Gastrointestinal tumors are the most common cancers with the highest morbidity and mortality worldwide. Surgery accompanied by chemotherapy, radiotherapy and targeted therapy remains the first option for gastrointestinal tumors. However, poor specificity for tumor cells of these postoperative treatments often leads to severe side effects and poor prognosis. Tumor immunotherapy, including checkpoint blockade and tumor vaccines, has developed rapidly in recent years, showing good curative effects and minimal side effects in the treatment of gastrointestinal tumors. National Comprehensive Cancer Network guidelines recommend tumor immunotherapy as part of the treatment of gastrointestinal tumors. However, the heterogeneity of tumor cells, complicacy of the tumor microenvironment and poor tumor immunogenicity hamper the effectiveness of tumor immunotherapy. Hydrogels, defined as three-dimensional, hydrophilic, and water-insoluble polymeric networks, could significantly improve the overall response rate of immunotherapy due to their superior drug loading efficacy, controlled release and drug codelivery ability. In this article, we briefly describe the research progress made in recent years on hydrogel delivery systems in immunotherapy for gastrointestinal tumors and discuss the potential future application prospects and challenges to provide a reference for the clinical application of hydrogels in tumor immunotherapy. In the hydrogel delivery system, OPBP-1 exerts good blocking activity against PD-1/PD-L1 in vitro and antitumor activity in vivo. Moreover, oral administration of TMC hydrogel can greatly increase the penetration of polypeptide drugs into the gut, thereby increasing their oral bioavailability. These results indicate that anti-proteolytic PD-1/PD-L1 polypeptide inhibitors can be administered orally in the treatment of gastrointestinal tumors, which opens up new prospects for the development of oral drugs in tumor immunotherapy.Based on clinical trials, PD-1/PD-L1 inhibitors have an effective rate of 80% against lymphoma and 60% against high-microsatellite instability (MSIH) neoplasms, and efficacy for other solid tumors ranges from 10% to 30%  is an immune checkpoint transmembrane protein expressed on T cells. Antigen presentation is prevented by CTLA-4’s ability to compete with CD28 for B7 molecules (CD80 and CD86) on APCs, resulting in the disruption of T-cell activation and proliferation  is a type of antitumor immunotherapy that is extremely attractive for its intelligence and patient-specific approach  are a novel type of immune antitumor therapy that uses genetic engineering technology to modify T cells of patients, express CAR molecules on their surfaces, and then transfuse them into patients . Nevertheless, only a few patients with specific neoplasms have responded favorably to immunotherapy to date  cells, MDSCs and tumor-associated macrophages (TAMs), to restrain antitumor immune responses  and adjuvants, which reactivate the immune system’s response to tumor cells and produce persistent antitumor efficacy. Tumor vaccines have shown inspiring potential in tumor immunotherapy by enhancing antitumor immunity that lasts for a long time. However, there are still a number of limitations for cancer vaccines, such as neoantigen discernment, low immunogenicity, and weak immune reaction  are emerging as promising and potential anticancer therapeutic agents  is a potentially powerful therapy that combines both conventional chemotherapy and present immunotherapy methods to suppress tumor growth, metastasis, and reappearance Emens, . In thisWang et al.  developeCurrently, for late-stage cancers with distant metastases, chemoimmunotherapy with reduced systemic toxicity and strong efficacy is essential. Several "cocktail" formulations have been reported that combine chemotherapeutics inducing immunogenic cell death (ICD) with immune adjuvants and alginate to induce localized chemoimmunization therapy  and photodynamic therapy (PDT), as two main strategies of phototherapy, have been widely investigated for their efficient local tumor clearance in a spatiotemporally controllable manner and have received much attention in the therapeutic application of gastrointestinal tumors. The method of photothermal therapy involves irradiating materials such as near-infrared (NIR) light that are highly photothermal convertible with light to kill cancer cells without invasive procedures, which causes a local thermal effect at the tumor site (Fan et al., Unlike PTT, photodynamic therapy kills tumors by producing cytotoxic ROS in cooperation with light irradiation, photosensitizer and tissue oxygen (Crous & Abrahamse, Wu et al.  designedIn conclusion, hydrogels have natural advantages in simulating the cell microenvironment due to their hydrophilicity. Most polymers can be modified with photoresponsive groups, and then a variety of light reactions occur under light irradiation. Therefore, many materials can be prepared by adding photoresponsive groups that can play an important role in gastrointestinal tumor immunotherapy.9.Therapeutic advances in tumor immunotherapy have rapidly developed in the past several years, reflecting the importance of the interaction between the human immune system and malignant tumorigenesis. Despite the successful application of tumor immunotherapy across a broad range of human cancers, only a minority of patients with gastrointestinal tumors received durable overall survival from these therapies. Hydrogels have emerged as a new research direction in recent years for antitumor drug delivery because of their unique characteristics, providing a prospecting treatment strategy for gastrointestinal tumors. Researchers are also designing matrix materials to endow gel with different chemical and physical properties so it can adapt to different environments following surgery, and by using encapsulated therapeutic agents, radiotherapy/chemotherapy, photothermal therapy, immunotherapy and other strategies to combat tumors are realized. In particular, hydrogels combining immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines have the potential to not only activate the immune system and prevent metastasis from spreading throughout the body but also prevent local recurrence, which may be an important trend of future application (Ishikawa et al., In view of the low response rate and potential irAEs of ICIs such as PD-1/PD-L1 in the treatment of gastrointestinal tumors. The hydrogel system can boost the host’s immune system against tumors and strengthen the effect of immunotherapy. Diverse immunomodulatory agent combinations have been established, as well as local delivery of dual or multiple immunomodulatory cargoes. In addition, in different tumor models, immunotherapeutic cargo combinations in hydrogel systems resulted in significantly heightened antitumor immune responses, especially ICI antibodies, with conventional antitumor approaches.Different from previous research ideas, the unique nature of hydrogels makes it easy to administer drugs by direct injection and creates a short-term inflammatory niche in vivo to enhance the expansion and activation of CAR-T cells and significantly improve the efficacy of treating solid tumors in mice. These hydrogels utilize highly scalable chemicals that can be modulated under moderate circumstances to easily encapsulate CAR-T cells and cytokines without modifying the cargo.Using the characteristics of hydrogels can improve the mild and transient immune response of the host. We can also design hydrogels with different environmental sensitivities and improve immunogenicity by combining the effects of immunogenic cell death induced by chemotherapy drugs. Therefore, the hydrogel system can be used not only as a slow-release system for chemotherapy but also as a carrier for cancer vaccines. It can not only reduce the toxicity and side effects of conventional chemotherapy but also enhance the antitumor effect of tumor vaccines.Despite the immense prospect of hydrogel-based delivery systems for antitumor immunotherapy, there are still some shortcomings in the development of a hydrogel drug delivery system to treat gastrointestinal tumors. First, most hydrogel drug delivery systems use in vivo testing on subcutaneous ectopic tumors, and further experiments in in situ tumor models are needed to investigate efficacy in vivo. Second, there are no long-term safety reports on the hydrogel system in vivo. Finally, hydrogel drug delivery systems are complex, and they are difficult to manufacture in large quantities or control their quality, so further optimization is needed.


Anti-reflux procedures have become a mainstay in managing gastroesophageal reflux disease (GERD) and hiatal hernia. Unfortunately, post-operative events such as breakdown of the wrap, downward slippage, or transdiaphragmatic herniation of an intact wrap cause these procedures to fail and create complications such as recurrent hiatal hernia and reflux dysphagia, regurgitation, and obstruction requiring revision surgery. We discuss a case of a rotational retro-esophageal herniation of the gastric body through a Nissen fundoplication presenting as obstruction, dysphagia, and regurgitation, highlighting the peculiar nature of this presentation and the ease of misdiagnosis given its rarity. Laparoscopic Nissen fundoplication is one of the most common anti-reflux procedures for surgical management of gastroesophageal reflux disease (GERD) and hiatal hernia. However, published failure rates vary widely, ranging from 3-30%, and these patients often require revision surgeries . AnatomiA 54-year-old male with hiatal hernia and medically refractory GERD underwent an uncomplicated laparoscopic Nissen fundoplication and was asymptomatic for four months. He then presented with a two-week history of sudden onset of epigastric pain, dysphagia, and intermittent regurgitation of food. These symptoms gradually worsened over two weeks until he presented to a healthcare institution where a computer tomography (CT) scan demonstrated an air/fluid collection underneath the left hepatic lobe, immediately lateral and to the right to the wrap Figure . The preOn arrival, the patient was hemodynamically stable and in no acute distress. His pain had improved slightly after the drain placement, but he still reported an inability to tolerate oral intake. His physical examination was significant for tenderness in the epigastric region but was otherwise unremarkable. His white blood cell count, hemoglobin level, and electrolytes were all within normal limits. We reviewed the imaging, suspecting that this was not an abscess but the stomach's body that had rotated axially behind the esophagus. We took the patient to the operating room, where, via a laparoscopic approach, we elevated the left lobe of the liver and noted that the transhepatic drain was entering a large bubble of the stomach. This part of the stomach was the gastric body rotated behind the wrap into a subhepatic position to the right of the wrap. The stomach was dissected entirely off the underside of the liver, and we removed the percutaneous drain clearly visualized on the esophagogastroduodenoscopy (EGD) Figure  before tThis case highlights an uncommon complication of the Nissen fundoplication. We identified a rotational retro-esophageal herniation of the gastric body, which acted essentially as an internal hernia, resulting in gastric body distension and functional gastroesophageal obstruction. This complication has not been well documented in the literature. Consequently, there is limited guidance regarding the presentation and management. In 2007, Morgenthal et al. published a case of a 73-year-old female who experienced eight months of nausea and vomiting after her laparoscopic Nissen fundoplication . She theLong-term post-fundoplication complications which result in recurrent reflux, dysphagia, and regurgitation occur in up to 30% of patients . Some auToupet fundoplication was previously thought to have an increased rate of GERD symptom recurrence compared to Nissen fundoplication -10. TherClinicians should consider uncommon presentations of common complications from anti-reflux procedures when patients present with dysphagia, poor oral intake, or increased GERD symptoms. Workup should be thorough and include anatomic and physiologic testing, maximizing the probability of obtaining the correct diagnosis and providing appropriate treatment.


