Performance can be defined as the accomplishment of goals by meeting or exceeding predefined standards . PerformThis Research Topic aimed to collect and disseminate the most current research examining on how stress, maturation, training load, and recovery tend to impact the performance and health of athletes at all ages. Since sport science research is still scarce on this Research Topic, scholars have provided an important contribution by investigating this stimulus-performance-adaptation relationship in different contexts and environments, with the aim of expanding our knowledge and the implications for practice.Liu et al. tried to develop a strategy to improve the functionality of professional firefighters and help their work. Through a pilot, randomized, and controlled study, they investigated the effects of a 12-week complex training program  on the strength, power, and rescue performance of professional firefighters. This pilot study demonstrated the effectiveness of complex training in inducing significantly greater improvements in the fire fighters’ strength and power compared to resistance training, thereby improving the firefighters’ ability to perform work-related tasks. In addition, the study provides tactical conditioning professionals with further suggestions for appropriately developing daily routine training programs. This study strengthens the previous findings of Jiang and Xu aimed to investigate the young basketball players’ lower limb explosive power training. Specifically, they explored the effects of the chain squat training with different chain load ratio  on the explosive power of the lower limbs of adolescent male basketball players. The findings showed that chain squat training with more chain load has better training effects on lower limb explosive strength and maximum strength, based on the improvement in 1RM squat and jumping performance. Besides, compared with traditional squat training, chain squat training with more chain load might not help to develop better velocity adaptation at a higher range of movement.Patti et al. on elite female futsal athletes.In their study, Milovančev et al. aimed to assess left ventricular morphology and function compared to non-athletes. The results showed that highly trained elite female judoka athletes exhibit significant changes in left heart morphology due to vigorous training compared to non-athletes. These findings suggest that the heart of female judoka athletes follows a pattern of chamber dilation rather than left ventricular wall hypertrophy.Since there is a paucity of data on physiological heart adaptation in elite-level judo female athletes, García et al. aimed to describe and compare the recovery status of basketball players that underwent the NESA neuromodulation treatment and a placebo group in weeks with one and two matches. The results suggested that players who underwent the ESA neuromodulation treatment tended to improve their sleep quality even though their biochemical markers and wellness status remained like the placebo group. In addition, no significant differences were found between weeks with one or two games, which could help basketball professionals establish that a congested calendar would not seem to affect recovery status adversely.Through a preliminary randomized controlled trial, Hu et al. aimed to evaluate the effectiveness of transcranial alternating current stimulation on motor performance and learning in healthy individuals. The results showed that transcranial alternating current stimulation effectively improves motor performance and motor learning in healthy individuals, which indicates that it may be a potential therapeutic tool to improve motor behavioral outcomes.Through a systematic review and meta-analysis, Kyselovičová et al. aimed to compare variables of dynamic balance and isokinetic leg muscle strength in rhythmic, artistic, and aerobic gymnasts. The results showed a significant association between the symmetry of the dominant limb and the isokinetic extension strength of the dominant limb; therefore, it can be concluded that both muscle strength and speed contribute to dynamic balance in adolescent gymnasts.Since it is unclear whether the different dynamic balance and power demands produced by the lower limb can be observed in sport-specific differences between gymnasts of various modalities, Xiao et al., through a systematic review and meta-analysis, have examined the effect of cold-water immersion on post-exercise fatigue recovery after high-intensity exercise. The results showed that cold water immersion could effectively reduce muscle soreness and speed up recovery from fatigue.Finally, In conclusion, this Research Topic provided multidisciplinary investigations on the physiological relationships between stimulus-performance-adaptation in different contexts and environments. We have observed how training stress, biological maturation, training load and recovery tend to influence the performance and health of tactical populations and athletes of different sports and ages.Overall, some researchers have encouraged future research to address open Research Topic about this topic. From previous studies, the need to develop more appropriate training programs for firefighters in their daily routine has emerged. Further studies are needed on warm-up as it is a complex Research Topic, as changes in volume and intensity and recovery could negatively affect performance. Further studies are needed to strengthen knowledge of the specific adaptations of cardiac structure and function in judokas, which play a crucial role in classifying cardiac remodeling and distinguishing between pathophysiology and sport-specific individual adaptations. Finally, more research evidence is needed to verify the efficacy of transcranial alternating current stimulation on motor learning.


The two most prevalent neurodevelopmental disorders—Attention Deficit Hyperactivity Disorder (ADHD) and Autism (ASD)—(ASD/ADHD) strongly impact individuals’ functions. This is worsened when individuals are undiagnosed and risks such as increased imprisonments, depression or drug misuse are often observed. This systematic review synthesizes the risks associated with late/undiagnosed ASD/ADHD.Four databases were searched . Published studies exploring the impact of undiagnosed ASD/ADHD were included. Exclusion criteria included, lack of diagnosis status, studies not solely on ASD or ADHD, gray literature and studies not in English. The findings were summarize through a narrative synthesis.Seventeen studies were identified, 14 on ADHD and three on ASD. The narrative synthesis identified three main themes: (1) Health, (2) Offending behavior, and (3) Day-to-day impact. The risks highlighted a significant impact on mental wellbeing and social interactions, higher risks of substance abuse, accidents and offending behavior as well as lower levels of income and education.The findings suggest that undiagnosed ASD/ADHD is linked to many risks and negative outcomes affecting individuals, their families, and the wider society. The restricted number of studies on ASD are a limitation to the generalization of these findings Implications for research and practice are discussed, highlighting the importance of screening and acknowledging the possibility of ASD/ADHD in many settings such as psychiatric and forensic. Neurodevelopmental disorders including Attention Deficit hyperactivity disorder (ADHD), autism (ASD), dyspraxia and tic disorders, affect around 6% to 8% of the adult population . They arIndividuals with ASD and/or ADHD (henceforth ASD/ADHD) report difficulties in obtaining appropriate support, diagnosis, and treatment for difficulties associated with their conditions . This leThese considerable risks are attenuated when ASD/ADHD are diagnosed, as diagnosis facilitates access to care or support . For insThere are multiple reasons why many children and adults are still undiagnosed. Socio-economic factors often play a role in recognition of ASD/ADHD. The gender perception gap in how these conditions are expressed and impact males and females for instance can bias recognition, as girls are often missed . AdditioWhile there is a wealth of knowledge regarding how ASD/ADHD impacts the lives of individuals, little is known about the traits of adults with ASD/ADHD who are undiagnosed or about the human costs incurred by the disorder among these people. This systematic review identifies and synthesizes the risks associated with late/undiagnosed ASD/ADHD reported in the published literature. No synthesis of these risks has been conducted to date and these novel findings may help to inform future research and policy development.This review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P) guidelines . A protoSupplemental Material as an example and included terms such as: Attention Deficit Disorder with Hyperactivity/(ADHD or ADDH or “attention deficit disorder*” or “attention deficit hyperactivity disorder*” or “hyperkinetic disorder*”), exp Autism Spectrum Disorder/(autis* or ASD or ASC or asperger*). Adaptation of the MEDLINE search strategies was made for the other databases according to their own search criteria. The search was performed on the 5th of December 2022, date limits were not imposed. While hand searching was not a strong component of our planned search strategy, the reference lists of all papers that meet the inclusion criteria were hand searched to check for any additional studies.Four databases  were searched. PROSPERO was checked for ongoing or already published systematic reviews on the subject. A full search strategy for Medline (MEDLINE In-Process & Non-Indexed Citations and OVID MEDLINE 1946 to present-Ovid) is detailed in Quantitative and qualitative studies were included. The qualitative component of this review considered qualitative studies of any design exploring the impacts, effects or risks associated with undiagnosed ADHD/ASD . The quantitative component of this review included quantitative studies of experimental and observational designs . Mixed method studies were also included, relevant qualitative and quantitative components extracted separately. Studies published in peer-reviewed publications were solely considered.This review covers studies examining individuals (adults and children) who have not yet received a diagnosis of ASD/ADHD but show traits/symptoms of these disorders on validated screening and