Jackson Foundation

BackgroundSpray cryotherapy (SCT) has been used as a bronchoscopic tool within the large airways for over a decade. SCT is unique in its non-contact method of flash freezing (up to −196 ℃) tissue versus a contact cryoprobe (up to −50 ℃). Techniques for venting nitrogen gas formed from liquid nitrogen during SCT are essential for safe use. Prospective data on SCT in bronchoscopy are lacking. The objective of this study was to evaluate the safety, dosimetry, and clinical outcomes of the trūFreeze SCT system in a prospective multicenter registry of patients with benign and malignant central airway disease.MethodsThis was a prospective observational registry of patients undergoing SCT enrolled at 4 participating institutions for up to 5-year follow-up (2013–2021). Data focusing on patient safety, diseases treated, dosimetry and selected efficacy measures were collected in a standardized electronic report form and central database.ResultsA total of 64 patients (47 with malignant disease and 17 with benign disease) were enrolled in the registry. A total of 114 SCT procedures were performed and 472 SCT freeze/thaw cycles delivered. The median observed follow-up for the malignant cohort was 520 days [interquartile range (IQR), 153–1,818 days]. The median observed follow-up for the benign cohort was 1,803 days (IQR, 1,769–1,832 days). Malignant disease included 14 different cancer types. Subglottic stenosis was the most common benign disease treated and only 3 patients needed more than 2 serial SCT treatments. SCT was used to treat endobronchial bleeding in 30% of cases, with complete success reported in 91%. Adverse events included one death which was unrelated to SCT and one small asymptomatic pneumothorax which did not require a chest tube.ConclusionsSCT can be safely used within the central airways, adding the unique capability of delivering flash-freezing temperatures to tissue. This approach shows potential utility in treatment strategies for a wide range of benign and malignant conditions, though further controlled studies would better define these roles.

Abstract Description Ng is acquiring increased resistance to antibiotics that is outpacing new antibiotic development. Treatment of gonorrhea remains problematic given that new annual cases approximate 82 million worldwide and 1.6 million in the US. Natural immunity to gonorrhea is ineffective. Thus, an efficacious gonococcal vaccine is much needed. The vaccine against Group B Neisseria meningitidis, 4CMenB, can confer partial cross-protection against gonorrhea, suggesting that a gonococcal vaccine is feasible. In light of this finding, we hypothesize that Snodgrassella alvi, which branches within the family Neisseriaceae, can be deployed as a naturally attenuated, nonpathogenic live vector vaccine for Ng. S. alvi is not expected to colonize humans due to its niche-restriction to bees. In silico analysis found that S. alvi lacks virtually all major virulence factors associated with pathogenic Neisseriaceae, including a dedicated machinery to retrieve iron from the host. To test our hypothesis, groups of mice were vaccinated by the intraperitoneal (IP) route three times, and elicited high serum and vaginal IgG antibody (Ab) titers that cross-react to Ng. Serum IgG Abs were robustly bactericidal. When groups of IP-vaccinated BALB/c females were subjected to vaginal Ng challenge, only 13% of S. alvi-vaccinated mice showed Ng colonization post-1 wk challenge compared to 76% unvaccinated controls. Thus, S. alvi confers exquisite protection against vaginal Ng challenge. Funding Sources Work supported by NIH AI151424. Topic Categories Mucosal and Regional Immunology (MUC)

Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts (median 4 days) between the last-negative and first-positive RNA tests, we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 38% in these as well as placebo recipients from the AMP trials was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. Viral populations exhibited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.

