Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Integration of Medical Legal Services into a Hospital-Based Violence Intervention Program: A Survey and Interview-Based Provider Needs Assessment.

BACKGROUND: Violent injury among trauma surgery patients is strongly associated with exposure to harmful social determinants of health and negative long-term health outcomes. Medical-legal partnerships in other settings successfully provide patients with legal services to address similar health-harming legal needs and may offer a promising model for the care of violently-injured patients. STUDY DESIGN: An electronic survey tool was distributed to clinicians and staff affiliated with the hospital-based violence intervention program at a single urban level one trauma center. Semi-structured follow up interviews were conducted with participants, and interviews were coded using thematic analysis and grounded theory. RESULTS: Participants reported many health-harming legal needs among their violently injured patients. The most commonly-identified needs were: health insurance denials (62.5%); difficulty accessing crime victims compensation funds (56.3%); trouble accessing official documents (50%); and problems with non-SSDI public benefits (50%). Participants reported inconsistent methods for learning about and responding to patients' health-harming legal needs. The most common barriers to addressing these needs included: lack of awareness that a lawyer could help with the issue (68.8%); prioritization of other needs (68.8%); previous negative legal experiences (62.5%); and cost (62.5%). Identified needs encompass issues traditionally-addressed by MLPs as well as more novel challenges faced by violent injury survivors. CONCLUSION: This survey and interview-based study identifies complex health-harming legal needs present among violently-injured trauma surgery patients. Medical-legal partnerships specially-designed for the setting of violent injury appear well-suited to meet these needs, potentially reducing risk of violent re-injury, long-term negative health outcomes, and healthcare system costs. LEVEL OF EVIDENCE: Level IV / Prognostic and Epidemiological.

Systematic review and meta-analysis of the etiology of heavy menstrual bleeding in 2,770 adolescent females.

BACKGROUND: Adolescent heavy menstrual bleeding(HMB), menorrhagia or abnormal uterine bleeding commonly occur in adolescent women. The differential diagnosis can be challenging. The pneumonic: PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified), is commonly used but it does not stratify as to the likelihood of a disorder. We have sought to develop a probability-based differential diagnosis for Adolescent HMB, menorrhagia or abnormal uterine bleeding. METHODS: A comprehensive literature search was conducted using PubMed, EMBASE, and SCOPUS databases. Case series describing adolescents from 10-19 years of age with HMB, menorrhagia or abnormal uterine bleeding was acceptable if: more than 10 patients were included; editorials, case reports, and secondary sources such as review articles, or book chapters were excluded. No language filter was used, but an English abstract was required. The etiology of HMB, menorrhagia or abnormal uterine bleeding, and the country of origin was extracted from articles that met inclusion criteria. Cumulative rate estimates were determined by Bayesian probability modeling. RESULTS: Seventeen full text articles were reviewed in detail; 2,770 patients were included. The most frequent causes of HMB were Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5%), Coagulation Disorders (19.4%; 95% CredI 17.8-21.1%), and Platelet Disorders (6.23%; 95% CredI 5.27-7.27%) with 45.9% (95% CredI 43.8-47.%9) of the cases of indeterminate origin. CONCLUSIONS: The leading causes of HMB in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of HMB. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of HMB in females, this systematic review assigns probabilities to the etiologies of HMB in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis.

Structural and functional characterization of triketone dioxygenase from Oryza Sativa.

The transgenic expression of rice triketone dioxygenase (TDO; also known as HIS1) can provide protection from triketone herbicides to susceptible dicot crops such as soybean. Triketones are phytotoxic inhibitors of plant hydroxyphenylpyruvate dioxygenases (HPPD). The TDO gene codes for an iron/2-oxoglutarate-dependent oxidoreductase. We obtained an X-ray crystal structure of TDO using SeMet-SAD phasing to 3.16 Å resolution. The structure reveals that TDO possesses a fold like that of Arabidopsis thaliana 2-oxoglutarate­iron-dependent oxygenase anthocyanidin synthase (ANS). Unlike ANS, this TDO structure lacks bound metals or cofactors, and we propose this is because the disordered flexible loop over the active site is sterically constrained from folding properly in the crystal lattice. A combination of mass spectrometry, nuclear magnetic resonance, and enzyme activity studies indicate that rice TDO oxidizes mesotrione in a series of steps; first producing 5-hydroxy-mesotrione and then oxy-mesotrione. Evidence suggests that 5-hydroxy-mesotrione is a much weaker inhibitor of HPPD than mesotrione, and oxy-mesotrione has virtually no inhibitory activity. Of the close homologues which have been tested, only corn and rice TDO have enzymatic activity and the ability to protect plants from mesotrione. Correlating sequence and structure has identified four amino acids necessary for TDO activity. Introducing these four amino acids imparts activity to a mesotrione-inactive TDO-like protein from sorghum, which may expand triketone herbicide resistance in new crop species.