assessment tools . If studies included multiple groups such as diagnosed and undiagnosed individuals, undiagnosed findings were extracted and reported separately. Studies where individuals are on the care pathway to get a diagnosis as well as studies looking into untreated/unsupported ADHD/ASD were included if the reason for lack of treatment was due to lack of diagnosis.This review is examining the impact of not receiving a diagnosis of ADHD/ASD when symptoms of ASD/ADHD are present and meet diagnostic or screening criteria. Within the context of this study, impacts are defined as any consequence from having these conditions in daily life and include consequences to the individuals, their environment , their families and any others impacted. This definition and concept of impact vary between each study therefore this review looked at broader concepts such as risks, effects, or consequences. This review considered studies focusing on ADHD/ASD throughout the lifespan and therefore included studies of children, adolescents, and adults.This review was conducted in any setting and took an international perspective. The period of the review was not restricted, covering all publications from inception up to the 5th of December 2022.Unpublished and gray literature were excluded. Studies were also excluded if they did not specify the status of diagnosis examined or focusing on diagnosed individuals and studies that do not mention the terms “Attention Deficit Hyperactivity Disorder,” “Autistic,” “ADHD,” “Autism” or “ASD.” Case studies and studies on genetics, medication and scale development were excluded as well as studies not published in English. Studies that did not separate findings from undiagnosed and diagnosed groups were also excluded.Supplemental Material S1. The study selection process is presented in Following the search, all identified citations were uploaded into a reference manager software (Zotero). Two of the review authors independently screened the titles and abstracts for assessment against the search inclusion criteria (BF and DD). Full reports were obtained for all titles that appear to meet the inclusion criteria. The same two review authors screened and assessed the full text reports in detail against the inclusion criteria. Disagreement on selected studies were resolved through discussion and/or presented to a third reviewer (SC). Studies that do not meet the inclusion criteria were excluded and a record of reasons for excluding studies can be found in The lead reviewer (BF) extracted qualitative and quantitative data from the included studies using a standardized data extraction tool . The datThe main outcome is the synthesis of risks associated with having undiagnosed ADHD/ASD. Multiple types of factors reported in the selected studies were evaluated such as societal factors  and health factors . These factors were grouped into themes within the synthesis phase.Due to the mixed-method nature of this review, a segregated synthesis is proposed where two distinct analyses of qualitative and quantitative evidence were made prior to conducting a mixed-methods synthesis .A meta-synthesis summarized the qualitative findings. This aggregation or synthesis of findings generated a set of statements representing the aggregation and categorizing them based on similarity in meaning. The findings were presented in narrative form. As statistical pooling was not possible for quantitative data, the findings were presented in a narrative form including tables and figures. The two analyses were then aggregated and combined in the form of qualitative themes . Two revFollowing mixed methods reviews guidelines , the proThe studies included in this review give an international view of the topic discussed with studies from nine different countries . The most common mental health reported difficulties were depression and anxiety but also included psychiatric inpatient admissions and suicidality. These mirror previous findings on the impact of lack of diagnosis on mental health . In a reOffending behaviors including imprisonment, aggression, criminality, and substance abuse were also a key theme from this review. These results reflect findings from many studies which have shown that high rates of prisoners have undiagnosed/untreated ADHD . ADHD isThe day-to-day impact of undiagnosed ASD/ADHD included many risks across different settings. These encompassed social difficulties and difficulties in relationships, difficulties with money, education and work as well as driving. Undiagnosed ADHD was consistently linked to lower income and lower educational attainment. While this impact was not researched directly in any of the studies, six studies demonstrated this as a key additional finding through demographic questionnaires. While these findings mirror current knowledge on the relationship between ADHD and lower educational outcomes , our revThis review demonstrates that the risks associated with undiagnosed ASD/ADHD are significant, greatly impairing and need to be taken seriously. While the rates of ASD/ADHD diagnosis has increased in the past decade  and the This review contains some strength and limitations. To the authors’ knowledge, this is the only review that has attempted to establish the specific risks and impacts arising from a lack of ASD/ADHD diagnosis. This review included all studies looking specifically at this topic, regardless of age group and the limited number of included studies suggest that this is an under-researched or difficult to study topic. The main limitation of this review is the small number of studies on ASD. Despite the similarity of topics between the ASD studies and the ADHD studies, with only three included studies on ASD, it is not possible to generalize or indeed differentiate the findings across disorders. While most studies conducted a thorough assessment of ASD/ADHD as part of their methodology (including but not limited to interviews and questionnaires), a few relied solely on screening questionnaires. While these may give a strong inclination of individuals having ASD/ADHD, they are limiting as no official diagnosis process was performed. Similarly, our search criteria aimed to specifically identify groups of “undetected,” “undiagnosed” and “unrecognized” ASD/ADHD. Studies which might have used different terminology would not have been capture by our search or identified in our review of titles, abstract or keywords. This was intentional to limit the number of non-relevant studies or studies where undiagnosed ASD/ADHD was not a key focus, however this may explain the limited number of ASD relevant studies, as many studies tended to assess autistic traits across a whole population, rather than identify a specific group of undiagnosed autistic people. Additionally, a few studies on undiagnosed ASD were excluded due to a lack of separate report of the findings which prevented us to draw conclusions on this population.A few recommendations can be made from this review, both on the clinical and research impacts of the findings. Understanding the psychosocial burden of undiagnosed ASD/ADHD will help teachers, clinicians, and policy makers pay more attention to the consequences of under-diagnosis of these conditions. Due to the high rate of undiagnosed ADHD in specific healthcare services such as emergency services (for accidents and injuries), psychiatric services  and forensic services (for substance misuse and prisons), it would be advisable that healthcare professionals in these settings regularly screen for potential ADHD, using standardized screening measures such as the adult ADHD self-report scale ASRS-  or the CClick here for additional data file.Supplemental material, sj-rtf-1-jad-10.1177_10870547231176862 for Risks Associated With Undiagnosed ADHD and/or Autism: A Mixed-Method Systematic Review by Blandine French, David Daley, Madeleine Groom and Sarah Cassidy in Journal of Attention Disorders


Apis mellifera;Hymenoptera:Apidae) are at an increased risk of exposure to adjuvant tank mixtures while providing agricultural pollination services. Colony losses attributed to pesticide applications thought to have low risk to honey bees have been reported, highlighting the need to better understand the toxicity of adjuvants included in pesticide tank mixtures. This review summarizes current literature on the risks posed to honey bees by agricultural adjuvants and tank mix combinations of adjuvants with pesticides. Based on the current state of knowledge, we make recommendations to pesticide applicators, product manufacturers, regulatory agencies, and researchers regarding adjuvant toxicity to honey bees with the goal of reducing risks that adjuvants pose to honey bees and other beneficial insects.Pesticide applications are often made as tank mixes containing multiple pesticide products and may include spray adjuvants to enhance pesticidal activities. The primary aim of adjuvant products is to increase the spreading and sticking of spray droplets and to increase the penetration of active ingredients through the cuticles of leaves or targeted pests, which can reduce the amount of active ingredient needed for effective pest control. Adjuvants are made up of compounds drawn from the “inert ingredient” list maintained by EPA but are identified as “principal functioning agents” when used in adjuvant products. These inert compounds do not undergo the same testing and risk assessment process that is required of pesticide active ingredients and generally have no mitigation measures that prevent application onto crops during bloom at times of day when bees are foraging. Honey bees ( Aethina tumida (Coleoptera: Nitidulidae) (Varroa destructor (Mesostigmata: Varroidae) mite  , and theae) mite , among oae) mite . The gloae) mite , demonstIn the United States, tests of pesticide active ingredients are required prior to product registration and sale. The pesticide label lists the exact chemical compound and composition of active ingredients included in the formulated product. There are federal laws for bee hazard labeling intended to mitigate the impacts of pesticide application to bees . In CaliThe same compounds that are inert ingredients in pesticide products often also serve as principal functioning agents in standalone adjuvant products. These can be classified by function, chemistry, or source (vegetable or petroleum oil derived), and different products contain different