Drosophila melanogaster is a highly tractable animal model to study various human diseases [Drosophila. Drosophila has a relatively short life span and produces a large number of progenies, allowing researchers to perform rapid experiments that can easily be reproduced, allowing reliable statistical analyses of biological data. In addition, there are fewer ethical concerns when using Drosophila for biomedical research compared to mammalian models. Importantly, sophisticated genetic experiments can be designed to answer complicated biological questions, and many mutants and transgenic lines are readily available from the public stock centers. As a result, this model system is now being actively used not only to studying in vivo functions of human disease-related genes, but also to screen and evaluate candidate substances for therapeutic research.The fruit fly diseases . Many bihttps://www.mdpi.com/journal/ijms/special_issues/Drosophila_Human_Diseases, accessed on 5 April 2022) which showcased specific examples or gave a general overview of the value of using Drosophila models to study a wide variety of human diseases. The diseases covered in the first volume include Alzheimer’s disease, epileptic encephalopathy, autism spectrum disorders, phosphoribosyl pyrophosphate synthetase (PRPS)-associated disorders, the transcription and nucleotide excision repair factor TFIIH-related diseases, central nervous system disorders associated with glial defects, multi sex combs (mxc)-associated lymphoma and alcohol use disorder. The second volume of this special edition  further expands this list to cover other human diseases and disorders, such as oral cancer in relation to noncoding microRNA (miRNA), obesity, maturity-onset diabetes of the young type 2 (MODY-2), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT) and infectious diseases through eight additional articles as summarized below.The first volume of this special edition included 11 manuscripts  human cell lines to study the roles of miRNAs in pathophysiology of oral cancer. They found that both Drosophila and human miRNA-31 (miR-31) regulates expression of wntless, a regulator of Wnt signaling pathway that has been linked to tumorigenesis and progression of various tumors [Drosophila models can be utilized to identify and characterize the functions of specific long noncoding RNAs (lncRNAs) related to neurological disorders [Drosophila obesity model to study the effect of Gomisin N (GN), a lignin derived from Schisandra chinensis [Drosophila, suggesting GN as a potential agent to prevent or treat obesity. In the third study, Mascolo et al. generated a fly model of MODY-2, a rare human disorder caused by pathogenic variants in glucokinase (GCK). By knocking down the fly homologs of GCK, the authors found that this manipulation leads to genomic instability, likely caused by reactive oxygen species production triggered by advanced glycation end-products [Three research articles published in this volume showcase that s tumors . This hyhinensis . The flyproducts . The autDrosophila biologists that significantly deepened our mechanistic understanding of various neurological disorders. PD is a common neurodegenerative disorder that is characterized by the progressive degeneration of dopaminergic neurons. α-Synuclein (αSyn) plays a major role in the pathogenesis of PD. Suzuki et al. summarized novel insights obtained through recent studies using various Drosophila PD models overexpressing human αSyn [Drosophila PD models and that majority of PD likely result from complex interaction of multiple genetic factors and αSyn. αSyn-expressing Drosophila PD models have been particularly useful in studying the function of a number of risk genes that have been identified in PD and their relationship with αSyn. Further characterization of these genes would be important to better understand the molecular pathophysiology of PD.Three of the five review articles published in this volume highlights seminal contributions made by man αSyn . The autDrosophila CMT models, covering molecules associated with mitochondria, endosomes/lysosomes, tRNA, axonal transport, and glucose metabolism [Drosophila CMT models, genetic interaction studies performed using these models are now advancing CMT research. Especially, Drosophila studies are beginning to provide molecular insights into phenotypic heterogeneity in CMT, elucidating potential genes and mechanisms that alter the characteristics of the disease presentation such as affected sites and age of onset, progression rate, and duration of disease. Similar phenotypic heterogeneity is also observed in patients with ALS, a progressive and devasting neurodegenerative disease. Identification of cellular mechanisms underlying heterogeneity of these and other disorders is important, since they could provide potential targets for the development of preventive or therapeutic strategies. Epigenetic regulation and its disruption may be one of such mechanisms that serve as important factors, dictating the initiation and/or progression in CMT and ALS. Yamaguchi et al. summarized pioneering studies using Drosophila models that linked ALS and CMT to epigenetic regulation associated with post-translational histone modifications and noncoding RNAs [Drosophila models reveal the importance of obtaining information from noncoding regions of the genome, recommending patients and clinicians to gain access to other types of genetic testing tools such as whole-genome sequencing for deeper understanding of the pathophysiology of both these disorders. Indeed, the authors discuss that genetic approaches using Drosophila models identified several epigenetic regulators as important modifiers of phenotypes seen in ALS and CMT model flies. Further characterization of these factors in relation to these diseases would be an important future direction, not only for ALS and CMT research but also for studies related to other types of neurological and neurodegenerative disorders.CMT is a type of inherited peripheral neuropathy, displaying slow progressing muscle weakness and sensory loss in a distal dominant pattern. More than 100 genes related to CMT have been identified so far. Kitani-Morii and Noto summarized recent insights obtained from studying tabolism . Taking ing RNAs . Whole-eDrosophila strains to overexpress pathogenic proteins produced by viruses and bacteria to elucidate host-pathogen interactions in vivo [Drosophila, insights into how pathogenic proteins alter these pathways have been investigated in vivo using Drosophila models, especially over the past decade. Notably, these studies often result in unexpected findings, revealing that certain pathogenic proteins alters biological pathways that were initially thought be unrelated. Furthermore, the authors discuss how expression of a single or multiple pathogenic protein(s) in Drosophila has allowed researchers to determine which host proteins mediate the effect of certain pathogenic factors, providing useful information to shed light onto disease mechanisms. Furthermore, expression of variant forms of pathogenic proteins allows quick and efficient evaluation of evolving pathogens such as the Zika virus and SARS-CoV-2. In addition, Drosophila models for infectious diseases can be used to screen and evaluate the efficacy of small compounds for therapy of infectious diseases.The recent COVID-19 pandemic has increased the importance of studying infectious diseases. In a comprehensive review article published in this volume, Harnish et al. introduced studies that used transgenic Drosophila, a sensitive in vivo genotoxicity test called the somatic mutation and recombination test (SMART) or wing spot test has been developed. In this article, the authors describe the principle of the SMART assay and summarize its application to various health-related industries [Drosophila are also being actively explored and adopted. For instance, many companies all over the world now provide outsourcing services in generating transgenic flies and gene knockout/knockin strains by offering microinjection and genome editing services in Drosophila. Some companies perform screening and evaluation of candidate drugs and bioactive substances using wild-type or various human disease Drosophila models. Cooperations and collaborations that cross-pollinate scientific community, medical society and industry provide exciting opportunities to greatly advance biomedical sciences [In the final review article in this volume, Pitchakarn et al. discuss the utility of flies as a ‘living test tube’ to rapidly screen for potential mutagens and carcinogens. In dustries . The SMAsciences .Drosophila in human disease research has been exponentially increasing, especially over the past two decades. In addition to elucidating fundamental mechanisms of conserved biological pathways involved in both rare and common diseases, Drosophila researchers are making breakthroughs in translational and clinical research. Excitingly, this is happening not only in academia but also in biotech and pharmaceutical industries. We hope the 19 articles featured in the first and second volume of our special edition of International Journal of Molecular Sciences provide the readership of this journal with exciting examples of Drosophila research that are making major contributions to human disease research. We look forward to the third volume of this special edition, which will likely reveal and highlight additional medical disciplines that benefit from utilization of Drosophila in research and development.In summary, the role of


Vaccination shows high variability in the elicited immuneresponsesamong individuals and populations for reasons still poorly understood.An increasing number of studies is supporting the evidence that gutmicrobiota, along with other interplaying variables, is able to modulateboth humoral and cellular responses to infection and vaccination.Importantly, vaccine immunogenicity is often suboptimal at the extremesof age and also in low- and middle-income countries (LMICs), wherethe microbiota is believed to have an important role on immune responses.Still, contrasting findings and lack of causal evidence are callingfor sophisticated methodologies to be able to overcome scientificand technical challenges to better decipher the immunomodulatory roleof microbiota. In this perspective, we briefly review the status ofthe vaccine field in relation to the microbiome and offer possiblescientific approaches to better understand the impact of the hostmicrobiome on vaccine responsiveness. Vaccine-induced antibody levels havesignificant variability between individuals conjugate vaccines). Cellular immune responses are also affected,as demonstrated by the ∼100-fold variability in cytokine responseelicited by the Bacille Calmette-Guerin (BCG) vaccination for tuberculosis.4 Importantly, vaccine immunogenicity is mainly impaired in populationsat the highest risk for disease, including vaccine recipients in low-and middle-income countries (LMICs),5 infants,6 and elderly.7 Manyfactors influence the immune response to a specific vaccine,3 including schedule, intrinsic host factors , perinatal factors ,and extrinsic factors . In addition, environmentalfactors ,behavioral factors , and nutritional factors  also influencehow individuals respond to vaccines. Understanding the influence ofthese variables on vaccine responses and designing new interventionsto strengthen the immune system’s response to vaccines is ofthe utmost importance.Vaccinations havehad an unparalleled impact on global health.3 and over the course of life.8 The microbiota also varies between different populationsat different geographic locals and on different diets.9 These are important factors modulating the immune responsesto vaccination.10 The makeup of the microbiotahas been correlated with the vaccination outcome and with other factorssuch as age, diet, metabolism, and chronic infection.11 The microbiota of humans contains many times more genesthan host-encoded genes,12 and the gastrointestinaltract is the largest reservoir for microbes, the so-called “secondgenome”. The microbial community of the host has been shownto be critical in shaping physiology and immune responses,15 regulating autoimmunity and allergy,19 