While many healthcare providers (HCPs) have navigated patients’ vaccine concerns and questions prior to the rollout of the COVID-19 vaccines, sentiments surrounding the COVID-19 vaccines have presented new and distinct challenges.To understand the provider experience of counseling patients about COVID-19 vaccinations, aspects of the pandemic environment that impacted vaccine trust, and communication strategies providers found supportive of patient vaccine education.7 focus groups of healthcare providers were conducted and recorded during December 2021 and January 2022, at the height of the Omicron wave in the United States. Recordings were transcribed, and iterative coding and analysis was applied.44 focus group participants representing 24 US states with the majority (80%) fully vaccinated at the time of data collection. Most participants were doctors (34%) or physician’s assistants and nurse practitioners (34%). The negative impact of COVID-19 misinformation on patient-provider communication at both intrapersonal and interpersonal levels as well as barriers and facilitators to patient vaccine uptake are reported. People or sources that play a role in health communication (“messengers”) and persuasive messages that impact behavior or attitudes towards vaccination (“messages”) are described. Providers expressed frustration in the need to continuously address vaccine misinformation in clinical appointments among patients who remained unvaccinated. Many providers found value in resources that provided up-to-date and evidence-based information as COVID-19 guidelines continued to change. Additionally, providers indicated that patient-facing materials designed to support vaccination education were not frequently available, but they were the most valuable to providers in a changing information environment.While vaccine decision-making is complex and hinges on diverse factors such as health care access  and individual knowledge, providers can play a major role in navigating these factors with their patients. But to strengthen provider vaccine communication and promote vaccine uptake, a comprehensive communication infrastructure must be sustained to support the patient-provider dyad. The findings provide recommendations to maintain an environment that facilitates effective provider-patient communication at the community, organizational and policy levels. There is a need for a unified multisectoral response to reinforce the recommendations in patient settings.The online version contains supplementary material available at 10.1186/s12913-023-09348-0. The importance of healthcare provider (HCP) patient communication has been thrust in the spotlight during the COVID-19 pandemic. Facing vaccine questions and concerns about vaccination in patient interactions is not a new challenge for many HCPs working in United States (US) health care settings. A large body of research suggests strategies that US providers can deploy to improve health communication and increase vaccine acceptance. Some recommendations include more time with patients during appointments , and allinfodemic. As a result of this swirling information environment, there was an increasing demand on providers to provide up-to-date information to patients, navigate information voids, and combat resulting questions, concerns, and vaccine hesitancy [Communication challenges have been exacerbated by the spread of false information on social media and other media outlets. This relentless misinformation coupled with an evolving information landscape submerged the public  in an overwhelming esitancy . Throughesitancy  in a higesitancy  and new esitancy .Unique environmental and policy factors in the US that persisted during COVID-19 pandemic and impacted HCP’s ability to provide patient care and education. In the US, controversies over compulsory vaccination have a complicated history, with COVID-19 as a prime example of the tension between protecting the health of the public and safeguarding the civil liberties of American citizens , 13. ManDue to high levels of institutional and government distrust, provider communication plays a key role in vaccine acceptance. In a report by WHO 2014), patient education during routine care led to the greatest increase in vaccine uptake . Evidenc14, patieIn an emerging body of literature, HCP experiences and perspectives are explored to assess how COVID-19 vaccine attitudes have impacted patient-provider relationships. Using a series of focus groups with HCP across the United States, the aim of this study was to capture and analyze the provider experience of patient counseling for COVID-19 vaccinations and how different aspects of the pandemic environment have impacted vaccine trust. We present our findings from these focus groups and offer recommendations for strategies to support provider health communication broadly.messengers and messages at each level. Each level of the model illustrates messengers that have an influence within that particular level based on the narrative provider data captured in this study. Additionally, the model provides a selection of various messages observed across each level of vaccine communication.Vaccine decision-making is influenced by a variety of psychosocial and environmental factors that form a complex ecosystem of factors that facilitate or create barriers to vaccine acceptance –24. KincTo screen and recruit focus group participants, we collaborated with Alligator Digital, a third-party panel provider to field a survey across the United States from October 19 – November 12, 2021. Alligator Digital conducted the survey with 524 complete opt-in computer-assisted web interviews (CAWI), composed of medical professionals. The panel data were used to support a purposive sampling strategy of eligible healthcare professionals to participate, including doctors, nurses, and other medical professionals. In line with the study’s research questions, the HCP sample was designed to capture and segment the perspectives of healthcare providers most likely to counsel patients on a regular basis. Participants who reported they did not discuss vaccination with patients were ineligible and excluded from focus group discussions (FGDs). HCPs interested in participating in a FGD provided their contact information when surveyed. All FGD recruitment was conducted by the research team via email.Based on the results from the national survey and input from an advisory group of experts in health communication, health behavior, and vaccine confidence, the following domains were identified as key areas to include in the focus group discussion guide (Appendix A): (1) best practices and strategies to discuss vaccination with patients; (2) preferred and helpful sources of information; (3) impacts of COVID-19 on the work environment; (4) perspectives on the HCP role in combating vaccine hesitancy; and (5) recommendations for supporting vaccine uptake. Through qualitative data collection and informed by our conceived model, data analysis aimed to define actionable items and communication strategies to improve vaccine acceptance among residents of the United States. This study was reviewed by the Internal Review Board at the City University of New York (CUNY) Graduate School of Public Health and Health Policy (SPH) as part of a larger mixed methods project, protocol number 2021-0330-PHHP. Findings from the full study are reported elsewhere , 28.All focus group discussions (FGD) were segmented by profession and vaccination status: two groups of vaccinated physicians, two with vaccinated nurse practitioners (NP), two with vaccinated registered nurses (RN), and physician’s assistants (PA) and one with unvaccinated HCPs of various professions. Focus group size ranged from 4 to 7 participants per session depending on attendance and lasted 60–75 min. FGD were conducted until reaching thematic saturation. All participants were compensated with a $250 online gift card for their participation in the study. Focus groups were conducted by two members of the research team in December 2021 and January 2022. Before participating in the FGD, all recruited HCPs provided verbal informed consent and explicitly provided permission to be audio recorded as approved by the Internal Review Board at CUNY SPH. All groups were conducted and recorded through Zoom and audio files were transcribed for qualitative analysis.The research team developed an initial codebook based on the interview guide domains and made iterative revisions through a first round of coding . To ensuTable Results at the intrapersonal and interpersonal level demonstrate the impact of COVID-19 misinformation on patient-provider communication and potential messengers and messages that can play a role in either promoting or combating misinformation. Results at the community, organizational and policy levels reveal key sources of information and recommended strategies to create an environment that supports vaccine acceptance. Table Overall, the focus group participants largely viewed their role as providing a source of scientific information and patient education during appointments. They saw themselves as trusted messengers for their patients, community, friends and family, but were quick to note communicating this information became more challenging during the COVID-19 pandemic. On the topic of COVID-19 vaccine hesitancy and refusal, most providers felt they had offered sufficient patient education and intervention in the year since the COVID-19 vaccine became widely available and that most unvaccinated individuals were no longer open to being counseled.Providers expressed that, for the first time, some of their patients had doubts about their clinical guidance, believing that they were influenced by pharmaceutical or other institutional forces. While most providers did not face direct accusations of purposely misleading patients , providers faced patients who expressed distrust of the accuracy of information they offered.A group of unvaccinated and/or “late adopting” providers (defined as being vaccinated after November 2021) indicated that they experienced a shift in perception of their own role in vaccine promotion. They expressed distrust stemming from their belief that vaccine mandates were implemented without comprehensive scientific evidence to support them, such as a lack of consideration for natural immunity in vaccine policy development. Importantly, these providers shared many of their patients’ COVID-19 vaccine concerns and reported that information provided by patients led them to question some key aspects of their medical training.The providers offered several strategies for promoting vaccine acceptance among patients. The most common strategy was to tailor information to each patient’s medical history and concerns related to the COVID-19 vaccine and to avoid generic guidance. In their view, this approach facilitated provider trust and mitigated any institutional mistrust. This communication strategy was echoed as effective and meaningful in subsequent in-depth interviews and focus groups with patients in the parent study reported elsewhere .