adjuvant compounds to serve different purposes. The function of these compounds can include pH buffering , anti-foNonionic surfactants are the most diverse chemical group and contain multiple subclasses. One sub-class of nonionic surfactant, the polyethoxylates, encompass primarily alcohol ethoxylates, fatty acid ethoxylates, and amine ethoxylates. These are made up of a hydrophobic head consisting of an alkyl or aryl alcohol, a fatty acid, or an amine bonded to a hydrophilic tail formed from ethylene oxide . The cheCrop oil concentrates and modified seed oils are mainly derivatives of naturally occurring plant oils, but also include petroleum-derived oils such as mineral oil. Crop oil concentrates include triglyceride oils and hydrocarbon oils, which are primarily isoalkanes, though petroleum-derived aromatics and naphthenes can be used to enhance product handling properties . The mosOrgano-silicones are often considered “super-spreaders” and can decrease surface tension and increase spreading on waxy surfaces even when used at rates as low as 10% of traditional surfactant use rates. Organo-silicone surfactants can be ring-structured, but most are chain-structured with a dimethylsiloxane polymer and a terminal or side organic reactive group . The dimHydrocolloid polymers are a diverse group of long-chain polymers that form viscous dispersions in water, which is intermediate between a true solution and a suspension and exhibit the properties of a colloid . They caWhile there are many different compounds used as adjuvants, they all share the goal of enhancing the efficacy of the active ingredients included in a pesticide application. Adjuvants can decrease the total quantity of active ingredient required for effective pest control, with benefits for both human and environmental safety. However, this apparent benefit of adjuvant use could be self-sabotaging if these chemicals carry their own risks to pollinators and the environment.To understand the risk adjuvants pose to honey bees, it is important to understand the likelihood, concentration, path, and duration of exposure associated with different routes as well as the inherent toxicity of adjuvants and potential interactive effects between the multiple components present in tank mixtures to honey bees. Beekeepers provide commercial pollination services to over 100 commercial crops in North America , with anThe ecological persistence of adjuvants is poorly understood, so the level of exposure beyond the initial application is not well characterized . Unlike Generally, adjuvant products do not claim any pesticidal activity, though Tergitol, a commercially available alcohol ethoxylate, is registered for use as a mosquito larvicide through reduced water surface tension to cause death of larvae through drowning . HoweverDiaeretiella rapae  caused midgut damage indicated by melanization, a reduction in appetite, weight loss, and increased mortality  when combined with nonionic and anionic adjuvants (Antagonistic effects, where the joint effect of 2 or more chemicals is less than predicted by additive toxicity, is also possible in adjuvant-pesticide combinations . Adjuvandjuvants . Salts odjuvants . Alcoholdjuvants  and orgadjuvants , 1993b hdjuvants . It has djuvants .Based on the current state of knowledge regarding adjuvant toxicity to honey bees, we recommend that pesticide applicators only add adjuvant products to pesticide tank mixes when recommended on the pesticide label. However, an adjuvant recommendation on a pesticide label does not imply that adjuvant-pesticide combinations were tested for bee safety but instead indicates that the pesticide manufacturer suggests use of an adjuvant to maximize efficacy of pest control. Adjuvants that are not recommended on pesticide labels can have unpredictable interactions with pesticides, such as synergistic interactions that may harm beneficial organisms or antagonistic interactions that reduce efficacy against the targeted pest. In addition to interactions affecting honey bees, the use of adjuvants when not recommended on the pesticide label can have negative effects on crop plants, such as reduced drought tolerance of crops , alteredResearchers should always clearly state whether the formulation or the active ingredient alone was used when reporting toxicities for pesticides and adjuvants. The use of an active ingredient name when testing a formulation containing inert ingredients results in confusion in the scientific literature that can lead to misunderstanding and inaccurate risk assessments for commercial pesticides and adjuvants . More woThe current state of research suggests that adjuvant and pesticide manufacturers should avoid the more toxic principal functioning agents in adjuvants and inert ingredients in pesticide formulations that will be applied on insect-pollinated crops, including some polyethoxylate and organo-silicone surfactants. If alcohol ethoxylates are used, it is recommended that compounds with fewer molar equivalents of ethoxylate are used, as contact toxicity in other insect species was inversely related to levels of ethoxylation . With thAs the literature summarized in this review demonstrates , the ter


Vulnerable populations in cancer care include a wide array of possible conditions see Table 1.The treatment of cancer patients with surgery, radiotherapy, and systemic anticancer drugs has reached an increasingly high level of effectiveness, sometimes shifting a cancer diagnosis towards the possibility of living a long life with a chronic cancer therapy treatment that takes place on a regular basis over a long period of time. Moreover, research is often so advanced that we may discuss “personalised cancer medicine” for different cancer types.Unfortunately, the progress that cancer research has made in cancer prevention, early detection, and treatment is not equitably accessible and applicable to vulnerable cancer patient populations. The main reason is that the patients included in clinical trials are not always representative of the whole target population. Indeed, the generalizability of trial results to all patients is usually hampered by the strict inclusion criteria of the clinical trials, leading potentially to overinflated reported benefits. In addition, the toxicity may be substantially higher in these vulnerable populations. Therefore, patients from the groups listed in A recent report by the ASCO focused on the necessity of an equal opportunity to participate in clinical trials and research in general. They proposed many strategies to improve equity in cancer research, such as broadening eligibility criteria . The neeNext to race and ethnicity, age has also been identified as a strict eligibility criterion leading to the underrepresentation of older patients with cancer in clinical trials. Older patients are not only numerically underrepresented in clinical trials, but the large heterogeneity within this population also causes the older patients included in clinical trials to be fitter than their real-life counterparts. The lack of evidence-based data related to the benefits and risks of cancer treatment in vulnerable older patients limits the applicability of trial results within the field of oncology to older patients with cancer who may have a vulnerable or frail profile in particular. Indeed, not automatically excluding patients of older age, or with lower ECOG Performance Status, would make trial results more reliable for the vulnerable older cancer patient population who actually represents the majority of cancer diagnoses and deaths. We have to acknowledge that there are also good reasons to exclude vulnerable patients from cancer clinical trials as cancer treatments may cause unique toxicities because of underlying conditions such as comorbidities. Other physiologic changes, such as reduced renal function, may also impact chemotherapy dosing for example. However, to deliver high-quality cancer care to vulnerable cancer patient populations, more research targeting this evidence gap will be required. In a previous study by our research group, we made suggestions for new trial designs to allow more vulnerable patients to receive upfront dose reductions or less intense regimens and stressed the concept of a dose-expansion cohort (DEC) dedicated to vulnerable older patients to be incorporated in phase 1b/2a protocols .The extrapolation of clinical trial results to a real-life population involves the risk of exposing many patients to strategies that have never proven to be effective in underrepresented subpopulations. The recently developed combination therapies involving immune checkpoint inhibitors have potentially serious immune-related and other adverse events, which might have a greater impact on older and more vulnerable patients. An upcoming phase IV clinical trial by our research group entails the investigation of the safety and tolerability of the first-line combinations of a PD-1 inhibitor with a CTLA-4 or tyrosine kinase inhibitor (TKI) in older patients with stage IV kidney cancer (mccRCC). We will include four currently approved first-line immunotherapy combination regimens in eight cohorts of fit and vulnerable older patients with mccRCC and compare the safety profiles of the cohorts to the reported proportions of the respective landmark trials . We expeThe outcomes of such post-marketing observational studies, whether reported adverse events leading to treatment discontinuation in older patients are maintained in real-life practice, are also of interest for the financial aspect of (phase IV) clinical trials. Cost-utility analysis results and health technology assessments (HTH) may not apply to vulnerable populations. Moreover, inadequate treatments pose a logistic and financial risk to the health systems.In conclusion, we want this special issue to serve as a tribute to cancer research groups who have made efforts to focus their research on vulnerable cancer patient populations. We hope the issue can serve as a motivation for others to pursue this type of research or pursue their current intentions and address the needs of vulnerable patient populations. We advocate for more inclusive criteria, giving access to vulnerable patient populations and thereby reducing disparities in clinical trial participation.LT, PS, TB, CP, and PD designed and wrote this editorial article. All authors contributed to the article and approved the submitted version.


