Parent Education and Adolescent Health Outcomes: The Potential Role of Adolescent Academic Intention.

Parental educational attainment significantly shapes child socioeconomic status, potentially influencing various aspects of adolescent health. This study aimed to uncover the relationships between parental education and self-reported adolescent health outcomes, including overall health, mental well-being, and body mass index (BMI). Analyzing data from 1,448 participants in the Future of Families and Child Wellbeing Study, we identified notable associations. Our findings revealed that higher maternal and paternal education correlated with reduced odds of adolescent obesity. Furthermore, increased adolescent academic intention was associated with better overall and mental health in adolescents. Notably, it also played a mediating role in lowering adolescent BMI, thereby potentially explaining the association between parent education and adolescent BMI category (overweight vs. obese). These findings emphasize the significant impact of both parent education and adolescent academic intention on adolescent health. Future research should explore interventions leveraging academic intention to positively influence the health trajectory of adolescents.

Differential effects of community involvement on eating disorder prevention outcomes in sexual minority men.

Prior research has been conflicted on whether gay community involvement serves as a risk or protective factor for body image and eating disorders (EDs) in sexual minority men (SMM), perhaps given that prior research has examined community involvement unidimensionally. The present study examined whether non-appearance-based ("social activism") and appearance-based ("going out/nightlife") community involvement differentially predicted ED prevention outcomes in SMM. SMM (N = 73) enrolled in a randomized controlled trial of an ED prevention program completed measures of community involvement, drive for muscularity, body dissatisfaction, and bulimic symptoms at pre-intervention, post-intervention, and 1-month follow-up. "Social activism" community involvement moderated intervention effects for drive for muscularity and body dissatisfaction scores, but not bulimic symptoms, such that those who placed higher importance on social activism demonstrated expected improvements, while those who placed lower importance on social activism did not exhibit expected improvements. "Going out/nightlife" community involvement did not moderate intervention outcomes; however, greater importance of going out/nightlife was associated with increased body dissatisfaction. Findings support that the impact of community involvement on body image and ED risk for SMM may be nuanced. Encouraging community involvement through activism could help enhance ED prevention efforts for SMM.

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.

Caffeine-induced release of small molecules from DNA nanostructures.

Several planar aromatic molecules are known to intercalate between base pairs of double-stranded DNA. This mode of interaction has been used to stain DNA as well as to load drug molecules onto DNA-based nanostructures. Some small molecules are also known to induce deintercalation in double-stranded DNA, one such molecule being caffeine. Here, we compared the ability of caffeine to cause deintercalation of ethidium bromide, a representative DNA intercalator, from duplex DNA and three DNA motifs of increasing structural complexity (four-way junction, double crossover motif, and DNA tensegrity triangle). We found that caffeine impedes the binding of ethidium bromide in all these structures to the same extent, with some differences in deintercalation profiles. Our results can be useful in the design of DNA nanocarriers for intercalating drugs, where drug release can be chemically stimulated by other small molecules.

Risk Factors for Multisystem Inflammatory Syndrome in Children: A Case-control Investigation.