“scare tactics” that appeal to patient fear, stating that patients have responded to other vaccine recommendations which cautioned of severe disease outcomes. One provider suggested this is an underused patient education tactic for the COVID-19 vaccine, citing the success of anti-smoking campaigns that highlighted severely impacted former smokers with chronic illness and disability. Providers also found that testimonials from recent adopters had an impact on their patients. Providers described the sharing of personal anecdotes, family stories, and introductions to other recently vaccinated patients as helpful for individuals still uncertain of their vaccination decision. Details about the unknown and prolonged effects of long-COVID would be an example of this communication strategy.A few providers touted When discussing successful strategies for patient communication, many providers acknowledged that addressing vaccine hesitancy often takes multiple appointments with the same patient, and adequate appointment time - both circumstances that many patients and providers cannot independently facilitate or control. Those who saw patients on a regular basis due to the type of care they provided  noted that the ability to have multiple touchpoints with the same patient facilitated a trusting dialogue around medical recommendations, including vaccination.Many providers discussed the pressure to stay up to date in an evolving information environment, especially during the first year of the pandemic. They had mixed opinions on whether they had adequate resources to answer patient questions about the COVID-19 vaccination but generally agreed about their main sources of vaccine information during the pandemic. Participants cited the Centers for Disease Control and Prevention (CDC) and professional organizations like the American College of Obstetricians and Gynecologists (ACOG) as helpful. Other helpful resources included local and state health departments whose regular updates mitigated pressure on healthcare providers to stay up to date.Several providers also indicated workplace communication digests and regular team meetings led by department heads as the most helpful resources to stay current on COVID-19 information. Some of these communications from employers also included patient-facing resources, which many providers reported as necessary to facilitate conversations with new information.Providers described the challenge of addressing COVID-19 vaccine questions and concerns in an environment that often left them unsupported to reduce barriers to vaccination. This discussion led to some clear guidance for policy and institutional practices to address providers’ barriers to vaccine counseling. Firstly, many providers recommended all vaccinations be provided free of charge to the patient. Providers highlight patient financial concerns surrounding the COVID-19 as well as previous vaccinations. Despite the national provision that vaccines be available free of charge, there continued to be confusion among patients about the financial cost of vaccination. This has implications for both communication strategies and ready access to vaccines.Some providers suggested continuing to offer vaccinations outside of the medical office or hospital environments  to prevent cold supply chain challenges and other barriers in small doctors’ offices. Many providers hoped that the lessons learned during the COVID-19 vaccine rollout will inform future vaccination availability.Providers indicated a strong need for a more centralized, unified vaccine communication response from regional and federal agencies to address the ongoing challenges that they face addressing oft-conflicting vaccine messages from health officials, and government representatives. While they recommend the policies and messaging come from a centralized effort, there is additional importance of engaging local messengers. They underscored the need for local, diverse and neutral messengers from trusted community leaders to combat further politicization and polarization. Some acknowledged this could involve collaboration between other sectors that may not be traditionally involved in public health campaigns .We discuss our findings in the context of this model, focusing specifically on solutions to mitigate the negative impacts of misinformation, or evolving or confusing information on the patient-provider relationship and suggestions to create a stronger communication infrastructure that anchors patient-provider relationships. The results of this study highlight the impact of the confusing and often chaotic information environment surrounding COVID-19 and COVID-19 vaccination on patient-provider communication and demonstrate the strain caused when HCPs are not supported to respond adequately to patient concerns during clinical interactions. The impacts of misinformation specifically on the patient-provider dyad during the pandemic may be indicative of a new chapter of vaccine sentiments influencing how HCPs approach conversations about vaccination  While HCOne of the most salient findings from our analysis was the provider recommendation for tailored interpersonal communication strategies that “meet patients where they are at.” This includes the empathetic recognition of patient questions and concerns but also the personalization of their advice to each patient’s medical needs – key strategies echoed in motivational interviewing and other tailored approaches , 34. ProOur findings echo current COVID-19 communication literature describing HCPs as the most effective messengers to present tailored messaging to their patients –39. HoweTo provide the best evidence-based communication approaches, providers require support to navigate changing medical advice while fielding patient’s questions and concerns. For example, our participants agreed that guidance condensed into digests at a regular cadence  was the easiest way to consume new information. Digests were most helpful when they came from local organizational-level messengers like a regional health department or an employer. Having hyper-local data snapshots, news and guidance mitigated the pressures felt by providers to be consistently up-to-date and helped them tailor their information to their patients given the regional nature of the pandemic experience. Unlike many web pages or e-newsletters, these channels should flow two ways to include feedback from the providers on the use and usefulness of the resources provided. While we found communication resources are most effective and impactful when tailored at the community-level, national policy and advocacy must support the collection and dissemination of up-to-date, evidence-based information that all can access and use.Furthermore, our findings indicate that providers seek resources to combat misinformation and overcome entrenched myths and misconceptions beyond currently available educational materials and resources. Bonnevie et al. (2021) have called for the development of partnerships to monitor and track sources of vaccine misinformation and responses to such campaigns through existing monitoring systems in our health infrastructure . Based oThe decline in government subsidies for COVID-19 vaccines and testing may impact the acceptability and uptake of vaccination and other mitigation measures . Our focThe polarized and politicized information environment during the COVID-19 pandemic had a significant impact on vaccine trust and literacy –46. Our While participants spanned the United States, the limited sample size prevents generalized conclusions or assessments of correlations in our results. Although attempts were made to recruit for racial and ethnic diversity, the final sample of participants was largely white and concentrated on the coastal regions of the US. These focus groups offer a preliminary understanding of barriers and facilitators HCPs face when promoting vaccine acceptance. This study highlights the need for further research on perspectives of vaccine trust and acceptance from marginalized and rural populations.HCPs faced various unique challenges throughout the COVID-19 pandemic, including unprecedented volumes of mis- and disinformation, often rendering pre-pandemic strategies to tackle vaccine hesitancy ineffective. There is a need to recognize provider perspectives in the creation of vaccine communication programs to mitigate HCP challenges and provide sufficient, up-to-date data to address patient concerns. Most important, HCPs require the support of policies and a communication infrastructure that builds patient trust in health care institutions and the science behind vaccination.Below is the link to the electronic supplementary material.Supplementary Material 1


Aging negatively affects tissue cellular homeostasis and regeneration, in part due to resident stem cell-intrinsic accumulation of damage and dysfunction, similar functional deterioration of niche cells  and increased inflammation (inflammageing) of the microenvironment .Cellular senescence, a key feature of aging, is classically reported as a passive cell state whereby senescent cells irreversibly cease proliferation, while it is instead a more dynamic and active cell state as senescent cells produce and secrete soluble factors  that can influence neighboring cells and tissues . SenesceClinical and experimental evidence have associated cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiovascular disease (CVD) such as myocardial ischaemia and infarction, diabetic cardiomyopathy and cancer drug-related cardiotoxicity and resulting heart failure –4. HowevGender  in mammals is a risk factor in many conditions, including aging, cardiovascular diseases, neurodegenerative diseases, cancer, and more. For each of these, males and females display distinct traits in disease development and progression. To date, studies on the cellular and molecular basis of such differences have largely focused on the role of sex hormones . IntriguImportant sex-specific differences in aging and the aged phenotype exist but the mechanism(s) by which this sex-related age interaction influences CVD development and progression remains elusive. Women live longer than men but there is a paradox. Women are frailer and have worse health at the end of life than men whereby older females are reported to be at a greater risk for CVD than age-matched men.Recently, it has been demonstrated that compounds termed senolytics, due to their ability to preferentially induce apoptosis in senescent cells, eliminate senescent cells preventing or reversing age-related CVD . In partTo close this gap, in a recent study from our group, we administered the combination of two senolytics, dasatinib and quercetin (D+Q) or just their vehicle to 22-24 months old C57BL/6 female mice after myocardial infarction (MI) . We haveThese data fill a gap of knowledge in the role of biological sex in determining senescence and cardiac muscle dysfunction with age, providing robust evidence that indeed female cardiac aging is driven by senescence. Concurrently, accumulating senescent cells are detrimental for the old female heart after ischemic injury as senescent cells removal by senolytics ameliorates cardiac remodeling after MI improving heart function. On the other hand, these data go against the view that senescence is at least in part a positive response to limit fibroblast proliferation limiting reactive fibrosis after MI.Nevertheless, relevant questions for the aging biology of the heart but also for all other body tissues remain to be addressed. Is senescence an irreversible phenotype or a functional and reversible one? What is the role of the chromosomal sex vs the hormonal milieu? Are these two views mutually exclusive and how are they regulated by biological sex? Is senescence mainly a response to damage or an irreversible cell fate independent from injury (despite being increased by injury)? Is therefore senescence stochastic or programmed? Are senescence cells heterogenous and if so, what this heterogeneity means? Is it senescence of tissue-specific stem cells or is it senescence of niche cells in the tissue microenvironment to dictate regenerative defect of the relative aged organ? More importantly, does “reversing” the aged phenotype with senolytics increases lifespan of either sex? Clearly, answering these questions will pave the way to a coherent and informed translation of senolytics therapy to first-in-human trial on aging and CVD. Lastly, the sex-related differences in the aged phenotype emphasize the need to include both sexes in the experimental design to address the questions raised above.


Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to examine neural responses with and without the use of a functional task. Indeed, fMRI has been used in clinical trials and pharmacological research studies. In mental health, it has been used to identify brain areas linked to specific symptoms but also has the potential to help identify possible treatment targets. Despite fMRI's many advantages, such findings are rarely the primary outcome measure in clinical trials or research studies. This article reviews fMRI studies in depression that sought to assess the efficacy and mechanism of action of compounds with antidepressant effects. Our search results focused on selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed treatments for depression and ketamine, a fast-acting antidepressant treatment. Normalization of amygdala hyperactivity in response to negative emotional stimuli was found to underlie successful treatment response to SSRIs as well as ketamine, indicating a potential common pathway for both conventional and fast-acting antidepressants. Ketamine's rapid antidepressant effects make it a particularly useful compound for studying depression with fMRI; its effects on brain activity and connectivity trended toward normalizing the increases and decreases in brain activity and connectivity associated with depression. These findings highlight the considerable promise of fMRI as a tool for identifying treatment targets in depression. However, additional studies with improved methodology and study design are needed before fMRI findings can be translated into meaningful clinical trial outcomes. Functional magnetic resonance imaging (fMRI) is a commonly-used, non-invasive technique used to study the living human brain. fMRI refers to the acquisition of data modulated with extrinsic  stimuli or allowed to follow intrinsic fluctuations . It is typically conducted using blood oxygen level dependent (BOLD) sensitivity methods—such as resting-state and task-based MRI.From Discovery to Cure, 2010). In later-stage clinical trials, fMRI can help detect the normalization of a disease-related signal at a treatment-relevant dose  during reward anticipation, were successfully used as a primary outcome measure to assess the efficacy of a κ-opioid receptor in a population with anhedonia and mood or anxiety disorder  and the glutamatergic modulator ketamine—to identify the brain areas and networks targeted by these compounds that could serve as potential biomarkers of antidepressant response. The results presented here can be used to consider fMRI as a primary outcome measure for clinical trials and experimental research studies. Broader lessons regarding what has been learned from the use of fMRI in clinical trials and research studies are also discussed, and issues that could impede its use as a primary outcome measure in clinical trials are addressed. Finally, future directions that could further enhance the role of the technique in pharmacological studies are proposed.clinicaltrials.gov  and the ISRCTN database (https://www.isrctn.com). Search terms included: “depression,” “completed,” “adult,” “interventional,” “with results,” and “imaging”. Our search terms were kept broad to be maximally inclusive, although this could result in a high exclusion rate. These search criteria were selected to identify completed studies with published results that have used imaging and pharmacological interventions in adult populations. Identified studies were assessed for their relevance in depression. An additional search was then conducted using the trial number for each study, in order to ensure that publications directly related to these trials but not listed in the clinical trials databases were also examined. All trials conducted using pharmacological compounds with antidepressant action that used fMRI (resting-state and/or task-based) to assess their efficacy and/or use in depression were included in this review. This selection process is outlined in Two clinical trial databases were searched to identify clinical trials of pharmacological compounds that target depression and have used fMRI: https://pubmed.ncbi.nlm.nih.gov). This was done to identify research studies relevant to depression that used fMRI (resting-state and/or task-based) to examine the effects of these compounds on brain activity and connectivity in healthy volunteers or patient groups but not in a clinical trial setting. Research studies that used compounds with antidepressant action solely as models for mental health disorders  without assessing the efficacy of these compounds in treating depression were excluded.As a second-level search, the antidepressants used in the clinical trials identified in the first search were entered as search terms in PubMed  study in healthy volunteers found that activity in the caudate, subgenual and anterior cingulate, hippocampus, amygdala, and frontal cortex increased after a single citalopram infusion compared to placebo  glutamatergic modulator ketamine as an antidepressant treatment.The amygdala Loureiro et al.  duloxetine, unmedicated individuals with depression who received 12 weeks of duloxetine showed normalized activation in the amygdala and ACC, a finding that was linked to symptom reduction  focused on the amygdala, a brain area involved in the processing of emotionally valenced stimuli. Research in individuals with depression has consistently observed increased activation in the amygdala during the presentation of fearful and negative stimuli  or longitudinal changes  that can confound imaging findings. Studying the antidepressant mechanisms of ketamine could also improve our understanding of antidepressant drug action in general, given that the pathways and brain areas that mediate antidepressant effects—for example the amygdala (Sheline et al., Concerning the fMRI modalities, task-based or resting-state, that different studies use to examine the effects of antidepressant treatments, resting-state fMRI, seems to be producing consistent findings, especially in relation to the brain connectivity responses induced by ketamine. However, it should be noted that imaging studies in general and particularly those involving resting-state fMRI, present the challenge of disentangling the antidepressant effects of pharmacological treatments from the neurovascular ones (De Simoni et al., Task-based fMRI studies use different paradigms to target specific brain areas and to examine drug effects in those regions. However, a large variety of tasks—as well as many variations of the same task—are used to elicit specific responses from participants. This is an excellent way to explore the neural responses that underlie different tasks and different drugs, but a high number of task variations also results in a lack of replicability. A recent review and meta-analysis found that commonly used fMRI tasks do not currently have the test-retest reliability necessary for biomarker discovery or brain-behavior mapping (Elliott et al., Another area that could be re-examined in order to enhance the reliability of fMRI measures as well as the quality of fMRI data—and especially task-based fMRI measures—would be a trade-off between the number of participants and the amount of data collected per participant that is needed to make a particular inference (Naselaris et al., Finally, data sharing between different labs and research centers would also enable the analyses of larger data sets that could increase the reliability of findings as well as help overcome the common problem of small sample sizes that most clinical trials and pharmacology research studies are faced with.However, several positive steps have already been made in this direction, with studies beginning to employ a standardized and uniform way of organizing imaging data (Gorgolewski et al., This review sought to examine the use of fMRI in clinical trials and research studies of compounds that target depression. Much of the work conducted to date has identified the amygdala as a particularly promising target region for antidepressant treatments. Indeed, most studies in this review found a consistent decrease in amygdala activity following antidepressant treatment. This review also highlighted the potential role of ketamine as a tool for studying antidepressant effects with fMRI, given that ketamine administration not only leads to very rapid antidepressant effects but consistently normalizes brain activity and connectivity in depression. These findings highlight the considerable promise of fMRI for studying and developing drugs targeted at mental health conditions in general and depression in particular. Nevertheless, a gap persists between the extensive use of fMRI in research and its systematic and primary use in clinical trials-related research. Efforts to develop more effective fMRI tasks and adapt existing study designs would help harness the advantages of fMRI and improve our ability to translate research findings into clinical trial outcomes.VK: conceptualization, research, analysis, and writing. JE: conceptualization, analysis, and writing. CP: research, analysis, and writing. CZ: analysis, editing for critical intellectual content, and supervision. All authors contributed to the article and approved the submitted version.