Cancer is one of the leading causes of death worldwide. Despite significant improvements in prevention and treatment, mortality remains high for many cancer types. Hence, innovative methods that use molecular data to stratify patients and identify biomarkers are needed. Promising biomarkers can also be inferred from competing endogenous RNA (ceRNA) networks that capture the gene–miRNA gene regulatory landscape. Thus far, the role of these biomarkers could only be studied globally but not in a sample-specific manner. To mitigate this, we introduce spongEffects, a novel method that infers subnetworks (or modules) from ceRNA networks and calculates patient- or sample-specific scores related to their regulatory activity.We show how spongEffects can be used for downstream interpretation and machine learning tasks such as tumor classification and for identifying subtype-specific regulatory interactions. In a concrete example of breast cancer subtype classification, we prioritize modules impacting the biology of the different subtypes. In summary, spongEffects prioritizes ceRNA modules as biomarkers and offers insights into the miRNA regulatory landscape. Notably, these module scores can be inferred from gene expression data alone and can thus be applied to cohorts where miRNA expression information is lacking.https://bioconductor.org/packages/devel/bioc/html/SPONGE.html. Despite recent advances in screening, diagnosis, and prognosis, and an increased understanding of the mechanisms driving tumorigenesis, progression, and maintenance, cancer deaths are estimated to be ∼400 000/year by 2040 in the US alone , highligA range of computational methods has been developed to identify potential miRNA–target interactions based on different inputs, such as gene expression data, protein–protein interaction networks, and sequence information . Such meWhile tools for inferring ceRNA networks exist , it is nHere, we introduce spongEffects, a new method to (i) extract ceRNA modules from previously inferred ceRNA networks [e.g. with SPONGE ] and  it We applied spongEffects to ceRNA networks inferred with two partial correlation-based methods  and the Molecular Taxonomy of Breast Cancer International Consortium (n = 1905). For both cohorts, we removed all samples for which the subtype was missing or not identified as one of the five classes of interest . Furthermore, we filtered out 19 samples from the TCGA cohort for which the tumor stage indication was missing (5 patients) or unclear . This step resulted in two final datasets: (1) TCGA-BRCA (n = 944), which we used for model training, and (2) METABRIC (n = 1699), both of them were used once as training and once as an independent external validation set to build subtype classifiers as in standard machine learning applications to control for potential overfitting   and strength of the inferred edges (corr > 0.1 for PC and mscor > 0.1 for SPONGE) to preserve significant associations with non-negligible effect sizes (A wide variety of methods for the identification of potent ceRNA interactions is available in the literature . These mPC) , Hermes PC) , and SPOPC) . Given tct sizes . This stct sizes , confirmTo compare the predictive power of modules calculated across different datasets and methods, we trained different types of classifier models to predict breast cancer subtypes based on spongEffects scores. Random Forest, Support Vector Machine with the linear kernel (linear SVM), and eXtreme Gradient Boosting (XGBoost) models were used to build two separate families of models in order to evaluate the robustness of the modules. The first one was trained with modules calculated on networks inferred from the TGCA-BRCA dataset and validated on the METABRIC modules. In the second one, the training and datasets were switched. Upon training, we investigated the prediction performances of the model families and the similarity of the modules driving predictions in both contexts.Despite the limited number of edges and dataset sizes, the resulting modules showed relatively good predictive performances independently of the type of machine learning model . While tWe next investigated if similar ceRNA modules were selected as top-performing classification features when training on TCGA or METABRIC data, respectively, as this would emphasize the robustness of our approach as well as the capacity of spongEffects scores to reflect important aspects of tumor biology. We ranked modules by their feature importance (mean decrease in Gini index) and investigated the overlap of the top 20 modules reported by the PC- and SPONGE-based models between the TCGA and the METABRIC-trained classifiers. 18/20 modules were identical in the PC-based models and 10/20 in the SPONGE models, indicating that the PC method is more robust in feature selection. We found only five of the top 20 modules to overlap from PC and SPONGE, which once more emphasizes that ceRNA inference methods following different concepts show comparably little agreement in results .Long non-coding RNAs have often been discussed for their relevance in breast cancer  and for uggested .We trained a Random Forest classifier on the TCGA-BRCA dataset and validated the resulting model on the METABRIC dataset. We repeated this analysis using different numbers of lncRNAs  to study the robustness of our approach and to highlight the relatively small influence of the number of initial lncRNAs (and thus modules) considered on the final results . To asseUpon closer inspection of the top 25 ceRNA modules across breast cancer subtypes in both datasets , we obseHere, as an example, we describe in more detail the CACNA1G-AS1 module and its miRNAs, which have been experimentally validated. Specifically, we investigate its role in the Basal subtype, one of the most aggressive breast cancer subtypes for which effective targeted therapies are still missing .Genes in module CACNA1G-AS1 have lower expression levels in the Basal subtype when compared to the other subtypes in TCGA-BRCA and METABRIC  and contIn order to check whether we could exploit our modules to explain such changes, we further investigated the most frequent miRNAs in the CACNA1G-AS1 module  and checIn addition, we investigated if the members of a module jointly contribute to important biological functions via gene set enrichment analyses with g: Profiler . The majspongEffects is a new method for extracting and interpreting ceRNA modules from pre-computed ceRNA networks. To the best of our knowledge, spongEffects is the first method that offers a sample- or patient-specific score that can quantify the regulatory activity of a ceRNA and its associated miRNAs. We demonstrated how the spongEffects method could be applied to ceRNA networks inferred with different approaches. Considering the use case of breast cancer subtype prediction, we could show that spongEffects module scores are robust features for subtype classification across independent cohorts and gene expression profiling technologies. Our analysis confirmed previous studies highlighting low agreement between ceRNA inference tools and the need for further research into method benchmarking and possibly the use of consensus strategies. While this is an active area of research, we see spongEffects as a way to identify ceRNA modules generalizable across different cohorts and suitable as potential biomarkers.We expect spongEffects scores to reflect two overlapping regulatory mechanisms. The first is miRNA-mediated ceRNA–target regulation, where an increase in the expression of a ceRNA leads to miRNA depletion, relieving other target genes from miRNA repression and, conversely, a decrease in ceRNA expression leaves more miRNA copies that can act as repressors of their target genes  middle. Using SPONGE-inferred ceRNA networks and RNA-seq data for TCGA breast cancer as inputs, we demonstrate how spongEffects scores can capture important aspects of cancer biology and be used in downstream machine learning tasks such as subtype prediction and biomarker identification. Using independent microarray-based gene expression data from the METABRIC consortium, we show that the inferred modules generalize to different cohorts. A particular strength of our approach is that spongEffects modules, once inferred from a ceRNA network, can also be computed for datasets or cohorts that lack miRNA data. For the modules that were predictive in subtype classification, spongEffects scores capture contributions of two different regulatory mechanisms: ceRNA regulation and miRNA regulation (see Section spongEffects scores). While it is challenging to separate the two, we observe that, in practice, our method returns a robust representation of microRNA-mediated regulatory effects.We presented an extensive use case on the application of spongEffects to study lncRNA- mediated miRNA regulation. Our analysis showed that ceRNA interactions calculated on coding and non-coding RNAs together have higher discriminative power than interactions calculated on mRNAs alone, probably due to the extended interaction space allowed by the integration of multiple classes of RNAs. Many gene regulatory mechanisms of lncRNAs are poorly understood and must be experimentally discovered . spongEfbtad276_Supplementary_DataClick here for additional data file.


But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring’s response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach.Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn’s response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus  But immunity to pertussis is considerably more complex, and although maternal vaccination appears to be quite effective, the mechanisms of transferred protection are unlikely to be simply antibody-mediated and are poorly understood  is a gram-negative bacterium  vaccine, which was approved and distributed starting in the 1940s. While it proved very effective in preventing disease, rare reports of severe side effects and high reactogenicity led to the development of vaccines with less severe side effects . The aceBordetella pertussis (Bp) to susceptible newborns. Initially, mothers were vaccinated postpartum but recently, this strategy was updated to have mothers receive the vaccine antepartum to generate anti-Bp antibodies that can be transferred from mother to child in utero during the later stage of pregnancy  recommended it for mothers and close family members of newborns (Even though preterm vaccinations against Tetanus and Diphtheria (Td) had been recommended for many years, this form of vaccination against pertussis did not seem feasible until the Boostrix (Tdap) vaccine was approved in 2005. Boostrix was a less potent formulation of the DTaP vaccine meant to boost the newborns  , a secreted protein from ammation , 29 and ammation –32, althBp challenge in terms of reduced colonization in the lungs. The power of the immunological tools in the mouse model makes it feasible to more fully dissect the immunological mechanisms involved.Animal models have the potential to allow mechanistic studies of immunological components transferred from mothers to offspring, and the specific effects of each. Experimental models have included mice , non-hum33.1Maternally-derived immune components are vertically transferred antenatally via the placenta and perinatally via breast feeding. Exposing mothers to pertussis during pregnancy allows for pathogen specific antibodies to be transferred from mother to child . IgG is Bp antibodies have been found in the stool samples of preterm newborns fed either donor or mother’s milk up to 22 days postpartum. This study measured sIgA, sIgM, and sIgG titers of anti-PT and anti-Filamentous Hemagglutinin Antigen (FHA). It was found that anti-FHA IgG, anti-PT IgG, and IgA titers were consistent or increased in the gastrointestinal contents compared to the breast milk from the mother  is transferred into the breast milk after binding to polymeric Ig receptors on the apical side of the breast tissue , 44, ande mother . A stronry tract –50. Theslearance  and neit3.2At the maternal-fetus interface, cells generated in the mother/fetus can be transferred from one to the other . These cBp.Stelzler et al.  recently4Bp infections. The pathology of those infections includes leukocytosis, bacterial pneumonia, and pulmonary hypertension. Maternal intervention during pregnancy can impact this response, skewing the immune system toward a different immune response that may be more protective. Maternal vaccination has been shown to impact neonatal immune development in utero. B and T cell immune responses to Influenza have been detected from cord blood of infants of vaccinated mothers. Newborn’s response to antigen transferred in utero was seen by the presence of anti-Fluzone and anti-matrix specific IgM as well as hemagglutinin (HA) specific CD4+ T Cells in the cord blood (Children under six months are highly susceptible to severe rd blood . This sh4.1Bp vaccine platforms available (wP and aP) prime different T cell responses. The wP vaccine primes a very protective Th1 response, which has been shown to be the most effective in the clearance of Bp and inducing immunity, while the aP primes a not-as-effective mixed Th1/Th2 profile , Pertactin (PRN), Filamentous hemagglutinin antigen (FHA), and Fimbriae 2/3 (FIM2/3). Englund et al.  originalBp-specific blunting, high concentrations of Bp-specific maternal antibodies would lead to the infant’s reduced anti-Bp antibody production. Other hypotheses include the inhibition of B cell responses. One of those is epitope masking, as maternal antibodies may cover the epitopes on vaccine antigens, preventing B cell recognition (γ receptor III via maternal antibodies (H and VK genes and have altered isotype switching ability, further showing how maternal antibody presence has effects on the newborn’s developing responses (Animal studies using murine and porcine models have shown that a pertussis toxoid vaccine does blunt the antibody response in offspring , althougognition . Anothertibodies . A recenesponses .To the relevancy of this blunting, there have been suggestions to alter the vaccination schedule to optimize the newborn’s response to vaccines. The suggestions range from increasing the number of boosters to delaying the vaccine schedule , 77. Doi5Bp vaccines need to induce protection and cannot impact neonatal response to other vaccines. Some techniques to bypass the blunting effects of antepartum maternal vaccination include the utilization of different adjuvants and altering the vaccination route by using mucosal vaccines on the newborn (Future directions in this field should aim to explore maternal vaccine options that confer protection from disease and colonization for the mother. By doing both, we can allow for herd immunity to protect the most susceptible. By focusing on vaccinating mothers during pregnancy, it will be possible to protect mothers and susceptible newborns with just one shot. These new  newborn , 79. Usi newborn  showed, Many factors that could potentially affect how the advantages of maternal vaccination are conferred across populations have yet to be addressed. There is substantial variability in human populations that is poorly represented in uniformly housed, inbred mouse populations. These factors can range from genetics and health to socioeconomic and ethnic backgrounds. Some populations in the United States have lower vaccinations rates due to a lack of access to care and medical information as well as there being vaccine hesitancy rooted in historic events. Lower maternal Tdap vaccination rates are seen among Hispanic and non-Hispanic Black populations therefore impacting seroprotection of the newborn, thus making these groups more vulnerable to infection –83. It i6Bp infections and can play a role in instructing and shaping the neonatal immune response to better protect against diseases. To fully understand these important effects, more research is necessary, especially concerning the efficacy of maternal vaccination in conferring protection to offspring. The recommendation for mothers to get vaccinated during pregnancy is less than two decades old. Clinical experience and experimental models have shown aP vaccination confers protection from disease but not colonization, possibly contributing to the increased asymptomatic transmission and vaccine evasion currently seen with circulating strains (Maternal vaccination leads to the passive transfer of protective immune components to the newborn. These components have been linked to decreased pathology in  strains . Along wMC and EH conceived the review. MC and EH wrote the manuscript. MC generated the figures. Both authors contributed to the article and approved the submitted version.