BACKGROUND: In a 2020 pilot case-control study using medical records, we reported that non-Hispanic Black children were more likely to develop multisystem inflammatory syndrome in children (MIS-C) after adjustment for sociodemographic factors and underlying medical conditions. Using structured interviews, we investigated patient, household, and community factors underlying MIS-C likelihood. METHODS: MIS-C case patients hospitalized in 2021 across 14 US pediatric hospitals were matched by age and site to outpatient controls testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the admission date. Caregiver interviews queried race/ethnicity, medical history, and household and potential community exposures 1 month before MIS-C hospitalization (case-patients) or after SARS-CoV-2 infection (controls). We calculated adjusted odds ratios (aOR) using mixed-effects multivariable logistic regression. RESULTS: Among 275 case patients and 496 controls, race/ethnicity, social vulnerability and patient or family history of autoimmune/rheumatologic disease were not associated with MIS-C. In previously healthy children, MIS-C was associated with a history of hospitalization for an infection [aOR: 4.8; 95% confidence interval (CI): 2.1-11.0]. Household crowding (aOR: 1.7; 95% CI: 1.2-2.6), large event attendance (aOR: 1.7; 95% CI: 1.3-2.1), school attendance with limited masking (aOR: 2.6; 95% CI: 1.1-6.6), public transit use (aOR: 1.8; 95% CI: 1.4-2.4) and co-resident testing positive for SARS-CoV-2 (aOR: 2.2; 95% CI: 1.3-3.7) were associated with increased MIS-C likelihood, with risk increasing with the number of these factors. CONCLUSIONS: From caregiver interviews, we clarify household and community exposures associated with MIS-C; however, we did not confirm prior associations between sociodemographic factors and MIS-C.

No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection.

BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Association of Asthma With Treatments and Outcomes in Children With Critical Influenza.

BACKGROUND: Hospitalization for severe influenza infection in childhood may result in postdischarge sequelae. OBJECTIVE: To evaluate inpatient management and postdischarge sequelae in children with critical respiratory illness owing to influenza with or without preexisting asthma. METHODS: This was a prospective, observational multicenter study of children (aged 8 months to 17 years) admitted to a pediatric intensive care or high-acuity unit (in November 2019 to April 2020) for influenza. Results were stratified by preexisting asthma. Prehospital status, hospital treatments, and outcomes were collected. Surveys at approximately 90 days after discharge evaluated postdischarge health resource use, functional status, and respiratory symptoms. RESULTS: A total of 165 children had influenza: 56 with preexisting asthma (33.9%) and 109 without it (66.1%; 41.1% and 39.4%, respectively, were fully vaccinated against influenza). Fifteen patients with preexisting asthma (26.7%) and 34 without it (31.1%) were intubated. More patients with versus without preexisting asthma received pharmacologic asthma treatments during hospitalization (76.7% vs 28.4%). Of 136 patients with 90-day survey data (82.4%; 46 with preexisting asthma [33.8%] and 90 without it [66.1%]), a similar proportion had an emergency department/urgent care visit (4.3% vs 6.6%) or hospital readmission (8.6% vs 3.3%) for a respiratory condition. Patients with preexisting asthma more frequently experienced asthma symptoms (78.2% vs 3.3%) and had respiratory specialist visits (52% vs 20%) after discharge. Of 109 patients without preexisting asthma, 10 reported receiving a new diagnosis of asthma (11.1%). CONCLUSIONS: Respiratory health resource use and symptoms are important postdischarge outcomes after influenza critical illness in children with and without preexisting asthma. Less than half of children were vaccinated for influenza, a tool that could mitigate critical illness and its sequelae.

Postdischarge Glucocorticoid Use and Clinical Outcomes of Multisystem Inflammatory Syndrome in Children.

Importance: Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C). Objectives: To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C. Design, Setting, and Participants: This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months. Exposures: Glucocorticoid treatment. Main Outcomes and Measures: Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness. Results: Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91). Conclusions and Relevance: In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

Health Impairments in Children and Adolescents After Hospitalization for Acute COVID-19 or MIS-C.

OBJECTIVES: To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients <21-years-old, hospitalized May 2020 to May 2021 for acute COVID-19 or MIS-C with follow-up 2 to 4 months after admission. We assessed readmissions, persistent symptoms or activity impairment, and new morbidities. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). RESULTS: Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04-1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06-1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55-6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35-4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C). CONCLUSIONS: Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C.

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5-11, 12-21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Ileal Pouch-Anal Anastomosis in the Older Adult: a Review of Postoperative Outcomes and Pouchitis Treatment.