What medical-legal partnerships can do for trauma patients and trauma care.

ABSTRACT: Trauma patients are particularly vulnerable to the impact of preexisting social and legal determinants of health postinjury. Trauma patients have a wide range of legal needs, including housing, employment, debt, insurance coverage, and access to federal and state benefits. Legal support could provide vital assistance to address the social determinants of health for injured patients. Medical legal partnerships (MLPs) embed legal professionals within health care teams to improve health by addressing legal needs that affect health. Medical legal partnerships have a successful track record in oncology, human immunodeficiency virus/acquired immune deficiency syndrome, and pediatrics, but have been little used in trauma. We conducted a scoping review to describe the role of MLPs and their potential to improve health outcomes for patients with traumatic injuries. We found that MLPs use legal remedies to address a variety of social and structural conditions that could affect patient health across several patient populations, such as children with asthma and patients with cancer. Legal intervention can assist patients in obtaining stable and healthy housing, employment opportunities, debt relief, access to public benefits, and immigration assistance. Medical legal partnership structure varies across institutions. In some, MLP lawyers are employed directly by a health care institution. In others, MLPs function as partnerships between a health system and an external legal organization. Medical legal partnerships have been found to reduce hospital readmissions, increase treatment utilization by patients, decrease patient stress levels, and benefit health systems financially. This scoping review outlines the potential of MLPs to improve outcomes for injured patients. Establishing trauma-focused MLPs could be a feasible intervention for trauma centers around the country seeking to improve health outcomes and reduce disparities for injured patients.

Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model.

Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.

Metabolic and bariatric surgery for obesity in Prader Willi syndrome: systematic review and meta-analysis.

Obesity is the leading cause of morbidity and mortality in patients with Prader-Willi Syndrome (PWS). Our objective was to compare changes in body mass index (BMI) after metabolic and bariatric surgery (MBS) for the treatment of obesity (BMI ≥35 kg/m2) in PWS. A systematic review of MBS in PWS was performed using PubMed, Embase, and Cochrane Central, identifying 254 citations. Sixty-seven patients from 22 articles met criteria for inclusion in the meta-analysis. Patients were organized into 3 groups: laparoscopic sleeve gastrectomy (LSG), gastric bypass (GB), and biliopancreatic diversion (BPD). No mortality within 1 year was reported in any of the 3 groups after a primary MBS operation. All groups experienced a significant decrease in BMI at 1 year with a mean reduction in BMI of 14.7 kg/m2 (P < .001). The LSG groups (n = 26) showed significant change from baseline in years 1, 2, and 3 (P value at year 3 = .002) but did not show significance in years 5, 7, and 10. The GB group (n = 10) showed a significant reduction in BMI of 12.1 kg/m2 in the first 2 years (P = .001). The BPD group (n = 28) had a significant reduction in BMI through 7 years with an average reduction of 10.7 kg/m2 (P = .02) at year 7. Individuals with PWS who underwent MBS had significant BMI reduction sustained in the LSG, GB, and BPD groups for 3, 2, and 7 years, respectively. No deaths within 1 year of these primary MBS operations were reported in this study or any other publication.

Association of Adverse Childhood Experiences and Resilience With Obesity, High Blood Pressure, and Parental Report of Behavioral Health Symptoms in Children: A Cross Sectional Study.