Digital health is an expanding field and is fundamentally changing the ways health care can be delivered to patients. Despite the changing landscape of health care delivery, medical trainees are not routinely exposed to digital health during training. In this viewpoint, we argue that thoughtfully implemented immersive elective internships with digital health organizations, including start-ups, during residency are valuable for residents, residency programs, and digital health companies. This viewpoint represents the opinions of the authors based on their experience as resident physicians working as interns within a start-up health navigation and telehealth company. First, residents were able to apply their expertise beyond the traditional clinical environment, use creativity to solve health care problems, and learn from different disciplines not typically encountered by most physicians in traditional clinical practice. Second, residency programs were able to strengthen their program’s educational offerings and better meet the needs of a heterogenous group of residents who are increasingly seeking nontraditional ways to learn more about care delivery transformation. Third, digital health companies were able to expand their clinical team and receive new insights from physicians in training. We believe that immersive elective internships for physicians in training provide opportunities for experiential learning in a fast-paced environment within a field that is rapidly evolving. By creating similar experiences for other resident physicians, residency programs and digital health companies have a key opportunity to influence future physician-leaders and health care innovators. Digital health is an expanding field and promises to be a significant disruptor of health care delivery . AlthougDespite the changing landscape of health care delivery and practice, medical trainees have not traditionally been exposed to digital health during training, and residency programs have not kept pace with opportunities to train physician-innovators in digital health. Currently, digital health education in medical training appears to be sparse, and it primarily takes the form of elective curricula for medical students ,5. This The inherent flexibility of using an elective internship to learn more about digital health aligns well with the ever-changing digital health care landscape. However, immersive experiential learning opportunities like this, which go beyond traditional medicine, are uncommon in residency.Resident physicians are uniquely positioned to benefit from an immersive elective internship at this point in their medical training; they have more substantial clinical experience than medical students, but they are not yet fully ingrained in the traditional health care system’s mindset and still maintain some level of career path flexibility. In this viewpoint, we argue that immersive elective internship experiences with a digital health company should be considered by resident physicians eager for unique, hands-on learning opportunities in care delivery transformation outside of usual residency training. We share our experiences in setting up an elective internship program for resident physicians at a start-up digital health company and summarize the benefits and learnings of the experience for resident physicians, residency programs, and digital health companies.We designed an immersive elective internship for 3 resident physicians from the University of California, San Francisco with interests in digital health and care delivery transformation. The internship involved working experientially as clinical strategy interns within a start-up telehealth and health care navigation company . Participants included 2 internal medicine residents and 1 pediatrics resident. These 3 internships took place between April 2019 and January 2022, in 4- to 6-week rotations.The origins of this internship program arose organically from conversations between the resident physicians and a leader in this digital health organization who is also an adjunct faculty member at University of California, San Francisco. Through sharing interests, experiences, and common goals, we found that there was an opportunity to set up an internship at this digital health organization in the clinical strategy group.To establish the internship program, we worked closely with the leadership of the residency program and the digital health organization to develop a proposed elective structure and curricular objectives. The curricular objectives were designed to align with fulfilling core competencies outlined by Accreditation Council for Graduate Medical Education, as summarized in We also made efforts to identify a dedicated internal mentor within the digital health organization for the resident physicians participating in the program. The mentor was a physician-leader in the organization who inherently understood the background, knowledge, and skills of resident physicians. This was beneficial for optimizing the learning experience and ensured that the resident physicians were efficiently deployed to well-scoped projects. The mentor met with the participating residents before each internship to shorten the onboarding learning curve and worked closely with the residents throughout the duration of the internship to guide them in their work.All 3 internship experiences were designed to meet the outlined curricular objectives. The specific content of each internship experience was significantly shaped by the digital health organization’s strategic and operational priorities during the respective period of each individual internship. The initiatives worked on by the resident physician interns included the development of pediatric care management programs, the design of integrating pharmacy services into telehealth primary care, the analysis of clinical patterns for telehealth primary care and behavioral health services, and the clinical vetting of telehealth and hybrid primary care service competitors. This work often entailed data analysis, clinical shadowing, secondary research, stakeholder interviews, and various other tasks.Based on our experience and supporting research, we believe there are multiple benefits of an immersive elective internship experience in digital health for residents, residency programs, and digital health organizations, including start-ups.All participating resident physicians agreed that the experience provided abundant hands-on learning in a fast-paced environment during a short time and that they were able to apply their knowledge of patient care delivery to their internship experiences. Moreover, all concurred that the internship was highly formative in influencing how they considered next steps in their careers as practicing clinicians. Voluntary qualitative feedback by participating resident physician interns highlighted the following key lessons learned by residents during the internship that can be applied to their future careers.. Participating residents worked with physician-leaders in the organization who played various roles, ranging from setting clinical strategy to leading clinical care delivery. According to one resident, “What struck me the most was the variety of ways that physicians can lend their clinical expertise to create impact within different functions.”First, the immersive internship allowed resident physicians to recognize how physician-leaders can apply their expertise in many ways beyond the traditional clinical environmentSecond, residents learned to collaborate with a diverse range of disciplines to solve health care problems. This experience provided the first opportunity for most residents to work closely with individuals from disciplines that are not typically encountered in the traditional clinical practice of a physician. From data scientists, product managers, designers, and engineers, residents learned about opportunities and challenges for designing solutions for patients and clinicians. Although many large health systems often employ individuals with backgrounds in these fields, physicians rarely have the opportunity to closely interact and collaborate with these disciplines on a daily basis to work toward a common goal. This immersive internship allowed physicians in training to enhance their skills in team-based professionalism and communication .Third, residents were able to experience how creativity can be used to approach health care problems in new ways. Traditional training in medicine tends to emphasize the role of repetition, pattern recognition, and clinical reasoning based on a repertoire of memorized facts and knowledge. Participating resident physicians agreed that they could see how novel approaches and design thinking were employed to approach problems in health care, such as improving patient messaging and clinical workflows to be more patient-centric and user-friendly. According to one resident, “I saw more discussions asking ‘what if?’ and ‘how should we?’ rather than ‘how can we make this work within existing constraints?’ and it felt like a shift in the default mindset that I am used to.”Residency programs that develop an opportunity for an immersive elective internship program at digital health start-ups may strengthen their program’s educational offerings and development of their resident physicians in several ways. First, residents may be able to gain valuable skills applicable to residency training from an immersive elective experience. A recent survey of residency program directors found that more than two-thirds of respondents believed that physicians in training can gain communication and leadership skills, organizational and team-based skills, and the ability to innovate from start-up experiences . Second,Digital health organizations, including start-ups, can benefit from a resident physician immersive internship program. Physicians in training can bring a new perspective to the company by applying their up-to-date knowledge of clinical practices, recent experiences of care delivery, and intimate knowledge of both physician and patient needs . For exaAs the field of digital health is constantly evolving and rapidly changing, elective internships for physicians in training provide opportunities for immersive experiential learning in a fast-paced environment. The impact of the internship can stretch far beyond the dedicated immersive experience alone; it can influence career steps and serve as a launching point for cultivating physician-leaders who can meaningfully engage across the traditional and digital health landscapes. By creating more experiences like this for other resident physicians, residency programs and digital health organizations have a key opportunity to influence physician-leaders and health care innovators of the future.