Spodoptera frugiperda, has become one of the most important pests on corn in China since it invaded in 2019. Although FAW has not been reported to cause widespread damage to rice plants in China, it has been sporadically found feeding in the field. If FAW infests rice in China, the fitness of other insect pests on rice may be influenced. However, how FAW and other insect pests on rice interact remains unknown. In this study, we found that the infestation of FAW larvae on rice plants prolonged the developmental duration of the brown planthopper ) eggs and plants damaged by gravid BPH females did not induce defenses that influenced the growth of FAW larvae. Moreover, co-infestation by FAW larvae on rice plants did not influence the attractiveness of volatiles emitted from BPH-infested plants to Anagrus nilaparvatae, an egg parasitoid of rice planthoppers. FAW larvae were able to prey on BPH eggs laid on rice plants and grew faster compared to those larvae that lacked available eggs. Studies revealed that the delay in the development of BPH eggs on FAW-infested plants was probably related to the increase in levels of jasmonoyl-isoleucine, abscisic acid and the defensive compounds in the rice leaf sheaths on which BPH eggs were laid. These findings indicate that, if FAW invades rice plants in China, the population density of BPH may be decreased by intraguild predation and induced plant defenses, whereas the population density of FAW may be increased.The fall armyworm (FAW),  Data from three or more treatments were compared using one-way ANOVA; if the ANOVA analysis was significant (p < 0.05), Tukey’s multiple comparison test was used to detect differences between groups. When necessary, data were log- or arc sine-transformed to meet requirements for the homogeneity of variance. All statistical analyses were conducted with SPSS software version 20 (SPSS).Two-treatment data were analyzed using Student’s


N > 10,000), we used newly developed Prophet forecasting and autoregressive-integrated moving average time-series models to examine the temporal dynamics of explicit and implicit self-harm cognitions. We created three groups . We found a general increase of negative self-harm cognitions across the six years and seasonality effects for mood and desire to die, particularly among those who previously made a suicide attempt. Negative explicit self-harm cognitions peaked in winter (December), with implicit self-harm showing a lagged peak of two months (February). Moreover, daily negative self-harm cognitions consistently peaked around 4–5 am, with implicit cognitions again showing a lagged effect (1-hour). Limitations include the volunteer sample not being representative and the cross-sectional nature of the data being unable to separate between-subject and within-subject structural trends in the time series. Our findings show that negative explicit and implicit cognitions precede the rise in suicidal behaviors in spring. We proposed a conceptual model of seasonal suicide risk that may offer fertile ground for theoretical advancements, including implications for clinical risk assessment and public policies regarding the availability of health services.Decades of research have established seasonality effects on completed and attempted suicides, with rates increasing in spring. Little advancements have been made to explain this phenomenon, with most studies focusing almost exclusively on the number of suicide attempts and deaths. Using more than six years of data collected among a US, UK, and Canadian online community sample ( Suicide is a major cause of mortality worldwide, and it constitutes a significant public health problem . In the Research on the impact of external time points such as traumatic events, negative or adverse life events as precipitants of suicide attempts, has been integrated into a broader discussion about seasonal patterns of suicide. Most studies examining seasonality effects report a consistent increase in suicides and suicide attempts during spring and early summer –10. ImpoSeasonal fluctuations of death by suicide have been widely studied, however, much less is known about patterns concerning the days of the week and the time of the day. A study of a Danish population showed more suicide attempt admissions during weekends, both among individuals with and without mood disorders . Other sA less extensively studied area of research concerns the effects of the time of the day on suicides. Both attempted and completed suicides are affected by diurnal and circadian rhythms: Several studies on suicide attempts in diverse populations showed that suicide attempts occurred most frequently during evenings and nights , 14. TheExisting research on seasonal and time effects on suicide almost exclusively focused on completed suicides  and suicide attempts . However, the existence of temporal patterns  in explicit self-report measures of self-harm and suicide remains largely unknown. Recently, labs have started using Ecological Momentary Assessment (EMA) to measure daily dynamics in suicidal cognitions . Our analyses aim to test the generalizability of time effects found at the level of suicide attempts and completed suicides reported in previous studies. In accordance with the literature, we predicted an increase in negative mood, explicit suicidality, and implicit self-harm associations between 2012–2018 and a peak in suicide/self-harm cognitions in spring and early summer. We predicted negative self-harm cognitions peaking towards the end of the week with a peak on Sundays or Mondays and during night hours. The unique contribution of our study is the analysis of structural, temporal trends of both explicit and implicit (cognitive risk factors) measures.www.projectimplicithealth.com) and included responses between April 2012 and November 2018. All respondents voluntarily visited the PIH website and chose to complete a self-harm Implicit Association Test (IAT). We included data from participants who were residing in the US, the UK, and Canada. The final sample was 10,448  section We used data from the Project Implicit Health (PIH) database (n = 1143); Suicide (n = 2674); Death (n = 2712); brief Death IAT (n = 1449). The four IATs have different target words and images  that are each presented on a screen with attributes . For instance, the death IAT with the “death” category contains target examples of “death”  and “life” . The categories differ between the IATs , cutting IAT . The selected IATs [After providing informed consent and selecting the ‘self-harm’ task on PIH, participants were randomly assigned to complete a self-harm IAT, where different words and images  were presented on a screen with attributes . Respondents were assigned to one of four IATs: Cutting , d , q (moving averages terms). In seasonal time series (see SM3), seasonal ARIMA models (SARIMA) incorporate both seasonal and non-seasonal components. The ARIMA models have the advantage of dealing with temporal autocorrelations due to their flexibility [ARIMA models use three parameters to describe a time series: xibility . Importaxibility .We used two advanced analytical approaches, namely Prophet models and ARIMA models, to examine the effect of temporal patterns (see SM3) on explicit and implicit cognitions. The Prophet models were used to characterize different temporal patterns  using all individual observations in the data. We used gold-standard ARIMA models to internally replicate the yearly seasonality effects identified by Prophet. ARIMA models have been widely used to characterize seasonality effects in suicide , and thet tests were used as a convergent, but less conservative method of testing differences between the months with the lowest and highest outcome scores. Separate group analyses using the Prophet models are available in the SM. The pre-processed dataset and analysis scripts can be accessed via the Open Science Framework (https://bit.ly/3s3rTdh).Additional First, we forecasted the distribution of all four outcome variables and decomposed them into trends across the years, yearly seasonality, weekly, and hourly effects. The decomposed effects shown in the following figures control for all other seasonal patterns.The Prophet models showed upwards trends in all outcome variables from 2012 to 2018 and an expected increase in the forecasted period until November 2019 for all outcome variables . There were no significant effects of the IAT D-Score predicting the desire to die at any of the lags, suggesting that change in the explicit desire to die likely precedes the implicit change. However, this effect was shown when all four IATs  were combined, but when the cutting IAT was removed from the analysis, weaker/inconsistent effects  were observed . The reverse direction was not significant, indicating that the change in the implicit measure likely follows changes in the explicit. However, again this result should be treated cautiously because when the cutting IAT is excluded . See Table For the daily seasonality see Fig. , we obseed Table , weaker Our Prophet forecasts showed nested seasonality effects with a yearly seasonal pattern. Thus, we aimed to further examine how risk factors  interact with these yearly seasonal changes. Table Our study investigated long-term changes and seasonal patterns in negative mood, explicit and implicit measures of self-harm, and suicide among a large online community sample. Due to data collection continually running for six years, we were also able to estimate negative cognitions for the day of the week and within the day (hourly).The Prophet models showed clear trends in our data with an increase in respondents’ negative self-harm cognitions across the six years. This finding is consistent with previous studies showing an increase in deaths by suicide , anxietyThe primary goal of our study was to test yearly seasonality effects in suicide-related cognitions with hypothesized peaks in spring and early summer, which would align with the seasonal patterns of completed and attempted suicide . Based oOverall, negative self-harm cognitions from this online community sample were similar to clinical observations of increases in suicidal behaviors towards the end/beginning of the week and early morning (4–5 am). The hourly estimate is consistent with less specific previous findings showing an increased number of suicide attempts and suicide deaths during night hours . This fiWe believe the most crucial finding from our analysis is the rise in negative mood and desire to die, especially among suicide attempters, occurring approximately three to four months before (December) the yearly seasonal peak of suicide attempts and deaths in spring and early summer. We propose a conceptual threshold model of seasonal suicide risk see Fig.  that mayFirst, we show that at-risk individuals for suicide gradually get more depressed, and their desire to die slowly increases as the day length becomes shorter (winter solstice). Affected individuals may become severely depressed and experience a lack of energy throughout the winter months. Essentially, this period may put them below a threshold of severe suicide risk as the high level of suicidal ideation coincides with a low level of energy. When the days get longer, brighter, and warmer, these changes likely improve an individuals’ mood. Hence, the most at-risk individuals become slightly less depressed and may gain more energy to contemplate and plan their method to attempt suicide. These improvements may result in them crossing a threshold into severe suicidal risk when a suicide attempt is most imminent. As the summer solstice approaches and passes, it is conceivable that some suicidal individuals may go above and beyond a severe suicidal risk. Therefore, a severe risk of seasonal suicides occurs when opportune conditions are met .Some studies have shown that the risk of suicidal behavior is particularly high during the first month after starting treatment with antidepressants, especially the first nine days, compared to those who have been taking antidepressants for 90 days or more . TherefoThere is also evidence that suicide risk peaks shortly after being discharged from psychiatric hospitalization, and the risk reduces over time . AnalogoAs shown in Fig. However, for our proposed conceptual model of seasonal suicide risk, we fully acknowledge that the two above situations are not comparable with respect to the level of intensity, and the window of sensitivity, including the specific antecedents that can increase the risk of suicide. For example, for the seasonality of suicide risk, it is possible that the relative comparison between an at-risk individual and others’ level of outdoor engagement, including perceived positive interactions between individuals/groups, may become especially poignant as there are more opportunities to observe people engaging in social activities as the weather improves in spring. In contrast, the relative loss of quick access to psychiatric support may be especially apparent after one leaves a hospital. Importantly, our proposed conceptual threshold model of seasonal suicide risk merely provides a potential explanation based on the temporal variation observed in both (a) suicidal ideation and (b) negative mood. Needless to say, there may be various other complex reasons for the peak in suicide rates in spring/early summer.Recent evidence suggests that within a clinical sample of participants with bipolar disorder, those participants with lifetime suicide attempts were particularly affected by climate and weather changes. The lowering of mood , weatherChanges in the explicit desire to die preceded the implicit associations  for both hours (lags of one hour) and months (lags of two months). No lagged effects were found for the days of the week (lags of one and two days), which is consistent with our finding indicating that weekly changes only explain little variance. This lagged association between explicit and implicit suicide cognition may speak to the predictive utility of implicit cognitions as useful markers of sensitive behaviors and attitudes . Thus, iTo the best of our knowledge, Charlesworth and Banaji (2019) are the only other authors to formally test the lagged effects between implicit (IAT) and explicit measures across social domains . In contrast to our results, they found more evidence in favor of implicit biases proceeding explicit biases (6 occurrences from 28 tests) than in the other direction (3 occurrences). However, the distinction between self-harm IATs which captures self-referent information (Me versus Not Me) rather than external social categories (White People versus Black People), may be crucial. To clarify, participants may need to be consciously aware and elaborate  on theirThe findings of the present study should be interpreted in light of several limitations. First, we estimated marginal/averaged structural temporal trends using cross-sectional data from a large group of respondents. Thus, our study cannot separate between- and within-subject effects in the time series. Future research should replicate the identified patterns of explicit and implicit cognition in longitudinal designs (multiple observations from the same subject) across both short  and longer  time windows. Moreover, the sample in our data is disproportionately young, female, and not representative of the general population. Internet-based surveys focused on mental health may show various biases with respect to self-selection that could potentially confound the observed temporal trends. However, other Project Implicit surveys showed explicit biases that parallel trends over time to nationally representative polls  and are Our study is the first to describe temporal patterns and long-term trends in explicit and implicit measures of self-harm and suicide. Despite significant advances in the last decade in understanding the prospective utility  and asseSupplemental Material


Point-of-care ultrasound (POCUS) is increasingly being adopted in the field of internal medicine, leading to the development of POCUS curricula in undergraduate and postgraduate medical education programs. Prominent internal medicine societies and organizations worldwide recognize the expanding utilization of POCUS by internal medicine physicians, emphasizing the need for practitioners to be aware of both its benefits and limitations. Despite the growing enthusiasm for POCUS, clinicians, particularly those with limited clinical experience, must be cautious regarding its inherent limitations and the potential impact on their clinical practice. This review aims to outline the limitations and potential drawbacks of POCUS for medical students, residents, and internists who wish to stay abreast of the escalating use of POCUS in internal medicine and have a desire, or have already commenced, to incorporate POCUS into their practice. Additionally, it provides recommendations for enhancing POCUS proficiency to mitigate these limitations. What is point-of-care ultrasound?Point-of-care ultrasound (POCUS) entails employing ultrasound techniques at the patient's bedside to address precise clinical inquiries that arise during encounters with patients. This approach diverges from conventional radiological ultrasound examinations commonly ordered by medical providers, executed by ultrasound technicians, and analyzed by radiologists . Consequently, POCUS can be regarded as an augmentation of physical examination and bedside evaluation -5.POCUS and internal medicineIt is not surprising that POCUS initially grew into a medical practice along the lines of the two specialties that need quick bedside diagnostic skills: emergency medicine and critical care units. Its utility has now expanded beyond these two specialties, encompassing various medical training such as anesthesia, obstetrics and gynecology, nephrology, and rheumatology -10. RecePotential benefits that POCUS can add to internal medicine practiceThe use of POCUS has emerged as a prevailing practice and, in some cases, the standard of care in various bedside medical procedures, including arterial line insertion, central venous line insertion, thoracentesis, and paracentesis . In addiShould novice POCUS users be concerned about bringing it to their practice?In spite of the growing enthusiasm surrounding the development and proliferation of POCUS utilization, it is imperative for clinicians, particularly novices, to exercise caution regarding the limitations of POCUS and its potential impact on their practice. Scant research exists pertaining to the integration of POCUS within the realm of daily internal medicine practice and its consequent influence on clinical outcomes. One plausible explanation is the historical dearth of POCUS curriculum available to internal medicine physicians and residents, in contrast to their counterparts in emergency medicine and critical care. The objective of this review is to elucidate the potential pitfalls and limitations of POCUS for medical students, residents, and internists who aspire to stay abreast of the escalating employment of POCUS in internal medicine, and are either interested in or have already implemented POCUS in their clinical practice.General concerns and pitfalls related to POCUS use for novice usersPOCUS Use and Associated Patient-Related OutcomesThe data on whether POCUS (outside of its use for procedures) improves patient-related outcomes is limited. One small randomized study in the ED by Atkinson et al. found that early use of POCUS in the ED for managing patients with undifferentiated hypotension in addition to standard care vs. standard care without POCUS did not show improvement in survival, inotropes or intravenous fluid use, ICU stay, or total length of stay . This 20Stakeholders in one academic center  mentioned in a survey that clinical impact, efficiency, and time are the main determinants for the adoption of POCUS . In thatPOCUS and Concerns Regarding Quality MeasuresQuality measures are meant to help providers improve their skills by creating standards set by experts that novice learners need to match. So far, few medical societies have created initiatives to try and standardize the use of POCUS in different specialties, including internal medicine, reflecting the relative novelty of this skill . Saving POCUS and Concerns Regarding Training and Curriculum DevelopmentThe Accreditation Council for Graduate Medical Education (ACGME) uses entrustable professional activities (EPA) in six core competencies to assess when residents are ready for independent practice. No such EPAs exist for POCUS training during internal medicine residency training yet, but the potential for that has been demonstrated in one program . In one POCUS and Concerns Regarding Physical Examination SkillsThere has been some concern regarding the decline in physicians' physical examination skills, especially among young physicians and physicians-in-training . WhetherPOCUS and Concerns Regarding Medico-Legal LiabilityAnother concern is whether physicians’ use of POCUS can lead to lawsuit generation due to adverse effects as a result of such use. One recent retrospective review showed that POCUS use by internal medicine, family medicine, pediatrics, or critical care physicians did not lead to lawsuits or legal consequences . In factCommon system-based pitfalls related to POCUS use for novice usersWith each POCUS examination come some pitfalls related to image acquisition and/or interpretation. It is important that novice learners pay attention to these pitfalls while practicing and learn how to avoid them since their findings can potentially affect the decision-making process. In addition to cognitive POCUS knowledge, most pitfalls can be learned and avoided with: (a) repetition and doing more exams under supervision; (b) looking at the target structure from more than one window or view; and (c) making sure to interpret the findings in the light of the clinical scenario and pre-test probability of the diagnosis the examiner is looking for. Here, we highlight common pitfalls that novice learners in internal medicine might face during their practice. Pitfalls Associated With POCUS Examination of the HeartEvaluation of left ventricular (LV) contractility is a common application of POCUS. Examiners need to have insight into pitfalls associated with acquisition and quality of the image because estimating LV contractility in POCUS is usually done with visual inspection using three concepts: anterior mitral valve septal movement during systole; thickening of ventricular myocardium during systole; and symmetrical movement of LV walls towards the center of the LV cavity during systole (myocardium excursion) . RecogniDuring the left parasternal long axis cardiac view examination, make sure not to confuse the apical epicardial fat (which looks more heterogenous and moves with heart beats) for pericardial effusion  Video .Care also needs to be exercised not to confuse pericardial effusion with left-sided pleural effusion during the long-axis left parasternal cardiac exam. The relationship of the fluid to the descending aorta can be useful in that regard Video .Findings of right ventricular (RV) strain with POCUS can be crucial in patients who present with acute chest pain or shortness of breath. When these patients are hemodynamically unstable, one important differential diagnosis associated with high mortality if untreated is acute pulmonary embolism (PE). While these findings can make a difference in management (treating with thrombolytics and/or thrombectomy first rather than anticoagulation), they are not specific to acute PE  e.g., s-4.Identifying signs of large PE using POCUS requires some experience, and obtaining good-resolution images is important to making appropriate management decisions. In one survey, internal medicine residents’ confidence to identify these signs was among the lowest compared to other POCUS skills such as determining inferior vena cava (IVC) diameter and collapsibility and identifying pleural effusion . Pitfalls Associated With POCUS Examination of the IVCProbably the most common pitfall for novice learners is mistaking the aorta for the IVC. The aorta usually runs more posteriorly and has thicker walls, so pulsations can be appreciated. The IVC can be obtained from the aorta window by tilting  the probe slowly towards the patient's right side Video .When examining the maximum diameter of the IVC in the longitudinal view, it