The interplay between Adverse Childhood Experiences (ACEs) and resilience on health in children is not well understood. Parents completed 3 questionnaires: ACEs, Child and Youth Resilience Measure (CYRM), and the Pediatric Symptom Checklist-17(PSC-17). BMI and blood pressure were measured. 19.8% of children had 4 or more ACEs, resilience ranged from 25 to 51, 14.3% had a positive PSC-17 score, 25.6% were obese, 3.1% had systolic hypertension, and 1.2% had diastolic hypertension. Higher ACEs (ACE OR: 1.398, 95% CI = 1.044-1.893, P = .026) and lower resilience (Resilience OR: 0.740, 95% CI 0.668-0.812; P = 1.13 × 10-9) were predictive of increased reports of behavioral health symptoms, but not obesity or hypertension. The personal resilience subscale was a predictor of positive PSC-17 score (OR 0.646, 95% CI = 0.546-0.749, P = 3.18 × 10-8); relationship subscale was not. Cultivating resilience, especially personal aspects, may provide an effective intervention for behavioral health symptoms in children.

Law enforcement in the trauma bay: a survey of members of the American Academy for the Surgery of Trauma.

Background: Trauma patients frequently come into contact with law enforcement officers (LEOs) during the course of their medical care, but little is known about how LEO presence affects processes of care. We surveyed members of the American Association for the Surgery of Trauma (AAST) to assess their perspectives on frequency, circumstances, and implications of LEO presence in trauma bays nationwide. Methods: Survey items addressed respondents' experience with the frequency and context of LEO presence and their perspectives on the impact of LEO presence for patients, clinical care, and public safety. Respondent demographics, professional characteristics, and practice setting were collected. The survey was distributed electronically to AAST members in September and October of 2020. Responses were compared by participant age, gender, race, ethnicity, urban versus rural location using χ2 tests. Results: Of 234 respondents, 189 (80.7%) were attending surgeons, 169 (72.2%) identified as white, and 144 (61.5%) as male. 187 respondents (79.9%) observed LEO presence at least weekly. Respondents found LEO presence was most helpful for public safety, followed by clinical care, and then for patients. Older respondents rated LEO presence as helpful more often than younger respondents regarding the impact on patients, clinical care, and public safety (p<0.001 across all domains). When determining LEO access, respondents assessed severity of the patient's condition, the safety of emergency department staff, the safety of LEOs, and a patient's potential role as a threat to public safety. Conclusions: Respondents described a wide range of perspectives on the impact and consequence of LEO in the trauma bay, with little policy to guide interactions. The overlap of law enforcement and healthcare in the trauma bay deserves attention from institutional and professional policymakers to preserve patient safety and autonomy and patient-centered care. Level of evidence: IV, survey study.

Cre-mediated autoexcision of selectable marker genes in soybean, cotton, canola and maize transgenic plants.

KEY MESSAGE: Efficient selectable marker gene autoexcision in transgenic plants of soybean, cotton, canola, and maize is achieved by effective Cre recombinase expression. Selectable marker genes are often required for efficient generation of transgenic plants in plant transformation but are not desired once the transgenic events are obtained. We have developed Cre/loxP autoexcision systems to remove selectable marker genes in soybean, cotton, canola and maize. We tested a set of vectors with diverse promoters and identified promising promoters to drive cre expression for each of the four crops. We evaluated both the efficiency of generating primary transgenic events with low transgene copy numbers, and the frequency of marker-free progeny in the next generation. The best performing vectors gave no obvious decrease in the transformation frequency in each crop and generated homozygous marker-free progeny in the next generation. We found that effective expression of Cre recombinase for marker gene autoexcision can be species dependent. Among the vectors tested, the best autoexcision frequency (41%) in soybean transformation came from using the soybean RSP1 promoter for cre expression. The cre gene expressed by soybean RSP1 promoter with an Arabidopsis AtpE intron delivered the best autoexcision frequency (69%) in cotton transformation. The cre gene expressed by the embryo-specific eUSP88 promoter from Vicia faba conferred the best marker excision frequency (32%) in canola transformation. Finally, the cre gene expressed by the rice CDC45-1 promoter resulted in 44% autoexcision in maize transformation. The Cre/loxP recombinase system enables the generation of selectable marker-free transgenic plants for commercial product development in four agriculturally important crops and provides further improvement opportunities for more specific and better marker excision efficiency.

Law Enforcement and Patient Privacy Among Survivors of Violence: A Nationwide Mixed-Methods Study.