Syndromic surveillance (SyS) is an important public health tool using de-identified healthcare discharge data from emergency department (ED) and urgent care settings to rapidly identify new health threats and provide insight into current community well-being. While SyS is directly fed by clinical documentation such as chief complaint or discharge diagnosis, the degree to which clinicians are aware their documentation directly influences public health investigations is unknown. The primary objective of this study was to evaluate the degree to which clinicians practicing in Kansas EDs or urgent care settings were aware that certain de-identified aspects of their documentation are used in public health surveillance and to identify barriers to improved data representation.We distributed an anonymous survey August–November 2021 to clinicians practicing at least part time in emergency or urgent care settings in Kansas. We then compared responses from emergency medicine (EM)-trained physicians to non-EM trained physicians. Descriptive statistics were used for analysis.A total of 189 respondents across 41 Kansas counties responded to the survey. Of those surveyed, 132 (83%) were unaware of SyS. Knowledge did not differ significantly by specialty, practice setting, urban region, age, nor by experience level. Respondents were unaware of which aspects of their documentation were visible to public health entities, or how quickly records were retrievable. When asked about improving documentation for SyS, lack of clinician awareness (71.5%) was perceived as a greater barrier than electronic health record platform usability or time available to document .This survey suggests that most practitioners in EM have not heard of SyS and are unaware of the invaluable role certain aspects of their documentation play in public health. Critical information that would be captured and coded into a key syndrome is often missing, but clinicians are unaware of what types of information may be most useful in their documentation, and where to document that information. Lack of knowledge or awareness was identified by clinicians as the single greatest barrier to enhancing surveillance data quality. Increased awareness of this important tool may lead to enhanced utility for timely and impactful surveillance through improved data quality and collaboration between EM practitioners and public health. Syndromic surveillance (SyS) is a data collection strategy that informs public health about concerning trends in near real-time by analyzing patient-reported symptoms and electronic health record (EHR) documentation from clinicians in emergency departments (ED) and urgent care.Epidemiologists actively use SyS tools in their day-to-day practice, and there is great opportunity for collaboration with frontline clinicians providing the data input. For example, e-cigarette or vaping-associated lung injury, was initially identified when astute healthcare clinicians alerted public health practitioners to cases of respiratory failure among young adults, prompting widespread SyS queries to further quantify this public health problem and identify cases for investigation.4Syndromic surveillance has also been used to prove the efficacy of vaccination initiatives by demonstrating a decrease in patients presenting to EDs for target diseases.As SyS systems use data generated from clinician documentation, the strength of the data collected is reliant on clinician awareness of the role of their documentation in SyS.We conducted a cross-sectional survey designed to assess emergency clinician (physician and midlevel practitioner) awareness and understanding of SyS through an electronic survey questionnaire. Twelve of 29 survey questions gathered respondent demographics, training level, primary practice setting, and assessed their understanding of SyS and perceived barriers toward improving documentation for public health purposes.  is a public health tool using de-identified ED visit records to rapidly assess current health threats.What was the research question?Are clinicians in emergency medicine aware their documentation is important for public health surveillance?What was the major finding of the study?Of 189 clinicians surveyed, 83% were unfamiliar with SyS or the role their charting plays in public health.How does this improve population health?Increasing awareness of SyS within emergency medicine will inform public health practice through collaboration to target surveillance and enhance data quality.Survey subjects were eligible to participate if they identified as practicing in an EM or urgent care (UC) setting in the state of Kansas . In rural counties, the ED did not have to be the primary practice setting provided the clinician identified as practicing in the ED at least part time. We acquired clinicians’ emails from the Kansas Board of Healing Arts database, and we contacted potential survey participants via email correspondence and the Kansas Chapter of the American College of Emergency Physicians (KS ACEP). Responses were anonymous. The survey was disseminated and stored with survey software  from August 1–November 12, 2021, and participants were contacted multiple times. We analyzed qualitative data using survey analytic descriptive statistics . Awareness and perception differences were compared with Pearson chi-square tests.Of 1,553 EM, FM, IM physicians and PAs queried, 189 responded. Of those queried, 480 were formally trained in EM. There is no existing source to quantify how many clinicians practice in Kansas EDs. Further, not all physicians queried may have been eligible to participate in the survey as outlined by our communication. The response rate for emergency physicians at our state’s large academic medical facility reached 38%. Responses were received from clinicians in 41 counties, reflecting excellent Kansas clinician representation given that three-quarters of the state population resides in just six counties.See The majority of survey respondents indicated they were unfamiliar with SyS, and the role that EHR documentation serves in public health. When discussing public health and SyS, 75% of respondents indicated “no” when asked “Have you heard of a subset of public health surveillance called syndromic surveillance?” Only 17% of respondents indicated they had heard of SyS, although none indicated where they had previously learned of SyS. Awareness of SyS did not significantly differ by practice setting, academic vs non-academic center, age, nor by clinician training . For theRespondents were unsure which aspects of documentation are visible to public health, how quickly data is received, and what conditions are monitored using SyS . When asThe data obtained in this survey supports our hypothesis that emergency physicians and other clinicians who practice in ED settings are unfamiliar with SyS. Respondents were also unclear about the role EHRs serve in capturing public health trends using SyS. Although not all clinicians identified as practicing primarily in an ED setting, the distribution of responses was similar to a 2020 study demonstrating that FM physicians represented nearly half of the overall physician workforce.This survey fills a gap in the literature addressing the understanding of SyS by clinicians. Our survey results indicate clinicians are unsure what types of information might be useful and where in the EHR documentation. They are not sure what types of conditions and social determinants of health epidemiologists are attempting to monitor. When asked about what this data is used for, respondents were more likely to select that public health monitors reportable infectious diseases or conditions only via state mandate of importance. In reality, public health is using SyS data to monitor a wide variety of health outcomes.13From direct conversations with the National Syndromic Surveillance Program and ACEP we suspect awareness of SyS is low nationally, not just in Kansas. In fact, Kansas has been one of the state programs leading the way in SyS outreach and application. Increasing awareness of SyS by clinicians has the potential to unearth many meaningful applications for this data through academic public health partnerships and applied public health research. Physicians in Kansas changed the way they document to include additional contextual diagnosis codes not included prior to knowledge about SyS. Codes or language of interest may be determined in collaboration with local public health agencies for emerging health threats or community events. This is also an opportunity to enhance the feedback loop between public health and medicine to target surveillance efforts and provide useful data back to clinicians. Improving the quality of SyS data at the clinician level through increased awareness has obvious implications for future advances in the way we predict, monitor, and respond to disease on a local and national level.Although our overall response rate was typical for e-mail-based survey studies of clinicians without incentives, our study is limited by the number of respondents. While our responses are representative of a wide variety of practice settings and experience levels, we cannot exclude the possibility of non-response bias or bias from the survey instrument itself. The length of the survey was likely a factor, as not all respondents answered every question. Additionally, while we suspect our results are likely generalizable to other states, the survey in this study was only administered to practitioners in Kansas. Many of our responses came from clinicians who are not formally EM trained or may be practicing in ED settings part time. While this could generate concerns about reaching our intended audience, it is also a strength of our study because it demonstrates that we captured responses from non-traditional, rural clinicians who practice in ED settings. Finally, the high response rate of academic practitioners in EM to the survey may introduce bias that makes the results less representative of the statewide ED workforce.Frontline clinicians practicing in ED settings in the state of Kansas are largely unaware of syndromic surveillance and the critical role their documentation plays within this facet of the public health system. Clinicians reported that a lack of understanding of SyS is a significant barrier to making changes to electronic health record-level documentation that would improve the quality of data collected for SyS. These findings represent an opportunity to increase education and collaboration between EM and public health for surveillance purposes.


