific days were approached and invited to take part in FGDs.Eligible women were provided with information about the study including the aims of the research and format of the FGDs. Those who agreed to participate provided written informed consent. The researchers did not know any of the participants prior to the study. A question guide was used as a prompt for discussions, allowing for flexibility in the topics covered ; a female research nurse fluent in Hindi, the local dialect of Pahari and English (DS); and a female obstetrician fluent in Hindi and English. FGDs were conducted in private spaces in the antenatal clinic, on the obstetric ward or within the Anganwadi centres. Questions were asked in English and repeated in Hindi, or at times asked directly in Hindi. Discussion between participants was mostly in Hindi and Pahari, with a small number of participants choosing to respond in English. Any comments made in English were repeated in Hindi by the faciliator to ensure everyone could understand and follow the discussion.In Karnataka, FGDs were facilitated by a female public health researcher (GF), a male clinical psychologist (MTK), a female clinical psychology PhD candidate (not a study author), a female senior staff nurse (not a study author) and a female psychiatric social worker (not a study author). At the NIMHANS Centre for Wellbeing, FGDs were conducted in a private room within the clinic. At the Primary Health Centres, due to space constraints, FGDs were conducted in a corner of the waiting room. Because many of the participants recruited at the Primary Health Centres had limited time available, it was at times necessary to conduct discussions in small groups of two or three, rather than as a larger group. Questions were asked in English and interpreted into Kannada or asked directly in Kannada. Discussions were in Kannada with a small number of participants speaking in English.FGDs were audio-recorded using a digital voice recorder. One researcher (GF) made notes during and immediately after each FGD on the dynamics of the group, interactions between participants and any non-verbal communication observed.Eight mental health assessment tools were shown to FGD participants: the Kessler Psychological Distress Scale (K10), a measure of generalised psychological distress; the Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire (PHQ-9), measures of depression; the Generalised Anxiety Disorder Scale (GAD-7) and Perinatal Anxiety Screening Scale (PASS), measures of anxiety; the PTSD Checklist (PCL-5), a measure of post-traumatic stress disorder (PTSD); the Scale for Assessment of Somatic Symptoms (SASS), a measure of somatic symptoms; and the Suicide Behaviour Questionnaire Revised (SBQ-R), a measure of suicidality. These assessment tools were selected on the basis of a systematic review of validated screening measures in India and through discussion within the research team who have extensive experience of working in the field of mental health in the study settings . ExistinNVivo 11 for coding [Audio recordings were transcribed directly into English by two members of the study team (GF and DS) and an experienced translator (not a study author). Transcripts were imported into r coding . Data anr coding . FamiliaWe acknowledge the possibility of unconscious biases held by the research team influencing data collection and interpretation. For each FGD, at least one facilitator came from the local community, ensuring cultural sensitivity. Of the three researchers conducting data analysis, two have extensive experience of working in mental health in the respective local settings and carrying out qualitative studies (PK and MTK) and the third is experienced in conducting qualitative studies across diverse low-income settings globally (GF). Results are reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist  . By contrast, when discussing contributing factors, women provided more personalised perspectives, often sharing examples from their own lives . Dynamics between participants varied across FGD groups but often one or two women contributed a lot while others spoke less. Efforts were made to encourage all women to join in the discussion, but nevertheless some women remained more reserved.FGD questions were deliberately phrased indirectly  to avoid participants feeling pressured to share personal experiences. Analysis of the transcripts showed that when discussing symptoms, women mostly used a third person narrative  was also considered unacceptable by some. These concerns were voiced by a minority, and others felt that questions about suicidality were important to ask. Rates of maternal suicide in India are high and identifying women at risk is important . BecauseIn resource-constrained settings, assessing mental health within clinics where staff are often already over-stretched presents considerable challenges. Stigma and time pressures may impact women’s willingness to discuss their mental health within the context of a clinic appointment. Holding discussions in a private space, informing women in advance and having a supportive, familiar health professional administer the questions may help to put women at ease, though these may not always be feasible. Future research should explore the challenges of implementing routine mental health assessments in resource-constrained community settings.The study has a number of limitations. It was not possible to separate women into different FGD groups on the basis of age, parity or educational level, and some women – for example those who were older or more experienced as mothers – may have felt more at ease than others at speaking within the group. We used various strategies to encourage participants to contribute to the discussion, including explaining confidentiality and that all views are equally important, using ice-breakers, informal language and humour, and directing some of the questions at the quieter participants. Stigma may also have impacted upon women’s willingness to speak within a group. Individual interviews may be better suited to eliciting in-depth understanding of mental health. FGDs were conducted in primary care settings which are often crowded, noisy and have little privacy. Many women had infants with them, and some were unable to remain for the full FGD duration due to long journeys home, jobs or domestic obligations. These factors may have led to lower engagement with the discussions and less in-depth responses. However, these are the realities of conducting FGDs in many low-resource settings , especiaThis qualitative study explored women’s awareness of mental health conditions and the acceptability of being asked about mental health. Difficult familial relationships, being expected to prioritise the needs of others and pressure to bear a male infant are key stressors for perinatal women in these settings in India. Stigma around mental health remains significant. Being asked about mental health conditions was generally felt to be acceptable, but questions relating to suicidal behaviours may be challenging in a community setting and require sensitivity by the interviewer. No preference for a specific mental health assessment tool was expressed; further research is required to confirm this and explore how questions are interpreted. Future studies should assess the acceptability of conducting mental health assessments in antenatal and postnatal clinics and explore ways of overcoming the associated challenges in resource-constrained community settings.Below is the link to the electronic supplementary material.Supplementary Material 1 - COREQ ChecklistSupplementary Material 2 - FGD Questions Guide


Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) above or below recommendations have been associated with increased paediatric health service utilization as well as increased risk of adverse birth outcomes, including small for gestational age (SGA) and preterm birth (PTB). SGA and PTB are associated with numerous adverse health outcomes in the child, including delayed growth, motor and cognitive impairment. Previous research has identified birth weight and gestational age on the causal pathway in the association between maternal pre-pregnancy BMI and child hospital admissions, there are no studies to date to quantify this relationship across other areas of health service utilization, nor the impact of gestational weight gain. This study aimed to assess if SGA or PTB partially explain the association between maternal weight and paediatric health service utilization.The study population consisted of all women who delivered a singleton, live infant in Ontario between 2012 and 2014, and was assembled from data contained in the provincial birth registry. Health service utilization over the first 24 months following birth was examined by linking data from the registry with other provincial health administrative databases housed at ICES. The mediating roles of PTB and SGA were assessed using the Baron-Kenny method and causal mediation analysis.A total of 204,162 infants were included in the analysis of maternal pre-pregnancy BMI and 171,127 infants were included in the GWG analysis. The small magnitude of association between maternal BMI and paediatric health service utilization impacted our ability to estimate the indirect effect of maternal BMI through adverse birth outcomes (adjusted indirect effect = 0.00). 56.7% of the association between below recommended GWG and increased hospitalizations was attributed to PTB, while 6.8% of the association was attributed to SGA.Paediatric hospitalizations may be partially attributable to PTB and SGA in children born to mothers with below-recommended GWG. However, maternal weight also appears to be related to increased paediatric health service utilization independent of PTB and SGA.The online version contains supplementary material available at 10.1186/s12884-023-05744-w. Elevated maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) both below and above the recommended range are associated with adverse birth outcomes, including small for gestational age (SGA) and preterm birth (PTB) , 2. SGA The association between maternal weight and paediatric health outcomes may be partly explained by adverse birth outcomes, such as SGA or PTB. Cameron et al. previously investigated the relationship between maternal pre-pregnancy BMI and child hospital admissions and noted that birth weight and gestational age were on the causal pathway of this relationship . This stwww.bornontario.ca). BORN is a high-quality, comprehensive registry with 100% coverage of all births in Ontario and demonstrated good agreement between the data elements and patient records . We . We 6]. 