Purpose of Review: Ileal pouch-anal anastomosis (IPAA) has become the preferred surgical treatment for patients with medically refractive ulcerative colitis (UC). Previous studies have suggested that outcomes of this procedure may be worse in older patients; however, more recent reports have suggested that IPAA in select patients is safe, feasible, and results in good quality of life. In this review, we discuss the recent literature surrounding clinical considerations and treatment management of IPAA in older adults. Recent Findings: IPAA complication rates and adverse events are similar in the older adult population, as compared to the younger adult patient population. Although fecal urgency and incontinence may be more common among older adults, chronological age alone is not a contraindication for IPAA surgery, as good quality of life can still be achieved. In this review, we will also discuss the development of pouchitis after IPAA, particularly among older adults, as the emergence of newer biologic drugs has shifted the treatment landscape. Summary: IPAA can be a safe and effective treatment modality for older adults with UC, with high self-reported patient satisfaction. Patient optimization and careful case selection are vital to achieving these outcomes, and specialized preoperative assessments and counseling can help facilitate the proper treatment.

Material Hardship and Stress from COVID-19 in Immigrant Chinese American Families with Infants.

Material hardship and stress, associated with poor infant outcomes, increased during the Coronavirus Disease 2019 pandemic. Chinese American families were vulnerable to racism-driven disparities. Little is known about maternal perceptions of pandemic impacts on their infants, family, and community. Purposive sampling of low-income Chinese American mothers (n = 25) with infants (1-15 months). Semi-structured qualitative interviews conducted in Mandarin, Cantonese, or English were audio-recorded, transcribed, and translated. Transcripts coded using applied thematic analysis in an iterative process of textual analysis until thematic saturation. Three themes emerged: (1) Heightened family hardship included financial strain, disruption of transnational childcare, experiences of racism; (2) Altered infant routines/developmental consequences included using protective equipment on infants, concerns about infant socio-emotional development; (3) Coping strategies included stockpiling essentials, adapting family diets. Strategies to mitigate disparities include expanding social needs screening, correcting misinformation, strengthening support networks, and including low-income Chinese Americans in these efforts.

Medical student anxiety and depression in the COVID-19 Era: Unique needs of underrepresented students.

Background: The COVID-19 pandemic has caused significant morbidity, mortality, and mental health consequences. Few studies have examined the mental toll of COVID-19 on United States (US) medical students, who experience greater rates of depression and anxiety than the general population. Students who identify as underrepresented in medicine (URM) may experience even greater mental health adversities than non-URM peers. This study examines COVID-19's impact on preclinical medical student anxiety and depression and unique challenges disproportionately affecting URM students during the initial phase of the pandemic. Methods: Medical students at four US institutions completed an anonymous survey including the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) questionnaires for depression and anxiety. Participants provided information on demographics, past mental health difficulties, and concerns during the pandemic. Chi-square and Mann-Whitney U tests were performed using SPSS. Results: During the initial phase of the pandemic, URMs were 3.71 times more likely to be in the at-risk category on GAD-7 than non-URM peers. Before COVID-19, there was no significant difference between self-reported feelings or diagnoses of anxiety between groups. During the COVID-19 pandemic, there were significant differences in feelings of increased anxiety between URM (Mdn = 76) and non-URM (Mdn = 49) students, U = 702.5, P < 0.001, feelings of increased sadness between URM (Mdn = 49) and non-URM (Mdn = 34) students, U = 1036.5, P = 0.042, concern for new financial difficulty between URM (Mdn = 50) and non-URM students (Mdn = 7), U = 950.5, P = 0.012, and concern about lack of mental health support from their academic institution between URM (Mdn = 18) and non-URM students (Mdn = 9), U = 1083, P = 0.036 (one-tailed). Discussion: Large-scale crises such as COVID-19 may exacerbate mental health disparities between URM and non-URM students. Medical schools should consider increasing financial and mental health support for URM students in response to these significant adverse events.

Implementing a regional standardized BK polyomavirus screening protocol across eleven transplant centres.