Research suggests injury/disability type and individual demographic factors both impact return-to-work trajectories of those with injuries/disabilities. These questions of disability and return to work/service are particularly relevant to the military where service members are at increased risk of experiencing work-related physical and mental health injuries. The Army Warrior Care and Transition Program (WCTP) is a comprehensive rehabilitation program launched in 2007 to address injured service members' needs. We sought to understand the WCTP's efficacy in returning soldiers with physical and mental health injuries to military service (including active duty, Reserve, and Guard). This retrospective cohort study utilized the WCTP tracking database (Medical Operations Data System-Warrior Transition, MODS-WT) to explore outcomes for soldiers who participated in the program 2005-2018. The type of injury at program entry was categorized as being a purely physical injury, a purely mental health injury, or both a physical and mental health injury, the impact of injury type on return to military service was explored. Chi-squared and Wilcoxon rank-sum test compared covariates of length of time in the program, sex, age, and marital status by group. Adjusted Logistic regression analysis calculated odds of returning to service, and Joinpoint analysis identified trends in data. A total of 83,274 soldiers who went through and completed the program 86,529 times 2005-2013 were included. A total of 54,032 program entries were for physical injuries, 7,898 entries for mental health injuries, and 24,599 entries were for both physical and mental health injuries. Odds of returning to military service were increased with officer and warrant officer rank (vs. enlisted), and decreased with age, female sex, and total months in the program. After adjustment for these factors, odds of returning to military service were 68% decreased for those with mental health injuries (OR 0.32 [95% CI 0.31-0.24]) and 72% decreased for those with physical and mental health injuries (OR 0.28 [95% CI 0.27-0.29]) as compared to those with purely physical injuries.For those with physical injuries, odds of returning to military service decreased 15% with every 3 months in the program. For those with purely mental health injuries, odds of returning to military service decreased dramatically the first 6 months, the decline was gradual from 6 to 18 months in the program, from 18 to 36 months in the program the rate of return to military service remained statistically consistent with a slight upward trend. For those with mental health and physical injuries, odds of return to military service declined by 40% over the first 6 months and by 12.5% thereafter. Mental health injuries and time in the Warrior Care program were associated with decreased likelihood of return to military service. Longer periods of care for those with mental health issues may relate to less standardized, tested, or known efficacious mental health treatments. The study is limited by inclusion of only those with serious injury, and an inability to assess injury severity, but strengthened by equal access to high-quality care and a large population of injured service members.

[This corrects the article DOI: 10.3389/fcimb.2024.1484448.].

Abstract Background SARS-CoV-2 myocarditis is a rare but serious complication of COVID-19. The host response correlates of SARS-CoV-2 myocarditis remain unclear, thereby limiting therapeutic development. We therefore performed proteomic and transcriptomic phenotyping of SARS-CoV-2 myocarditis in Military Health System (MHS) beneficiaries. We included a bioenergetics focus given the emerging role of mitochondrial function in enteroviral myocarditis. Early (<30 days post infection) plasma proteomic biomarkers measured by the Ella 20-plex ELISA assay in cases (SARS-CoV-2 infections with myocarditis) versus controls (SARS-CoV-2 infections without myocarditis). Values are log10 transformed, and p-values are adjusted for multiple comparisons across the full twenty biomarkers (six shown here; * indicates a p-value < 0.05). CRP = C-Reactive Protein; IFNG = Interferon Gamma ; PCT= Procalcitonin; TNFR1 = Tumor necrosis factor receptor-1; DDIMER = D-dimer; and IL1RA = Interleukin-1 receptor antagonist. Methods We previously adjudicated five unvaccinated pre-Delta SARS-CoV-2 myocarditis cases among 5265 MHS beneficiaries who enrolled into the EPICC study with COVID-19; four of these cases had blood collected. We matched myocarditis cases 1:10 with sex, age, comorbidity, and blood sampling-time matched controls (SARS-CoV-2 infection with no myocarditis) from the EPICC study. Cases and controls underwent comparison of early (< 30 days post infection) plasma proteomic biomarkers measured by the Ella 20-plex ELISA assay (with multiplicity adjustment). We also performed early whole blood transcriptomic sequencing with DESeq2 and GSEA analysis of custom mitochondrial pathways, including mitochondrial (mtDNA) regulated innate immune pathways (with FDR for multiple comparisons). Gene set enrichment analysis of custom mitochondrial pathways in cases (SARS-CoV-2 infections with myocarditis) versus controls (SARS-CoV-2 infections without myocarditis). FDR = False Discovery Rate; NES = Normalized enrichment score. Results We detected higher post-infection Tumor Necrosis Factor Receptor-1 (TNFR1) and procalcitonin (PCT) plasma concentrations in myocarditis cases versus matched controls (TNFR1: 0.33 log10 pg/mL difference, p = 0.032; PCT: 0.59 log10 pg/mL difference, p = 0.02) (Fig 1). We noted no statistically significant difference in the 18 other proteomic markers tested. GSEA analysis noted upregulated mitochondrial central dogma and OXPHOS pathway genes, and downregulated mtDNA innate immune genes, in cases versus controls (FDR < 0.05) (Fig 2). Conclusion In this MHS study, SARS-CoV-2 myocarditis was associated with elevation of TNFR1 and PCT secretion, upregulated mitochondrial central dogma and OXPHOS gene expression, and downregulated mtDNA innate immunity. While constrained by small sample sizes of a rare complication, these biomarker associations prompt mechanistic studies which may direct development of therapies for myocarditis due to SARS-CoV-2 and perhaps other respiratory viral pathogens. Disclosures Simon Pollett, MBBS, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response David Tribble, MD, DrPH, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response Timothy Burgess, MD, MPH, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response