0 kg/m2) .The outcomes were measures of paediatric health service utilization, including rates of hospitalizations, ED visits, and physician visits  in childa priori and included infant sex, maternal age, maternal smoking status, pre-existing maternal medical conditions , and neighbourhood income quintile. [Potential confounders of the relationship between maternal pre-pregnancy BMI/GWG and infant health service utilization  were ideuintile. .The following mediators were included in the analysis: gestational age < 37 weeks (PTB) and SGA (< 10th percentile), informed by previous research .We first described baseline characteristics of mothers and children using frequency distributions. Rates of health service utilization during the first 24 months of life were calculated separately for each type of health service . The totTo compare rates of infant health service utilization by maternal pre-pregnancy BMI and by GWG, we first reported unadjusted incidence rate ratios (IRRs) for health service utilization across BMI/GWG categories. We then used multivariable regression analysis to adjust for potential confounders. Due to over-dispersion, we used negative binomial regression  in two sThe Baron-Kenny approach was used to identify potential mediation and causal mediation analysis was used to investigate mediation when the Baron-Kenny approach indicated that it was present. The possible mediation of the relationship between maternal pre-pregnancy BMI or GWG and paediatric health service utilization, by PTB and small for gestational age , was assIn this mediation analysis approach, each step must demonstrate a significant relationship (either positive or negative) in order to proceed to the next step . A conseFor mediation relationships that were apparent following the four steps described, SAS PROC CAUSALMED was used to ascertain the total, natural direct, and natural indirect effects to estimate the effect decomposition  and percWe identified 258,833 birth records in BORN from April 1, 2012 to March 31, 2014. Following exclusions   and 21% had GWG in the recommended range.Characteristics of the entire study population are presented in Table Figure The results suggested an increased rate of hospitalizations and ED visits for children born to overweight and obese persons compared to those born to normal weight persons. However, none of the other associations between pre-pregnancy BMI and paediatric health service use were strong enough to meet criteria for continuation to step 2 Table .The results suggested that children born to mothers who were overweight or obese prior to pregnancy had lower rates of SGA Table  relativeResults suggested that children born SGA had an increased rate of hospitalizations and a small decrease in the rate of ED visits compared to children who were not born SGA Table .step 2) limited the potential for a causal mediation interpretation given that the direction of association was opposite to what would be expected for a causal mediator.Steps 1–3 in the adjusted analyses had thus suggested that SGA may partially explain the relationship between maternal weight and paediatric hospitalization. However, the decreased rate of SGA among children born to mothers who were overweight or obese prior to pregnancy :Results suggested an increased rate of hospitalizations for children born to persons with below recommended GWG. Children born to mothers with above recommended GWG had an increased rate of ED visits compared to those born to mothers with recommended GWG. However, all other associations were small or nonsignificant and removed from all subsequent analyses Table .Results suggested that children born to mothers with below recommended GWG had an increased rate of PTB and SGA, compared to children born to mothers with recommended GWG. Children born to mothers with above recommended GWG were not measurable in this model due to a Hessian error, likely attributed to low cell sizes and lack of variation within the matrix. The model for above recommended GWG was unable to achieve an estimate after adjustment for number of iterations and was thus omitted from subsequent analyses Table .Children born preterm and those with SGA had increased rates of hospitalizations Table .As a result of Steps 1–3 in the adjusted analyses, it was suggestive that PTB and SGA may be mediators in the relationship between below recommended GWG and infant hospitalizations.The association of below recommended GWG with increased hospitalizations was diminished and non-significant after controlling for PTB and was diminished after controlling for SGA Table .Casual Mediation Analysis:Causal mediation analyses were completed to assess the roles of SGA and PTB in the association between below recommended GWG and infant hospitalizations Table . As showThe results of the study suggested that PTB and SGA  may be contributing factors to increased hospitalizations in children born to mothers with below recommended GWG. However, the magnitude of association between maternal weight and paediatric health service utilization was relatively small, impacting the ability to estimate the indirect effect of maternal weight through adverse birth outcomes.The results of this study regarding pre-pregnancy BMI are suggestive of inconsistent mediation. When a relationship within the causal pathway has a different direction of association compared to the other effects, it can result in suppression of the total effect . Within PTB and to a lesser extend SGA appeared to partially explain the observed higher rates of child hospitalizations in the first 24 months of life among children born to mothers with below recommended maternal GWG, compared to children born to mothers with recommended GWG, but was not associated with pre-pregnancy BMI. PTB and SGA are associated with longstanding health implications . The resOur findings are consistent with other studies in that children born to overweight or obese mothers have increased health service utilization . ChildreA strength of this study is availability of maternal weight and height information, linked with paediatric health service utilization in a large population, given the scarcity of maternal weight and height in electronic databases. Population-based information from a birth registry augments the generalizability of the findings to other populations with similar characteristics. A key limitation was the high proportion of missing data on maternal pre-pregnancy BMI and GWG. Self reported pre-pregnancy weight should be interpreted with caution given the potential for reporting bias. Additionally, there may be other factors not explored that may explain the relationship between maternal weight and health service utilization, including the impact of maternal metabolic disease, beyond maternal diabetes or hypertension, on the child during in utero development. Finally, GWG is impacted by gestational length, which can be shortened by PTB. Despite the small proportion of preterm births within the cohort, this is an important limitation within this study, given that it may inflate the perceived role of PTB as a mediator in the relationship of maternal GWG to paediatric hospitalizations. Additionally, other biological mechanisms not captured in this study may lead to PTB, and thereby contribute to future health service utilization.In conclusion, PTB may be a contributor to the increased hospitalizations in children born to mothers with below recommended GWG. Increased paediatric health service utilization in children born to mothers who were overweight or living with obesity prior to pregnancy does not appear to be related to SGA or PTB, suggesting that this observed association is due to either maternal weight status alone or due to other unmeasured mediators. These findings are important as they indicate that adverse birth outcomes may mediate the relationship between maternal weight and pediatric health service utilization and warrants further investigation.Below is the link to the electronic supplementary material.Supplementary Material 1


AKI is a frequent complication in critically ill patients and portends poor short and long-term outcomes, including an increase in readmissions, cardiovascular events, and progression to chronic kidney disease (CKD) . The impAKIKI was a large French multicentre randomised controlled trial on renal replacement therapy (RRT) initiation strategy for AKI . Chaibi These findings are consistent with a body of literature that was summarized in a comprehensive meta-analysis published in 2014 . The metSince that publication, several other studies have examined HRQOL outcomes with similar findings Table . FurtherThere are additional limitations to interpreting HRQOL data following critical illness. First, the findings are impacted by the heterogeneity in study design and participants, timing of assessment, and tools used. Second, most studies reported a high loss to follow-up . DespiteThe study by Chaibi and colleagues provides important data to our field on how patients survive after critical illness. However, it is unclear how these results should influence clinical management. Should rehabilitation, optimisation of nutrition and psychosocial support to reduce frailty be as much part of follow-up care after AKI as measuring urinary albumin and serum creatinine? The study by Chaibi et al. serves as a reminder that more research in AKI survivors is urgently needed to inform management strategies so that patients with AKI do not just survive but thrive after ICU.


