Publications

OBJECTIVE: The objective of our study is to determine whether the use of a self-retaining panniculus retraction device (traxi) in patients with obesity will improve operative time, pulmonary function, or patient and provider experience for non-emergent cesarean delivery.

METHODS: Pregnant patients with body mass index (BMI) ≥40 kg/m2 undergoing non-emergent cesarean delivery were recruited from two academic hospitals and randomized to traxi panniculus retraction or to no traxi. Computer-generated block randomization, stratified by prior abdominal surgery, was used to randomize participants in a 1:1 ratio to the traxi or standard care. Demographic information was collected by self-report. Surgical time from skin incision to closure and clinical data was collected by review of the electronic health record. Pulmonary function testing via spirometer was performed before and after application of retraction. Participant and provider experience was collected postoperatively. Intention-to-treat analysis was performed using a Wilcoxon rank-sum test and a chi-squared test for continuous and dichotomous variables, respectively.

RESULTS: We enrolled 135 participants from 2018 to 2024 at two academic hospitals; 67 were randomized to traxi and 68 were randomized to no traxi. Of these, 43 (31.9%) reported no prior abdominal surgery (including prior cesarean or other laparotomy) and the median BMI was 48.9 (interquartile range [IQR] 45.0, 52.5). The trial was terminated before the target sample size of 220 participants was achieved due to slow accrual and waning clinical equipoise. Baseline characteristics of each group were similar. Median surgical time was 65.0 min (IQR 55.0, 81.0) in the traxi group and 70.0 min (IQR 57.0, 86.0) in the no traxi group, but this difference was not statistically significant (p = 0.31). There was less restrictive pulmonary physiology associated with application of traxi compared to no traxi; the forced expiratory volume in 1 second (FEV1) difference was -0.03 L (-0.20, 0.10) and -0.11 L (-0.45, -0.02) (p = 0.048), respectively. Providers were significantly more likely to report that the traxi was very effective, not really difficult to use, not really physically uncomfortable to use, very satisfying to use, and a form of retraction that they would very likely recommend to another colleague. All patients in the traxi arm reported they would choose this retraction method in a future cesarean delivery compared to 91% of patients in the no traxi arm; however, this finding was not statistically significant (p = 0.05). "A little bit" of rash where the method of taping was used within 2 days of surgery was reported by 0% of patients in the traxi arm, compared to the no traxi arm (20%, p = 0.0048).

CONCLUSIONS: Traxi panniculus retraction did not significantly improve surgical time but was associated with less restrictive pulmonary function testing compared with the control arm; these findings should be interpreted in the context of the study's limited sample size. There were higher reports of provider satisfaction with use of traxi compared to the control arm. Patient-reported satisfaction with use of traxi was high but not statistically different when compared to the control arm with the exception of patient-reported rash (less in traxi arm).

The innate immune system is rapidly activated following antigen exposure and plays a critical role in shaping the ensuing adaptive immune responses. In this study, we performed bulk RNA sequencing and proteomic profiling in a cohort of 25 rhesus macaques following Ad26.COV2.S immunization to characterize early innate correlates of vaccine immunogenicity and protection. Our results show that innate immune activation occurred as early as day 1 post-vaccination and demonstrated an systemic enrichment of antiviral interferon pathways, interleukin signaling, and innate immune cell signatures. These early transcriptomic signatures correlated positively with humoral and cellular immune responses at 6 weeks following vaccination and correlated inversely with viral loads following SARS-CoV-2 challenge. Similar correlates of immunogenicity were observed in a cohort of 25 adult healthy participants vaccinated with Ad26.COV2.S. Taken together, these findings highlight the importance of early activation of the innate immune system for Ad26.COV2.S vaccine immunogenicity and protective efficacy.

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRβ (TRB), and TCRδ (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination and infection are associated with longer non-productively recombined IGHs, suggesting an effect that precedes clonal selection. We found that TRB repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned approximate or "fuzzy" matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.