INTRODUCTION: During the emergent treatment of violently injured patients, law enforcement (LE) officers and health care providers frequently interact. Both have duties to protect patient health, rights, and public health, however, the balance of these duties may feel at odds. The purpose of this study is to assess hospital-based violence intervention program (HVIP) representatives' experiences with LE officers among survivors of violence and the impact of hospital policies on interactions with LE officers. MATERIALS AND METHODS: A nationwide survey was distributed to the 35 HVIPs that form the Health Alliance for Violence Intervention. Data regarding respondent affiliation, programs, and perceptions of hospital policies outlining LE activity were collected. Follow-up video interviews were open coded and qualitatively analyzed using grounded theory. RESULTS: Respondents from 32 HVIPs completed the survey (91%), and 22 interviews (63%) were conducted. Common themes from interviews were: police-patient interactions; racism, bias, and victims' treatment as suspects; and training and education. Only 39% of respondents knew that policies existed and were familiar with them. Most representatives believed their hospitals' existing policies were inadequate, ineffective, or biased. Programs that reported good working relationships with LE officers offered insight on how their programs maintain these partnerships and work with LE officers towards a common goal. CONCLUSIONS: Unclear or inadequate policies relating to LE activity may jeopardize the health and privacy of violently injured patients. Primary areas identified for improvement include clarifying and revising hospital policies, education of staff and LE officers, and improved communication between health care providers and LE officers to better protect patient rights.

Health Effects of Policing in Hospitals: a Narrative Review.

IMPORTANCE: Law enforcement activity, in the form of outside agencies or hospital security forces, is increasingly common in American healthcare. Little is known about the potential effects of this prevalent, modifiable exposure on hospital staff and patient health. This narrative review characterizes existing evidence on the direct and indirect health effects of law enforcement activity in hospitals. OBSERVATIONS: Law enforcement activity in hospitals can affect health outcomes through four mechanisms: (1) physical health effects related to workplace violence, restraint use, excessive force, and weapon use; (2) mental health effects involving perceptions of safety and psychological distress; (3) social effects related to the patient-provider relationship, mistrust, and bias and discrimination; and (4) legal and ethical considerations affecting overall well-being. CONCLUSIONS AND RELEVANCE: Unchecked law enforcement activity in hospitals may risk patient physical and mental health, reduce patient trust, result in bias and discrimination, and contribute to legal and ethical rights violations. Importantly, law enforcement activity in hospitals may also contribute to staff perceptions of safety. To fill knowledge gaps on the measurable impact of law enforcement activity in the hospital on staff and patients, hospitals should collect and publicly share robust data on law enforcement activity in their facilities, create and adopt patient-centered policies to ensure safety and protect patient health and privacy, and implement evidence-based interventions that safely reduce law enforcement involvement with patients.

Addressing Legal Needs as Violence Prevention: A National Survey of Legal Services Offered through Hospital-based Violence Intervention Programs.

Hospital-based violence intervention programs (HVIPs) provide comprehensive services to survivors of community violence to address social determinants of health (SDOH) as risks factors for future violence. Medical-legal partnerships (MLPs) integrate lawyers into health care teams to address SDOH through the application of the law. Despite shared purposes, it is unknown if HVIP-MLPs exist. We sought to quantify the existing landscape of legal services provided by HVIPs, identify HVIP-MLPs, and characterize barriers to formation. Surveys and interviews were conducted in 2020 with 35 HVIPs of the Health Alliance for Violence Intervention (HAVI) concerning civil legal services. Most HVIPs screened for civil legal needs though none had an official MLP. Common civil legal needs included housing, mental health, and education. Barriers included no memorandum of understanding, legal confusion, funding, and overwhelming need. In 2021, no HVIP-MLP partnerships existed within HAVI. Establishing HVIP-MLPs may further support survivors of violence and address health inequity.

Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach.

BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. OBJECTIVE AND METHODS: Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. RESULTS: Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. CONCLUSION: This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.

Compounding Trauma: the Intersections of Racism, Law Enforcement, and Injury.