Wearable technologies are becoming ever more popular as suggested tools for use in modern medicine. Studies evidence their growing pragmatism and provision of objective data for a more informative and personalised approach to patient care. Yet many wearables are one dimensional, despite the underlying technology being common across a large array of tools. That is primarily due to the accompanying software, unmodifiable or black box-based scripts that generally lack accessibility or modification, meaning wearables may often get discarded. Use of wearables for sustainable healthcare needs careful consideration. Investment and innovation are in demand to combat the other ‘silent pandemics’ i.e., common health conditions that are omnipresent and include but are not limited to dementia, high blood pressure, diabetes, and depression, all requiring different options/tools for measurement and treatment2. Those varied, and diverse conditions are well researched but still greatly impact the ability to age well. Correspondingly, a 10-year UN-based strategy strives to improve lives by harmonising agencies to take actions pertaining to age and ageing by drawing notable attention to e.g., data and innovation3. It has been written that information is power and when applied and discussed within the context of healthcare, information/data is an extremely valuable commodity: it is the new blood4. Accordingly, data capture for improved measurement and treatment is paramount within this decade of a global agenda to improve a plethora of health conditions.The UK life sciences is set to enter a decade of investment, innovation, and practice, coinciding with a national vision launched in 20215. Indeed, this aligns with concepts referring to independent living, whereby the person/patient can remain in their routine environment without needing to regularly visit a hospital/clinic6. That has two immediate benefits such as reduced burden on (i) the patient, who may have mobility and transport limitations and (ii) the clinician, by ensuring his/her/their time is optimised for those most at need of personal attention/examination. Most interestingly, by keeping the patient at home, it evokes habitual behaviours (regular habits) which can be more informative during data capture compared to ad hoc/snap-shot assessment(s) in the hospital/clinic. It is in that context wearable-based technology is shining through, enabling prolonged and remote data capture that offers more insight and personalised approaches in healthcare.The spectral themes of data and innovation would be challenging to capture within the confines of this editorial alone. Yet, one emergent trend of interest we would like to draw attention to is within the field of data and diagnostics with the methodological shift in location of where measurement(s) and treatment(s) occur. Here, the rise and improvements in digital technologies such as wearables facilitates a realisation of the paradigm, hospitals without wallsnpj Digital Medicine, highlighted what the future of wearables may be while considering the perspectives of numerous stakeholders from diverse backgrounds 7. The conclusion and insights from that perspective reflected that advancements in wearable technology are facilitating data capture trends greater than just superficial activity monitoring. More interestingly, data capture on disease monitoring and progression is becoming feasible with previous research demonstrating the wide utility wearables can have in a variety of health conditions from Parkinson’s disease to mild traumatic brain injury, with new opportunities afforded during remote assessment12. Taking the leap of routinely using wearables (of any description) in everyday clinical life across the spectrum of the medical profession is still premature but methodologies to enable transition from research playthings to care solutions are being proposed15. Thus, the potential for wearables in healthcare is enormous but challenges remain, and there are many. For the purposes of this editorial, we draw attention to the challenge of sustainability, which is often overlooked in comparison to the technical, professional, policy and social issues. We believe that opportunities exist to drive sustainable implementation through wearables in clinical practice. Firstly, we broadly discuss how wearables could routinely enable  medicine and later why sustainability in healthcare needs to be considered.A recent perspective in 17. Additionally, there is little consideration of the materials or carbon footprint of the hardware deployed, from the materials used, durability, energy charging capacity and efficiency16. Thankfully, there have been exciting sustainability developments in hardware. For example, the ability to detect blood pressure and movement using a small skin patch built from inexpensive, widely available tissue paper as well as use of graphene to create a stretchable health monitor powered by the movement of the wearer to negate a reliance on (disposable) batteries19. How those innovations evolve and become more common place to meet sustainability demands is yet to be determined but suggest exciting developments in hardware, amongst others20.The rise of wearable technologies has positively impacted the capacity and opportunity to deliver personalised care with greater medical resolution. However, any rapid development and deployment of products/devices (as well as affiliated infrastructure and services) could be viewed as both an exemplar of brilliance and error in practice. Consider the physical wearable devices themselves. There are high rates of ‘hibernating’ devices where consumers hold onto devices no longer used is hindering the recycling and circular economy of wearables and mobile devices11 while (ii) intensities of physical activity may be the useful outcome in managing diabetes21. Although seeking different outcomes to different research questions, both study examples are linked by hardware technologies (accelerometery) to detect movement . Consequently, possible methods of sustainability emerge: the underlying sensing is of equivalence, but the software determines how the accelerometery data is interpreted. Theoretically, generic accelerometer (and/or gyroscope) based wearables could be used in a ‘circular’ fashion across the field of medicine but the software would/could be prescribed to address different clinical questions. Within the field of gait research alone there are a range of different algorithms that could be prescribed12 but there is a lack of ICT infrastructure and harmonisation between academic research, commercial entities, and healthcare practitioners. In short, decoupling software from the hardware may drive sustainability through flexibility.Where are the sustainability opportunities for software? The days of closed loop/black-box commercial systems for physiological monitoring are fading away, certainly for higher level-based software that e.g., analyses data to inform clinical decisions compared to underlying machine code (firmware) to make the hardware tick/operate. Accordingly, there is a growing trend to make analysis software fully transparent so arising digital outcomes can be used with confidence and trust. Moreover, the ability to create and develop algorithms to post process wearable data is abundant through the open creation of powerful coding packages . Those resources are made accessibly by the abundance of online video tutorials and code sharing sites . Therefore, it can be reasoned that the proliferation of code and arising algorithms is growing considerably faster than the underlying hardware . For example, consider common wearables such as accelerometer-based devices. With that hardware, (i) derived gait outcomes  may help examine effectiveness and digital endpoint of a pharmacological treatment in Parkinson’s disease22.The following examples are within the context of low-resource, observational or remote assessment and may provide some food for thought. Recently, some of the same authors highlighted wearable opportunities within the topic of mild traumatic brain injury (mTBI) arising in sports but the prevalence of mTBI is much broader when considering e.g., older adult fallers or road traffic accidents23. Perhaps they already have the accelerometer at home from a previous meeting with the responder or it is embedded within a watch that was purchased for private use. The latter  may negate some of the challenges of deploying useful wearables already equipped with useful hardware  but providing ubiquitous sensing to healthcare. Indeed, the proliferation of consumer driven digital technologies and 5G-enabled telemedicine could enable decentralised real-time multidisciplinary decision-making involving doctors, first responders and other healthcare professionals. By relaying vital signs and live images to trauma centres, alongside the data captured from wearables, second opinions could be used to help triage and prioritise those with the most urgent clinical need for hospital intervention, while enabling those with less severe clinical need to be monitored in alternative settings during their recovery. This may help reduce the risk of unnecessary A&E assessment while improving the reassurance provided to patients during their recovery24.Those working as first responders in the community (or in sport) often have the challenge of making rapid decisions on the severity of a head injury. Consider the scenario that a generic accelerometer-based wearable could be programmed with a validated algorithm and then attached to the person with suspected mTBI to assess their gait and balance, offering the responder more objective and high-resolution data to better inform their decision-making process. Alternatively, consider a scenario that the person may have repeated a mTBI th largest contributor if it were a country25. Therefore, attention should be focussed on implementing sustainable practice in healthcare design and future strategies. Recently, the UK-based National Health Service set two ambitious aims of (i) becoming net carbon zero through direct emissions by 2040  and (ii) reducing indirect emissions by 80% around 2036, which is greatly influenced by e.g., information and communication technology (ICT), and medical devices. Accordingly, there is a real and pressing demand for reliable alternatives in those current examples to aid healthcare services to improve their environmental and economic impact while striking a careful balance in maintaining robust and clinically suitable healthcare services27.Globally, healthcare is a significant contributor to net carbon emissions, which would equate to be the 5Wearables should be carefully considered against the wider determinants of health, where sustainability is of utmost importance. Defined impact will only be possible when viewing change through an ecosystem which will bring about the desired actions and outcomes much faster than without collective action. Wearables could directly provide more sustainable healthcare as well as indirectly offering personalised and decentralised approaches in medicine. Fundamental sensing requirements exist across a range of conditions (silent pandemic) but actioning novel approaches through prescribed software could provide the necessary steps in the overall journey in concurrent health and sustainability ambitions.Improved objectivity and precision in assessment offered through remote assessment,Increased equity and access regardless of location and or geography,Opportunities to innovate with analytics due to low barriers to entry with accessible software,Developments in product durability and longevity.Emissions associated with storing of data,Typically, high changeover of devices by consumer, but low recycling rates and many ‘hibernating’ devices,Software locked to hardware.


