The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates.

Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.

Long-Term Immunological Consequences of Radiation Exposure in a Diverse Cohort of Rhesus Macaques.

PURPOSE: The aim of this study was to develop an improved understanding of the delayed immunologic effects of acute total body irradiation (TBI) using a diverse cohort of nonhuman primates as a model for an irradiated human population. METHODS AND MATERIALS: Immune recovery was evaluated in 221 rhesus macaques either left unirradiated (n = 36) or previously irradiated (n = 185) at 1.1 to 8.5 Gy TBI (median, 6.5 Gy) when aged 2.1 to 15.5 years (median, 4.2 years). Blood was drawn annually for up to 5 years total between 0.5 and 14.3 years after exposure. Blood was analyzed by complete blood count, immunophenotyping of monocytes, dendritic cells (DC) and lymphocytes by flow cytometry, and signal joint T-cell receptor exclusion circle quantification in isolated peripheral blood CD4 and CD8 T cells. Animals were categorized by age, irradiation status, and time since irradiation. Sex-adjusted means of immune metrics were evaluated by generalized estimating equation models to identify cell populations altered by TBI. RESULTS: Overall, the differences between irradiated and nonirradiated animals were subtle and largely restricted to younger animals and select cell populations. Subsets of monocytes, DC, T cells, and B cells showed significant interaction effects between radiation dose and age after adjustment for sex. Irradiation at a young age caused transient increases in the percentage of peripheral blood myeloid DC and dose-dependent changes in monocyte balance for at least 5 years after TBI. TBI also led to a sustained decrease in the percentage of circulating memory B cells. Young irradiated animals exhibited statistically significant and prolonged disruption of the naïve/effector memory/central memory CD4 and CD8 T-cell equilibrium and exhibited a dose-dependent increase in thymopoiesis for 2 to 3 years after exposure. CONCLUSIONS: This study indicates TBI subtly but significantly alters the circulating proportions of cellular mediators of adaptive immune memory for several years after irradiation, especially in macaques under 5 years of age and those receiving a high dose of radiation.

Myocardial perfusion imaging failed to improve patient risk classification compared with the revised cardiac risk index for early cardiac complications after major non-cardiac surgery.

BACKGROUND: Myocardial perfusion imaging (MPI) is frequently used for cardiac risk assessment before major non-cardiac surgery, but its ability to improve patient risk classification beyond simple clinical assessment is unknown. AIM: To explore the prognostic utility of MPI above a simple clinical risk calculator, the revised cardiac risk index (RCRI). METHODS: A retrospective cohort study of at-risk patients who underwent MPI before major non-cardiac surgery in a tertiary hospital was conducted. Major adverse cardiac events (MACE) was defined as any myocardial infarction, acute pulmonary oedema, ventricular arrhythmia or cardiac death within 30 days of surgery. We analysed the predictive value of MPI for MACE using multivariable logistic regression and categorical net reclassification index. RESULTS: MACE occurred in 47 (7.4%) cases from 635 surgical procedures in 629 patients. MPI-identified medium or large-sized reversible perfusion defects (P = 0.02; odds ratio 2.9; 95% confidence interval 1.1-7.1) and RCRI score two or more (P = 0.03; odds ratio 2.3; 95% confidence interval 1.1-4.8) were significantly associated with MACE after adjusting for age, coronary revascularisation, surgical priority, need for general anaesthesia, left ventricular ejection fraction (LVEF) and fixed perfusion defects. MPI risk factors (LVEF, reversible perfusion and fixed perfusion defects) did not improve risk classification above baseline risk factors (age, RCRI and surgical priority). CONCLUSION: MPI risk factors are weak predictors for early cardiac complications after major non-cardiac surgery and failed to improve patient risk classification beyond essential assessment using age, RCRI and surgical priority. Clinicians should consider alternative risk assessment strategies because of MPI's poor prognostic utility and its associated time and financial costs.

Adjustable intragastric balloon for treatment of obesity: a multicentre, open-label, randomised clinical trial.

BACKGROUND: Intragastric balloons are anatomy-preserving, minimally invasive obesity therapies. Enhanced tolerance and durability could help broaden clinical adoption. We investigated the safety and efficacy of an adjustable intragastric balloon (aIGB) in adults with obesity. METHODS: In this prospective, multicentre, open-label, randomised clinical trial done at seven US sites, adults aged 22-65 years with obesity were randomly assigned (2:1) to aIGB with lifestyle intervention or lifestyle intervention alone (control) for 32 weeks. Balloon volume could be increased to facilitate weight loss or decreased for tolerability. Coprimary endpoints included mean percentage total bodyweight loss and responder rate (≥5% total bodyweight loss) at 32 weeks. We used a multiple imputed intention-to-treat population analysis. This study was registered with ClinicalTrials.gov, NCT02812160. FINDINGS: Between Aug 9, 2016, and Dec 7, 2018, we randomly assigned 288 patients to aIGB (n=187 [65%]) or control (n=101 [35%]) groups. Mean total bodyweight loss at 32 weeks was 15·0% (95% CI 13·9-16·1) in the aIGB group versus 3·3% (2·0-4·6) in the control group (p<0·0001). Clinical response was observed in 171 (92%) patients in the aIGB group. Adjustments to the aIGB occurred in 145 (80%) patients for weight loss plateau or intolerance. Upward volume adjustment facilitated an additional mean 5·2% (4·5-5·8) total bodyweight loss. Downward volume adjustment allowed 21 (75%) patients in the aIGB group to complete the full duration of therapy. Intolerance caused early removal of the device in 31 (17%) patients. No micronutrient deficiencies were observed in the aIGB cohort. Device-related serious adverse events were observed in seven (4%) patients, without any deaths. INTERPRETATION: When aIGB was combined with lifestyle modification, significant weight loss was achieved and maintained for 6 months following removal. Balloon volume adjustability permitted individualised therapy, maximising weight loss and tolerance. FUNDING: Spatz Medical.