As hubs of metabolism, mitochondria contribute critical processes to coordinate and optimize energy and intermediate metabolites. Drosophila Clueless (Clu) and vertebrate CLUH are ribonucleoproteins critical for supporting mitochondrial function yet do so in multiple ways. Clu/CLUH bind mRNAs and CLUH regulates mRNA localization and translation of mRNAs encoding proteins destined for mitochondrial import. In addition, Clu associates with ribosomal proteins and translation factors, yet whether it is required for fundamental ribosome function in vivo is not clear. In this study, we examine the Clu interactome and probe Clu’s requirement in ribosome biogenesis. We previously showed that Clu associates with ribosomal proteins. In this study, we extend these observations to show that clu null mutants display a significant decrease in overall protein synthesis. In addition, Clu associates with ribosomal proteins in an mRNA-independent manner, suggesting Clu’s core ribosomal function may be separate from its role in localizing and translating specific mRNAs. We find that Clu is present in the nucleus and associates with the ribosomal RNA (rRNA) processing protein fibrillarin but, surprisingly, that processed rRNA products are normal in the absence of Clu. Furthermore, Clu loss does not affect ribosomal protein levels, but does result in a decrease in 40S and 60S ribosomal subunits abundance. Together, these results demonstrate that Clu is present in the nucleus and required for 40S and 60S biogenesis and global translation in vivo. These results highlight the multifaceted role of Clu in supporting cell function through regulation of mRNA encoding mitochondrial proteins and ribosome biogenesis.

Expanding access to simple blood collection tools is essential to monitor, control, and eliminate malaria in low resource settings where the disease is endemic. The most common method to preserve blood is depositing fingerstick samples onto filter paper—the dried blood spot (DBS) card. While DBS cards offer more optimal storage solutions than venous blood in vacutainers, they do not provide sample cleanup or enrichment of Plasmodium DNA. These samples retain high host-to-parasite DNA ratios, which negatively affect the quality of downstream sequencing. We developed a Leukocyte Depletion Card (LDC) that substantially depletes host white blood cells from whole blood to enrich Plasmodium-infected red blood cells in a hematocrit-independent volume (9.0 ± 0.5 μL). Using quantitative PCR, we evaluate the performance of the LDC using blood collected from 16 P. falciparum-infected patients at a clinic in Cape Coast, Ghana. The LDC achieved an average 32.5-fold parasite enrichment over venous blood. Promisingly, the LDC also provides a 36.6-fold parasite enrichment over a DBS card. Initial testing of targeted sequencing demonstrates significant (p < 0.01) improvement in P. falciparum read counts and coverage for the LDC. The LDC represents a unique microsampling device with potential applications in epidemiological studies of malaria.

Pacemaker insertion is a daily occurrence in the United States of America, and it is a relatively common procedure; however, complications can occur. One common complication includes the development of a pneumothorax; however, there are rare instances where patients can develop a pneumopericardium as well.We present a case of a patient who underwent dual chamber pacemaker implantation complicated by a pneumothorax and left-sided pneumopericardium, which is a rare finding. This patient initially presented with syncopal episodes and a dual chamber pacemaker was inserted; however, not long after, the patient developed pericarditis and was found to have a pneumothorax and a pneumopericardium. In these cases, patients can be treated with chest tube insertion, lead extraction, or even conservatively, depending on the patient's clinical status. Various reasons exist for the development of a pneumothorax andpneumopericardium; however, the guidelines on management are still unclear and require further study. In our patient, his pneumothorax and contralateral pneumopericardium were treated conservatively with stable follow-up post-hospitalization.