BK polyomavirus (BKPyV) reactivation is regularly monitored after kidney transplant to prevent progression to BK associated nephropathy (BKAN). The New England BK Consortium, made up of 12 transplant centres in the northeastern United States, conducted a quality improvement project to examine adherence to an agreed upon protocol for BKPyV screening for kidney transplants performed in calendar years 2016-2017. In a total of 1047 kidney transplant recipients (KTR) from 11 transplant centres, 204 (19%) had BKPyV infection, defined as detection of BKPyV in plasma, with 41 (4%) KTR progressing to BKAN, defined by either evidence on biopsy tissues or as determined by treating nephrologists. BKPyV infection was treated with reduction of immune suppressants (RIS) in >70% of the patients in all but two centres. There was no graft loss because of BKAN during the two-year follow-up. There were nine cases of post-RIS acute rejection detected during this same period. Adherence to the protocol was low with 54% at 12 months and 38% at 24 months, reflecting challenges of managing transplant patients at all centres. The adherence rate was positively correlated to increased detection of BKPyV infection and was unexpectedly positively correlated to an increase in diagnosis of BKAN.

Case report: The use of netarsudil to improve corneal edema after laser peripheral iridotomy and Descemet's membrane endothelial keratoplasty.

PURPOSE: To report a case in which netarsudil ophthalmic solution 0.02% improved refractory corneal edema after laser peripheral iridotomy (LPI) and Descemet's membrane endothelial keratoplasty (DMEK). OBSERVATIONS: A 63-year-old female presented with decreased vision due to corneal edema secondary to iatrogenic endothelial cell loss from previous YAG and argon laser peripheral iridotomy. Initial treatment with topical sodium chloride 5% solution was unsuccessful in resolving the edema. As a result, topical netarsudil was initiated off-label. Improvement in corneal thickness and visual acuity was noted, but after a few months, the left eye decompensated with worsening edema. Cataract surgery with DMEK was performed. Surgery was prolonged and intraoperative floppy iris was encountered. Post-operatively, the patient's best-corrected visual acuity (VA) fluctuated between 20/30 to 20/70 with persistent corneal edema. The central corneal thickness (CCT) ranged from 758 to 779 three months after surgery. Topical netarsudil was started again off-label for cornea edema once nightly. Over the next two months, visual acuity and CCT improved to 20/25 and 650, respectively. Stabilization of visual acuity and cornea edema has been maintained for eight months after initiation of topical netarsudil. CONCLUSIONS: Netarsudil, a commercially available rho-kinase inhibitor, may be an effective, non-invasive adjunctive therapy for refractory corneal edema. Our case demonstrates improvement in BCVA and CCT using topical netarsudil, which has been maintained without any vision threatening side effects.

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines. Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses. Design, Setting, and Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S. Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group). Main Outcomes and Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses. Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced. Conclusion and Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine. Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.

Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.

The rise of multidrug-resistant (MDR) "superbugs" has created an urgent need to develop new classes of antimicrobial agents to target these organisms. Oligothioetheramides (oligoTEAs) are a unique class of antimicrobial peptide (AMP) mimetics with one promising compound, BDT-4G, displaying potent activity against MDR Pseudomonas aeruginosa clinical isolates. Despite widely demonstrated potency, BDT-4G and other AMP mimetics have yet to enjoy broad preclinical success against systemic infections, primarily due to their cytotoxicity. In this work, we explore a prodrug strategy to render BDT-4G inactive until it is exposed to an enzyme secreted by the targeted bacteria. The prodrug consists of polyethylene glycol (PEG) conjugated to BDT-4G by a peptide substrate. PEG serves to inactivate and reduce the toxicity of BDT-4G by masking its cationic charge and antimicrobial activity is recovered following site-specific cleavage of the short peptide linker by LasA, a virulence factor secreted by P. aeruginosa. This approach concurrently reduces cytotoxicity by greater than 1 order of magnitude in vitro and provides species specificity through the identity of the cleavable linker.