Implementation science aims to improve the integration of evidence-based interventions in real-world settings. While its methods and models could potentially apply to any field with evidence-based interventions, most research thus far has originated in clinical settings. Community settings often have fewer resources, missions beyond health, and a lack of support and expertise to implement evidence-based interventions when compared to many clinical settings. Thus, selecting and tailoring implementation strategies in community settings is particularly challenging, as existing compilations are primarily operationalized through clinical setting terminology. In this debate, we (1) share the process of using an existing match tool to select implementation strategies to increase uptake of nutrition and physical activity policy, systems, and environment interventions in community settings and (2) discuss the challenges of this process to argue that selecting implementation strategies in community settings has limited transferability from clinical settings and may require a unique implementation strategy compilation and pragmatic matching tool.The impetus for this debate paper came from our work selecting implementation strategies to improve the implementation and eventual scaling of nutrition and physical activity policy, systems, and environment interventions in a community settings. We conducted focus groups with practitioners and used the Consolidated Framework for Implementation Research-Expert Recommendations for Implementing Change match tool to select potential implementation strategies to overcome prominent barriers. There was limited congruence between tool outputs and optimal strategies, which may in part be due to differences in context between clinical and community settings. Based on this, we outline needs and recommendations for developing a novel and pragmatic matching tool for researchers and practitioners in community settings.More work is needed to refine the implementation barrier-strategy matching process to ensure it is relevant, rapid, and rigorous. As leading implementation strategy scholars note, as more researchers document contextual factors and strategies selected to address them, the knowledge base will increase, and refined mapping processes can emerge. Contributions to the literature•Implementation science methods and models could be broadly applied to settings outside of health services research, but terminology and transferability are challenges•Suggested methods for matching implementation determinants to strategies are resource intensive and less feasible in community public health settings.•We argue that due to differences between settings and the need for pragmatic, practitioner-friendly tools, a new implementation strategy compilation and matching tool for community settings is neededImplementation science seeks to understand and improve the integration of evidence-based interventions (EBIs) within specific settings , 2. ThusConsider the differences between clinical and community settings. Community practice settings implement chronic disease prevention interventions where people live, work, and play –14. ThesTherefore, selecting and tailoring implementation strategies   in commuOne method of selecting and tailoring implementation strategies that may be more feasible for community settings is the Consolidated Framework for Implementation Research (CFIR)—Expert Recommendations for Implementing Change (ERIC) match tool . CFIR isThe purpose of this debate is twofold. First, we document the process of using the CFIR-ERIC match tool to select implementation strategies to increase uptake of nutrition and physical activity policy, systems, and environment (PSE) interventions in community settings. Second, we discuss limitations of this process to argue that selecting implementation strategies in community settings has limited transferability from clinical settings. A unique implementation strategy compilation and pragmatic matching tool that researchers and practitioners in community settings can easily use may be required.The impetus for this debate paper came from our work selecting implementation strategies to improve the implementation and eventual scaling of PSEs delivered through Louisiana Cooperative Extension Service (LCES) . ExtensiWe used the identified barriers as inputs to the CFIR-ERIC match tool and reviewed the resultant output of implementation strategies. However, it was difficult to determine which implementation strategies to select, given inconsistencies with our community setting. For example, “Build a coalition” is often already the starting point for community work, including for LCES delivery agents , and othDespite the promise of the CFIR-ERIC match tool, it did not work as an easy, accurate matching system for the PSE intervention-LCES context. First, we acknowledge that this may be due to known limitations of the matching tool. As the authors note, the tool should be used with caution given a lack of consensus in specific barrier-implementation strategy matches  . Thus, tSome of the challenges with using the matching tool could also be due to the differences in context between clinical and community settings. Implementation determinants are often different in clinic and community settings and may add challenges to implementation strategy matching — even when using a broad determinant framework such as CFIR , 32. ForAnother challenge is the difference in feasibility and importance of implementation strategies  in commuTo overcome these limitations and speed the translation of research to practice in community settings, we provide ideas and recommendations to inform the development and dissemination of a novel and pragmatic set of implementation strategies and accompanying matching tool. First, this tool should be accessible to practitioners overseeing the delivery of evidence-based interventions without access to research partnerships and resources. Community settings do not have the time, staffing, or implementation science expertise to engage in detailed processes of selecting and tailoring implementation strategies. For example, community settings (without research partners bringing in grant funding) usually do not have the resources to devote to reviewing all possible implementation strategies . OveralCommunity setting practitioners are already using implementation strategies and will continue to use them with or without research partnerships. Providing practitioners with a tool they could use to select implementation strategies could improve practice in community settings. Use of a broader range of implementation strategies that address multiple levels of contextual factors could provide more “practice-based evidence” to inform evidence-based practice . OtherwiSecond, we recommend a future matching tool employ a strength-based approach. Public health literature recommends using a strength-based approach to assess both needs and resources –51. For Overall, there is a need for specific guidance on incorporating facilitators into implementation strategy selection and tailoring. This could include changing which strategies are selected to complement existing strengths within systems or providing recommendations to tailor implementation strategies to capitalize on facilitators. For example, working with community coalitions has been identified as both a barrier and facilitator to integrate nutrition and physical activity PSE interventions in community settings , 35, 36.Third, we recommend the new matching tool be developed for and by community setting practitioners and researchers across multiple settings. As recommended by implementation strategy experts, the tool should avoid jargon and embody real-world perspectives . With diThe goal of this debate was to share our approach to selecting implementation strategies in a community setting to inform pragmatic tools for researchers and practitioners. More work is needed to refine the implementation barrier-strategy matching process to ensure it is relevant, rapid, and rigorous for community public health work . As lead


Carotenoids are lipophilic isoprenoid compounds synthesized by photosynthetic organisms and some non-photosynthethic prokaryotes and fungi. They are widely present throughout nature and approximately one thousand have been described to date. As humans cannot synthesize carotenoids, they must be obtained from the diet. It is worth noting that, in a varied diet containing fruit and vegetables, approximately 50 carotenoids are available for absorption, but only 6 found in the human bloodstream have been studied in depth , in order to verify their impact on human health/disease. Some carotenoids of undeniable nutritional importance are used as vitamin A precursors . Carotenoids also perform other biological activities that may confer their beneficial effects against some chronic diseases  . Since tTM to estimate carotenoid intake [However, concerning the relationship between the dietary intake of carotenoids and their concentrations in tissue and human health, both positive and negative effects/correlations have been described in the literature ,3. Thered intake . Regardid intake , while td intake  and phytd intake .TM, which employs an image-based algorithm to identify dietary patterns, is proposed to estimate the nutrient intake in general, as well as the carotenoid intake [When assessing the dietary intake of carotenoids, it is important to evaluate food consumption, which can be studied using a wide variety of methods, and to access food composition tables containing individual carotenoid data. Food intake can be assessed in different ways, each featuring strengths and weaknesses . To mitid intake . CarotenIt should also be noted that food composition tables/databases rarely show individual carotenoid data and that the important issue of bioavailability is missing as well . This apTwo papers in this Special Issue report results from a lutein-rich fruit or vegetables (three pieces/day) intervention study of normolipidemic adults consuming normal dietary amounts of these foods  over a period of four weeks. This study elicited varying responses in terms of status biomarkers, while the serum lutein concentration increased by 37%  and the macular pigment optical density did not exhibit any variation, nor did it correlate with the contrast sensitivity [This review of the current research trends looking into the correlation between carotenoids and human health is presented in the form of an overview of the registered clinical trials , mainly covering studies on foods and food supplements, but also a combination of both sources . Among tThe studies featured in this Special Issue contribute: to shedding light on long-ignored colourless carotenoids; to expanding our knowledge of lutein, a carotenoid of public health interest for its role in visual performance and reducing the risks of age-related macular degeneration, by studying the lutein status marker responses following a lutein-rich food intake in healthy subjects consuming amounts compatible with their habitual diet; to the proposal of a carotenoid dietary assessment method; and to identifying the current research trends regarding carotenoids and human health through a review of the registered clinical trials from the last twenty years.