An open label Phase-1 proof-of-concept study evaluated the safety and immunogenicity of IMNN-101, a DNA vaccine based on an expression plasmid and a synthetic delivery carrier (the PlaCCine vaccine), in healthy human adults previously vaccinated or infected with SARS-CoV-2. Study participants received a single intramuscular dose of 0.5 mg, 1.0 mg, or 2.0 mg of IMNN-101 DNA vaccine (n = 8 participants per group). Mild to moderate reactogenicity events were observed in 67% (16/24) of participants, including tenderness, hardening, pain, redness, swelling, and itching at the injection site, as well as fatigue, muscle aches, headache, and nausea/vomiting. Fourteen grade 1 or 2 treatment-emergent adverse events were reported: none of those attributed to IMNN-101. There were no reports of myocarditis or pericarditis. The immunization with IMNN-101 resulted in an increase in neutralizing antibody (NAb) titers against XBB.1.5 and other circulating variants of SARS-CoV-2, with 2-3-fold increase in NAb titers that were maintained during the 6-month follow up. This first-in-human evaluation of a PlaCCine-based DNA vaccine demonstrates a favorable safety profile and durable humoral immune response. The PlaCCine vaccine is thermostable, does not require a device or virus for delivery, and offers a viable alternative approach to immunization.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to evolve five years after the initial outbreak. Although mRNA vaccines encoding the JN.1 and KP.2 Spike proteins were authorized in fall 2024, it remains unclear whether vaccine updates will be necessary for variants containing antigenically closely related Spike proteins. In this study, we evaluated the immunogenicity of JN.1 and KP.2 mRNA boosters in participants from Germany and the United States, respectively. Both vaccines induced robust and similar neutralizing antibody responses against JN.1, KP.2, and other globally relevant variants such as LP.8.1.1 and NB.1.8.1. These data suggest that updating the vaccine formulation to closely related strains will likely offer only modest additional benefits against currently circulating variants.

OBJECTIVE: Preeclampsia (PE) is a common complication of pregnancy linked to increased lifetime risk of multiple comorbidities. However, the link between PE and development of adverse neurologic conditions is still poorly understood. Our objective was to investigate the risk of neurodegenerative disorders for women with PE compared to those without PE.

STUDY DESIGN: We utilized the TriNetX database including electronic health records from 66 healthcare organizations and identified women 18+ years old with their last delivery between January 2000 and December 2023. PE was defined using ICD-10 codes that occurred before delivery up until December 2020. The comparator group included pregnant women in the same period without PE diagnosis. After 1:1 propensity score matching on age at index pregnancy, demographics, health utilization, comorbidities, depression, reproductive factors, and body mass index, hazard ratios (HR), and 95% confidence intervals (CIs) for cognitive disorders were estimated between the PE and comparator group using a Cox proportional hazard regression model. Cognitive outcomes were identified by ICD-10 codes and censored until one of the following conditions was met: (1) development of an outcome, (2) July 26, 2024, or (3) loss to follow-up in the system.

RESULTS: The PE group had a 9% increased risk of symptomatic cognitive impairment (HR 1.09; 95% CI 1.03, 1.16) and a 9% increased risk of composite cognitive impairment outcomes, including clinical, symptomatic, mild cognitive impairment, dementia, or related medication use (HR 1.09; 95% CI 1.03, 1.15) compared to the non-PE group. Similar trends were observed in the term birth subgroup for symptomatic cognitive impairment (HR 1.06; 95% CI 1.00, 1.12) and composite outcomes(HR 1.06; 95% CI 1.01, 1.13). No significant associations were found in the preterm subgroup due to limited events. Risk of Parkinson's disease, parkinsonism, or related outcomes was not statistically different in the main model but was higher in sensitivity analyses with natural language processing (NLP) and accounting for death as competing risk. Cognitive impairment, dementia/Alzheimer's, and vascular dementia showed no differences in the main or NLP sensitivity analyses but were elevated in the competing risk sensitivity analysis.

CONCLUSION: Our findings demonstrate an increased risk of cognitive impairment among individuals with a history of PE, with additional associations for Parkinson's disease and parkinsonism identified in sensitivity analyses. These results highlight the importance of obstetrical health as a predictor of lifelong neurocognitive health, underscoring the need for targeted surveillance and early intervention strategies for neurodegenerative diseases in this population.

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRβ (TRB), and TCRδ (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination and infection have an effect on non-productively recombined IGHs, suggesting an effect that precedes clonal selection. We found that repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned approximate or "fuzzy" matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.