is important to avoid the 'cylinder effect', which is examining the IVC in an off-axis view, not the maximum diameter, and this can underestimate diameter and collapsibility and wrongly suggest hypovolemia. This can be easily avoided by slowly fanning the probe right and left over the full diameter of the IVC and measuring the maximum diameter seen. Although the correlation between IVC diameter and collapsibility with volume status is fair, other conditions can affect IVC diameter and distensibility, leading to variable and false results, especially in non-ventilated patients  . Pitfalls Associated With POCUS Examinations of the LungsNovice POCUS users need to get acquainted with ultrasound lung artifacts seen in healthy and diseased lungs . These aThe finding of 'lung point' is said to be virtually diagnostic of pneumothorax, but care should be exercised not to confuse this useful sign with what looks like lung point but is not  -57. OthePitfalls Associated With POCUS Examination of KidneysA common reason to perform kidney POCUS in internal medicine is to check for hydronephrosis as an indicator of the post-renal cause of acute kidney injury. Hydronephrosis can readily be identified by POCUS, but many conditions can mimic hydronephrosis, including pregnancy, dilated renal parenchymal vessels , and renal cysts -61. RenaAlthough rare, the absence of hydronephrosis on POCUS does not entirely rule out obstruction since nondilated obstructive uropathy can occur . Also, tPitfalls Associated With POCUS Examination of the Lower Extremity Venous System for Deep Venous Thrombosis The Society of Radiologists in Ultrasound recommends using an extended compression method (from thigh to knee) rather than the 2-region compression method  to reduce the chance of missing isolated femoral vein deep venous thrombosis (DVT) . DetectiInadequate pressure during the exam may give the false impression of a positive study. To avoid this in obese patients, examiners should consider placing their hands behind the patient’s thigh and pushing anteriorly towards the probe (2-hand technique). The compression method has shown low sensitivity in detecting isolated calf vein thrombosis compared to the more proximal femoral vein area . This isPitfalls Associated with POCUS Examination for Abdominal Aortic Aneurysm ScreeningOne study suggested that lack of experience and body habitus are important factors associated with difficulty visualizing and measuring the aorta. Most abdominal aortic aneurysms (AAA) are fusiform, but saccular aneurysms do exist and require follow-up as well ,72. TheyHow novice learners can improve their POCUS skills and minimize pitfalls early during POCUS training Table Handheld devices are now more available than ever and are more affordable than traditional cart-based ultrasound machines. Interested physicians or programs should try to obtain one or more of the handheld ultrasound devices to improve their POCUS skills. The portability of handheld devices can encourage physicians to practice POCUS more because it is of immediate availability to them compared to cart-based ones. Novice learners can start by using the larger machines first if they appreciate images and anatomy being clearer with the larger machines.Image acquisition is usually more difficult than image interpretation. Ultrasound technicians, with their immense practical experience, can be a valuable source for physicians starting to use POCUS to learn maneuvers and different probe movements that help find the best window for each exam. When a consultative ultrasound exam is done for a patient, the treating physician can compare their findings to the official report, and if there is any discrepancy, they can repeat their POCUS exam again or seek help from an expert as feedback to improve their skill for the next exam.Deliberate practice, with focus on and repetition of a particular aspect of skill or exam  and receipt of direct feedback from an expert during these practices, has shown to improve procedural and psychomotor skills. Although it has not been extensively studied for sonography skills, it is a promising method to improve POCUS skills. It can be part of the POCUS curriculum so that learners can practice particular POCUS skills that seem to be more difficult for them to learn compared to others -76. As sInterested physicians can pursue any of the certificates of completion available at this time, with the expectation that more will be available in the future -79. SuchThe utilization of POCUS is anticipated to undergo further expansion, whereby a greater number of internal medicine trainees and practitioners are expected to incorporate it into their medical practice across diverse clinical environments in the imminent future. Nonetheless, similar to any other clinical tool, it is imperative for novice users to possess a comprehensive understanding of its limitations and remain cognizant of the potential pitfalls associated with its implementation, in addition to being acquainted with its merits and advantages. Such awareness is crucial to preventing potential harm to patients, mitigating the risk of erroneous decision-making, and averting unnecessary delays in conducting appropriate investigations and administering suitable management strategies. Moreover, this knowledge can enable practitioners to maximize the potential benefits of investing considerable time, effort, and financial resources in mastering the utilization of POCUS. With more use, more studies and research can be conducted to inform best practices and add to the body of evidence related to POCUS applications in internal medicine.


Childhood adversity indicated by involvement with child welfare services (ICWS) is associated with increased risks of disease and injuries in young adulthood. It is yet unknown whether such risks are limited to external causes and mental and behavioural disorders or whether they extend beyond early adulthood and to non-communicable diseases (NCDs) with later onset. Moreover, it has not been explored whether ICWS associates with decreased survival prospects following hospitalisation.Based on prospective data for a 1953 Stockholm birth cohort (n=14 134), ICWS was operationalised distinguishing two levels in administrative child welfare records ). Hospitalisations and all-cause mortality (ages 20–66) were derived from national registers. Hospitalisation records were categorised into external causes and NCDs, and nine subcategories. Negative binomial regression models were used to estimate differences in hospitalisation risks between those with and without experiences of ICWS and Cox survival models to estimate mortality after hospitalisation.Placement in OHC was associated with higher risks of hospitalisation due to external causes and NCDs and all investigated subcategories except cancers. Risks were generally also elevated among those investigated but not placed. ICWS was further linked to higher mortality risks following hospitalisation.Differential risk of morbidity and differential survival may explain inequalities in mortality following childhood adversity. We conclude that the healthcare sector might play an important role in preventing and mitigating the elevated risks of externally caused morbidity, disease and premature mortality observed among those with a history of ICWS. People with experiences of involvement with child welfare services (ICWS) have often high levels of adverse childhood experiences and experience higher risks of hospitalisation in adulthood due to external causes as well as mental and behavioural disorders. As most previous prospective studies have ended their follow-ups by early adulthood, it remains unclear whether there are also increased risks for other non-communicable diseases with a later onset and whether childhood adversity is linked to differences in survival after onset of disease.This study demonstrates that adults with experiences of ICWS generally have higher risks of being hospitalised due to external causes and non-communicable diseases. Following an initial hospitalisation, they have lower chances of survival.The findings highlight several possible entry points for policy and intervention, which include preventing experiences of childhood adversity, mitigating health-related consequences of such experiences and improving healthcare outcomes in this vulnerable group of individuals.Experiences of childhood adversity are highly prevalent and result in high costs not only to the individual but also to all of society.Theoretically, experiences of childhood adversity—and, particularly, those so severe that they lead to ICWS—can be assumed to ‘get under the skin’, changing the epigenome and other biological and psychological response systems.Thus far, morbidity among individuals with experiences of ICWS has primarily been examined in terms of external causes or mental and behavioural disorders.Evidence is scarcer concerning risks of diseases with a later age at onset, including cardiovascular diseases (CVDs), cancers, respiratory diseases and diabetes. Alongside mental and behavioural disorders, they represent the main types of NCDs with an extensive individual and societal burden. These five subcategories—most of which are considered preventable—are together estimated to account for 90% of deaths in the European region.Looking into the broader literature on childhood adversity, retrospective studies have indicated increased risks of developing NCDs among those with adverse childhood experiences.With the aim to explore the role of childhood adversity in relation to hospitalisation risks and survival prospects following hospitalisation, the present study draws on longitudinal prospective data from a Swedish cohort born in 1953 (n=14 134). Childhood adversity is approximated by experiences of ICWS (ages 0–19). Two groups of ICWS are differentiated, indicating the severity of ICWS experiences: individuals who were investigated but not placed, and individuals for whom the involvement resulted in placement in OHC. Following an outcome-wide approach to epidemiology,Individuals with experiences of ICWS are at higher risk of being hospitalised due to external causes (including self-harm) and NCDs  when compared with individuals without experiences of ICWS.Individuals with experiences of ICWS have a shorter time to death after initial hospitalisation due to external causes and NCDs compared with their majority population peers.The relationships in hypotheses 1 and 2 follow a gradient that reflects the severity of ICWS experienced.The data material is the Stockholm Birth Cohort Multigenerational study (SBC Multigen). The cohort is defined as all children born in 1953 and living in the greater Stockholm metropolitan area in 1963, who could be probability matched to follow-up data from nationwide registers .In this cohort, ICWS has been shown to be a viable proxy for childhood adversity because of its predictive power for long-term health outcomes such as premature mortality.The SBC Multigen contains child welfare records from municipal social registers covering the period between 1953 and 1972 (ages 0–19). Besides placement in OHC, these data include referrals to child welfare services that did not result in the child being taken out of the family but rather cases that were dismissed or resulted in warnings or in-home services. This offers an interesting alternative comparison group, encompassing individuals who have displayed signs of adversity severe enough to come to the attention of the child welfare services but not severe enough to justify a placement in OHC. Based on this, we distinguished three mutually exclusive ICWS groups following the severity of ICWS: (1) those without any record in the child welfare register , (2) child welfare investigations not resulting in OHC placement (‘investigated’), (3) placement in OHC, including foster and institutional care (‘placed’). The highest order took precedence in coding these groups.From the Swedish National Patient Register, we derived data on in-patient care between 1973 and 2019 (ages 20–66), that is, cases of disease that required hospitalisation . A total of 11 cause groups were selected based on both primary and secondary diagnoses and