Long-Term Recovery of the Adaptive Immune System in Rhesus Macaques After Total Body Irradiation.

PURPOSE: Ionizing radiation causes acute damage to hematopoietic and immune cells, but the long-term immunologic consequences of irradiation are poorly understood. We therefore performed a prospective study of the delayed immune effects of radiation using a rhesus macaque model. METHODS AND MATERIALS: Ten macaques received 4 Gy high-energy x-ray total body irradiation (TBI) and 6 control animals received sham irradiation. TBI caused transient lymphopenia that resolved over several weeks. Once white blood cell counts recovered, flow cytometry was used to immunophenotype the circulating adaptive immune cell populations 4, 9, and 21 months after TBI. Data were fit using a mixed-effects model to determine age-dependent, radiation-dependent, and interacting effects. T cell receptor (TCR) sequencing and quantification of TCR Excision Circles were used to determine relative contributions of thymopoiesis and peripheral expansion to T cell repopulation. Two years after TBI, the cohort was vaccinated with a 23-valent pneumococcal polysaccharide vaccine and a tetravalent influenza hemagglutinin vaccine. RESULTS: Aging, but not TBI, led to significant changes in the frequencies of dendritic cells, CD4 and CD8 T cells, and B cells. However, irradiated animals exhibited increased frequencies of central memory T cells and decreased frequencies of naïve T cells. These consequences of irradiation were time-dependent and more prolonged in the CD8 T cell population. Irradiation led to transient increases in CD8+ T cell TCR Excision Circles and had no significant effect on TCR sequence entropy, indicating T cell recovery was partially mediated by thymopoiesis. Animals that were irradiated and then vaccinated showed normal immunoglobulin G binding and influenza neutralization titers in response to the 4 protein antigens but weaker immunoglobulin G binding titers to 10 of the 23 polysaccharide antigens. CONCLUSIONS: These findings indicate that TBI causes subtle but long-lasting immune defects that are evident years after recovery from lymphopenia.

Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.

Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose radiation to live normal life spans. These "elite-survivors" harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa Lachnospiraceae and Enterococcaceae were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.

Improving Hemostasis in Sleeve Gastrectomy With Alternative Stapler.

BACKGROUND: Staple line bleeding can be a major intra-operative complication during laparoscopic sleeve gastrectomy, requiring reinforcing interventions that may diminish the integrity of the staple line and put patients at risk for postoperative hemorrhage or leak. To improve outcomes associated with surgery, surgeons may benefit from an alternative stapler that produces a drier staple line and requires less staple line manipulation. METHODS: Sixty consecutive laparoscopic sleeve gastrectomy procedures were performed by three surgeons; 30 sleeves using the AEON™ Endostapler on THICK MODE and 30 using the Echelon Flex™ Powered Stapler with pulse technique. Stapler performance was measured by incidence and degree of staple line bleeding. Images of the first firing and fundus were taken with the laparoscope 10 seconds after the final firing. Images were evaluated by a third-party blinded evaluator and given a "bleeding score," a qualitative measure of intra-operative staple-line bleeding (1 = no bleeding to 5 = profuse bleeding). RESULTS: The AEON™ Endostapler demonstrated a lower mean (± standard error) "bleeding score" versus the Echelon Flex™ (2.1 ± 0.1 vs. 2.6 ± 0.1; p = 0.01). The AEON™ Endostapler had 15 cases (50%) with no bleeding at the fundus; the Echelon Flex™ had 7 cases (23%) with no bleeding at the fundus. The AEON™ Endostapler had 0 cases (0%) with profuse bleeding; the Echelon Flex™ had 2 cases (7%) with profuse bleeding. CONCLUSION: The AEON™ Endostapler is a significantly drier alternative to the Echelon Flex™ Powered Stapler, producing a much drier staple line and decreasing the need for other bleeding control methods.

Update on radiation for restenosis.

Coronary stenting is now used in most coronary interventions and reduces the restenosis rate to 20% or less. However, repeat in-stent restenosis occurs in 40%-60% of these patients. Radiation therapy, guided by intravascular ultrasound, can further reduce the incidence of repeat in-stent restenosis, and clinical trials have shown that all patient subgroups benefit from it. The mechanism appears to be reduction in neointimal hyperplasia. Studies are now evaluating use of medication with stents and radiotherapy, implantation of radiation-eluting stents, longer radiation sources to adequately cover lesions, and catheter balloons inflated with radioisotope solution. Intravascular radiation may soon be the standard of treatment for patients with in-stent restenosis and has the potential to reduce the recurrence rate to below 10%.