preventing HIV infection,20 and modulating anti-PD1 cancer immunotherapy.21 While most of the evidence in support of themicrobiome’s impact on response to vaccination comes from workin mouse models, several observational clinical cohort and interventionalstudies have investigated, with conflicting findings, the possibilitythat gut microbiota can modulate immune responses to vaccination.8 The possible role of microbiota in modulating immune responses tovaccinations is of particular concern in LMICs, where extensive useof antibiotics in neonates and infants can cause long lasting microbiotachanges.22Evidenceindicates that the gut microbiota is variable between individuals26 Immune responses to oral vaccines and oral polio vaccines (OPVs))are lower in LMICs when compared with high-income countries, and thereforethese interventions have been the focus of many studies investigatingthe role of microbiota in modulating immune responses. Of note, infantstudies in Ghana23 and Pakistan24 reported a significant association between thefecal microbiota and the response to ORVs. Harris et al. reporteda nested case-control study showing that microbiome composition ofGhanian infants was different between ORV responders and nonresponders.23 The microbiota of Ghanaian responders was morelike that of Dutch infants who were assumed to respond well to vaccinations.In this study, an increased relative abundance of Streptococcusbovis was significantly correlated with an enhanced responseto vaccination, whereas the relative abundance of Bacteroides and Prevotella species were negatively correlated.23 In a similar study conducted in Pakistan, theORV response was correlated with a higher relative abundance of bacteriabelonging to Clostridium cluster XI and Proteobacteria.24 Both studies reported an increased ratio of Enterobacteriaceae to Bacteroides speciesin vaccine responders. In contrast, other studies in infants in bothIndia and Nicaragua did not find any significant associations betweenthe fecal microbiota and responses to ORVs.28 However, in these latter two studies, the authors speculated thatinfants might have harbored a microbiota that was inhibitory to rotavirusvaccine replication. As for OPV, a study in China found that the relativeabundance of Bifidobacterium in the infant fecalmicrobiota was correlated with increased poliovirus-specific IgA responses.25 By contrast, another study conducted in infantsin India29 did not find any significantdifferences in the relative abundances of specific taxa between respondersand nonresponders to OPV. Enteric viruses were shown to have a greaterimpact on OPV response than the bacterial microbiota, with recententerovirus infections having a greater inhibitory effect than persistentinfections, a finding that suggested a possible role also for thehost virome. Interestingly, in both studies,29 greater microbiota diversity was associated with poor vaccinationresponses, but it is also possible that this is only a marker of exposureto enteric infections. In a prospective observational study, the relativeabundance of Bifidobacterium in early infancy hasalso been found to be significantly associated with CD4+ T cell and antibody responses to several parenteral vaccines assessedat 2 years of age,26 indicating that anincrease in the abundance of Bifidobacterium mayenhance the protective efficacy of vaccines and suggesting that microbiotamight also modulate responses to nonorally administered vaccines.Interestingly, a unique immunomodulatory role for Bifidobacteria has been evidenced in regulating the response to checkpoint inhibitorimmunotherapy in mice, which could suggest a potential role for thisbacterium also in regulating vaccine responses.51Associationsbetween infant microbiota and vaccine responsiveness have been reportedin several observational clinical studies.30 Interestingly, as in the Ghanian infant study on responseto ORVs conducted by the same group,23 anincrease in the ratio of Enterobacteriaceae to Bacteroides in vaccinatedadults was associated with enhanced IgA boosting.30 However, the same study also reported that antibioticsdid not affect either the pneumococcal polysaccharide (no adjuvant)or the adjuvanted tetanus toxoid responses.30 An investigation targeting Indian infants showed that antibioticsdid not improve the immunogenicity of OPV, despite reducing biomarkersof enteropathy and pathogenic intestinal bacteria.31An increasing numberof conflicting observational and interventional studies have investigatedthe role of antibiotic-driven perturbations of the gut microbiotain vaccine responses. In Dutch adults, narrow-spectrum but not broad-spectrumantibiotics, administered to reduce bacterial-derived enteropathyassociated with impaired oral vaccine immunogenicity, resulted inmore effective day-7 antirotavirus IgA boosting. An increased proportionof volunteers with more than a 2-fold increase in anti-rotavirus IgAtiter and enhanced ORV antigen shedding was interpreted as an indicationof better replication and response to vaccination.13 Broadspectrum antibiotics were administered to groups of healthy youngadults before and after vaccination. The antibiotics resulted in asignificant reduction in gut bacterial numbers and diversity but hadno significant impact on antibody responses. Importantly, these subjectshad pre-existing humoral immunity with high influenza-specific microneutralizingantibody titers before vaccination. Remarkably, analysis of the vaccineresponses in a second trial of subjects with low pre-existing antibodytiters revealed a significant impairment in both neutralizing andbinding antibodies. Antibiotic treatment led to a significant reductionin the IgG1 and IgA antibody response toward the H1N1 strain as wellas to a decrease in the antibody neutralization to the same strain.This finding suggests that microbiota immunomodulation of adaptiveresponse to vaccination is playing a minor role in the presence ofpre-existing humoral immunity. Interestingly, the impairment in IgG1and IgA responses was only observed against one of the three influenzastrains contained in the vaccine, the H1N1 strain, and not againstthe H3N2 or B strains. This outcome was hypothesized to be relatedto different prior exposure to the different influenza strains, whichcould lead to a different threshold of memory responses.22Remarkably, a systems vaccinology approach has beenrecently used to comprehensively assess the impact of broad-spectrumantibiotics on the innate and adaptive immune response to tetravalentinactivated influenza vaccination.32 a result indicating the possibility that long-termusage of antibiotics may lead to a chronic stage of low-grade inflammationand contribute to the pathogenesis of age-associated diseases. Antibioticadministration also led to divergent metabolic trajectories, highlycorrelated with immune signaling. Among other changes, a reductionin bile acids, such as lithocholic acid (LCA), was observed.13 Given the role of secondary bile acids in suppressinginflammation, a potential mechanism by which the microbiota can regulatesecondary bile acid production, and consequently, inflammatory responsesin humans affecting therefore vaccine response could be envisioned.22In addition to influencing the adaptiveresponse, the analysisof transcriptional signatures revealed that treatment with antibioticsled to altered innate immune responses. Several gene expression programsassociated with transcription factors playing key roles in inflammatoryresponses were up-regulated under antibiotic treatment. Interestingly,the same transcriptional modules were increased in healthy elderlysubjects immunized with the seasonal influenza vaccine,34 Probiotics, microorganisms introducedinto the body for their beneficial qualities, have been effectivelyused to prevent important diseases such as necrotizing enterocolitis35 and acute diarrhea.36 Synbiotics, mixtures of probiotics and prebiotics , have shown to be able to prevent sepsis amonginfants in rural India37 and to improveefficacy of oral cholera vaccination in a mouse model of childhoodundernutrition.38 However, studies of probioticimpact on boosting vaccine responses in infants and adults have reportedvariable results . This result was shown to be dependent on multiple variablesincluding the immunizing antigen, the strain of probiotic and thegeographical region of the study. Unfortunately, most of the studiesreported so far have important limitations that do not allow for directcomparison and there are no real generalizations of results that canbe made. These limits include sample size, differences in the probioticstrains investigated, and the administration schedule. Finally, thelack of studies directly focusing on participants with already disruptedmicrobiota who are those most likely to receive benefit is anothercomplicating variable.39Interventionstudies targeting possible alterations of the microbiota, such asdiet, prebiotics, probiotics, symbiotics, fecal microbiota transplant(FMT), and small-molecule drugs, are increasingly being conducted.Research suggests that modulating the microbiota may not only improvesymptoms but also can have a significant effect on reducing life-threatingdisease, such as for the prevention of sepsis and necrotizing enterocolitisin infants.44 and vaccination.45 Germ-free (GF) and/or antibiotic-treatedanimals are often used to study the effect of the microbiota on thedevelopment and homeostasis of the host immune system and on the immuneresponse to the vaccination.46 In one study,both antibiotic-treated and GF mice showed enhanced IgG and IgA responsesto an orally administered mouse rotavirus strain.40 In contrast, following immunization with ovalbumin, germ-freepups as well as pups born to antibiotic-treated dams showed reducedIgG responses when compared to immunized microbiota-competent controls.However, these differences were modest and depended upon the immunizationschedule.45 In another study, the responseto nonadjuvanted influenza vaccine was found to be impaired in GF,antibiotic-treated, and Toll-like receptor 5 (Tlr5)-deficient mice,15 suggesting that TLR5-mediated sensing of flagellinproduced by the microbiota could act as a natural adjuvant for nonadjuvantedvaccines.Numerous investigations have demonstrateda role for microbiota in modulating immune responses to both infection14 Dams were exposed to antibioticsprenatally. As a result of maternal treatment, antigen-specific IgGresponses to live attenuated BCG and four adjuvanted vaccines in youngmice were found to be significantly impaired.14More recently, age has been shown to be particularlyrelevant to vaccine responses, reinforcing the concept that microbiota-dependentimmunomodulatory effects may be more important in the early stagesof life.4 including (1) the natural adjuvant hypothesis, i.e., theability of microbiota-associated immunomodulatory molecules, suchas flagellin15 and peptidoglycan,47 to modulate vaccine responses by stimulatingpattern recognition receptors (PRRs) on antigen-presenting cells (APCs),such as toll-like receptors (TLRs)15 andNOD2;47 (2) microbiota-induced antigenpresentation by DCs,49 such as the regulation of typeI INF expression by plasmacytoid DCs (pDCs), which can instruct aspecific metabolic and epigenomic state in conventional DCs (cDCs)enhancing T cell priming;49 (3) immuneactivation by microbiota-derived metabolites, such as short-chainfatty acids (SCFAs), which have been shown to increase B cell metabolismto support antibody production and to increase expression of genesinvolved in class switching and plasma cell differentiation;43 and (4) microbiota-derived B cell and T cellepitopes, which could potentially cross-react with pathogen-encodedepitopes and alter the responses to vaccination.4 Potential redundancies between these and other commensal-dependentpathways and the context-dependent role of specific microbiota compositioncomplicate the study of microbiota-dependent immunomodulatory mechanismsof action.Overall, the mechanisms by which the microbiota modulate immuneresponses to vaccination are not well understood, but it is safe toassume that different pathways are acting contemporaneously. Severalimmunoregulatory mechanisms have been proposed,Several complicatingfactors may explain the current lack of criticalknowledge