classified according to the 10th revision of the International Classification of Diseases and the corresponding codes in the eighth and ninth revisions see . We iden10.1136/jech-2022-219851.supp1Supplementary dataMortality data were drawn from the National Cause of Death Register as death by any cause between 1 January 1973 and 31 December 2019 (ages 20–66). Since chronic diseases tend to co-occur, cause-specific mortality might include uncertainty in the registered causes of death. For this reason and to ensure sufficient statistical power, we preferred using all-cause mortality.ICWS is associated with the socioeconomic conditions of the family, and such factors have also been shown to influence adulthood morbidity and mortality. Therefore, we included the following covariates: born out of wedlock; mother’s age at birth; occupational status of family at birth  and family education at age 10.All analyses are reported separately for men and women, based on the biological sex assigned at birth.Follow-up started on 1 January 1973 and ended at death, emigration or end-of follow-up on 31 December 2019. Within this observation window, 519 people got censored at the date of emigration, and 1635 people died.We analysed hospitalisation between ages 20 and 66 for each major cause group and subcategory, stratified by sex and ICWS group. First, we calculated hospitalisation prevalence (expressed as %), deriving 95% CIs from predicted margins based on logistic regression analysis. Next, we calculated incidence rates of hospitalisation per 1000 person-years at risk. Incidence measures the occurrence of new cases during a certain period and, thus, signifies a person’s probability of being hospitalised with a disease.To further examine the first hypothesis, we conducted multivariate modelling to predict frequencies of hospitalisation within each cause group . Model fit statistics for the count variable were derived for the covariate-adjusted Poisson, zero-inflated Poisson and negative binomial models . The negThe second hypothesis concerns differential survival after hospitalisation. To investigate this, we used Cox survival models estimating the chances of survival on a calendar time scale from the date of the first cause-specific hospitalisation to death from all causes. The few tied failure times were dealt with by the Efron method. We adjusted these models for covariates and for age at first cause-group-specific hospitalisation, reporting HRs over the follow-up period with 95% CIs.In order to counteract the likelihood of false-positive chance findings due to multiple outcomes, we used Bonferroni correction to correct α (the significance level considered) to <0.004. However, in the tables, we reported CIs at a 95% level to not confuse readers, whereas p<0.004 is marked with a bold face. Data management was conducted in R (V.4.1.0), and descriptives and analyses were made in Stata (V.17.0) using commands ‘nbreg’ and ‘stcox’. Plots were produced in R.Characteristics of the study population are shown in The results from the adjusted negative binomial regression of experiences of ICWS on cause-group-specific hospitalisation are plotted in Based on a 1953 birth cohort from Stockholm, followed over almost seven decades, our findings could largely confirm the initial hypotheses. Individuals with experiences of childhood adversity, by proxy of ICWS, had higher risks of being hospitalised in adulthood due to most of the major causes included here . Overall, they were also more likely to die after being hospitalised . The results generally followed a gradient reflecting the severity of ICWS, which suggests that the results are driven by the underlying exposure to adversity rather than solely being due to placement in OHC itself. Moreover, there were no clear differences between men and women.Extending the follow-up to mid-adulthood, our study corroborates findings from earlier studies showing that individuals with experiences of OHC have increased risks for hospitalisation due to external causes and mental and behavioural disorders—especially substance use disorders and self-harm.The findings also highlight that cancers are an exception, potentially because we could not differentiate the types of cancers with stronger behavioural risk factors. Our results are nonetheless in line with two of the most comprehensive earlier prospective inquiries into hospitalisation risks, which found a higher incidence across many conditions, but not neoplasms among individuals with a history of foster care.This study uniquely investigates the association between childhood adversity and survival prospects following hospitalisation. Individuals with experiences of ICWS generally had higher mortality risks and died sooner after hospitalisation due to external causes or NCDs than individuals without such experiences. These results were consistent in the subcategory of CVDs but not in the other subcategories. The worse survival prospects after a CVD-related hospitalisation could mean that individuals with experiences of ICWS are more vulnerable to the adverse consequences of such diseases, perhaps due to comorbidities, worse mental health or other coinciding risk factors for worse prognoses. Alternatively, it could reflect differences in disease severity when they present to the hospital, or differences in quality, access or response to treatment. These worse survival prospects might point to unmet care needs among individuals with experiences of childhood adversity; something which has been shown in OHC-experienced populations already during their childhoods.et al).This study has several strengths. Most importantly, the population-based birth cohort data that could be followed up to age 66. Based on national registers, there was minimal attrition and selection. Some limitations should, however, be considered. We cannot exclude the possibility of measurement error. Our indicators of ICWS were based on child welfare records from the Social Registers kept locally by municipalities in Stockholm; not all cohort members lived in Stockholm before age 10 and we might miss some cases that were solely recorded outside the metropolitan area.There are possible unmeasured confounders, such as baseline health, and other factors related to genetic predisposition to disease or risk-taking behaviours. There are also a number of potential mediators that have been not included in this study, for instance, life style behaviours, mental health, cognitive ability and educational attainment. Our results, nonetheless, lend some support to the hypothesis that mental and behavioural problems might be important explanatory factors. How much, for example, of the worse survival prospects, might be explained by mental health warrants further investigation: in patients with several comorbidities who experienced ICWS, mental health problems are very common . NeverthIt remains a question whether our findings may explain previously reported inequalities in premature all-cause mortality between those with and without experiences of ICWS.As this study only reports associations for one cohort born in one city, future research would need to verify the results in other contexts, and use designs and methods better equipped for making causal inferences. Regardless, the impact of adversity seems to persist across the life course, making it a relevant issue for public health and the inquiry into health inequalities. Our results further have implications for healthcare policy, as they strongly suggest that populations with experiences of childhood adversity might not be optimally served by the healthcare system, whether due to intrinsic susceptibility, help-seeking behaviours, comorbidity or other barriers. With their higher risks of disease and death following diseases, much could be gained from improving access to and quality of care in this vulnerable population.


Tumors arising in the brain are the most common solid cancers in children . They arThe lack of advancements in childhood brain cancer treatment had previously been due to deficiencies in knowledge about the underlying biological causes. However, pediatric neuro-oncology has undergone an exciting and dramatic transformation during the past 20 years, driven by advances in genomic technology, international collaboration, and the generosity of families willing to share tissue samples for research. Next-generation sequencing and other molecular profiling techniques, have revealed that the underlying biology of many childhood brain cancer entities are varied and complex –7. ArmedMost childhood brain tumors are still treated using three main therapeutic modalities: surgery, radiotherapy, and chemotherapy . HoweverWalker provides important perspective, highlighting that a focus on survival as the primary outcome for clinical trials can often fail to recognize the acquisition of brain injury that occurs and persists for the remaining life of brain cancer survivors. From a societal perspective, the economic benefit of reducing cancer therapy-induced late effects is significant, yet preclinical studies often fail to assess or report on long term side effects. While seeking new clinical trials to improve survival, the long term impacts of therapy and quality of life for survivors must also remain a priority. There is an opportunity for the field to better assess the developmental impacts of experimental therapies using preclinical models, and such studies – potentially investigating neurostructural impacts of treatment or behavioral changes – should be valued and encouraged. An example of the balance between brain tumor therapy and quality of life is described by Walker et al. in the setting of optic pathway and hypothalamic glioma (OPHG). Guided by careful analysis of retrospective clinical data, they pose that multi-disciplinary factors should be taken into account when selecting patients for observation versus treatment. Especially given that up to half of OPHG cases are associated with the inherited cancer predisposition syndrome neurofibromatosis type 1 (NF1), treatment decisions should include oncologists, ophthalmologists, endocrinologists, neurodevelopmentalists and geneticists, among other specialties. Such a “total care” approach is broadly adopted in many world class pediatric oncology centers and is the gold standard internationally.This Research Topic aims to address these challenges and raises important considerations in preclinical childhood brain cancer research. Importantly, within this Research Topic, Knox et al. report a fractionated radiotherapy protocol they designed and evaluated in a preclinical model of diffuse midline glioma (DMG). Studies such as these are essential to improve how we evaluate radiosensitizing strategies for childhood brain cancers.There are many more promising cancer therapies emerging than can be tested clinically for rare cancers like pediatric CNS tumors. As such preclinical modelling is an essential step that can focus the field on agents active in the brain and prevent the evaluation of ineffective or sub-optimal agents in children. For preclinical models to inform clinical response more accurately, it is important that the methodologies applied in the research setting better represent those of the clinic. Preclinical radiotherapy has been hampered in the past by the inability of small animal radiotherapy devices to precisely target tissues of interest, while sparing normal healthy tissue. Moreover, the linear quadratic model , which aIn vivo preclinical testing is highly valued as it is better able to mimic drug distribution, metabolism, and excretion compared to in vitro testing. Different routes of administration and schedules can be evaluated, with pharmacokinetic studies and pharmacodynamic measures of drug action within tumor cells essential in the interpretation of any effect of a novel compound against CNS tumor cells in an orthotopic setting (or lack thereof). While the use of small animals remains fundamental in cancer research, there is an obligation to consider alternative methods that may reduce the number of animals used in experimentation, to support their welfare and enable researchers to use animal models only when strictly necessary. As mentioned