A lymph node mediastinal foreign body reaction mimicking nodal metastasis: a case series” and published on “Frontiers in Medicine” (I read the article of Lina Zuccatosta and colleagues entitled “edicine” .The Authors report a series of eight patients with enlarged on CT and PET-FDG positive lymphadenopathies due to foreign body inflammatory reaction to Oxidized Cellulose (OC) after lung surgery .I would like to take inspiration from this article in order to urge the scientific community about other possible serious problems associated with the use of OC as haemostatic biomaterial in surgery.OC is derived from plant-derived cellulose and is treated with oxidizing agents to create a product that helps control bleeding in surgery .However, even if OC is widely used and generally considered safe, there are some potential problems associated with its use that should be carefully considered.- Allergic reaction: although rarely, some patients may be allergic to OC and experience localized skin reactions or more severe systemic allergic reactions; A 10% rate of allergic skin reactions, presenting with rash, itching, redness, irritation and hives, was observed after breast conserving surgery (BCS) , 4.- Seroma: OC may contribute to the formation of seroma, which is a pocket of fluid that accumulate at the surgical site due to a redundant OC digestion; significant postoperative seroma, resolved within weeks with repeated percutaneous aspirations, was reported in 45% of patients after BCS –4.- Surgical site infection: OC may act as a foreign body and create a breeding environment for bacteria with an increased risk of infections; some cases of abscess formation that required surgical drainage were reported in literature , 5.- Delayed wound healing: the presence of OC within the surgical site may interfere with the migration of cells, collagen deposition, and angiogenesis and potentially delay wound closure , 6.- Foreign body reaction: the body's immune system may perceive OC as a foreign substance, leading to an inflammatory response with fibrogenic reaction; this reaction may cause the formation of granulomas or fibrous capsules and hinder the healing process; various foreign body reactions due to not optimal bioabsorption of OC, that needed surgical removal, were reported in different types of surgery , 7–9; Zu- Adhesions formation: although OC is designed to be absorbed over time, in some cases, it may not fully degrade, leading to the formation of adhesion between tissues and organs; when OC comes into contact with nearby tissues, it may cause them to adhere together during the healing process; these adhesions may cause complications such as nerve compression, pain and interference with normal tissue function , 8, 9.- Ischemic complication: overuse or improper placement of OC at surgical site may also lead to excessive clot formation and limited absorption that can potentially impede normal tissue perfusion and cause ischemic complications; in this regard, some Authors observed a full-thickness necrosis involving the epidermis up to the periosteal layer when OC was applied above the periosteum to control bleeding and prevent haematoma formation after a scalp laceration .- Misdiagnosis during follow-up: sometimes, the OC-induced fibrogenic reaction may create a three-dimensional fibrotic structure with a peculiar imaging that leads to diagnostic misinterpretation during postoperative follow-up , 12.Every surgeon must be aware of the aforementioned problems and adopt some appropriate precautions to mitigate them, such as :- Careful patient selection: the use of OC should not be considered in patients with some specific pathologies  that have an increased risk of postoperative infections.- Proper technique of OC application: OC should not be used directly under the surgical suture to avoid the risk of its extrusion; the amount of OC to be used should be calibrated to prevent overdose; OC should adequately fill the surgical cavity but it should not be oversized to avoid excessive fibrosis and foreign body reactions.- Strict compliance with rules of asepsis: the OC should be handled with great caution and antibiotic therapy should be prescribed in the postoperative period to prevent infections.- Close postoperative monitoring: a careful clinical evaluation of the patient is necessary as the prompt management of postoperative complications, even with possible removal of the OC from the surgical site, should begin as soon as possible in order to minimize problems and optimize results.- Detailed surgical report: the surgeon should always describe the use of the OC in the surgical report so that radiologists can correctly interpret the imaging and avoid misdiagnoses during follow-up.In conclusion, while research and technological advances try to overcome the issues associated with OC, skilled surgeons should carefully evaluate the risks and benefits of this biomaterial on a case-by-case basis in clinical practice and, if necessary, also consider alternative haemostatic agents or techniques  .GF: Conceptualization, Writing—original draft, Writing—review and editing.


Environmental restraints like cold, drought and heat adversely affect growth and development in different ways and at different plant developmental stages, leading to reduced crop yield. The reduction in global crop production is also exacerbated by rapid changes in climate conditions that affect duration, timing of seasonal occurrence and severity of abiotic stress events. To address the threat of climate change and secure food supplies for a growing world population (estimated to reach 9.7 billion people by 2050), plant breeders are faced with the challenge of stabilising crop productivity through identification of key genetic traits for better adaptation to abiotic stresses and climatic extremes. Abiotic stress tolerance is controlled by complex gene networks. Although genetic variation in abiotic stress tolerance appears to be present in populations adapted to different climates, the complexity and redundancy of gene networks controlling abiotic stress tolerance has made it very difficult for scientists to come up with straightforward genetic solutions. QTL mapping for drought, heat and chilling tolerance has always led to the identification of multiple QTL with a low phenotypic contribution. This makes it impossible to reliably fine-map QTL for marker development. Another issue is the lack of reliable and objective phenotyping methods: what is the quintessential trait to be phenotyped for drought, heat or cold tolerance? This is directly related to our lack of understanding of how plants respond to environmental challenges. It is likely that plants need a combination of different traits to provide sufficient stress tolerance. These traits will need to be identified first before they are used in phenotyping, mapping and marker development. They will then need to be combined in a stepwise breeding process to produce stress-tolerant crops. During these steps, any negative effects on yield and quality traits will need to be evaluated and eliminated. The emergence during the last decade of various “-omics” technologies  has offered powerful new methods to study the responses of plants to abiotic stress conditions. These technologies allow researchers to dissect which genes and regulatory/metabolic processes differ in the stress responses of “tolerant” and “sensitive” varieties. The papers presented in this Special Issue illustrate how our approach towards unravelling abiotic stress responses in plants is changing.Solanum tuberosum). Various shoot and root morphological, physiological and gas-exchange traits were scored for their contribution to growth and improved productivity under these three stress conditions, and cultivars with superior performance were identified for inclusion in breeding programmes. In the paper presented by  a varietAnother study on sweet potato  used RNAPennisetum glaucum (Pearl millet) is known to have a high tolerance to several environmental stresses, especially heat stress. Huang et al. explored the transcriptional changes in pearl millet under short- to long-term heat stress to identify key molecular mechanisms and genes related to heat tolerance [olerance . Their sOryza sativa) [Weighted correlation network analysis (WGCNA) is a system biology method used to describe gene association patterns between different biological samples. Wang et al. used this methodology to identify core genes linked to heat stress in heat-tolerant and heat-sensitive rice seedlings ( sativa) . The resRanunculus kuepferi. The results show that tetraploids have a better cold acclimation potential than diploids, enabling them to better adapt to colder habitats in the mountains. Gene expression profiling was also used by . to explTriticum aestivum). By comparing the response of drought-tolerant and drought-sensitive wheat varieties, it was revealed that the control of stomatal conductance differs remarkably between the varieties. The transcriptome profiles also show major differences in the expression of genes involved in hormone metabolism and signalling . Transcriptome profiling was used by  to exploThe reproductive stage in crop plants is generally highly sensitive to a variety of abiotic stresses. This was further illustrated by  who studA major stumbling block in improving abiotic stress tolerance is reliable phenotyping. This is particularly true for field phenotyping, where plants are often challenged by different stresses at the same time. Controlled environment experiments can be used to avoid the variability of field phenotyping, but in crop species , field performance under stress conditions is the ultimate litmus test to judge which varieties are truly stress tolerant. This Special Issue, therefore, also includes one paper to illustrate the challenges met when conducting field phenotyping of chilling and frost tolerance in wheat. The unreliability of chilling/frost conditions in the field due to day-to-day and season-to-season variation in weather conditions has necessitated Leske and Biddulph to look for new methods to conduct their field experiments by using automated diesel heaters to create a temperature contrast between field plots . Although plant biologists can make use of the many powerful tools provided by the “omics” era, it will ultimately depend on progress made in understanding what is required for improving abiotic stress tolerance in plants and how to apply this knowledge for improving phenotyping methods that will ultimately lead to breakthroughs in abiotic stress tolerance in crop plants.