regarding the microbiota-dependent immunomodulation of vaccineresponses. While sophisticated mechanistic studies in mice have demonstratedthe impact of microbiota on both physiology and pathology, their relevancein humans is unclear with most evidence coming from correlative studies.Causal evidence for the role of the microbiota in modulating humanphysiology and susceptibility to disease is still scarce and hamperedby scientific and technical challenges. We report below some of thecurrent challenges in this field and comment on possible actions toenable a better understanding of the role of microbiota in the responseto vaccination 1.52 A critical “windowof opportunity” exists in early childhood where the microbiotacould have a major effect on the modulation of vaccine responses.Impaired responses to five licensed infant vaccines was reported ininfant, but not adult, mice when exposed to antibiotics.14Vaccine immunogenicity is often suboptimalin populations at high risk for acquiring infectious diseases, includingneonates, infants, elderly, and LMICs regions. The evolution of themicrobiome in newborns coincides with a crucial maturation periodfor the immune system. Since the earliest stages of life coincidewith the time the first vaccinations are given, it is highly probablethat during this period the imprinting of the microbiota can havesignificant long-term and permanent effects on the development ofimmune responses.53 Furthermore, a greater impact of microbiota on antibody responsesin humans with low levels of pre-existing immunity has been observed,13 suggesting a more pronounced immunomodulatoryrole with the priming doses of vaccines administered at less than6 months of age, rather than on booster responses.Previous findings have also shown theimportance of a “weaning reaction” to microbiota forimmune ontogeny and to reduced susceptibility to colitis, allergicinflammation, and cancer later in life.24 Nevertheless, most of the antibiotic-based interventional investigationsperformed so far have assessed the impact of antibiotics on vaccineresponses in adults and were limited by a small sample size and ashort time window between antibiotic-treatment and vaccine administration.4 LMICs are also a target of great interest, aswidespread use of antibiotics in these populations, mainly neonatesand infants, is associated with long lasting microbiota changes whichcould affect the immune development and the response to vaccination.22 The composition of the gut microbiota is highlyvariable between individuals, particularly between Westernized andnon-Westernized populations and high-income countries (HICs) vs LMICs.Given the differences in the microbiota, it is foreseeable to conceivethat a commensal/probiotic beneficial in infants in HICs will nothave the same effect in LMICs. Therefore, well-powered randomizedcontrolled trials are needed to evaluate the beneficial effects ofmicrobiota in modulating the response to vaccination in these targetpopulations.Associationsbetween the infant microbiota and responses to vaccinationhave been reported in several observational clinical studies.11 Several studies that aimed to assess the impact of the microbiomeon vaccine response have been conducted in geographically differentpopulations, as in LMICs and HICs, with different microbiome compositions.30 Furthermore, the administration of antibiotics before vaccinationcan generate potential off-target effects, which could impact theimmune responses and influence the interpretation of the study.30The microbiota is only one of the interdependent determinants associatedwith the magnitude of vaccine responses. Other factors, includinggenetic and environmental variables , shape the physiological state of individualsand their response to antigen stimulation.54 Next generationsequencing (NGS) approaches , used to characterize the microbiota composition,can be integrated with advanced immunological profiling  by systemsbiology approaches to better correlate the influence of the intestinalmicrobiome on vaccine responses. Given the complexity of this interaction,systems-level integrated studies can help identify microbiota-associatedmolecular and cellular signatures associated with protective immunity.This complexity calls for a sophisticatedsystems vaccinology approach to define the microbiota-dependent cellularand molecular changes that occur in response to vaccination. Systemsvaccinology, i.e., the application of systems biology methods to analyzevaccine responses, has emerged with the need to integrate large setsof data coming from new high-throughput technologies using mathematicaland computational modeling. Systems vaccinology approaches have delivereduseful information about adjuvants and innate immunity, and they areundoubtedly necessary to help disentangle the complexity of microbiota-immuneresponse interactions.100 (3) the developmentof robust signatures of protective immune responses capable of predictingvaccine efficacy in clinical settings; and (4) the need to translatethe data generated into meaningful understanding about the mechanismsof microbiota-induced immune regulation to vaccine responses. Achievingthese capabilities require fruitful collaborations between scientistswith different expertise .55Some current limitations need to be overcome to fully exploit thepotential of system vaccinology. Several areas require attention including(1) the identification of predictors of immune responses in tissues,(2) challenges that face current proteomic technologies such as complexsample preparation, reproducibility, limited dynamic range, and detectionof post-translational modifications;26 Identifying clinically relevant microbial taxawith immunomodulatory potential will be essential to prove the causalrelationship and to elucidate mechanisms of action. In this regard,the application of newer sequencing technologies, such as shotgunmetagenomics, which comprehensively sample all genes in all organismspresent in a given complex sample, could allow for higher resolutionup to species- and strain-specific levels.4 This is quite relevant as the ability of microbes to induce similarimmunophenotypes is unrelated to their phylogeny, with distant phylacapable of inducing similar immunomodulatory effects while differentspecies from the same genus can induce opposing ones.56An increasing number of observational studiesin infants have acknowledged associations between specific commensalphyla and families with immune responses to vaccination.57 including the identification of commensals responsiblefor the intestinal immune system development,59 and are essential to explore how host–microbe interactionsmodulate vaccine responses.60 Our lab haspreviously characterized the immunomodulatory effects of over 60 differenthuman gut-derived bacteria.56 Germ-free(GF) mice were monocolonized with a commensal microbe followed byimmunoprofiling and microarray analysis of the immune system. Mostmicrobes exerted several specialized, complementary, and redundanttranscriptional and immunomodulatory effects which were, remarkably,independent of microbial phylogeny. Similar studies could pave theway for the analysis of microbiota-vaccine response interplay usingmicrobiota samples of clinical relevance. Causal relationships betweenmicrobiota and vaccine responses could be established by transferringselected human microbiota (HMB) to GF mice for mechanistic evaluationand screening of immunomodulatory taxa. After mono- or selected-colonizationof GF mice with HMB, extensive and unrestricted immunophenotypingand transcriptomics, as were previously performed56 before and after vaccination, could lead to key informationregarding the immunomodulatory roles of key identified taxa. Ultimately,one could evaluate if the selected immunomodulatory taxa are ableto also elicit an immunomodulatory role in the specific-pathogen free(SPF) setting. Although the use of GF or selected-microbiota modelsdoes not fully represent the complex interactions that occur withinthe microbiota-competent environment of conventional mice, this deconvolutionis necessary to control complexity and interdependency of additionalvariables  associated with the immune response.Gnotobiotic models, including GF and antibiotic-treatedmice, have provided key insights on the microbiota-immune system interplay,Further efforts are needed to understandthe microbiome-immuneinteraction and how this influences vaccine response. Although thegut microbiota is known to modulate both B cell and T cell responsesto vaccination, additional work is necessary to move from correlationto causation by defining clinically relevant microbiota-dependentimmunomodulatory mechanisms. Areas for improvement include 1: (1) de


The COVID-19 pandemic spread between neighboring countries through land, water, and air travel. Since May 2020, ministries of health for the Democratic Republic of the Congo, Tanzania, and Uganda have sought to clarify population movement patterns to improve their disease surveillance and pandemic response efforts. Ministry of Health–led teams completed focus group discussions with participatory mapping using country-adapted Population Connectivity Across Borders toolkits. They analyzed the qualitative and spatial data to prioritize locations for enhanced COVID-19 surveillance, community outreach, and cross-border collaboration. Each country employed varying toolkit strategies, but all countries applied the results to adapt their national and binational communicable disease response strategies during the pandemic, although the Democratic Republic of the Congo used only the raw data rather than generating datasets and digitized products. This 3-country comparison highlights how governments create preparedness and response strategies adapted to their unique sociocultural and cross-border dynamics to strengthen global health security. Border health systems are structured to prevent, detect, and respond to and mitigate the effects of public health events among mobile populations, notably those traveling across international boundaries  provides less data for analysis and decision making. Scientists and public health practitioners continue to advance the use of social media and mobile phone data to understand mobility (The US Centers for Disease Control and Prevention (CDC) developed the Population Connectivity Across Borders (PopCAB) toolkit as a resource for governments and other stakeholders to gather and analyze data about population mobility to inform public health interventions (The Democratic Republic of the Congo (DRC), Tanzania, and Uganda ministry of health (MOH) offices sought to develop COVID-19 border health surveillance and mitigation measures better adapted to their unique community connectivity and population mobility patterns . LOIs represented origins, destinations, or locations along domestic and international travel routes, such as markets, health facilities, border towns, or transit towns. In the visualization phase, the team used the data from the characterization phase to identify, analyze, and visualize population movement and connectivity patterns by creating maps and narrative reports that illustrated population movement with respect to the LOI. Finally, the team used the application phase to adapt and improve programs and strategies with the results. Teams repeated these phases to address evolving public health needs, ensuring that they regularly identified opportunities to share experiences and develop plans to improve adapted materials and implementation approaches.We compared the approaches that teams used to design and implement PopCAB. We compared, by country and PopCAB phase, details about the implementation timelines, team compositions, project goals, priority geographic areas or population groups of interest, data collection strategies, analytic approaches, and the application of results. To consolidate information for the comparative analysis, we gathered qualitative, quantitative, and spatial data from project implementation materials and outputs and qualitative data from discussions with the teams. Here, we intend to present a broad overview of PopCAB results from each country, rather than specific details.During May 2020–March 2022, teams implemented 94 PopCAB events to inform COVID-19 