Over the past decades, studies of human brain networks have received growing attention as the assessment and modelling of connectivity in the brain is a topic of high impact with potential application in the understanding of human brain organization under both physiological as well as various pathological conditions. Under specific diagnostic settings, human neuronal signal can be obtained from intracranial EEG (iEEG) recording in epilepsy patients that allows gaining insight into the functional organisation of living human brain. There are two approaches to assess brain connectivity in the iEEG-based signal: evaluation of spontaneous neuronal oscillations during ongoing physiological and pathological brain activity, and analysis of the electrophysiological cortico-cortical neuronal responses, evoked by single pulse electrical stimulation (SPES). Both methods have their own advantages and limitations. The paper outlines available methodological approaches and provides an overview of current findings in studies of physiological and pathological human brain networks, based on intracranial EEG recordings. Over the past decades, the world neuroscience society became increasingly interested in human brain connectivity so that the yearly number of publications available under these keywords shows sustainable growth from several hundred in the early 2000s to several thousands in the last years. The attention shifts from a single brain region, traditionally considered a functional module, to interactions among distributed neuronal populations and brain areas. Modern neuroscience theories do not consider the brain as a number of fragmented components with a particular functional role, but rather emphasize the role of dynamically organized neuronal systems, probably underlying flexible cognitive operations and complex human behaviour . This apBrain connectivity can be described as structural , functional, and effective connectivity. Structural connectivity refers to existing neuroanatomical links and can be evaluated over various neuroimaging modalities that provide comprehensive network maps of anatomical connections among neural elements. Although MRI-based tractography can identify fiber locations of white matter bundles , it is lUnder specific diagnostic settings, neural activity can be recorded directly from the living human brain by means of intracranial EEG. This method offers the opportunity to record neuronal signals precisely defined in space and time, also from deep brain structures not accessible for non-invasive EEG . Here weIntracranial EEG (iEEG) signal in the living human brain can be recorded in tertiary epilepsy centres in patients with therapy resistant epilepsy as a part of presurgical evaluation. Presurgical epilepsy diagnostics is designed to delineate an epileptogenic focus that can be surgically removed in order to cure or substantially reduce seizures . Due to There are two most common methods for recording directly from the cortex in epilepsy patients: stereoelectroencephalography (SEEG) and subdural electrode recordings (SDEs) . SEEG reProviding a great opportunity for human brain research, intracranial EEG studies have certain limitations. Although intracranial recording can be potentially performed in any brain region, the indication to undergo invasive EEG and the sites of electrode implantation are based exclusively on clinical reasons in order to localize the seizure onset zone, and cannot be justified by scientific interest only . Therefofunctional connectivity, and analysis of the electrophysiological neuronal responses, evoked by a SPES, single pulse electrical stimulation  than long-range connections over the whole brain . These metrics nevertheless allow to rank the explored structures according to their degree of connectivity .The first attempts to probe connectivity in the living human brain date back to 1980’s when bidirectional connections between human amygdala and hippocampus were stated through electrical stimulation in one structure and recording of the elicited response in another structure in the intracranial EEG . Nearly CCEP-based effective connectivity has been traced in numerous brain circuits, including language system , motor sCCEPs frequently contain two major components: an early negative component  cortical regions and confirm epileptogenic cortex . The SPESeveral studies have reported changes in the morphology, latency and response rate of evoked potentials in epileptogenic brain regions . Higher Several studies have provided evidence that focal epilepsy arises from disordered neural connectivity in localized cortical regions that involves a concept of abnormal cortical networks with nodes and pathological connections also beyond the seizure onset zone. Epileptic networks have been found to include highly interconnected nodes with the highest number of outgoing connections  or ingoiin vitro using hippocampal slices obtained from epileptic patients who had undergone epilepsy surgery did not reveal any effect on stimulus-evoked action potential in slices with mesiotemporal sclerosis compared to the hippocampal samples without a structural lesion  or cortical malformations . Influence of structural brain abnormalities on CCEP properties has not been systemically explored yet. Electrophysiological study l lesion . Neverthl lesion .Regarding malformational lesions such as a focal cortical dysplasia (FCD), a single report is available that demonstrates a difference in the amplitude of the SPES-responses with larger responses in patients with FCD type I compared to FCD type II . AnotherEvaluation of spontaneous neuronal oscillations during ongoing brain activity does not require any direct intervention in the nervous system and can be implemented either in the absence of identifiable stimulus or during task performance as well as in the context of specific brain activity such as sleep or epileptic seizure. Neural activity evaluated as statistical dependencies among time series can be termed “Neural Information Flow,” meaning how much information is transferred between regions within the nervous system, the process which might underlie communicational processes within the brain . DespiteIntracerebral functional connectivity has been mostly investigated within auditive and language networks. Regarding auditive perception, the timing and distribution of left perisylvian electrophysiological activity has been analysed using the Granger causality method in a single patient during a speech processing task and revealed a widespread activation over all temporal structures involved in the ventral speech processing pathway . In anotin vivo, suggesting unlike the evoked connectivity that revealed to be stable under different conditions, functional connectivity can be a dynamic process in spatial and temporal scales and probably vary state-dependently.Several recent studies addressed the issue of verification the results of functional connectivity methods by comparing them with CCEP networks. Intracranial EEG is aimed to delineate the epileptogenic area, and the seizure onset zone is traditionally defined visually by treating epileptologists that can be sometimes very challenging. In order to support clinical iEEG interpretation, a computer-assisted approach named Epileptogenicity Index has been proposed . The metFocal epilepsy is considered to result from disordered local hyperexcitability and connectivity, originating from “driver” regions . In the Functional connectivity studies suggest that epileptogenic networks exhibit aberrant dynamics not only at the time of seizure onset, but also during interictal seizure-free periods. A causality-based analysis has revealed that persistence of inflows and outflows of high frequency activity was a good indicator of the seizure onset zone, also observed during interictal periods . Intericf-tract.eu; iEEG is a valuable tool for neuroscience studies in the living human brain, however, its scientific implementation can be challenging. Firstly, invasive EEG recording is restricted to investigations in epilepsy patients, and can be performed only in clinically relevant cortical regions in a given patient limiting the area of investigation. This issue can be overcome by collecting iEEG data from many patients in multiple tertiary epilepsy centers and fusing them to a large database (for example, see iEEG-based connectivity assessment has a promising application in mapping epileptogenic networks. Nowadays, the identification of the SOZ during presurgical evaluation is a manual, time-consuming process which operates with large amounts of disparate neural data and has a basically unexplored reliability . AlthougBesides spontaneous neural activity, intracranial EEG recording can be performed in association with stimuli of different modalities, allowing investigation of human event-related potentials. This found application in studies of cognitive or affective activity involved in processing the stimulus or preparing an action . Event-rLastly, the assessment of electrophysiological connectivity can add an extra-layer of information onto structural networks derived from brain topography methods such as DWI, or supplement functional fMRI-based networks in the context of task performance or other psychological processes. Future studies may integrate data from the iEEG-based connectivity research with the MRI tractography methods to determine the precise relationship between cognition and observed structural networks.


The concept of a “community” as a form of organization for natural biological systems is both widespread and widely accepted within the ecological and biological sciences. Communities have been defined as groups of organisms that interact in ways that denote interdependence between individuals and taxa (e.g. as defined by “food webs”) but they have also been defined as groups of co-occurring organisms that are assumed to interact by virtue of their shared spatiotemporal existence. The latter definition has been debated and challenged in the literature, with mounting evidence for co-occurrence being more indicative of coincident ecological niches in space and time rather than being evidence of ecological interaction or dependency. Using a dataset of 460 Costa Rican bird species divided into breeding and non-breeding season datasets, we empirically demonstrate the ways in which co-occurrence can create illusory communities based on similar occupied ecological niches and similar patterns of co-occurrence at different times of year. We discuss the importance of discerning coincidental co-occurrence from true ecological interactions that would manifest a true community, and further address the importance of differentiating communities of co-occurrence from communities of demonstrable ecological interaction. While co-occurrence is a necessary aspect of interspecific interactions, we discuss and demonstrate here that such co-occurrence does not make a community, nor should explicit patterns of co-occurrence be seen as evidence for evolutionarily important ecological interactions. In North America, the Pileated Woodpecker (pephilus . Likewisractions .Buteo jamaicensis) and Buffy-crowned Wood-Partridge (Dendrortyx leucophrys) in the same stable community within the biogeographically-constrained data. Our analyses show these taxa are largely found in similar areas of Costa Rica; however, in a continental context, it is clear these taxa are not part of a community, as B. jamaicensis is a widespread North American taxon that becomes increasingly montane as one moves south, and D. leucophrys is exclusively montane in southern North America [B. jamaicensis, never truly belong to any given community of species, but rather that they are able to exploit ecological niches that overlap with a variety of different species’ pools and reside within a species’ geographically accessible niche space [For the most part, we find stable community composition in regionally unique habitats that differ from the surrounding geographic matrix, such as the montane highlands or the northern Caribbean lowlands . These r America . Microha America . It is the space .Chlorostilbon mellisugus) and the Garden Emerald (C. assimilis)), lacked the differences in niche similarity between different classifications of community. Neutral theory, wherein species can colonize and move freely about a matrix, may therefore be more informative in certain contexts for differentiating communities assembled only through overlapping ecological niches at coarse scales [The existence of stable and diffuse communities within our Costa Rican dataset, and the fact that the proportions of these communities in a biologically relevant subset of our data are indiscernible from random subsets of the data, illustrate the danger in treating co-occurring organisms as a community. While ecological interactions do exist and are extremely important for species at the local  level, these interactions are somewhat mutable, such that even the classic mixed-species flocks of the Neotropical lowlands are perhaps better considered a character of specific taxonomic groups rather than stable and defined communities that exist across a broad swath of territory. The role of ecology in bolstering the illusion of community cohesion is reinforced by the significance of ecological niche differences within the neutral dataset, but not within the biogeographically-constrained dataset. Neutral models, which allowed species to occupy all suitable habitats, recovered significant differences between communities, likely because species with similar ecologies were allowed to co-occur more broadly across the study region. Constrained models, which separated ecologically similar, but geographically isolated taxa  incorporate interaction into their inferences or conclusions . Studies5.It is often easy  to consider co-occurring species as a “community” for understanding patterns of richness and for identifying potential ecological interactions. However, it is important to understand that every species within a community may be operating under its own unique and independent biogeographic histories, and that communities may simply be a human construct to understand coincidental spatiotemporal co-occurrence. Using our case study of the Costa Rican avifauna, we empirically demonstrate that apparent community cohesion drawn from co-occurrence can also be explained by ecological niche similarity between non-interacting taxa, a pattern that is even more prominent when viewed through a neutral biogeographic lens. Our study underscores the importance of classical ecological studies within co-occurring taxa to truly understand which taxa possess ecological interactions of the magnitude classically associated with ecological communities.Supplementary Material