In recent years, the relationship between dietary choices and their influence on various aspects of health has garnered significant attention , 2. PartInverse association of daily fermented soybean paste ('jang') intake with metabolic syndrome risk, especially body fat and hypertension, in men of a large hospital-based cohort,” Jeong et al. present findings that suggest a potential link between fermented soybean paste consumption and a reduced risk of metabolic syndrome. This study sheds light on the intricate relationship between soy-based dietary components and metabolic health.Soy, a versatile legume, has gained significant attention due to its potential health benefits –7. In thThe health effects of soy: a reference guide for health professionals” Messina et al. provide a comprehensive reference guide that aids health professionals in understanding the various health implications of soy consumption. This resource serves as a valuable tool for practitioners seeking evidence-based insights into the benefits and potential concerns associated with incorporating soy into the diet.In “Messina discusses the role of soybeans in meeting the caloric and protein needs of a growing population. This perspective, titled “Soybeans can help address the caloric and protein needs of a growing global population,” underscores the significance of soy as a sustainable and nutritious food source for a burgeoning world population.Addressing global food security challenges, Fan et al. titled “Intake of soy, soy isoflavones and soy protein and risk of cancer incidence and mortality”. This study delves into the nuanced relationship between soy components and cancer outcomes, providing valuable insights for public health considerations.The potential link between soy consumption and cancer risk is explored in the systematic review by Messina et al.). Moreover, the multifunctional properties of soy-derived bioactive compounds call for further investigations into their molecular mechanisms, potentially uncovering novel therapeutic avenues (As the field of nutritional science advances, these findings are instrumental in guiding evidence-based dietary recommendations and health interventions. With the growing interest in personalized nutrition, the diverse effects of soy on various health facets provide a basis for tailoring dietary strategies to individual needs  (Messina avenues .To further explore the intricate relationship between soy and human health, it is crucial to consider the interaction with environmental issues. As global attention to sustainability grows, understanding the link between soy consumption and environmental issues opens up new directions for research. Sustainable agricultural practices, supply chain dynamics and the environmental impact of soybean production merit investigation to fully understand the implications of soy consumption on human health and disease. This holistic perspective is in line with the growing interest in addressing food security challenges while promoting individual wellbeing .The manuscripts featured in this Research Topic collectively illustrate the complex relationship between soy consumption and human health. From metabolic syndrome and cancer risk to food security, these contributions provide a holistic perspective on the role of soy in shaping our wellbeing. As the field continues to evolve, we expect that these findings will contribute to evidence-based dietary recommendations and strategies for promoting health and preventing disease. However, in order to make further progress in this field, interdisciplinary collaborations between nutritional researchers and environmental scientists are essential. Exploring the connections between soy's nutritional value, potential health benefits and environmental implications can lead to comprehensive knowledge that informs dietary guidelines, health interventions and sustainable practices. By embracing this integrative approach, researchers can lead the way to a more sustainable and health-conscious future, in which the link between soy, human health, and the environment is thoroughly understood and effectively disseminated to both practitioners and the general public.ML: Writing—original draft, Writing—review and editing. AF: Writing—review and editing. GR: Writing—review and editing.


Overprescribing of antibiotics in paediatrics accounts for a significant proportion of inappropriate antibiotic use in human healthcare, thereby contributing to the global health emergency of antimicrobial resistance. Antimicrobial stewardship efforts are complicated by the unique social dynamics in paediatric healthcare, with a specific challenge being the prominent role of parents and carers who act as intermediaries between prescribers and paediatric patients. In this Perspective article concentrating on healthcare of the United Kingdom, we describe this complicated interplay of different decision stakeholders , outline four dimensions of decision challenges  and provide a number of theory-based strategies for supporting different stakeholders during the decision process, ultimately with the aim of improving antimicrobial stewardship. Key decision challenges for patients and carers include limited knowledge and experience of managing infections, which were exacerbated during the COVID-19 pandemic and frequently result in health anxiety and inappropriate health-seeking behaviours. Challenges for medical prescribers span societal pressures from prominent patient litigation cases, cognitive biases, and system pressures to specific diagnostic problems . Strategies for mitigating decision challenges in paediatric infection management will need to include a range of context- and stakeholder-specific actions, including improvements of integrated care and public health education as well as better clinical decision tools and access to evidence-based guidelines. Antimicrobial resistance (AMR) is a global health threat that was associated with approximately 4.95 million deaths in 2019 alone ,4,5. YetTreatment decisions for suspected bacterial infections including sepsis are complicated by high levels of risk and uncertainty ,7. In paAll doctor–patient relationships can be conceptualised as principal–agent relationships , where aNotably, the roles of principal and intermediary are likely to be blurred at times, especially in cases of pre-teenage patients who lack the capacity to voice their own interests. In those cases, where the parent/carer takes on a particularly prominent role, it may be difficult to recognise the true principal in the relationship. We conceptualise the paediatric patient as the principal throughout, because core texts of ethical guidance including the United Kingdom’s (UK) General Medical Council’s  “Good Medical Practice”  highlighIn order to understand the unique challenges to diagnosis of paediatric infections and appropriate antibiotic prescribing decisions, it is essential to consider the role of each stakeholder within the principal–agent relationship and identify the interplay of different factors that may bias judgement or impede an optimal decision process.Parents, clinicians and society as a whole conceptualise children as an inherently vulnerable patient group in need of special protection . PaediatSocial pressures around good parenting  increase parents’ likelihood to engage in health-seeking behaviours such as the consultation of clinicians . FurtherFinally, the persuasiveness of health-seeking behaviours and actions may not be related to the actual accuracy of the parents’ judgement or the objective severity of their children’s symptoms. Research on the candidacy or eligibility for care suggests that certain psychosocial characteristics  determine the level of healthcare attention and resources allocated to each patient . SimilarTaken together, pressures around good parenting, high levels of parental anxiety, lack of experience with infectious diseases, and limited knowledge of different pathways to seeking healthcare support might lead to increased health-seeking behaviours such as overconsultation by parents and carers. Depending on the parents’ abilities to negotiate their children’s eligibility for care, overconsultation may lead to overdiagnosis of bacterial infections and consequent overprescribing of antibiotics.Prescriber judgement is affected by societal pressures stemming from a prominent history of patient litigation in paediatric care. High court cases punishing the so-called negligence of clinicians permeate the media. A recent example includes the case of paediatrician Bawa-Garba, who missed symptoms of kidney failure in a 6-year-old patient with Down syndrome and was subsequently found guilty of manslaughter by gross negligence . Many puA range of psychological factors further promotes these tendencies for overdiagnosis and overtreatment. Medical prescribers often operate under conditions of limited information and undue time pressures. This decision context necessitates quick decision making under uncertainty and is inherently prone to the influence of cognitive biases. For example, when judging a patients’ medical history conveyed by the parent/carer, prescribers are likely to be unduly influenced by parents’ emotional reactions and misguided judgements  describeFinally, specific challenges related to diagnoses and treatment of paediatric infections add to the complexity of prescriber decision making. Many