response measures at binational, national, and local government and POE levels : 8 in DRThe national MOH port health director (in Tanzania and DRC) or border health focal point (in Uganda) led the PopCAB teams; their overall goal was to gather information about cross-border movement and community connectivity to inform border health strategies ,3,4. EacThe teams implemented their PopCAB activities over 2 years of the COVID-19 response . DRC levAcross these events, the teams in all 3 countries implemented PopCAB to address a few consistent objectives. One focused on a priority to adapt strategies for surveillance and risk communication at POEs and POCs to limit the spread of COVID-19 across international and domestic administrative boundaries. A second aimed to enhance public health benefit and judicious use of resources for surveillance and community outreach by identifying and prioritizing specific geographic areas visited by cross-border travelers. A third consistent objective was to prioritize secondary travel routes and areas of interest for mobile populations, including formal and informal POEs, health facilities, and community areas, for enhanced staff training and surveillance. The teams also implemented PopCAB to inform cross-border collaboration. Unique objectives included understanding the influence of COVID-19 lockdown measures on cross-border population movement in Uganda and addressing human activity associated with livestock husbandry in Tanzania.All teams implemented PopCAB events at national and community levels in administrative areas along international borders and in their countries’ large urban areas, e.g., Kinshasa, Dar es Salaam, and Kasese. DRC and Uganda also implemented events specifically at POEs; DRC implemented all their community-level events at POEs.The teams invited various stakeholders to participate in PopCAB events, including security officers, truck drivers, traditional healers, village health volunteers, sex workers, and pastoralists . These gThe countries’ teams developed narratives and reports that listed all the LOIs and routes. The reports also described themes from the informal qualitative analyses completed by those who directly conducted the discussions or recorded notes. For example, these reports provided details about cross-border travel patterns to seek care from traditional healers, travel routes community members took when seeking healthcare to conceal residence status, or routes to avoid lockdown policies. The teams included photos of the annotated base maps and photos of participants during the events.Each team followed a different approach to managing and analyzing the gathered information. The DRC team completed detailed reports rapidly, within 1 week, after each PopCAB event; however, they did not develop qualitative or spatial datasets of LOIs or routes for future visualizations and analyses. They took this approach because they intended to focus on applying results immediately after the discussions and their staff availability to process and manage the data over time was limited. The Tanzania team developed detailed FGD transcripts after each event to facilitate their ability to integrate and analyze results across multiple PopCAB activities. They also developed, in collaboration with CDC, summary tables listing all annotated LOIs. The Tanzania team worked closely with CDC team members on qualitative data analysis, use of geographic information systems, and cartography to learn new skills in analyzing the qualitative data and geocoding the LOIs. These dedicated data management and analysis efforts led to detailed, formal spatial datasets of the LOIs and routes and initial qualitative thematic analyses. Although a compiled report from each event or group of events took longer to create, the team could use those results to develop improved visualizations for already-defined and future program goals.The Uganda team focused on developing detailed FGD and KII transcripts after each event, along with detailed summary tables of all mentioned and annotated LOIs and travel routes. This process was supported by dedicated team members who had expertise in qualitative and spatial data management. The team analyzed the qualitative data for themes about reasons and routes for movement. The spatial analysts and cartographers geocoded the results, building robust spatial datasets of >1,000 unique LOIs and routes. The team also combined the results with other data-gathering initiatives completed by partners on the team, including Infectious Diseases Institute and Baylor Uganda, to characterize cross-border healthcare-seeking behaviors.The data management approaches of Tanzania and Uganda led to the ability to develop more broadly effective reports and presentations. They were able to include visualizations to address various MOH objectives identified during the preparation phase or newly identified during pandemic response initiatives.All teams used PopCAB results to adapt national, district, and POE-level policies, programs, and resource allocation plans . All teaThe teams implemented various contextually-specific initiatives using the results to address consistent and unique objectives. The DRC MOH used PopCAB results from FGDs in and around Kinshasa to identify 3 urban locations for new mobile COVID-19 surveillance to increase the ability to detect illness at key traveler congregation points. In addition, the DRC MOH maintained a plan to routinely conduct PopCAB in Kinshasa to guide when and where to adjust the locations of those mobile urban surveillance sites. They also rapidly applied results to extend operating hours for certain POEs to accommodate unique movement patterns identified through the FGDs.The Tanzania Port Health unit identified areas for increased engagement with village committees and security authorities to strengthen border health surveillance. As part of that effort, they identified community health workers in areas with increased cross-border connectivity in Dar es Salaam and Tanga Provinces and provided them with additional training on event-based surveillance. The MOH also used the data to select high-traffic locations where they enhanced community outreach and installed handwashing stations.District-level officials in Uganda on the Tanzania border worked with owners of nighttime bars visited by persons from across the border to increase COVID-19 surveillance. The Uganda team also identified mobile phone market vendors that serve cross-border communities to support them in distributing COVID-19 risk communication materials to high-priority population groups. Along that border and the western border with DRC, the Uganda team applied results to identify schools and markets preferred by cross-border communities for enhanced risk communication in preparation for and during the COVID-19 response lockdown. Like Tanzania, Uganda also applied results to identify village health volunteers who worked in areas with increased cross-border connectivity, including those along routes used by persons fleeing conflict from DRC into Uganda, for prioritized refresher training on community-based surveillance.All of the teams applied the results from the binational PopCAB events during cross-border meetings to prioritize official and unofficial POEs and other LOIs along travel routes across their shared borders for enhanced risk communication and traveler surveillance. They also prioritized groups of contiguous administrative areas in cross-border surveillance zones for more robust and sustained collaboration and information sharing.Throughout the COVID-19 pandemic, the DRC, Tanzania, and Uganda MOHs, in collaboration with CDC and other partners, adapted bilateral, national, and local-level strategies to their complex, cross-border sociocultural contexts by gathering and analyzing community-level information on population movement patterns. Although the countries’ MOHs developed implementation goals and plans independently, all 3 followed consistent approaches for developing multisectoral collaboration for participation and applying the results. However, they differed in the intensity of data management and analysis methods, reflecting varying availability of resources including staff time and expertise. Those unique analytic approaches influenced the magnitude of tabulations of locations and routes and qualitative analytical results compiled in formal datasets. Regardless of the depth of analyses, the countries, each with unique COVID-19 epidemiology, border health and public health policies and infrastructure, and cross-border dynamics, provide various examples of ways to incorporate population mobility, a key driver of communicable disease spread, into mitigation measures. Despite differences in data compilation and analysis, their approaches highlight opportunities to achieve impacts across varying staff and financial commitments for creating qualitative and spatial databases.The teams’ experiences revealed challenges with implementing PopCAB overall and during a pandemic. Although the resources needed to implement any one PopCAB event is low, requiring only field travel support and person-time from the implementers and participants to complete the 1.5-hour event in addition to a printed map and supplies such as markers, pens, and paper, leadership had to secure additional funding and person-time to train staff on the toolkit and to process the gathered data. In addition, the teams had to adhere to COVID-19 mitigation measures preventing in-person trainings and field events at different times throughout the pandemic. To address these considerations, the teams designed and employed online training techniques. They also ensured that previously-trained staff participated in subsequent PopCAB implementation over the 2 years with minimal refresher training, introducing a few new staff at a time rather than entirely new field teams. The teams also adjusted field-based protocols to incorporate COVID-19 mitigation measures during FGDs and KIIs, including physical distancing, with only the facilitator annotating the maps, and use of cloth face coverings. Also, highlighted by the DRC MOH’s approach, teams adjusted expectations for data processing and analyses to accommodate the available resources.The teams were not able to attribute trends in COVID-19 epidemiology in their countries to changes they made to mitigation measures and policies using PopCAB data because of the complexity of SARS-CoV-2 translocation among mobile populations and difficulty differentiating travel-associated spread from domestic transmission. However, national MOH leadership overseeing these PopCAB activities expressed confidence that their interventions more appropriately supported their communities because they were adapted to the unique, multisectoral and sociocultural environments and were designed through community-engagement efforts. In addition, district-level leadership participated in the initiatives ensuring continuity of these efforts in local programming and resource allocation decisions.The 3 governments in East and Central Africa implemented community-engagement efforts using the PopCAB toolkit following various staff-time and data management approaches over 2 years of the pandemic to design COVID-19 mitigation strategies. More specifically, they adjusted public and border health policies and programming to address formal and informal cross-border movement patterns, to enhance surveillance and capacity building at newly identified community-based locations and healthcare facilities, and to strengthen cross-border collaboration between neighboring countries. Those MOH-led, community-based initiatives can complement other analytic methods using existing travel and mobility data to incorporate community dynamics more accurately in border health and other preparedness and response strategies for COVID-19 and other communicable diseases. Furthermore, the MOHs can continue to apply the results to other public health goals, including broader outbreak preparedness strategies and cross-border collaboration priorities. Their experiences reveal options government leadership can follow to integrate population mobility and sociocultural factors into public health preparedness and response strategies.