Purpose of Review: Traumatic injury sits at the nexus of law enforcement and structural racism. This narrative review aims to explore the major impacts of law enforcement on health, its intersections with US structural racism, and their joint impacts on traumatic injury and injury care. Recent Findings: Many of the same forces of systemic disadvantage that put Black people, other people of color, and other marginalized groups at risk for violent injury also expose these same individuals and communities to intensive policing. Recent evidence speaks to the broad impact of police exposure and police violence on individual and community physical and mental health. Moreover, injured patients who are exposed to law enforcement during their care are at risk for erosion of trust in and relationships with their healthcare providers. To optimize the role of law enforcement agencies in injury prevention, collaboration across sectors and with communities is essential. Summary: A broad approach to the prevention of injury and violence must incorporate an understanding of the intersecting impacts of law enforcement and structural racism on health and traumatic injury. Clinicians who seek to provide trauma-informed injury care should incorporate an understanding of the role of law enforcement in individual and community health.

Urbanization increases floral specialization of pollinators.

Understanding how urbanization alters functional interactions among pollinators and plants is critically important given increasing anthropogenic land use and declines in pollinator populations. Pollinators often exhibit short-term specialization and visit plants of the same species during one foraging trip. This facilitates plant receipt of conspecific pollen-pollen on a pollinator that is the same species as the plant on which the pollinator was foraging. Conspecific pollen receipt facilitates plant reproductive success and is thus important to plant and pollinator persistence. We investigated how urbanization affects short-term specialization of insect pollinators by examining pollen loads on insects' bodies and identifying the number and species of pollen grains on insects caught in urban habitat fragments and natural areas. We assessed possible drivers of differences between urban and natural areas, including frequency dependence in foraging, species richness and diversity of the plant and pollinator communities, floral abundance, and the presence of invasive plant species. Pollinators were more specialized in urban fragments than in natural areas, despite no differences in the species richness of plant communities across site types. These differences were likely driven by higher specialization of common pollinators, which were more abundant in urban sites. In addition, pollinators preferred to forage on invasive plants at urban sites and native plants at natural sites. Our findings reveal indirect effects of urbanization on pollinator fidelity to individual plant species and have implications for the maintenance of plant species diversity in small habitat fragments. Higher preference of pollinators for invasive plants at urban sites suggests that native species may receive fewer visits by pollinators. Therefore, native plant species diversity may decline in urban sites without continued augmentation of urban flora or removal of invasive species.

The Case for Integrating Medical-Legal Partnerships Into Trauma Care.

INTRODUCTION: Medical-legal needs are health-harming adverse social conditions with a legal remedy. Medical-legal partnerships in primary care settings have been proposed to address these needs for at-risk patients already seeking medical care. Our hypothesis is that trauma patients represent a unique population that may be more likely to have baseline medical-legal needs. METHODS: A trauma-specific medical-legal needs survey was developed. Adult trauma patients who were able to give consent and were admitted to our urban Level I hospital were surveyed. Medical-legal needs were tabulated from the surveys. Those patients in the top decile of medical-legal needs were categorized as having a High Burden of medical-legal needs. Multivariate logistic regression was used to identify those independent risk factors for having a High Burden of medical-legal needs. RESULTS: A total of 566 participants completed the survey (78.2% response rate). The mean number of medical-legal needs for our population was 2.5 (SD = 3.1). 73% of our respondents had at least one medical-legal need. The most common needs were Housing (n = 229, 40%) and Education/Employment (n = 223, 39%). Older age (aOR = 3.01, 95% CI 1.2-8.1, P = 0.02), being separated or divorced (aOR = 4.25, 95% CI 1.2-14.0, P = 0.02), self perceived poor health (aOR = 8.4, 95% CI 2.61-26.86, P < 0.001), penetrating mechanism of injury (aOR = 2.52, 95% CI 1.22-5.2, P = 0.01), and having been admitted to the hospital for a longer period of time (aOR = 5.48, 95% CI 1.55-19.4, P = 0.008) were all independently associated with a High Burden of medical-legal needs. CONCLUSIONS: Trauma patients have a high baseline burden of medical-legal needs. Medical-legal partnerships embedded in trauma teams may offer an innovative strategy to help address long-term health outcomes in a highly vulnerable population that would not otherwise have contact with the healthcare system.

Vaccine Hyporesponse Induced by Individual Antibiotic Treatment in Mice and Non-Human Primates Is Diminished upon Recovery of the Gut Microbiome.

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in the disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.