junior prescribers are likely to have gained limited clinical experience in the area of general infection management during the pandemic, and they are dependent on either local senior clinical advice or national clinical guidelines, which sometimes contain conflicting directions. Additionally, non-specialist prescribers such as primary care and Emergency Department clinicians may perceive medical prescribing for children as more challenging. Reasons for this might include limited availability of clinical scoring systems for distinguishing viral and bacterial infections in children and the fact that the FeverPain score for tonsillitis is not validated for children aged below three years . In addiImproving infection management in paediatric care requires careful consideration of different areas of decision challenges and the stakeholders who are implicated. With the majority of patient-related decision challenges pertaining to the psychosocial dimension, key recommendations for improvement centre around the delivery of more integrated care include greater engagement with traditionally under-served patient groups. Additional actions may include improvement of public education, for example, by integrating health education within the core school curriculum . All schBoosting the decision capacity of parents and carers likely requires a similar approach. An evidence-based suite of resources across a range of languages and materials needs to be freely available in all regions to address inexperience in managing children’s infections. A successful example was set by the “Healthier Together” programme , a commuIn the context of medical prescribers, strategies to improve the management of acute paediatric infections need to span all for four dimensions of decision challenges discussed in this article. Social challenges such as the pressures resulting from prominent cases of patient litigation need to be addressed through increased social support of prescribers, for example, involving better access to expert prescriber advice and senior review . The UK’TM. The use of these and other relevant decision tools should undergo research to evaluate whether access to specific decision tools improves clinical outcomes which, if validated, could then become clinical quality indicators. Carefully designed decision tools not only provide prescribers with more detailed information, but also have the additional potential to reduce intuitive or heuristic decision making and thereby decrease the harmful influence of cognitive biases. Indeed, previous trials of computerised decision support systems have shown such tools’ potential to improve clinical decision making, although adherence to the system’s recommendations and correct system use are likely to be prerequisites [With regard to individual psychological challenges, access to evidence-based guidelines and decision support tools on infection management is likely to be paramount. A recent review of antimicrobial stewardship programmes indicates that decision support tools such as electronic treatment algorithms may contribute to a significant reduction in antibiotic use (approximately 15%), while more traditional approaches of training appear to have comparatively little impact . A speciquisites .To tackle systemic decision challenges, system leaders must prospectively test the impact of national guidance on clinician behaviour to ensure their specificity and sensitivity in practice as well as minimise unintended consequences (such as work-arounds). Finally, strategies to support prescriber choices in the context of specific paediatric diagnostic and treatment challenges need to include further development and evaluation of age-appropriate scoring systems and point-of-care tests validated in children.Decision making for infection management in paediatric care is complicated by an intrinsically difficult relationship between multiple stakeholders. Each stakeholder—principal/patient, intermediary/parent and agent/prescriber—faces particular challenges pertaining to social, psychological, systemic and specific diagnostic or treatment factors. Only a nuanced approach, which takes into account each stakeholder’s perspective as well as the nature of the challenge, is likely to result in an improvement of current practice. Key strategies may include the better delivery of integrated care and health education for paediatric patients and their parents/carers as well as a shift in the public debate around adverse patient outcomes. Strategies to support prescribers need to include improved organisational safety-netting, provision of decision tools, and access to evidence-based guidelines and diagnostic tools for paediatric prescribing.


Evidence indicates that poor glycemic control is associated withincreased morbidity and length of stay in hospital. There are awide range of guidelines published, which seek to ensure safeand effective inpatient glycemic control in the hospitalsetting. However, the implementation of these protocols islimited in practice. In particular, the feasibility of “flash”and continuous glucose monitoring (CGM) remains untested ongeneral wards.Scoping Review.If used in the general ward hospital settings, CGM and flashglucose monitoring (FGM) systems could lead to improved glycemiccontrol, decreased length of stay, and reduced risk of severehypoglycemia or hyperglycemia. Potential problems include lackof experience with this technology and costs of sensors. Rapidanalysis of glucose measurements can facilitate clinicaldecision making and therapy adjustment in the hospital setting.In addition, people with diabetes may be empowered to betterself-manage their condition in hospital as they have directaccess to their glucose data.More studies are required in which the feasibility, benefits andlimitations of FGM and CGM in non–intensive care unit hospitalsettings are elucidated. We need evidence on which types ofhospital wards might benefit from the introduction of thistechnology and the contexts in which they are less useful. Wealso need to identify the types of people who are most likely tofind FGM and CGM useful for self-management and for whichpopulations they have the most benefit in terms of clinicaloutcomes and length of stay. Advances in glucose monitoring and insulin delivery systems haveimproved clinical outcomes and quality of life for people with type 1diabetes (T1D) in the outpatient setting. Use of factory-calibratedsubcutaneous glucose monitoring licensed for nonadjuvant insulin dosing hasbeen shown to attenuate hypoglycemic risk while reducing the burden ofcapillary blood glucose testing.8 Automated insulindelivery systems, known as artificial pancreas or closed-loop, have beenshown in free-living unsupervised home studies to improve glycemic controland to reduce the burden of hypoglycemia in people with T1D.10Emerging data suggest that automated insulin delivery technology may alsobenefit inpatient hyperglycemia management in those with type 2 diabetes(T2D).12Diabetes technology has progressed greatly over the past decade. Devices that do this are called continuous glucose monitoring (CGM)or flash glucose monitoring (FGM). Devices on the market include FreeStyleLibre, Dexcom G4 Platinum, Dexcom G5 Mobile, Dexcom G6,Senseonics-Eversense, and Medtronic Guardian Connect. The key differencebetween CGM and FGM is that the former measures glucose levels continuouslyand sends data automatically to a monitor, smart device, or insulin pump. With CGM, service users and providers can set alerts for high or lowglucose levels, or the rate of change. Continuous glucose monitoring devicesoften have to be calibrated twice daily. By contrast, FGM devices such asFreeStyle Libre and Dexcom G6 are factory-calibrated. In addition, they onlyprovide an immediate reading when the sensor is scanned by a handset orsmart phone with the relevant software app and show trends in the data. Thismust be done at least every 8 hours. FGM represents a potentially cost-effective solution, allowing nearreal-time, accurate, and accessible measurement of glucose levels withoutthe need for frequent calibration.5In addition to traditional monitoring of blood glucose using point-of-carecapillary blood glucose testing (POCT), there are now a wide variety oftechnologies available that allow continuous measurement of glucose levelsin interstitial fluid. Recent reviews and commentaries suggest that the use of FGM and CGMsystems in the non-ICU inpatient setting could improve overall glycemiccontrol and decrease hypoglycemia.6 Several FGM and CGMsystems have been evaluated in the hospital setting, and interest inadopting these technologies more widely has grown during the COVID-19 pandemic. These technologies may be useful in increasing the efficiency ofhospital care and reducing length of stay for people with diabetes. This has become particularly pertinent in light of the fact thatdiabetes increases the risk of hospitalization and death associated withcoronavirus infection.While the use of FGM and CGM in the community setting is rising and hasdemonstrated benefits on glycemic control, the utility of these devices inthe hospital setting, and particularly outside the intensive care unit(ICU), is less well understood.The aim of this article is to provide an overview of the current status andfuture outlook of FGM and CGM in non-ICU care settings, to identify anddescribe evidence of potential benefits of FGM