BackgroundAlthough 8-10% of pediatric residents pursue a career in Pediatric Hospital Medicine (PHM), many report an incomplete understanding of PHM careers and would benefit from a PHM elective.MethodologyWe followed Kern’s six-step curriculum development framework. A general needs assessment via literature review revealed a lack of published PHM elective curricula. A targeted needs assessment was conducted by surveying national PHM fellowship program directors, national PHM fellows, local junior PHM attendings, and local pediatric residents. Content analysis from these surveys was used to develop a PHM resident elective curriculum. The curriculum was implemented and evaluated through an experience log and written reflections.ResultsNeeds assessment surveys were completed by fellowship directors , fellows , attendings , and residents . Common themes included the importance of academic experiences, mentorship, non-teaching and non-inpatient clinical experiences, community hospital experience, and the desire to address knowledge gaps. Significant variability in survey responses suggested the importance of an individualized curriculum. Goals, objectives, and aligned educational strategies were developed to provide a breadth of clinical experiences, mentorship, and PHM-focused academic activities, with an emphasis on individualization. Implementation of the curriculum began in July 2021 and four residents enrolled in 2021-2022. The curricular evaluation demonstrated the achievement of objectives and improved resident awareness of PHM opportunities, clinical skill development, ancillary shadowing, and academic opportunities.ConclusionsA PHM resident elective was developed using Kern’s six-step approach with input from national fellows and fellowship program directors to address educational gaps and increase exposure to PHM careers. The next steps include the evaluation of the impact of the PHM elective on career choice and preparedness of residents. Over the last 20 years, the field of Pediatric Hospital Medicine (PHM) has been steadily growing and evolving. Historically, outpatient pediatricians followed their patients both in and out of the hospital ; howeverThe ACGME requires that pediatric residents spend a minimum of 10 months on inpatient care, with at least five months dedicated specifically to inpatient general medicine and subspeciality rotations to learn the practice of hospital medicine . HoweverA PHM residency elective offers the opportunity to educate residents about a hospitalist career and expose them to hospital medicine fellows and attendings. At our 300-bed academic free-standing children’s hospital, a PHM resident elective existed previously; however, it was under-utilized (between zero and two residents enrolled yearly) and not inclusive of new PHM fellowship opportunities. National trends in PHM elective curricula within residency programs are unknown, the current literature lacks any recently published PHM elective curriculum, and the curricula that do exist likely vary widely given the recent developments in the field of hospital medicine.There is also minimal data about new hospitalists or fellow perspectives on PHM resident electives, though studies have examined areas of perceived deficits and strengths in training and career preparedness. One study found that while most new hospitalists feel that residency provided adequate clinical skills and communication training, quality improvement (QI) methods and administration duties are areas of inadequate training . Early cPublished literature on PHM resident elective curriculum development is scarce. Indiana University created a PHM elective and shared their curriculum material on MedEdPortal in 2009 ; howeverThis article was previously presented in part as a meeting abstract at the Central Group on Educational Affairs Association of American Medical Colleges virtual regional meeting (March 2022).We followed Kern’s six-step approach to curriculum development: (1) General needs assessment; (2) targeted needs assessment; (3) goals and objectives; (4) educational strategies; (5) implementation; and (6) evaluation and feedback. A general needs assessment was performed through a literature review, which revealed a lack of published PHM elective curriculum models. This study was approved with a waiver of consent by our local institutional review board (IRB #2021-4442).Targeted needs assessmentA targeted needs assessment was conducted by surveying categorical pediatric residents at a single academic institution, pediatric hospitalists in their first or second year of post-residency practice  at the same institution, national PHM fellows, and national PHM fellowship program directors in May 2021. This group of respondents was chosen to investigate and contrast the opinions among individuals with different levels of training in the field of PHM. All local categorical pediatric residents (PGY 1-3) were included to elicit opinions on what residents consider generally important in electives, as well as specifically in a PHM elective. Local junior attendings (one to two years post-residency) were surveyed to capture the opinions of those who are still transitioning into the role of attending. Only junior attendings who did not complete a PHM fellowship were included, allowing them to provide insight regarding gaps in their pediatric residency training that a PHM elective may have filled to better prepare them for their role as an attending. As part of the junior hospitalist survey, participants were asked if they would like to be involved with the PHM elective  as a means of recruitment for faculty participation in the elective. Although more senior attendings (greater than two years post-residency) were not surveyed due to concern regarding their recall accuracy in identifying early-career knowledge and skill gaps; they were later recruited for mentorship participation in the elective (see “curriculum development and implementation” below). National PHM fellows were surveyed to elicit opinions on what elective experiences would increase preparedness for PHM fellowship. Finally, national PHM fellowship program directors were surveyed to elicit insight about what leaders in the field of PHM believe should be included in PHM electives to prepare trainees for PHM fellowship and data on what PHM elective curriculums currently exist at institutions nationally.Local pediatric residents, local junior hospitalists, and national PHM program directors were contacted by email for recruitment, with a follow-up reminder email sent two weeks later. National PHM fellows were contacted via the PHM fellows group chat using the application WhatsApp. Email scripts and a scripted WhatsApp message contained an electronic link to one of four surveys. Participation was voluntary and participants were free to opt-out of the study at any time. All survey answers were completely anonymous.Statistical analysisAll four surveys were completed using the software Qualtrics. Descriptive statistics examined the frequencies and percentages for categorical variables, including demographic information, existing elective knowledge/details, and ideal elective logistics. Average results for impact on elective choice, preferences in elective experiences, and preferences for learning modality were calculated. For specific elective experience and learning modality preferences, respondents indicated their top four (ranked) priorities; for analysis, the first ranked (top) priority was given a score of four, and the fourth (lowest) priority was given a score of one; those not indicated as a priority were given a score of zero. Differences between groups were assessed using analysis of variance for normally distributed outcomes and Kruskal-Wallis tests for non-normal outcomes. A p-value of <0.05 was assigned to denote significance. Qualitative data from free-response questions were analyzed for major themes by two investigators using content analysis. All analyses were completed using SAS version 9.4 .Curriculum development and implementationGoals, objectives, and aligned educational strategies Tables , 2 were Descriptive data from the surveySurveys were completed by pediatric residents , junior hospitalists 10/26, 38%), PHM fellows , and PHM fellowship program directors . Most program directors who completed the survey  reported the existence of a PHM elective at their institution, with the majority reporting either zero to three  or four to six 3/22, 14%) yearly participants  resident respondents did not know an elective was offered at their institution Table . There wTargeted needs assessment based on survey responsesResidents, hospitalists, and fellows all reported that addressing gaps in knowledge was the main motivation in selecting a PHM elective, followed by networking and maintaining quality of life during the elective Table . There wResidents, hospitalists, and fellows preferred additional non-teaching inpatient general medicine clinical experience , whereas program directors prioritized clinical experience on an inpatient teaching service to prepare trainees for PHM fellowship Table . CommuniThere was a significant difference among respondent groups in the value placed on hospitalist (p < 0.001) and PHM fellow (p = 0.023) mentorship, with fellows and program directors prioritizing these opportunities Table . There wDesign of PHM curriculum goals, objectives, and educational strategiesCurriculum goals were developed to focus on addressing major themes from the general and targeted needs assessments Table . ObjectiImplementationImplementation of the PHM resident elective curriculum began as a pilot program in July, 2021. Four residents completed the elective for the academic year 2021-2022. Notably, no residents had enrolled in the previously offered PHM resident elective for the academic year 2020-2021.Evaluation and feedbackEvaluation of the curriculum is ongoing via an experience log and written reflection form Figures , 2. FourThe four PHM resident elective participants also completed a written reflection Figure  to evaluAn individualized PHM resident elective was developed using Kern’s six-step approach with input from national PHM fellows and program directors, as well as local residents and hospitalists. Although our needs assessment revealed the existence of PHM elective curricula at multiple institutions nationally, only one PHM elective from 2009 was published . Our curLimitationsThis study was limited by a low response rate to the survey-based needs assessment across all categories. The response rate was the lowest among residents, likely reflecting participation by those most interested in pursuing a PHM elective and/or career. Similarly, pilot implementation and curriculum evaluation included a small sample size, which limits the generalizability of the results; however, the number of residents in the pilot is consistent with national trends in the typical number of yearly PHM elective participants, and the initial findings support a continuation of this work. While resident participants achieved the curricular objectives and reported a satisfactory experience, possible implications of the elective experience on educational outcomes  and career choices  require future evaluation.Next stepsThe PHM resident elective will continue recruiting and enrolling residents and soliciting feedback on the curriculum. Using ongoing elective evaluation in the form of an experience log and written reflection, the curriculum will continue undergoing modifications to ensure it meets the educational needs of trainees. Further investigation is required to assess the longer-term impacts of a PHM resident elective on career choice and preparedness.While specific experiences may differ between institutions, this new PHM elective was designed with sound curricular methodology and input from national PHM fellows and leaders via targeted needs assessment, which increases its generalizability. The curricular framework can be piloted at other academic institutions, with the tailoring of experiences based on minor institutional variations. The investigators aim to support the implementation of this curriculum at other institutions, with the goal of further improving the experience based on ongoing feedback from a larger number of participants.