above, the BBB limits the brain penetration of many anti-cancer drugs. However, it is well established that the integrity of the BBB can be compromised in tumors and is often more accurately referred to as the blood-brain-tumor-barrier (BBTB). Several recent studies, summarized in this Research Topic by Morris et al., report that the BBTB has different properties across pediatric brain cancer types. They also discuss innovative and complementary model systems that can be used as an alternative to small mammal research, such as zebrafish or intricate 3-dimentional co-culture models of vasculature and tumor cells. Given experimentation in mice is laborious, costly, and requires specialist research and veterinary skills, the application of diverse model systems in preclinical CNS cancer research may facilitate a more rapid and refined selection of which agents should progress to small mammal experimentation. Such an approach is consistent with the 3 Rs , and ensures the rational and respectful use of laboratory animals.Lazow et al. describe their investigation of a radionuclide therapy, 177Lu-DOTATATE (Lutathera®), which binds somatostatin receptors and has demonstrated clinical efficacy in adult neuroendocrine tumors, in a pediatric CNS cohort. They show that the targets of Lutathera, somatostatin type-2A receptors (SST2A), are highly expressed in certain high-risk pediatric CNS tumors and meningiomas. This agent is currently being investigated in a phase I/II trial (NCT05278208), and there is now a preclinical opportunity to begin assessing Lutathera in combination with current standard of care therapies with the goal of providing additional information to guide future clinical trial design. Their observation that SST2A has highest expression in non-SHH medulloblastomas, enables this preclinical assessment to be undertaken in the most appropriate models.Translational research is often described as bench to bedside, however a more comprehensive perspective is to think of cancer research as a cycle from bedside to bench and back around. Here, Sengupta et al. describe the assessment of a telomerase inhibitor in the context of high-risk, MYC-amplified Group 3 medulloblastoma. In this study, they show that even with very promising in vitro and in vivo evidence that telomerase inhibition can slow medulloblastoma growth; when the drug imetelstat was combined with radiotherapy, it appeared to antagonize the anti-tumor effects of radiotherapy, although some tumor growth delay was observed . With early phase clinical trials data suggesting this drug is not well tolerated in children . This has been facilitated in large part through the generous donation of surgical or autopsy tumor tissue for research, establishment of a large number of preclinical DMG/DIPG models, combined with the international collegiality, collaboration and sharing of these models. The molecular analyses of large numbers of high-grade gliomas (HGGs) have identified key mutations which drive gliomagenesis, with certain molecular features now officially recognized in the latest 2021 WHO classification of CNS tumors . Of noteYang et al. provide critical data in this Research Topic regarding the experience of the national health center for children in China highlighting some notable differences compared to other reports. With ongoing international generation and sharing of preclinical models, laboratory techniques and molecular data, alongside careful monitoring of ongoing clinical trial findings, and robust scientific discussion, achieving international consensus on the optimal clinical trials to benefit children affected by brain cancer will be achievable.Importantly, epidemiological and molecular data for pediatric brain cancers has mostly relied on North American or European populations, and while these data hint at racial differences among brain tumors, limited global information is available. RE: Conceptualization, Writing – original draft, Writing – review & editing. BW: Writing – review & editing. NG: Conceptualization, Writing – review & editing.


The result of the movement restrictions during the COVID-19 pandemic was an impromptu and abrupt switch from in-person to online teaching. Most focus has been on the perception and experience of students during the process. The aim of this international survey is to assess staffs' perspectives and challenges of online teaching during the COVID-19 lockdown. Cross-sectional research using a validated online survey was carried out in seven countries  between the months of December 2021 and August 2022, to explore the status of online teaching among faculty members during the COVID-19 pandemic. Variables and response are presented as percentages while logistic regression was used to assess the factors that predict levels of satisfaction and the challenges associated with online instruction. A total of 721 response were received from mainly male (53%) staffs. Most respondents are from Brazil (59%), hold a Doctorate degree (70%) and have over 10 years of working experience (62%). Although, 67% and 79% have relevant tools and received training for online teaching respectively, 44% report that online teaching required more preparation time than face-to-face. Although 41% of respondents were uncertain about the outcome of online teaching, 49% were satisfied with the process. Also, poor internet bandwidth (51%), inability to track students' engagement (18%) and Lack of technical skills (11.5%) were the three main observed limitations. Having little or no prior experience of online teaching before the COVID-19 pandemic , and not supporting the move to online teaching mode  were two main factors independently linked with dissatisfaction with online teaching. While staffs who support the move to online teaching were twice likely to report no barriers . Although, relevant tools and training were provided to support the move to online teaching during COVID-19 lockdown, barriers such as poor internet bandwidth, inability to track students’ engagement and lack of technical skills were main limitations observed internationally by teaching staffs. Addressing these barriers should be the focus of higher education institution in preparation for future disruptions to traditional teaching modes. This resulted in disruption to the face-to-face teaching. We conducted a cross-sectional survey of staff members in higher education around the globe to evaluate their perception of the abrupt transfer to online teaching during the COVID-19 lockdowns. Poor internet bandwidth, inability to track students’ engagement and lack of technical skills were a global barrier to online teaching at the peak of the COVID-19 pandemic.2In 2019, the coronavirus disease (COVID-19) was identified in Wuhan, China and declared as a pandemic by the World Health Organization (WHO) in March 2020 , and not supporting the move to online teaching mode  are two main factors independently linked with dissatisfaction with online teaching. Conversely, prior support for online teaching is also independently associated with no barriers [OR, 2.14 ; 5In this international survey of higher education institution teaching staffs, we investigated the general perception and barriers to the switch to online teaching during the global COVID-19 restrictions. Our findings showed that the general perception of online teaching due to COVID19 pandemic was mostly positive among teaching staffs who also report been provided with relevant equipment and technology as well as training for online teaching. Further, most teaching staffs surveyed also supported the move to online teaching under global COVID-19 restrictions with mostly positive expectations and satisfaction level. However, barriers such as poor internet bandwidth and the inability to track students’ engagement were highlighted.The COVID-19 pandemic resulted in restrictions to general movement and closure of schools, including higher education institutions around the world . The conIn terms of limitations and barriers, this and previous studies show that the problem of poor internet bandwidth is universal. Indeed, Dost et al. surveying over 2700 medical students from the United Kingdom reported that aside family distraction, poor internet connection was the main reported barrier to smooth online learning . SimilarResult of multivariate logistic regression analysis to evaluate the factors that may predict the tendency to be satisfied with online teaching or experience barriers showed that staffs with previous experience of online teaching as well as those that supported the movement of all teaching online were more likely to be relatively satisfied. Also, staffs that supported online teaching mode have a lower propensity to report barriers. Conversely, this may be interpreted as follows. Intuitively, staffs with frequent previous use of online teaching modes have better experience with the online teaching tools and are more trained. This consequently mean that their use of online teaching platforms is less phased with barriers resulting in a better teaching experience. Also, this group are more likely to have the relevant resources and tools for delivery of online class as well as a better understand of the pedagogic dynamics of online teaching delivery. Further, support for the switch to online mode may be based on the perceived need to protect loved ones or the “fear of COVID” which may be provide a balance against any perceived barriers. Indeed, the effect of “fear of COVID” on preventative behavior is well documented .This study has limitations. Firstly, because of the retrospective nature of the survey, there is a problem of recollection error which may result in potential bias. However, this is a general limitation of studies that depends on self-reported data. Also, Africa, a continent with unique sets of teaching challenges, is not represented in the dataset and some of the included countries have significantly low respondent. Thus, the result may not be generalizable to countries from these affected regions. Thirdly considering that this is a multinational study, a larger and more uniform representative samples size may provide a stronger result with higher significance. However, this is the first survey conducted across countries and continent assessing the perception and barriers to moving teaching online as experienced by teaching staff members. Future studies could consider this limitation for a better understanding of the factors that limits the efficiency of online teaching.6Although staffs were positive about and well prepared for the switch to online teaching during COVID-19 pandemic, barriers such as poor internet speed and inability to perceive student understanding, limits the quality of teaching delivery. Also, previous frequent use of online teaching platform is a driving factors for positive staffs’ experience. Policy makers should consider implementing plans that allow for increased exposure to online teaching platform in preparation for future disruption to traditional teaching modes. This may be in the form of increased training and continuous professional development that focuses on improving knowledge of online teaching technologies and tools. Because online teaching has unique pedagogic challenges that differs from traditional teaching techniques exploring innovative methods such as virtual reality, artificial intelligence, machine learning, gamifications and other techniques could be introduced to enhance remote teaching in future.Tope Oyelade; Jaber S Alqahtani: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Renata G Mendes; Maria Isabel Triches; Tatiana de Oliveira Sato; Jithin K Sreedharan; Abdulelah M Aldhahir; Abdullah A Alqarni; Reynie Raya Purnama; Mohammed Alkhathami; Arulanantham; Zechariah Jebakumar; Ayadh Yahya AlAyadi; Abdullah S Alqahtani; Saeed M Alghamdi; Ibrahim A AlDraiwiesh; Musallam Alnasser; Rayan A Siraj; Abdallah Y Naser; Hassan Alwafi; Saad M AlRabeeah; Mohammed D AlAhmari; Ami Kamila; Heba Bintalib; Eman M Alzahrani: Performed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper.Data will be made available on request.No additional information is available for this paper.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.