in hospital settings foradults with T1D and T2D diabetes as well as limitations of the technologyand its application. In addition, we outline key gaps in the emergingliterature and fruitful lines of inquiry for future research.A scoping review was conducted to determine the scope of the literature arounduse of FGM and CGM in the non-ICU inpatient setting and to provide adetailed overview of the ways that these technologies are used, who they areapplied to, where and when, as well as the potential benefits and limitations. As these devices are not yet tried and tested technologies, are moresophisticated and expensive, and use in the inpatient setting has not beenevaluated, we focused on continuous glucose measuring devices alone. Only papers reporting primary research were included; those reportingcommentary and reviews were excluded. The target populations under study inthe various articles covered T1D and T2D. We excluded articles that focusedexclusively on children or the critically ill. Articles included in thereview came from the United States, Europe, the United Kingdom, Australia,Austria, Japan, and Canada.An electronic search was conducted in January 2021 on MEDLINE, PubMed, Googlescholar, EMBASE, CINAHL, and The Cochrane Library to review the availableliterature. We searched the titles and abstracts of papers, and the timeperiod covered was from January 2010 to September 2021. Keywords included“Flash Glucose Monitor,” “Flash Glucose Monitoring,” “Continuous GlucoseMonitor,” “Continuous Glucose Monitoring,” “FGM,” “CGM,” “Inpatient,” and“Hospital.” Publications that examined CGM and FGM use in the non-ICUsetting were included, and those in the ICU setting were excluded from thisreview article because there is abundant research in this context already.We also excluded “closed-loop” systems of glucose monitoring. A closed-loopsystem uses a smart phone app to automatically adjust the insulin deliveryon an insulin pump based on glucose readings from a continuous glucose sensor.In analyzing the literature gathered, we used thematic analysis that allowed usto identify common benefits and issues across the literature and to outlinehow the introduction for CGM and FGM technologies affects the provision ofcare in non-ICU hospital settings.Supplementary Table 1).We identified 30 primary research papers relevant to the topic. The process ofselection is detailed in the Preferred Reporting Items for SystematicReviews and Meta-Analyses (PRISMA) flow diagram . Most of12 Several clinical studies comparedPOCT with CGM in hospitalized patients and found variousbenefits of CGM use in the general ward settings.1420 In one study in general wards, CGMdetected 15 times more nocturnal hypoglycemic episodes (definedby the study team as <3.9 mmol/L) than those detected by POCT. The number of hyperglycemic episodes (defined by thestudy team as >13.9 mmol/L) detected by CGM was also 12.5times greater than that by POCT. In observational studies, ahigher number of hypoglycemic episodes were also detected by CGMcompared with POCT. Although some studies showed no difference in mean dailyglucose concentrations, significantly greater numbers ofhypoglycemic and hyperglycemic events were detected. Thishighlights CGM as a potentially valuable tool in detecting andpreventing hypoglycemic events at times when POCT is lessfrequently conducted, especially in inpatients known to be atincreased risk of hypoglycemia. The increased detection of adverse glycemic events hasbeen found in both T1D populations requiring insulin and T2Dpopulations on basal-bolus and subcutaneous insulin in non-ICUsettings.22Existing evidence suggests that both FGM and CGM are accurate andreliable systems when applied to noncritical situations inhospital. In outpatient settings, real-world data demonstrate thatthe use of CGM improves well-being and may be associated with adecreased disease burden. Although the costs and benefits require careful analysis,it appears that non-ICU usage of CGM and FGM could prove aneffective preventive measure, which could ultimately makeinpatient care for people with diabetes more efficient.Use of CGM and FGM devices does not appear to increase the risk ofadverse effects in hospital in relation to severe hypoglycemiaor hyperglycemia.24Because patients and clinicians can monitor glucose levels atany time, trends in glucose levels can be observed  and corrective actioncan be taken earlier, behavior modified, and therapy, diet, andmeal times tailored to specific persons’ needs. This also means that when a patient needs to bequarantined and isolated, blood glucose can be monitoredremotely without the need for close contact.Further potential benefits of CGM and FGM include the fact thatglucose levels can be monitored continuously throughout the dayand night without the need for more painful and disruptivecapillary blood glucose testing, potentially leading to improvedpatient satisfaction and added convenience for staff.27 However we could find no data onwhether this can be replicated in non-ICU inpatient settingswhere disempowerment can be an issue. A recent randomizedcontrolled trial showed that glucose control by clinical staffmay be enhanced. The trial, involving 110 adults with T2D, demonstratedthat the CGM group had significantly lower mean glucose (M∆ =−18.5 mg/dL) and percentage of time in hyperglycemia >250mg/dL (−11.41%) and higher time in the range of 70-250 mg/dL(+11.26%) compared with the control group (P< .05).Two studies excluded from the review indicate that CGM and FGM canempower people with diabetes to better self-manage glucoselevels outside the hospital setting.28 Continuous glucose monitoringdevices and FreeStyle Libre 2 have an alarm that can be set topersonalized high and low levels, thus increasing the chancethat rapid change will be immediately detected. In addition,glucose telemetry systems allow remote monitoring and supportmore sophisticated management of glucose levels by clinical staff.Although a number of papers provide evidence that FGM and CGM usagein noncritical inpatient hospital wards can have benefits inimproved glycemic control, it is not yet demonstrated that thiscan result in reduced length of stay.Where the full potential of FGM and CGM data is realized,clinicians and service users may observe trends associated withfood intake and insulin use so that preventive action can betaken and care can be tailored to specific needs. However, using this technology as a tool to improveglucose management in insulin-dependent people with T2D appearsto be effective. There appear to be no studies yet undertakeninvestigating whether FGM and CGM could be used to individualizedietary advice and diabetes management plans for people with T1Dand those with T2D who are diet controlled, but continuous bloodglucose data could be useful for these purposes also.As one of the main benefits of FGM and CGM usage is in tailoringand optimizing insulin therapy, the population of people withdiabetes who are most frequently subject to these interventionsare people with T1D.29 Evidence suggests that FGM devicesare user-friendly, easy to set up and insert, and generallywell-reviewed by service users. The “on-demand” glucose data appear accessible for nursesand service users and provide real-time glucose monitoring whichcan be scanned at any time.Continuous glucose monitoring has been shown to be relativelysimple to implement in general wards with the use of telemetrysystems. This review provides evidence that, in the right settingsand with engaged teams of health care professionals, this canlead to improved glycemic control and reduced incidences ofhypoglycemia and hyperglycemia. These are a major contributor toprolonged hospital stay, so it follows logically that thesedevices offer the potential to improve inpatient care for peoplewith diabetes and decrease length of stay.28The FGM and CGM technologies facilitate more frequent andconvenient monitoring of glucose levels in the non-ICU hospitalsetting. This means that FGM and CGM could be used to improveclinical decision making in non-ICU hospital settingspotentially with much reduced use of POCT. With devices such as the FreeStyle Libre, warning systemsare in place to detect rapidly falling or increasing glucose tocounter these issues, but in most jurisdictions capillary bloodglucose tests are still preferred even if FGM or CGM devices arein use as this is the more accurate, reliable, and up-to-date measure. Blood glucose measures are also under the scrutiny of thehospital laboratories, so quality assurance processes are inplace.There is a time lag between interstitial fluid and blood glucoseconcentrations, and so rapidly changing glucose levels may givea misleading reading on some CGM devices. This indicates that it may not be the technology per sebut the increased clinical attention that a patient attractswith greater glucose monitoring that could be a decisive factor.Further studies are needed to isolate the causal mechanisminvolved in improving outcomes for inpatients with diabetes anddetermine whether it is more cost-effective to invest inspecialist staff rather than such devices.At least one study has shown that without using CGM or FGM, earlyidentification and management of inpatients with diabetes byspecialist teams decreased hyperglycemia, and hospital-acquiredinfections increased. The use of glucose telemetry systems may be one way ofimproving and simplifying the process of