By providing detailed information on actual glucose fluxes in vivo, proof-of-concept studies have illustrated the potential  application of dynamic stable isotope techniques to define biochemical and clinical phenotypes of inherited metabolic diseases associated with hypoglycemia. According to the textbooks, individuals with glycogen storage disease type I (GSD I) display the most severe hypoglycemia/fasting intolerance. In this review, three dynamic methods are discussed which may be considered during both diagnostic work-up and monitoring of children with hypoglycemia: 1) functional in vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope techniques. Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.Hypoglycemia results from an imbalance between glucose entering the blood compartment and glucose demand, caused by a defect in the mechanisms regulating postprandial glucose homeostasis. Hypoglycemia represents one of the most common metabolic emergencies in childhood, potentially leading to serious neurologic sequelae, including death. Therefore, appropriate investigation of its specific etiology is paramount to provide adequate diagnosis, specific therapy and prevent its recurrence. In the absence of critical samples for biochemical studies, etiological assessment of children with hypoglycemia may include dynamic methods, such as  Appropriate investigation of the etiology and simultaneous management in children with hypoglycemia is paramount to prevent (irreversible) brain injury or even death , althougMultiple metabolic pathways cooperate to maintain normal blood glucose concentrations in the fed and fasted state, such as glycogenolysis, gluconeogenesis, mitochondrial fatty acid oxidation, ketogenesis and ketolysis, ensuring energy homeostasis. These pathways are tightly regulated by hormonal  and autonomic  responses  to maintCompared to adults, children are at an increased risk of developing hypoglycemia, as they have smaller hepatic glycogen and muscle protein stores, together with an increased energy expenditure and higher brain/body weight ratio . ConsequThe most used diagnostic approach to childhood hypoglycemia consists of pattern recognition by combining a variety of information, including medical history , physical examination , and laboratory tests. If critical samples (i.e. samples collected during metabolic stress) of plasma and urine can be obtained, static or single-point concentrations of biomarkers  can provide crucial information to establish an etiological diagnosis . When crin vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope tracing, focusing on glycogen storage disease type I (GSD I). Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.In this narrative review, we illustrate several dynamic methods which may be considered in the diagnostic work-up and monitoring of children with hypoglycemia. Three methods are presented: 1) functional in vivo tests have been used for the etiological clarification of fasting intolerance, unexplained hypoglycemia, and to diagnose specific IMDs  tests can be found elsewhere  or an IMD (n=15) in a group of 138 patients undergoing fasting studies . Bappal in vivo functional tests have the advantage of triggering metabolic stress in a supervised setting, they are burdensome and inconvenient for young patients and their parents. If IMDs are not yet excluded, these tests can cause serious complications in unexperienced hands . Therefore, psychological burden due to unexpected hypoglycemia for patients and their families should be balanced against the stress and risks associated with in vivo functional testing. Additionally, in vivo functional tests pose a significant organizational and logistical burden  by including several samples to be collected at specific time points , under strictly supervised conditions, and requiring hospital admission.Although in vivo functional tests have fallen into disuse. A few tests are nowadays even abandoned and considered obsolete , introduction of expanded population newborn screening, and implementation of next-generation sequencing. Still, some functional in vivo tests -with slight modifications - may be useful to provide phenotypic information to support genetic variant classification, or to define outcome in clinical trials. In such situations, these tests remain the major (monitoring) methods allowing the assessment of metabolic changes in vivo in response to external factors . In addition, controlled fasting test may guide the diagnostic process in suspected congenital hyperinsulinism when critical samples are not available   , 33.Via an enzymatic technology (glucose oxidase), the sensor generates an electric current proportional to the glucose concentration in the interstitium. The electric current flows through a continuously shifting algorithm to generate a glucose value which is eventually transmitted to the receiver (receiving unit or compatible smartphone). The algorithm is finetuned via calibration by patient or factory to ensure accuracy over the recording periods (Continuous glucose monitoring (CGM) constitutes another dynamic method in the diagnostic work-up and monitoring of children with hypoglycemia. Progress has been made since CGM was firstly described in 1979 for a patient with insulinoma . Modern  periods . Major aCurrently, CGM devices are only licensed for patients with diabetes mellitus (DM), for whom CGM-related outcome parameters  are defined to guide dietary changes and/or medication adjustments . AdditioA significant correlation between CGM values and capillary glucose values has been found in patients with GSD I , 46. CGMFor patients with ketotic fasting intolerance , parallel documentation of point-of-care capillary beta-hydroxybutyrate (BHB) concentrations by a portable ketone meter may provide important additional information. To the best of our knowledge, reference values for capillary BHB during the day are not available in the pediatric population, but information on BHB normal values after overnight fasting can be extrapolated from historical publications Table 4.in vivo metabolic profiling  may replace the historical approach in patients suspected with hepatic GSDs. Such approach will likely further decrease the use of diagnostic in vivo fasting tests. Indeed, the combination of information collected through different testing approaches will likely represent the future strategy to characterize childhood hypoglycemia, including both the diagnostic and monitoring phase. Additional factors  may result in variations in local practice, even between specialized centers.Currently, only the BHB meters can be used for minimally invasive home monitoring to guide dietary management after a working diagnosis has been established. To our opinion, the combination of real-time CGM with alarm function and a portable ketone meter may be used in children undergoing parallel diagnostic and therapeutic metabolic profiling for hypoglycemic disorders  is metabolically indistinguishable from the tracee . Ideally2H2]-glucose, or D-[1-2H]- galactose) or a carbon isotope . Since tracer loss without net conversion to product, that may be due to recycling (for example in case of recycling of D-[2-2H2]-glucose by conversion of glucose-6-phosphate to fructose-6-phosphate and back), may occur at specific metabolic steps, appropriate selection of the tracer is crucial for accurate analysis  represents endogenous glucose production (EGP) in the absence of an additional input of glucose. Moreover, at this steady state Ra equals the rate of glucose disposal (Rd). Experimentally, Ra is estimated during a continuous infusion of a solution of labeled glucose from the measured dilution of stable isotope labeled glucose (for example D-[U-13C]-glucose) in the pool of plasma glucose at isotopic steady state. In general, the rate of infusion of labeled glucose (I) cannot be neglected in comparison with Ra. Therefore, during a stable isotope tracer infusion experiment the total rate of appearance of glucose (Rt) into the circulation is considered as, the sum of Ra and I: Rt = Ra + I = Rd. At isotopic steady state, the Rt can be calculated from the dilution of infused labelled glucose in the plasma glucose pool, as the ratio of fractional isotopologue enrichment of infusate over the fractional isotopologue enrichment of blood glucose, multiplied with the infusion rate. When D-[U-13C]-glucose, with 6 13C carbon atoms, is applied as a glucose label a can be calculated as: For glucose metabolism during fasting, at biological steady state the rate of appearance of glucose into the circulation (R)−1)∗I. .However, there are situations in which additional variables play a role and in which tracer enrichment can vary (non-steady state). For example, inflow of glucose  or hormonal response  drives glucose through different compartments before entering (and possibly re-entering) the bloodstream. Such complex conditions can still be simplified to a single-compartment model by including a pool volume of the total blood glucose pool and the changes in the [tracer]/([tracer]+[tracee]) enrichments over time in the calculations . Still, in vivo dynamics of glucose metabolism and conditions associated with hypoglycemia. As previously mentioned, Ra and Rd are the key variables when performing tracer studies. For blood glucose, Ra reflects the EGP in fasted conditions in the absence of any exogenous input -glycerol intravenous infusion   secondarinfusion ] were noeveloped .As the liver accounts for ∼80% of EGP (with the rest accounted for mainly by the kidneys), a particular interest has developed to assess glucose kinetics with stable isotopes tracers in IMDs in which hypoglycemia is mainly due to the enzyme defect in the liver. A detailed report on the use of stable isotope methodology in IMDs goes beyond the scope of the present work [see for a review ]. SpecifFlux analysis in a mouse model of medium chain acyl-CoA dehydrogenase deficiency (MCADD) has shown that pharmacological inhibition of mitochondrial fatty acid oxidation does not affect EGP . InsuffiG6PC1) or in the microsomal glucose 6-phosphate transporter  cause GSD Ia and GSD Ib, respectively. Impaired glycogenolysis and gluconeogenesis result in fasting intolerance with hypoglycemia, elevated lactate, metabolic acidosis and secondary metabolic derangements. Uncooked cornstarch (UCCS) or extended-release cornstarch (Glycosade®) and/or continuous gastric drip-feeding is the cornerstone of the treatment  and eventually genetic confirmation . Howeverin vivo tests have the advantage of characterizing metabolic pathways, such as glycogenolysis, gluconeogenesis, mitochondrial fatty acid oxidation, ketogenesis, and ketolysis, in a dynamic fashion. Yet, their use is progressively decreasing. Therefore, we do not recommend performing such tests in unexperienced centers. Several functional in vivo tests  are currently designed to monitor management after novel, innovative treatments  in centers of expertise. Fasting test may still play a role in the diagnostic process of congenital hyperinsulinism. Yet, the development of safer and simpler diagnostic and monitoring tools for clinical research/care remains a compelling need  monitor glucose levels in a dynamic fashion in patients with hypoglycemia –41, 45. in vivo dynamics of hypoglycemia from a pathophysiological perspective. In principle, this may prevent a late diagnosis in patients presenting with milder phenotypes  conception and design of the study and/or analysis and interpretation of data, and (b) revising the article critically for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All authors confirm the absence of previous similar or simultaneous publications. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a past co-collaboration with the authors.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Although the manifestation of trauma in the body is a phenomenon well-endorsed by clinicians and traumatized individuals, the neurobiological underpinnings of this manifestation remain unclear. The notion of somatic sensory processing, which encompasses vestibular and somatosensory processing and relates to the sensory systems concerned with how the physical body exists in and relates to physical space, is introduced as a major contributor to overall regulatory, social-emotional, and self-referential functioning. From a phylogenetically and ontogenetically informed perspective, trauma-related symptomology is conceptualized to be grounded in brainstem-level somatic sensory processing dysfunction and its cascading influences on physiological arousal modulation, affect regulation, and higher-order capacities. Lastly, we introduce a novel hierarchical model bridging somatic sensory processes with limbic and neocortical mechanisms regulating an individual’s emotional experience and sense of a relational, agentive self. This model provides a working framework for the neurobiologically informed assessment and treatment of trauma-related conditions from a somatic sensory processing perspective. Sensoryironment . This alnication .somatic (vestibular and somatosensory) senses given their direct relevance to the physical body, their positions of phylogenetic and ontogenetic primacy, and the major roles they play in attenuating and orchestrating our multisensory experience in the present moment. Somatic sensory processing is hypothesized to give rise to adequate and efficient processing of interoceptive and exteroceptive  sensory information. The overall aim of this review is to offer a transdisciplinary, neuroscientifically informed perspective of how somatic sensory processing contributes to trauma-related symptomology. We review (1) an overview of the vestibular and somatosensory systems; (2) phylogenetic and ontogenetic development of the somatic sensory systems; (3) the neurobiology of sensory processing as mediated by the periaqueductal gray; (4) trauma as an assault on the senses; (5) somatic sensory contributions to the sense of self after trauma; and (6) what neuroscience can teach us about connecting somatic sensory processing and trauma-related disorders.Here, we introduce a neurobiologically informed perspective from which to view trauma-based conditions considering how sensory processing contributes to an organism’s ability to regulate physiological arousal, emotions, and actions . SpecifiThe vestibular system, comprised of angular motion-detecting semicircular canals and linear motion-detecting otolith organs in the inner ear, informs us of three-dimensional head acceleration as a function of the linear pull of gravity . It is aVestibular stimulation occurs when crystals and fluid are displaced in the otoliths and semicircular canals, respectively, sending signals to the vestibular nuclei via the pontomedullary junction  or the fOriginally thought as solely involved in balance and oculomotor processes, vestibular projections are now known to be multifaceted in their influences given their widespread innervation of the brain and body  and theiVestibular input purportedly modulates and manages sensory integrative processes by balancing sensory signals in response to internal and external environmental demands . This moAlthough the vestibular system’s unusually widespread influences on the brain support the notion that it contributes toward cognitive and emotional processes in health and disease , its conThe somatosensory system is comprised of the skin, muscles, and joints which detect light touch, deep pressure, pain, temperature, and proprioceptive input. The somatosensory system contributes toward both interoceptive and exteroceptive processing due to its perception of stimuli originating inside and outside of the body, impacting higher order awareness of the physiological state of the body and the immediate external environment, respectively . TactileTouch is detected through specialized cutaneous mechanoreceptors  and can Affective touch is experienced through the activation of low-threshold tactile mechanoreceptors (C-LTMR) which respond preferentially to gentle, stroking, skin-temperature touch on the hairy regions of the skin . UnmyeliWhile tactile receptors provide information about the body’s contact with its environment and others, proprioceptors inform where the physical body is in space. Proprioception is detected through Golgi tendon bodies in the joints and muscle spindle fibers in muscle tissue, and informs of joint position and muscle fiber recruitment . Skin meSeveral somatosensory tracts exist depending on the location and type of input . Non-affSomatosensory information of homeostatic relevance  is conveyed by unmyelinated, phylogenetically older afferent tracts . Pain anGiven its recent discovery as a separate somatosensory phenomenon, the neural pathway taken by affective touch remains speculative. “Most full-grown trees have a remarkable canopy of branches and leaves that interact dynamically with the environment. However, the spreading branches cannot function or survive without the nourishment and support they receive from the roots and trunk. We may appreciate the tree for its spreading leaves, but our understanding must begin with the seed, the roots, and the emerging trunk.”  and interoceptive stimulation  with contextual information regarding safety or potential danger at the level of the midbrain. The direct connections these somatic sensory systems have with brainstem and mesencephalic regions influence a subconscious maintenance of homeostasis and a felt sense of relational security with our surroundings and with others.While subcortical brain regions integrate somatic and exteroceptive sensory information to create a coherent body representation, they are implicated in evolutionarily conserved threat detection and response circuitry  as well Where traumatization is strongly characterized by incapacitated arousal modulation , the senBoth hyper- and hypoarousal are common phenomena in traumatized individuals. Hyperarousal results in heightened sensory and emotional reactivity , and falArousal can be attenuated through rhythmical linear vestibular stimulation , deep toAn optimal baseline level of muscle tonicity, innervated by the vestibulospinal and reticulospinal tracts, allows for adaptive motor actions and responses. Increased muscle tension occurs during states of high stress or fear to prepare the physical body for fighting or fleeing . If an aand nurturing interpersonal contact (The superior colliculi (SC) of the midbrain tectum  are powerful multisensory integrative centers containing layered topographical maps of the visual, auditory, and somatosensory systems . The SC  contact , playing contact . Aberran contact .Taken together, heavy involvement of somatic sensory processing is likely in defensive posturing and motoric responses to traumatic events. Post-traumatically, the somatic sensory systems may prioritize their role of self-protection and defense, superseding their roles in orienting toward social contacts and maintaining a coherent multisensory experience. Further, primal defensive responses may remain online as a person feels “stuck” between an activated (or hypo-activated) autonomic response and the completion of self-protective action . When thThe periaqueductal gray (PAG), a region of gray matter surrounding the cerebral aqueduct of the midbrain, acts as both a sensory relay and a sensory-affective integrative center that coordinates subcortical defense or approach behaviors in light of contextual information . The dorThe PAG is a node of the salience network (SN), an intrinsic connectivity network that activates when presented with unexpected, intense, or instinctually relevant sensory or emotional input . The SN Where a traumatic event poses a perceptual threat to one’s own bodily safety, or that of another, while eliciting feelings of extreme fear, helplessness, or horror , it can Solidity in subcortical somatic sensory integration from a secure attachment history may act as a buffer against long-term ramifications of trauma. An individual with a history of secure attachment during critical developmental periods is better equipped to tolerate sensory and affective stress through fluid bottom-up and top-down integrative information processing and return to a solid baseline functioning post-stressor . HoweverWhen presented with sensory stimulation construed as threatening, less integration or “talking” between neocortical and subcortical regions may result in cortical and subcortical “loops” that take on a life of their own. A subcortical loop from the body to the midbrain and back again short-circuits the frontal regions for efficiency, priming the traumatized individual for rapid defensive responding . Corticosoma generated through somatic sensory integration, exteroceptive input such as bright lights, sudden noises, and unexpected touch can over-activate the SN, disturb the DMN, and throw multisensory integrative balance off kilter  is not very good at denial”  therapy utilizes saccadic eye movements to elicit an innate relaxation response and integrate maladaptively stored trauma memories . AlthougElectroencephalographic (EEG) neurofeedback (NFB) training is a non-invasive technique based on the premise that cognitive and motor function depend upon proper communication of neuronal assemblies organized into constellatory networks . The proFor the traumatized child, play-based approaches inclusive of vestibular and somatosensory feedback and affective interpersonal dynamics invite the clinician into the child’s primordial relational world. The richness of vestibular and somatosensory input in classical childhood games spanning generational and cultural boundaries such as “peek-a-boo,” “hide-and-seek,” and “tag” informs the importance of somatic sensory systems in neurodevelopment and in navigating social relationships. For the traumatized child, engaging in these games within a therapeutic context has the promise of re-organizing brainstem level sensory and affective circuitry. By further exploiting the power of a basic affective motivational (PLAY) system at the level of the PAG , movemenThe importance of mindful movement and proprioceptive feedback to ground the body and attune to its needs has been implicit in yogic tradition for centuries. Trauma-informed yoga practitioners guide clients in tolerating titrated somatic sensation and/or the affective states somatic sensory input can arouse. Additionally, mindful movements and postures support top-down regulation of somatically induced arousal. Trauma-Sensitive Yoga TSY;  is one sFor individuals with severe early life trauma and attachment disruptions, feeling safe within any human relationship may be difficult or impossible. Equine-facilitated psychotherapy (EFP) facilitates attunement to horses , where iExpressive arts therapy, including the therapeutic application of music, dance, theatre, art, and creative writing, is another approach that consistency engages the body through purposeful action . Here, tBoth authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.