surveillance; however,effectively interpreting and acting on this information willrequire training and staff engagement.29 The CGM devices will only have apositive impact if service users know how to read and act onout-of-range readings and if staff have appropriate training andprotocols to follow. Glucose levels recorded from interstitialfluid often have to be verified by measuring blood glucose atpresent, so awareness of the time lag is vital. It is envisagedthat, when appropriate, quality assurance processes are in placefor CGM/FGM that POCT may no longer be required.Inexperience with the technology for both service users andclinicians may mean that the benefits of FGM and CGM use may bereduced. One recent study found that the development ofprotocols to use CGM trend arrows, alerts, and alarms isnecessary to improve implementation. In addition to the costs of the devices, significantinvestment may be necessary for hospital staff training and fordevelopment of infrastructure to support inpatient use of CGMand FGM devices.34 The continuous measurement ofglucose levels alongside POCT may create potential for anincreased workload for nursing and clinical staff in the shortterm. In particular, diabetes specialist teams may findincreased demand for advice and engagement based on the hugeamount of data available to patients themselves and attendantnursing staff. The potential inaccuracy of interstitial glucosemeasurements due to medication interferences, sensor lag, ordrift may mean that some of this increased demand may proveunnecessary and wasteful. Clinicians and service users may getoverloaded with data, which might create unnecessary confusionor worry.Additional limitations include costs related to supplies of FGM andCGM scanners and sensors. These can be expensive, and it is notclear whether increased efficiency, for example, reductions inlength of stay, can offset the costs of the intervention. Some service users may experience skin irritation due tothe adhesive or discomfort caused by wearing the device forprolonged periods in hospital. In addition, routine scans and procedures and medicationsapplied in hospital mean that glucose sensors might have to beremoved and replaced often to avoid interference.28The FGM devices may not be appropriate for everyone and may be besttargeted to those service users who need additional support toeffectively self-manage their glucose.38However, current evidence remains controversial and at timessomewhat contradictory. A summary of potential benefits andlimitations of FGM and CGM in hospital settings can be found inIn noncritical care settings, both CGM and FGM have been associatedwith improved clinical outcomes, and there is a clear consensusin the clinical community that these devices have greatpotential.Questions remain as to whether FGM and CGM can be effective inreducing length of stay and whether it can improve clinicaloutcomes, patient self-management, and/or patient experiences.In addition, there is a lack of health economics perspectivesand detailed cost-benefit analysis of non-ICU applications.Often hospital inpatients have more significant care needs thanpeople in the community and will therefore require additionalassistance from staff to monitor and manage their glucoselevels. More research is needed to determine what resources andpolicies are effective in meeting these needs and adapting FGMand CGM use to these contexts. Inpatients are also oftendependent on staff to provide food, and flexibility aroundmealtimes is often reduced in hospital settings, partly due toinfection prevention and control policies restricting food beingbrought in from outside the hospital. In addition, glucosesensors may be problematic for patients in hospital should theyrequire medication/procedures that could interfere with glucosemeasurements. There are no sociological studies investigatingthe way the introduction of these novel technologies affects theability of people with diabetes in hospital to self-manage theirglucose levels and whether there are any beneficial or adverseeffects on the power dynamics between service users andproviders.In conducting this scoping review, there were several constraints andlimitations. There is limited literature in the specific area ofnon-ICU hospital application of FGM and CGM. This meant that ratherthan a comprehensive synthesis of the evidence on FGM/CGM applicationin non-ICU hospital settings, we had to approach it as a scopingexercise that would enable us to review the available evidence andidentify the gaps in the literature to inform future research. Thequality of the studies included was not assessed, although all werepeer-reviewed and published articles.The picture is further complicated by the differences and similaritiesbetween CGM and FGM and “closed-loop” systems. The literature wasdifficult to assess in terms of comparisons in application to non-ICUsettings as there is a broad overlap in the way these technologies arereferred to in the literature. Conceptually speaking, “non-ICUhospital settings” cover a huge variety of very different contextswhere the introduction of new technologies such as FGM and CGM mighthave widely divergent effects.Our findings point to the need for future research to plug gaps in the existingevidence base. More studies are required in which the feasibility, benefits,and limitations of FGM and CGM in non-ICU hospital settings are elucidatedas well as evaluations of the impact on inpatient self-management. Thecurrent literature does not make it clear which types of hospital wardsmight benefit most from the introduction of this technology and the contextsin which the devices may be less useful. There is also a need to identifythe characteristics of people who are most likely to benefit from FGM andCGM in terms of patient experiences, clinical outcomes, and length of stay.In addition, the health economics of FGM and CGM introduction needs to becomprehensively modeled so that we can understand whether the introductionof these novel devices is cost-effective and an efficient use of resources.Both FGM and CGM are tools that can facilitate clinical decision making andempower patients to self-manage their condition. However, withoutappropriate training, support, and institutional flexibility, theirpotential will never be realized.Click here for additional data file.Supplemental material, sj-docx-1-dst-10.1177_193229682111053652 for Useof Continuous Glucose Monitoring in Non-ICU Hospital Settings forPeople With Diabetes: A Scoping Review of Emerging Benefits and Issuesby Benjamin Clubbs Coldron, Vivien Coates, Amjed Khamis and SandraMacRury in Journal of Diabetes Science and Technology


Post-traumatic stress disorder (PTSD) is defined by an exaggerated fear responses (FA) which fails to extinguish over time and cannot be inhibited in safe contexts. Studies report that traumatic experiences (TE) affect hormonal systems mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic system. Oxytocin (OXT) is a neurohormone produced in the hypothalamus that has social functions like the promotion of prosocial and affiliative behaviors, increased self-confidence and positive social memories. In PTSD there is a diminished inhibitory top-down control over the FA, which is characterized by amygdala hyperactivity, ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between both areas, which results in anxiety increase and dysregulated autonomic and endocrine FA. In parallel, TE decrease the synthesis and release of OXT, resulting in the dysfunction of the negative feedback mechanism on the HPA, leading to hypercortisolemia and maximizing the response to a stressful stimulus. Previous studies report that the administration of OXT can reduce cortisol levels as well as attenuating amygdala hyperactivity and normalizing the connectivity of this structure with frontal areas, diminishing the FA. Therefore, OXT has been investigated as a potential therapeutic agent administered intranasally early after trauma as a strategy to prevent PTDS on individuals having high risk.The aim of this work is to review the potential of intranasal OXT administration as early preventive intervention for PTSD.Systematic review of the literature published in Pubmed, using the terms “Oxytocin”, “Post-traumatic Stress Disorder”, “Stress”.Studies found significant associations between TE and OXT and report that TE and PTSD are strongly associated with reductions in OXT. Literature report that the acute effects of OXT administrations in individuals with TE tend to be anxiolytic only in less severe forms, by modulating the HPA axis and the autonomic nervous system. Moreover, in recent TE, OXT seems to increase the re-experience of traumas and restore the function of different networks associated with fear control in PTSD patients. FMRI studies indicate that intranasal OXT attenuates amygdala hyperactivity and enhances amygdala´s connectivity with vmPFC, resulting in increased control over the FA. Finally, studies report that a single oxytocin administration increases neuronal fear processing but repeated administration reduces PTSD symptoms up to 6 months post trauma in patients with high acute symptoms.Repeated administration of intranasal oxytocin early after trauma seems to diminish the acute symptoms in early stages of PTDS, being a potential pharmacological strategy to prevent PTDS in individuals at high risk by increasing the control of FA.None Declared